Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review Summarise this article #The objective:
To determine an evidence-based update regarding epidemiology, risk factors, pathophysiology, type of transmission, diagnostic challenges, treatment challenges and the impact of TB in KT recipients. #Introduction:
*Renal transplantation is best solution regarding renal replacement therapy in ESRD patients; however, infection after KT is still an important limitation for graft and patient outcomes.
*Tuberculosis (TB) in (KTx) recipients is an important opportunistic infection with greater prevalence than in the community and is associated with important morbidity and mortality rate.
*Active TB is mainly associated with an immunosuppression condition with a higher incidance in KTRs, also there are recipient- and donor-associated risk factors that could lead to development of TB in KTRs.
*Understanding the epidemiological risk, risk factors, transmission modalities, diagnosis and treatment challenges is critical for clinicians in providing an appropriate management for KT with TB. #Method:
This is an extensive literature review of articles published between 1 January 2000 and 15 June 2022 to provide an evidence-based review of epidemiology, pathogenesis, diagnosis, treatment and outcomes of TB in KT recipients. #The results:
*The prevalence of active TB in KT recipients ranges between 0.3–15.2%. KT recipients with active TB could have a rejection rate up to 55.6%, a rate of graft loss that varies from 2.2% to 66.6% and a mortality rate up to 60%. #Risk Factors for Tuberculosis in Kidney Transplantation: *Recipient- associated:
-Old age
-Male gender
-Smoking
-Malnutrition
-Diabetes
-COPD
-Latent TB (pre-transplant)
-Chronic liver disease
-HCV infection
-Opportunistic co-infection CMV, pneumocystis
-Autoimmune disease
-Long term HD *Donor- associated:
-Donor type (cadaveric)
-Social factors (homeless)
-Medical risk factors (DM, BMI) *Transplant- associated:
-AR
-IS
-Chronic graft dysfunction *Others:
TB burden of the country #Diagnostic Challenges
-Delayed the diagnosis of TB in KT patients.
-Atypical clinical
-Association with other co-infections and extrapulmonary localization in ~50%of cases.
-Paraclinical issues. For example, tuberculin skin test (TST) and interferongamma release assay (IGRA) are not useful in the diagnosis of active TB
-Wide range of radiographic manifestations in pulmonary TB and the frequent need for invasive procedures (bronchoscopy with bronchoalveolar lavage).
-Molecular tests based on rapid nucleic acid amplification techniques, such asmycobacteriumtuberculosis complex and resistance to rifampin test could provide false negative results when mycobacterial load is low. #Treatment Challenges
-Drug–drug interactions,
-Drug toxicity
-Treatment adherence
*It is recommended that the management of KT patients with TB be carried out by an experienced clinician and special attention must be paid to drug–drug interactions and potentially adverse events
#Conclusions:
*Close collaboration between kidney transplant and infectious disease physicians.
*Donor-derived TB and latent TB in KT are under recognized conditions that should be carefully evaluated.
* Development of tests with helpful predictive values, which are not based on T cell immunity, could bring important improvement in the diagnosis of latent TB in KT recipients.
*Newly discovered regimens or pipeline drugs could have an important contribution in the future limitation of drug–drug interactions, improvement of treatment efficacy and reduction of adverse events.
What is the level of evidence provided by this article?
Level of evidence is level (5).
TB is the leading infectious cause of mortality worldwide (exclude COVID-19) and a common cause of death (exclude COVID-19). Active TB is more prevalent in transplant patients due to immunosuppression than in the general population.
Limiting the occurrence of the disease requires proper donor and recipient evaluation.
Methods
From January 1, 2000, to June 15, 2022, a literature search was conducted using PubMed and Embase electronic databases.
Included were all studies that provided epidemiological and/or outcome data on TB in KT.
Risk Factors and Epidemiology of Tuberculosis in Kidney Transplantation
The prevalence of active tuberculosis among patients with solid organ transplants varies greatly by geographic region.
The incidence of active TB in solid organ transplant recipients is 20–74 times that of the general population, depending on whether or not the area is endemic.
Tuberculosis in Kidney Transplantation: Epidemiology
The prevalence of active TB in recipients of kidney transplants ranges from 0.3% to 15.2%, which is higher than the prevalence in the general population.
Risk Factors for Tuberculosis in Kidney Transplants The primary cause of tuberculosis in kidney transplants is the reactivation of latent disease.
Donor tissue
Infection acquired from a new source.
Transplant-related risk factors, including immunosuppression therapy, acute rejection episodes, and chronic graft dysfunction.
In general, however, the risk factor depends on the recipient and the donor.
Recipient:
Advanced age
Male
Smoking Malnutrition
DM
COPD
Latent tuberculosis
HCV
CMV
Pneumocystis
Auto immune disease
Donor risk element
Type of donor (cadaveric)
Smoking
Alchol DM
BMI (in excess of 18.5kg/m)
Transmission and Pathogenesis of Tuberculosis in Patients Receiving Kidney Transplants
Transmission of tuberculosis in KT recipients is contingent on reactivation of latent tuberculosis.
In 20% of cases within the first two years after a kidney transplant, latent infection conversion was positive.
Diagnostic Difficulties
Active TB typically develops during the first year following a kidney transplant.
TB diagnosis requires:
The diagnosis of tuberculosis necessitates a high index of suspicion, but atypical clinical manifestations in recipients of kidney transplants reduce the clinical suspicion of TB.
TST and IGRA are not useful for diagnosing active TB unless it is associated with other co-infections.
Latent Tuberculosis.
20% of recipients reported a prevalence of latent TB following KT.
Before transplantation, latent TB must be screened for in all KT candidates and donors.
IGRA is preferable to TST in ESRD patients.
The predictive value of IGRA assays for latent TB in KT recipients with negative TST results is high.
The sensitivity of IGRA tests in KT recipients was minimal.
The IGRA test cannot rule out latent TB.
Donors for kidney transplants should be screened more frequently.
Treatment Obstacles:
Due to adverse events, drug-drug interactions, drug toxicity, and treatment adherence, the treatment of TB in KT recipients should be administered by a seasoned clinician.
Infectious Tuberculosis:
Once an active TB diagnosis has been made, treatment must commence. 6 to 24 month treatment duration
According to AST-IDCOP, the initial treatment should consist of four medications.
The standard regimen includes a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide, and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin. Rifamycin is recommended not only for its sterilization capacity and efficacy but also for its ability to decrease the risk of resistance. In the absence of rifamycin, the intensive phase should consist of isoniazid, ethambutol, pyrazinamide, or levofloxacin for two months, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide.Rifampicin is a potent inducer of cytochrome P450 3A4 and P-glycoprotein, which are inhibitors of CNI (cyclosporin and tacrolimus).
When using rifampin, the CNI must be monitored.Additionally, hepatotoxicity, neurotoxicity, cytopenia, visual disturbances, cutaneous lesions, hyperuricemia, and interstitial nephritis are being monitored.
Fluoroquinolones are another safe and efficacious alternative to rifampicin for KT recipients.
Outcomes
Up to 55.6% of KT recipients with TB may experience graft rejection. The prevalence of graft loss in KT patients with active TB ranges from 2.2% to 66.6%; mortality was reported in 41.4% of patients with active TB following KT; and in 14.4% of cases, mortality was associated with anti-TB therapy.
Conclusions
In kidney transplantation, tuberculosis is associated with negative outcomes for both the recipient and the patient.
Clinicians should be aware of the diagnostic and treatment difficulties associated with TB after KT.
The optimal management strategy should be implemented by an experienced clinician.
Donor-derived tuberculosis and latent tuberculosis in KT are recognized conditions that require cautious evaluation.
The creation of instruments with beneficial predictive values
New regimens or therapies may have a significant impact on the future limitation of drug-drug interactions, enhancement of treatment efficacy, and reduction of adverse effects.
What level of substantiation does this article provide?
Level V.
TB is considered the thirteen most common cause of death worldwide. In kidney transplantation, TB has negative impact on patient and graft survival.
Due to immunosuppression, active TB is higher among kidney transplant recipients.
So this comprehensive review aimed to provide an evidence based update regarding TB and kidney transplantation
Epidemiology
The incidence of active TB in SOT is 20 to 74 times higher than general population
Prevelance of active TB in SOT varies according to geographic area.In low endemic areas for TB, the prevelance is 0.3 to 6.4% but the prevelance in high endemic area is 15.2%.
The prevelance of TB among kidney transplant patients varies from 0.3 to 15.2% . It is higher than general population but less
than its prevelance among lung transplant patients.
Risk factors for TB in kidney transplant patients
Recipient-associated: old age, male gender, smoking, malnutrition, DM,COPD,latent TB,autoimmune diseases, chronic liver disease, hepatitis C, confections, long term dialysis.
Donor associated: cadaveric, social risk( homeless,incarceration, smoking, alcohol abuse, known TB contact,medical risk factors ( DM,history of untreated TB)
Transplant associated : immunosuppression, acute rejection and chronic graft dysfunction.
TB burden in the country
Transmission and pathogenesis of TB in kidney transplantation
Inhalation of droplets containing mycobacterium tuberculosis leads to primary infection (immediate onset of active disease or latent infection)
Transmissionof TB in kidney transplant recipients runs in 3 scenario
….Active TB may ariseafter kidneytransplantation as result of reactivation of latent infection present in the recipient prior to transplantation. This is the commonest form in SOT
…..TB couldbe transmitted to kidney recipient via kidney graft from infected donor and it occurs in 4.8 % of cases.
….. TB could occur due to denovo infection after KT due to exposure to a patient with active TB especially in high endemic areas and it is not common.
Diagnostic challenges
In active TB
1. Atypical clinical manifestations, the association with other confections and extrapulmonary localization confuse TB suspicion.
2.TST and IGRAs are not useful for diagnosis of active TB
3. The need to invasive procedures for diagnosis as bronchoscopy
In latent TB
There is no gold standard test for diagnosis, but IGRAs carries some advantages over TST in patients with ESRD
Treatment challenges
In active TB
1. Drug interaction between rifampcin and transplant associated immunosuppression
2. Adverse effects of TB therapy
3. Treatment adherence
4. Reduction of immunosuppression in case of severe TB
In latent TB the major challenge is Isoniazide related hepatoxicity
Outcomes
Graft rejection in kidney recipients is about 55% due to reduction of immunosuppression secondary to drug interactions .
Graft loss occurs in 2.2 to 66 .6% of cases due to
Infection itself
Sepsis
Acute and chronic rejection
Mortality
Mortality of patients with TB after KT may reach 60%
This is a literature search from 1 January 2000 to 15 June 2022 which has provide an evidence-based review of epidemiology, pathogenesis, diagnosis, treatment and outcomes of TB in KT recipients. Rate of active TB in renal recipients was 0.3–15.2% and their rejection was 55.6%. the graft loss rate was 2.2% – 66.6% and a mortality rate was 60%. The challenges are:
1- diagnostic time delay which lead to delay in management
2- atypical clinical presentation
3- association with co-infections
4- decreased predictive values of screening tests
5- diverse radiological aspects and particular diagnostic methods
6- drug interactions
7- drug toxicities
8- Compliance
This requires close collaboration between kidney transplant and infectious disease physicians. Donor-derived TB and latent TB in KT are underrecognized conditions that should be carefully evaluated. Development of tests with helpful predictive values, which are not based on T cell immunity, could bring important improvement in the diagnosis of latent TB in KT recipients.
level of evidence is 5
Summarise this article
A comprehensive review between 1/1/2000 and 15/6/2022 articles of post kidney transplantation TB infection. The review includes epidemiology, pathogenesis, diagnosis, treatment and outcome.
Epidemiology
Post-transplant active TB prevalence is 0.3% – 15.2%
Pathogenesis
Primary disease- immediate onset after MBT inhaled (de novo infection)
Latent infection reactivation
Donor-derived
Diagnosis
Pre-transplant (diagnosis of latent TB-TST, IGRA)
High index of suspicion (epidemiological risk, history)
Atypical presentation
Imaging
BAL or drainage fluid (disseminated infection)
Treatment
Treatment duration varies (9 – 12 months) – in the setting of lung cavity, culture positive up to 2 months and disseminated ds.
First line – regime consists of a rifamycin (EHRZ)- 2 months intensive phase
Drug interaction remains a challenge
Rifamycin potent inducer
Outcome
Rejection rate up to 55.6%
Graft loss between 2.2% – 66.6%
Mortality up to 60%
What is the level of evidence provided by this article?
Level 5 evidence – a review
-The prevalence of active TB in transplanted patients is higher than general population 20-74 times either through activation of latent TB ,acquiring the disease from the graft or recent infection after recent exposure.
treatment of latent TB Isoniazid for 6-9 months. – Rifampicin containing regimen:
Rifampicin+ INH+ ethambutol + pyrazinamide for 2 months, followed by a 2-drug regimen of Rifampicin + INH for 4 months
increase the duration of treatment to at least 9-12 months if there is disseminated disease, cavitary disease with positive sputum culture after 2 months of treatment, bone and joint disease, CNS disease. – Rifampicin free regimen.
Kidney transplantation (KT) is the preferred treatment for end-stage renal disease (ESRD), but post-transplant infections, including tuberculosis (TB), remain a significant concern.
TB is a leading infectious cause of death worldwide, and its incidence is higher in KT recipients due to immunosuppression and other risk factors.
Screening measures for TB are necessary in KT candidates and recipients to prevent active TB post-transplantation.
The prevalence of active TB in KT recipients varies from 0.3% to 15.2% and is higher than in the general population.
Risk factors for TB in KT include immunosuppression therapy, acute rejection episodes, chronic graft dysfunction, and endemicity of TB in the population.
TB in KT can be transmitted through latent infection reactivation, transmission from an infected donor, or de novo infection after transplantation.
The impairment of T-cell-mediated immunity by immunosuppressive drugs increases the risk of TB development in KT recipients.
Diagnosis of TB in KT recipients can be challenging due to atypical clinical presentations, diverse manifestations, co-infections, and extrapulmonary localization.
Prompt diagnosis and appropriate treatment are crucial to prevent negative outcomes such as graft rejection, graft loss, and increased mortality rates.
Treatment challenges in KT recipients with TB include drug interactions, toxicities, and the need for tailored therapeutic approaches.
The treatment of tuberculosis (TB) in kidney transplant (KT) recipients involves a multidimensional approach to achieve effective management while considering the immunosuppressive regimen and potential drug interactions.
Anti-tuberculosis therapy (ATT) remains the cornerstone of treatment for TB in KT recipients. The standard ATT regimen typically includes a combination of isoniazid, rifampicin, pyrazinamide, and ethambutol.
However, the selection and duration of ATT may vary depending on factors such as drug susceptibility testing, drug interactions, and the presence of co-infections or comorbidities.
Careful consideration is required when choosing anti-tuberculosis drugs due to potential interactions with immunosuppressive medications commonly used in KT recipients, such as calcineurin inhibitors (e.g., tacrolimus, cyclosporine) and corticosteroids. Dose adjustments or drug substitutions may be necessary to minimize drug interactions.
Therapeutic drug monitoring is essential to ensure therapeutic drug levels of both anti-tuberculosis and immunosuppressive medications. Close monitoring of renal function is also crucial to adjust drug dosages appropriately.
KT recipients with TB may require a longer duration of treatment compared to the general population. Treatment duration typically lasts for a minimum of six months and may extend up to 12-18 months or longer, depending on the severity of the disease, drug susceptibility, and individual patient factors.
Surgical interventions, such as drainage of abscesses or resection of localized disease, may be necessary in some cases, especially when drug therapy alone is insufficient.
Regular follow-up and close monitoring of the patient’s clinical response, radiological findings, and laboratory parameters are necessary during the treatment period.
Adherence to the prescribed treatment regimen is critical to achieve successful outcomes. Patient education, counseling, and support play a crucial role in ensuring treatment compliance.
It is important to consider potential drug toxicities and manage adverse effects associated with both anti-tuberculosis and immunosuppressive medications.
Collaboration and coordination between the transplant team and infectious disease specialists are vital for optimal management of TB in KT recipients, ensuring a balance between controlling the infection and preserving graft function.
The prognosis of KT recipients with TB depends on early diagnosis and effective management.
This article is an extensive literature review of articles published between 1 January 2000 and 15 June 2022 to provide an evidence-based review of epidemiology, pathogenesis, diagnosis, treatment and outcomes of TB in KT recipients
. Introduction
As KT is associated with an immunosuppression status, active TB is higher in KT recipients than in the general population.Active TB after KT could arise from reactivation of latent infection in the recipient or donor tissue or can result from de novo infection after transplantation. Endogenous reactivation after KT is the most common form of transmission.
Epidemiology of Tuberculosis in Kidney Transplantation
The prevalence of active TB in KT recipients varies from 0.3% to 15.2% and is higher than in the general population but lower than in patients with lung transplantation .
Risk Factors for Tuberculosis in Kidney Transplantation
The risk is mainly influenced by endemicity of TB in the population, but key factors associated with the recipient, donor and transplantation increase it . Among them, of particular importance are transplant-associated risk factors, such as immunosuppression therapy, presence of acute rejection episodes and chronic graft disfunction.Immunosuppression used in KT impairs T-cell-mediated immunity involved in TB control and favors latent infection reactivation.Acute rejection significantly increases the risk of TB by 7.6 times.The number of rejections after transplant is an independent risk factor for TB appearance.Another transplant-related factor is chronic graft dysfunction, which could increase the risk of TB development by amplifying the immunosuppression status .
Recipient related Risk factors–
Older age,Male gender,Smoking,Diabetes ,Malnutrition,COPD,Latent Tb (Pre transplant),CLD,Hepatitis C infection,Opportunistic infection like CMV,pnemocystis,Nocardia,Long term Dialysis,Autoimmune disease
Transmission of TB in KT recipients could be possible according to three scenarios.-
. In the first scenario, active TB could arise after KT as a result of reactivation of the latent infection present in the recipient prior to transplantation This form of transmission is the most common found in all solid organ transplantation, including KT
.In the second scenario, TB could be transmitted to KT recipients via kidney graft from an infected donor .This type of transmission is responsible for only 4.8% of cases
In the third scenario, TB could occur as a de novo infection after KT, in a recipient with exposure to a patient with active TB . This type of transmission is not common; it is associated with very high risk of progression, and it is more frequent in endemic areas
.
Diagnostic Challenges-
KT recipients have atypical clinical presentations or diverse manifestations, which reduce the clinical suspicion of TB .Extrapulmonary localization in ~50% of cases adds a supplementary confusing element to the clinical picture. tuberculin skin test (TST) and interferon-gamma release assay (IGRA) are not useful in the diagnosis of active TB . Molecular tests based on rapid nucleic acid amplification techniques, such as mycobacterium tuberculosis complex (Xpert® MTB/RIF, ), could provide false negative results when mycobacterial load is low.
Prevalence of latent TB after KT was reported in ~20% of recipients Current guidelines provide recommendations for latent TB screening in all KT candidates and donors before transplantationThere are no gold standard tests for diagnosing latent TB accurately in KT candidates, but IGRA seems to present some advantages over TST in patients with ESRD Even so, the evaluation of latent TB in KT recipients is challenging because data regarding prediction capacity of TST and IGRA tests are discordant in this category of patients
Donor-derived TB is considered an under-recognized condition with early onset after KT in the majority of cases and should be suspected in KT recipients with one of the following features: non-specific symptoms, frequent fever in the first 3 months after KT, fluid collections, extrapulmonary manifestations or lack of response to empirical antibiotic therapy.Recognizing latent infection or undiagnosed active TB in the kidney donors is critical in preventing post-transplant infection As active disease in donors is a contraindication for donation, identification of latent TB in deceased donors remains a real challenge in KT.Nevertheless, in deceased donors, and the screening tests for latent TB (TST and IGRA) have low feasibility and accuracy .
Treatment Challenges
One challenge in the treatment of KT recipients with active TB is the drug interaction between rifampicin and transplant-associated immunosuppression .Specifically, rifampicin usage decrease the levels of calcineurin inhibitors (cyclosporine, tacrolimus), the mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus), and affects glucocorticoids metabolization, which increases the risk of rejection .Another challenge is linked to the adverse effects of TB therapy, which are more frequent than in the general population.
Latent Tuberculosis-
Treatment of latent TB should be considered only after active TB has been excluded. Treatment of KT recipients with latent TB is important for preventing the risk of reactivation. Treatment in this category of patients is indicated in one of the following conditions: a positive TST or IGRA test, a history of untreated TB, a history of recent contact with an active TB patient and when the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB .In the KT setting, the preferred treatment of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months.
. Risk of Rejection,graft loss and mortality-
KT recipients with active TB could have a rejection rate up to 55.6%, a rate of graft loss that varies from 2.2% to 66.6% and a mortality rate up to 60%
What is the level of evidence provided by this article?
Level 5
Introduction
best therapy for ESRD is kidney transplantation (KT)
Tuberculosis (TB) is a major post-transplant infection.
It is the thirteenth-highest cause of mortality globally and the top infectious cause in Post Tx period. Method
A search on PubMed and Embase electronic databases performed from 1 January 2000 to 15 June 2022. All studies that provided epidemiological and/or outcome data regarding TB in KT were included. Tuberculosis in SOT
Active TB in solid organ transplantation varies in different regions but TB prevalence ranges from 0.3–6.4% in low-endemic regions to 15.2% in high-endemic areas. Risk Factors
Post transplant cases are more likely to acquire TB. High prevalence in community along with donor, and transplantation variables like immunosuppression medication, rejection episodes, and chronic graft dysfunction.
Immunosuppression inhibits T-cell-mediated TB control and promotes latent infection reactivation. T-cell-depleting medications, calcineurin inhibitors, anti-metabolites, and glucocorticoids all enhance the risk of TB. Each rejection episodes increases TB risk 7.6 times. Transmission and Pathogenesis
Active TB could result due to reactivation. TB could also be transmitted to KT recipients via kidney graft from an infected donor or TB could occur as a de novo infection after KT or exposure to active TB patients. Diagnostic and Treatment Active TB; Treatment lasts 6–24 months, but at least 9–12.
American Society of Transplantation IDCOP recommends 6 months for active uncomplicated pulmonary TB and 9 months for cavity lesion.
AST-IDCOP recommends a 4-drug regimen for first-line treatment: Latent TB
It has also should be treated to stop it from becoming active. Positive TST or IGRA test, a history of treated tuberculosis, a history of recent contact with an active TB patient, donor-derived latent TB in an infected graft, a history of untreated tuberculosis, or recent exposure to active tuberculosis, makes a person venerable to tuberculosis.
INH combined with vitamin B6 is used to treat latent tuberculosis for a period of nine months. Ethambutol with either levofloxacin or moxifloxacin is another treatment option for those at high risk. Conclusions
TB is a common opportunistic infection in KT patients.
It has negative impact on graft and patient survival.
Preventive strategies include TB risk stratification and monitoring.
Donor-derived TB and latent TB in KT are underdiagnosed.
In KT recipients, non-T cell immunity-based assays with good predictive values might enhance latent TB diagnosis in future.
What is the level of evidence provided by this article?
TB is more frequent in kidney transplant than general population but less common than post lung Tx.
The prevalence ranges from 0.3–6.4% in low TB endemicity to 15.2% in high endemic areas. The incidence of active TB in SOT is 20 to 74 times higher than general population.
Latent TB infection: based on WHO is defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically active TB. Prevalence of latent TB after KT was reported in around 20% of recipients.
Source of Tb after transplant : reactivation of latent infection in recipients ,Donor tissues (reactivation of latent infection)&De Novo infection. Diagnostic issues
High index of suspicion
Tuberculin skin test (TST)
IGRA
Bronchoscopy with BAL, fluid collections evaluated by smear and mycobacterium culture and histopathology
Molecular tests based on rapid nucleic acid amplification techniques eg : mycobacterium tuberculosis complex
Recognizing latent infection or undiagnosed active TB in the kidney donors is crucial in prevention of post-transplant infection.
Treatment of Active TB:
Duration of treatment is at least 9 to12 months.
American Society of TX infection disease community of practice guidelines recommend in case of active uncomplicated pulmonary TB duration should be not less than 6 months.
If a cavity is present or persistence of culture-positive after 2 months of therapy, duration must be 9 months.
-CNS infection: duration of treatment 19-18 months
– According to AST- IDCOP four-drug regimen including rifampicin ,INH, Ethambutol &Pyrazinamide
-Diagnosis of latent TB: includes
High clinical suspicion
Tuberculin skin test (TST)
IGRA
Indications to treat latent TB in transplant recipient and donor:
Positive TST or a positive IGRA
Close contact to an active TB case
If recipient had graft from donor with latent TB and did not receive treatment
Regimen for treatment of latent TB
INH for 6t o 9 months.
Rifampicin to be avoided due to possible drug-drug interactions ; rifabutiun can be used alternatively.
Level of evidence: V ( Narrative review).
1. Summarise this article Introduction: Outcomes of kidney transplant are greatly affected by infections, especially tuberculosis (TB) which is a major cause of morbidity, rejection, graft loss, and mortality. TB prevalence is high in kidney transplant recipients (KTRs), due to either reactivation of latent infection (LTBI) or donor-derived infection or de novo infection. Epidemiology of TB in KTR: The incidence and prevalence of active TB in solid organ transplant (SOT) recipients are 20 to 74 times higher than in general population, with prevalence varying from 0.3 – 15.2% in different geographical areas and endemicity. The prevalence in dialysis patients is 3.6 times, and in KTRs is 11.36 times that of general population; is higher in lung transplant recipients. Risk factors for TB in KTRs: · TB burden of the country (endemicity) · Recipient-associated factors – smoker, COPD – malnutrition, diabetes, older age, male gender – latent tuberculosis – chronic liver disease, HCV infection – CMV infection, pneumocystis, nocardia – long-term haemodialysis – autoimmune diseases · Donor-related factors – Cadaveric donor – history of untreated TB, h/o contact with known TB patient – smoker, alcohol abuse – low BMI, incarceration, homeless – donor with diabetes · transplant associated factors – Acute / Chronic Rejection, graft dysfunction – Acute rejection increases the risk of TB by 7.6 times – Intense immunosuppression – ATG, Belatacept, CNI, MMF, high dose steroid Transmission and pathogenesis of TB in KTRs: Aerosol droplets containing mycobacterium (m-TB) reaches lungs through inhalation – mostly cleared by the innate or acquired immunity, or develop primary disease (within 2 years), or remain latent for reactivation to happen many years later. CD4+ T cell producing interferon gamma and interleukin-2 (IL2) are increased, during latent TB (LTBI), whereas these are markedly reduced in active TB. Immunosuppression in KTRs leads to reduced T cells, IL2, and Th1 type cytokines, with reduced activation and proliferation of T cells and decreased cellular immunity leading to reactivation of LTBI. Transmission of TB in KTRs is most commonly due to reactivation of latent TB infection (LTBI) – 20% in 2 years post-transplant (median 11.5 months), mostly in old-aged recipients, BCG vaccinated, and having high DSA. Donor-derived TB, accounts for 4.8% cases, seen within first 3 months; frequently present with fever, fluid / pus collection, extrapulmonary features with no response to antibiotics. De novo TB infection is uncommon, seen in endemic regions, and is associated with increased risk of progression. Diagnostic challenges: TB in KTRs have increased extrapulmonary features and co-infections (50% of cases) with atypical presentations, requiring high index of suspicion. Donor detail history on TB, may not be obtained / The tuberculin skin test (TST) and interferon gamma release assay (IGRA) are not useful in active TB diagnosis. Radiologic manifestations have wide range, and there is need for invasive procedures like bronchoscopy and bronchoalveolar lavage (BAL). Nucleic acid amplification technique (NAAT) based molecular tests can be false negative. Screening with TST and IGRA for LTBI have low feasibility and accuracy with false negative results. For screening in LTBI, IGRA is better than TST. Treatment challenges: These could be due to drug-drug interactions, drug toxicities as well as maintaining treatment adherence. Soon after diagnosis of active TB infection, treatment should be immediately started using Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol in intensive phase followed by Isoniazid and Rifampicin in maintenance phase. The optimal treatment period varies according to the clinical picture: 6 months for uncomplicated pulmonary TB, 9 months for cavitary lesions, or if sputum test is positive at 2 months, 6-9 months for disseminated or bone and joint disease, and 9-12 months for central nervous system (CNS) involvement. For localized TB (non-severe) – Isoniazid, Ethambutol and Pyrazinamide or Levofloxacin can be used for 2 months followed by 12-18 months of Isoniazid and Ethambutol or Pyrazinamide. Rifampicin, acytochrome P450 3A4 inducer, decreases levels of CNI, mTOR inhibitors, and steroids requiring increased doses (3-5 times for CNI and mTOR inhibitors, and 2 times for steroids). Severe TB requires reduction in immunosuppression. Rifampicin can be replaced with rifabutin or fluoroquinolones. Adverse effects of antitubercular drugs include hepatotoxicity, neurotoxicity, skin lesions, ophthalmic toxicity, cytopenia, hyperuricemia, interstitial nephritis, and immune reconstitution inflammatory syndrome. Liver function tests should be monitored twice a week initially for first 2 months and then monthly. Doses of the drugs should be adjusted as per creatinine clearance. Treatment adherence can be monitored using the directed observed therapy (DOTs) program. Latent TBI – positive IGRA or TST, history of untreated TB or recent TB contact, or donor kidney with LTBI without treatment, untreated TB or TB exposure. Treatment includes isoniazid (5 mg/kg/day) for 9 months, or ethambutol with levofloxacin or moxifloxacin. Liver enzymes should be monitored. Outcomes:
TB in KTRs has challenges in diagnosis, increased extrapulmonary features, and immunosuppressed state leading to increased mortality and morbidity. Immunosuppression reduction leads to allograft rejection in up to 55.6%, and graft loss in 1/3rd of patients. Graft loss can also be due to infection, sepsis, rejection (acute or chronic), or reduction in immunosuppression, seen in up to 66.6% patients. Mortality up to 60% have been seen; higher mortality rates in those with co-infections by fungi, nocardia, CMV, hepatitis viruses, chronic liver disease, diabetes, or those who received anti-rejection treatment. Conclusions: · TB in KTRs, an important opportunistic infection, has higher incidence and prevalence than in the general population, and is associated with poor outcomes (high rates of rejection, graft loss and mortality). · Effective preventive measures (pre-op screening), high index of suspicion for early diagnosis and proper treatment are required for good patients and graft outcomes.
· Early diagnosis and treatment of TB in KTR are challenging – requires high index of suspicion and optimal management approach, collaboration between transplant team and infectious disease physicians.
· Donor-derived TB and LTBI in KTRs are underrecognized – need careful evaluation by tests not based on T cell immunity (preferably).
· Newly discovered regimens or pipeline drugs could have an important contribution in the future limitation of drug–drug interactions, improvement of treatment efficacy and reduction of adverse events 2. What is the level of evidence provided by this article? Level of evidence: level 5 – Narrative review.
Summary: Introduction
This article is relating TB infection following kidney transplant. This is an important topic because of the different clinical presentations that recipients can present with when infected with TB, some of which are diagnosed late, and cause great damage to the graft as well as increasing chances of patient mortality.
This review is aimed at giving an evidence based result regarding epidemiology, risk factors, pathophysiology, type of transmission, diagnostic challenges, treatment challenges and impact of infection on recipients. Discussion
When delving into the world of TB, discussion of risk factors needs to be the first. These are as follows :
Recipient associated risk factors –
old age
male gender
smoking habit
malnutrition
diabetes
COPD
latent TB
chronic liver disease
hepatitis C liver disease
opportunistic co infection such as CMV, pneumocystis, nocardia
autoimmune disease
long term hemodialysis
Donor associated risk factors –
deceased donor
social risk factors such as homeless donor, incarceration, smoking habits, alcoholic, known exposure to TB
medical risk factors such as diabetes, overweight or obese, history of untreated TB
Transplant associated risk factors –
immunosuppression
acute rejection
chronic graft dysfunction
Others –
TB endemic areas
TB pathogenesis in kidney transplant recipients
Transmission of TB in kidney transplant recipients has three known routes :
active TB could be due to reactivation of latent infection which was present in the recipient prior to transplantation. Latent infection has been seen to be associated with factors such as lack of BCG vaccine scar, older age of recipient, and presence of DSA.
Kidney graft from infected donor
De novo infection after kidney transplant, if recipient has been exposed to a TB patient
Diagnostic challenges
Active TB usually presents in the first year post transplantation, from latent infection reactivation or de novo infection. Challenges begin when there is atypical presentation of TB leading to late diagnosis and treatment. In addition, the usually tests that can diagnose TB include tuberculin skin test, and IGRA are not useful in this case to identify active TB in these patients.
Careful evaluation of epidemiological risk, personal medical history, physical exam and chest X ray of the donor are required to make sure that there is no transmission of TB from the donor to the recipient.
Latent TB is even more difficult to identify because it is a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB. There are no gold standard tests to diagnose latent TB but IGRA can help more than TST in diagnosis. Treatment challenges
Treatment of kidney transplant recipients with TB can be challenging because of drug interactions between immunosuppressive drugs and TB treatment drugs, along with the chances of drug toxicity and tendency for patients to not adhere strictly to treatment protocol.
Monitoring medication adherence of recipients is essential and needs to be a focus especially in the case of TB. Suspected non adherence needs to be dealt with appropriately to ensure that the patient gets the maximum benefit from the drug regimen.
In the case of active TB, the recommended duration of treatment is 9-12 months. In the case of uncomplicated TB, treatment can be given for 6 months, but after 2 months if complications persist or the patient has cavitary lesions, then treatment duration must be increased to 9 months.
Rifampicin is recommended as part of first line treatment because it is very efficient and reduces the risk of resistance.However, the challenge associated with Rifampicin is the interaction it has with the patient’s immunosuppressive regimen by interfering with drug metabolization. It is a potent inducer of p450 system and p glycoprotein. It decreases the levels of IS drugs such as CNIs, mTORi along with affecting glucocorticoid metabolization. All of this increases the risk of rejection. Due to this, IS drug levels need to be closely monitored, and dosage needs to be increased three to five fold, with glucocorticoids being increased to double dose. Once Rifampicin is stopped, IS dose needs to be reduced to the value of before start of Rifampicin. In this situation, adequate IS can be difficult to achieve increasing the risk of rejection as well as infection.
Treatment of latent TB needs to be started only after active TB has been excluded. Adequate treatment is essential to prevent reactivation of TB. Treatment can be started with a positive IGRA or TST, history of untreated TB and a history of recent contact with an active TB patient. Non adherence to medication can be a big challenge especially when the patient is not seeing any active symptoms that they need to treat, leading to laxity in taking dosage at the right time with proper frequency. Conclusion
Undiagnosed TB or imeffective treatment of TB can lead to acute or chronic rejection, increased mortality risk for the recipient, and poor quality of life overall. The interactions between Tb drug regimen and IS drug protocol can be challenging to set fixed dosages and frequencies of these drugs. In addition to this, fluid test levels and difficulty in standardization can lead to misdiagnosis or late treatment.
Despite all these challenges, close monitoring of the patient, along with regular collaboration with infectious disease physicians can make the whole process smoother and more effective for both the transplant team as well as the patient. Level of analysis
This is a narrative review, and thus level of evidence is 5.
1. Summarise this article Opportunistic infection has been a major problem in SOT. This extensive literature review of articles done between 1 January to June 2022 to provide evidence based epidiolmology, pathogenesis, diagnosis, treatment, in KT recipient it may present with atypical symptoms, its delay in diagnosis, and treatment could determine poor prognosis and may increases the risk of rejection. Prevalence of active TB in KT recipient ranges between 0.3 to 15.2%, and risk of rejection with active tuberculosis is up-to 55.6%, Graft loss 2.2 to 66.6%, Mortality up-to 60%. Methods; The literature search was on PUBMED, EMBASE ELECTRONIC DATABASES. All studies done on TB their epidemiological, and outcomes were included. The article were checked by two reviewers and checked by a third reviewer. Epidemiology and risk factors for tuberculosis in SOT; Prevalence is variable in different geographical areas, a systemic review and meta-analysis of 60 studies shows the prevalence of TB in SOT of 3%, and its 20-74 times higher than in general population. The study done in 16 centers showed 512 cases per 100000 patients per year ( 26.6 times higher than general population). Epidemiology and risk factors for tuberculosis in kidney transplantation; Prevalence of active TB is 0.3 to 15.2%. it was reported with lowest in Iran (0.4%), highest in Pakistan 15.2%. It was observed that TB is more prevalent lung transplant than KT recipient. Risk factors; there are several risk factors like mainly epidemiology, immunosuppression, episodes of rejection, other risk are smoking, malnutrition, comorbid, lungs conditions, and LTBI. Transmission and pathogenesis; Transmission could be, 1. LTBI, reactivation, the most common form, it was found that 20% conversion rate within 2 years of transplantation. 2. Could be transmitted from donor during donation, this responsible for 4.8% of cases. 3. Could occur as de novo infection, it’s more frequent in endemic areas. The protection against TB is Th1-type cells which proliferate to CD4, 8 and other T-cells as protective response, post-transplantation immunosuppression suppresses all cellular immunity completely, and increases the risk of reactivation of latent tuberculosis. Diagnosis and treatment challenges; 1. Active TB à it was seen usually within first year with median time of 11.5months, donor derived within 3 months. TST and IGRA are not useful in the diagnosis of active TB, if low load with mycobacterium and associated MT Complex and resistant rifampicin the NAT (GENEXPERT) can be false negative. DDTB has poor prognosis and high mortality secondary to high risk of extra pulmonary manifestation, to prevent this need careful history from family with exposure, previous treatment. The optimal period of treatment 6-24 months, otherwise recommended is 9-12 months. According to AST-IDCOP guidelines for uncomplicated TB duration is 6 months, if positive culture continue for 9 months. Drug interaction, and toxicities should be kept in mind. 2. Latent tuberculosis à according to WHO a state of persistent immune response to stimulation by MBT Ag with no evidence of active infection. It’s recommended for latent TB screening is mandatory. IGRA has superiority on TST test. Its treatment is important to prevent risk of reactivation. Preferred Rx is INH 5mg/kg for 9 months +vit B6. In KT rifampicin regimen is not recommended, consist of ethambiotol+ levo/ moxifloxacine. Outcomes; 1. Rejection, possible reach up-to 55.6%, 2. Graft loss, prevalence 2.2 to 66.6%. 3. Mortality; in SOT its around 20%, while in KT recipient its 0 to 60%. Conclusion; Tb incidence is higher in KT recipient then general population. It’s associated with negative outcomes. DDTB and LTBI are unrecognized conditions should be monitored carefully. level of evidence V
Tuberculosis is an opportunistic infection of great importance for immunosuppressed patients, especially Renal Transplant (KT) recipients, the prevalence of active TB in KT recipients varies between 0.3–15.2%. KT recipients with active TB can have a rejection rate of up to 55.6%, a graft loss rate ranging from 2.2% to 66.6%, and a mortality rate of up to 60%. Understanding the epidemiological risk, risk factors, modes of transmission, diagnosis and treatment challenges is critical for clinicians to provide appropriate treatment for KT with TB.
Recognizing latent infection or undiagnosed active TB in kidney donors is critical in preventing post-transplant infection. As active disease in donors is a contraindication for donation, identification of latent TB in deceased donors remains a real challenge in KT, despite the current recommendation for screening. Current guidelines (American Society of Transplantation Infectious Diseases Community of Practice and European Society of Clinical Microbiology and Infectious Diseases) recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors
Active TB after KT may arise from reactivation of latent infection in the recipient or donor tissue or may result from de novo infection after transplantation. Endogenous reactivation after KT is the most common form of transmission. Candidates and recipients of KT with TB represent a real challenge regarding diagnosis and treatment due to atypical or diverse clinical presentation, limitations of screening tests for latent infection, drug interactions and toxicities. Delay in diagnosis and treatment can determine negative consequences, such as graft rejection, graft loss and increased mortality rate.
The risk factors associated with transplantation stand out, such as immunosuppressive therapy, the presence of acute episodes of rejection and chronic graft dysfunction. The immunosuppression used in KT impairs the immunity mediated by T cells involved in TB control and favors the reactivation of the latent infection, through multiple mechanisms, such as:
– Depletion of all types of T cells,
– Decreased activation and proliferation of T cells,
– Decreased synthesis of IL-2,
– Decreased production of Th-1-type cytokines or almost total impairment of cellular immunity.
TB transmission in KT receivers may be possible according to three scenarios:
– In the first, it could arise after KT as a result of the reactivation of the latent infection present in the recipient before the transplant. It is the most common form of transmission found in all solid organ transplants, including KT. Advanced age, absence of Bacillus Calmette-Guérin vaccine scars, presence of donor-specific antibodies, and KT status were factors associated with latent infection
– In the second scenario, TB could be transmitted to KT recipients through a kidney graft from an infected donor, corresponding to only 4.8% of cases.
– In the third scenario, TB could occur as a de novo infection after KT, in a recipient with exposure to a patient with active TB. This type of transmission is not common; it is associated with a very high risk of progression, being more frequent in endemic areas.
Active Tuberculosis
Although the treatment of active TB in KT recipients respects the principles of treatment for immunocompetent patients, some particularities make it complex and challenging. The optimal period of treatment could vary from 6 to 24 months and, in some cases, based on experts’ opinion, the duration of treatment is recommended to be at least 9–12 months. In case of active uncomplicated pulmonary TB, treatment duration should be at least 6 months, but if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months. In case of severe disseminated disease or bone and joint disease, treatment duration is recommended for at least 6–9 months. Patients with central nervous system involvement should be treated for at least 9–12 months.
latent tuberculosis
According to the WHO, latent tuberculosis infection is defined as a state of persistent immune response to stimulation by MBT antigens without evidence of clinically manifest active tuberculosis. There are no gold standard tests for accurately diagnosing latent TB in KT candidates, but IGRA appears to have some advantages over TST in patients with ESRD. Even so, the evaluation of latent TB in KT recipients is challenging because the data are
Treatment challenges
Treatment of KT recipients with TB can be challenging due to drug interactions, drug toxicity, and treatment adherence.
Interaction is a highlight. Rifampicin, a potent inducer of cytochrome P450 3A4 and P-glycoprotein, interferes with the metabolism of immunosuppression. Specifically, rifampicin use decreases levels of calcineurin inhibitors (cyclosporine, tacrolimus), inhibitors of the mammalian target of rapamycin (mTOR) (sirolimus, everolimus) and affects glucocorticoid metabolism, which increases the risk of rejection. Therefore, when a rifampicin-based regimen is used, calcineurin and mTOR inhibitor levels should be closely monitored, the calcineurin and mTOR inhibitor dose should be increased three to five times, and the glucocorticoid dose should be doubled. during treatment and adjusted later to obtain the therapeutic target. Additionally, after discontinuing rifampicin, immunosuppression doses should be reduced to the value prior to starting rifampicin and then adjusted to obtain the therapeutic target. An alternative to rifampicin is rifabutin, which is a weaker inducer of cytochrome P450 3A4 and P-glycoprotein, but with similar efficacy, but likewise immunosuppressive doses can be modified and levels must be closely monitored.
Another challenge is linked to the adverse effects of TB therapy, which are more frequent than in the general population. Patients treated with anti-TB drugs should be carefully monitored for hepatotoxicity (isoniazid, rifampicin, pyrazinamide), neurotoxicity (isoniazid, ethambutol), cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol), visual disturbances (rifabutin, ethambutol), (rifampicin), hyperuricemia (pyrazinamide), or interstitial nephritis (rifampicin, pyrazinamide). The most common adverse event associated with anti-TB therapy is hepatotoxicity; therefore, liver enzymes should be closely monitored with biweekly assessment during the intensive phase of treatment and monthly thereafter.
What is the level of evidence provided by this article?
This is has a level 5 of evidence, because is a Narrative Reviews.
Introduction: Kidney transplant is the treatment of choice for end stage renal disease (ESED) and its outcomes get affected by infections, with tuberculosis (TB) being an important cause of morbidity (graft rejection and loss) and mortality. TB prevalence is high in kidney transplant recipients (KTRs), and it could be either due to reactivation of latent infection, a de novo infection, or could be donor-derived infection.
Epidemiology and risk factors for TB in KTR: The incidence and prevalence of active TB in solid organ transplant ranges from 20 to 74 times the general population, and 0.3% to 15.2% prevalence depending on the geographical areas (with low and high endemicity respectively). TB prevalence in dialysis patients is 3.6 times, and in KTRs is 11.36 times that of in the general population with lung transplant recipients having still higher prevalence.
Risk factors for TB in KTRs: The risk factors include TB burden of the country (endemicity), recipient-associated factors (older age, males, smoker, malnutrition, history of diabetes, chronic obstructive pulmonary disease, latent tuberculosis, chronic liver disease, hepatitis C virus infection, cytomegalovirus infection, pneumocystis, nocardia, long-term hemodialysis, or presence of autoimmune disease), donor-related factors (cadaveric donor, donor with diabetes, low BMI, and history of untreated TB, homeless, smoker, alcohol abuse, incarceration, or known TB contact), or transplant associated factors (acute rejection, chronic graft dysfunction, and immunosuppression used like ATG, belatacept, calcineurin inhibitors, MMF, azathioprine and steroid use). Acute rejection increases the risk of TB by 7.6 times.
Transmission and pathogenesis of TB in KTRs: Aerosol droplets containing mycobacterium tuberculosis, once inhaled, reach lungs and either get cleared by the innate or acquired immunity, or develop primary disease (onset within 2 years), or latent infection (with reactivation happening many years after primary infection).
In latent TB, CD4+ T cell producing interferon gamma and interleukin-2 (IL2) are increased, while they get markedly reduced in active TB. Immunosuppression in KTRs leads to reduced T cells, IL2, and Th1 type cytokines, with reduced activation and proliferation of T cells and decreased cellular immunity leading to activation of TB.
Transmission of TB in KTRs is most commonly due to reactivation of latent TB infection (LTBI), seen in 20% within 2 years post-transplant (median 11.5 months), in patients with older age, BCG vaccinated, and having DSA. Another form is donor-derived TB, responsible for 4.8% cases, seen within first 3 months, presenting with frequent fever, fluid collection, and extrapulmonary features with no response to antibiotics. De novo TB infection is uncommon, seen in endemic regions, and is associated with increased risk of progression.
Diagnostic challenges: TB in KTRs have increased extrapulmonary features and co-infections (50% of cases) with atypical presentations, requiring high index of suspicion. The tuberculin skin test (TST) and interferon gamma release assay (IGRA) are not useful in active TB diagnosis. Radiologic manifestations have wide range, and there is need for invasive procedures like bronchoscopy and bronchoalveolar lavage (BAL). Nucleic acid amplification technique (NAAT) based molecular tests can be false negative. Donor history might be unobtainable, screening with TST and IGRA for LTBI have low feasibility and accuracy with false negative results. For screening in LTBI, IGRA is better than TST.
Treatment challenges: These could be due to drug-drug interactions, drug toxicities as well as maintaining treatment adherence. Once the diagnosis of active TB is made, treatment should be immediately started using Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol in intensive phase followed by Isoniazid and Rifampicin in maintenance phase. The optimal treatment period varies according to the clinical picture: 6 months for uncomplicated pulmonary TB, 9 months for cavitary lesions, or if sputum test is positive at 2 months, 6-9 months for disseminated or bone and joint disease, and 9-12 months for central nervous system (CNS) involvement. For localized non-severe TB, Isoniazid, Ethambutol and Pyrazinamide or Levofloxacin can be used for 2 months followed by 12-18 months of Isoniazid and Ethambutol or Pyrazinamide.
Rifampicin, acytochrome P450 3A4 inducer, decreases levels of calcineurin inhibitors (CNI), mTOR inhibitors, and steroids requiring increased doses (3-5 times for CNI and mTOR inhibitors, and 2 times for steroids). Severe TB might require reduction in immunosuppression. Rifampicin can be replaced with rifabutin or fluoroquinolones. Adverse effects of antitubercular drugs include hepatotoxicity, neurotoxicity, skin lesions, ophthalmic toxicity, cytopenia, hyperuricemia, interstitial nephritis, and immune reconstitution inflammatory syndrome. Liver function tests should be monitored twice a week initially for first 2 months and then monthly. Doses of the drugs should be adjusted as per creatinine clearance. Treatment adherence can be monitored using the directed observed therapy program.
Latent TB treatment is important in those with a positive IGRA or TST, history of untreated TB or recent TB contact, or donor kidney with LTBI without treatment, untreated TB or TB exposure. Treatment includes isoniazid (5 mg/kg/day) for 9 months, or ethambutol with levofloxacin or moxifloxacin. Liver enzymes should be monitored.
Outcomes: TB in KTRs has challenges in diagnosis, increased extrapulmonary features, and immunosuppressed state leading to increased mortality and morbidity. Graft rejection is seen, due to associated reduction in immunosuppression, in upto 55.6%, leading to graft loss in 1/3rd of patients. Graft loss (due to infection, sepsis, rejection (acute or chronic), or reduction in immunosuppression) can be seen in to 66.6% patients. Mortality rates of upto 60% have been seen, with higher rates in those with co-infections like fungi, nocardia, cytomegalovirus, hepatotropic viruses, chronic liver disease, diabetes, or those who received anti-rejection treatment.
Conclusions: The incidence and prevalence of TB in KTRs is higher than general population, and it needs high index of suspicion for diagnosing and treating such patients. The outcomes in such patients are not good with high rates of rejection, graft loss and mortality.
2. What is the level of evidence provided by this article?
This article is relating TB infection following kidney transplant. This is an important topic because of the different clinical presentations that recipients can present with when infected with TB, some of which are diagnosed late, and cause great damage to the graft as well as increasing chances of patient mortality.
This review is aimed at giving an evidence based result regarding epidemiology, risk factors, pathophysiology, type of transmission, diagnostic challenges, treatment challenges and impact of infection on recipients.
Discussion
When delving into the world of TB, discussion of risk factors needs to be the first. These are as follows :
Recipient associated risk factors –
old age
male gender
smoking habit
malnutrition
diabetes
COPD
latent TB
chronic liver disease
hepatitis C liver disease
opportunistic co infection such as CMV, pneumocystis, nocardia
autoimmune disease
long term hemodialysis
Donor associated risk factors –
deceased donor
social risk factors such as homeless donor, incarceration, smoking habits, alcoholic, known exposure to TB
medical risk factors such as diabetes, overweight or obese, history of untreated TB
Transplant associated risk factors –
immunosuppression
acute rejection
chronic graft dysfunction
Others –
TB endemic areas
TB pathogenesis in kidney transplant recipients
Transmission of TB in kidney transplant recipients has three known routes :
active TB could be due to reactivation of latent infection which was present in the recipient prior to transplantation. Latent infection has been seen to be associated with factors such as lack of BCG vaccine scar, older age of recipient, and presence of DSA.
Kidney graft from infected donor
De novo infection after kidney transplant, if recipient has been exposed to a TB patient
Diagnostic challenges
Active TB usually presents in the first year post transplantation, from latent infection reactivation or de novo infection. Challenges begin when there is atypical presentation of TB leading to late diagnosis and treatment. In addition, the usually tests that can diagnose TB include tuberculin skin test, and IGRA are not useful in this case to identify active TB in these patients.
Careful evaluation of epidemiological risk, personal medical history, physical exam and chest X ray of the donor are required to make sure that there is no transmission of TB from the donor to the recipient.
Latent TB is even more difficult to identify because it is a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB. There are no gold standard tests to diagnose latent TB but IGRA can help more than TST in diagnosis.
Treatment challenges
Treatment of kidney transplant recipients with TB can be challenging because of drug interactions between immunosuppressive drugs and TB treatment drugs, along with the chances of drug toxicity and tendency for patients to not adhere strictly to treatment protocol.
Monitoring medication adherence of recipients is essential and needs to be a focus especially in the case of TB. Suspected non adherence needs to be dealt with appropriately to ensure that the patient gets the maximum benefit from the drug regimen.
In the case of active TB, the recommended duration of treatment is 9-12 months. In the case of uncomplicated TB, treatment can be given for 6 months, but after 2 months if complications persist or the patient has cavitary lesions, then treatment duration must be increased to 9 months.
Rifampicin is recommended as part of first line treatment because it is very efficient and reduces the risk of resistance.However, the challenge associated with Rifampicin is the interaction it has with the patient’s immunosuppressive regimen by interfering with drug metabolization. It is a potent inducer of p450 system and p glycoprotein. It decreases the levels of IS drugs such as CNIs, mTORi along with affecting glucocorticoid metabolization. All of this increases the risk of rejection. Due to this, IS drug levels need to be closely monitored, and dosage needs to be increased three to five fold, with glucocorticoids being increased to double dose. Once Rifampicin is stopped, IS dose needs to be reduced to the value of before start of Rifampicin. In this situation, adequate IS can be difficult to achieve increasing the risk of rejection as well as infection.
Treatment of latent TB needs to be started only after active TB has been excluded. Adequate treatment is essential to prevent reactivation of TB. Treatment can be started with a positive IGRA or TST, history of untreated TB and a history of recent contact with an active TB patient. Non adherence to medication can be a big challenge especially when the patient is not seeing any active symptoms that they need to treat, leading to laxity in taking dosage at the right time with proper frequency.
Conclusion
Undiagnosed TB or imeffective treatment of TB can lead to acute or chronic rejection, increased mortality risk for the recipient, and poor quality of life overall. The interactions between Tb drug regimen and IS drug protocol can be challenging to set fixed dosages and frequencies of these drugs. In addition to this, fluid test levels and difficulty in standardization can lead to misdiagnosis or late treatment.
Despite all these challenges, close monitoring of the patient, along with regular collaboration with infectious disease physicians can make the whole process smoother and more effective for both the transplant team as well as the patient.
Level of analysis
This is a narrative review, and thus level of evidence is 5.
TB is more prevalent in kidney transplant than the general population but less common post lung Tx.
The prevalence varies between 0.3–6.4% in low TB endemicity to 15.2% in high endemic areas. The incidence of active TB in SOT is 20–74 times higher than in the general population.
Latent TB infection: according to WHO is defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB. Prevalence of latent TB after KT was reported in ~20% of recipients.
source of Tb after transplant : Recipients (reactivation of latent infection),Donor tissues (reactivation of latent infection),DeNovo infection.
Diagnostic Challenges
High index of suspicion
Tuberculin skin test (TST)
Interferon gamma release assay (IGRA)
Bronchoscopy with bronchoalveolar lavage, fluid collections subsequently evaluated by smear and mycobacterium culture and histopathology
Molecular tests based on rapid nucleic acid amplification techniques, such as mycobacterium tuberculosis complex
Recognizing latent infection or undiagnosed active TB in the kidney donors is critical in preventing post-transplant infection.
Treatment of Active TB Duration of treatment is recommended to at least 9-12 months. American Society of TX infection disease community of practice guidelines recommend in case of active uncomplicated pulmonary TB duration should be at least 6 months. If a cavity exists or persistence is culture-positive after 2 months of therapy duration should be 9 months. -CNS infection 19-18 months -> according to AST- IDCOP four-drug regimen contains rifampicin,INH,Ethambutol,Pyrazinamide
Diagnosis of latent TB
high clinical suspicious
tuberculin skin test (TST)
IGRA
Indications of treatment of latent TB in transplant recipient and donor
Positive TST or a positive IGRA
History of close contact to an active TB case
If recipient received graft from donor has latent TB and did not receive treatment
Protocol for treatment of latent TB
INH for 6-9 months.
Rifampicin better to be avoided in transplant patient because of drug-drug interactions and rifabutiun is an alternative.
Level of evidence -is level 5 for Narrative review
T cell immunity , T1 cells , is most important to prevent TB in recipient
BUT due to IS after KT T cells are dysfunctional
DIAGNOSIS
High index of suspicion , personal history and clinical and radiologocal manifestation
TST AND IGRA are not useful in active TB but ccan be used to diagnose LATENT TB
Donor deriived TB – recipient having fever in first 3 months , non specific symptoms , perigraft fluid , no response to empirical antibiotics
LATENT TB
Diagnosis based on – immune response to TB antigen is present BUT symptoms of TB are absent
Should be screened for in all KT candidates and donors
NO GOLD STANDARD TEST
IGRA is better than TST
Some study showed even low sensitivity for IGRA in KT patients
TREATMENT
ACTIVE TB
National TB policy applies to such patient
duration 6-24 months
standard 4 drugs consolidation and then 2 drug maintanence
DRUG INTERACTION is common due to rifampicin which reduces the level and INH which increases the level of IS drugs
Doses of IS need strict monitering
TREATMENT OF LATENT TB
positive TST or IGRA test,
history of untreated TB,
history of recent contact with an active TB patient
when the kidney graft originates from a donor with known latent
TB without chemoprophylaxis,
known history of untreated TB or
recent exposure to active TB
INH single agent for 9 month
rifampicin is avoided for latent TB in KT patient
REJECTION can be as high as 50 % in recipient with TB
GRAFT LOSS ( 2% – 60 %) can be due to infection , and rejection due to reduction in IS
MORTALITY is high (0-50%)
CONCLUSION
TB is more common after KT and associated with more rejection and increased moratlity
LATENT TB detection and treatment is the best way to avoid this but it is a complex clinical job
Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review
Tuberculosis (TB) in kidney transplant (KT) recipients is an important opportunistic infection with higher incidence and prevalence than in the general population and is associated with important morbidity and mortality.
Prevalence of active TB in KT recipients ranges between 0.3–15.2%. KT recipients with active TB could have a rejection rate up to 55.6%, a rate of graft loss that varies from 2.2% to 66.6% and a mortality rate up to 60%.
Introduction
infection after KT is still an important limitation for graft and patient outcomes .One of the most common infections with negative impact post-transplantation is tuberculosis.
As KT is associated with an immunosuppression status, active TB is higher in KT recipients than in the general population.
Active TB after KT could arise from reactivation of latent infection in the recipient or donor tissue or can result from de novo infection after transplantation. Endogenous reactivation after KT is the most common form of transmission.
KT candidates and recipients with TB represent a real challenge regarding the diagnosis and treatment due to atypical or diverse clinical presentation, limitations of screening tests for latent infection, drug interactions and toxicities .
The delay in diagnosis and treatment could determine negative consequences, such as graft rejection, graft loss and increased mortality rate.
Epidemiology of Tuberculosis in Solid Organ Transplantation
The prevalence of active TB among patients with solid organ transplantation is highly variable according to the geographic area. In areas with low TB endemicity, the prevalence varies between 0.3–6.4%, compared to prevalence of TB in high, endemic areas which could rise to 15.2%.
The incidence of active TB in solid organ transplantation is 20–74 times higher than in the general population.
Epidemiology of Tuberculosis in Kidney Transplantation
The prevalence of active TB in KT recipients varies from 0.3% to 15.2% and is higher than in the general population but lower than in patients with lung transplantation.
an unadjusted TB risk ratio of 11.36 (95% CI: 2.97–43.41) times higher in KT recipients, compared to the general population and an adjusted risk ratio for patients on dialysis of 3.62 (95% CI 1.79–7.33) times higher than those from the general population.
Risk Factors for Tuberculosis in Kidney Transplantation
There are several risk factors that predispose KT recipient to develop TB more frequently than the general population .
The risk is mainly influenced by endemicity of TB in the population, but key factors associated with the recipient, donor and transplantation increase it.
immunosuppression therapy, presence of acute rejection episodes and chronic graft disfunction .
Immunosuppression used in KT impairs T-cell-mediated immunity involved in TB control and favors latent infection reactivation.
Some immunosuppressive drugs or combinations certainly increase the risk of TB development: Tcell-depleting agents (anti-thymocyte globulin), cytotoxic T-lymphocyte-associated protein-4 inhibitors (belatacept), calcineurin inhibitors (tacrolimus, cyclosporine), anti-metabolites (mycophenolate, azathioprine) and glucocorticoids.
number of rejections after transplant is an independent risk factor for TB appearance.
chronic graft dysfunction, which could increase the risk of TB development by amplifying the immunosuppression status on its own or due to drug overdosing, a condition similar to advanced CKD.
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients
According to the natural history of infection, after the aerosol droplets containing mycobacterium tuberculosis (MBT) are inhaled into the lungs, the evolution could be as follows: clearance of MBT by the organism either due to innate immune response or acquired T cell immunity, development of primary disease which means an immediate onset of active disease (first 24 months after primary infection) or latent infection reactivation meaning a late onset of active disease many years following primary infection.
Using immunosuppression in the setting of KT could disrupt the protection against TB and increase the risk of reactivation through multiple mechanisms, such as: depletion of all types of T cells, decrease in activation and proliferation of T cells, decrease in IL-2 synthesis, decrease in the production of Th-1 type cytokines or impairment of cellular immunity almost completely.
Diagnostic and Treatment Challenges
Diagnostic Challenges
Active Tuberculosis
The diagnosis after of latent TB requires infection a high and index earlier of in suspicion the based on case of donor-derived the epidemiological infection (in risk, the personal history, manifestations and imagistic lesions.
For example, tuberculin skin test (TST) and interferongamma release assay (IGRA) are not useful in the diagnosis of active TB .
Additionally, the wide range of radiographic manifestations in pulmonary TB and the frequent need for invasive procedures (bronchoscopy with bronchoalveolar lavage, derange of fluid collections subsequently evaluated by smear and mycobacterium culture and histopathological evaluation) could represent diagnostic challenges .
Moreover, molecular tests based on rapid nucleic acid amplification techniques, such as mycobacterium tuberculosis complex and resistance to rifampin test (Xpert ® MTB/RIF, Cepheid, Sunnyvale, CA, USA), could provide false negative results when mycobacterial load is low .
Recognizing latent infection or undiagnosed active TB in the kidney donors is critical in preventing post-transplant infection [10]. As active disease in donors is a contraindication for donation, identification of latent TB in deceased donors remains a real challenge in KT, despite the current recommendation for screening [12,13]. Current guidelines (American Society of Transplantation Infectious Diseases Community of Practice and European Society of Clinical Microbiology and Infectious Diseases) recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors [12,13]. Nevertheless, in deceased donors, the patient’s medical history might be unobtainable, and the screening tests for latent TB (TST and IGRA) have low feasibility and accuracy .In these circumstances, details regarding donor history of previous active TB, specific treatment or exposure to active TB within the last 2 years should be obtained from the donor’s family or relatives .
Additionally, if an IGRA test is performed, a series of aspects should be considered—the result might not be available in time, the result could be false negative in donors with head injury due to depressed cell-mediated immunity and, in high-risk donors from low endemic areas with positive tests, the decision of donation should be correlated with personal history and chest imaging .
Latent Tuberculosis
Prevalence of latent TB after KT was reported in ~20% of recipients Current guidelines provide recommendations for latent TB screening in all KT candidates and donors before transplantation .
There are no gold standard tests for diagnosing latent TB accurately in KT candidates, but IGRA seems to present some advantages over TST in patients with ESRD.
IGRA tests have a good predictive potential for latent TB in KT recipient with negative TST
The importance of diagnosis is supported by the fact that undiagnosed and untreated latent TB after KT significantly increases the risk of active TB.
Treatment Challenges
Treatment of KT recipients with TB could be challenging due to drug–drug interactions, drug toxicity and treatment adherence. For this reason, it is recommended that the management of KT patients with TB be carried out by an experienced clinician and special attention must be paid to drug–drug interactions and potentially adverse events.
Active Tuberculosis
The treatment of active TB should be promptly started immediately after the diagnosis has been established. Additionally, the epidemiological features from the area of patient’s origin and drug resistance patterns should be assessed .
The optimal period of treatment could vary from 6 to 24 months and, in some cases, based on experts’ opinion, the duration of treatment is recommended to be at least 9–12 months
● Infection after KT is still an important limitation for graft and patient outcomes
● Active TB is higher in KT recipients than in general population . It could arise from:
☆ Reactivation of latent infection in the recipient
☆ Donor tissue
☆ can result from de novo infection after
transplantation.
● Endogenous reactivation after KT is the most common form of transmission
● KT candidates and recipients with TB are a real challenge in diagnosis and treatment due to:
☆ Atypical or diverse clinical presentation, ☆ Limitations of screening tests for latent infection
☆ Drug interactions and toxicities
● Factors associated with latent infection:
☆ Older age
☆ Absence of Bacillus Calmette–Guérin vaccine scars
☆ Presence of donor specific antibodies
● Positive latent infection conversion was found in ~20% of cases within the first 2 years after KT
Epidemiology of Tuberculosis in SOT Transplantation
● The prevalence of active TB in SOT is 0.3–6.4% with low TB endemicity and 15.2% in high endemic areas
● The incidence of active TB in SOT is
20–74 times more than in the general population
Epidemiology of Tuberculosis in Kidney Transplantation
● The prevalence of active TB in KT recipients varies from 0.3% to 15.2%
● Active TB incidence in KT recipients is lower than in lung transplant recipients
Risk Factors for Tuberculosis in Kidney Transplantation
● Recipient-associated :
* Older age
* Male gender
* Smoking
* Diabetes
* Malnutrition
* Latent TB before transplantation
* Chronic obstructive lung disease
* Hepatitis C virus infection
* Chronic liver disease
* Opportunistic co-infection : CMV , nocardia ,Pneumocystic
* Autoimmune disease
* Long term hemodialysis
● Donor associated :
☆ Donor type (cadaveric )
☆ Social risk factors ( homeless , alcohol abuse, incarceration , known TB contact , smoking )
☆ Medical risk factors : ( diabetes , history of untreated TB , BMI < 18.5 )
● Transplantation associated :
☆ Immunosuppression therapy
☆ Acute rejection episodes
☆ Chronic graft disfunction
● Others: TB burden of the country
Transmission and Pathogenesis of Tuberculosis in KT Recipients
● Aerosol droplets containing (MBT) are inhaled into the lungs, the evolution could be as follows:
☆ Clearance of MBT
☆ Development of primary disease which means an immediate onset of active disease
☆ Latent infection reactivation meaning a late onset of active disease many years following primary infection
● Transmission of TB in KT recipients:
☆ Reactivation of latent infection present in the recipient prior to transplantation prevalence of latent infection is higher in KT recipients than candidates
☆ Via kidney graft from an infected donor (4.8% of cases)
☆ A de novo infection after KT, in a recipient with exposure to a patient with active TB ( it is not common and associated with very high risk )
● The protection against MBT infection is mainly based on cellular immunity, more specifically, it depends on ( Th1) response
Diagnostic and Treatment Challenges
● active TB : Appears in the first year after KT in reactivation of latent infection and in first 3 months in donor-derived infection which associated with severe extrapulmonary manifestations and mortality
● KT recipients have atypical clinical presentations which reduce the suspicion of TB
● Co-infections and extrapulmonary localization in ~50% of cases
● (TST) and (IGRA) are not useful in the diagnosis of active TB
● Donor-derived TB is suspected in KT recipients with one of following features:
☆ Non-specific symptoms
☆ Frequent fever in first 3 months after KT
☆ Fluid collections
☆ Extrapulmonary manifestations or lack of response to antibiotic
● Current guidelines recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors
● IGRA test might not be available in time, and it could be false negative in donors with head injury
● In high-risk donors from low endemic areas with positive tests, the decision of donation should be correlated with personal history and chest imaging
Latent Tuberculosis
● IT is a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB
● Prevalence of latent TB after KT was reported in ~20% of recipients
● IGRA seems to present some advantages over TST in patients with ESRD
● The incidence and prevalence of latent TB in KT recipients is higher than in KT candidates and therefore KT recipients should be more frequently screened
Treatment of Active Tuberculosis
● In active uncomplicated pulmonary TB, treatment duration should be at least 6 M extended to 9 M in cavitary lesions and persistent culture-positive sputum after
2 M of therapy
● In severe disseminated disease or bone
and joint disease, treatment duration is at least 6–9 M
● Patients with central nervous system involvement should be treated 9–12 M
● The first-line treatment should be a four-drug regimen containing rifamycin and consists of a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin
● Second-line regimen without rifamycin the 2-month contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a phase of 12–18 months with isoniazid and ethambutol or pyrazinamide. Here a longer period of treatment is recommended
● One challenge is the drug interaction between rifampicin and IS drugs
☆ Rifampicin decrease the levels of CNi , mTORi and affects steroid metabolization,
which increases the risk of rejection
☆ Therefore calcineurin and mTOR inhibitors levels should be monitored and increased three- and five-fold and the glucocorticoid dose should be doubled
☆ An alternative to rifampicin is rifabutin, which is a weaker inducer of cytochrome P450 or fluoroquinolones
● Another challenge is AEs of TB therapy
☆ Hepatotoxicity (isoniazid, rifampicin,pyrazinamide, ethambutol)
☆ Neurotoxicity (isoniazid, ethambutol),
☆ Cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol)
☆ Visual disturbances (rifabutin, ethambutol)
☆ Skinlesions (rifampicin)
☆ Hyperuricemia (pyrazinamide)
☆ Interstitial nephritis (rifampicin , pyrazinamide)
☆ liver enzymes should be monitored with bi-weekly during intensive phase of treatment and monthly thereafter
● Another challenge is treatment adherence which can improve by directed observed therapy programs
● Reduction of immunosuppression in the case of severe TB or when a vital organ is involved should be considered.
Treatment of Latent Tuberculosis
● Considered only after active TB has been excluded.
● Treatment indicated in one of the following conditions:
☆ A positive TST or IGRA test
☆ A history of untreated TB
☆ A history of recent contact with an active TB patient
☆ When the kidney graft originates from a donor with known latent TB without chemoprophylaxis
☆ Known history of untreated TB or recent exposure to active TB
● The preferred treatment of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6
● An alternative regimen for KT recipients consists of ethambutol and levofloxacin or
moxifloxacin
Outcomes
● Rejection
☆ Can reach up to 55.6%
☆ Associated with reduced levels of IS secondary to CNi–rifampicin interaction and responsible for ~1/3 of graft losses
● Graft Loss
☆ Prevalence with active TB varies from 2.2% to 66.6%
☆ Due to infection especially in donor-derived TB
☆ Or through the sepsis produced by TB
☆ Or due to acute or chronic rejection
☆ Risk factors associated with non-recovery of graft function were :
*severe TB disease
*acute kidney injury stage 2 or 3
*acute rejection
*value of serum creatinine
● Mortality
☆ 0% to 60%
☆ 65% of KT recipients with active-TB who died had co-infections with fungi, CMV, nocardia, hepatotropic viral infections and chronic liver disease or received anti-rejection treatment before the TB development and had diabetes
Conclusions
● TB in KT is an opportunistic infection with higher incidence and prevalence and is associated with significant negative graft and patient outcomes.
● It requires close collaboration between kidney transplant and infectious disease
● Donor-derived TB and latent TB in KT are should be carefully evaluated.
● Newly discovered regimens could limit drug–drug interactions, improvement of treatment efficacy and reduction of adverse events.
● Level : 5
Summary: Introduction :
The optimal treatment for ESRD is KT. Kidney transplant recipients have a higher incidence of tuberculosis than the overall population. Active TB in the recipient could be the result of reactivation of latent infection in recipient or donor tissue, or it could be the result of de novo infection in the recipient. The diagnosis and treatment of tuberculosis in recipients sometimes remains difficult.
Methodology :
This study performed an extensive literature review of articles published between 1 January 2000 and 15 June 2022 to provide an evidence-based review of epidemiology, pathogenesis, diagnosis, treatment and outcomes of TB in KT recipients. We included all studies which reported epidemiological and/or outcome data regarding active TB in KT, and we approached the diagnostic and treatment challenges according to the current guidelines.
Epidemiology:
Prevalence varies depending on geographic location; places with low endemicity vary from 0.3-6.4%, while those with high endemicity can reach 15%. The incidence of solid organ transplantation is between 20 and 74 times that of the general population. The prevalence is higher than in the general population but lower than in people who have had lung transplants.
Risk factors in kidney transplant recipients:
Recipients are more likely to develop TB than the general population due to several risk factors, such as immunosuppression therapy, acute rejection episodes and chronic graft dysfunction. Some immunosuppressive drugs or combinations increase the risk of TB development as it impairs T-cell-mediated immunity , such as T cell-depleting agents and cytotoxic T-lymphocyte-associated protein-4 (belatacept ) , calcineurin inhibitors, anti-metabolites, rejection, chronic graft dysfunction, and drug overdosing.
Transmission and pathogenesis in kidney transplant recipients:
There are three possible ways for TB to manifest in Kidney transplat recipient.
– Through reactivation of the latent infection (the most common).
– Through transmission from an infected donor kidney (4.6% of cases).
– Through de novo infections (rare, more common in endemic areas), which carry a high risk of progression.
Diagnostic Challenges: Active tuberculosis
High index of suspicion is needed as unusual clinical presentations, and likelihood of co-infection make active TB diagnosis difficult. Mycobacterium tuberculosis complex and resistance to rifampin test may give false negative results when mycobacterial load is minimal.
Kidney transplant patients with vague symptoms, frequent fever, fluid accumulation, extra-pulmonary signs, or no response to empirical antibiotic therapy should be investigated.
Current guidelines demand a detailed epidemiological risk, personal medical history, physical exam, and chest radiography in all donors, although screening assays for latent TB (TST and IGRA) have low feasibility and accuracy.
Latent tuberculosis
Latent TB infection is an immunological response to MBT antigens without clinical symptoms.
Around 20% of KT recipients developed latent TB, and current recommendations urge screening all candidates and donors before transplantation.
In ESRD patients, IGRA may be better than TST for identifying latent TB in KT candidates.
In this group, TST and IGRA prediction findings are inconsistent.
Shu et al. recommend screening KT recipients more often than candidates since they have a higher latent TB rate.
Undiagnosed and untreated latent TB raises the likelihood of active TB, highlighting its relevance.
Treatment: Active Tuberculosis:
The treatment of TB in transplant recipients may be complicated because to drug–drug interactions, drug toxicity, and treatment adherence.
The appropriate duration of treatment could range from six months to twenty-four months, and in some circumstances, according to the decision of specialists. The duration of treatment should be at least nine to twelve months. In cases of active, uncomplicated pulmonary tuberculosis, the American Society of Transplantation Infectious Diseases Community of Practice (AST-IDCOP) recommends a treatment duration of at least 6 months. However, if cavitary lesions are present or culture-positive sputum persists after 2 months of therapy, the treatment duration may be extended to 9 months. In cases of severe disseminated disease or bone and joint disease, at least 6–9 months of treatment is advised. Individuals with involvement of the central nervous system should be treated for at least 9–12 months.
A four-drug combination comprising rifamycin should be the first-line treatment for both severe and non-severe patients.
Latent tuberculosis:
Active TB should be excluded before treatment of latent TB is considered , which is isoniazid 5 mg/kg/day for 9 months, plus vitamin B6 supplement . Follow up of liver enzymes during treatment is recommended.
Conclusion:
Prevalence of active TB in KT recipients ranges between 0.3–15.2%. KT recipients with active TB could have a rejection rate up to 55.6%, a rate of graft loss that varies from 2.2% to 66.6% and a mortality rate up to 60%. Understanding the epidemiological risk, risk factors, transmission modalities, diagnosis and treatment challenges is critical for clinicians in providing an appropriate management for KT with TB.
MTB AFTER KIDNEY TRANSPLANTATION;A COMPREHENSIVE REVIEW.
Introduction.
-Covid aside, TB is the leading infection cause of death post transplant. Immunosuppression has made TB to be more prevalent in the transplant cohort compared to the general population.
-Active TB post transplant is from ; LTBI, donor tissue or de-novo infection post transplant.
-This article looks into updates on epidemiology, risk factors, pathophysiology. type of transmission, diagnostic challenges, infection challenges and TB impact on KTR.
Methods.
-Literature search on pubmed and embaca data bases was done using specific words to help the study.
-Inclusion criteria ;Studies wit epidemiological data or outcomes in TB in KTR
-Exclusion criteria ; Articles in non english, articles with inadequate information, Articles on non kidney transplants.
-All articles were reviewed by 2 reviewers and later cross checked by a 3rd reviewer.
Epidemiology and risk factors for TB in KT.
Epidemiology;
-Prevalence in SOT -Low endemic areas 0.3-6.4% vs 15.2% in high endemic areas. Incidence is x20-74 higher than the general population.
-Prevalence in KT -0.3-15.2% ,Higher than the general popn but lower than lung transplant recipients.
-Higher than in pts with ESRD pre dialysis but lower than those on PD and HD.
Risk factors for TB in KT.
–Transplant associated risk factors; Immunosuppressive therapy, acute rejection and graft dysfunction all impair the immune system and favor TB infection.
-Recipient associated risk factors; old age, male ,smoking, DM,COPD,LTBI pre transplant, CLD, hep c infection, CMV,PCP and Norcardia infections ,Autoimmune dx and long term hemodialysis.
-Donor associated factors; cadaveric donor, homeless, smoking, alcohol use, DM. low BMI <18.5 and hx of untreated TB.
-Others ;TB burden in the country.
Transmission and pathogenesis of TB in KTR.
-Transmitted with aerosol spread into lungs where it is cleared by the immune response, develops into primary dx or LTBI.
-In KTR ,transmission occurs via; LTBI, donated kidney or de-novo infection post exposure to pt with active TB.
-Post transplant, immunosuppression destroys the immune system and leads to either reactivation or increased susceptibility to TB infection.
Diagnostic and treatment challenges.
Diagnostic challenges.
>Active TB.
-Median time of 11.5monthd for LTBI while 3/12 for DDI for active TB to appear, Atypical presentation makes diagnosis challenging.
-TST and IGRA not useful in diagnosing active TB with the CXR being quite non specific.
-Donor derived TB has mostly extrapulmonary presentation.
-Invasive procedures might be needed to get samples for evaluation by smear and mycobacterial culture which could be a challenge in doing.
>Latent TB.
-All transplant pairs to be screened for LTBI pre-transplant. IGRA preferred to TST pre transplant.
Treatment challenges.
.>Active TB.
Optimal duration ;6-24 months, AST-IDCOP guidelines ;Active uncomplicated;6/12,cavitary or persistent +VE sputum post intensive phase ;9/12,severe disseminated /bone or joint dx;6-9/12,CNS dx 9-12/12
1st line;4 drugs with rifampicin-severe and non severe- 2RHZE +4 RH + Pyridoxine.
ESCMID guidelines – Duration > 6/12,localized- use regimen without rifampicin if no resistance to isoniazid. Without RIF ;2/12 intensive; INH, ethambutol+ pyrazinamide/levofloxacin, continuation 12-18/12 with INH+ Ethambutol/ pyrazinamide.
-RIF is a cytochrome 450 +P glycoprotein inducer and thus decreases CNI and MTOR inhibitors and thus dose to be increased x3-5 while steroids dose doubles during treatment and readjusted thereafter. Readjust immunosuppression to pre treatment levels post TB tx with adequate trough levels to avert graft dysfunction.
-Other challenges include SE and Adherence to Tx, RIS to be considered in those with severe TB infection.
>LTBI.
-Tx once active TB has been excluded.
-Tx; INH -9/12+Pyridoxine.Rifampicin based regimens discouraged. Alternative; Ethambutol + levofloxacin or moxifloxacin.
TB Outcomes in KTR; Rejection, mortality or graft loss.
Conclusion.
TB in KTR is fatal with higher prevalence than the general popn. It has both diagnostic and treatment challenges and need careful consideration and approach.
As KT is associated with an immunosuppression status, active TB is higher in KT recipients than in the general population.
Active TB after KT could arise from reactivation of latent infection in the recipient or donor tissue or can result from de novo infection after transplantation.
Endogenous reactivation after KT is the most common form of transmission.
In order to limit or prevent the occurrence of active TB post-KT, it is necessary to implement screening measures for both recipients and donors according to the current guidelines.
Methods:
A literature search on PubMed and Embase electronic databases was performed from 1 January 2000 to 15 June 202.
Epidemiology and Risk Factors for Tuberculosis in Kidney Transplantation:
Epidemiology of Tuberculosis in Solid Organ Transplantation:;
The prevalence of active TB among patients with solid organ transplantation is highly variable according to the geographic area.
In areas with low TB endemicity, the prevalence varies between 0.3–6.4%, compared to prevalence of TB in high, endemic areas which could rise to 15.2%.
Epidemiology of Tuberculosis in Kidney Transplantation:
The prevalence of active TB in KT recipients varies from 0.3% to 15.2%.
Risk Factors for Tuberculosis in Kidney Transplantation:
Transplant associated factors:
Immunosuppression therapy,
Presence of acute rejection episodes
Chronic graft dysfunction.
Donors and recipient related factors:
Type of donors ,medical conditions ,social factor’s ,smoking.
OLD MALE RECPIENT ,DIABETIC ,SMOKING ,MALNUTRTION ,LIVER DIASES ,COPD ,LONGTERM DIALYSIS ,LIVER DISAES ,LATENT INFECTION ,COINFECTION.
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients:
Aerosol droplets containing mycobacterium tuberculosis (MBT) are inhaled into the lungs,
Clearance of MBT by the organism
Development of primary disease.
Or latent infection reactivation meaning a late onset of active disease many years following primary infection.
Transmission of TB in KT recipients:
Reactivation of the latent infection. ~20% of cases.
Transmitted to KT recipients via kidney graft from an infected donors. 4.8% more risk of progression, and more frequent in endemic areas.
Diagnostic and Treatment Challenges:
Diagnostic Challenges :
Active Tuberculosis:
High index of suspicion:
Based on epidemiologic risk, personal history
Atypical clinical presentation.
Extra pulmonary localization in ~50%
And coinfection.
TST and iGRA are not useful in the diagnosis of active TB.
Various radiological manifestation, need of invasive test, Xpert® MTB/RIF, Cepheid, Sunnyvale, CA, USA), could provide false negative results when mycobacterial load is low.
Donor-derived TB, it is described in a minority of cases, it is associated with severe extra pulmonary manifestations and mortality.
Should be suspected in KT recipients with one of the following features:
non-specific symptoms, frequent fever in the first 3 months after KT, fluid collections, extra pulmonary manifestations or lack of response to empirical antibiotic therapy.
Current guidelines recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors.
For deceased donors:
Details regarding donor history of previous active TB, specific treatment or exposure to active TB within the last 2 years should be obtained from the donor’s family or relatives.
IGRA test is performed, false negative and false positive in donors .
Latent Tuberculosis :
According to WHO, latent TB infection is defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB.
The evaluation of latent TB in KT recipients is challenging because data regarding prediction capacity of TST and IGRA tests are discord.
Treatment Challenges Treatment of KT recipients with TB could be challenging due to drug–drug interactions, drug toxicity and treatment adherence.
Duration of treatment:
AST-IDCOP guidelines recommends
Case of active uncomplicated pulmonary TB ,6 months, but if Cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months.
In case of severe disseminated disease or bone and joint disease, is recommended for at least 6–9 months.
Patients with CNS should be treated for at least 9–12 month.
The European Society of Clinical Microbiology and Infectious Diseases suggests:
A standard regimen used for a period longer than 6 months, and, in cases of localized non-severe TB, a regimen without rifampicin could be used if no resistance to isoniazid is present.
If a regimen without rifamycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide
if second-line drugs are used, a longer period of treatment is recommended.
Drug interaction:
Rifampicin, a potent inducer of cytochrome P450 3A4 and P-glycoprotein, interferes decrease the levels
CNI
Mtor.
Calcineurin and mTor inhibitors levels should be closely monitored, the dose of calcineurin and mTOR inhibitor should be increased between three- and five-fold and the glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target.
Rifampicin is rifabutin, which is a weaker inducer of cytochrome P450 3A4 and P-glycoprotein but with similar efficacy. Follow and monitor IS.
Another safe and effective alternative to rifampicin in KT recipients is treatment with fluoroquinolones.
Adverse effects:
Hepatotoxicity (isoniazid, rifampicin, pyrazinamide, ethambutol).
Neurotoxicity (isoniazid, ethambutol).
Cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol),
Visual disturbances (rifabutin, ethambutol),
Skin lesions (rifampicin), hyperuricemia (pyrazinamide) or interstitial nephritis (rifampicin, pyrazinamide)
Creatinine clearance and adjust the doses for pyrazinamide and ethambutol
Reduction of immunosuppression in the case of severe TB or when a vital organ is involved should be considered.
Monitor LFT Biweekly, then monthly.
Latent Tuberculosis:
Suspect LTBI following conditions:
a positive TST or IGRA test, a history of untreated TB, a history of recent contact with an active TB patient and when the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB
The preferred treatment of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6.
Alternative regimen for KT recipients, mainly for those with high risk, consists of ethambutol and levofloxacin or moxifloxacin.
Outcomes:
Risk of rejection and graft loss.
The mortality:
patients with TB after KT has been reported to range from 0% to 60% .
Conclusions:
TB in KT is an important opportunistic infection with higher incidence and prevalence than in the general population and is associated with significant negative graft and patient outcome, high suspicion and early diagnosis reduce this risk, in collaboration with infectious disease specialist.
Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review Introduction
· Although kidney transplantation is the best choice for patients with ESKD, infection, mainly TB still a main cause of poor outcomes of the graft.
· Active TB is higher in KT recipients than in the general population, mainly due to the reactivation of latent infection in the recipient or donor tissue.
· To prevent the activation of TB, it is crucial to screen both recipients and donors according to the current guidelines.
· This review provides a full revision of TB in KT recipients.
Inclusion Criteria
· All studies about epidemiological and/or outcomes data regarding TB in KT from 2000 to 2022 Exclusion Criteria
· Articles in languages other than English,
· articles that evaluated other types of transplantation than kidney only
· articles with inadequate information Epidemiology and Risk Factors for Tuberculosis in Kidney Transplantation
· The incidence of active TB in solid organ transplantation is 20–74 times higher than in the general population
· The prevalence of active TB in KT recipients varies from 0.3% to 15.2% and is higher than in the general population but lower than in patients with lung transplantation.
· Risk Factors that predispose to TB in KT recipients: immunosuppression therapy, presence of acute rejection episodes, and chronic graft dysfunction.
· Immunosuppressive drugs that increase the risk of TB: ATG, belatacept, CNI, mycophenolate, azathioprine, and glucocorticoids.
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients
· Transmission of TB in KT recipients could be possible according to three scenarios
1) reactivation of the latent infection presents in the recipient prior to transplantation (the most common in all solid organ transplantation)
2) TB could be transmitted to KT recipients via kidney graft from an infected donor (only 4.8% of cases)
3) TB could occur as a de novo infection after KT, in a recipient with exposure to a patient with active TB (uncommon) Diagnostic and Treatment Challenges
· The diagnosis of TB requires a high index of suspension, but KT recipients present with atypical manifestations, and tuberculin skin test and IGRA are not useful in the diagnosis of active TB.
· Diagnosis mostly needs invasive procedures (BAL, fluid collections drainage and then to be examined by smear and mycobacterium culture and histopathological evaluation)
· Donor-derived TB is considered an under-recognized condition with early onset after KT in the majority of cases.
· Donor-derived TB should be suspected in KT recipients with: non-specific symptoms, frequent fever in the first 3 months after KT, fluid collections, extrapulmonary manifestations, or lack of response to empirical antibiotic therapy
· Current guidelines recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam, and chest radiography in all donors
· In deceased donors details about a history of previous active TB, specific treatment or exposure to active TB within the last 2 years should be obtained from the donor’s family or relatives
Latent Tuberculosis
· Defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifested active TB
· Current guidelines recommend for latent TB screening in all KT candidates and donors before transplantation
· IGRA hasactive uncomplicated pul[1]monary TB, treatment duration should be at least 6 month some advantages over TST in the diagnosis of latent TB in patients with ESRD
Treatment Challenges
· due to drug–drug interactions, drug toxicity and treatment adherence. Active Tuberculosis
· For active uncomplicated pulmonary TB, treatment duration should be at least 6 months
· If there is a cavitary lesion or there is a persistent positive sputum culture after 2 months of therapy, the duration of treatment may be extended to 9 months
· For severe disseminated disease or bone and joint disease, treatment duration is recommended for at least 6–9 months
· For CNS involvement, treatment for at least 9–12 months is required
· the first-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases
· The regimen consists of a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin
· in cases of localized non-severe TB, a regimen without rifampicin could be used if no resistance to isoniazid is present
· In rifamycin free regimen, the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide
· Rifampicin decreases the levels of CNI, the mTORi, and affects glucocorticoids metabolization, which increases the risk of rejection
Treatment of latent TB
· Indicated in one of the following conditions: positive TST or IGRA test, a history of untreated TB, a history of recent contact with an active TB patient and when the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB.
· In the KT setting, the preferred treatment of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6
· An alternative regimen for KT recipients, mainly for those with high risk, consists of ethambutol and levofloxacin or moxifloxacin
Outcomes
· immunosuppression associated with morbidity and mortality, and increased extrapulmonary disease
· Graft rejection in KT recipients with TB can reach up to 55.6%, mostly due to CNI–rifampicin interaction
· graft loss in KT patients with TB can be due to infection of the graft, or sepsis from TB
· Graft loss can be due to acute or chronic rejection post-reduction or withdrawal of immunosuppression
· mortality in SOT recipients about 20%, and of patients with TB after KT from 0-60%
Conclusions
· TB in KT has a higher incidence and prevalence than in the general population and has bad graft and patient outcomes
· Transplant physicians should be oriented about the diagnosis and management of TB after KT.
· physicians should be alert about donor-derived TB and latent TB in KT.
· New diagnostic tools and new regimens without drug-drug interaction are needed.
II. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review
Summarise the article
Introduction
– kidney transplantation is the preferred treatment among ESKD patients
– TB is an important opportunistic infection in kidney transplant recipients (KTRs)
– the incidence and prevalence of TB is higher among KTRs compared to the general population due to the state of immunosuppression
– it is also associated with significant morbidity and mortality
– active TB infection in KTRs can be as a result of reactivation of LTBI in the recipient or the donor tissue or de novo infection post-transplantation
– endogenous reactivation of LTBI is the most common mode of transmission
– screening measures for both recipients and the donor should be implemented to limit/ prevent occurrence of active TB post-kidney transplantation
Methods
– literature search on PubMed and Embase electronic databases for articles published between 1 January 2000 and 15 June 2022
– inclusion criteria – all studies that reported epidemiological and/ or outcome data regarding active TB in KTRs
– exclusion criteria – articles in other languages apart from English, articles evaluating non-kidney transplantation, articles with missing information
– the investigators looked at the diagnostic and treatment challenges according to the current guidelines
Epidemiology and risk factors for TB in kidney transplantation
– prevalence of active TB among SOTs varies from 0.3 – 15% depending on the geographical area
– incidence of active TB in SOT is 20 – 74times higher than in the general population
– prevalence of TB in KTRs varies from 0.3 – 15%, it is higher than in the general population but lower than in lung transplant recipients
– the risk for developing TB is mostly influenced by endemicity of TB in the population
– risk factors for TB development in KTRs include: –
Donor-associated risk factors like donor type i.e., deceased donor; social factors i.e., smoking, alcohol abuse, homelessness, incarceration, known TB contact; medical risk factors i.e., DM, history of untreated TB, BMI <18.5
– Acute rejection increases risk of TB by 7.6 times and the number of rejections is an independent risk factor for TB development
– Immunosuppression impairs T-cell immunity which is involved in TB control and favours LTBI reactivation
– Immunosuppressive agents which increase the risk of TB development include ATG, Belatecept, CNIs, antimetabolites, glucocorticoids
– Chronic graft dysfunction amplifies the immunosuppression state on its own
Other factors i.e., TB burden in the country
Transmission and pathogenesis of TB in kidney transplant recipients
– there are 3 possible outcomes following inhalation of the aerosol droplets i.e.,
the MTb organism can be cleared by the innate immunity or the acquired T-cell immunity
development of primary disease resulting in immediate onset of active TB (first 24 months after primary infection) or
LTBI reactivation I.e., late onset of active TB many years after the primary infection
– transmission of TB in KTRs can occur in three modes i.e.,
Reactivation of LTBI in the KTR after kidney transplantation – most common, occurs within the first year
Donor-derived infection through an infected kidney graft, occurs within the first 3 months
Development of de novo TB infection in the KTR following kidney transplantation
Diagnostic challenges
o Active TB
– prognosis depends on early diagnosis and appropriate treatment
– diagnosis requires a high index of suspicion
– diagnostic challenges include atypical or diverse clinical presentation, co-infections, extrapulmonary localization, diverse radiological manifestations, decreased predictive values of screening tests, false negative results, limitations of screening, need for invasive procedures like bronchoscopy
– donor-derived TB is associated with severe extrapulmonary manifestations and mortality
– active TB in the donor is a contraindication to donation
– identification of LTBI in deceased donors remains a challenge
– treatment challenges include drug interactions and toxicities
– these diagnostic and treatment challenges may result in delayed management which can lead to graft rejection, graft loss and increased mortality
o Latent TB (LTBI)
– LTBI is defined as persistent immune response to stimulation by mycobacterium antigens without any evidence of active TB clinically
– evaluation of LTBI in KTRs remains a challenge
– there are no gold standard tests for diagnosing LTBI accurately in KTRs
– IGRA seems to be advantageous than TST in ESKD patients
– undiagnosed and untreated LTBI following kidney transplantation increases the risk of active TB significantly
Treatment challenges
– challenges encountered in treatment of TB in KTRs are due to drug-drug interactions, drug toxicity/ adverse events and treatment adherence
o Active TB
– duration of treatment varies: –
6 months for active uncomplicated PTB
9 months for cavitary disease or in cases of persistent culture-positive sputum after 2 months of therapy
6-9 months for severe disseminated disease or bone and joint disease
9-12 months for CNS disease
– 1st line treatment is a four-drug regimen containing rifamycin, this is used for both severe and non-severe cases
– rifamycin is recommended due to its sterilization capacity and efficiency, it also reduces the risk of resistance
– standard regimen entails 2-month intensive phase of RHZE followed by a 4-month continuation phase of RH
– the main challenge in treatment of active TB in KTRs is the drug interactions between rifampicin and the immunosuppressive agents
– rifampicin is a potent inducer of cytochrome P450 3A4 and P-glycoprotein hence it decreases the levels of CNIs, mTORi, and affects metabolization of glucocorticoids; this in effect increases the risk of rejection
– it is advised that the CNI and mTORi dose be increased by 3- to 5-fold and the glucocorticoid dose doubled during treatment with a rifampicin-based regimen, and the trough levels should be closely monitored
– once rifampicin is stopped, the immunosuppression dose should be reduced to the pre-rifampicin treatment level and dose adjusted accordingly depending on the trough level
– rifabutin is an alternative to rifampicin, it is a weaker inducer of cytochrome P450 3A4 and P-glycoprotein but with similar efficacy
– fluoroquinolones are another safe and effective alternative to rifampicin in KTRs
– the 2nd challenge is adverse effects of anti-TBs which are more frequent among KTRs than in the general population
– the 3rd challenge is treatment adherence but this has improved with DOTs (direct observed therapy) programs
– adjust dose of pyrazinamide and ethambutol based on the kidney function
– immunosuppression modulation should be considered in cases of severe TB or when there is involvement of a vital organ
– IRIS can occur with use of rifampicin and reduction in immunosuppression
o Latent TB
– LTBI treatment is only considered after ruling out active TB
– LTBI treatment in KTRs prevent risk of reactivation
– indications for LTBI treatment among KTRs include: – a positive TST or IGRA test, history of untreated TB, history of recent active TB contact, graft kidney from a donor with untreated LTBI, untreated TB or recent exposure to active TB
– the preferred treatment of LTBI in KTRs is 9 months of isoniazid and pyridoxine, closely monitor the LFTs
– a rifampicin-based regimen is not recommended in KTRs
– an alternative regimen is ethambutol and levofloxacin or moxifloxacin especially for those at high risk
Outcomes – graft rejection, graft loss, mortality
– among KTRs, TB is associated with significant morbidity and mortality due to the state of immunosuppression, increased extrapulmonary disease and challenges in diagnosis which result in delayed treatment
-the risk of graft rejection in KTRs with TB can reach 55% and is mainly due to low levels of immunosuppression as a result of the interaction between CNIs and rifampicin; this can also account for 1/3rd of the graft losses
– graft loss among KTRs with TB can reach 66%, it occurs: –
directly due to the infection especially in cases of donor-derived TB,
indirectly through sepsis secondary to TB, or
due to acute or chronic rejection following immunosuppression minimization or withdrawal, or
due to CNI-rifampicin interaction resulting in reduced CNI dose
– mortality of KTRs with TB ranges from 0-60% with most cases being associated with coinfections (fungi, CMV, HCV), diabetes, anti-rejection treatment
Conclusions
– incidence and prevalence of TB in KTRs is higher than that in the general population and is associated with significant negative patient and graft outcomes
– preventive measures should be implemented by careful identification of the risk factors
– there are diagnostic and treatment challenges encountered hence a multidisciplinary approach is advocated for
– donor derived TB and LTBI should be carefully evaluated in KTRs
– graft and patient outcomes can be improved by development of tests with better predictive values, drug regimens with less drug-drug interactions, adverse effects and improved efficacy
This review by Bogdan Marian Sorohan and collaegues did an extensive literature review of articles published between 1 January 2000 and 15 June 2022 to provide an evidence-based review of epidemiology,pathogenesis,diagnosis,treatyand outcome of TB in KT recipients.
According to World Health Organization (WHO),
~10 million cases of TB (were reported in 2020 worldwide, corresponding to an incidence rate of 127 cases per 100,000 people per year .This shows that TB is quite prevalent all over the world and the risk of infection increases markedly in SOT patients.
Epidemiology of Tuberculosis in Solid Organ Transplantation
The prevalence of active TB among patients with solid organ transplantation is highly variable according to the geographic area. In areas with low TB endemicity, the prevalence varies between 0.3–6.4%, compared to prevalence of TB in high, endemic areas which could rise to 15.2% .The incidence of active TB in solid organ transplantation is 20–74 times higher than in the general population.
Epidemiology of Tuberculosis in Kidney Transplantation.
The prevalence of active TB in KT recipients varies from 0.3% to 15.2% and is higher than in the general population but lower than in patients with lung transplantation.
Risk Factors for Tuberculosis in Kidney Transplantation.
The risk factors are
Recipient associated like older age, Malnutrition, Diabetes, COPD, CLD, latent TB , opportunistic infections, autoimmune disease.
Donor associated
Donor type ( Cadaveric)
Homeless
DM , BMI less than 18.5
History of untreated TB
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients
According to the natural history of infection, after the aerosol droplets containing mycobacterium tuberculosis (MBT) are inhaled into the lungs, the evolution could be as follows: clearance of MBT by the organism either due to innate immune response or acquired T cell immunity, development of primary disease which means an immediate onset of active disease (first 24 months after primary infection) or latent infection reactivation meaning a late onset of active disease many years following primary infection.
Diagnostic Challenges
Active Tuberculosis. A high index of suspicion is needed to diagnose active TB in this group of patients as at times the clinical picture is not classical and labs tests might not support the diagnosis.
Latent Tuberculosis
According to WHO, latent TB infection is defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB. The epidemiology and survey of latent TB after KT remain scarce. Prevalence of latent TB after KT was reported in ~20% of recipients. TST and IGRA should be used appropriately to diagnose latent TB.
Treatment Challenges
Treatment of KT recipients with TB could be challenging due to drug–drug interac- tions, drug toxicity and treatment adherence. For this reason, it is recommended that the management of KT patients with TB be carried out by an experienced clinician and special attention must be paid to drug–drug interactions and potentially adverse events.
Latent Tuberculosis
Treatment of latent TB should be considered only after active TB has been excluded. Treatment of KT recipients with latent TB is important for preventing the risk of reactivation. Treatment in this category of patients is indicated in one of the following conditions: a positive TST or IGRA test, a history of untreated TB, a history of recent contact with an active TB patient and when the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB.
Outcomes
TB in KT is associated with important morbidity and mortality due to immunosup- pression status, increased extrapulmonary disease and challenges in diagnosis that delay the initiation of treatment.
Rejection
Graft rejection in KT recipients with TB can reach up to 55.6%, often being associated with reduced levels of immunosuppression secondary to calcineurin inhibitors–rifampicin interaction and could be responsible for ~1/3 of graft losses
Graft Loss
The causes of graft loss among KT patients with TB can be directly due to infection, especially in the case of donor-derived TB, or indirectly through the sepsis produced by sepsis.
Mortality
The mortality of patients with TB after KT has been reported to range from 0% to 60%
CONCLUSION This article has again reiterated the importance of vigilance in diagnosing TB in post kidney transplant patients and prompt treatment as otherwise it can lead to mortality and graft loss far more than General population.
Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Introduction.
TB infection is more common in post kidney transplant recipients than general population due to immunosuppressed status, mainly it is due to reactivation of latent TB in recipient or in donor tissue but might be de novo infection after transplantation, hence, TB screening and treatment for donor and recipient is such important to avoid the negative impact on graft and recipient survival. Aim of the work and Methods.
Trying to provide an evidence-based update regarding epidemiology, risk factors, pathophysiology, type of transmission, diagnostic challenges, treatment challenges and the impact of TB in KT recipients by collecting data from published studies from 1 January 2000 to 15 June 2022 after review. Epidemiology and Risk Factors for Tuberculosis in Kidney Transplantation.
The incidence of active TB in solid organ transplantation is 20–74 times higher than in the general population and the incidence varies according to low versus high endemic areas.
The prevalence of active TB in KT recipients varies from0.3% to 15.2% and is higher than in the general population but lower than in patients with lung transplantation and one study shown that the pooled incidence of active TB in KT recipients was higher than in patients with ESRD in pre-dialysis but lower than in those on peritoneal dialysis and hemodialysis.
Many risk factors such as (endemicity of TB in the population, immunosuppression therapy, presence of acute rejection episodes and chronic graft dysfunction, latent TB, DM, malnutrition, smoking, CLD and others). Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients.
The most common scenario is reactivation of the latent infection in the recipient prior to transplantation, second scenario, TB could be transmitted to KT recipients via kidney graft from an infected donor, finally, TB could occur as a de novo infection after KT, in a recipient with exposure to a patient with active TB. Diagnostic challenges of active Tuberculosis.
Many conditions make TB diagnosis in PKX is a challenge such as atypical clinical presentations, probability of association with other co-infections and extra pulmonary localization in ~50%of cases also low sensitivity of diagnostic tests such as mycobacterium tuberculosis complex and resistance to rifampin test could provide false negative results when mycobacterial load is low.
Many guidelines recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors, and in deceased donor, donor history of previous active TB, specific treatment or exposure to active TB within the last 2 years should be obtained from the donor’s family or relatives. Latent Tuberculosis.
A state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB, IGRA seems to present some advantages over TST in patients with ESRD but still no gold standard test for diagnosis. Treatment Challenges/ Active Tuberculosis.
Treatment should start immediately after diagnosis and the most important challenges during treatment are drug–drug interactions, drug toxicity and treatment adherence, the optimal period of treatment could vary from 6 to 24 months and (AST-IDCOP) guidelines recommends that in case of active uncomplicated pulmonary TB, treatment duration should be at least 6 months, but if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months. Rifampicin is recommended for its sterilization capacity and efficiency but also to reduce the risk of resistance, but once started, calcineurin and mTOR inhibitors levels should be closely monitored to avoid risk of rejection and graft loss, also another important point is to follow drugs side effects and the most common adverse event associated with anti-TB therapy is hepatotoxicity; therefore, liver enzymes should be closely monitored with bi-weekly. Treatment of latent Tuberculosis.
The preferred treatment of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6 and treatment should be for patients with one of the following conditions: a positive TST or IGRA test, a history of untreated TB, a history of recent contact with an active TB patient and when the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB. Outcomes.
1-Graft rejection in KT recipients with TB can reach up to 55.6%, often due to calcineurin inhibitors–rifampicin interaction and could be responsible for ~1/3 of graft losses.
2-A study from France with a long follow-up period, graft survival rates in KT patients with TB at 1 year, 5 years and 10 years after KT were 97%, 85% and 67%, respectively and mainly due to sepsis, acute rejection, interstitial fibrosis and tubular atrophy were causes of graft loss.
3-The mortality of patients with TB after KT has been reported to range from0% to 60%, and More than half of patients who died received anti-rejection treatment before the TB development and had diabetes, hepatitis C virus infection or fungal infection. Conclusion:
TB post kidney transplant is one of the common infection that occurred more than general population, it is diagnosis and treatment is still challenging and need high suspicion and still new tools for diagnosis with high sensitivity is required and treatment plan with high efficacy and short time plan is required with low drug- drug interaction. Level of evidence: (v).
Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review:
It’s literature research done in 1 January 2000 to 15 June 2022 from Pubmed. Epidemiology of Tuberculosis in Solid Organ Transplantation:
The prevalence of active TB among patients with solid organ transplant is generally high and depend on geographical areas.
In low endemic area is 0.3% to 4%. in high endemic area reach to 15%.
The incidence of active TB in solid organ transplantation is 20–74 times higher than in the general population. Epidemiology of Tuberculosis in Kidney Transplantation:
Many retrospective cohort studies shows Prevalence of active TB in kidney transplant is higher than in general population but lower in comparison with lung transplant.
In a recent meta analysis studies shows prevalence and incidence of active TB in recipient of kidney transplant is more in patients previously known case of ESRD and on haemodialysis in comparison to peritoneal dialysis . Risk Factors for Tuberculosis in Kidney Transplantation: Recipient factors:
Endemic area
Old age
Male
History of smoking
Presence of comorbidity
Malnutrition
Positive serology of HCV , HIV, HBsAg
Donor factors:
Cadaveric
Homeless
Previous exposure to tuberculosis
Presence of comorbidity
Transplant factors:
Immunosuppressive therapy especially ATG, calcinurine inhibitors and steroid and MMF.
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients According to the natural history of infection:
Mode of transmission is aerosol droplets, reactivation of latent TB, donor derived tuberculosis or de novo infection. Diagnosis and treatment :
It’s by clinical suspicion and radiological manifestations while tuberculin skin test (TST) and interferon gamma release assay (IGRA) are not helpful in the diagnosis of active TB.
Donor derived tuberculosis is suspected when there is extra pulmonary manifestations.
Symptoms of tuberculosis appear early after kidney transplant and radiological manifestation of activation of latent tuberculosis.
The current screening and guidelines (American Society of Transplantation Infectious Diseases Community of Practice and European Society of Clinical Microbiology and Infectious Diseases) recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors; However still activation of latent infection higher in appearance.
The prevalence of latent TB 20% in all kidney transplant patients and There are no gold standard tests for diagnosing latent TB.
The under diagnosis and untreated latent tuberculosis increase risk of active tuberculosis and mortality after kidney transplant. Treatment:
Treatment of active tuberculosis need multidisciplinary team and infectious specialist regarding drug drug interaction and drug toxicity.Treatment is indicated if TST or IGRA test are positive or presence history of untreated TB, or history of recent contact with an active TB patient and when the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB. The drugs recommended in kidney transplant is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6. A regimen based on rifampicin is not recommended. Other regimen is ethambutol and levofloxacin or moxifloxacin. The main adverse event associated to isoniazid is hepatotoxicity, so evaluation of liver enzymes during treatment is recommended initially biweekly for 6 weeks and then monthly. Outcomes:
TB in KT is associated with high risk of morbidity and mortality due to immunosuppression status and increase extra-pulmonary disease.
What is the level of evidence provided by this article?
Summary of Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Reviewintroduction
Active TB is higher in KR recipient than in the general population and active TB after KT result from reactivation in the recipient or donor tissue or can result from de novo infection after transplantation.
This review aimed to provide evidence Based on updates regarding epidemiology risk factors, pathophysiology, type of transmission, diagnostic challenge treatment challenges, and the impact of TB in KT recipient methods:-
A literature search or PubMed and Embrace electronic database was performed from I January 2000 to 15 Jan 2022. Epidemiology and risk factors for tuberculosis in Kidney Transplantation.
Epidemiology of TB in SOT:-
The prevention of active TB among patients with SOT in the area with low endemicity is between 0.3-6.4% but in high T.B endemic areas 15.2% Risk Factors For TB in Kidney Transplantation:-
Risk Factors that predispose KT recipients to develop TB more frequently than general population
. endemicity of TB in the population.
. Immunosuppression therapy
. acute rejection episodes
. chronic graft dysfunction
. any immunosuppression used in KT impaired T-cell mediated immunity involved in TB control and favor latent infection reactivation such as ATG, abatacept CNI, antimetabolite, and glucocorticoids. Transmission and pathogenesis of TB in Kidney Transplant recipients:-
1- The reactivation of latent TB in the recipient prior to transplantation (20%).
2- TB could be transmitted to KT recipient via Kidney graft from or infected donor at 4.8%
3- TB can occur as de novo infection after KT uncommon, has a very high risk of progression, and it more frequent in an endemic area. Diagnostic and treatment challenges
Diagnostic challenges
Active TB
If from reactivation of later TB in the first year of KT (11.5 months).
In the case of the donor derived infection (in the first 3 months).
The diagnosis of TB based on epidemiology risks personal History, manifestation, and imagistic lesions.
KT has a typical chemical presentation and the probability of association with other co-infections and extrapulmonary realization in the 50% of cases adds a supplementary confusing element to the clinical pictures and donor-devised TB should be suspected in KT recipients with one of the following features:-
. non-specific symptoms
. frequent fever in the first 3 months after KT.
. fluid collection
. extrapulmonary manifestation
. lack of response to empirical antibiotics therapy.
Current guidelines recommend a careful evaluation of the epidemiological risk, personal medical history physical exam, and chest radiography in all donors.
In the deceased donor, the details negativity donor history of previous active TB-specific treatment or exposure to active TB within the last 2 years should be obtained from the donor family or relatives. Laten TB
Guidelines recommended screening for laten TB in all KT candidates and donors before transplantation.
No gold standard test to diagnose latent TB accurately in KT candidates by IGRA has some advantages are TST in patients with ESRD. Treatment challenges Active TB
Duration of treatment is recommended to at least 9-12 months.
American Society of TX infection disease community of practice guidelines recommend in case of active uncomplicated pulmonary TB duration should be at least 6 months.
If a cavity exists or persistence is culture-positive after 2 months of therapy duration should be 9 months.
->CNS infection 19-18 months
-> according to AST- IDCOP
-> four-drug regimen contains rifampicin
->2 months of INH, rifampicin pyrazinamide, and ethambutol forward by 4 months of INH and rifampicin
->ESCMID European suggests standard therapy longer than 6 months.
-> rifampicin-free region if looked no severe TB regimen includes INH, ethambutol, and pyrazinamide or levofloxacin following 12 -18 months with INH and ethambutol or pyrazinamide.
If the second line of drug use longer period of treatment is recommended.
Rifampicin enzyme inducer of cytochrome p45 decrease the level of CNI and mTOR and also affect glucocorticoid metabolism and causes acute rejection
CNI and mTOR monitoring and increase 3-5 fold should be increased and glucocorticoid dose should be doubled the dose.
Rifabutin is alternative to rifampicin and is a weaker enzyme inducer of cytochrome p45 but even in a rifabutin based regimen is dose could be modified and level closely monitored.
Also fluoroquinolone is a safe and effective alternative to rifampicin, patients should be monitored for side effects of anti T.B medication
Treatment adherence is crucial with KT if not offer DOT.
Sever T.B can reduce IS therapy however the possible occurrence of immune reconstitution inflammatory syndrome which is associated with the reduction of IS therapy and use of rifampicin Laten T.B
First exclude active T.B and treatment indicated of LTBI when positive TST or IGRA test a history of untreated T,B ,history of recent contact with active T. B patent and when the graft with donor known LTBI without chemoprophylaxis.
Treated by INH 5mg/kg /day(300mg od) for 9 months plus vit B6.
Alternative regimen with high-risk ethambutol and levofloxacin or moxifloxacin .
Follow up liver enzyme weekly for 6 months and then monthly Outcomes
T.B in KT associated with morbidity and mortality . Rejection
Graft rejection in KT recipients with T.B can reach up to 55.6% due to decrease level of IS. Mortality
The mortality of patients with T.B after KT ranges 0-60%. Conclusion
T.B in KT is associated with significant negative graft and patient outcome.
Donor-derived T.B and laten T.B in KT are under-recognized conditions that should be evaluated carefully.
Newly discovered regimens of drugs in the future limit the drug-drug interaction and reduce the side effects
level of evidence is 5
Introduction: TB is one of the most important opportunistic infections in post kidney transplant, causing morbidity & mortality. TB infection can occur as reactivation of latent TB in the recipient or derived from the donor or de-novo. This review aimed to provide an evidence-based update regarding epidemiology, risk factors, pathophysiology, type of transmission, diagnostic challenges, treatment challenges and the impact of TB in KT recipients. Review was done by Searching the literatures on PubMed and Embase electronic databases from 1 January 2000 to 15 June 2022. Epidemiology of Tuberculosis in Solid Organ Transplantation: Active TB in solid organ transplant recipients varies by region. TB prevalence ranges from 0.3–6.4% in low-endemic areas to 15.2% in high-endemic areas. Active TB in solid organ transplant recipients was 3%. Active TB is 20–74 times more common in solid organ donation. In a study of 4388 solid organ transplant recipients in 16 Spanish transplant facilities, TB incidence was 512 cases per 100,000 patients per year, 26.6 times higher than in the general population. In 1989 solid organ transplantation recipients in a low-TB country, the incidence of active TB was 41 cases per 100,000 patients per year, 8.5 times higher than the general population. Epidemiology of Tuberculosis in Kidney Transplantation: Active TB in KT recipients range from 0.3% to 15.2%, higher than in the general population but lower than in lung transplant recipients. In a case-control analysis of 12,820 KT recipients from 12 main Iranian KT centers, Basiri et al. found 0.3% prevalence. Two comprehensive reviews and meta-analyses found 2.51% and 3% prevalence of active TB following KT. In another meta-analysis, Al-Efraiji et al. showed an uncorrected TB risk ratio of 11.36 times higher among KT recipients compared to the general population and an adjusted risk ratio for dialysis patients of 3.62 times higher. In a recent meta-analysis, Alemu et al. found that KT patients had a pooled incidence of active TB of 2700 per 100,000 patient-years, ranging from 340 in low-TB burden countries to 14,680 in high-endemic countries. In the same study, the pooled incidence of active TB in KT recipients was higher than in patients with ESRD in pre-dialysis (2700 vs. 913 per 100,000 person-years) but lower than in those on peritoneal dialysis and haemodialysis (2700 vs. 3533 and 5611 per 100,000 person-years, respectively). KT recipients have a lower active TB rate than lung transplant recipients. Risk Factors for Tuberculosis in Kidney Transplantation: figure 1 Types of transmission: 1- Reactivation of latent TB after transplantation 2- Transmission via infected graft 3- De-novo infection Diagnosis: 1- Active TB: – Needs high level of suspicion based on risk factors. – Presentation &X-ray findings may be atypical – Tuberculin test &IGRA test are not useful – Molecular test may be false negative if low bacterial load – frequent need for invasive procedures (bronchoscopy with bronchoalveolar lavage, derange of fluid collections subsequently evaluated by smear and mycobacterium culture and histopathological evaluation) – should be suspected one of the following features: non-specific symptoms, frequent fever in the first 3 months after KT, fluid collections, extrapulmonary manifestations or lack of response to empirical antibiotic therapy – important to consider in deceased donor the detailed history of previous TB & that IGRA results may be not available yet or falsely negative & correlate this with imaging before decision of donation 2- latent TB: – Current guidelines provide recommendations for latent TB screening in all KT candidates and donors before transplantation – Kim et al. showed that IGRA tests have a good predictive potential for latent TB in KT recipient with negative TST however, Hadaya and colleagues observed that IGRA tests had a low sensitivity in KT recipients and cannot be used to exclude latent TB. – Screening should be more frequent Treatment: 1- Active TB: The American Society of Transplantation Infectious Diseases Community of Practice (AST-IDCOP) recommends at least 6 months of treatment for active uncomplicated pulmonary TB, but 9 months if cavitary lesions present or if culture-positive sputum persists after 2 months. In severe disseminated or bone and joint disease, treatment should last 6–9 months. Treat central nervous system patients for 9–12 months. AST-IDCOP recommends a four-drug regimen with rifamycin as first-line treatment for severe and non-severe patients. Rifamycin is suggested for sterilizing and resistance reduction. A 2-month intense phase of isoniazid, rifampicin, pyrazinamide, and ethambutol is followed by a 4-month continuation phase. the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) recommends a conventional regimen for longer than 6 months and a regimen without rifampicin for localized non-severe TB if isoniazid resistance is absent. If rifamycin is not used, the 2-month intensive phase should include isoniazid, ethambutol, and pyrazinamide or levofloxacin, followed by a 12- to 18-month continuation phase. Second-line medicines require lengthier treatment. Drug drug interaction between rifampicin & immunosuppression: – Rifampicin is potent enzyme inducer to Cyp450 , leading to decrease level of CNIs , MTORi , glucocorticoid& increase risk of rejection – If rifampicin used, increase dose of CNIs & MTORi to 3-5 times & double the glucocorticoid dose with frequent monitoring of drug levels & graft function – Alternatives is rifabutin which has weaker enzyme inducer effect with same efficacy or fluroquinolones Ø S/E of the ttt: Hepatotoxicity, neurotoxicity(INhðambutol), cytopenia, visual abnormalities(rifabutin ðambutol), skin lesions(riafmpoicin), hyperuricemia(pyrizinamide), and interstitial nephritis(rifampicin&pyrizinamide) should be watched in patients on anti-TB medicines. Hepatotoxicity, the most prevalent side effect of anti-TB therapy, should be examined bi-weekly during rigorous treatment and regularly thereafter. – Adjust dose of pyrazinamide & ethambutol to eGFR – Consider to Reduce immunosuppression if vital organs affected 2- Latent TB: – consider latent TB treatment After excluding active TB only. – Treating latent TB in KT patients prevents reactivation. – treatment is suggested if the patient has a positive TST or IGRA test, a history of untreated TB, recent contact with an active TB patient, or a kidney graft from a donor with known latent TB without chemoprophylaxis. – treatment is suggested if the patient has a positive TST or IGRA test, a history of untreated TB, recent contact with an active TB patient, or a kidney graft from a donor with known latent TB without chemoprophylaxis. – Isoniazid 5 mg/kg/day (maximum 300 mg/day) for 9 months with vitamin B6 is the optimal treatment for latent TB in KT. Rifampicin is not advised . Ethambutol plus levofloxacin or moxifloxacin are a high-risk KT regimen. Outcomes: – Graft rejection in KT recipients with TB can reach up to 55.6% – f graft loss in KT patients with active TB varies from 2.2% to 66.6% – The mortality of patients with TB after KT has been reported to range from 0% to 60%
Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review
A Summary-of this article:
Kidney transplantation is the best modality of renal replacement therapy in individuals with end stage kidney disease. However, infections is one the important cause of morbidity and mortality among these patients. One example of an infection is tuberculosis which occurs due to immune suppression with higher rates in transplant recipients compared to the general populations.
Active tuberculosis developed due to reactivation of latent infection(most common) in recipient or donor tissue or de novo after transplantation.
Diagnosis and management of tuberculosis is difficult because of atypical presentation, problems with screening for latent TB, drug interactions and side effects.
Late diagnosis is associated with risk of rejection, graft loss, and even death.
Method: This article reviewed many articles published between 1 January 2000 and 15 June 2022 regarding epidemiology, pathogenesis, diagnosis, treatment and outcomes of active TB in kidney transplant recipients
Excluded articles: studies in language other than English, studies include other organ
transplant other than kidney only & studies with inadequate information.
The prevalence of active TB is significantly higher in KTx than general population; around 20-74 times higher than general population. It differ according to geographic area, it ranges from 0.3–6.4%, in developed countries and in up to 15% in endemic regions
Aim of the study:
Provide evidence-based update of epidemiology, risk factor, pathophysiology of transmission, diagnostic challenge, treatment challenge and impact of TB infection in Solid organ kidney transplant recipient.
Mode of transmission:
Activation of latent TB (the most common)
Acquiring the disease from the graft (DD)
Acquiring new infection through air born transmission (not common, associated with
aggressive disease and is more commonly seen in endemic areas)
Risk factors for TB in Kidney Transplantation:
Recipient related:
Older age
Male gender
Smoking
Other Comorbidities including DM, COPD, chronic liver disease, malnutrition
HCV infection and opportunistic co-infection such as CMV, PCJ and nocardia
Prolonged hemodialysis before renal transplantation
Latent TB before transplantation
Use of aggressive immunosuppressive therapy
Acute rejection (increase the risk of TB 7.6 times) and chronic allograft dysfunction
Donor related:
Deceased donor transplantation
High Risk DD TB: Social risk factors including homeless patients, smoking, alcohol abuse and contact to TB case
Medical risk factors including the presence of DM, history of previous TB or underweight
Community Related Factors:
TB burden in the community
Pathogenesis of TB in KTx. recipients:
After inhalation of the organism, the patient deal in one of 3 ways : Complete clearance of the organism, primary disease (active TB) or latent TB which may be reactivated later
Recipients with latent TB are at high risk of conversion to active TB after transplantation, it was estimated that around 1/5th of patients with latent TB develop active disease 2 years after transplantation
On the other hand, If the donor has latent TB and did not receive treatment it carry a risk of transmission to the recipient and if that happen the recipient should be treated for latent TB before possible progression to active disease
So all recipients and donors should both be undergo careful evaluation of the risk, history, examination and CXR, together with test for latent TB
Diagnosis of Latent TB:
Latent TB is estimated to involve 20% of transplant recipients
In general, all transplant recipients and donors should be evaluated for the presence of latent TB and once detected treatment should be given.
Two test are used to detect latent TB, tuberculin skin test (TST) and IGRA, both are usually negative in immunosuppressed patients due to their dependence on the host immune response which is impaired in these sets of patients
Which test to use:
In SOT candidates with ESRD, it is preferred to use IGRA over TST due to its higher sensitivity in these sets of patients
In SOT candidates without ESRD, either TST or IGRA can be used.
Patients who have received BCG vaccination in early life can have false positive TST, so they should be evaluated by IGRA
If TST is negative it is better to do IGRA if the patient is living in country with high TB prevalence or if the patient has TB risk factors.
Indications of treatment of latent TB in transplant recipient and donor:
Positive TST or a positive IGRA
History of positive TST or pervious history of TB
Negative TST and/or IGRA in a patient with close contact to an active TB case
If the donor has latent TB and did not receive treatment (treat the recipient), but if the
donor received treatment there is no need to treat the recipient
Protocol for treatment of latent TB:
INH in a dose of 5 mg/kg (maximum dose 300 mg) together with oral pyridoxine 25 to 50 mg daily for 9 months.(The preferred regimen)
Patient should be monitored for liver enzymes and bilirubin at baseline then monthly
Rifampicin containing regimen are not preferred after renal transplantation due to several drug drug interactions
Timing of active TB after transplantation:
Most of cases occur at a median of 11.5 months after tranplantation. Donor-derived TB usually occur earlier within the first 3 months
The diagnosis is challenging (needs high index of suspicion) due to the following:
Atypical clinical presentation is more common in immunocompromised compared to immunocompetent patients
The presence of co-infections which may delay the diagnosis
Around 50% of cases presents with extra pulmonary or disseminated TB (much higher than immunocompetent hosts)
Tuberculin test and IGRA are usually negative
Sputum smear for TB is usually negative despite active TB.
PCR from specimen can be falsely negative if the TB load is low
It is uncommon for the transplant recipients to have the classic picture of TB
To reach diagnosis invasive procedure is usually required including bronchoscopy and BAL or lung biopsy
The treatment of TB in SOT is challenging due to the following
Drug-drug interaction between Rifampicin =The corner stone of TB treatment and immunosuppressive medications used in transplantation
Loss of host immune response to TB due to the use of immunosuppressive drugs
Toxicity of anti-TB medications including hepatotoxicity (the most common side efcect) and cytopenia (isoniazid, rifampicin,pyrazinamide, ethambutol), neurotoxicity (isoniazid, ethambutol), visual disturbances (rifabutin, ethambutol), skin lesions (rifampicin), hyperuricemia (pyrazinamide) and interstitial nephritis (rifampicin,pyrazinamide)
Adherence to the treatment may be a problem in multi-medicated patients like transplant recipients
Protocols used in treatment of TB:
1) Rifampicin containing regimen:
Regimen A– 4-drug regimen of Rifampicin+ INH+ ethambutol + pyrazinamide for 2
months, followed by a 2-drug regimen of Rifampicin + INH for 4 months
It is recommended to increase the duration of treatment to at least 9-12 months if one of
the following is present
-Disseminated disease
-Cavitary disease with positive sputum culture after 2 months of treatment
-Bone and joint disease
-CNS disease.
-Some recommends extending the duration of treatment to 9-12 months in all SOT
recipients since there is improvement in the mortality when using extended duration
2) Rifampicin free regimen:
Regimen A – 3-drug regimen of INH+ ethambutol + pyrazinamide or levofloxacin are used for 2 months, followed by a 2-drug regimen of INH + either ethambutol or pyrazinamide for 12 to 18 months
Regimen B – 3 drugs (INH+ ethambutol + pyrazinamide or levofloxacin are used for 12 months
Regimen C – Rifabutiun can be used instead of rifampicin due to its lesser effect on cytochrome p450, so minimal drug-drug interactions but experience is little when using this drug in transplantation, although it seems effective in HIV TB patients.
It is strongly recommended to use Rifampicin containing regimen especially in patients with severe (cavitary or multilobar) or disseminated disease or if there is an evidence of INH resistance.
In non-severe cases with no evidence of INH resistance, Rifampicin is usually avoided due to its intense drug-drug interactions with immunosuppressive drug (Induction of CYP3A4) with subsequent increase in the risk of rejections so it is better to use rifampicin free protocols
Once rifampin is used, it is recommended to increase the dose of CNI or rapamycin 3-5 folds, with close follow up of serum level and corticosteroid dose should be doubled.
In SOT it is recommended to save Rifampicin for severe and resistant cases , and avoid streptomycin due to its nephrotoxicity
Avoid extreme reduction of the immunosuppressive agents to decrease the possibility of anti-tuberculous therapy – induced immune reconstitution inflammatory syndrome (IRIS). So mild to moderate reduction is advised
Prognosis:
Up to half of the renal transplant recipients with active TB may develop rejection
Graft loss occur in 2.2% to 66.6%
Mortality occur in up to 60 % of patients
What is the level of evidence provided by this article?
A-narrative review =====> level of evidence is (V)
DIAGNOSIS AND TREATMENT CHALLANGES IN TB IN KT RECEPIENTS Diagnosis is challenging
· Tuberculin skin test (TST) and interferon- gamma release assay (IGRA) are not useful in the diagnosis of active TB .
· the wide range of radiographic manifestations in pulmonary TB and the frequent need for invasive procedures (bronchoscopy with bronchoalveolar lavage, derange of fluid collections subsequently evaluated by smear and mycobacterium culture and histopathological evaluation) could represent diagnostic challenges
· molecular tests based on rapid nucleic acid amplification techniques, such as mycobacterium tuberculosis complex and resistance to rifampin test could provide false negative results when mycobacterial load is low
Latent Tuberculosis
· latent TB infection is defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB
· There are no gold standard tests for diagnosing latent TB accurately in KT candidates,
· IGRA seems to present some advantages over TST in patients with ESRD ,IGRA tests have a good predictive potential for latent TB in KT recipient with negative TST
· The importance of diagnosis is supported by the fact that undiagnosed and untreated latent TB after KT significantly increases the risk of active TB Treatment Challenges in KT recepients
1- the drug interaction between rifampicin and transplant-associated immunosuppression .Rifampicin, a potent inducer of cytochrome P450 3A4 and P-glycoprotein, interferes with immuno- suppression metabolization . it decrease the levels of calcineurin inhibitors (cyclosporine, tacrolimus), mTOR) inhibitors (sirolimus, everolimus), and affects glucocorticoids metabolization, calcineurin and mTOR inhibitors levels should be closely monitored, and the glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target.
2- TB drugs should be closely monitored for
· hepatotoxicity (isoniazid, rifampicin, pyrazinamide, ethambutol),
· neurotoxicity (isoniazid, ethambutol),
· cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol),
· visual disturbances (rifabutin, ethambutol),
· skin lesions (rifampicin), hyperuricemia (pyrazinamide)
· interstitial nephritis (rifampicin, pyrazinamide) .
· The most common adverse event associated with anti-TB therapy is hepatotoxicity; therefore, liver enzymes should be closely monitored with bi-weekly evaluation during the intensive phase of treatment and monthly thereafter
3- Treatment adherence could also be an issue in KT recipients.
4-The patients with KT could have different degrees of graft function it is very important to evaluate creatinine clearance and adjust the doses for pyrazinamide and ethambutol .
5-Reduction of immunosuppression in the case of severe TB or when a vital organ is involved should be considered.
6- there are some concerns regarding the possible occurrence of immune reconstitution inflammatory syndrome, which is associated with the reduction of immunosuppression and the use of rifampicin
Treatment of latent TB in KT recipient
· Treatment of latent TB should be considered only after exclusion of active TB
· Treatment of KT recipients with latent TB is important for preventing the risk of reactivation.
· Treatment is indicated in one of the following conditions:
1- a positive TST or IGRA test,
2- a history of untreated TB,
3- a history of recent contact with an active TB patient
4- when the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB
5- the preferred treatment of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6. A regimen based on rifampicin is not recommended .
6- An alternative regimen for KT recipients, mainly for those with high risk, consists of ethambutol and levofloxacin or moxifloxacin
Treatment of active TB the first-line treatment
· a four-drug regimen containing rifamycin used both in severe and non-severe cases the same as regimen for general population
· consists of a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin .
· if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treat- ment may be extended to 9 months
· severe disseminated disease or bone and joint disease, treatment duration is recommended for at least 6–9 months .
· Patients with central nervous system involvement should be treated for at least 9–12 months .
the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) suggests
· a standard regimen used for a period longer than 6 months,
· and, in cases of localized non-severe TB, a regimen without rifampicin could be used if no resistance to isoniazid is present.
· If a regimen without rifamycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide.
Outcomes Rejection
Graft rejection in KT recipients with TB can reach up to 55.6%, often being associated with reduced levels of immunosuppression secondary to calcineurin inhibitors–rifampicin interaction Graft Loss
The causes of graft loss among KT patients with TB can be directly due to infection, especially in the case of donor-derived TB, or indirectly through the sepsis produced by TBand due to the acute or chronic rejection that occurred after minimization or withdrawal of immunosuppression. Mortality
The mortality of patients with TB after KT has been reported to range from 0% to 60% .
This is a review of articles published between 1 January 2000 and 15 June 2022 to provide an evidence-based review of epidemiology, pathogenesis, diagnosis, treatment and outcomes of TB in KT recipients. TB is one of the most common infections. The delay in diagnosis and treatment could determine negative consequences, such as graft rejection, graft loss and increased mortality rate.
Active TB after KT could arise from reactivation of latent infection in the recipient or donor tissue or can result from de novo infection after transplantation. In order to limit or prevent the occurrence of active TB post-KT, it is necessary to implement screening measures for both recipients and donors according to the current guidelines. In this review all studies that provided epidemiological and/or outcomes data regarding TB in KT were included.
Epidemiology and Risk Factors for Tuberculosis in Kidney Transplantation
A recent systematic review and meta-analysis including 60 studies analyzed the prevalence of active TB in solid organ transplant recipients and showed a pooled prevalence of 3%. The incidence of active TB in solid organ transplantation is 20–74 times higher than in the general population. In a study performed in 16 transplant centers from Spain, which included 4388 solid organ transplantation recipients, the incidence of TB was 512 cases per 100,000 patients per year (95% CI: 317–783), which was 26.6 times higher than in the general population.The prevalence of active TB in KT recipients varies from 0.3% to 15.2%
Risk Factors for Tuberculosis in Kidney Transplantation
Transplant-associated risk factors- immunosuppression therapy, presence of acute rejection episodes and chronic graft disfunction.
Recipient associated- old age, malnutrition, diabetes, COPD, Latent tb, CLD, Long term HD
Donor associate- cadaveric, homeless, incarceration, smoking, alcohol abuse, diabetes, BMI<18.5
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients
After the aerosol droplets containing mycobacterium tuberculosis (MBT) are inhaled into the lungs, the evolution could be as follows: clearance of MBT by the organism either due to innate immune response or acquired T cell immunity, development of primary disease which means an immediate onset of active disease (first 24 months after primary infection) or latent infection reactivation meaning a late onset of active disease many years following primary infection.
Diagnostic Challenges
High index of suspicion based on epidemiological risk, personal history manifestation and imagistic lesion. Kt recipient may have atypical presentation.
Tuberculin skin test (TST) and interferon gamma release assay (IGRA) are not useful in the diagnosis of active TB.
Bronchoscopy with bronchoalveolar lavage, fluid collections subsequently evaluated by smear and mycobacterium culture and histopathological evaluation could represent diagnostic challenges.
Molecular tests based on rapid nucleic acid amplification techniques, such as mycobacterium tuberculosis complex and resistance to rifampin test could provide false negative results when mycobacterial load is low.
Recognizing latent infection or undiagnosed active TB in the kidney donors is critical in preventing post-transplant infection.
Current guidelines (American Society of Transplantation Infectious Diseases Community of Practice and European Society of Clinical Microbiology and Infectious Diseases) recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors.
Kim et al. showed that IGRA tests have a good predictive potential for latent TB in KT recipient with negative TST
Treatment Challenges
Treatment of KT recipients with TB could be challenging due to drug–drug interactions, drug toxicity and treatment adherence.
American Society of Transplantation Infectious Diseases Community of Practice (AST-IDCOP) guidelines recommends that in case of active uncomplicated pulmonary TB, treatment duration should be at least 6 months.
If cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months.
In case of severe disseminated disease or bone and joint disease, treatment duration is recommended for at least 6–9 months.
Patients with central nervous system involvement should be treated for at least 9–12 months.
This standard regimen consists of a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin
In cases of localized non-severe TB, a regimen without rifampicin could be used if there is no resistance to isoniazid. If a regimen without rifamycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide. Additionally, if second-line drugs are used, a longer period of treatment is recommended.
Interation
Rifampicin, a potent inducer of cytochrome P450 3A4 and P-glycoprotein, interferes with immunosuppression metabolization.
It decrease the levels of calcineurin inhibitors (cyclosporine, tacrolimus), the mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus), and affects glucocorticoids metabolization, which increases the risk of rejection.
When a rifampicin-based regimen is used, calcineurin and mTOR inhibitors levels should be closely monitored, the dose of calcineurin and mTOR inhibitor should be increased between three- and five-fold and the glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target.
After the rifampicin is stopped, the immunosuppression doses should be reduced to the value before the start of rifampicin and then adjusted to obtain the therapeutic target.
An alternative to rifampicin is rifabutin, which is a weaker inducer of cytochrome P450 3A4 and P-glycoprotein but with similar efficacy.
Another safe and effective alternative to rifampicin in KT recipients is treatment with fluoroquinolones
Adverse effect
Patients should be closely monitored for hepatotoxicity (isoniazid, rifampicin, pyrazinamide, ethambutol), neurotoxicity (isoniazid, ethambutol), cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol), visual disturbances (rifabutin, ethambutol), skin lesions (rifampicin), hyperuricemia (pyrazinamide) or interstitial nephritis (rifampicin, pyrazinamide)
Reduction of immunosuppression in the case of severe TB or when a vital organ is involved should be considered but there are some concerns regarding the possible occurrence of immune reconstitution inflammatory syndrome.
Latent TB treatment
In the KT setting, the preferred treatment of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6. A regimen based on rifampicin is not recommended. An alternative regimen for KT recipients, mainly for those with high risk, consists of ethambutol and levofloxacin or moxifloxacin
Outcomes Rejection
Graft rejection in KT recipients with TB can reach up to 55.6%, often being associated with reduced levels of immunosuppression secondary to calcineurin inhibitors–rifampicin interaction and could be responsible for approx. 1/3 of graft losses.
Graft Loss
The causes of graft loss among KT patients with TB can be directly due to infection, especially in the case of donor-derived TB, or indirectly through the sepsis produced TB and due to the acute or chronic rejection that occurred after minimization or withdrawal of immunosuppression.
One study that analyzed graft function and survival in KT recipients with active TB showed a prevalence of graft loss of 14.7% and an association of TB with acute kidney injury and incomplete recovery of graft function after treatment
Mortality
In a recent meta-analysis, Mamishi et al. found that mortality rate in solid organ transplantation recipients was 20% . The mortality of patients with TB after KT has been reported to range from 0% to 60% .
Conclusions
TB in KT is an important opportunistic infection with higher incidence and prevalence than in the general population and is associated with significant negative graft and patient outcomes.
Level of evidence -is level 5 for Narrative review.
The optimal treatment for ESRD is KT , but infections like TB post-transplantation can have a negative impact on graft and patient outcomes, so screening measures and evidence-based updates are needed to reduce or prevent TB post-KT.
Methodology :
A literature search on PubMed and Embase was conducted from 1 January 2000 to 15 June 2022 to identify studies that provided epidemiological and/or outcomes data related to TB in kidney transplantation (KT).All articles were analyzed by two reviewers for inclusion/exclusion criteria, and the process was checked by a third reviewer.
Epidemiology and Risk Factors for Tuberculosis in Kidney Transplantation :
The prevalence of active TB among patients with solid organ transplantation is highly variable according to the geographic area . The incidence of active TB in solid organ transplantation is 20–74 times higher than in the general population but lower than in patients with lung transplantation .
A recent meta-analysis found that patients with KT had a pooled incidence of active TB of 2700 per 100,000 patient-years, which ranged from 340-14,680 in low TB burden countries to 14,680 in countries with high endemicity.
Risk Factors for Tuberculosis in Kidney Transplantation:
T recipients are more likely to develop TB than the general population due to several risk factors, such as immunosuppression therapy, acute rejection episodes and chronic graft dysfunction. Some immunosuppressive drugs or combinations increase the risk of TB development as it impairs T-cell-mediated immunity , such as T cell-depleting agents and cytotoxic T-lymphocyte-associated protein-4 (belatacept ) , calcineurin inhibitors, anti-metabolites, rejection, chronic graft dysfunction, and drug overdosing.Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients
Transmission and pathogenesis of tuberculosis in kidney transplant recipients (KT) is possible according to three scenarios:
Clearance of MBT, Development of primary diseaseLatent infection reactivation. KT is a risk factor for TB reactivation in candidates with latent infection due to initiation of induction and maintenance specific immunosuppression. This could disrupt the protection against TB and increase the risk of reactivation through multiple mechanisms, such as depletion of all types of T cells, decrease in activation and proliferation, decrease in IL-2 synthesis, and decrease in production of Th-1 type cytokines.
Diagnosis and treatment challenges :
Diagnosis and treatment of TB can be challenging due to the particularities associated with KT which should be addressed because the patients’ prognosis depends on the early diagnosis and the appropriate therapeutic approach , but atypical clinical presentations or diverse manifestations can reduce clinical suspicion. Donor-derived TB is an under-recognized condition with early onset after KT, and should be suspected in KT recipients with non-specific symptoms, frequent fever, fluid collections, extrapulmonary manifestations or lack of response to empirical antibiotic therapy.
Latent TB :
Latent TB infection is defined as a persistent immune response to stimulation by MBT antigens with no evidence of active TB. The reported prevalence of latent TB after KT is in ~20% of recipients, and current guidelines recommend screening in all KT candidates and donors before transplantation. IGRA test is better than TST in patients with ESRD,however, data regarding prediction capacity of TST and IGRA tests are discordant. The incidence and prevalence of latent TB in KT recipients is higher than in KT candidates and should be more frequently screened. Undiagnosed and untreated latent TB after KT significantly increases the risk of active TB.
Treatment Challenges: Management of KT patients with TB should be carried out by an experienced clinician because it is challenging due to drug–drug interactions, drug toxicity and treatment adherence. Also special attention must be paid to drug–drug interactions and potentially adverse events .
Active Tuberculosis:
The treatment of active TB in KT recipients is complex and challenging. AST-IDCOP recommends a four-drug regimen containing rifamycin, followed by a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol.
The duration of treatment ranges from 6-12 and may extend to 24 months according to severity and site of involvement .
Adverse effects such as hepatotoxicity, neurotoxicity, cytopenia, visual disturbances, skin lesions, hyperuricemia, and interstitial nephritis are common. Drug interaction is common , especially rifampicin which is a potent enzyme inducer that reduces the level of immunosuppressant and increases the risk of rejection .
Reduction of immunosuppression in severe TB or when a vital organ is involved should be considered, but there are concerns about immune reconstitution inflammatory syndrome.
Latent TB: Active TB should be excluded before treatment of latent TB is considered , which is isoniazid 5 mg/kg/day for 9 months, plus vitamin B6 supplement . Follow up of liver enzymes during treatment is recommended.
Outcomes : There is increased morbidity and mortality in KT when developed TB due to immunosuppression status, increased extrapulmonary disease and challenges in diagnosis that delay the initiation of treatment .
Rejection : The commonest cause of graft rejection in KT recipients with TB is reduced levels of immunosuppression secondary to calcineurin inhibitors–rifampicin interaction and could be responsible for ~1/3 of graft losses .
Graft Loss: Graft loss among KT patients with active TB is caused by infection, sepsis, acute rejection, interstitial fibrosis, tubular atrophy, and suboptimal levels of immunosuppression. It varies from 2.2% to 66.6%, with the highest rate reported in a study by Vandermarliere et al. (66.6%) with active TB.
Mortality:
Mortality rates in solid organ transplantation recipients have been reported to range from 0% to 60% . Active TB after 2 years post-KT is an independent risk factor. 65% of KT recipients with active-TB who died had co-infections with fungi, cytomegalovirus, nocardia, hepatotropic viruses, and chronic liver disease.
Conclusion :
TB in KT has higher incidence and prevalence than in the general population, requiring close collaboration between kidney transplant and infectious disease physicians.
Introduction A common infection after kidney transplant is tuberculosis (TB), and it is associated with a negative impact on the patient. Due to the immune suppression after kidney transplant, the cases of TB are higher in kidney transplant recipients than the general population. There are also other risk factors favoring the development of TB present in the transplant recipients, apart from the immune suppression. After kidney transplantation, active TB could arise from reactivation of a latent infection in the recipient or donor tissue, or can occur de novo after transplantation. Endogenous reactivation of TB is the most common form of transmission. Screening measures are required for both the donor and recipients according to the current guidelines. Diagnosis and treatment of TB among kidney transplant recipients is challenging because of the atypical or diverse clinical presentation, the limitations of screening tests to detect latent infection, drug interactions and drug toxicities. These reasons can cause delays in treatment and diagnosis of the infection, hence lead to complications such as graft rejection, graft loss and an increased mortality rate. The aim of this review was to provide an evidence-based update regarding epidemiology, risk factors, pathophysiology, type of transmission, diagnostic challenges, treatment challenges and the impact of TB in kidney transplant recipients.
Methodology A literature search was performed from 1st January 2000 to 15th June 2022, on PubMed and Embase databases. All studies that provided epidemiological and/or outcomes data regarding tuberculosis in kidney transplant were included.
Epidemiology and risk factors for TB in Kidney transplantation Epidemiology of TB in solid organ transplantation In low TB endemic areas, the prevalence of TB among patients with sold organ transplantation was 0.3 to 6.4% compared to up to 15.2% in high TB endemic areas. The incidence of active TB in solid organ transplant recipients is 20-74 times higher than in the general population, approximately 512 cases per 100,000 patients per year.
Epidemiology of TB in kidney transplantation The prevalence of TB in kidney transplant recipients can vary from 0.3 to 15.2%. It has a higher prevalence than the general population, but lower than lung transplant recipients. The highest prevalence of active TB in kidney transplant recipients was reported from Pakistan, a country with high rates of TB. Another study showed that the prevalence was also higher among patients on dialysis.
Risk factors of TB in kidney transplantation Recipient-associated risk factors Older age, male gender, history of cigarette smoking, malnutrition, diabetes, chronic obstructive pulmonary disease, latent TB (pre-transplant), chronic liver disease, Hepatitis C virus infection, opportunistic co-infections (e.g. CMV, pneumocystis, nocardia), autoimmune disease, long-term hemodialysis. Donor-associated risk factors Donor type (cadaveric), social risk factors (homeless, incarceration, smoking, alcohol abuse, known TB contact), medical risk factors (diabetes, BMI > 18.5kg/m2, history of untreated TB). Transplant-associated risk factors Immune suppression, acute rejection, chronic graft dysfunction. Others TB burden of the country.
Transmission and pathogenesis of TB in kidney transplant recipients The natural history of the infection begins with inhalation of the aerosol droplets containing mycobacterium tuberculosis (MTB). The infection may be cleared by the innate immune system or acquired T-cell immunity, development of primary disease leading to an immediately active (first 24 months after the primary infection) or latent infection reactivation.
Transmission of TB in kidney transplant recipients can occur by:
Active TB from reactivation of the latent infection that was present in the recipient prior to transplantation
A kidney graft from an infected donor
A de novo infection after kidney transplant, when the kidney transplant recipient is exposed to a patient with active TB.
The protection against MTB infection is mainly based on cellular immunity. The use of immune suppression medications after kidney transplants disrupts the protection against TB and increases the risk of reactivation through many mechanisms, such as, depletion of all types of T cells, decrease in activation and proliferation of T cells, decrease in IL-2 synthesis, decrease in the production of Th-1 type of cytokines or impairment of cellular immunity.
Diagnostic challenges Active TB The diagnosis of TB requires a high index of suspicion, based on the epidemiological risk, personal history, manifestations and lesions on imaging. Kidney transplant recipients have atypical clinical presentations. Co-infections and extra-pulmonary localizations may add to the confusion. These reasons may delay the diagnosis of TB in kidney transplant recipients. Tuberculin skin test (TST) and interferon-gamma release assay (IGRA) are not useful in the diagnosis of active TB. TB also has a wide range of radiologic manifestations, and it may require invasive procedures to obtain samples. Some molecular tests may provide false negatives when the mycobacterial load is low. Donor-derived TB should be suspected in kidney transplant recipients with non-specific symptoms, frequent fevers in the first 3 months after transplantation, fluid collections, extra-pulmonary manifestations or lack of response to empirical antibiotic therapy. All donors should undergo a careful evaluation of epidemiological risk, personal medical history physical exam and chest radiography.
Latent TBLatent TB is a state of persistent immune response to stimulation by MTB antigens with no evidence of clinically manifested active TB. There are no gold standards for diagnosing latent TB accurately in kidney transplant recipients. It has been shown that IGRA has advantages over TST. It is important to diagnoses latent TB in kidney transplant recipients, as undiagnosed and untreated latent TB after kidney transplant significantly increases the risk of active TB.
Treatment challenges Active TBThe treatment of active TB should be promptly initiated after the diagnosis has been established. Guidelines recommend that in the case of uncomplicated active pulmonary TB, treatment should be for 6 months. If there are cavitary lesions or persistence of culture-positive sputum after two months of treatment initiation, treatment should extend for 9 months. In the case of severe disseminated disease or bone and joint disease, treatment duration is recommended for 6-9 months. Patients with central nervous system involvement should undergo treatment at least 9-12 months. First line treatment should include rifamycin. The 2 month intensive phase includes isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4 month continuation phase with isoniazid and rifampicin. Rifampicin is a potent inducer of cytochrome P450 3A4 and P-glycoprotein, and so it interferes with immune suppression metabolism. It decreases the levels of CNIs, mTORIs and affects glucocorticoid metabolism. Therefore, the immune suppression levels require monitoring and their levels adjusted accordingly during treatment. An alternative for rifampicin in kidney transplant recipients is treatment with fluoroquinolones. The adverse effects include hepatotoxicity, nephrotoxicity, cytopenia, visual disturbances, skin lesions, hyperuricemia or interstitial nephritis.
Latent TBTreatment of latent TB should be considered only after active TB has been excluded. Treatment of kidney transplant recipients with latent TB is important for preventing the risk of reactivation. Treatment in indicated if there is a positive TST or IGRA test, a history of untreated TB, a history of recent contact with an active TB patient and when the graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB. The preferred treatment of latent TB is isoniazid 5mg/kg/day (maximum dose of 300mg/day) for 9 months, supplemented with vitamin B6. The main adverse effect associated with isoniazid is hepatotoxicity.
Outcomes It has been noted that graft rejection in kidney transplant recipients is approximately 55.6%. The losses were due to acute rejection. Graft loss can be due to the infection, or the acute and chronic rejection. The mortality of patients with TB after kidney transplant has been reported between 0 and 60%.
Conclusions For kidney transplant recipients, TB is an important opportunistic infection with a higher incidence and prevalence than in the general population. It is associated with negative graft and patient outcomes. It is important for clinicians to recognize the diagnostic and treatment challenges of TB in kidney transplant recipients. It will assist in better management of the patients, and therefore better outcomes.
In endemic areas, it would be important to offer prophylaxis with INH after ruling out latent TB
Since there is no clearly defined question, and there is no PICO format, I would not call it a systematic review article with LOE I. It is a narrative review, hence level 5 of evidence.
Introduction: Tuberculosis (TB) in kidney transplant (KT) recipients is an important opportunistic in[1]fection with higher incidence and prevalence than in the general population and is associated with important morbidity and mortality. TB is the thirteenth-most common cause of death and the leading infectious cause of death, excluding coronavirus disease 2019 (COVID-19), worldwide. The incidence rate of 127 cases per 100,000 people per year, according WHO 2000 report. This article performed an extensive literature review of articles published between 1 January 2000 and 15 June 2022 to provide an evidence-based review of epidemiology, pathogenesis, diagnosis, treatment and outcomes of TB in KT recipients.
Epidemiology of Tuberculosis in Solid Organ Transplantation: The prevalence of disease is related to endmecity of the disease, 0.3-6.4% in low endemic areas, to 15% in high endemic areas. The incidence of active TB in solid organ transplantation is 20–74 times higher than in the general population.
Risk Factors for Tuberculosis in Kidney Transplantation: Recipient associated risk factors are: older age, male gender, smoking, malnutrition, diabetes mellitus, chronic obstructive lung disease, latent TB, chronic liver disease, hepatitis c virus infection, co-infection with CMV,PCP, and Nocardia, autoimmune diseases, long time on HD. Donor associated risk factors are: cadaveric donors, social risk factors (homeless, iv drug abuse, alcohol, smoking, known TB contact, and incarcination), medical riks factors (diabetes, BMI<18, history of untreated TB). Transplant associated risk factors are: immunosuppression, acute rejection, chronic allograft dysfunction). TB burden of the country.
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients: Reactivation of latent TB. Donor derived TB infection. Post transplantation exposure to infected TB patient. Use of immunosuppression in Kidney transplnatation could disrupt the T cell mediated(CD4+/CD8+) immune system.
Diagnostic Challenges: 1- Active Tuberculosis: Active TB post-transplant usually occur at the first year after transplantation, in case of latent TB reactivation, and within 3 months in case of donor derived TB. The diagnosis of TB requires a high index of suspicion based on the epidemiological risk, personal history, manifestations and imagistic lesions (non-specific) , co-infections, extra-pulmonary manifestations. Tuberculin skin test (TST) and interferon gamma release assay (IGRA) are not useful in the diagnosis of active TB infection. Bronchoscopy with bronchoalveolar lavage, derange of fluid collections subsequently evaluated by smear and mycobacterium culture and histopathological evaluation, may require weeks to months. Molecular tests based on rapid nucleic acid amplification techniques, such as mycobacterium tuberculosis complex and resistance to rifampin test, could provide false negative results when mycobacterial load is low. Donor-derived TB is suspected with early onset after KT presents with one of the following features: non-specific symptoms, frequent fever in the first 3 months after KT, fluid collections, extrapulmonary manifestations or lack of response to empirical antibiotic therapy. The American Society of Transplantation Infectious Diseases Community of Practice(AST-IDCOP) and European Society of Clinical Microbiology and Infectious Diseases(ESCMID) recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors. 2- Latent TB: Latent TB infection (WHO) is defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB. Prevalence of latent TB after KT was reported in ~20% of recipients, so current guidelines recommend latent TB screening in all KT candidates and donors before transplantation. Both TST and IGRA are not sensitive, so frequent monitoring and screening of post transplant recipient should be carried out.
Treatment Challenges 1- Treatment of active disease: (AST-IDCOP) guidelines recommends that in case of active uncomplicated pulmonary TB, treatment duration should be at least 6 months. If cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, severe disseminated disease, and bone/ joint disease, the duration of treatment may be extended to 9 months. Patients with central nervous system involvement should be treated for at least 9–12 months. Rafamycin based regimen: 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin. (ESCMID) suggests treatment more than 6 months: Rifampicin, a potent inducer of cytochrome P450 3A4 and P-glycoprotein, interferes with immunosuppression metabolization. Specifically, rifampicin usage decreases the levels of calcineurin inhibitors (cyclosporine, tacrolimus), the mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus) the dose should be increased 3-5 times the used dose, and affects glucocorticoids metabolization, which increases the risk of rejection, mandates frequent monitoring of drug level as well as monitor for drug toxicity (hepatotoxicity). Rifamycin free regimen: 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide. Directed observed therapy programs has improved the adherence of patients to anti-TB therapy and their outcomes. Reduction of immunosuppression in the case of severe TB or when a vital organ is involved should be considered. 2- Latent Tuberculosis: Treatment of KT recipients with latent TB is indicated in one of the following conditions: a positive TST or IGRA test, a history of untreated TB, a history of recent contact with an active TB patient and when the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB. Treatment regimen of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6, or ethambutol and levofloxacin or moxifloxacin in isoniazid resistant and toxicity.
Outcomes: 1- Rejection: Graft rejection in KT recipients with TB can reach up to 55.6%, often being associated with reduced levels of immunosuppression secondary to calcineurin inhibitors–rifampicin interaction and could be responsible for ~1/3 of graft losses. 2- Graft Loss: The causes of graft loss among KT patients with TB can be directly due to donor-derived TB infection, or through the sepsis/ disseminated infection and due to the acute or chronic rejection that occurred after minimization or withdrawal of immunosuppression. Rejection could be precipitated by suboptimal levels of immunosuppression in the context of rifampicin-based regimen use. The prevalence of graft loss in KT patients with active TB varies from 2.2% to 66.6%. 3- Mortality: Mortality rate in solid organ transplantation recipients was 20%, ranging from 0-60% in kidney transplants, increased when anti-rejection used, diabetic recipient, and co- infection with hepatitis c or fungal infections.
Conclusion: TB post transplantation is a challenging infection in diagnosis and treatment, requiring high index of suspicion, early detection and treatment in order to reduce the bad disease outcomes. Multidisciplinary team work (infectious, nephrologist, microbiologist and pathologist) are required for better outcome with understanding the drug-drug interaction, and side effects.
What is the level of evidence provided by this article? Level of evidence is V- erratic review.
Introduction
For people with ESKD, the optimum treatment is a kidney transplant. Infections, however, limit graft efficacy and patient outcomes. TB remains the biggest infectious cause of death worldwide. Kidney transplant recipients have a higher incidence of tuberculosis than the overall population. Active TB in the recipient could be the result of reactivation of latent infection in recipient or donor tissue, or it could be the result of de novo infection in the recipient. The diagnosis and treatment of tuberculosis in recipients remains difficult.
Epidemiology in solid organ transplantation
Prevalence varies depending on geographic location; places with low endemicity vary from 0.3-6.4%, while those with high endemicity can reach 15%. The incidence of solid organ transplantation is between 20 and 74 times that of the general population.
Epidemiology in kidney transplant recipients
The prevalence is higher than in the general population but lower than in people who have had lung transplants.
Risk factors in kidney transplant recipients
TB endemicity affects recipient, donor, and transplant factors. Immunosuppressive drugs, acute rejection, and chronic graft malfunction are transplant-related. Immunosuppressive drugs decrease T cell-mediated immunity, reactivating latent TB infection. Immunosuppressive drugs used to treat rejection may reactivate TB and cause rejection episodes. Overdosing on immunosuppressive drugs also causes chronic graft malfunction. Older age, male gender, smokers, COPD, DM, longer dialysis, opportunistic infection, and latent TB are recipient-related variables.
Transmission and pathogenesis in kidney transplant recipients
Aerosol droplets can be cleared from the body by inherent or acquired immunity, or the disease can become active during the first 24 months after exposure or stay latent.
Consequently, there are three possible ways for TB to manifest in KTX: through reactivation of the latent infection (the most common), through transmission from an infected donor kidney (4.6% of cases), or through de novo infections (rare, more common in endemic areas), which carry a high risk of progression.
Cellular immunity, specifically T helper cells, interferon beta, and interleukin-2, is what protects against MTB.
Immunosuppressive drugs used during induction and maintenance phases of treatment have been linked to a reduction in T-cells, a drop in IL-2 production, and overall cellular immunity impairment.
Diagnostic Challenges
Active tuberculosis
Kidney transplant patients’ high index of suspicion, unusual clinical presentations, and likelihood of coinfection make active TB diagnosis difficult.
Paraclinical difficulties can delay diagnosis, and TST and IGRA are useless.
Mycobacterium tuberculosis complex and resistance to rifampin test may give false negative results when mycobacterial load is minimal.
Early-onset donor-derived TB following kidney donation is underdiagnosed.
Kidney transplant patients with vague symptoms, frequent fever, fluid accumulation, extrapulmonary signs, or no response to empirical antibiotic therapy should be investigated.
Current guidelines demand a detailed epidemiological risk, personal medical history, physical exam, and chest radiography in all donors, although screening assays for latent TB (TST and IGRA) have low feasibility and accuracy.
Personal history and chest imaging should influence donation.
Latent tuberculosis
Latent TB infection is an immunological response to MBT antigens without clinical symptoms.
Around 20% of KT recipients developed latent TB, and current recommendations urge screening all candidates and donors before transplantation.
In ESRD patients, IGRA may be better than TST for identifying latent TB in KT candidates.
In this group, TST and IGRA prediction findings are inconsistent.
Shu et al. recommend screening KT recipients more often than candidates since they have a higher latent TB rate.
Undiagnosed and untreated latent TB raises the likelihood of active TB, highlighting its relevance.
Active Tuberculosis treatment
The treatment of TB in transplant recipients may be complicated because to drug–drug interactions, drug toxicity, and treatment adherence.
The appropriate duration of treatment could range from six to twenty-four months, and in some circumstances, according to the advice of specialists, the duration of treatment should be at least nine to twelve months. In cases of active, uncomplicated pulmonary tuberculosis, the American Society of Transplantation Infectious Diseases Community of Practice (AST-IDCOP) recommends a treatment duration of at least 6 months. However, if cavitary lesions are present or culture-positive sputum persists after 2 months of therapy, the treatment duration may be extended to 9 months. In cases of severe disseminated disease or bone and joint disease, at least 6–9 months of treatment is advised. Individuals with involvement of the central nervous system should be treated for at least 9–12 months.
A four-drug combination comprising rifamycin should be the first-line treatment for both severe and non-severe patients.
Treatment of latent tuberculosis
After excluding active TB, treat latent TB. In this category of individuals, treatment is suggested if the patient has a positive TST or IGRA test, a history of untreated TB, recent contact with an active TB patient, or a kidney graft from a donor with known latent TB without chemoprophylaxis. Isoniazid 5 mg/kg/day (maximum 300 mg/day) for 9 months plus vitamin B6 is the recommended treatment for latent TB in KT. Avoid rifampicin-based treatment. Ethambutol with levofloxacin or moxifloxacin are a high-risk KT regimen. Hepatotoxicity is the major side effect of isoniazid, but KT individuals may have a lower risk. Nonetheless, liver enzymes should be checked bi-weekly for 6 weeks and then monthly during treatment.
Outcomes of Tb in kidney transplant recipients
The possibility of graft rejection in KT patients with TB is up to 55.6%. This is brought on by inadequate IS levels in the setting of rifampicin-based therapy. Infection can cause graft loss directly, especially when the infection comes from the donor. Graft loss occurs in 2.2% to 66.6% of KT patients with active TB. SOT recipients have a death risk of 20%. After KT, TB patients can experience mortality ranging from 0% to 60%.
What is the level of evidence provided by this article? Level V
Review Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review
1. Epidemiology of Tuberculosis in Kidney Transplantation
· The prevalence of active TB in KT recipients varies from 0.3%to15.2%, which is higher than the general population.
2. Risk Factors for Tuberculosis in Kidney Transplantation
Immunosuppression therapy
Presence of AR
Chronic graft dysfunction
Age and male gender
Diabetes and CLD
Latent TB
Co-infection, CMV,PCP and nocardiasis
Cadaveric donor type
TB burden of the country
3. Transmission and Pathogenesis of TB in Kidney Transplant Recipients
The most common mode of transmission of TB in KT recipients is reactivation of latent TB, with positive latent TB conversion in around 20% within the first 2 years.
The second mode of transmission of TB in KT could be via kidney graft from an infected donor (4.8%) of cases.
TB could occur as a de novo infection after KT, it is not common and associated with high risk of progression.
Using IS in the setting of KT could disrupt the protection against TB and increase the risk of reactivation through, depletion and decrease proliferation of T cells, decrease in IL-2synthesis, and total impairment of cellular immunity.
4. Diagnostic Challenges
a. Active Tuberculosis
KT recipients have atypical clinical presentations which reduce the clinical suspicion of TB. Furthermore, the probability of association with other co-infections and extrapulmonary localizationin~50% of cases adds to the problem.
Other diagnostic challenges include that tuberculin skin test (TST) and IGRA are not useful in the diagnosis of active TB and the frequent need for invasive procedures (bronchoscopy with BAL).
Molecular tests based on rapid nucleic acid amplification techniques, could provide false negative results when mycobacterial load is low.
Donor-derived TB is associated with severe extrapulmonary manifestations and mortality, current guidelines recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors. Nevertheless, in deceased donors this could be unobtainable.
b. Latent Tuberculosis
Current guidelines recommend latent TB screening in all KT candidates and donors before transplantation.
For diagnosing latent TB accurately in KT candidates, IGRA seems to present some advantages over TST in patients with ESRD.
Data regarding prediction capacity of TST and IGRA tests are conflicting in KT recipient.
The incidence and prevalence of latent TB in KT recipients is higher than in KT candidates and therefore KT recipients should be more frequently screened.
5. Treatment Challenges
a. Active Tuberculosis
The optimal period of treatment could vary from 6 to 24 months, based on organ involved and experts’ opinion.
The first-line treatment should be a four-drug regimen containing rifamycin as in the general population.
If second-line drugs are used, a longer period of treatment is recommended.
Rifampicin usage decrease the levels of calcineurin inhibitors, mTOR inhibitors and affects glucocorticoids metabolism, which increases the risk of rejection. Care full adjustment of does is necessary during and after stopping treatment.
An alternative to rifampicin is rifabutin, which is a weaker inducer of cytochrome P450 3A4 and P-glycoprotein but with similar efficacy.
Another safe and effective alternative to rifampicin in KT recipients is treatment with fluoroquinolones.
Another challenge is linked to the adverse effects of TB therapy, they are more frequent than in the general population.
The most common adverse event associated with anti-TB therapy is hepatotoxicity; therefore, liver enzymes should be closely monitored.
Implementation of directed observed therapy programs has improved the adherence of patients to anti-TB therapy and their outcomes.
Doses for pyrazinamide and ethambutol should be adjusted according to creatinie clearance.
Reduction of immunosuppression in the case of severe TB or when a vital organ is involved should be considered.
b. Latent Tuberculosis
Treatment of latent TB is indicated if we have a positive TST or IGRA test, a history of untreated TB, a history of recent contact with an active TB patient and when the kidney graft originates from a donor with known latent TB without chemoprophylaxis.
In the KT setting, the preferred treatment of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6.
6. Outcomes
TB in KT is associated with important morbidity and mortality due to immunosuppression status, increased extrapulmonary disease and challenges in diagnosis that delay the initiation of treatment.
a. Rejection
· Graft rejection in KT recipients with TB can reach up to 55.6%, often being associated with calcineurin inhibitors–rifampicin interaction and could be responsible for ~1/3 of graft losses.
b. Graft Loss
· The prevalence of graft loss in KT patients with active TB varies from 2.2% to 66.6%.
· The graft loss could be directly due to TB infection, especially in the case of donor-derived TB, or indirectly through the sepsis produced by TB and due to the acute or chronic rejection that occurred after minimization or withdrawal of immunosuppression.
7. Mortality
The mortality of patients with TB after KT has been reported to range from 0% to 60%.
Mortality could be due to the development of hemophagocytic syndrome, co-infections with fungi, cytomegalovirus, nocardia, use anti-TB therapy, receiving anti-rejection treatment, diabetes, and hepatitis C.
Conclusions
Successful implementation of preventive measures is of paramount.
Donor-derived TB and latent TB in KT are under recognized conditions that should be carefully evaluated.
Development of tests which are not based on T cell immunity, could bring important improvement in the diagnosis of latent TB in KT recipients.
Newly discovered drugs could have an important contribution in limitation of drug–drug interactions, improvement of treatment efficacy and reduction of adverse events.
The burden of TB in the Latin has reduced in the Latin American continent in the last decades, although according to WHO classification, Bazil still remains one of the countries with the highest burden of the disease with 110,000 prevalence disease and 7700 TB death. Moreso, the national incidence varies from as low as 11 cases per 100000 in the capital city to as high as 300 per 100000 in underprivileged communities. A more challenging situation is the emergence of MDR which is known to be quite common among those previously treated with TB
TB after solid organ transplantation
The risk and the incidence of TB is higher among SOT patient, especially in lung transplant patients
TB infection can be contracted by; reactivation of primary infection, infection from the environment of donor organs especially diseased donors
Immigration from or to an endemic country after SOT can also influence the risk of contracting TB especially if staying more than 3 months in an endemic country.
Immigration of donors or organs can contributes to the incidence of TB in SOT
Other at risk are humanitarian staff that work in high-risk places like homeless homes, prisons, and minimal report documents on long haul flight
Diagnosis of Latent TB
TST
IGRA
Advantages of IGRA over TST
it avoids interpreting bias,
it reduces false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination,
probably more sensitive in candidates with chronic renal failure and advanced cirrhosis, because they show a higher yield and a better correlation with clinical risk factors for LTBI in these patients
Limitation of IGRA
suboptimal negative predictive value
high cost of the assays
The advice given by some specialists is to use IGRA in low-risk patients and in those with high risk for TB
Diagnosis of active TB
It relies on the detection of M. Tuberculosis in samples via tests like
Culture
Nucleic acid testing
molecular test like gene-Xpert – limitation is the detection of false positives in previously treated TB patient
Risk assessment of transplant patient-recipients
Clinical history and radiological test for TB
Use of TST and IGRA in suspected LTBI
Exclude active TB infection from transplantation
Risk assessment of transplant patient-donors and diseased donor
medical history of exposure to treatment for TB
History of diagnosis or treatment for LTBI
radiological investigation
TST, IGRA
Lungs with residual TB lesions should not be used for donation
Treatment for LTBI in transplant and recipient patient
INH 300mg/ day + pyridoxine for 9 months (close LFT check) OR
Rifampicin 600mg daily for 4 months OR
INH + Rifapentine weekly for 4 months
Transplant patient that travels to an endemic country during first year post KTP, should take INH as a prophylaxis
Treatment of active infection
The general local guideline of the country or region be followed based on the endemicity of TB in the area and it has been advised that the treatment should be at least 9 months. The treatment comprises the intensive phase (INH+RIF+ PYRAZINAMIDE + EHTAMBUTO), for 2 months then followed by 6-9 months of the maintenance phase of INH + RIF.
The major challenge is a rifampicin drug interaction with CNIs, mTORs, and corticosteroids by reducing their trough level and this could result in allograft rejection or loss.
Other toxicities of concern are neurotoxicity, hepatotoxicity, and nephrotoxicity
Type of article: A Comprehensive Review with evidence V
Date :27 August 2022
Journal: MDPI /pathogens with impact factor 4.6 in 2021 Summarize this article The prevalence of active TB in transplanted patients is significantly higher than general population 20-74 times. It differs according to geographic area ranging from 0.3–6.4%, in developed countries and in up to 15% in endemic regions Mode of transmission
Activation of latent TB (the most common)
Acquiring the disease from the graft (donor derived)
Recent infection after recent exposure
Risk factors for TB in Kidney Transplantation Recipient related
Older age
Male gender
Smoking
Latent TB before transplantation
Comorbidities including DM, COPD, chronic liver disease, malnutrition and HCV infection
Prolonged hemodialysis before renal transplantation
Use of aggressive immunosuppressive therapy like depleting induction by ATG.
Acute rejection (increase the risk of TB 7.6 times) and chronic allograft dysfunction
Donor related
Deceased donor transplantation
Social risk factors including homeless patients.
Smoking.
alcohol abuse.
contact to TB case.
Medical risk factors including the presence of DM, history of previous TB or underweight.
Diagnosis of latent TB There is clear specific test for diagnosis and diagnosis is based on high clinical suspicious as tuberculin skin test (TST) and IGRA which usually used in diagnosis can be negative in immunosuppressed patients due to absence of immune response. Indications of treatment of latent TB in transplant recipient and donor
Positive TST or a positive IGRA
History of close contact to an active TB case
If recipient received graft from donor has latent TB and did not receive treatment
Protocol for treatment of latent TB
INH for 6-9 months.
Rifampicin better to be avoided in transplant patient because of drug-drug interactions and rifabutiun is an alternative.
The diagnosis of active TB is challenging
Atypical clinical presentation and around 50% of cases presents with extra pulmonary or disseminated TB.
Tuberculin test and IGRA are usually negative.
Sputum smear for TB is usually negative despite active TB.
PCR falsely negative if the TB load is low.
To reach diagnosis invasive procedure is usually required including bronchoscopy and BAL or lung biopsy.
The treatment of active TB in SOT is challenging due to the following
Rifampicin is the corn-stone of TB treatment which has enzyme inducer effect exposing patients to low CNI level and hence rejection.
Toxicity of anti-TB medications.
Protocols used in treatment of TB I- Rifampicin containing regimen
Rifampicin+ INH+ ethambutol + pyrazinamide for 2 months, followed by a 2-drug regimen of Rifampicin + INH for 4 months
It is recommended to increase the duration of treatment to at least 9-12 months if there is disseminated disease, cavitary disease with positive sputum culture after 2 months of treatment, bone and joint disease, CNS disease. II- Rifampicin free regimen
In which levofloxacin and rifabutiun can replace rifampicin due to its lesser effect on cytochrome p450, so minimal drug-drug interactions but experience is little when using this drug in transplantation, although it seems effective in HIV TB patients. Prognosis
Up to half of the renal transplant recipients with active TB may develop rejection
I like your summary, level of evidence, analysis and take home messages.
Stating that, “Mortality occurs in up to 60 % of patients” is a NOT correct reflection in some studies but it may be as little as zero in some reports.
Summary Introduction
Kidney transplantation is the optimal treatment in patients with ESKD.
However infections limits graft function and patient outcomes.
TB remains to be a leading cause of infectious death worldwide.
Incidence of TB in kidney transplant recipients is higher than the general population.
Active TB in the recipient could be due; to reactivation of latent infection in recipient or donor tissue or due to de novo infection in the recipient.
Diagnosis and treatment of TB in recipients remains to be challenging.
Epidemiology in SOT
Prevalence is variable depending with the geographical area; areas with low endemicity ranges between 0.3-6.4% while high endemic areas could be as high as 15%.
Incidence in SOT is 20-74 times higher that of general population.
Epidemiology in kidney transplant recipients
Prevalence ranges between 0.3-15%; its is higher than the general population but lower than lung transplant recipients.
Risk factors in kidney transplant recipients
There are recipient, donor and transplant related factors which are all influenced by the endemicity of TB in the area.
Transplant related factors include the use of immunosuppressive agents, presence of acute rejection episode and chronic graft dysfunction.
Immunosuppressive agents impair the T cell mediated immunity that controls TB infection hence reactivation of latent infection.
Rejection episodes and TB could be explained by the use of immunosuppressive agents to treat rejection that leads to TB reactivation.
Similarly chronic graft dysfunction is associated with amplification or overdosing of immunosuppressive agents.
Recipients related factors include:older age, male gender, smokers, COPD, DM, longer dialysis duration, presence of opportunistic infection, presence of latent TB.
Donor related factors include:donor type-cadaveric, social risk factors- homeless, incarcerated and medical risk factors-DM, untreated TB.
Transmission and pathogenesis in kidney transplant recipients
After inhalation of aerosol droplets the body can either; clear it through innate or acquired immunity, or active disease can occur within the first 24 months, or remains latent.
Thus TB can occur in KTX in 3 scenarios: through reactivation of the latent infection this is the most common form, or transmitted from infected donor kidney that accounts for 4.6% of cases, or de novo infections that is rare, more frequent in endemic areas and has a high risk of progression.
Protection against MTB is through cellular immunity- T helper cells , IFN γ and IL2.
Some immunosuppressive agents used in induction and maintenance may deplete T cells, decreases synthesis of IL2 or impair the whole cellular immunity.
Diagnostic challenges Active TB
The diagnosis of TB requires high index of suspicion, however KTX have atypical presentation which lowers the clinical suspicion.
TST and IGRA have no role in the diagnosis of active TB.
Donor derived TB should be suspected in KTX who presents with: unexplained fever, fluid collections, extra-pulmonary manifestation and lack of response to empirical antibiotics therapy. Latent TB
Prevalence of LTBI is reported to be 20% in kidney transplant recipients.
There is no gold standard test.
Data on capacity of TST and IGRA are contraindicating.
Treatment challenges Active TB
Treatment follows the principles of immunocompetent individuals and should be began promptly.
Optimal treatment period varies between 6-24 months.
The AST-IDCOP recommends the following:
For pulmonary TB that is uncomplicated the duration should be 6 months.
For pulmonary TB that smear remains positive after 2 months of intensive phase or cavitary lesions the duration should be 9 months
For bone or disseminated disease the duration should be 6-9 months
For CNS disease the treatment should be for 9-12 months
First line should be 4 drug regimen in both severe and non-severe cases that is rifampicin based
However the ESCMID recommends in cases of non-severe localised disease with no rifampicin resistance, then a non-rifampicin based regimen can be used for 2 months followed by an intensive phase of 12-18 months.
Rifampicin is a potent cytochrome P 450 inducer hence interferes with the metabolisation of immunosuppressive agents.
Thus CNI and MTOR inhibitors should be increased to 3 and 5 fold and steroids doubled during treatment and doses adjusted to pretreatment doses after discontinuation.
Rifabutin is a weaker inducer of cytochrome P 450 and hence an alternative to rifampicin with similar efficacy.
Another alternative to rifampicin is fluoroquinolones.
Adverse events to monitor for include:
Hepatotoxicity associated with Rifampicin, isoniazid, ethambutol and pyrazinamide
Neurotoxicity associated with isoniazid and ethambutol
Cytopenias associated with ethambutol, rifampicin, isoniazid and pyrazinamide
Visual disturbance associated with rifabutin and ethambutol
Skin lesion associated with rifampicin
Hyperuricaemia associated with pyrazinamide
Interstitial nephritis associated with rifampicin and pyrazinamide.
Most common adverse event is hepatotoxicity thus liver enzymes should be monitored bi-weekly in the intensive phase and there after monthly.
Latent TB
Treatment indicated if:
Positive TST or IGRA
History of untreated TB
Recent contact with persons with active TB
Graft kidney was from a donor with LTBI not on treatment
Preferred drug is Isoniazid 5mg/kg/day with maximum 300mg/day for 9 months with vitamin B6 supplementation.
Rifampicin based regimen is not recommended
Other alternative is ethambutol with levofloxacin or moxifloxacin.
Outcomes
Incidence of rejection in KTX with TB is high, could be due to interactions of rifampicin with the immunosuppressants leading to 1/3 of graft losses.
There is also increased mortality in KTX with TB.
Conclusion
TB is an opportunistic infection with increased prevalence in KTX than general population and associated with negative graft and patient outcomes.
Due to the diagnostic and treatment challenges, collaboration between the transplant physicians and infectious disease specialist is required.
Donor derived TB and latent TB are under recognised conditions that should be evaluated.
Development of new test and treatment regimens is required.
Summary Introduction
best therapy for ESRD is kidney transplantation (KT)
Tuberculosis (TB) is a major post-transplant infection.
It is the thirteenth-highest cause of mortality globally and the top infectious cause in Post Tx period. Method
A search on PubMed and Embase electronic databases performed from 1 January 2000 to 15 June 2022. All studies that provided epidemiological and/or outcome data regarding TB in KT were included.
Tuberculosis in SOT
Active TB in solid organ transplantation varies in different regions but TB prevalence ranges from 0.3–6.4% in low-endemic regions to 15.2% in high-endemic areas.
Risk Factors
Post transplant cases are more likely to acquire TB. High prevalence in community along with donor, and transplantation variables like immunosuppression medication, rejection episodes, and chronic graft dysfunction.
Immunosuppression inhibits T-cell-mediated TB control and promotes latent infection reactivation. T-cell-depleting medications, calcineurin inhibitors, anti-metabolites, and glucocorticoids all enhance the risk of TB. Each rejection episodes increases TB risk 7.6 times.
Transmission and Pathogenesis
Active TB could result due to reactivation. TB could also be transmitted to KT recipients via kidney graft from an infected donor or TB could occur as a de novo infection after KT or exposure to active TB patients.
Diagnostic and Treatment
Active TB; Treatment lasts 6–24 months, but at least 9–12.
American Society of Transplantation IDCOP recommends 6 months for active uncomplicated pulmonary TB and 9 months for cavity lesion.
AST-IDCOP recommends a 4-drug regimen for first-line treatment:
Latent TB
It has also should be treated to stop it from becoming active. Positive TST or IGRA test, a history of treated tuberculosis, a history of recent contact with an active TB patient, donor-derived latent TB in an infected graft, a history of untreated tuberculosis, or recent exposure to active tuberculosis, makes a person venerable to tuberculosis.
INH combined with vitamin B6 is used to treat latent tuberculosis for a period of nine months. Ethambutol with either levofloxacin or moxifloxacin is another treatment option for those at high risk.
Conclusions
TB is a common opportunistic infection in KT patients.
It has negative impact on graft and patient survival.
Preventive strategies include TB risk stratification and monitoring.
Donor-derived TB and latent TB in KT are underdiagnosed.
In KT recipients, non-T cell immunity-based assays with good predictive values might enhance latent TB diagnosis in future.
1- Renal transplantation is only hope to ESRD receiving regular dialysis.
2- Infections is common complication among SOT patients.
3- TB prevalence in SOT is varied from 0.3-15% according to endemic area or not.
4- There are risk factors related to increase incidence of TB among SOT than general population.
5- TB infection in SOT can happen either primary infection (new infection ) or reactivation of latent infection in the recipient which is the most common type of infection or reactivation from the side of the donor so can be donor-derived which constitute 4.8% of the infected cases.
6- Proper screening of the donor and recipient pre-transplantation is very important to discover latent infection and manage it before transplantation, but there is a limitation of the screening tests.
7- The story of TB in SOT remains challenging because of limited screening tests to diagnose latent infection, confusing clinical picture, treatment carries a possibility of drug-drug interaction with multiple toxicity, with risk of graft rejection.
8- Remains undiagnosed and untreated carries high morbidity and mortality.
9- Risk factors related to recipient: old age, male gender, chronic liver disease, HCV, smoking, malnutrition, DM, COPD, associated co-infection like CMV and PCP, pre-transplant latent TB, autoimmune disease, long time on hemodialysis
10- Risk factors related to the donor; donor type (cadaveric), social risk (homeless, known TB contact, smoking, alcohol abuse), medical risk (DM, obesity, history of untreated TB)
11- Risk factors related to transplantation; immunosuppression, graft rejection either acute or chronic
12- Other risk factors like TB country burden
13- reactivation of latent infection occurs through multiple mechanisms, such as: depletion of all types of T cells, decrease in activation and proliferation of T cells, decrease in IL-2 synthesis, decrease in the production of Th-1 type cytokines or impairment of cellular immunity almost completely.
14- Diagnosis:
a- TB occurs in the first year post-transplant in cases of reactivation of latent infection in the recipient , but occurs in the first three months in cases of reactivation of latent infection from the infected graft (donor derived).
b- Diagnosis can be initiated by high index of suspicion because of atypical clinical picture in immunosuppressed patients and confusing manifestations because of associated co-infections.
c- tuberculin skin test (TST) and interferongamma release assay (IGRA) are not useful in the diagnosis of active TB.
d- molecular tests based on rapid nucleic acid amplification techniques, such as mycobacterium tuberculosis complex and resistance to rifampin test (Xpert® MTB/RIF, Cepheid, Sunnyvale, CA, USA), could provide false negative results when mycobacterial load is low.
e- Radiological diagnosis either CXR or CT can be confused with other pathological diagnosis.
f- Donor-derived TB is considered an under-recognized condition with early onset after KT in the majority of cases and should be suspected in KT recipients with one of the following features: non-specific symptoms, frequent fever in the first 3 months after KT, fluid collections, extrapulmonary manifestations or lack of response to empirical antibiotic therapy.
g- Current guidelines (American Society of Transplantation Infectious Diseases Community of Practice and European Society of Clinical Microbiology and Infectious Diseases) recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors.
h- In cadaveric donor, donor history of previous active TB, specific treatment or exposure to active TB within the last 2 years should be obtained from the donor’s family or relatives.
i- IGRA test if performed, a series of aspects should be considered—the result might not be available in time, the result could be false negative in donors with head injury due to depressed cell-mediated immunity and, in high-risk donors from low endemic areas with positive tests, the decision of donation should be correlated with personal history and chest imaging.
j- latent TB infection is defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB . it constitute 20% of cases of TB in the recipients.
k- no gold standard tests for diagnosing latent TB accurately in KT candidates, but IGRA seems to present some advantages over TST in patients with ESRD.
15- Treatment remains challenging because of drug interaction, toxicity and risk of rejection.
a- In active TB ; duration of treatment 6-24 months , in some recommendations at least 9-12 months
1- In active uncomplicated pulmonary TB should be 6 months
2- but if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months
3- severe disseminated disease or bone and joint disease, treatment duration is recommended for at least 6–9 months
4- Patients with central nervous system involvement should be treated for at least 9–12 months
5- first-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases
6- Rifamycin is recommended for its sterilization capacity and efficiency but also to reduce the risk of resistance
7- Protocol is 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin as general population.
8- In localized non-severe TB, a regimen without rifampicin could be used if no resistance to isoniazid is present
9- If a regimen without rifamycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide.
10- if second-line drugs are used, a longer period of treatment is recommended.
11- Rifampicin, a potent inducer of cytochrome P450 3A4 and P-glycoprotein, interferes with immunosuppression metabolization.
12- It decreases the trough level of CNI so the dose of CNI should be increased 3- f times so the toxicity and the cost also will increase
13- Rifampicin also decrease the trough level of mTORI and affect steroid metabolism hence increase risk of rejection
14- Dose of steroid should be doubled during treatment with rifampicin
15- after the rifampicin is stopped, the immunosuppression doses should be reduced to the value before the start of rifampicin and then adjusted to obtain the therapeutic target.
16- Rifabutin is alternative to rifampicin, which is a weaker inducer of cytochrome P450 3A4 and P-glycoprotein but with similar efficacy and less drug interaction
17- safe and effective alternative to rifampicin in KT recipients is treatment with fluoroquinolones
18- Patients treated with anti-TB drugs should be closely monitored for hepatotoxicity (isoniazid, rifampicin, pyrazinamide, ethambutol), neurotoxicity (isoniazid, ethambutol), cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol), visual disturbances (rifabutin, ethambutol), skin lesions (rifampicin), hyperuricemia (pyrazinamide) or interstitial nephritis (rifampicin, pyrazinamide) same as general population
19- The most common adverse event associated with anti-TB therapy is hepatotoxicity; therefore, liver enzymes should be closely monitored with bi-weekly evaluation during the intensive phase of treatment and monthly thereafter
20- adjust the doses for pyrazinamide and ethambutol according to renal function
21- RIS should be implemented in severe cases when vital organ involved
b- In latent TB its criteria to be diagnosed:
1- Exclusion of active TB
2- positive TST or IGRA test,
3- history of untreated TB
4- history of recent contact with an active TB patient
5- kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB
preferred treatment of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6.
alternative regimen for KT recipients, mainly for those with high risk, consists of ethambutol and levofloxacin or moxifloxacin
monitor liver enzymes during treatment, initially bi-weekly for 6 weeks and monthly thereafter.
Use of rifampicin is not recommended
16- outcome: there is increase risk o morbidity and mortality in immunosuppressed patient with TB as we deal with pulmonary and extra pulmonary complications , and its treatment is challenging with drug interaction and risk of rejection and graft loss and the toxicity of the drugs itself, another issue is the compliance to treatment, and of course the mortality is high when left untreated or late in diagnosis or development of co-infection or died from the toxicity of the drugs itself.
This review of TBC in kidney transplantation recipients encompasses literature between January 2000- June 2022. The level of evidence is 5
TBC in Kidney transplant recipients has a higher incidence and prevalence than the general population. Excluding covid 19, TBC was reported as the 13th and leading cause of death in general. İncidence was reported 127/100.000/year. The source of infection in Kidney recipients can be de novo or donor-derived. Depending on geographical area, there is a numerical variance of numbers but the prevalence and incidence, but it was reported to be eight times more prevalent in solid organ recipients.
TBC risk factors in KT recipients can be related to transplant and immunosuppression but can be either recipient-associated or donor-related.
Donor-associated factors include donor type, social status (higher with low), medical situation and immune status. Recipients’ related factors include diabetes, smoking, COPD, latent tbc and long-term dialysis. Acute rejection was reported to have an increased risk of 7.6 (Thitisuriyarax et al.). Immunosuppression potency seems to have an important role. As shown in figure 2, the source of infection could be the reactivation of latent TBc, Denovo infection or donor-derived.
Diagnosis may be challenging. Although more prevalent in the first year, high suspicion is needed to diagnose. Nonspecific symptoms and coinfections may withdraw attention apart from TBC and contribute to the delay in diagnosis. In addition, TST and IGRA are not useful in active TBC definite diagnosis. IGRA may be false negative in some cases with T cell depression, like in head injury cases. Even TST may be unattainable and overlocked.
Donor-derived infections are expected to have been reported more, especially in poor emigration areas.
Regarding Latent infection, both TST and IGRA can be utilized, with IGRA being more sensitive and predictive, according to some reports.
Treatment of TBC may be challenging because of toxicity and drug interactions. The length of treatment may vary from 6-24 months. Rifampicin usage entails close monitoring of Calcinurine/mTOR levels, as lowering the effect may put the patient in risk of rejection. Although lower cytochrome P450 3A4 induction of Refabutine, caution and monitoring are still needed.
The risk of graft rejection can reach up to 55.6%. Mortality doubles in the case of active TBC. HR was found to be 1.8. Usually, patients have co-infections, either bacterial or fungal. Collaboration between infectious diseases and transplant follow-up teams is essential.
TB in kidney transplant (KT) recipients is an important opportunistic infection with higher incidence and prevalence than in the general population, and is associated with morbidity and mortality.
Diagnostic and treatment challenges include atypical clinical presentation, association with co-infections, decreased predictive values of screening tests, diverse radiological aspects and particular diagnostic methods.
Treatment challenges include drug interactions, drug toxicities and therapeutical adherence.
==================================================================== Summarise this article
Introduction
KT is the optimal treatment for ESRD, but infection posttransplantation is a major limitation.
Active TB after KT is higher in recipients than in general population due to immunosuppression and other risk factors, and screening measures should be implemented to limit or prevent it.
KT candidates and recipients with TB face challenges in diagnosis and treatment, which can lead to graft rejection, graft loss, and increased mortality.
This review provides an evidence-based update on the epidemiology, risk factors, pathophysiology, type of transmission, diagnostic challenges, and treatment challenges of TB in KT recipients.
A literature search on PubMed and Embase was conducted to identify studies that provided epidemiological and/or outcomes data on TB in KT,excluding articles in languages other than English, articles that evaluated other types of transplantation, and articles with inadequate information.
Epidemiology and Risk Factors for Tuberculosis in Kidney Transplantation
1. Epidemiology of Tuberculosis in Solid Organ Transplantation
The prevalence of active TB in solid organ transplantation is highly variable, ranging from 0.3-6.4% in areas with low TB endemicity to 15.2% in high endemic areas.
A recent systematic review and meta-analysis showed a pooled prevalence of 3% (95% confidence interval (CI): 2-3).
In a study in 16 transplant centers from Spain, the incidence of TB was 512 cases per 100,000 patients per year (95% CI: 317-783), 26.6 times higher than in the general population.
2. Epidemiology of Tuberculosis in Kidney Transplantation
The prevalence of active TB in KT recipients varies from 0.3% to 15.2%, and is higher than in the general population but lower than in patients with lung transplantation.
Basiri et al. reported a low preva-lence of TB in a case-control study, while Vandermarliere et al. (0.4%) reported a high prevalence in a retrospective cohort study.
Two systematic reviews and meta-analyses found an unadjusted TB risk ratio of 11.36 times higher in KT recipients, compared to the general population, and an adjusted risk ratio for patients on dialysis of 3.62 times higher than those from the general population.
A meta-analysis found that patients with KT had a pooled incidence of active TB of 2700 (95% CI: 1878–3522) per 100,000 patient-years, higher than those with ESRD in pre-dialysis and lower than those on peritoneal dialysis and hemodialysis.
3. Risk Factors for Tuberculosis in Kidney Transplantation
Risk factors for Tuberculosis in Kidney Transplantation (KT) include transplant-associated risk factors such as immunosuppression therapy, presence of acute rejection episodes and chronic graft disfunction.
Immunosuppression used in KT impairs T-cell-mediated immunity involved in TB control and favors latent infection reactivation.
Acute rejection significantly increases the risk of TB by 7.6 times and the number of rejections after transplant is an independent risk factor for TB appearance.
Chronic graft dysfunction is also a risk factor.
=================================================================== Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients
Mycobacterium tuberculosis (MBT) can be transmitted to KT recipients via latent infection reactivation, active TB reactivation, or de novo infection after transplantation, which is the most common form of transmission in all solid organ transplantation.
A prospective study conducted by Shu et al. found that latent infection is higher in KT recipients than candidates, and that older age, absence of Bacillus Calmette–Guérin vaccine scars, presence of donor specific antibodies and status of KT were factors associated with latent infection.
A strategy for posttransplantation latent infection evaluation could be helpful in addition to pre-transplant screening.
KT generates a favorable response for TB reactivation in candidates with latent infection, based on cellular immunity and Th1-type CD4+ T cells and type-1 cytokines.
Immunosuppression can disrupt the protection against TB and increase the risk of reactivation through depletion of all types of T cells, decrease in activation and proliferation, decrease in IL-2 synthesis, decrease in the production of Th-1 type cytokines, or impairment of cellular immunity.
Diagnosis and treatment of TB can be challenging due to KT, but early diagnosis and therapeutic approach are essential.
1. Diagnostic Challenges
1.1. Active Tuberculosis
The diagnosis of active TB in KT patients is challenging due to the high index of suspicion, atypical clinical presentations, and the probability of association with other coinfections.
Additionally, paraclinical issues can delay the diagnosis, and diagnostic tests such as tuberculin skin test (TST) and interferon-gamma release assay (IGRA)are not useful.
Molecular tests based on rapid nucleic acid amplification techniques, such as mycobacterium tuberculosis complex and resistance to rifampin test (Xpert® MTB/RIF, Cepheid, Sunnyvale, CA, USA), could provide false negative results when mycobacterial load is low.
Donor-derived TB is an under-recognized condition with early onset after kidney transplantation (KT).
It should be suspected in KT recipients with nonspecific symptoms, frequent fever, fluid collections, extrapulmonary manifestations or lack of response to empirical antibiotic therapy.
Current guidelines recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors, but screening tests for latent TB (TST and IGRA) have low feasibility and accuracy.
The decision of donation should be correlated with personal history and chest imaging.
1.2. Latent Tuberculosis
Latent TB infection is defined as a persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB.
Prevalence of latent TB after KT was reported in ~20% of recipients, and current guidelines recommend screening in all KT candidates and donors before transplantation.
There are no gold standard tests for diagnosing latent TB accurately in KT candidates, but IGRA seems to present some advantages over TST in patients with ESRD.
However, data regarding prediction capacity of TST and IGRA tests are discordant in this category of patients.
According to Shu et al., the incidence and prevalence of latent TB in KT recipients is higher than in KT candidates and therefore KT recipients should be more frequently screened.
The importance of diagnosis is supported by the fact that undiagnosed and untreated latent TB increases the risk of active TB.
Treatment of KT patients with TB should be managed by an experienced clinician with special attention to drug-drug interactions and adverse events.
2.1. Active Tuberculosis
The treatment of active TB in KT recipients is complex and challenging due to the epidemiological features from the area of origin and drug resistance patterns.
The optimal period of treatment could vary from 6 to 24 months and is recommended to be at least 9-12 months.
The American Society of Transplantation Infectious Diseases Community of Practice of active(AST-IDCOP) guidelines recommend that in case uncomplicated pulmonary TB, treatment duration should be at least 6 months, but if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months.
The first-line treatment should be a four-drug regimen containing rifamycin, which is recommended for its sterilization capacity and efficiency but also to reduce the risk of resistance.
The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) suggests a standard regimen used for a period longer than 6 months, and, in cases of localized non-severe TB, a regimen without rifampicin could be used if no resistance to isoniazid is present.
Rifampicin, a potent inducer of cytochrome P450 3A4 and P-glycoprotein, interferes with immuno-suppression metabolization, increasing the risk of rejection and graft loss.
To adjust immunosuppression, calcineurin and mTOR inhibitors should be increased, glucocorticoid doses should be doubled, and immunosuppressive doses should be reduced to the value before the start.
Alternatives include rifabutin and fluoroquinolones.
TB therapy can lead to adverse effects, such as hepatotoxicity, neurotoxicity, cytopenia, visual disturbances, skin lesions, hyperuricemia, and interstitial nephritis.
Treatment adherence is an issue, but implementation of directed observed therapy programs has improved adherence.
It is important to evaluate creatinine clearance and adjust doses for pyrazinamide and ethambutol.
Reduction of immunosuppression in severe TB or when a vital organ is involved should be considered, but there are concerns about immune reconstitution inflammatory syndrome.
2.2. Latent Tuberculosis
Treatment of latent TB should be considered only after active TB has been excluded, and isoniazid is the preferred treatment for KT recipients.
Ethambutol and levofloxacin are recommended for KT recipients,but evaluation of liver enzymes during treatment is recommended.
TB in KT is associated with morbidity and mortality due to immunosuppression, extrapulmonary disease, and challenges in diagnosis.
1. Rejection
Graft rejection in KT recipients with TB is associated with reduced levels of immunosuppression and can lead to ~1/3 of graft losses.
2. Graft Loss
Graft loss among KT patients with active TB can be caused by infection, sepsis, acute rejection, interstitial fibrosis and tubular atrophy, or by suboptimal levels of immunosuppression.
The prevalence of graft loss varies from 2.2% to 66.6%.
One study found that kidney graft function was significantly decreased at the time of diagnosis and during the treatment of TB and remained permanently impaired
Other studies found that severe TB disease, acute kidney injury stage 2 or 3, acute rejection and value of serum creatinine were risk factors for graft loss.
The highest rate of graft loss was reported in the study by Vandermarliere et al., in which six out of nine KT patients (66.6%) with active TB lost their grafts.
3. Mortality
Mamishi et al. found that the mortality rate in solid organ transplantation recipients was 20%, with mortality ranging from 0% to 60%. John et al. showed a high rate of mortality (31.9%) in KT recipients with active TB and found that active TB after 2 years post-KT is an independent risk factor.
Chen et al. reported 41.4% of patients with active TB after KT and an increased rate of mortality in a cohort of 545 KT recipients from Mexico.
TB in KT is an important opportunistic infection with higher incidence and prevalence than in the general population, and is associated with negative graft and patient outcomes.
Pinpointing risk factors for both TB development and negative outcomes after KT should be the basis for preventive measures, and clinicians should recognize diagnostic and treatment challenges for an optimal management approach.
Donor-derived TB and latent TB in KT are underrecognized conditions that should be evaluated, and tests with helpful predictive values should be developed.
Newly discovered regimens or pipeline drugs could have an important contribution to drug-drug interactions, improvement of treatment efficacy and reduction of adverse events.
==================================================================== What is the level of evidence provided by this article?
Kidney transplantation remains the best option of renal replacement therapy for those with end-stage kidney disease, but one of its downsides is the occurrence of infection post-transplant due to a reduced immune system.
One such common infection is tuberculosis, which could either be reactivated in the recipient or even be transmitted from the donor despite adequate screening pre-transplantation
Aim of the study
to provide an evidence-based update regarding epidemiology, risk factors, pathophysiology, type of transmission, diagnostic challenges, treatment challenges, and the impact of TB on KT recipients
Methods
The database was searched majorly for tuberculosis, kidney transplantation,e.t.c, between 1st January 2000 to 15th June 2022
Studies on the epidemiology of TB and its outcome were also recruited
Epidemiology
A systematic review and meta-analysis analyzed the prevalence of active TB in solid organ transplant recipients and showed a pooled prevalence of 3%
The incidence of TB in SOT is 20 -70 times more than in the general population
transmission could be from aerosols, reactivation of latent infection, de-novo, and from infected kidney graft
Th1-type CD4+ T cells and type-1 cytokines are crucial for protection against
CD4+ and CD8+ T cells and interferon-gamma and interleukin-2 production act as a protective response.
Patients with latent TB have an increased signature of CD4+ T cells producing IFN-γ and IL-2, compared to active TB
Using immunosuppression in the setting of KT could disrupt the protection against TB and increase the risk of reactivation
The depletion of all types of T cells, decrease in activation and proliferation of T cells, decrease in IL-2 synthesis, impair the cellular immunity almost totally
Diagnosis
The diagnosis is generally challenging and it requires a high index of suspicion not to lose the patient eventually
TST
IGRA
BAL fluid for AFB, culture, and molecular test
Imagine the chest and other extrapulmonary sites
Active TB treatment
The optimal treatment period could vary from 6- 24 months depending on the sites and severity. Treatment is usually in two phases comprising intensive and maintenance.
If treatment with rifampicin is been planned, then then the 2-month intensive phase should contain isoniazid, ethambutol, and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide
Latent TB treatment
INH at 5mg/kg, maximum dose of 300mg daily for 9 months +vitamine B6
Another alternative is ethambutol + levofloxacin or moxifloxacin
Challenges with drug therapy
Rifampicin effect CNI or mTORi by reducing their trough level
Toxicity effect of all TB medication on different organs of the body
Possibility of development of IRIS
Graft rejection or loss
Conclusion
The impact of TB infection on the kidney transplant recipient could be fatal if early diagnosis and prompt treatment are not administered on time. The development of better diagnostic tools will help more in the accurate diagnosis of latent TB infection plus medication with less drug interaction
Summarise this articleSummarise this article
TB is common cause of death and the leading infectious cause of death worldwide (exclude covid 19).because of immunosuppression in transplantation ,active TB is higher than general population..
Proper assessment for donor and recipient is limited occurrence of the disease. Methods
A literature search on PubMed and Embase electronic databases was performed from 1 January 2000 to 15 June 2022.
All studies that provided epidemiological and/or outcomes data regarding TB in KT were included. Epidemiology and Risk Factors for Tuberculosis in Kidney Transplantation
The prevalence of active TB among patients with solid organ transplantation is highly variable according to the geographic area.
The incidence of active TB in solid organ transplantation is 20–74 times higher than in the general population,but differ upon the area which endemic or not. Epidemiology of Tuberculosis in Kidney Transplantation
The prevalence of active TB in kidney transplantation recipients varies from 0.3%to15.2%,and is higher than in the general population. Risk Factors for Tuberculosis in Kidney Transplantation
main cause of TB in kidney transplant is:
1. reactivation of latent disease .
2.donor tissue .
3. Denovo infection.
Transplant-associated risk factors, such as immunosuppression therapy, presence of acute rejection episodes and chronic graft disfunction.
But generally the risk factor depending on recipient and donor: Recipient :
Old age
Male
Smoking
Malnutrition
DM
COPD
Latent tuberculosis
HCV
CMV
Pneumocystis
Auto immune disease Donor risk factor
Donor type (cadaveric )
Smoking
Alchol
DM
BMI(more than 18.5kg/m)
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients
Transmission of TB in KT recipients depend on:
Reactivation of latent TB.
Positive latent infection conversion was found in ~20% of cases within the first 2 years after kidney transplant. Diagnostic Challenges
Active TB usually appears in the first year after kidney transplantation.
Diagnosis of TB need :
The diagnosis requires a high index of suspicion but kidney transplant recipients have atypical clinical presentations which reduce the clinical suspicion of TB,
Is it associated with other co-infections,
TST and IGRA are not useful in the diagnosis of active TB . Latent Tuberculosis.
Prevalence of latent TB after KT was reported in ~20% of recipients.
latent TB must be screening in all KT candidates and donors before transplantation.
IGRA is superior to TST in patient with ESRD.
IGRA tests have a good predictive potential for latent TB in KT recipient with negative TST.
IGRA tests had a low sensitivity in KT recipients .
IGRA test cannot be used to exclude latent TB.
Kidney transplant recipients should be more frequently screened. Treatment Challenges:
Treatment of KT recipients with TB should carried out by an experienced clinician due to adverse events and drug –drug iteractions ,drug toxicity and treatment adherents .
Active Tuberculosis:
Once diagnosis of active TB established ,treatment must be start. treatment period from 6 to 24 months.
According to AST-IDCOP, the first-line treatment should be a four-drug regimen.
Standard regimen consists of a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed bya4-month continuation phase of isoniazid and rifampicin as in general. Rifamycin is recommended for its sterilization capacity and efficiency but also to reduce the risk of resistance. If a regimen without rifamycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide.Rifampicin, a potent inducer of cytochrome P450 3A4 and P-glycoprotein that interfere with CNI (cyclosporin and tacrolimus).
That must be monitoring the CNI when use rifampicin.also monitoring for hepatotoxicity ,neurotoxicity ,cytopenia ,visual disturbances ,skin lesions,hyperuricaemia,and interstitial nephritis.
Another safe and effective alternative to rifampicin in KT recipients is treatment with fluoroquinolones. Outcomes
Graft rejection in KT recipients with TB can reach up to 55.6%. The prevalence of graft loss in KT patients with active TB varies from 2.2% to 66.6% ,mortality was described in 41.4% of patients with active TB after KT and in 14.4% of cases mortality was associated with anti-TB therapy. Conclusions
Tuberculosis in kidney transplantation is associated with significant negative graft and patient outcome .
clinicians should recognize the diagnostic and treatment challenges of TB after KT.
optimal management approach should be done by experience clinician .
Donor-derived TB and latent TB in KT are under recognized conditions that should be carefully evaluated.
Development of tests with helpful predictive values.
Newly discovered regimens or could have an important contribution in the future limitation of drug–drug interactions, improvement of treatment efficacy and reduction of
adverse events.
What is the level of evidence provided by this article? Level V.
I like your detailed summary, level of evidence, analysis and conclusions. I appreciate your debate regarding the uncertainty on optimal duration of therapy
Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review
Epidemiology of TB in SOT
· The prevalence varies between 0.3–6.4% in low TB endemicity to 15.2% in high endemic areas.
· The incidence of active TB in SOT is 20–74 times higher than in the general population.
· Latent TB infection: according to WHO is defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB.Prevalence of latent TB after KT was reported in ~20% of recipients.
Epidemiology of TB in Kidney Transplantation
· The prevalence of active TB in KT recipients varies from 0.3% to 15.2%.
· The prevalence is higher than in the general population but lower than in patients with lung transplantation.
· The pooled incidence of active TB in KT recipients was higher than in patients with ESRD in pre-dialysis but lower than in those on peritoneal dialysis and hemodialysis.
Risk Factors for TB in Kidney Transplantation
· Endemicity of TB in the population.
· Transplant-associated risk factors: immunosuppression therapy, presence of acute rejection episodes and chronic graft disfunction.
· Donor-associated risk factors: donor type(cadaveric), social risk factors(homeless, incarceration, smoking, alcohol abuse and known TB contact) and medical risk factors(DM, BMI< 18.5 Kg/m2, history of untreated TB).
Transmission of TB in KTRs
There are three possible scenarios for transmission of TB in KTRs: 1. Reactivation of the latent infection that occurred in the pre-transplant period. This is the most common form in all solid organ transplantation, including KT. 2. Via kidney graft from an infected donor, this type of transmission is responsible for only 4.8% of cases. 3. A de novo infection after KT. · in a recipient with exposure to a patient with active TB and is more frequent in endemic areas. · This type of transmission is not common. · It is associated with very high risk of progression.
Pathogenesis of TB in KTRs:
1. The protection against MBT infection is mainly based on cellular immunity, and, more specifically, it depends on T helper 1 (Th1) response. Th1-type CD4+ T cells and type-1 cytokines are crucial for protection against MBT.
2. Proliferative capacities of CD4+ and CD8+ T cells and interferon gamma (IFN-γ) and interleuqin-2 (IL-2) production are essential effectors in the protective response.
3. Using immunosuppression in the setting of KT could disrupt the protection against TB and increase the risk of reactivation through multiple mechanisms:
a) depletion of all types of T cells.
b) decrease in activation and proliferation of T cells.
c) decrease in IL-2 synthesis.
d) decrease in the production of Th-1 type cytokines.
e) impairment of cellular immunity almost completely.
Diagnosis of TB in KTRs and diagnostic challenges:
a) The diagnosis of TB requires a high index of suspicion based on the epidemiological risk, personal history, manifestations and imagistic lesions.
· Atypical clinical presentations or diverse manifestations reduce the linical suspicion of TB.
· Donor-derived TB should be suspected in KTR with one of the following features: non-specific symptoms, frequent fever in the first 3 months after KT, fluid collections, extrapulmonary manifestations or lack of response to empirical antibiotic therapy.
b) Tuberculin skin test (TST) and interferon- gamma release assay (IGRA) are not useful in the diagnosis of active TB.
c) Molecular tests based on rapid nucleic acid amplification techniques, such as mycobacterium tuberculosis complex and resistance to rifampin test (Xpert® MTB/RIF, Cepheid, Sunnyvale, CA, USA), could provide false negative results when mycobacterial load is low.
d) Screening tests for latent TB (TST and IGRA) have low feasibility and accuracy.
e) Data regarding prediction capacity of TST and IGRA tests are discordant in category of patients with latent TB.
Treatment of KT recipients with TB
1. Treatment Challenges: drug–drug interactions, drug toxicity and treatment adherence. 2. Active Tuberculosis: a) The optimal period of treatment could vary from 6 to 24 months. Recommended to be at least 9–12 months. b) According to AST-IDCOP, the first-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases. c) The standard regimen is similar to that used for the general population and consists of a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin. d) Adjustment of immunosuppression as Rifampicin reduces the level of CNIs and mTORi: · the dose of CNIs and mTORi should be increased between three- and five-fold and the glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target. 3. Treatment of latent TB should be considered only after active TB has been excluded. a) Treatment in this category of patients is indicated in one of the following conditions: a positive TST or IGRA test, a history of untreated TB, a history of recent contact with an active TB patient and when the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB. b) In the KT setting, the preferred treatment of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6. c) An alternative regimen for KT recipients, mainly for those with high risk, consists of ethambutol and levofloxacin or moxifloxacin.
Outcomes of TB in KT: 1. TB in KT is associated with important morbidity and mortality due to: · immunosuppression status. · increased extrapulmonary disease. · challenges in diagnosis that delay the initiation of treatment. 2. Rejection: · Graft rejection in KT recipients with TB can reach up to 55.6% and could be responsible for ~1/3 of graft losses.
3. Graft Loss:The prevalence of graft loss in KT patients with active TB varies from 2.2% to 66.6%. · Sepsis, acute rejection, interstitial fibrosis and tubular atrophy were causes of graft loss. 4. Mortality: · The mortality of patients with TB after KT has been reported to range from 0% to 60%. · Active TB after 2 years post-KT is an independent risk factor for mortality.
The level of evidence provided by this article:
This is an extensive literature review of articles published between 1 January 2000 and 15 June 2022. It is a retrospective study with level of evidence grade 3.
Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review
Bogdan MS and colleagues in this review article aimed to provide an evidence-based update regarding epidemiology, risk factors, pathophysiology, type of transmission, diagnostic challenges, treatment challenges and the impact of TB in KT recipients.
Methods
All studies that provided epidemiological and/or outcomes data regarding TB in KT from PubMed and Embase electronic databases from 1 January 2000 to 15 June 2022 were included except those in other languages or without complete information.
Epidemiology and Risk Factors for Tuberculosis in Kidney Transplantation
The prevalence of active TB in KT recipients varies from 0.3% to 15.2% and is higher than in the general population but lower than in patients with lung transplantation.
Transplant-associated risk factors for TB in KT includes immunosuppression therapy, presence of acute rejection episodes and chronic graft dysfunction. Immunosuppression used in KT impairs T-cell-mediated immunity involved in TB control and favors latent infection reactivation. T cell-depleting agents (anti-thymocyte globulin), cytotoxic T-lymphocyte-associated protein-4 inhibitors (belatacept), calcineurin inhibitors (tacrolimus, cyclosporine), anti-metabolites (mycophenolate, azathioprine) and glucocorticoids all increase the risk of development of TB.
Recipient risk factors for TB in KT includes older age, male sex, smoking, malnutrition, diabetes mellitus, malnutrition, COPD, latent TB before transplant, CLD, HCV infection, opportunistic infection (such as CMV, norcardia), autoimmune disease, long dialysis vintage.
Donor associated risk factors includes cadaveric donors, social risks (homelessness, incarceration, smoking, alcohol,), medical risk (DM, BMI<18.5, history of untreated TB).
Others are burden of TB and its endemicity.
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipient
Transmission is via aerosol droplets containing mycobacterium tuberculosis (MBT) that are inhaled into the lungs. The outcome of exposure could be as follows: clearance of MBT by the organism either due to innate immune response or acquired T cell immunity, development of primary disease which means an immediate onset of active disease (first 24 months after primary infection) or latent infection reactivation meaning a late onset of active disease many years following primary infection.
The most common mode of disease transmission in KTP is through activation of latent infection acquired prior to transplantation. In 4.8% of cases, TB could be transmitted to KT recipients via kidney graft from an infected donor. Lastly, though very uncommon, TB could occur as a de novo infection after KT in a recipient with exposure to a patient with active TB. This mode of transmission associated with very high risk of progression, and it is more frequent in endemic areas.
The protection against MBT infection is mainly based on T helper 1 (Th1) response. Th1-type CD4+ T cells and type-1 cytokines are crucial for protection against MBT. In addition, proliferative capacities of CD4+ and CD8+ T cells and interferon gamma (IFN-γ) and interleukin-2 (IL-2) production are essential effectors in the protective response. Using immunosuppression in the setting of KT could disrupt the protection against TB and increase the risk of reactivation through multiple mechanisms, such as: depletion of all types of T cells, decrease in activation and proliferation of T cells, decrease in IL-2 synthesis, decrease in the production of Th-1 type cytokines or impairment of cellular immunity almost completely.
Diagnostic and Treatment Challenges Active tuberculosis
The diagnosis of TB requires a high index of suspicion based on the epidemiological risk, personal history, manifestations and imagistic lesions. Delay in diagnosis could result from atypical presentations which could occur in KT recipients. Additionally, the probability of association with other co-infections and extrapulmonary localization in ~50% of cases add a supplementary confusing element to the clinical picture. Paraclinical issues such as poor utility of IGRA and tuberculin skin testing in diagnosis. The need for invasive procedures such as bronchoalveolar lavage for diagnosis could also represent a diagnostic challenge sometimes. False negative test can occur with molecular tests when mycobacterial load is low, and this can be challenging.
Latent tuberculosis
According to WHO, latent TB infection is defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB. There are no gold standard tests for diagnosing latent TB accurately in KT candidates, but IGRA seems to present some advantages over TST in patients with ESRD. Even so, the evaluation of latent TB in KT recipients is challenging because data regarding prediction capacity of TST and IGRA tests are discordant in this category of patients.
Treatment Challenges Active Tuberculosis
Treatment of KT recipients with TB could be challenging due to drug–drug interactions, drug toxicity and treatment adherence.
The optimal period of treatment could vary from 6 to 24 months and, in some cases, based on experts’ opinion, the duration of treatment is recommended to be at least 9–12 months. American Society of Transplantation Infectious Diseases Community of Practice (AST-IDCOP) guidelines recommends that in case of active uncomplicated pulmonary TB, treatment duration should be at least 6 months, but if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months. In case of severe disseminated disease or bone and joint disease, treatment duration is recommended for at least 6–9 months. Patients with central nervous system involvement should be treated for at least 9–12 months.
The first-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases.
Latent Tuberculosis
Treatment of latent TB should be considered only after active TB has been excluded. Treatment in this category of patients is indicated in one of the following conditions: a positive TST or IGRA test, a history of untreated TB, a history of recent contact with an active TB patient and when the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB [13]. In the KT setting, the preferred treatment of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6. A regimen based on rifampicin is not recommended. An alternative regimen for KT recipients, mainly for those with high risk, consists of ethambutol and levofloxacin or moxifloxacin. The main adverse event associated to isoniazid is hepatotoxicity, but the risk of liver damage seems to be reduced in KT patients. Nonetheless, evaluation of liver enzymes during treatment, initially bi-weekly for 6 weeks and monthly thereafter, is recommended.
Outcomes
TB in KT is associated with important morbidity and mortality due to immunosuppression status, increased extrapulmonary disease and challenges in diagnosis that delay the initiation of treatment.
Rejection
Graft rejection in KT recipients with TB can reach up to 55.6%, often being associated with reduced levels of immunosuppression secondary to calcineurin inhibitors–rifampicin interaction and could be responsible for ~1/3 of graft losses. Graft Loss
Increased risk of graft loss from rejection sepsis and donor derived TB and varies between 2.2 and 66%.
Conclusions
TB in KT is an important opportunistic infection with higher incidence and prevalence than in the general population and is associated with significant negative graft and patient outcomes.
TB is one of the most prevalent illnesses with adverse effects after transplantation.
As KT is associated with an immunosuppression status, KT recipients have greater rates of active TB than the overall population.
Active tuberculosis following KT may result from de novo infection or from the reactivation of latent infection in the recipient or donor tissue.
In this review article, the epidemiology, etiology, diagnosis, treatment, & outcomes of TB among KT recipients are examined using evidence-based methods.
Epidemiology & Risk Factors for TB
The prevalence of active TB among SOT recipients varies from 0.3–6.4% in low-endemic areas to 0.3–6.4% in high-endemic areas.
Active TB is 20–74 times more common among SOT recipients than in the general population.
KT recipients had a prevalence of active TB from 0.3% to 15.2%; this rate is higher than in the general population, but lower than that of patients with lung TX.
Risk Factors for TB in KTX
The endemicity of TB in the population has a major impact on the risk, but important factors related to the recipient, donor, and transplantation raise it.
Transplant-associated risk factors:
Immunosuppression therapy
Presence of AR episodes
Chronic graft dysfunction
Recipient-associated risk factors:
Older age
Male gender
Smoking
Malnutrition
DM
COPD
Pre-TX LBTI
Chronic liver disease
HCV infection
Long term hemodialysis
Autoimmune diseases
Opportunistic co-infections: CMV, PJP, nocardia
Donor-associated risk factors:
Donor type (cadaveric)
Social risk factors (homeless, alcohol abuse, known TB contact)
Medical (DM, low BMI, history of untreated TB)
Pathogenesis
The aerosol droplets containing MBT are inhaled into the lungs. Subsequent evolution is one of the following:
Clearance of MBT by the organism either due to innate immune response or acquired T cell immunity.
Immediate onset of active disease (first 24 months after primary infection).
Latent infection reactivation many years after primary infection.
Types of TB transmission
Re-activation after KT of a latent infection in recipient.
Donor-derived infection.
De novo infection after KT.
Diagnostic Challenges of active TB in KTX recipients:
KT recipients have atypical clinical presentations or diverse manifestations, which reduce the clinical suspicion of TB.
Association with other co-infections confuses clinical picture & delays diagnosis.
TST & IGRA not useful in the diagnosis of active TB
Variable radiographic manifestations in pulmonary TB
The frequent need for invasive procedures (bronchoscopy)
Molecular tests based on rapid NAT techniques, could provide false negative results when mycobacterial load is low.
Diagnostic Challenges of LTBI in KTX recipients:
There are no gold standards for diagnosis, but IGRA is preferable to TST in ESRD patients.
Data on the TST & IGRA tests’ ability to predict outcomes in KTX recipients are inconsistent.
Treatment challenges of active TB
Drug interaction between rifampicin & transplant- associated immunosuppression.
If a rifamycin free regimen is used, a longer (12–18 months) continuation phase is used with INH & ethambutol or pyrazinamide.
Longer treatment times are advised if second-line medications are utilized.
The risk of rejection is increased by the use of rifampicin because it lowers levels of CNIs, the mTOR inhibitors, & alters glucocorticoids metabolism.
To reach the therapeutic target, the doses of these IS agents must be increased three- and five-fold, and the dose of glucocorticoids must be doubled during treatment and then adjusted.
Rifabutin is an alternative to rifampicin that has comparable efficacy but a weaker enzyme inducer.
TB therapy side effects are more common than in the general population.
Patients should be closely monitored for hepatotoxicity, neurotoxicity, cytopenia, visual disturbances, skin lesions, hyperuricemia or interstitial nephritis.
Outcomes of TB in KT
Up to 55.6% of KT patients with TB may have graft rejection. This is due to suboptimal levels of IS in the context of rifampicin-based regimen use.
Graft loss can be directly due to infection, especially in the case of donor-derived TB.
Between 2.2% to 66.6% of KT patients with active TB have graft loss.
The mortality rates in SOT recipients are 20%.
The mortality of patients with TB after KT ranges from 0% to 60%.
Future
The diagnosis of LTBI could be significantly improved by the development of diagnostics with useful predictive values that do not rely on T cell immunity.
Newly discovered drug regimens can improve limitations of drug–drug interactions, improve treatment efficacy & reduce adverse events.
====================== 2. What is the level of evidence provided by this article?
Level V
Do you think you would like to use a test or battery of tests with good likelihood ratio of >10, rather than those with high predictive value, of diagnosing TB in an immuno-suppressed patients?
Introduction
· Kidney transplantation is the optimal treatment for end-stage renal disease, but infection post-transplantation is an important limitation.
· TB is the leading cause of death post-transplantation, with an incidence rate of 127 cases per 100,000 people.
· Kidney transplantation is linked to an immunosuppressive condition, which can cause patients to have greater rates of active TB than the general population.
· To reduce or eliminate the occurrence of active TB following transplantation, screening procedures should be put into place.
· Kidney transplantation candidates and recipients with TB are a major challenge for diagnosis and management, with potential adverse effects such as transplant rejection, graft loss, and death. Methods
· An evidence-based review of TB in kidney transplantation recipients.
· Current guidelines used to diagnose and treat active TB in kidney transplantation.
· Epidemiology and Risk Factors for Tuberculosis in Kidney Transplantation Epidemiology of Tuberculosis in Kidney Transplantation
· The prevalence of active TB in kidney transplantation recipients varies from 0.3% to 15.2% and is higher than in the general population but lower than in patients with lung transplantation.
· Two systematic reviews and meta-analyses found similar results, with an unadjusted TB risk ratio of 11.36 times higher and an adjusted risk ratio for dialysis of 3.62 times higher than those from the general population.
· Kidney transplantation recipients had a pooled incidence of active TB of 2700-14,680 per 100,000 patient-years, higher than ESRD in pre-dialysis and lower than those on peritoneal dialysis and hemodialysis. Risk Factors for Tuberculosis in Kidney Transplantation
· Immunosuppressive medication, (T-cell depleting medicines, cytotoxic T-lymphocyte-associated protein-4 inhibitors, calcineurin inhibitors, anti-metabolites, and glucocorticoids)
· Acute rejection episodes,
· Chronic graft malfunction,
· Chronic graft dysfunction,
· Quantity of rejections following a transplant is a separate risk factor for the development of TB. Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients
· The natural history of infection involves clearance of MBT, development of primary disease, or latent infection reactivation.
· Transmission of TB in kidney transplantation recipients could occur in three scenarios: reactivation of latent infection, transmission via kidney graft, or de novo infection.
· In a prospective study, latent infection was found to be higher in recipients than candidates, and older age, absence of Bacillus Calmette–Guérin vaccine scars, and donor-specific antibodies were associated with latent infection. A strategy for post-transplantation latent infection evaluation could be helpful in addition to pre-transplant screening.
· Kidney transplantation generates a favorable path for TB reactivation in candidates with latent infection due to initiation of induction and maintenance-specific immunosuppression.
· This could disrupt the protection against TB and increase the risk of reactivation through depletion of all types of T cells, decrease in activation and proliferation, decrease in IL-2 synthesis, decrease in the production of Th-1 type cytokines, or impairment of cellular immunity. Diagnostic and Treatment Challenges
· Patients’ prognosis depends on the early diagnosis and the appropriate therapeutic approach. Diagnostic Challenges Active Tuberculosis
· The diagnosis of active TB in kidney transplantation patients is challenging due to the high index of suspicion, atypical clinical presentations, and the probability of association with other co-infections.
· Diagnostic challenges such as tuberculin skin test (TST) and interferon-gamma release assay (IGRA) are not useful, and molecular tests based on rapid nucleic acid amplification techniques may provide false negative results when the mycobacterial load is low.
· Donor-derived TB is an under-recognized condition with early onset after kidney transplantation and should be suspected in recipients with:
o Non-specific symptoms.
o Frequent fever.
o Fluid collections,
o Extrapulmonary manifestations.
o Lack of response to empirical antibiotic therapy.
o Screening tests for latent TB have low feasibility and accuracy.
o Donor history, treatment, and exposure to active TB should be obtained from family or relatives. Latent Tuberculosis
· Latent TB infection is defined as a persistent immune response to stimulation by MBT antigens with no evidence of clinically manifested active TB.
· Prevalence of latent TB after kidney transplantation was reported in ~20% of recipients, and current guidelines recommend screening before transplantation.
· There are no gold standard tests for diagnosing latent TB accurately, but IGRA seems to present some advantages over TST in patients with ESRD.
· However, data regarding the prediction capacity of TST and IGRA tests are discordant in this category of patients.
· The importance of diagnosis is supported by the fact that undiagnosed and untreated latent TB significantly increases the risk of active TB. Treatment Challenges
· Treatment of kidney transplantation patients with TB should be managed by an experienced clinician with special attention to drug-drug interactions and adverse events. Active Tuberculosis
· Treatment of active TB in kidney transplantation recipients should be promptly started and assessed for epidemiological features and drug resistance patterns.
· The optimal period of treatment for active uncomplicated pulmonary TB is recommended to be at least 6 months, but if cavitary lesions exist or there is a persistent culture-positive sputum, it may be extended to 9 months.
· The first-line treatment should be a four-drug regimen containing rifamycin, which is recommended for its sterilization capacity and efficiency but also to reduce the risk of resistance.
· Rifampicin is a potent inducer of cytochrome P450 3A4 and P-glycoprotein that interferes with immuno- suppression metabolization, increasing the risk of rejection and graft loss in kidney transplantation recipients with active TB.
· To manage this, calcineurin and mTOR inhibitor levels should be increased, and immunosuppression doses should be reduced or adjusted to obtain the therapeutic target. Rifabutin and fluoroquinolones are safe and effective alternatives.
· The most common adverse effects of TB therapy are hepatotoxicity, neurotoxicity, cytopenia, visual disturbances, skin lesions, hyperuricemia, and interstitial nephritis.
· Treatment adherence is an issue in kidney transplantation recipients, but the implementation of directed observed therapy programs has improved adherence.
· Reduction of immunosuppression in severe TB or when a vital organ is involved should be considered, but there are concerns about immune reconstitution inflammatory syndrome. Latent Tuberculosis
· Treatment of kidney transplantation recipients with latent TB is important for preventing reactivation and is indicated in one of the following conditions:
o Positive TST or IGRA test,
o History of untreated TB,
o Recent contact with an active TB patient,
o Kidney graft originates from a donor with known latent TB,
· Isoniazid 5 mg/kg/day for 9 months, supplemented with vitamin B6.
· Evaluation of liver enzymes during treatment is recommended. Outcomes
· TB in kidney transplantation is associated with increased morbidity and mortality. Rejection
· Graft rejection in kidney transplantation recipients with TB can be associated with reduced levels of immunosuppression, with acute rejection being responsible for ~1/3 of graft losses. Graft Loss
· Graft loss among kidney transplantation patients with active TB can be caused by infection, sepsis, acute rejection, interstitial fibrosis, and tubular atrophy, and can be precipitated by suboptimal levels of immunosuppression.
· The prevalence of graft loss varies from 2.2% to 66.6%. Mortality
· Mortality rates for patients with active TB have been reported to range from 0-60%. 65% of participants with active TB who died had co-infections with fungi, cytomegalovirus, Nocardia, hepatotropic viral infections, and chronic liver disease.
· Mortality was also associated with anti-TB therapy in 14.4% of cases.
· More than half of patients who died received anti-rejection treatment before the TB development and had diabetes, hepatitis C virus infection, or fungal infection. Conclusions
· A serious opportunistic infection that affects patients and grafts adversely after kidney transplantation, TB has a greater incidence and prevalence than in the general population.
· Medical professionals who specialize in kidney transplantation and infectious diseases must work closely together to eliminate the risk factors for both the development of TB and its harmful effects.
· Latent TB and donor-derived TB should be thoroughly assessed and tested with useful predictive values.
· Newly developed regimens or medications in the pipeline may have a significant role in limiting drug-drug interactions, increasing treatment effectiveness, and lowering adverse effects in the future.
==================================================== What is the level of evidence provided by this article?
I like your summary, level of evidence, analysis and take home messages. I like that you state, “Medical professionals who specialise in kidney transplantation and infectious diseases must work closely together.”
As KT is associated with an immunosuppression status, active TB is higher in KT recipients than in the general population
Active TB after KT could arise from reactivation of latent infection in the recipient or donor tissue or can result from de novo infection after transplantation. Endogenous reactivation after KT is the most common form of transmission.
Epidemiology of Tuberculosis in Solid Organ Transplantation
In areas with low TB endemicity, the prevalence varies between 0.3–6.4%, compared to prevalence of TB in high, endemic areas which could rise to 15.2%
The incidence of active TB in solid organ transplantation is 20–74 times higher than in the general population.
Epidemiology of Tuberculosis in Kidney Transplantation
The prevalence of active TB in KT recipients varies from 0.3% to 15.2%
Incidence of active TB of 2700 per 100,000 patient-years.
Risk Factors for Tuberculosis in Kidney Transplantation
Recipient factors
Old
Male
DM
Smoking
Malnutrition
COPD
LTBI
Chronic liver disease
HCV
Longterm HD
Autoimmune disease
Opportunistic infections
Donor associated
Cadaveric
Homeless, smoking, alcohol, known TB contact
DM, untreated TB, BMI <18.5
Transplant associated
Immunosuppression
Acute rejection
Chronic graft dysfunction
Transmission of TB in KT recipients
In the first scenario, active TB could arise after KT as a result of reactivation of the latent infection present in the recipient prior to transplantation (Most common)
Positive latent infection conversion was found in ~20% of cases within the first 2 years after KT
In the second scenario, TB could be transmitted to KT recipients via kidney graft from an infected donor ( 4.8% of cases )
In the third scenario, TB could occur as a de novo infection after KT, in a recipient with exposure to a patient with active TB ( more frequent in endemic areas)
The protection against MBT infection is mainly based on cellular immunity, and, more specifically, it depends on T helper 1 (Th1) response
In patients with latent TB there is an increased signature of CD4+ T cells producing IFN-γ and IL-2, compared to active TB patients, in which this type of cells are sparsely represented
Using immunosuppression in the setting of KT could disrupt the protection against TB and increase the risk of reactivation through multiple mechanisms, such as: depletion of all types of T cells, decrease in activation and proliferation of T cells, decrease in IL-2 synthesis, decrease in the production of Th-1 type cytokines or impairment of cellular immunity almost completely.
Diagnosis
Active TB
tuberculin skin test (TST) and interferon gamma release assay (IGRA) are not useful in the diagnosis of active TB
Additionally, radiographic manifestations in pulmonary TB and the frequent need for invasive procedures (bronchoscopy with bronchoalveolar lavage, derange of fluid collections subsequently evaluated by smear and mycobacterium culture and histopathological evaluation) could represent diagnostic challenges
Molecular tests based on rapid nucleic acid amplification techniques, such as mycobacterium tuberculosis complex and resistance to rifampin test (Xpert® MTB/RIF, Cepheid, Sunnyvale, CA, USA), could provide false negative results when mycobacterial load is low
Donor-derived TB should be suspected in KT recipients with one of the following features: non-specific symptoms, frequent fever in the first 3 months after KT, fluid collections, extrapulmonary manifestations or lack of response to empirical antibiotic therapy
As active disease in donors is a contraindication for donation
Identification of latent TB in deceased donors remains a real challenge in KT,
American Society of Transplantation Infectious Diseases Community of Practice and European Society of Clinical Microbiology and Infectious Diseases recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors
In deceased donors, the patient’s medical history might be unobtainable, and the screening tests for latent TB (TST and IGRA) have low feasibility and accuracy
In these circumstances, details regarding donor history of previous active TB, specific treatment or exposure to active TB within the last 2 years should be obtained from the donor’s family or relatives
Latent Tuberculosis
defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB
Prevalance 20 %
There are no gold standard tests for diagnosing latent TB accurately in KT candidates, but IGRA seems to present some advantages over TST in patients with ESRD
Management
Active Tuberculosis
American Society of Transplantation Infectious Diseases Community of Practice (AST-IDCOP) guidelines recommends that in case of active uncomplicated pulmonary TB, treatment duration should be at least 6 months, but if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months.
In case of severe disseminated disease or bone and joint disease, treatment duration is recommended for at least 6–9 months
Patients with central nervous system involvement should be treated for at least 9–12 months
the first-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases
Rifamycin is recommended for its sterilization capacity and efficiency but also to reduce the risk of resistance
This standard regimen is similar to that used for the general population and consists of a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin
If a regimen without rifamycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide.
Rifampicin, a potent inducer of cytochrome P450 3A4 and P-glycoprotein, interferes with immunosuppression metabolization
Specifically, rifampicin usage decrease the levels of calcineurin inhibitors (cyclosporine, tacrolimus), the mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus), and affects glucocorticoids metabolization, which increases the risk of rejection
Therefore, when a rifampicin-based regimen is used, calcineurin and mTOR inhibitors levels should be closely monitored, the dose of calcineurin and mTOR inhibitor should be increased between three- and five-fold and the glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target.
Additionally, after the rifampicin is stopped, the immunosuppression doses should be reduced to the value before the start of rifampicin and then adjusted to obtain the therapeutic target
An alternative to rifampicin is rifabutin, which is a weaker inducer of cytochrome P450 3A4 and P-glycoprotein but with similar efficacy
The most common adverse event associated with anti-TB therapy is hepatotoxicity; therefore, liver enzymes should be closely monitored with bi-weekly evaluation during the intensive phase of treatment and monthly thereafter
Reduction of immunosuppression in the case of severe TB or when a vital organ is involved should be considered
Latent Tuberculosis
Treatment in this category of patients is indicated in one of the following conditions: a positive TST or IGRA test, a history of untreated TB, a history of recent contact with an active TB patient and when the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB
In the KT setting, the preferred treatment of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6
A regimen based on rifampicin is not recommended
The main adverse event associated to isoniazid is hepatotoxicity, but the risk of liver damage seems to be reduced in KT patients
The evaluation of liver enzymes during treatment, initially bi-weekly for 6 weeks and monthly thereafter, is recommended
Introduction: Kidney transplantation (KT) remains the optimal treatment for patients with end-stage renal disease (ESRD) One of the most common infections with negative impact post-transplantation is tuberculosis (TB) According to World Health Organization (WHO), >10 million cases of TB (were reported in 2020 worldwide, corresponding to an incidence rate of 127 cases per 100,000 people per year Active TB after KT could arise from reactivation of latent infection in the recipient or donor tissue or can result from de novo infection after transplantation. Endogenous reactivation after KT is the most common form of transmission KT candidates and recipients with TB represent a real challenge regarding the diagnosis and treatment due to atypical or diverse clinical presentation, limitations of screening tests for latent infection, drug interactions and toxicities . The delay in diagnosis and treatment could determine negative consequences, such as graft rejection, graft loss and increased mortality rate objective :
to provide an evidence-based update regarding epidemiology, risk
factors, pathophysiology, type of transmission, diagnostic challenges, treatment challenges and the impact of TB in KT recipients
Methods: literature review of articles published between 1 January 2000 and 15 June 2022 to provide an evidence-based review of epidemiology, pathogenesis, diagnosis, treatment and outcomes of TB in KT recipients. And included all studies which reported epidemiological and/or outcome data regarding active TB in KT, and we approached the diagnostic and treatment challenges according to the current guidelines Epidemiology and Risk Factors for Tuberculosis in Kidney Transplantation:
The prevalence of active TB among patients with solid organ transplantation is highly variable according to the geographic area. In areas with low TB endemicity, the prevalence varies between 0. 3 to 6.4%, while the prevalence of tuberculosis can reach 15.2% in highly endemic areas. KT recipients ranged from 0.3% to 15.2% Prevalence of tuberculosis in the population. Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipient 1-active TB could arise after KT as a result of reactivation of the latent infection present in the recipient prior to transplantation 2-donor -derived infection. 3-De novo infection after KT. TB—tuberculosis Diagnostic and Treatment Challenges:
High index of susciption based on : Epidemiological risk Personal history Imaging lesion
(bronchoscopy with bronchoalveolar lavage, derange of fluid collections
subsequently evaluated by smear andmycobacteriumculture and histopathological evaluation Donor-derived TB is considered an under-recognized condition: non-specific symptoms, frequent fever in the first 3 months after KT, fluid collections, extrapulmonary manifestations or lack of response to empirical antibiotic therapy active disease in donors is a contraindication for donation, identification of latent TB in deceased donors remains a real challenge in KT, despite the current recommendation for screenin Current guidelines (American Society of Transplantation Infectious Diseases Community of Practice and European Society of Clinical Microbiology and Infectious Diseases) recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors in deceased donors, the patient’s medical history might be unobtainable, and the screening tests for latent TB (TST and IGRA) have low feasibility and accuracy , In these circumstances, details regarding donor history of previous active TB, specific treatment or exposure to active TB within the last 2 years should be obtained from the donor’s family or relatives Latent Tuberculosis According to WHO, latent TB infection is defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB Treatment Challenges:
Treatment of KT recipients with TB could be challenging due to drug–drug interactions, drug toxicity and treatment adherence Active Tuberculosis
The optimal period of treatment could vary from 6 to 24 months and, in some
cases, based on experts’ opinion, the duration of treatment is recommended to be at least 9–12 months
American Society of Transplantation Infectious Diseases Community
of Practice (AST-IDCOP) guidelines recommends that in case of active uncomplicated pulmonary TB, treatment duration should be at least 6 months, but if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months
challenge in the treatment of KT recipients with active TB is the drug interaction between rifampicin and transplant-associated immunosuppression Outcomes Rejection Graft Loss Mortality
Summarise this article Tuberculosis (TB) in kidney transplant (KT) recipients is an important opportunistic infection with higher incidence and prevalence than in the general population and is associated with important morbidity and mortality. Active TB after KT could arise from reactivation of latent infection in the recipient or donor tissue or can result from de novo infection after transplantation.
Methodology Search was done for articles published between 1 January 2000 and 15 June 2022 to provide an evidence-based review of epidemiology, pathogenesis, diagnosis, treatment and outcomes of TB in KT recipients.
Epidemiology of Tuberculosis in Solid Organ Transplantation Prevalence of active TB in KT recipients ranges between 0.3–15.2%. KT recipients with active TB could have a rejection rate up to 55.6%, a rate of graft loss that varies from 2.2% to 66.6% and a mortality rate up to 60%. A recent systematic review and meta-analysis including 60 studies analyzed the prevalence of active TB in solid organ transplant recipients and showed a pooled prevalence of 3%.
Risk Factors for Tuberculosis in Kidney Transplantation Important risk factors include: Immunosuppression therapy, presence of acute rejection episodes and chronic graft dysfunction. Immune suppression can lead to impairs T-cell-mediated immunity involved in TB control and favors latent infection reactivation. Drugs- anti-thymocyte globulin, cytotoxic T-lymphocyte-associated protein-4 inhibitors (belatacept), calcineurin inhibitors (tacrolimus, cyclosporine), anti-metabolites (mycophenolate, azathioprine) and glucocorticoids increase risk of TB. Acute rejection significantly increases the risk of TB by 7.6 times Chronic graft dysfunction, can increase the risk of TB development by amplifying the immunosuppression status.
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients Active TB could arise after KT as a result of reactivation of the latent infection present in the recipient prior to transplantation Transmission by infected graft Denovo development of TB after exposure
Diagnostic and Treatment Challenges
Active Tuberculosis Diagnosis of TB requires high index of suspicion KT recipients have atypical clinical presentations Tuberculin skin test (TST) and interferongamma release assay (IGRA) are not useful in the diagnosis of active TB Molecular tests Bronchoscopy with bronchoalveolar lavage–Fluid for smear and mycobacterium culture Bronchoscopy and biopsy
Latent Tuberculosis Current guidelines provide recommendations for latent TB screening in all KT candidates and donors before transplantation IGRA seems to present some advantages over TST in patients with ESRD Untreated latent TB after KT significantly increases the risk of active
Treatment of Active TB The optimal period of treatment could vary from 6 to 24 months American Society of Transplantation Infectious Diseases Community of Practice (AST-IDCOP) guidelines recommends- – Treatment for 6 months, but if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months – severe disseminated disease or bone and joint disease, treatment duration is recommended for at least 6–9 month -CNS involvement- 12 months Recommendations-2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin ESCMID suggests a standard regimen used for a period longer than 6 months If Regimen without rifamycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide.
Latent TB Isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6 Another regimen consists of ethambutol and levofloxacin or moxifloxacin
Conclusions · TB in KT is an important opportunistic infection with higher incidence and prevalence than in the general population · Clinicians should recognize the diagnostic and treatment challenges of TB after KT for an optimal management approach · Close collaboration between kidney transplant and infectious disease physicians is mandatory · More diagnostic test which are not based on T cell immunity are required · Newly discovered regimens or pipeline drugs could have an important contribution in the future management
What is the level of evidence provided by this article? Level V
1-Summarise this article; Introduction;
-Tuberculosis (TB) in kidney transplant (KT) recipients is an important opportunistic infection with higher incidence and prevalence than in the general population and is associated with important morbidity and mortality.
-Active TB after KT could arise from reactivation of latent infection in the recipient or donor tissue or can result from de novo infection after transplantation.
-Endogenous reactivation after KT is the most common form of transmission. Aim;
-Provide an evidence-based update regarding epidemiology, risk factors, pathophysiology, type of transmission, diagnostic challenges, treatment challenges and the impact of TB in KT recipients. Methodology;
-An extensive literature review of articles were performed and published between 1 January 2000 and 15 June 2022 to provide an evidence-based review of epidemiology, pathogenesis, diagnosis, treatment and outcomes of TB in KT recipients.
-They included all studies which reported epidemiological and/or outcome data regarding active TB in KT, and they approached the diagnostic and treatment challenges according to the current guidelines. Risk factors for re-activation LTBI;
-Occur when conditions of immunosuppression are present such as diabetes, malnutrition, HIV, and prescription of biologics and immunosuppressive agents including anti-rejection therapies in transplant patients. Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients;
-Transmission of TB in KT recipients could be possible according to three scenarios.
*Active TB could arise after KT as a result of reactivation of the latent infection present in the recipient prior to transplantation,
*TB could be transmitted to KT recipients via kidney graft from an infected donor,
*TB could occur as a de novo infection after KT, in a recipient with exposure to a patient with active TB. Diagnostic challenges; Screening and diagnosis of LTBI;
-There is no gold standard test for diagnosing LTBI accurately.
-WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs); (QFT & T-SPOT).
-The TST may be unreliable in patients with advanced chronic kidney disease and in those on immunosuppressive agents.
-IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients & more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation.
-British Thoracic Society guidelines suggest screening for LTBI where tuberculosis incidence rates are high or in patients with risk factors for developing tuberculosis in low incidence areas: need to be evaluated with chest radiography and other screening tests as part of the screening for latent tuberculosis. Active Tuberculosis; -Occurs in the first year after KT (a median time of 11.5 months) in the case of reactivation and earlier in the case of donor-derived infection (in the first 3 months) -The diagnosis requires a high index of suspicion but KT recipients have atypical clinical presentations which reduce the clinical suspicion of TB, -Probability of association with other co-infections, -TST and IGRA are not useful in the diagnosis of active TB, -Molecular tests based on rapid nucleic acid amplification techniques could provide false negative results when mycobacterial load is low. Treatment challenges;
-Regarding treatment challenges in KT recipients with TB, drug interactions, drug toxicities and therapeutical adherence must be considered. Treatment of LTBI in donor and recipient;
-The WHO 2018 guidelines for treatment options for LTBI;
-Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
-Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy.
-Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy. Active Tuberculosis; Duration of treatment is recommended to be at least 9–12 months. AST-IDCOP guidelines treatment: -First-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases (2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-months of isoniazid and rifampicin) Challenge in the treatment of KT recipients: -Rifampicin is a potent inducer of cytochrome P450 3A4 and P-glycoprotein. -Rifampicin decrease the levels of CNIs, mTOR inhibitors, and affects glucocorticoids. -The dose of CNIs and mTOR inhibitor should be increased between 3-5 folds and the glucocorticoid dose should be doubled during treatment. -Rifabutin (alternative to rifampicin):weaker inducer of cytochrome P450 3A4 and P-glycoprotein but with similar efficacy. -Immunosuppression doses could be modified, and levels should be closely monitored. -Fluoroquinolones: it is safe alternative to rifampicin -The most common adverse event is hepatotoxicity (liver enzymes should be closely monitored with bi-weekly evaluation during the intensive phase of treatment and monthly thereafter) Outcome; –KT recipients with active TB could have a rejection rate up to 55.6%, a rate of graft loss that varies from 2.2% to 66.6% and a mortality rate up to 60%. Conclusions;
-Prevalence of active TB in KT recipients ranges between 0.3–15.2%.
-Clinicians should recognize the diagnostic and treatment challenges of TB after KT for an optimal management approach.
-This requires close collaboration between kidney transplant and infectious disease physicians.
-Donor-derived TB and latent TB in KT are under recognized conditions that should be carefully evaluated.
-Development of tests with helpful predictive values, which are not based on T cell immunity, could bring important improvement in the diagnosis of latent TB in KT recipients.
2-What is the level of evidence provided by this article? This is a comprehensive Review with (LOE V).
I like your summary, level of evidence, and analysis. You mention 3 possible options for prophylaxis against latent TB in recipients. Which one would you choose for your patients?
1- Summary: Epidemiology among KT:
The prevalence of active TB in KT recipients varies from0.3% to 15.2% and is higher than in the general population but lower than in patients with lung transplantation and more than those on dialysis.
Risk factors:
1- TB endemicity in the population
2- Recipient-associated factors: Old age, male, malnutrition, DM, long dialysis duration, latent T.B, chronic obstructive pulmonary disease, chronic liver disease, opportunistic co-infections.
3- Donor related factors: Cadaveric donor, homeless, alcoholic, drug abuse, latent T.B, DM
4- Transplant-associated factors: Immunosuppression, acute rejection, chronic allograft dysfunction Transmission of T.B:
1- Reactivation of the latent infection present in the recipient. The most common form among KT.
2- Donor-derived infection: 4.8% of cases
3- Do-Novo infection: This type of transmission is not common; it is associated with very high risk of progression, and it is more frequent in endemic areas. Pathogenesis among KT:
Using immunosuppression disrupt the protection against TB and increase the risk of reactivation through multiple mechanisms, such as: depletion of all types of T cells, decrease in activation and proliferation of T cells, decrease in IL-2 synthesis, decrease in the production of Th-1 type cytokines or impairment of cellular immunity almost completely.
Diagnostic challenges: 1- Active T.B:
Active TB usually appears in the first year after KT, at a median time of 11.5months in the case of reactivation after latent infection and earlier in the case of donor-derived infection (in the first 3months)
Challenges:
– KT recipients have atypical clinical presentations or diverse manifestations
– The probability of association with other co-infections and extrapulmonary localization in ~50% – Paraclinical issues. For example, tuberculin skin test (TST) and interferon gamma release assay (IGRA) are not useful in the diagnosis of active TB. Additionally, the wide range of radiographic manifestations in pulmonary TB and the frequent need for invasive procedures.
Current guidelines recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors
The diagnosis requires high suspicious index.
2- Latent T.B:
– According to WHO, latent TB infection is defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB. – Current guidelines recommend latent TB screening in all KT candidates and donors before transplantation. There are no gold standard tests for diagnosing latent TB accurately in KT candidates, but IGRA seems to present some advantages over TST in patients with ESRD. Treatment challenges: Active T.B: – The optimal period of treatment 6-24 months (not less than 6-9 months)
– The first-line treatment should be a four-drug regimen containing rifampicin used both in severe and non-severe cases.
– Consists of a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin Challenges: 1- Drug interaction between rifampicin and IS: Rifampicin is an inducer of cytochrome P 450 and P glycoprotein, so enhance the metabolism of IS drugs and decreases the doses of CNI, -TOR inhibitors and glucocorticoids. So the drug dose should be increased. 2- Adverse effect of the drugs:
– Hepatotoxicity (isoniazid, rifampicin, pyrazinamide, ethambutol): most common
– Neurotoxicity (isoniazid, ethambutol)
– Cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol),
– Visual disturbances (rifabutin, ethambutol)
– Skin lesions (rifampicin), hyperuricemia (pyrazinamide) or interstitial nephritis (rifampicin, pyrazinamide) 3- Drug adherence 4- Associated graft dysfunction require dose modification 5- Reduction of IS in severe cases Latent T.B
Indication of treatment:
– positive TST or IGRA test, a history of untreated TB, a history of recent contact with an active TB patient
– When the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active.
The preferred treatment of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6. Outcome:
1- Rejection:
Graft rejection in KT recipients with TB can reach up to 55.6%
2- Graft loss:
It varies from 2.2-66.6%
Causes: infection especially in donor-derived infection, impact of sepsis, acute and chronic rejection from reduction of IS.
3- Mortality:
The mortality of patients with TB after KT has been reported to range from0% to 60%
o TB is the thirteenth-most common cause of death and the leading infectious cause of death (excluding COVID-19) worldwide
o ~10 million cases of TB in 2020 worldwide with an incidence rate of 127 cases per 100,000 people per year (WHO)
o Active TB is higher in KT recipients than in the general population
o Reactivation of LTBI after KT is the most common form of transmission
Aim of this review: update of epidemiology, risk factors, pathophysiology, type of transmission, diagnostic challenges, treatment challenges and the impact of TB in KT recipients
Methods
Literature review of articles published between 2000-2022 to provide an evidence-based review of epidemiology, pathogenesis, diagnosis, treatment and outcomes of TB in KT recipients
Epidemiology of Tuberculosis
Epidemiology of Tuberculosis in SOT
o Prevalence of active TB in KT recipients ranges between 0.3–15.2% (0.3–6.4% in areas with low TB endemicity and up to 15.2% in high TB endemic areas)
o The incidence of active TB in SOT is 20–74 times higher than in the general population (26.6 times in a study from Spain)
Epidemiology of Tuberculosis in Kidney Transplantation
o The prevalence of active TB in KT recipients varies from 0.3%-15.2% (higher than in the general population but lower than in patients with lung transplantation)
Risk Factors for Tuberculosis in Kidney Transplantation
The risk is mainly influenced by endemicity of TB
Donor causes:
1. Donor type (cadaveric)
2. Social risk factors (homeless, incarceration, smoking, alcohol abuse, known TB contact)
3. Medical risk factors (diabetes, BMI<18, history of untreated TB)
Transplant-associated:
1. Immunosuppression
2. Acute rejection (increases the risk of TB by 7.6 times)
3. Chronic graft dysfunction
Others: TB burden
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients
After inhalation of mycobacterium tuberculosis (MBT) into the lungs, the fate could be:
1. Clearance of MBT by the organism either due to innate immune response or acquired T cell immunity
2. Development of primary disease with immediate onset of active disease (first 24 months after primary infection)
3. Latent infection with reactivation many years latter
Types of TB transmission in KT recipients:
1. Reactivation after KT of a latent infection (the most common and occurs in ~20% of cases within the first 2 years after)
2. Donor-derived infection (responsible for only 4.8% of cases)
3. De novo infection after KT (exposure in patient with active TB): it is not common, associated with very high risk of progression, and more frequent in endemic areas
Immunosuppression mechanisms increasing the risk of reactivation:
1. Depletion of all types of T cells
2. Decrease in activation and proliferation of T cells
3. Decrease in IL-2 synthesis
4. Decrease in the production of Th-1 type cytokines
5. Impairment of cellular immunity completely
Diagnostic challenges
Active Tuberculosis
Usually occurs in the first year after KT (a median time of 11.5 months) in the case of reactivation and earlier in the case of donor-derived infection (in the first 3 months)
Why diagnosis is challenging?
1. The diagnosis requires a high index of suspicion but KT recipients have atypical clinical presentations which reduce the clinical suspicion of TB
2. Probability of association with other co-infections
3. Extra pulmonary localization (in 50%)
4. TST and IGRA are not useful in the diagnosis of active TB
5. wide range of radiographic manifestations in pulmonary TB and the frequent need for invasive procedures
6. Molecular tests based on rapid nucleic acid amplification techniques could provide false negative results when mycobacterial load is low
Donor-derived TB:
Associated with severe extrapulmonary manifestations and mortality
Under-recognized with early onset after KT in the majority of cases
Suspected in KT recipients with one of the following features:
1. Non-specific symptoms
2. Frequent fever in the first 3 months after KT
3. Fluid collections
4. Extrapulmonary manifestations
5. Lack of response to empirical antibiotic therapy
Current guidelines recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors
Latent Tuberculosis
o Defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB (WHO)
o Prevalence after KT was reported in ~20% of recipients
o Current guidelines recommend screening for latent TB in all KT candidates and donors before transplantation
o IGRA has some advantages over TST in patients with ESRD
o IGRA tests have a good predictive potential for latent TB in KT recipient with negative TST (in another study it has sensitivity and cannot be used to exclude latent TB)
Treatment challenges
Active Tuberculosis
Duration of treatment is recommended to be at least 9–12 months
AST-IDCOP guidelines recommend:
1. active uncomplicated pulmonary TB (treatment duration should be at least 6 months)
2. if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy (9 months)
3. Severe disseminated disease or bone and joint disease (at least 6–9 months)
4. CNS involvement (at least 9–12 months)
AST-IDCOP guidelines treatment:
First-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases (2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-months of isoniazid and rifampicin)
ESCMID guidelines treatment:
A standard regimen used for a period longer than 6 months
In cases of localized non-severe TB, a regimen without rifampicin could be used if no resistance to isoniazid (the 2-month intensive phase contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid ande thambutol or pyrazinamide)
Challenge in the treatment of KT recipients:
o Rifampicin and transplant-associated immunosuppression interaction
o Rifampicin is a potent inducer of cytochrome P450 3A4 and P-glycoprotein
o Rifampicin decrease the levels of CNIs, mTOR inhibitors, and affects glucocorticoids
o CNIs and mTOR inhibitors levels should be closely monitored during rifampicin-based regimen
o The dose of CNIs and mTOR inhibitor should be increased between 3-5 folds and the glucocorticoid dose should be doubled during treatment
Rifabutin (alternative to rifampicin):
o Weaker inducer of cytochrome P450 3A4 and P-glycoprotein but with similar efficacy
o Immunosuppression doses could be modified, and levels should be closely monitored Fluoroquinolones: it is safe alternative to rifampicin
Another challenge is the adverse effects of TB therapy:
The most common adverse event is hepatotoxicity (liver enzymes should be closely monitored with bi-weekly evaluation during the intensive phase of treatment and monthly thereafter)
1. Hepatotoxicity (isoniazid, rifampicin, pyrazinamide, ethambutol)
2. Neurotoxicity (isoniazid, ethambutol)
3. Cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol)
4. Visual disturbances (rifabutin, ethambutol)
5. Skin lesions (rifampicin)
6. Hyperuricemia (pyrazinamide)
7. Interstitial nephritis (rifampicin, pyrazinamide)
Severe TB or when a vital organ is involved:
Reduce immunosuppression (risk of immune reconstitution inflammatory syndrome, which is associated with the reduction of immunosuppression and the use of rifampicin)
Latent Tuberculosis
Should be considered only after exclusion of active TB Treatment indicated in one of:
1. A positive TST or IGRA test
2. A history of untreated TB
3. A history of recent contact with an active TB patient
4. When the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB
In the KT recipients:
o The preferred treatment is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6
o Rifampicin is not recommended
o Ethambutol and levofloxacin or moxifloxacin is an alternative regimen mainly for those with high risk
o The main adverse event of isoniazid is hepatotoxicity (but the risk of liver damage seems to be reduced in KT patients)
o Evaluate for liver enzymes during treatment (initially bi-weekly for 6 weeks and monthly thereafter)
Outcomes Rejection
o Graft rejection in KT recipients with TB can occur in up to 55.6% (often associated with reduced levels of immunosuppression secondary to CNIs–rifampicin interaction and responsible for ~1/3 of graft losses
o Treatment of acute rejection before TB significantly increased the risk of graft loss 2.5 times
Graft Loss Causes of graft loss KT patients:
1. Directly due to infection (donor-derived TB)
2. Indirectly through the sepsis produced by TB
3. Acute or chronic rejection after minimization or withdrawal of immunosuppression or rifampicin-based regimen use
The prevalence of graft loss in KT patients with active TB varies from 2.2-66.6%
Mortality
o Mortality rate in SOT is 20%
o Mortality of patients with TB after KT range from 0%-60%
Conclusions
o TB in KT has a higher incidence and prevalence than in the general population and is associated with morbidity and mortality
o Diagnostic and treatment challenges of TB after KT should be recognized for an optimal management approach
o Donor-derived TB and latent TB in KT should be carefully evaluated
o Tests that are not based on T cell immunity could improve the diagnosis of latent TB in KT recipients
o New drugs with low drug–drug interactions and adverse effects could have an important contribution in the future management
What is the level of evidence provided by this article?
Level V (narrative review)
Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review
Summary
· TB in KT has an incidence of 0.3–15.2% and it represents a great cause of morbidity and mortality.
· It increased risk of acute allograft rejection rate up to 55.6%, graft loss 2.2% to 66.6% and a mortality rate up to 60%.
· Source of infection is either reactivation of latent infection either from the donor or recipient source, or denovo infection acquired after transplantation (due to immunosuppressed status after transplantation).
1. Reactivation of latent infection (recipient source) is the most common form in KT and other SOT, mostly presented with reactivation and active disease 2 years after transplantation.
2. Donor derived infection occurs only in 4.8 % of KT, characterized by early onset around 2-3 months post-transplant, rapid progressive course and mainly extra-pulmonary and atypical presentation.
3. denovo infection (due to exposure to open TB cases in high endemic area, rare but progressive course).
· Hence, TB screening is a must for both recipient and potential donors in every case.
· Diverse clinical presentation, atypical presentation and inaccurate screening tests represent a challenge to diagnose latent TB infection.
· Incidence of TB in kidney transplantation:
o Differs according to the geographical area (low or high endemicity of the disease).
o It is lower in kidney than heart and lung transplantation.
o it is higher in KT than in HD and PD patients.
· Additional risk factors for TB in KT as use of potent immunosuppressive drugs as depleting antibodies as ATG and use of belatacept and CNI, MMF and steroids as all impair T cell mediated immunity and increase risk of reactivation of latent TB. In addition, repeated episodes of rejection with their subsequent treatment and chronic graft dysfunction also increase risk of TB activation and progression from latent to active TB disease.
· older age recipient, male gender, smoking and presence of comorbidities as HCV, diabetes, other nosocomial infections as CMV and PCP all increase risk of TB reactivation.
· As regard donor related risk factors, deceased donor with drug and alcohol abuse, low BMI and low socioeconomic state all increase risk of donor derived TB.
· In all cases, pulmonary manifestations present in about half of KT cases.
· mode of transmission: air droplet.
· Natural history:
o 1ry disease (clinical presentation within 1 st year after infection)
o latent disease (organism remains dormant and become reactivated and symptoms of the disease appear after years from infection).
· Diagnosis of TB:
o High index of suspicion.
o Challenge is that difficult suspicion in case of extra-pulmonary and disseminated disease.
o Take care of epidemiological history and prior history of exposure.
o Specific bacteriological investigations:
§ Smear with special stain for acid fast bacilli (AFB) by ziel nelseen stain (ZN stain).
§ Culture on special L J (lowenstien Jenseen) media is more sensitive, but takes 4-6 weeks so rapid culture technique using BACTEC system is helpful (result within 10 days) , but obtaining sputum specimen may need invasive bronchoscopy and BAL to get it.
o Molecular tests based on rapid nucleic acid amplification techniques can give false negative results when low load of the organism.
o Tuberculin skin test and quantiferron or TB blood tests are negative in active TB cases (only useful in diagnosis of latent TB).
· DD-TB should be suspected in unexplained fever, in 1st 3 months post transplantation, with peri-graft collection and unresponsive to empirical antibiotics.
· Latent TB is defined as state of persistent immune response to MBT antigens with no evidence of any clinical manifestations of active TB.
· The problem is that latent tuberculosis is difficult to diagnose especially in deceased donor and contributes to DD TB in spite of careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors.
· The screening tests for latent TB (TST and IGRA) have very low sensitivity, so obtaining history of previous TB disease in donor or family is crucial, but sometimes it is difficult and unfeasible.
· IGRA may give false negative results in any case with depressed cell mediated immunity as severe head trauma and false positive if living in high endemic area.
· Screening for latent TB is essential in both kidney transplant potential and actual recipients. IGRA has better sensitivity than TST. It is essential to do screening and give prophylactic therapy to prevent progression to active TB disease.
· Treatment of active TB;
o Start immediately after diagnosis.
o Consider epidemiological criteria of the disease and drug resistant strains.
o Duration of therapy ranges from 6-24 months, at least 6 months,
§ If cavitary lesions exist or there is a persistent positive sputumculture after 2 months of therapy, the duration may be extended to 9 months.
§ In case of severe disseminated disease or bone and joint disease, treatment duration is recommended for at least 6–9 months.
§ Patients with CNS involvement should be treated for at least 9–12 months
· Regimen:
1. Rifampin containing regimen:
· Intensive therapyfor 2 months with 4 drugs (isoniazid, rifampicin, pyrazinamide and ethambutol) followed by continuation phaseof 2 drugs (isoniazid and rifampicin) for 4 months.
· Rifampin is enzyme inducer and lower trough level of CNI and mTORi so increase their dose 3-5 folds and double dose of steroids to avoid risk of rejection.
· After stoppage of rifampin, decrease dose according to the trough level is essential.
· Rifabutin is an alternative, less enzyme inducer but not well-studied in transplant cases. While fluoroquinolones are another safe and effective alternative in transplant cases.
2. Rifampin free regimen (2nd line regimen):
· Intensive phase of 2-month of 3 drugs (should contain isoniazid, ethambutol and pyrazinamide or levofloxacin), followed by a continuation phase of 12–18 months with 2 drugs (isoniazid and ethambutol or pyrazinamide). Longer period of treatment is recommend.
· Monitoring of adverse effects as hepatotoxicity and cytopenias in all drugs (isoniazid, rifampicin, pyrazinamide, ethambutol), neurotoxicity (isoniazid, ethambutol), visual disturbances (rifabutin, ethambutol), skin lesions (rifampicin), hyperuricemia (pyrazinamide) or interstitial nephritis (rifampicin, pyrazinamide).
· Hepatotoxicity is The most common adverse event associated with anti-TB therapy; therefore, liver enzymes should be closely monitored with bi-weekly evaluation during the intensive phase of treatment and monthly thereafter.
· Ensure adherence to treatment, and adjust doses according to EGFR.
· IRIS (immune reconstitution inflammatory syndrome) in anti tuberculous especially rifampin.
· Treatment of latent TB in KT recipients:
o Indications:
§ +ve TST or IGRA test
§ History of untreated TB, a history of recent contact with an active TB patient and when the kidney graft originates from a donor with known latent TB without chemoprophylaxis
§ known history of untreated TB or recent exposure to active TB.
· Regimen either INH alone for 9 months or combined (ethambutol and levofloxacin or moxifloxacin) in high risk recipinets. Level of evidence.
· Prognosis: TB increase risk of graft rejection, graft loss,also sepsis that can leads to loss of the graft and patient life. In addition, co-infections with fungi, CMV, nocardia, HCV and chronic liver disease increased risk of mortality.
· Future perspectives:
o New diagnostic modalities of latent TB not depending on cell mediated immunity that are impaired in such immunocompromised SOT recipients.
I like your detailed summary, level of evidence, analysis and conclusions. I appreciate your debate regarding the uncertainty of the value of IGRA in head trauma cadaveric donors.
Introduction
ESRD patients’ best therapy is kidney transplantation (KT) [1]. Nevertheless, post-KT infection limits transplant and patient outcomes. Tuberculosis (TB) is a major post-transplant infection [5]. It is the thirteenth-highest cause of mortality globally and the top infectious cause, excluding COVID-19.
Methods
A literature search on PubMed and Embase electronic databases was performed from 1 January 2000 to 15 June 2022. . All studies that provided epidemiological and/or outcome data regarding TB in KT were included.
Solid Organ Transplantation Tuberculosis Epidemiology
Active TB in solid organ transplant recipients varies by region. TB prevalence ranges from 0.3–6.4% in low-endemic regions to 15.2% in high-endemic areas. A 60-study systematic review and meta-analysis found 3% of solid organ transplant patients had active TB.
Kidney Transplant Tuberculosis Risk Factors
KT recipients are more likely to acquire TB. TB endemicity in the community and recipient, donor, and transplantation variables enhance risk. Immunosuppression medication, acute rejection episodes, and chronic graft dysfunction are important transplant-related risk factors. KT immunosuppression inhibits T-cell-mediated TB control and promotes latent infection reactivation. T-cell-depleting medications, cytotoxic T-lymphocyte-associated protein-4 inhibitors, calcineurin inhibitors, anti-metabolites, and glucocorticoids all enhance the risk of TB. Acute rejection increases TB risk 7.6 times. It was found that post-transplant rejections independently increase TB risk.
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients
-Active TB could arise after KT as a result of reactivation of the latent infection present in the recipient prior to transplantation.
-TB could be transmitted to KT recipients via kidney graft from an infected donor
-TB could occur as a de novo infection after KT, in a recipient with exposure to a patient with active TB
Diagnostic and Treatment Challenges
Active TB; Start soon after diagnosis.
Treatment lasts 6–24 months, but at least 9–12.
American Society of Transplantation IDCOP recommends 6 months for active uncomplicated pulmonary TB and 9 months for cavity lesion or persistent culture-positive after 2 months of treatment.
AST-IDCOP recommends a 4-drug regimen for first-line treatment: intense dosage for 2 months (Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol) and 4 months of Isoniazid and Rifampicin.
ESCMID; regular regiment greater than 6 months, and in localized non-severe TB, rifampicin-free regiment, so intense phase should contain (Iso, Eth, Pyr, or levofloxacin), followed by 12-18 months of Iso and Eth or Pyr.
Latent TB
It has to be treated to stop it from becoming active again.
If you have a positive TST or IGRA test, a history of untreated tuberculosis, a history of recent contact with an active TB patient, donor-derived latent TB in an infected graft, a history of untreated tuberculosis, or recent exposure to active tuberculosis, you may have tuberculosis.
INH combined with vitamin B6 is used to treat latent tuberculosis for a period of nine months.
Ethambutol with either levofloxacin or moxifloxacin is another treatment option for those at high risk.
Conclusions
TB is a common opportunistic infection in KT that negatively impacts graft and patient outcomes. Preventive strategies should be based on TB risk factors and KT results. For optimum therapy, doctors should know TB’s diagnostic and therapeutic problems following KT. Kidney transplant and infectious disease doctors must work together. Donor-derived TB and latent TB in KT are underdiagnosed and should be examined. In KT recipients, non-T cell immunity-based assays with good predictive values might enhance latent TB diagnosis. Novel regimens or pipeline medications may help reduce drug–drug interactions, therapeutic effectiveness, and side effects.
What is the level of evidence provided by this article?
I like your detailed summary, level of evidence, analysis and conclusions. I appreciate your debate regarding the uncertainty on optimal duration of therapy.
Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review
7 August 2022
***Summary****
TB is more prevalent in kidney transplant than the general population but less common post lung Tx.
Risk factors are nicely written in the diagram from donor to recipient specific to the immunosuppression state.
Natural history of infection: After the aerosol droplets containing mycobacterium tuberculosis (MBT) are inhaled into the lungs
clearance of MBT by the organism either due to innate immune response or acquired T cell immunity
development of primary disease which means an immediate onset of active disease (first 24 months after primary infection)
latent infection reactivation meaning a late onset of active disease many years following primary infection
Kidney Tx can got infected either by
Activation of latent infection (onset around 1 year post Tx)
De novo infection
Donner derived infection (first three month post Tx)
****Active infection: Diagnosis: It is challenging due to a wide range of radiographic manifestations and need for invasive procedures. Molecular tests like (Xpert® MTB/RIF, Cepheid) could provide false negative results when mycobacterial load is low Donor-derived TB should be suspected in KT recipients: non-specific symptoms, frequent fever in the first 3 months after KT, fluid collections, extrapulmonary manifestations or lack of response to empirical antibiotic therapy
Treatment Treatment of KT recipients with TB could be challenging due to drug–drug interactions, drug toxicity and treatment adherence.
American Society of Transplantation Infectious Diseases Community of Practice (AST-IDCOP) guidelines recommends: 2-month intensive phase of RIPE (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol) followed by a 4-month continuation phase of RI.
Duration varies:
active uncomplicated pulmonary TB, treatment duration should be at least 6 months,
If cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months.
In case of severe disseminated disease or bone and joint disease, treatment duration is recommended for at least 6–9 months.
Patients with central nervous system involvement should be treated for at least 9–12 months
European Society of Clinical Microbiology and Infectious Diseases (ESCMID) suggests a standard regimen used for a period longer than 6 months, and, in cases of localised non-severe TB, a regimen without rifampicin. Two month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide.
***Latent infection: Diagnosis latent TB infection is defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB. The epidemiology and survey of latent TB after KT remain scarce. Prevalence of latent TB after KT was reported in ~20% of recipients.
Treatment: It is Considered if; +ve TST, or IGRA test, a history of untreatd TB, history of recent contact, or donated kidney from donor with latent TB, untreated TB or recent exposure.
Isoniazide for 9 months with vitB6.
High risk: Ethambutol and Levo or Moxifloxacin.
A regimen based on rifampicin is not recommended
Rejection: can reach up to 50 % of cases and caused by reduced levels of immunosuppression secondary to CNI–rifampicin interaction and could be responsible for ~1/3 of graft losses.
I like your detailed summary, level of evidence, analysis and conclusions. I appreciate your debate regarding the uncertainty on optimal duration of therapy.
Rather than “Kidney Tx can got infected either by…”, you should type “Kidney Transplant recipient can got infected either by…”
This is an article that review many articles published between 1 January 2000 and 15 June 2022 regarding epidemiology, pathogenesis, diagnosis, treatment and outcomes of active TB in kidney transplant recipients
The prevalence of active TB is significantly higher than general population; around 20-74 times higher than general population. It differ according to geographic area, it ranges from 0.3–6.4%, in developed countries and in up to 15% in endemic regions
Mode of transmission
Activation of latent TB (the most common)
Acquiring the disease from the graft (donor drived)
Acquiring new infection through air born transmission (not common, assoxiated with aggressive disease and is more commonly seen in endemic areas)
Risk factors for TB in Kidney Transplantation
Recipient related
Older age
Male gender
Smoking
Comorbidities including DM, COPD, chronic liver disease, malnutrition
HCV infection and opportunistic co-infection such as CMV, PCJ and nocardia
Prolonged hemodialysis before renal transplantation
Latent TB before transplantation
Use of aggressive immunosuppressive therapy
Acute rejection (increase the risk of TB 7.6 times) and chronic allograft dysfunction
Donor related
Deceased donor transplantation
Social risk factors including homeless patients, smoking, alcohol abuse and contact to TB case
Medical risk factors including the presence of DM, history of previous TB or underweight
Community related factors
TB burden in the community
Pathogenesis and natural history of TB in kidney transplant recipients
After inhalation of the organism, the patient deal in one of 3 ways : Complete clearance of the organism, primary disease (active TB) or latent TB which may be reactivated later on
Recipients with latent TB are at high risk of conversion to active TB after transplantation, it was estimated that around 1/5th of patients with latent TB develop active disease 2 years after transplantation
On the other hand, If the donor has latent TB and did not receive treatment it carry a risk of transmission to the recipient and if that happen the recipient should be treated for latent TB before possible progression to active disease
So all recipients and donors should both be undergo careful evaluation of the risk, history, examination and CXR, together with test for latent TB
Diagnosis of latent TB
Latent TB is estimated to involve 20% of transplant recipients
In general, all transplant recipients and donors should be evaluated for the presence of latent TB and once detected treatment should be recived
2 test are used to detect latent TB, tuberculin skin test (TST) and IGRA, both are usually negative in immunosuppressed patients due to their dependence on the host immune response which is impaired in these sets of patients
Which test to use?
In SOT candidates with ESRD, it is preferred to use IGRA over TST due to its higher sensitivity in these sets of patients
In SOT candidates without ESRD, either TST or IGRA can be used.
Patients who have received BCG vaccination in early life can have false positive TST, so they should be evaluated by IGRA
If TST is negative it is better to do IGRA if the patient is living in country with high TB prevalence or if the patient has TB risk factors.
Indications of treatment of latent TB in transplant recipient and donor
Positive TST or a positive IGRA
History of positive TST or pervious history of TB
Negative TST and/or IGRA in a patient with close contact to an active TB case
If the donor has latent TB and did not receive treatment (treat the recipient), but if the donor received treatment there is no need to treat the recipient
Protocol for treatment of latent TB
INH in a dose of 5 mg/kg (maximum dose 300 mg) together with oral pyridoxine 25 to 50 mg daily for 9 months.(The preferred regimen)
Patient should be monitored for liver enzymes and bilirubin at baseline then monthly
Rifampicin containing regimen are not preferred after renal transplantation due to severeal drug drug interactions
Timing of active TB after transplantation
Most of cases occur at a median of 11.5 months after tranplantation. Donor-derived TB usually occur earlier within the first 3 months
The diagnosis is challenging (needs high index of suspicion) due to the following
Atypical clinical presentation is more common in immunocompromsied compared to immunocompetent patients
The presence of co-infections which may delay the diagnosis
Around 50% of cases presents with extra pulmonary or disseminated TB (much higher than immunocompetent hosts)
Tuberculin test and IGRA are usually negative
Sputum smear for TB is usually negative despite active TB.
PCR from specimen can be falsely negative if the TB load is low
It is uncommon for the transplant recipients to have the classic picture of TB
To reach diagnosis invasive procedure is usually required including bronchoscopy and BAL or lung biopsy
The treatment of TB in SOT is challenging due to the following
Drug-drug interaction between rifampicin (the cornstone of TB treatment) and immunosuppressive medications used in transplantation
Loss of host immune response to TB due to the use of immunosuppressive drugs
Toxicity of anti-TB medications including hepatotoxicity (the most common side efcect) and cytopenia (isoniazid, rifampicin,pyrazinamide, ethambutol), neurotoxicity (isoniazid, ethambutol), visual disturbances (rifabutin, ethambutol), skin lesions (rifampicin), hyperuricemia (pyrazinamide) and interstitial nephritis (rifampicin,pyrazinamide)
Adherence to the treatment may be a problem in multi-medicated patients like transplant recipients
Protocols used in treatment of TB
I- Rifampicin containing regimen
Regimen A– 4-drug regimen of Rifampicin+ INH+ ethambutol + pyrazinamide for 2 months, followed by a 2-drug regimen of Rifampicin + INH for 4 months
It is recommended to increase the duration of treatment to at least 9-12 months if one of the following is present
Disseminated disease
Cavitary disease with positive sputum culture after 2 months of treatment
Bone and joint disease
CNS disease.
Some recommends extending the duration of treatment to 9-12 months in all SOT recipients since there is improvement in the mortality when using extended duration
II- Rifampicin free regimen
Regimen A – 3-drug regimen of INH+ ethambutol + pyrazinamide or levofloxacin are used for 2 months, followed by a 2-drug regimen of INH + either ethambutol or pyrazinamide for 12 to 18 months
Regimen B – 3 drugs (INH+ ethambutol + pyrazinamide or levofloxacin are used for 12 months
Regimen C – Rifabutiun can be used instead of rifampicin due to its lesser effect on cytochrome p450, so minimal drug-drug interactions but experience is little when using this drug in transplantation, although it seems effective in HIV TB patients.
It is strongly recommended to use Rifampicin containing regimen especially in patients with severe (cavitary or multilobar) or disseminated disease or if there is an evidence of INH resistance.
In non-severe cases with no evidence of INH resistance, Rifampicin is usually avoided due to its intense drug-drug interactions with immunosuppressive drug (Induction of CYP3A4) with subsequent increase in the risk of rejections so it is better to use rifampicin free protocols
Once rifampin is used, it is recommended to increase the dose of CNI or rapamycin 3-5 folds, with close follow up of serum level and corticosteroid dose should be doubled.
In SOT it is recommended to save Rifampicin for severe and resistant cases , and avoid streptomycin due to its nephrotoxicity
Avoid extreme reduction of the immunosuppressive agents to decrease the possibility of anti-tuberculous therapy – induced immune reconstitution inflammatory syndrome (IRIS). So mild to moderate reduction is advised
Prognosis
Up to half of the renal transplant recipients with active TB may develop rejection
Graft loss occur in 2.2% to 66.6%
Mortality occur in up to 60 % of patients
What is the level of evidence provided by this article?
I like your detailed summary, level of evidence, analysis and conclusions. I appreciate your debate regarding the uncertainty on optimal duration of therapy
Mycobacterium Tuberculosis following kidney transplantation Summary of the Article Introduction Post-transplant infection is a risk for graft loss and affects recipient survival. TB infection is highest among transplant recipient as they receive immunosuppressants medications. Source of TB infection post-trasnplantation
Recipients (reactivation of latent infection)
Donor tissues (reactivation of latent infection)
DeNovo infection
A screening strategy and protocols to prevent occurence of reactivation of latent or active disease is to be applied. Challenges
Limitation of screening, and diagnpsis.
Drug interaction and toxicity.
Balanced immunosuppressant reduction in sever disease vs graft survivals.
Delay diagnosis and management may results in graft and recipient life loss.
Epimeilogy of TB in SOT;
Varies from 0.3 to 6.4% in low endemicity area upto 15.2% in endemic areas.
Incidence is 20-74 higher among solid transplat recipients compared to general population.
Study done in 16 centers in Spain found taht prevalence of TB post-transplant was 26.6 times higher in transplant recipients compared to genearl population.
Another study found taht the incidence was about 8.5 times higher.
Epedimiology of TB in kidney transplantation
The prevalence varies from 0.3% to 15.2%, higher than in general population and lower than lung transplant consition.
Basiri et al; 0.3%.
Vandermarliere et al; 0.4%.
Klote et al; 0.4%.
Naqvi et al; 15.2%, in Pakistan an endemic country.
Alemu et al; 340 per 100,000 in low endemicity countries, while 14,680 pert 100,000 in high endemicity countries, and the incidence in kidney Tx compared to ESKD on no dialysis was (2700 vs 913 respectively), and lower in Tx than in PD and HD patients (2700 vs 3533 vs 5611respectively).
Social (homeless, incarceration, smoking, alcoholic, and exposure)
Medical risk factors; (DM, BMI<18.5 kg/m2, and history of untreated TB).
3.Transplan associated;
Immunosuppressants.
Acute rejection.
Chronic graft dysfunction.
4.Others;
TB burden of the country.
Transmission and pathogenesis;
Recipient latent infection == TB reactivation post tansplan.
Infected grafted kidney == DD-TB.
De novo TB infection.
Diagnostic challenges;
Active TB;
Diagnosis based on high suspicion, epidemiology, clinical manifestation, and imaging, but atypical presenatation may decrease the clinical suspicoin.
Co-infction and extarpulmonary TB added some challenges.
TST and IFGRA are not usefull in the diagnosis of active TB.
Wide range of pulmonary TB radiograph.
Invasive proceudure needed for diagnosis.
Molecular tests may give rise a false negative results when th mycobacterium laod is low.
2.DD-TB;
Associated with sever extrapulmonary TB.
Unrecognised in the majority of patients so suspicion shpuld be raised when; non-specific symptoms, frequent fever in the first 3 months folowwing transplantation, fluid collection, extrapulmonary manifestation, and lack of response to protocol antibiotics.
All donors should underwent; epidemiological risk, personal history, physical exam., and radiograph.
In deceased donation, history from the family should be obtained.
3.Latent TB;
Prevalence was reported to be about 20%,
Screening should be performed in all recipients and donors candidate for transplantation.
Kim et al; show that IGRA have a good prediction for latent TB in KT recipients with negative TST.
Another study; Hadaya et al; IGRA cannot be used for exclusion for latent infection post KT because of low sensitivity.
Treatment challenges;
Active TB;
Should be started immediately after diagnosis.
Period of traetment range from 6 to 24 months, but recommended to be at least 9-12 months.
American Society of Transplantation IDCOP; recommend 6 month for active uncomplicated pulmonary TB, and 9 month for cavity lesion or persistant culture positive after 2 month of therapy.
AST-IDCOP recommend first line treatment should be 4 drugs regiment; intensive dose for 2 months (Rifampicin, Isoniazide, Pyrazinamide and ethambutol), and 4 month contiuation phaseof isoniazide and rifampicin.
ESCMID; standard regiment more than 6 months, and in localized non-sever TB, rifamocicn free regiment , so intensive phase should include (Iso, Eth, Pyr, or levofloxacin , followed by a continuation phase of 12-18 months with Iso and Eth or Pyr.
2.Latent TB;
Considered after exclusion of active TB.
Considered if; +ve TST, or IGRA test, a history of untreatd TB, history of recent contact, or donated kidney from donor with latent TB, untreated TB or recent exposure.
Isoniazide 5mg/kg/D, for 9 months with supplement vitB6.
Alternative regiment consist of ethambutol and levo or moxifloxacin.
Drug interaction and side effects;
Rifampicin; potent cytochrome P450 inducer, so decrease the level of CNIs, mTORi, and affect glococorticoids, hence the risk of rejection, drug level monitoring is mandatory with optomising the immunosuppressants doses.
Iso, Rif, Pyr, and Eth. == hepatotoxicity, and cytopenia.
Iso and Eth.== neurotoxicity.
Rif. and Eth. == visual disturbance.
Rif. == skin lesion.
Pyr. == hyperuricemia.
Rif. and Pyr. == interstitial nephritis.
Outcomes;
Rejection;
Upto 55% aossicaiated with immunosuppressants reduced level in rifampicin regiment.
Graft loss;
Related to infection, or indirectly to sepsis, rejection.
Mortality;
Range from 0-60% by many studies. Conclusion
TB is an important opportuinistic infection.
Associtaed with significat rate of graft and recipient death.
Recommeneded routine specicfic test and imaging for recipients and donors should be done.
High clinical suspicion for suspected cases should be ensure.
DD-TB is a risk after KT and considering the false -ve results and low sensitivity tests on diagnosing the disease.
Duration and type of treatment should be based on disease grades.
Drud interaction and side effects should be monitored and assessed
This is a narrative review study, whose level of evidence is V, on tuberculosis after kidney transplantation.
Introduction
The consequences of renal transplantation of a late diagnosis of tuberculosis in the context of this patient’s immunosuppression lead to a significant increase in graft loss and death. Treatment, prophylaxis and its context in the interaction with immunosuppressants.
Methods
Studies from January 2000 to June 2022
Epidemiology
The incidence varies depending on the geographic area. with an increased risk of disease when compared to patients in the general population.
Risk factors such as immunosuppression, graft dysfunction, use of antimetabolites, and T-cell depleting drugs.
Donor
– corpse
– Homeless
– Deprived of liberty
– Smoker
– alcohol abuse
– Contact with tuberculosis
– Malnourished, diabetes, abandonment of TB treatment
Associated with transplantation
– Immunosuppression
– acute rejection
– Chronic graft dysfunction
– Prevalence of tuberculosis in the country
Brazil, Turkey, and India are the countries with the highest prevalence, both due to their sociocultural aspects and also limitations in diagnosis, leading to late treatment (either due to inadequate screening or diagnosis when there is disseminated disease). Another form of transmission is contact with a patient infected by the mycobacteria and the patient in the context of immunosuppression.
Diagnosis
TST and IGRA do not seem to be suitable for diagnosis. The Xpert gene can help in the pre-emptive diagnosis, but the culture is the gold standard, however, limited by the delay in making the test positive.
The risk of reactivating latent TB is extremely high in this group of patients and adequate chemoprophylaxis should be carried out.
Treatment in immunosuppressed patients can be extended from 9 to 24 months depending on the immunosuppression and the extent of the disease.
The lack of exams to control the disease and the classic scheme with high drug interaction, mainly Rifampicin. It is necessary to replace this scheme with Rifabutin and to measure serum levels of immunosuppressants.
Outcomes
HR 2.5 rejection, graft loss, and mortality are higher in this group. The risk of death is 20%.
Conclusions
Tuberculosis has a high incidence and prevalence, especially in developing countries. The lack of adequate tests for screening and diagnosis increases the risk of the disease being reactivated or passed on by the donor.
New treatment regimens that minimize drug interactions may help improve efficacy and reduce adverse effects.
Yes, in general, we use 19th-century diagnosis methods
Baciloscopy with Koch and Leweenhok at 1870
Skin tests with CG in early 1900
X rays with Roentgen at 1896
We need PCR and molecular methods with good sensibility and specificity
For an endemic country, the challenge is even higher, because exposure is very common.
Introduction
TB is the thirteenth-most common cause of death and the leading infectious cause of death, apart from coronavirus disease 2019 (COVID-19) all over the world.
Kidney transplant (KT) recipients are at risk of developing TB due to immunocompromising status and due to donor recipient risk factors.
Active TB in KT can occur either due to reactivation of latent infection which is the most common forum or due to denovo infection
Current guidelines recommend that screening for the donor and the recipient is mandatory.
In fact diagnosing and treating TB is challenging in those group of patients .
This review covers multiple updated aspects of TB for KT recipients Methods
A literature review of articles published nearly within the last 22 years was done to provide an evidence-based review of epidemiology, pathogenesis, diagnosis, treatment and outcomes of TB in KT recipients according to latest guidelines. Epidemiology and Risk Factors for TB in KT
Active TB prevalence in SOT is variable according to geographical area.
A recent metanalysis revealed that it’s pooled prevalence could be 3%
Incidence of active TB in SOT is 20–74 times higher than in general population
Prevalence of active TB in KT recipients ranges 0.3% -15.2% but it is higher compared to the general population and lower than in lung transplantation recipients.
Another study showed that the pooled incidence of active TB in KT recipients was higher than in ESRD in pre-dialysis but lower than in those on peritoneal dialysis and hemodialysis.
Risk factors for TB development in KT recipients are related to endemicity ,donor ,recipient and transplantation factors.
Transplantation risk factors include immunosuppressive therapy, acute rejection attacks and chronic graft dysfunction.
Donor factors involve medical risk factors, his type and social risk factors.
Recipient factors include age ,gender ,age ,COPD ,and DM Transmission and Pathogenesis of TB in KT Recipients
It occurs through aerosol droplet infection, then mycobacterium T cell is manged by either innate immunity or acquired T cell immunity leading to either active disease occurrence or reactivation .
In KT transmission occurs due to either reactivation of latent infection in the recipient that was already present before transplantation which is a common scenario, therefore post-transplantation latent infection assessment is needed with pre-transplant screening .
Or it can be transmitted through an infected renal graft from the donor.
Or another method common in endemic area is de novo infection of the recipient after transplantation due to exposure to activeTB case.
T helper 1 response is the main response in front of TB infection and immunosuppressive therapy disrupts T cell and cellular mediated immunity response. Diagnostic and treatment challenges
Active TB usually occur in the first year post transplant.
TB diagnosis needs high suspicion index because the clinical picture and diagnosis are diverse.
As Tuberculin skin test (TST) and interferon gamma release assay (IGRA) are not conclusive for active TB diagnosis also radiological findings in pulmonary TB is variable necessitating invasive procedures also molecular tests have false negative results .
Donor derived TB infection has an early onset post transplant leading to extrapulmonary manifestations and high mortality rate.
Detecting latent or undiagnosed active TB in the donor is challenging but crucial.
Current recommendations include evaluation of the epidemiological risk, personal
medical history, physical exam and chest radiography in all donors but for deceased donor it is difficult therefore extra care need to be done to take history from the deceased donor’s family and If IGRA test was done need to be followed and raise suspicion for further evaluation .
Prevalence of latent TB after KT recipients is 20% .
There is no gold standard test for latent TB but IGRA test have a good predictive potential for latent TB in KT recipient with negative TST on the other hand it has a low sensitivity in KT recipients and cannot be used to exclude latent TB.
KT recipients are more liable to reactivation of latent TB more than KT candidates so more frequent screening is needed in the KT recipients. Treatment
Drug–drug interactions, drug toxicity and treatment adherence render therapy difficult. Active TB treatment
Diagnosing active TB in KT recipients necessitate immediate treatment considering epidemiological and drug resistance aspects.
The optimum treatment period ranges 6-24 months according to case severity if uncomplicated 6 months is recommended but in CNS affection at least 9-12 months are adviced.
4drug regimen including rifamycin is the main treatment used both in severe and non severe cases.
2-month isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation of isoniazid and rifampicin.
There is interaction between rifampicin as enzyme inducer and immunosuppressives therefore m TORI , CNI and glucocorticoids doses need to be increased and after finishing rifampicin course the immunosuppressives dose have to be reduced and adjusted to avoid the risk of rejection and graft loss.
Rifabutin and fluoroqiunolones are alternatives to rifampicin.
If second line treatment is used long treatment duration will be needed.
Another aspect is the anti TB drugs side effects including hepatotoxicity therefore monitoring liver functions is mandatory, neurotoxicity, cytopenia and visual disturbances .
Anti TB drug therapy adherence is challenging.
In case of severe TB immunosuppression need to be reduced. Latent TB
It has to be treated to prevent reactivation.
Positive TST or IGRA test, history of untreated TB, history of recent contact with active TB patient ,donor derived latent TB in infected graft,history of untreated TB or recent exposure to active TB.
Latent TB is treated by INH with vitamin B6 for 9months
Another regimen for high risk is ethambutol and levofloxacin or moxifloxacin Outcomes Graft rejection
Graft rejection in KT recipients having TB can reach 55.6% due to decreased levels of immunosuppression because of CNI–rifampicin interaction leading to graft loss. Graft Loss
Due to donor-derived TB or indirectly through sepsis caused by acute or chronic rejection
It’s prevalence with active TB ranges from 2.2% to 66.6%
A study demonstrated that severe TB disease, AKI stage 2 or 3, acute rejection and value of serum creatinine were risk factors leading to graft loss. Mortality
Mamishi et al. showed that mortality rate in SOT recipients was 20% .
Another study published that active TB after 2 years post-KT is an independent risk
factor for mortality Conclusion
KT recipients are at high risk of developing TB compared to general population leading to graft loss and mortality ,therefore preventive measures should be applied and early detection and treatment will be crucial.
I think following up the results and maintaining direct communication methods between institutes where diagnostic tests are done and transplant centers are essential
Kidney transplantation is the best treatment option for ESRD patients. But it associated with several complications.
Infection is one of the most important post transplant complication, & TB infection is the 13th common cause of death worldwide(excluding COVID-19).
Active TB prevalence is higher in KTR than general population.
Careful screening of donor & recipient is essential for limiting or prevent post transplant active TB.
Delayed diagnosis of TB associated with increased risk of rejection, graft loss & increase mortality.
Aim of the study:
Provide evidence-based update of epidemiology, risk factor, pathophysiologyof transmission, diagnostic challenge, treatment challenge & impact of TB infection in KTR.
Method:
Literature search performed from 1Jan,2000 -15 June 2022.
Included studies should include epidemiology of TB & outcome of KTR.
Excluded articles: studies in language other than English, studies include other organ transplant other than kidney only & studies with inadequate information.
Epidemiology of TB in SOT:
Prevalence depend on endemicity e.g. in low TB endemicity prevalence 0.3-6.4, in endemic area the prevalence can reach 15.2%.
Incidence of active TB is 20-74 times higher than general population.
Epidemiology of TB in kidney transplantation:
Prevalence 0.3-15.2% which is higher than general population, but lower than lung transplant.
Incidence 2700/100000person /year.
Risk factors of TB:
Recipient-associated factors: old age, male gender, smoking, malnutrition, DM, COPD, pre-transplant LTB, CLD, HCV infection, opportunistic co-infection(CMV, PJ), autoimmune disease & long term HD.
Donor-associated factors: donor type(cadaveric), social risk factor( e.g. homeless, alcohol abuse, smoking), & medical risk factors(e.g. DM, low BMI <18.5 & history of untreated TB).
After inhalation of aerosol droplets containing MTB it may be:
Clearance MBT by innate immunity response or acquired T cell immunity.
Development of primary disease
Latent infection: late onset reactivation by many years of primary infection.
Post-transplant transmission route:
Reactivation of pre-transplant LTB. It is the most common route in all SOT recipients. Risk factors include absence of CG scar, old age, presence of DSA.
Organ-derived transmission (4.8% of cases).
De novo TB infection after exposure to infected person, uncommon route of transmission & associated with very high risk of progression.
Immunosuppression can increase risk of LTB reactivation by several mechanisms:
depletion of all types of T cells.
reduce in activation & proliferation of T cells.
reduce in IL-2 synthesis.
reduce production of Th-1 type cytokines.
impairment of cellular immunity.
Challenges of active TB diagnosis:
Atypical presentation, diverse manifestations, presence of co-infection & extra pulmonary disease.
TST & IGRA test are non useful in diagnosis.
Wide-range radiological features of pulmonary TB & need for invasive procedure.
Molecular tests can be false negative due to low mycobacterial load.
Donor derived TB should be suspected if there was non specific symptoms, frequent fever in first 3 months post transplantation, fluid collection, extra-pulmonary manifestation or absence of response to empirical antibacterials.
Current guidelines recommend careful evaluation of epidemiological risk, personal medical history, physical examination & CXR.
In deceased donor, careful history from family or relative about history of TB infection or treatment in last 2 years in addition to IGRA test if available.
Diagnosis of latent TB infection:
WHO define latent TB as a state of persistent immune response to stimulation by MBT antigen without clinical manifestation of active TB.
LTB present in 20% of KTR.
No gold standard test to confirm diagnosis of LTB in KT candidates, but IGRA test has some advantage on TST in patients with ESRD.
Treatment of active TB:
Treatment duration vary from 6-24 months.
AST-IDCOP guidelines recommend treatment of uncomplicated active TB for 6 months, presence of cavity or persistent culture +ve sputum after 2 months extend treatment to 9 months, severe dissemination disease or bone or joint disease treatment for 6-9 months, & CNS involvement need treatment for at least 9 months.
First line treatment is 4 drug regime containing rifamycin in severe & non severe cases.
If second line drugs used, longer period of treatment is recommended.
Rifampicin is a potent inducer of cytochrome P4503A4 so it can reduce level of CNI & mTOR-I & affect steroid metabolism which increase risk of rejection.
The dose of CNI & mTOR-I should be increased 3-5 folds with doubling of steroid dose to achieve therapeutic target.
Rifabutin is a weak cytochrome inducer with similar efficacy to rifampicin.
Flouroquinolones is safe & effective alternative to rifampicin in KTR.
Which kind of recipients would you keep on INH prophylaxis for 6 months after renal transplant? I like your summary, level of evidence, analysis and take home messages.
Introduction Kidney transplantation (KT)remains the optimal treatment for patients with end stage renal disease. Infection after KT is still an important limitation for graft and patient outcomes. One of the most common infections with negative impact post-transplantation is tuberculosis (TB). It is considered the thirteenth-most common cause of death and the leading infectious cause of death, excluding coronavirus disease 2019 (COVID-19), worldwide. As KT is associated with an immunosuppression status, active TB is higher in KT recipients than in the general papulation. Active TB after KT could arise from reactivation of latent infection in the recipient or donor tissue or can result from de novo infection after transplantation. In order to limit or prevent the occurrence of active TB post-KT, it is necessary
Objectives This review aimed to provide an evidence-based update regarding epidemiology, risk factors pathophysiology, type of transmission, diagnostic challenges, treatment challenges and the impact of TB in KT recipients
Methods A literature search on PubMed and Embase electronic databases was performed from 1 January 2000 to 15 June 2022. We used a combination of the following words: “tunerculosis “mycobacterium tuberculosis “kidney transplant”, “prevalence”, “incidence”, “frequency”, “graft”, “loss”, “failure”, “rejection”, “survival”, “mortality”, “death”, “donorderived” and “latent”. All studies that provided epidemiological and/or outcomes data regarding TB inKT were included. Articles in languages other than English, articles that evaluated other types of transplantation than kidney only and articles with inadequate information were excluded. All articles were analyzed by two reviewers for inclusion/exclusion criteria, and the process was checked by a third reviewer. Epidemiology and risk factors for tuberculosis in kidney transplantation.
Findings In areas with low TB endemicity, the prevalence varies between 0.3–6.4%, compared to prevalence of TB in high, endemic areas which could rise to 15.2%. The pooled prevalence of active TB after KT was analyzed in two systematic reviews and meta-analyses, and the results were relatively similar: 2.51% and 3%. In another meta-analysis, Al-Efraiji et al found an unadjusted TB risk ratio of 11.36 times higher in KT recipients, compared to the general papulation and an adjusted risk ratio for patients on dialysis of 3.62 times higher than those from the general papulation. In a recent meta-analysis, Alemu et al reported that patients with KT had a pooled incidence of active TB of 2700 per 100,000 patient-years, which ranged from 340 per 100,000 patient-years in low TB burden countries to 14,680 per 100,000 patientyears in countries with high endemicity. Viana et al showed that treatment of acute rejection before TB significantly increased the risk of graft loss 2.5 times (HR = 2.51, 95%CI: 1.17–5.39, p = 0.01). An increased rate of mortality (50%) was reported in a cohort of 545 KTrecipients from Mexico
conclusion TB in KT is an important opportunistic infection with higher incidence and prevalence than in the general papulation and is associated with significant negative graft and patient outcomes. Pinpointing the risk factors for both TB development and negative outcomes after KT should be the basis for successful implementation of preventive measures. Clinicians should recognize the diagnostic and treatment challenges of TB after KT for an optimal management approach. This requires close collaboration between kidney transplant and infectious disease physicians. Development of tests with helpful predictive values, which are not based on T cell immunity, could bring important improvement in the diagnosis of latent TB inKT recipients. Discovered regimens or pipeline drugs could have an important contribution in the future limitation of drug–drug interactions, improvement of treatment efficacy and reduction of adverse events
Do you think you would like to use a test or battery of tests with good likelihood ratio, rather than those with high predictive value, of diagnosing TB in an immuno-suppresed patients?
The most typical recommendation for LTBI screening in immunosuppressed people included a combination of TST and/or IGRA tests, chest X-ray, full background history (including prior exposure to people with TB), and risk factor assessment (travel or migration from endemic areas).
The available and affordable test options affected the suggested selection of screening modalities and their frequency.The TST is reasonably priced and widely accessible.
TST and IGRA were recommended for screening in guidelines for medical immunosuppression, although there were significant differences between the two.
Screening and prevention for latent tuberculosis in immunosuppressed patients at risk for tuberculosis: a systematic review of clinical practice guidelines Tasnim Hasan,1 Eric Au,2 Sharon Chen,1,3 Allison Tong,4,5 and Germaine Wong2,5
Introduction
Pulmonary tuberculosis (TB) is considered one of the most important serious infections after kidney transplantation (KT) and is associated with increased frequency compared to the general population and carries a high risk of morbidity and mortality. The prevalence of active TB after KTX was in the range of 0.5-15.2 %, with an increased risk of rejection up to 55% and risk of graft loss in the range of 2.2-66%, with a high risk of death up to 60%. many challenges should be taken into consideration while treating active TB in immunocompromised patients like kidney transplant recipients the diagnostic challenges, atypical presentations co-infections with reduced prognostic values of some laboratory tests, and a variety of radiological findings, which can delay the diagnosis and management, also challenges regarding the interaction of the drug with immunosuppression and drug intolerance, toxicity, and non-adherence, all these factors should be taken into consideration while dealing with active TB infection after KTX. This study reviewed in depth the diagnostic and management challenges of active TB after kidney transplantation through an extensive review of the available epidemiological and interventional statistics from different studies between 2000-2022. The aim of the study is to keep us informed with the best available evidence regarding the epidemiology, diagnosis, and management challenges of this devastating opportunistic infection post-KTX. The source of Active TB post-KT, risk factors
1. Donor source, reactivation of latent TB from donor tissues
2. Recipient source (latent TB reactivation) with IS
3. Denovo infection
4. Endogenous reactivation (most common form)
The best preventive strategy is to screen both donor and recipient as per current guidelines especially those from an endemic area
Methods
They review all studies that address the epidemiology or intervention outcome by reviewing the database from Embase and MEDLINE with search keywords including epidemiology, prevalence, incidence, diagnosis, and intervention by reviewing the electronic data by two reviewers, they exclude articles with inadequate information over 22years (2000-2022. Epidemiology and Risk Factors for Tuberculosis in Kidney Transplantation
The overall prevalence of active TB post-transplantation is higher compared to the general population and the prevalence is quite variable based on geographical distribution with a higher rate of infection in the endemic area. In a recent meta-analysis, Alemu et al. reported that patients with KT had a collective
incidence of active TB of 2700 (95% CI: 1878–3522) per 100,000 patient-years, which ranged from 340 per 100,000 patient-years in low TB burden countries to 14,680 per 100,000 patient-years in countries with high endemicity. The table1 summarizes all the studies between 2000-2022 which show diverse results in the prevalence of TB based on geographical distribution, more extrapulmonary TB was reported from donor-derived Its associated with severe extrapulmonary manifestations and mortality in India, Egypt, Turkey, and Brazil with even longer time for the diagnosis in the range between 40-60 months ( this can be explained by the extrapulmonary or atypical presentation c compared to pulmonary TB which can be diagnosed even earlier 6 months or even less, some reports missing data about death as an outcome and the mortality also varies.
Active TB is higher in PKTX compared to hemodialysis or PD patients, but a lower incidence is reported in KTX recipients compared to lung transplantation recipients.
Risk Factors for Tuberculosis in Kidney Transplantation Recipient factors
Age (older)
Gender (male)
Comorbid (DM, Liver disease, COPD, malnutrition)
Chronic HCV infection
Smoking history
Reactivation of latent TB
Co-infections (CMV, Nocardia, PJP)
Autoimmune disease
Duration of dialysis Donor Factors
Donor type (DD), social background (homeless, sick contact, smoking history, Alcoholic abuse)
Medical risk factorsLike DM, BMI < 18, Reactivation of latent TB, History of previous exposure, untreated TB Transplantation related factors
Immunosuppression, rejections, chronic allograft dysfunction Community burden and endemicity Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients
Prevalence reactivation of latent TB is higher after KTX and the main risk factors include old age, absence of BCG scar, and the formation of DSA
Positive latent infection conversion was found in ~20% of cases within the first 2 years after KT as per one prospective study. The protection against MBT is through the activation and proliferation of the Th1 c4d cellular immunity and type 1cytokine protection in addition to the proliferative bulks of CD4+ and CD8+ T cells and interferon-gamma (IFN-γ) and interleukin-2 (IL-2) production are vital effectors in the defensive response. So use of induction and maintenance IS leads to impaired cellular immune response via T-cell depletion and deactivation and increased risk of denovo TB or reactivation of latent TB in previously exposed recipients. Diagnostic and Treatment Challenges
The key to a better outcome after MBT infection after KT is early diagnosis and effective treatment, so the diagnosis of MTB should keep a high index of clinical suspicion, especially in early MBT, which is likely of donor source (DD, endemic area)so personal and social history important, while late after 1 year should consider denovo or reactivation of latent TB. Limitations of diagnostic tests like both tuberculin skin test (TST) and interferon-gamma release assay (IGRA) are not useful in the diagnosis of active TB.
Additional diagnostic challenges include the diverse radiological manifestation, limitations with sputum culture, and BAL fluid assay, even molecular testing by using gene experts can give false negative results in case of low mycobacterial load.
Identifying latent infection or undiagnosed active TB in kidney donors is serious in preventing post-transplant infection. as we know active TB is a contraindication for donation but latent TB or reactivation of latent TB remained a big challenge in KTX, both TB (TST and IGRA) have low feasibility and accuracy as a screening test for TB, so the donor history including previous history of the active TB or previous exposure or treated case of MBT, social history, from the DD family, friends including ethnicity ( endemic area) is very important in addition to IGRA Test and chest radiology.
Current guidelines recommend for latent TB screening should include all KT candidates and donors before transplantation.
treatment challenges include drug-drug interactions especially in rifampicin-based anti-TB ( with CNI reduction risk and might trigger rejection ), drug side effects, non-compliance, and anti-TB resistance, especially in an endemic area.
What is the level of evidence provided by this article?
level 5 narrative review ( review of non homogenous studies with diverse epidemiology and intervention outcome , small sample size )
Molecular genetic testing by using gene experts is preferred and gives faster results compared to culture , tissue biops,y especially for extrapulmonary TB and other radiological imaging
Introduction
– Tuberculosis (TB) is one of the most common infections in KTRs that has negative consequences, such as graft rejection, graft loss and increased mortality rate
– It can result from reactivation of latent infection or de novo infection, several risk factors that favor the development of TB in KTRs.
– The diagnosis and treatment is challenging, and implement screening measures is necessary to limit and prevent occurrence of active TB.
Epidemiology:
-The prevalence and incidence of active TB is higher than general population(GP) and varies according to geographic area. SOT recipients: The prevalence 0.3–6.4% in low TB endemicity and 15.2% in endemic areas. The incidence is 20–74 times higher than in GP.
KTRs: The prevalence is lower than lung transplantation and varies from 0.3% to 15.2%.The incidence in KTRs was higher than in patients with ESRD in pre-dialysis but lower than dialysis population.
Risk Factors
–Endemicity of TB is the main influence risk.
–Transplant-associated risk factors;
Immunosuppression therapy; impairs T-cell-mediated immunity which control TB replication.
Acute rejection episodes: increases the risk of TB by 7.6 times
Chronic graft disfunction: by amplifying the immunosuppression status
-Donor- related risks; cadaveric donor, social risks; homeless donor, incarceration, smoking, alcohol abuse, TB contact, diabetes, low BMI, & previous history of untreated TB.
-Recipients- related risks; old age, mal gender, smoking, malnutrition, COBD, DM, chronic liver disease, HCV infection, other infection CMV, PCP, nocardia, autoimmune disease, latent TB and long term HD.
Transmission and Pathogenesis
Natural after inhalation of droplets containing the organism, then it will evolute as follows:
-Clearance of MBT by immune response
-Development of primary disease ( active disease ), in the first 24 months after primary infection
-Latent infection might reactivate many years following primary infection Transmission of TB in KT recipients – Reactivation of the latent infection present in the recipient prior to transplantation. (the most common), Latent TB conversion was found in 20% of cases within the first 2 years after KT.
– Donor-derived TB infection, responsible for only 4.8% of cases
– De novo infection after KT, mainly in endemic areas.
Diagnostic Challenges Active Tuberculosis
-The diagnosis require high index of suspicion.
-KTRs have atypical clinical presentations or diverse manifestations, which reduce the suspicion of TB.
-The probability of other co-infections and extrapulmonary localization in ~50% of cases is another challenge.
-Tuberculin skin test (TST) and interferon gamma release assay (IGRA) are not useful in the diagnosis of active TB.
-Wide range of radiographic manifestations in pulmonary TB
-The need for invasive procedures BLA/ bronchoscopy is another diagnostic challenge.
– PCR could provide false negative results when mycobacterial load is low.
Donor-derived TB
-It is associated with severe extrapulmonary manifestations and mortality
– It is an under-recognized condition with early onset after KT.
– It should be suspected in KTRs with one of the following features: non-specific symptoms, frequent fever in the first 3 months after KT, fluid collections, extrapulmonary manifestations or lack of response to empirical antibiotic therapy
– Donors screening is highly recommended; reviewing medical and social data, CXR.
– IGRA result might not be available in time.
– IGRA could be false negative in donors with head injury.
Latent Tuberculosis
-There are no gold standard tests for diagnosing latent TB accurately in KT candidates.
-The prediction capacity of TST and IGRA tests are discordant in KTRs.
– IGRA has a low sensitivity in KTRs and cannot be used to exclude latent TB
– IGRA has some advantages over TST in patients with ESRD
– Undiagnosed and untreated latent TB after KT significantly increases the risk of active TB, therefore , screening and diagnosis is essential. Treatment Challenges
Active Tuberculosis
-The duration of treatment is vary from 6 to 24 months.
* Active uncomplicated pulmonary TB, treatment; at least 6 months,
* Cavitary lesions or persistent positive culture; treatment may be extended to 9 months
* Disseminated disease or bone and joint disease; least 6–9 months.
*CNS involvement ; at least 9–12 months
– First-line treatment should be a four-drug regimen, follows the principles of treatment for immunocompetent patients
Drug-Drug interaction:
– Rifampicin potent enzyme inducer, its usage decrease the levels of CNI, mTORi and affects glucocorticoids metabolization, which increases the risk of rejection.
-Therefore, levels should be closely monitored, and doses should be adjusted to obtain the therapeutic target.
– Rifabutin; is a weaker enzyme inducer with similar efficacy to rifampicin.
– Fluoroquinolones is another safe and effective alternative to rifampicin.
Adverse effects of TB therapy
– More frequent than GP.
– Hepatotoxicity (isoniazid, rifampicin, pyrazinamide, ethambutol). The most common
– Neurotoxicity (isoniazid, ethambutol).
– Cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol)
– Visual disturbances (rifabutin, ethambutol)
– Skin lesions (rifampicin)
– Hyperuricemia (pyrazinamide)
– Interstitial nephritis (rifampicin, pyrazinamide)
Treatment adherence directed observed therapy programs has improved the adherence Different degrees of graft function; evaluate creatinine clearance and adjust the doses. Reduction of immunosuppression
The possible occurrence of immune reconstitution inflammatory syndrome, which is associated with the
reduction of immunosuppression and the use of rifampicin
Latent Tuberculosis
-To preventing the risk of reactivation, should be after exclusion of active TB
-Indications:
– Positive TST or IGRA test
– History of untreated TB, or recent contact with an active TB patient
– Graft from a donor with latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB
-Regimen: isoniazid for 9 months with vitamin B6. An alternative ethambutol and levofloxacin or Moxifloxacin. Outcomes; Rejection
-Reach up to 55.6%,
-Associated with reduced levels of immunosuppression secondary to rifampicin.
– 50% of graft failure cases were 2ry to acute rejection.
Graft Loss
– Graft loss in KTRs with active TB varies from 2.2% to 66.6% – Can be directly due to infection or through the sepsis, AKI, acute or chronic rejection that occurred after reduction of IS.
Mortality
-The mortality rate in SOT was 20% while in KTRs ranging from 0% to 60% – Cases of mortality was associated with anti-TB therapy, active TB, and other co-infections (virus, fungal), rejection episode.
Conclusions
-TB in KT is a highly prevalent opportunistic infection in KTRs and is associated with significant negative graft and patient outcomes.
– The diagnosis and treatment is challenging, and implement screening measures is necessary to limit and prevent occurrence of active TB.
I like your summary, and level of evidence. What kind of screening program would you suggest that all those clinicians (stakeholders) can be informed well in time?
-Screening fro both donor and recipient should be screened.
-Results should be reported directly to transplant centers to guide managing patients.
-At the time being using both TST and IGRA together to have better result.
–National screening program, initiation of central registry and enhance public health reporting. -looking for newer screening method with better sensitivity and specificity.
Kidney transplantation is the best modality of renal replacement therapy (RRT) in individuals with end stage kidney disease (ESKD). However, infections is one the important cause of morbidity and mortality among these patients. One example of an infection is tuberculosis which occurs due to immune suppression with higher rates in transplant recipients compared to the general populations.
Active tuberculosis developed due to reactivation of latent infection(most common) in recipient or donor tissue or de novo after transplantation.
Diagnosis and management of tuberculosis is difficult because of atypical presentation, problems with screening for latent TB, drug interactions and side effects.
Late diagnosis is associated with risk of rejection, graft loss, and even death.
Epidemiology
The prevalence in renal transplant is ranging from 0.3 to 15% depending of the geography of the place and this is higher than the general population but lower compared to lung transplantation.
Cadaveric donor, homeless donor, incarceration, smoking, alcohol abuse, TB contact, low BMI, & previous history of untreated TB
Transplant-related
Immune suppression, & allograft dysfunction
Others: TB burden of the country
Transmission: Aerosol droplets, latent infection, infected donor organ
Pathogenesis: The fate of inhaled TB in the droplets is either;
Clearance by the host immune system or
Development of the primary disease i.e., immediate onset active infection within the two years of the primary infection or
Latent infection reactivation: i.e a late onset of active disease many years after the primary infection ( most common mode of transmission in all solid organ transplantation ~ 20%) present with the first year after transplantation
Other important mode of transmission in transplant recipients are;
Infected donor organs ~ 4.8% and present within the first 3 months after transplantation.
De novo( less common but mostly in endemic areas with high risk of progression)
Diagnosis challenges:
1.Active tuberculosis
Atypical presentation
Extra-pulmonary in ~50%
Co-infections e.g with CMV
Tuberculin test & interferon gamma release assays (IGRA) are not diagnostic
The need for bronchoscopy & BAL due to non-specific radiological features
2.Donor-derived
This can be associated with severe extra-pulmonary presentation and high mortality
Present in the first 3 months
Usually under recognized
History of exposure or TB contact may not be obtainable
IGRA test results may take some time
IGRA test may be false negative in those with impaired-immunity e.g., head injury
3.Latent TB
Assessments is difficult
No gold standard tests for accurate diagnosis
IGRA may have some advantage over TST
Treatment challenges
1.Active tuberculosis
Drug interactions between rifampicin, & CNIs, mTORi.
Rifampicin affect metabolism of glucocorticoids
Increasing the dosages of these medicines
Increased costs
Side effects of the anti-TB which is more common than in the general populations e.g., hepatotoxicity, neurotoxicities
Adherence to treatment
Allograft dysfunction
Drug-dosage adjustment for ethambutol & pyrazinamide
Risk of IRIS with reduction of immune suppression in severe disease
2.Latent tuberculosis
Exclude active TB
Consider treatment in cases of +ve TST or IGRA test, history of untreated TB or recent contact with active TB, or kidney donor has latent TB but not treated
Give isoniazide 5mg/kg for 9 months plus B6
Outcomes
Rejection; up to 55% of cases
Graft loss; 2 to 66%
Mortality; 0 to 60% this can be accelerated by co-infections and comorbidities
Conclusion
TB is one of the infections associated with poor outcomes in transplant recipients. Transmission is mainly through latent infection reactivation and less commonly by infected donor organs. the diagnosis is difficult and there is a lot of therapeutic challenges. Development of a new diagnostic methods may be important for early diagnosis and management of TB.
I like your summary, level of evidence, analysis and take home messages. What kind of network would you suggest? What is your suggestion regarding communication gap between availability of newer diagnostic tests and promptness of action on these reports?
Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review
Summarise this article
#The objective:
To determine an evidence-based update regarding epidemiology, risk factors, pathophysiology, type of transmission, diagnostic challenges, treatment challenges and the impact of TB in KT recipients.
#Introduction:
*Renal transplantation is best solution regarding renal replacement therapy in ESRD patients; however, infection after KT is still an important limitation for graft and patient outcomes.
*Tuberculosis (TB) in (KTx) recipients is an important opportunistic infection with greater prevalence than in the community and is associated with important morbidity and mortality rate.
*Active TB is mainly associated with an immunosuppression condition with a higher incidance in KTRs, also there are recipient- and donor-associated risk factors that could lead to development of TB in KTRs.
*Understanding the epidemiological risk, risk factors, transmission modalities, diagnosis and treatment challenges is critical for clinicians in providing an appropriate management for KT with TB.
#Method:
This is an extensive literature review of articles published between 1 January 2000 and 15 June 2022 to provide an evidence-based review of epidemiology, pathogenesis, diagnosis, treatment and outcomes of TB in KT recipients.
#The results:
*The prevalence of active TB in KT recipients ranges between 0.3–15.2%. KT recipients with active TB could have a rejection rate up to 55.6%, a rate of graft loss that varies from 2.2% to 66.6% and a mortality rate up to 60%.
#Risk Factors for Tuberculosis in Kidney Transplantation:
*Recipient- associated:
-Old age
-Male gender
-Smoking
-Malnutrition
-Diabetes
-COPD
-Latent TB (pre-transplant)
-Chronic liver disease
-HCV infection
-Opportunistic co-infection CMV, pneumocystis
-Autoimmune disease
-Long term HD
*Donor- associated:
-Donor type (cadaveric)
-Social factors (homeless)
-Medical risk factors (DM, BMI)
*Transplant- associated:
-AR
-IS
-Chronic graft dysfunction
*Others:
TB burden of the country
#Diagnostic Challenges
-Delayed the diagnosis of TB in KT patients.
-Atypical clinical
-Association with other co-infections and extrapulmonary localization in ~50%of cases.
-Paraclinical issues. For example, tuberculin skin test (TST) and interferongamma release assay (IGRA) are not useful in the diagnosis of active TB
-Wide range of radiographic manifestations in pulmonary TB and the frequent need for invasive procedures (bronchoscopy with bronchoalveolar lavage).
-Molecular tests based on rapid nucleic acid amplification techniques, such asmycobacteriumtuberculosis complex and resistance to rifampin test could provide false negative results when mycobacterial load is low.
#Treatment Challenges
-Drug–drug interactions,
-Drug toxicity
-Treatment adherence
*It is recommended that the management of KT patients with TB be carried out by an experienced clinician and special attention must be paid to drug–drug interactions and potentially adverse events
#Conclusions:
*Close collaboration between kidney transplant and infectious disease physicians.
*Donor-derived TB and latent TB in KT are under recognized conditions that should be carefully evaluated.
* Development of tests with helpful predictive values, which are not based on T cell immunity, could bring important improvement in the diagnosis of latent TB in KT recipients.
*Newly discovered regimens or pipeline drugs could have an important contribution in the future limitation of drug–drug interactions, improvement of treatment efficacy and reduction of adverse events.
What is the level of evidence provided by this article?
Level of evidence is level (5).
TB is the leading infectious cause of mortality worldwide (exclude COVID-19) and a common cause of death (exclude COVID-19). Active TB is more prevalent in transplant patients due to immunosuppression than in the general population.
Limiting the occurrence of the disease requires proper donor and recipient evaluation.
Methods
From January 1, 2000, to June 15, 2022, a literature search was conducted using PubMed and Embase electronic databases.
Included were all studies that provided epidemiological and/or outcome data on TB in KT.
Risk Factors and Epidemiology of Tuberculosis in Kidney Transplantation
The prevalence of active tuberculosis among patients with solid organ transplants varies greatly by geographic region.
The incidence of active TB in solid organ transplant recipients is 20–74 times that of the general population, depending on whether or not the area is endemic.
Tuberculosis in Kidney Transplantation: Epidemiology
The prevalence of active TB in recipients of kidney transplants ranges from 0.3% to 15.2%, which is higher than the prevalence in the general population.
Risk Factors for Tuberculosis in Kidney Transplants The primary cause of tuberculosis in kidney transplants is the reactivation of latent disease.
Donor tissue
Infection acquired from a new source.
Transplant-related risk factors, including immunosuppression therapy, acute rejection episodes, and chronic graft dysfunction.
In general, however, the risk factor depends on the recipient and the donor.
Recipient:
Transmission and Pathogenesis of Tuberculosis in Patients Receiving Kidney Transplants
Transmission of tuberculosis in KT recipients is contingent on reactivation of latent tuberculosis.
In 20% of cases within the first two years after a kidney transplant, latent infection conversion was positive.
Diagnostic Difficulties
Active TB typically develops during the first year following a kidney transplant.
TB diagnosis requires:
The diagnosis of tuberculosis necessitates a high index of suspicion, but atypical clinical manifestations in recipients of kidney transplants reduce the clinical suspicion of TB.
TST and IGRA are not useful for diagnosing active TB unless it is associated with other co-infections.
Latent Tuberculosis.
20% of recipients reported a prevalence of latent TB following KT.
Before transplantation, latent TB must be screened for in all KT candidates and donors.
IGRA is preferable to TST in ESRD patients.
The predictive value of IGRA assays for latent TB in KT recipients with negative TST results is high.
The sensitivity of IGRA tests in KT recipients was minimal.
The IGRA test cannot rule out latent TB.
Donors for kidney transplants should be screened more frequently.
Treatment Obstacles:
Due to adverse events, drug-drug interactions, drug toxicity, and treatment adherence, the treatment of TB in KT recipients should be administered by a seasoned clinician.
Infectious Tuberculosis:
Once an active TB diagnosis has been made, treatment must commence. 6 to 24 month treatment duration
According to AST-IDCOP, the initial treatment should consist of four medications.
The standard regimen includes a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide, and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin. Rifamycin is recommended not only for its sterilization capacity and efficacy but also for its ability to decrease the risk of resistance. In the absence of rifamycin, the intensive phase should consist of isoniazid, ethambutol, pyrazinamide, or levofloxacin for two months, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide.Rifampicin is a potent inducer of cytochrome P450 3A4 and P-glycoprotein, which are inhibitors of CNI (cyclosporin and tacrolimus).
When using rifampin, the CNI must be monitored.Additionally, hepatotoxicity, neurotoxicity, cytopenia, visual disturbances, cutaneous lesions, hyperuricemia, and interstitial nephritis are being monitored.
Fluoroquinolones are another safe and efficacious alternative to rifampicin for KT recipients.
Outcomes
Up to 55.6% of KT recipients with TB may experience graft rejection. The prevalence of graft loss in KT patients with active TB ranges from 2.2% to 66.6%; mortality was reported in 41.4% of patients with active TB following KT; and in 14.4% of cases, mortality was associated with anti-TB therapy.
Conclusions
In kidney transplantation, tuberculosis is associated with negative outcomes for both the recipient and the patient.
Clinicians should be aware of the diagnostic and treatment difficulties associated with TB after KT.
The optimal management strategy should be implemented by an experienced clinician.
Donor-derived tuberculosis and latent tuberculosis in KT are recognized conditions that require cautious evaluation.
The creation of instruments with beneficial predictive values
New regimens or therapies may have a significant impact on the future limitation of drug-drug interactions, enhancement of treatment efficacy, and reduction of adverse effects.
What level of substantiation does this article provide?
Level V.
TB is considered the thirteen most common cause of death worldwide. In kidney transplantation, TB has negative impact on patient and graft survival.
Due to immunosuppression, active TB is higher among kidney transplant recipients.
So this comprehensive review aimed to provide an evidence based update regarding TB and kidney transplantation
Epidemiology
The incidence of active TB in SOT is 20 to 74 times higher than general population
Prevelance of active TB in SOT varies according to geographic area.In low endemic areas for TB, the prevelance is 0.3 to 6.4% but the prevelance in high endemic area is 15.2%.
The prevelance of TB among kidney transplant patients varies from 0.3 to 15.2% . It is higher than general population but less
than its prevelance among lung transplant patients.
Risk factors for TB in kidney transplant patients
Recipient-associated: old age, male gender, smoking, malnutrition, DM,COPD,latent TB,autoimmune diseases, chronic liver disease, hepatitis C, confections, long term dialysis.
Donor associated: cadaveric, social risk( homeless,incarceration, smoking, alcohol abuse, known TB contact,medical risk factors ( DM,history of untreated TB)
Transplant associated : immunosuppression, acute rejection and chronic graft dysfunction.
TB burden in the country
Transmission and pathogenesis of TB in kidney transplantation
Inhalation of droplets containing mycobacterium tuberculosis leads to primary infection (immediate onset of active disease or latent infection)
Transmissionof TB in kidney transplant recipients runs in 3 scenario
….Active TB may ariseafter kidneytransplantation as result of reactivation of latent infection present in the recipient prior to transplantation. This is the commonest form in SOT
…..TB couldbe transmitted to kidney recipient via kidney graft from infected donor and it occurs in 4.8 % of cases.
….. TB could occur due to denovo infection after KT due to exposure to a patient with active TB especially in high endemic areas and it is not common.
Diagnostic challenges
In active TB
1. Atypical clinical manifestations, the association with other confections and extrapulmonary localization confuse TB suspicion.
2.TST and IGRAs are not useful for diagnosis of active TB
3. The need to invasive procedures for diagnosis as bronchoscopy
In latent TB
There is no gold standard test for diagnosis, but IGRAs carries some advantages over TST in patients with ESRD
Treatment challenges
In active TB
1. Drug interaction between rifampcin and transplant associated immunosuppression
2. Adverse effects of TB therapy
3. Treatment adherence
4. Reduction of immunosuppression in case of severe TB
In latent TB the major challenge is Isoniazide related hepatoxicity
Outcomes
Graft rejection in kidney recipients is about 55% due to reduction of immunosuppression secondary to drug interactions .
Graft loss occurs in 2.2 to 66 .6% of cases due to
Infection itself
Sepsis
Acute and chronic rejection
Mortality
Mortality of patients with TB after KT may reach 60%
Level of evidence 5
This is a literature search from 1 January 2000 to 15 June 2022 which has provide an evidence-based review of epidemiology, pathogenesis, diagnosis, treatment and outcomes of TB in KT recipients. Rate of active TB in renal recipients was 0.3–15.2% and their rejection was 55.6%. the graft loss rate was 2.2% – 66.6% and a mortality rate was 60%. The challenges are:
1- diagnostic time delay which lead to delay in management
2- atypical clinical presentation
3- association with co-infections
4- decreased predictive values of screening tests
5- diverse radiological aspects and particular diagnostic methods
6- drug interactions
7- drug toxicities
8- Compliance
This requires close collaboration between kidney transplant and infectious disease physicians. Donor-derived TB and latent TB in KT are underrecognized conditions that should be carefully evaluated. Development of tests with helpful predictive values, which are not based on T cell immunity, could bring important improvement in the diagnosis of latent TB in KT recipients.
level of evidence is 5
Summarise this article
A comprehensive review between 1/1/2000 and 15/6/2022 articles of post kidney transplantation TB infection. The review includes epidemiology, pathogenesis, diagnosis, treatment and outcome.
Epidemiology
Pathogenesis
Diagnosis
Treatment
Outcome
What is the level of evidence provided by this article?
Level 5 evidence – a review
-The prevalence of active TB in transplanted patients is higher than general population 20-74 times either through activation of latent TB ,acquiring the disease from the graft or recent infection after recent exposure.
treatment of latent TB Isoniazid for 6-9 months.
– Rifampicin containing regimen:
Rifampicin+ INH+ ethambutol + pyrazinamide for 2 months, followed by a 2-drug regimen of Rifampicin + INH for 4 months
increase the duration of treatment to at least 9-12 months if there is disseminated disease, cavitary disease with positive sputum culture after 2 months of treatment, bone and joint disease, CNS disease.
– Rifampicin free regimen.
This is a narrative review of level 5 evidence .
level of evidence 5
Summarise this article-
This article is an extensive literature review of articles published between 1 January 2000 and 15 June 2022 to provide an evidence-based review of epidemiology, pathogenesis, diagnosis, treatment and outcomes of TB in KT recipients
. Introduction
As KT is associated with an immunosuppression status, active TB is higher in KT recipients than in the general population.Active TB after KT could arise from reactivation of latent infection in the recipient or donor tissue or can result from de novo infection after transplantation. Endogenous reactivation after KT is the most common form of transmission.
Epidemiology of Tuberculosis in Kidney Transplantation
The prevalence of active TB in KT recipients varies from 0.3% to 15.2% and is higher than in the general population but lower than in patients with lung transplantation .
Risk Factors for Tuberculosis in Kidney Transplantation
The risk is mainly influenced by endemicity of TB in the population, but key factors associated with the recipient, donor and transplantation increase it . Among them, of particular importance are transplant-associated risk factors, such as immunosuppression therapy, presence of acute rejection episodes and chronic graft disfunction.Immunosuppression used in KT impairs T-cell-mediated immunity involved in TB control and favors latent infection reactivation.Acute rejection significantly increases the risk of TB by 7.6 times.The number of rejections after transplant is an independent risk factor for TB appearance.Another transplant-related factor is chronic graft dysfunction, which could increase the risk of TB development by amplifying the immunosuppression status .
Recipient related Risk factors–
Older age,Male gender,Smoking,Diabetes ,Malnutrition,COPD,Latent Tb (Pre transplant),CLD,Hepatitis C infection,Opportunistic infection like CMV,pnemocystis,Nocardia,Long term Dialysis,Autoimmune disease
Transmission of TB in KT recipients could be possible according to three scenarios.-
. In the first scenario, active TB could arise after KT as a result of reactivation of the latent infection present in the recipient prior to transplantation This form of transmission is the most common found in all solid organ transplantation, including KT
.In the second scenario, TB could be transmitted to KT recipients via kidney graft from an infected donor .This type of transmission is responsible for only 4.8% of cases
In the third scenario, TB could occur as a de novo infection after KT, in a recipient with exposure to a patient with active TB . This type of transmission is not common; it is associated with very high risk of progression, and it is more frequent in endemic areas
.
Diagnostic Challenges-
KT recipients have atypical clinical presentations or diverse manifestations, which reduce the clinical suspicion of TB .Extrapulmonary localization in ~50% of cases adds a supplementary confusing element to the clinical picture. tuberculin skin test (TST) and interferon-gamma release assay (IGRA) are not useful in the diagnosis of active TB . Molecular tests based on rapid nucleic acid amplification techniques, such as mycobacterium tuberculosis complex (Xpert® MTB/RIF, ), could provide false negative results when mycobacterial load is low.
Prevalence of latent TB after KT was reported in ~20% of recipients Current guidelines provide recommendations for latent TB screening in all KT candidates and donors before transplantationThere are no gold standard tests for diagnosing latent TB accurately in KT candidates, but IGRA seems to present some advantages over TST in patients with ESRD Even so, the evaluation of latent TB in KT recipients is challenging because data regarding prediction capacity of TST and IGRA tests are discordant in this category of patients
Donor-derived TB is considered an under-recognized condition with early onset after KT in the majority of cases and should be suspected in KT recipients with one of the following features: non-specific symptoms, frequent fever in the first 3 months after KT, fluid collections, extrapulmonary manifestations or lack of response to empirical antibiotic therapy.Recognizing latent infection or undiagnosed active TB in the kidney donors is critical in preventing post-transplant infection As active disease in donors is a contraindication for donation, identification of latent TB in deceased donors remains a real challenge in KT.Nevertheless, in deceased donors, and the screening tests for latent TB (TST and IGRA) have low feasibility and accuracy .
Treatment Challenges
One challenge in the treatment of KT recipients with active TB is the drug interaction between rifampicin and transplant-associated immunosuppression .Specifically, rifampicin usage decrease the levels of calcineurin inhibitors (cyclosporine, tacrolimus), the mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus), and affects glucocorticoids metabolization, which increases the risk of rejection .Another challenge is linked to the adverse effects of TB therapy, which are more frequent than in the general population.
Latent Tuberculosis-
Treatment of latent TB should be considered only after active TB has been excluded. Treatment of KT recipients with latent TB is important for preventing the risk of reactivation. Treatment in this category of patients is indicated in one of the following conditions: a positive TST or IGRA test, a history of untreated TB, a history of recent contact with an active TB patient and when the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB .In the KT setting, the preferred treatment of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months.
.
Risk of Rejection,graft loss and mortality-
KT recipients with active TB could have a rejection rate up to 55.6%, a rate of graft loss that varies from 2.2% to 66.6% and a mortality rate up to 60%
What is the level of evidence provided by this article?
Level 5
Introduction
best therapy for ESRD is kidney transplantation (KT)
Tuberculosis (TB) is a major post-transplant infection.
It is the thirteenth-highest cause of mortality globally and the top infectious cause in Post Tx period.
Method
A search on PubMed and Embase electronic databases performed from 1 January 2000 to 15 June 2022. All studies that provided epidemiological and/or outcome data regarding TB in KT were included.
Tuberculosis in SOT
Active TB in solid organ transplantation varies in different regions but TB prevalence ranges from 0.3–6.4% in low-endemic regions to 15.2% in high-endemic areas.
Risk Factors
Post transplant cases are more likely to acquire TB. High prevalence in community along with donor, and transplantation variables like immunosuppression medication, rejection episodes, and chronic graft dysfunction.
Immunosuppression inhibits T-cell-mediated TB control and promotes latent infection reactivation. T-cell-depleting medications, calcineurin inhibitors, anti-metabolites, and glucocorticoids all enhance the risk of TB. Each rejection episodes increases TB risk 7.6 times.
Transmission and Pathogenesis
Active TB could result due to reactivation. TB could also be transmitted to KT recipients via kidney graft from an infected donor or TB could occur as a de novo infection after KT or exposure to active TB patients.
Diagnostic and Treatment
Active TB; Treatment lasts 6–24 months, but at least 9–12.
American Society of Transplantation IDCOP recommends 6 months for active uncomplicated pulmonary TB and 9 months for cavity lesion.
AST-IDCOP recommends a 4-drug regimen for first-line treatment:
Latent TB
It has also should be treated to stop it from becoming active. Positive TST or IGRA test, a history of treated tuberculosis, a history of recent contact with an active TB patient, donor-derived latent TB in an infected graft, a history of untreated tuberculosis, or recent exposure to active tuberculosis, makes a person venerable to tuberculosis.
INH combined with vitamin B6 is used to treat latent tuberculosis for a period of nine months. Ethambutol with either levofloxacin or moxifloxacin is another treatment option for those at high risk.
Conclusions
TB is a common opportunistic infection in KT patients.
It has negative impact on graft and patient survival.
Preventive strategies include TB risk stratification and monitoring.
Donor-derived TB and latent TB in KT are underdiagnosed.
In KT recipients, non-T cell immunity-based assays with good predictive values might enhance latent TB diagnosis in future.
Level V
TB is more frequent in kidney transplant than general population but less common than post lung Tx.
The prevalence ranges from 0.3–6.4% in low TB endemicity to 15.2% in high endemic areas. The incidence of active TB in SOT is 20 to 74 times higher than general population.
Latent TB infection: based on WHO is defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically active TB. Prevalence of latent TB after KT was reported in around 20% of recipients.
Source of Tb after transplant : reactivation of latent infection in recipients ,Donor tissues (reactivation of latent infection)&De Novo infection.
Diagnostic issues
High index of suspicion
Tuberculin skin test (TST)
IGRA
Bronchoscopy with BAL, fluid collections evaluated by smear and mycobacterium culture and histopathology
Molecular tests based on rapid nucleic acid amplification techniques eg : mycobacterium tuberculosis complex
Recognizing latent infection or undiagnosed active TB in the kidney donors is crucial in prevention of post-transplant infection.
Treatment of Active TB:
Duration of treatment is at least 9 to12 months.
American Society of TX infection disease community of practice guidelines recommend in case of active uncomplicated pulmonary TB duration should be not less than 6 months.
If a cavity is present or persistence of culture-positive after 2 months of therapy, duration must be 9 months.
-CNS infection: duration of treatment 19-18 months
– According to AST- IDCOP four-drug regimen including rifampicin ,INH, Ethambutol &Pyrazinamide
-Diagnosis of latent TB: includes
High clinical suspicion
Tuberculin skin test (TST)
IGRA
Indications to treat latent TB in transplant recipient and donor:
Positive TST or a positive IGRA
Close contact to an active TB case
If recipient had graft from donor with latent TB and did not receive treatment
Regimen for treatment of latent TB
INH for 6t o 9 months.
Rifampicin to be avoided due to possible drug-drug interactions ; rifabutiun can be used alternatively.
Level of evidence: V ( Narrative review).
1. Summarise this article
Introduction:
Outcomes of kidney transplant are greatly affected by infections, especially tuberculosis (TB) which is a major cause of morbidity, rejection, graft loss, and mortality. TB prevalence is high in kidney transplant recipients (KTRs), due to either reactivation of latent infection (LTBI) or donor-derived infection or de novo infection.
Epidemiology of TB in KTR:
The incidence and prevalence of active TB in solid organ transplant (SOT) recipients are 20 to 74 times higher than in general population, with prevalence varying from 0.3 – 15.2% in different geographical areas and endemicity. The prevalence in dialysis patients is 3.6 times, and in KTRs is 11.36 times that of general population; is higher in lung transplant recipients.
Risk factors for TB in KTRs:
· TB burden of the country (endemicity)
· Recipient-associated factors
– smoker, COPD
– malnutrition, diabetes, older age, male gender
– latent tuberculosis
– chronic liver disease, HCV infection
– CMV infection, pneumocystis, nocardia
– long-term haemodialysis
– autoimmune diseases
· Donor-related factors
– Cadaveric donor
– history of untreated TB, h/o contact with known TB patient
– smoker, alcohol abuse
– low BMI, incarceration, homeless
– donor with diabetes
· transplant associated factors
– Acute / Chronic Rejection, graft dysfunction
– Acute rejection increases the risk of TB by 7.6 times
– Intense immunosuppression – ATG, Belatacept, CNI, MMF, high dose steroid
Transmission and pathogenesis of TB in KTRs:
Aerosol droplets containing mycobacterium (m-TB) reaches lungs through inhalation – mostly cleared by the innate or acquired immunity, or develop primary disease (within 2 years), or remain latent for reactivation to happen many years later.
CD4+ T cell producing interferon gamma and interleukin-2 (IL2) are increased, during latent TB (LTBI), whereas these are markedly reduced in active TB. Immunosuppression in KTRs leads to reduced T cells, IL2, and Th1 type cytokines, with reduced activation and proliferation of T cells and decreased cellular immunity leading to reactivation of LTBI.
Transmission of TB in KTRs is most commonly due to reactivation of latent TB infection (LTBI) – 20% in 2 years post-transplant (median 11.5 months), mostly in old-aged recipients, BCG vaccinated, and having high DSA.
Donor-derived TB, accounts for 4.8% cases, seen within first 3 months; frequently present with fever, fluid / pus collection, extrapulmonary features with no response to antibiotics.
De novo TB infection is uncommon, seen in endemic regions, and is associated with increased risk of progression.
Diagnostic challenges:
TB in KTRs have increased extrapulmonary features and co-infections (50% of cases) with atypical presentations, requiring high index of suspicion.
Donor detail history on TB, may not be obtained /
The tuberculin skin test (TST) and interferon gamma release assay (IGRA) are not useful in active TB diagnosis.
Radiologic manifestations have wide range, and there is need for invasive procedures like bronchoscopy and bronchoalveolar lavage (BAL). Nucleic acid amplification technique (NAAT) based molecular tests can be false negative.
Screening with TST and IGRA for LTBI have low feasibility and accuracy with false negative results. For screening in LTBI, IGRA is better than TST.
Treatment challenges:
These could be due to drug-drug interactions, drug toxicities as well as maintaining treatment adherence. Soon after diagnosis of active TB infection, treatment should be immediately started using Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol in intensive phase followed by Isoniazid and Rifampicin in maintenance phase.
The optimal treatment period varies according to the clinical picture: 6 months for uncomplicated pulmonary TB, 9 months for cavitary lesions, or if sputum test is positive at 2 months, 6-9 months for disseminated or bone and joint disease, and 9-12 months for central nervous system (CNS) involvement. For localized TB (non-severe) – Isoniazid, Ethambutol and Pyrazinamide or Levofloxacin can be used for 2 months followed by 12-18 months of Isoniazid and Ethambutol or Pyrazinamide.
Rifampicin, a cytochrome P450 3A4 inducer, decreases levels of CNI, mTOR inhibitors, and steroids requiring increased doses (3-5 times for CNI and mTOR inhibitors, and 2 times for steroids).
Severe TB requires reduction in immunosuppression. Rifampicin can be replaced with rifabutin or fluoroquinolones.
Adverse effects of antitubercular drugs include hepatotoxicity, neurotoxicity, skin lesions, ophthalmic toxicity, cytopenia, hyperuricemia, interstitial nephritis, and immune reconstitution inflammatory syndrome. Liver function tests should be monitored twice a week initially for first 2 months and then monthly. Doses of the drugs should be adjusted as per creatinine clearance. Treatment adherence can be monitored using the directed observed therapy (DOTs) program.
Latent TBI – positive IGRA or TST, history of untreated TB or recent TB contact, or donor kidney with LTBI without treatment, untreated TB or TB exposure. Treatment includes isoniazid (5 mg/kg/day) for 9 months, or ethambutol with levofloxacin or moxifloxacin. Liver enzymes should be monitored.
Outcomes:
TB in KTRs has challenges in diagnosis, increased extrapulmonary features, and immunosuppressed state leading to increased mortality and morbidity.
Immunosuppression reduction leads to allograft rejection in up to 55.6%, and graft loss in 1/3rd of patients. Graft loss can also be due to infection, sepsis, rejection (acute or chronic), or reduction in immunosuppression, seen in up to 66.6% patients.
Mortality up to 60% have been seen; higher mortality rates in those with co-infections by fungi, nocardia, CMV, hepatitis viruses, chronic liver disease, diabetes, or those who received anti-rejection treatment.
Conclusions:
· TB in KTRs, an important opportunistic infection, has higher incidence and prevalence than in the general population, and is associated with poor outcomes (high rates of rejection, graft loss and mortality).
· Effective preventive measures (pre-op screening), high index of suspicion for early diagnosis and proper treatment are required for good patients and graft outcomes.
· Early diagnosis and treatment of TB in KTR are challenging – requires high index of suspicion and optimal management approach, collaboration between transplant team and infectious disease physicians.
· Donor-derived TB and LTBI in KTRs are underrecognized – need careful evaluation by tests not based on T cell immunity (preferably).
· Newly discovered regimens or pipeline drugs could have an important contribution in the future limitation of drug–drug interactions, improvement of treatment efficacy and reduction of adverse events
2. What is the level of evidence provided by this article?
Level of evidence: level 5 – Narrative review.
Summary:
Introduction
This article is relating TB infection following kidney transplant. This is an important topic because of the different clinical presentations that recipients can present with when infected with TB, some of which are diagnosed late, and cause great damage to the graft as well as increasing chances of patient mortality.
This review is aimed at giving an evidence based result regarding epidemiology, risk factors, pathophysiology, type of transmission, diagnostic challenges, treatment challenges and impact of infection on recipients.
Discussion
When delving into the world of TB, discussion of risk factors needs to be the first. These are as follows :
Recipient associated risk factors –
Donor associated risk factors –
Transplant associated risk factors –
Others –
TB pathogenesis in kidney transplant recipients
Transmission of TB in kidney transplant recipients has three known routes :
Diagnostic challenges
Active TB usually presents in the first year post transplantation, from latent infection reactivation or de novo infection. Challenges begin when there is atypical presentation of TB leading to late diagnosis and treatment. In addition, the usually tests that can diagnose TB include tuberculin skin test, and IGRA are not useful in this case to identify active TB in these patients.
Careful evaluation of epidemiological risk, personal medical history, physical exam and chest X ray of the donor are required to make sure that there is no transmission of TB from the donor to the recipient.
Latent TB is even more difficult to identify because it is a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB. There are no gold standard tests to diagnose latent TB but IGRA can help more than TST in diagnosis.
Treatment challenges
Treatment of kidney transplant recipients with TB can be challenging because of drug interactions between immunosuppressive drugs and TB treatment drugs, along with the chances of drug toxicity and tendency for patients to not adhere strictly to treatment protocol.
Monitoring medication adherence of recipients is essential and needs to be a focus especially in the case of TB. Suspected non adherence needs to be dealt with appropriately to ensure that the patient gets the maximum benefit from the drug regimen.
In the case of active TB, the recommended duration of treatment is 9-12 months. In the case of uncomplicated TB, treatment can be given for 6 months, but after 2 months if complications persist or the patient has cavitary lesions, then treatment duration must be increased to 9 months.
Rifampicin is recommended as part of first line treatment because it is very efficient and reduces the risk of resistance.However, the challenge associated with Rifampicin is the interaction it has with the patient’s immunosuppressive regimen by interfering with drug metabolization. It is a potent inducer of p450 system and p glycoprotein. It decreases the levels of IS drugs such as CNIs, mTORi along with affecting glucocorticoid metabolization. All of this increases the risk of rejection. Due to this, IS drug levels need to be closely monitored, and dosage needs to be increased three to five fold, with glucocorticoids being increased to double dose. Once Rifampicin is stopped, IS dose needs to be reduced to the value of before start of Rifampicin. In this situation, adequate IS can be difficult to achieve increasing the risk of rejection as well as infection.
Treatment of latent TB needs to be started only after active TB has been excluded. Adequate treatment is essential to prevent reactivation of TB. Treatment can be started with a positive IGRA or TST, history of untreated TB and a history of recent contact with an active TB patient. Non adherence to medication can be a big challenge especially when the patient is not seeing any active symptoms that they need to treat, leading to laxity in taking dosage at the right time with proper frequency.
Conclusion
Undiagnosed TB or imeffective treatment of TB can lead to acute or chronic rejection, increased mortality risk for the recipient, and poor quality of life overall. The interactions between Tb drug regimen and IS drug protocol can be challenging to set fixed dosages and frequencies of these drugs. In addition to this, fluid test levels and difficulty in standardization can lead to misdiagnosis or late treatment.
Despite all these challenges, close monitoring of the patient, along with regular collaboration with infectious disease physicians can make the whole process smoother and more effective for both the transplant team as well as the patient.
Level of analysis
This is a narrative review, and thus level of evidence is 5.
1. Summarise this article
Opportunistic infection has been a major problem in SOT.
This extensive literature review of articles done between 1 January to June 2022 to provide evidence based epidiolmology, pathogenesis, diagnosis, treatment, in KT recipient it may present with atypical symptoms, its delay in diagnosis, and treatment could determine poor prognosis and may increases the risk of rejection.
Prevalence of active TB in KT recipient ranges between 0.3 to 15.2%, and risk of rejection with active tuberculosis is up-to 55.6%,
Graft loss 2.2 to 66.6%,
Mortality up-to 60%.
Methods;
The literature search was on PUBMED, EMBASE ELECTRONIC DATABASES.
All studies done on TB their epidemiological, and outcomes were included.
The article were checked by two reviewers and checked by a third reviewer.
Epidemiology and risk factors for tuberculosis in SOT;
Prevalence is variable in different geographical areas, a systemic review and meta-analysis of 60 studies shows the prevalence of TB in SOT of 3%, and its 20-74 times higher than in general population.
The study done in 16 centers showed 512 cases per 100000 patients per year ( 26.6 times higher than general population).
Epidemiology and risk factors for tuberculosis in kidney transplantation;
Prevalence of active TB is 0.3 to 15.2%. it was reported with lowest in Iran (0.4%), highest in Pakistan 15.2%.
It was observed that TB is more prevalent lung transplant than KT recipient.
Risk factors; there are several risk factors like mainly epidemiology, immunosuppression, episodes of rejection, other risk are smoking, malnutrition, comorbid, lungs conditions, and LTBI.
Transmission and pathogenesis;
Transmission could be,
1. LTBI, reactivation, the most common form, it was found that 20% conversion rate within 2 years of transplantation.
2. Could be transmitted from donor during donation, this responsible for 4.8% of cases.
3. Could occur as de novo infection, it’s more frequent in endemic areas.
The protection against TB is Th1-type cells which proliferate to CD4, 8 and other T-cells as protective response, post-transplantation immunosuppression suppresses all cellular immunity completely, and increases the risk of reactivation of latent tuberculosis.
Diagnosis and treatment challenges;
1. Active TB à it was seen usually within first year with median time of 11.5months, donor derived within 3 months.
TST and IGRA are not useful in the diagnosis of active TB, if low load with mycobacterium and associated MT Complex and resistant rifampicin the NAT (GENEXPERT) can be false negative.
DDTB has poor prognosis and high mortality secondary to high risk of extra pulmonary manifestation, to prevent this need careful history from family with exposure, previous treatment.
The optimal period of treatment 6-24 months, otherwise recommended is 9-12 months.
According to AST-IDCOP guidelines for uncomplicated TB duration is 6 months, if positive culture continue for 9 months.
Drug interaction, and toxicities should be kept in mind.
2. Latent tuberculosis à according to WHO a state of persistent immune response to stimulation by MBT Ag with no evidence of active infection.
It’s recommended for latent TB screening is mandatory. IGRA has superiority on TST test.
Its treatment is important to prevent risk of reactivation.
Preferred Rx is INH 5mg/kg for 9 months +vit B6. In KT rifampicin regimen is not recommended, consist of ethambiotol+ levo/ moxifloxacine.
Outcomes;
1. Rejection, possible reach up-to 55.6%,
2. Graft loss, prevalence 2.2 to 66.6%.
3. Mortality; in SOT its around 20%, while in KT recipient its 0 to 60%.
Conclusion;
Tb incidence is higher in KT recipient then general population.
It’s associated with negative outcomes.
DDTB and LTBI are unrecognized conditions should be monitored carefully.
level of evidence V
Tuberculosis is an opportunistic infection of great importance for immunosuppressed patients, especially Renal Transplant (KT) recipients, the prevalence of active TB in KT recipients varies between 0.3–15.2%. KT recipients with active TB can have a rejection rate of up to 55.6%, a graft loss rate ranging from 2.2% to 66.6%, and a mortality rate of up to 60%. Understanding the epidemiological risk, risk factors, modes of transmission, diagnosis and treatment challenges is critical for clinicians to provide appropriate treatment for KT with TB.
Recognizing latent infection or undiagnosed active TB in kidney donors is critical in preventing post-transplant infection. As active disease in donors is a contraindication for donation, identification of latent TB in deceased donors remains a real challenge in KT, despite the current recommendation for screening. Current guidelines (American Society of Transplantation Infectious Diseases Community of Practice and European Society of Clinical Microbiology and Infectious Diseases) recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors
Active TB after KT may arise from reactivation of latent infection in the recipient or donor tissue or may result from de novo infection after transplantation. Endogenous reactivation after KT is the most common form of transmission. Candidates and recipients of KT with TB represent a real challenge regarding diagnosis and treatment due to atypical or diverse clinical presentation, limitations of screening tests for latent infection, drug interactions and toxicities. Delay in diagnosis and treatment can determine negative consequences, such as graft rejection, graft loss and increased mortality rate.
The risk factors associated with transplantation stand out, such as immunosuppressive therapy, the presence of acute episodes of rejection and chronic graft dysfunction. The immunosuppression used in KT impairs the immunity mediated by T cells involved in TB control and favors the reactivation of the latent infection, through multiple mechanisms, such as:
– Depletion of all types of T cells,
– Decreased activation and proliferation of T cells,
– Decreased synthesis of IL-2,
– Decreased production of Th-1-type cytokines or almost total impairment of cellular immunity.
These immunosuppressants are:
– T-cell depleting agents (antithymocyte globulin),
– inhibitors of cytotoxic T lymphocyte-associated protein 4 (belatacept),
– calcineurin inhibitors (tacrolimus, cyclosporine),
– antimetabolites (mycophenolate, azathioprine),
– glucocorticoids
TB transmission in KT receivers may be possible according to three scenarios:
– In the first, it could arise after KT as a result of the reactivation of the latent infection present in the recipient before the transplant. It is the most common form of transmission found in all solid organ transplants, including KT. Advanced age, absence of Bacillus Calmette-Guérin vaccine scars, presence of donor-specific antibodies, and KT status were factors associated with latent infection
– In the second scenario, TB could be transmitted to KT recipients through a kidney graft from an infected donor, corresponding to only 4.8% of cases.
– In the third scenario, TB could occur as a de novo infection after KT, in a recipient with exposure to a patient with active TB. This type of transmission is not common; it is associated with a very high risk of progression, being more frequent in endemic areas.
Active Tuberculosis
Although the treatment of active TB in KT recipients respects the principles of treatment for immunocompetent patients, some particularities make it complex and challenging. The optimal period of treatment could vary from 6 to 24 months and, in some cases, based on experts’ opinion, the duration of treatment is recommended to be at least 9–12 months. In case of active uncomplicated pulmonary TB, treatment duration should be at least 6 months, but if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months. In case of severe disseminated disease or bone and joint disease, treatment duration is recommended for at least 6–9 months. Patients with central nervous system involvement should be treated for at least 9–12 months.
latent tuberculosis
According to the WHO, latent tuberculosis infection is defined as a state of persistent immune response to stimulation by MBT antigens without evidence of clinically manifest active tuberculosis. There are no gold standard tests for accurately diagnosing latent TB in KT candidates, but IGRA appears to have some advantages over TST in patients with ESRD. Even so, the evaluation of latent TB in KT recipients is challenging because the data are
Treatment challenges
Treatment of KT recipients with TB can be challenging due to drug interactions, drug toxicity, and treatment adherence.
Interaction is a highlight. Rifampicin, a potent inducer of cytochrome P450 3A4 and P-glycoprotein, interferes with the metabolism of immunosuppression. Specifically, rifampicin use decreases levels of calcineurin inhibitors (cyclosporine, tacrolimus), inhibitors of the mammalian target of rapamycin (mTOR) (sirolimus, everolimus) and affects glucocorticoid metabolism, which increases the risk of rejection. Therefore, when a rifampicin-based regimen is used, calcineurin and mTOR inhibitor levels should be closely monitored, the calcineurin and mTOR inhibitor dose should be increased three to five times, and the glucocorticoid dose should be doubled. during treatment and adjusted later to obtain the therapeutic target. Additionally, after discontinuing rifampicin, immunosuppression doses should be reduced to the value prior to starting rifampicin and then adjusted to obtain the therapeutic target. An alternative to rifampicin is rifabutin, which is a weaker inducer of cytochrome P450 3A4 and P-glycoprotein, but with similar efficacy, but likewise immunosuppressive doses can be modified and levels must be closely monitored.
Another challenge is linked to the adverse effects of TB therapy, which are more frequent than in the general population. Patients treated with anti-TB drugs should be carefully monitored for hepatotoxicity (isoniazid, rifampicin, pyrazinamide), neurotoxicity (isoniazid, ethambutol), cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol), visual disturbances (rifabutin, ethambutol), (rifampicin), hyperuricemia (pyrazinamide), or interstitial nephritis (rifampicin, pyrazinamide). The most common adverse event associated with anti-TB therapy is hepatotoxicity; therefore, liver enzymes should be closely monitored with biweekly assessment during the intensive phase of treatment and monthly thereafter.
This is has a level 5 of evidence, because is a Narrative Reviews.
1. Summarise this article
Introduction: Kidney transplant is the treatment of choice for end stage renal disease (ESED) and its outcomes get affected by infections, with tuberculosis (TB) being an important cause of morbidity (graft rejection and loss) and mortality. TB prevalence is high in kidney transplant recipients (KTRs), and it could be either due to reactivation of latent infection, a de novo infection, or could be donor-derived infection.
Epidemiology and risk factors for TB in KTR: The incidence and prevalence of active TB in solid organ transplant ranges from 20 to 74 times the general population, and 0.3% to 15.2% prevalence depending on the geographical areas (with low and high endemicity respectively). TB prevalence in dialysis patients is 3.6 times, and in KTRs is 11.36 times that of in the general population with lung transplant recipients having still higher prevalence.
Risk factors for TB in KTRs: The risk factors include TB burden of the country (endemicity), recipient-associated factors (older age, males, smoker, malnutrition, history of diabetes, chronic obstructive pulmonary disease, latent tuberculosis, chronic liver disease, hepatitis C virus infection, cytomegalovirus infection, pneumocystis, nocardia, long-term hemodialysis, or presence of autoimmune disease), donor-related factors (cadaveric donor, donor with diabetes, low BMI, and history of untreated TB, homeless, smoker, alcohol abuse, incarceration, or known TB contact), or transplant associated factors (acute rejection, chronic graft dysfunction, and immunosuppression used like ATG, belatacept, calcineurin inhibitors, MMF, azathioprine and steroid use). Acute rejection increases the risk of TB by 7.6 times.
Transmission and pathogenesis of TB in KTRs: Aerosol droplets containing mycobacterium tuberculosis, once inhaled, reach lungs and either get cleared by the innate or acquired immunity, or develop primary disease (onset within 2 years), or latent infection (with reactivation happening many years after primary infection).
In latent TB, CD4+ T cell producing interferon gamma and interleukin-2 (IL2) are increased, while they get markedly reduced in active TB. Immunosuppression in KTRs leads to reduced T cells, IL2, and Th1 type cytokines, with reduced activation and proliferation of T cells and decreased cellular immunity leading to activation of TB.
Transmission of TB in KTRs is most commonly due to reactivation of latent TB infection (LTBI), seen in 20% within 2 years post-transplant (median 11.5 months), in patients with older age, BCG vaccinated, and having DSA. Another form is donor-derived TB, responsible for 4.8% cases, seen within first 3 months, presenting with frequent fever, fluid collection, and extrapulmonary features with no response to antibiotics. De novo TB infection is uncommon, seen in endemic regions, and is associated with increased risk of progression.
Diagnostic challenges: TB in KTRs have increased extrapulmonary features and co-infections (50% of cases) with atypical presentations, requiring high index of suspicion. The tuberculin skin test (TST) and interferon gamma release assay (IGRA) are not useful in active TB diagnosis. Radiologic manifestations have wide range, and there is need for invasive procedures like bronchoscopy and bronchoalveolar lavage (BAL). Nucleic acid amplification technique (NAAT) based molecular tests can be false negative. Donor history might be unobtainable, screening with TST and IGRA for LTBI have low feasibility and accuracy with false negative results. For screening in LTBI, IGRA is better than TST.
Treatment challenges: These could be due to drug-drug interactions, drug toxicities as well as maintaining treatment adherence. Once the diagnosis of active TB is made, treatment should be immediately started using Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol in intensive phase followed by Isoniazid and Rifampicin in maintenance phase. The optimal treatment period varies according to the clinical picture: 6 months for uncomplicated pulmonary TB, 9 months for cavitary lesions, or if sputum test is positive at 2 months, 6-9 months for disseminated or bone and joint disease, and 9-12 months for central nervous system (CNS) involvement. For localized non-severe TB, Isoniazid, Ethambutol and Pyrazinamide or Levofloxacin can be used for 2 months followed by 12-18 months of Isoniazid and Ethambutol or Pyrazinamide.
Rifampicin, a cytochrome P450 3A4 inducer, decreases levels of calcineurin inhibitors (CNI), mTOR inhibitors, and steroids requiring increased doses (3-5 times for CNI and mTOR inhibitors, and 2 times for steroids). Severe TB might require reduction in immunosuppression. Rifampicin can be replaced with rifabutin or fluoroquinolones. Adverse effects of antitubercular drugs include hepatotoxicity, neurotoxicity, skin lesions, ophthalmic toxicity, cytopenia, hyperuricemia, interstitial nephritis, and immune reconstitution inflammatory syndrome. Liver function tests should be monitored twice a week initially for first 2 months and then monthly. Doses of the drugs should be adjusted as per creatinine clearance. Treatment adherence can be monitored using the directed observed therapy program.
Latent TB treatment is important in those with a positive IGRA or TST, history of untreated TB or recent TB contact, or donor kidney with LTBI without treatment, untreated TB or TB exposure. Treatment includes isoniazid (5 mg/kg/day) for 9 months, or ethambutol with levofloxacin or moxifloxacin. Liver enzymes should be monitored.
Outcomes: TB in KTRs has challenges in diagnosis, increased extrapulmonary features, and immunosuppressed state leading to increased mortality and morbidity. Graft rejection is seen, due to associated reduction in immunosuppression, in upto 55.6%, leading to graft loss in 1/3rd of patients. Graft loss (due to infection, sepsis, rejection (acute or chronic), or reduction in immunosuppression) can be seen in to 66.6% patients. Mortality rates of upto 60% have been seen, with higher rates in those with co-infections like fungi, nocardia, cytomegalovirus, hepatotropic viruses, chronic liver disease, diabetes, or those who received anti-rejection treatment.
Conclusions: The incidence and prevalence of TB in KTRs is higher than general population, and it needs high index of suspicion for diagnosing and treating such patients. The outcomes in such patients are not good with high rates of rejection, graft loss and mortality.
2. What is the level of evidence provided by this article?
Level of evidence: level 5 – Narrative review.
Summary
Introduction
This article is relating TB infection following kidney transplant. This is an important topic because of the different clinical presentations that recipients can present with when infected with TB, some of which are diagnosed late, and cause great damage to the graft as well as increasing chances of patient mortality.
This review is aimed at giving an evidence based result regarding epidemiology, risk factors, pathophysiology, type of transmission, diagnostic challenges, treatment challenges and impact of infection on recipients.
Discussion
When delving into the world of TB, discussion of risk factors needs to be the first. These are as follows :
Recipient associated risk factors –
Donor associated risk factors –
Transplant associated risk factors –
Others –
TB pathogenesis in kidney transplant recipients
Transmission of TB in kidney transplant recipients has three known routes :
Diagnostic challenges
Active TB usually presents in the first year post transplantation, from latent infection reactivation or de novo infection. Challenges begin when there is atypical presentation of TB leading to late diagnosis and treatment. In addition, the usually tests that can diagnose TB include tuberculin skin test, and IGRA are not useful in this case to identify active TB in these patients.
Careful evaluation of epidemiological risk, personal medical history, physical exam and chest X ray of the donor are required to make sure that there is no transmission of TB from the donor to the recipient.
Latent TB is even more difficult to identify because it is a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB. There are no gold standard tests to diagnose latent TB but IGRA can help more than TST in diagnosis.
Treatment challenges
Treatment of kidney transplant recipients with TB can be challenging because of drug interactions between immunosuppressive drugs and TB treatment drugs, along with the chances of drug toxicity and tendency for patients to not adhere strictly to treatment protocol.
Monitoring medication adherence of recipients is essential and needs to be a focus especially in the case of TB. Suspected non adherence needs to be dealt with appropriately to ensure that the patient gets the maximum benefit from the drug regimen.
In the case of active TB, the recommended duration of treatment is 9-12 months. In the case of uncomplicated TB, treatment can be given for 6 months, but after 2 months if complications persist or the patient has cavitary lesions, then treatment duration must be increased to 9 months.
Rifampicin is recommended as part of first line treatment because it is very efficient and reduces the risk of resistance.However, the challenge associated with Rifampicin is the interaction it has with the patient’s immunosuppressive regimen by interfering with drug metabolization. It is a potent inducer of p450 system and p glycoprotein. It decreases the levels of IS drugs such as CNIs, mTORi along with affecting glucocorticoid metabolization. All of this increases the risk of rejection. Due to this, IS drug levels need to be closely monitored, and dosage needs to be increased three to five fold, with glucocorticoids being increased to double dose. Once Rifampicin is stopped, IS dose needs to be reduced to the value of before start of Rifampicin. In this situation, adequate IS can be difficult to achieve increasing the risk of rejection as well as infection.
Treatment of latent TB needs to be started only after active TB has been excluded. Adequate treatment is essential to prevent reactivation of TB. Treatment can be started with a positive IGRA or TST, history of untreated TB and a history of recent contact with an active TB patient. Non adherence to medication can be a big challenge especially when the patient is not seeing any active symptoms that they need to treat, leading to laxity in taking dosage at the right time with proper frequency.
Conclusion
Undiagnosed TB or imeffective treatment of TB can lead to acute or chronic rejection, increased mortality risk for the recipient, and poor quality of life overall. The interactions between Tb drug regimen and IS drug protocol can be challenging to set fixed dosages and frequencies of these drugs. In addition to this, fluid test levels and difficulty in standardization can lead to misdiagnosis or late treatment.
Despite all these challenges, close monitoring of the patient, along with regular collaboration with infectious disease physicians can make the whole process smoother and more effective for both the transplant team as well as the patient.
Level of analysis
This is a narrative review, and thus level of evidence is 5.
TB is more prevalent in kidney transplant than the general population but less common post lung Tx.
The prevalence varies between 0.3–6.4% in low TB endemicity to 15.2% in high endemic areas. The incidence of active TB in SOT is 20–74 times higher than in the general population.
Latent TB infection: according to WHO is defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB. Prevalence of latent TB after KT was reported in ~20% of recipients.
source of Tb after transplant : Recipients (reactivation of latent infection),Donor tissues (reactivation of latent infection),DeNovo infection.
Diagnostic Challenges
High index of suspicion
Tuberculin skin test (TST)
Interferon gamma release assay (IGRA)
Bronchoscopy with bronchoalveolar lavage, fluid collections subsequently evaluated by smear and mycobacterium culture and histopathology
Molecular tests based on rapid nucleic acid amplification techniques, such as mycobacterium tuberculosis complex
Recognizing latent infection or undiagnosed active TB in the kidney donors is critical in preventing post-transplant infection.
Treatment of Active TB
Duration of treatment is recommended to at least 9-12 months.
American Society of TX infection disease community of practice guidelines recommend in case of active uncomplicated pulmonary TB duration should be at least 6 months.
If a cavity exists or persistence is culture-positive after 2 months of therapy duration should be 9 months.
-CNS infection 19-18 months
-> according to AST- IDCOP four-drug regimen contains rifampicin,INH,Ethambutol,Pyrazinamide
Diagnosis of latent TB
high clinical suspicious
tuberculin skin test (TST)
IGRA
Indications of treatment of latent TB in transplant recipient and donor
Positive TST or a positive IGRA
History of close contact to an active TB case
If recipient received graft from donor has latent TB and did not receive treatment
Protocol for treatment of latent TB
INH for 6-9 months.
Rifampicin better to be avoided in transplant patient because of drug-drug interactions and rifabutiun is an alternative.
Level of evidence -is level 5 for Narrative review
T cell immunity , T1 cells , is most important to prevent TB in recipient
BUT due to IS after KT T cells are dysfunctional
DIAGNOSIS
High index of suspicion , personal history and clinical and radiologocal manifestation
TST AND IGRA are not useful in active TB but ccan be used to diagnose LATENT TB
Donor deriived TB – recipient having fever in first 3 months , non specific symptoms , perigraft fluid , no response to empirical antibiotics
LATENT TB
Diagnosis based on – immune response to TB antigen is present BUT symptoms of TB are absent
Should be screened for in all KT candidates and donors
NO GOLD STANDARD TEST
IGRA is better than TST
Some study showed even low sensitivity for IGRA in KT patients
TREATMENT
ACTIVE TB
National TB policy applies to such patient
duration 6-24 months
standard 4 drugs consolidation and then 2 drug maintanence
DRUG INTERACTION is common due to rifampicin which reduces the level and INH which increases the level of IS drugs
Doses of IS need strict monitering
DRUG TOXICITY
Hepato-toxicity
cytopenia
neuro toxicity
visual disturbaances
increased uric acid
TREATMENT OF LATENT TB
positive TST or IGRA test,
history of untreated TB,
history of recent contact with an active TB patient
when the kidney graft originates from a donor with known latent
TB without chemoprophylaxis,
known history of untreated TB or
recent exposure to active TB
INH single agent for 9 month
rifampicin is avoided for latent TB in KT patient
REJECTION can be as high as 50 % in recipient with TB
GRAFT LOSS ( 2% – 60 %) can be due to infection , and rejection due to reduction in IS
MORTALITY is high (0-50%)
CONCLUSION
TB is more common after KT and associated with more rejection and increased moratlity
LATENT TB detection and treatment is the best way to avoid this but it is a complex clinical job
LEVEL 4 EVIDENCE
Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review
Tuberculosis (TB) in kidney transplant (KT) recipients is an important opportunistic infection with higher incidence and prevalence than in the general population and is associated with important morbidity and mortality.
Prevalence of active TB in KT recipients ranges between 0.3–15.2%. KT recipients with active TB could have a rejection rate up to 55.6%, a rate of graft loss that varies from 2.2% to 66.6% and a mortality rate up to 60%.
Introduction
infection after KT is still an important limitation for graft and patient outcomes .One of the most common infections with negative impact post-transplantation is tuberculosis.
As KT is associated with an immunosuppression status, active TB is higher in KT recipients than in the general population.
Active TB after KT could arise from reactivation of latent infection in the recipient or donor tissue or can result from de novo infection after transplantation. Endogenous reactivation after KT is the most common form of transmission.
KT candidates and recipients with TB represent a real challenge regarding the diagnosis and treatment due to atypical or diverse clinical presentation, limitations of screening tests for latent infection, drug interactions and toxicities .
The delay in diagnosis and treatment could determine negative consequences, such as graft rejection, graft loss and increased mortality rate.
Epidemiology of Tuberculosis in Solid Organ Transplantation
The prevalence of active TB among patients with solid organ transplantation is highly variable according to the geographic area. In areas with low TB endemicity, the prevalence varies between 0.3–6.4%, compared to prevalence of TB in high, endemic areas which could rise to 15.2%.
The incidence of active TB in solid organ transplantation is 20–74 times higher than in the general population.
Epidemiology of Tuberculosis in Kidney Transplantation
The prevalence of active TB in KT recipients varies from 0.3% to 15.2% and is higher than in the general population but lower than in patients with lung transplantation.
an unadjusted TB risk ratio of 11.36 (95% CI: 2.97–43.41) times higher in KT recipients, compared to the general population and an adjusted risk ratio for patients on dialysis of 3.62 (95% CI 1.79–7.33) times higher than those from the general population.
Risk Factors for Tuberculosis in Kidney Transplantation
There are several risk factors that predispose KT recipient to develop TB more frequently than the general population .
The risk is mainly influenced by endemicity of TB in the population, but key factors associated with the recipient, donor and transplantation increase it.
immunosuppression therapy, presence of acute rejection episodes and chronic graft disfunction .
Immunosuppression used in KT impairs T-cell-mediated immunity involved in TB control and favors latent infection reactivation.
Some immunosuppressive drugs or combinations certainly increase the risk of TB development: Tcell-depleting agents (anti-thymocyte globulin), cytotoxic T-lymphocyte-associated protein-4 inhibitors (belatacept), calcineurin inhibitors (tacrolimus, cyclosporine), anti-metabolites (mycophenolate, azathioprine) and glucocorticoids.
number of rejections after transplant is an independent risk factor for TB appearance.
chronic graft dysfunction, which could increase the risk of TB development by amplifying the immunosuppression status on its own or due to drug overdosing, a condition similar to advanced CKD.
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients
According to the natural history of infection, after the aerosol droplets containing mycobacterium tuberculosis (MBT) are inhaled into the lungs, the evolution could be as follows: clearance of MBT by the organism either due to innate immune response or acquired T cell immunity, development of primary disease which means an immediate onset of active disease (first 24 months after primary infection) or latent infection reactivation meaning a late onset of active disease many years following primary infection.
Using immunosuppression in the setting of KT could disrupt the protection against TB and increase the risk of reactivation through multiple mechanisms, such as: depletion of all types of T cells, decrease in activation and proliferation of T cells, decrease in IL-2 synthesis, decrease in the production of Th-1 type cytokines or impairment of cellular immunity almost completely.
Diagnostic and Treatment Challenges
Diagnostic Challenges
Active Tuberculosis
The diagnosis after of latent TB requires infection a high and index earlier of in suspicion the based on case of donor-derived the epidemiological infection (in risk, the personal history, manifestations and imagistic lesions.
For example, tuberculin skin test (TST) and interferongamma release assay (IGRA) are not useful in the diagnosis of active TB .
Additionally, the wide range of radiographic manifestations in pulmonary TB and the frequent need for invasive procedures (bronchoscopy with bronchoalveolar lavage, derange of fluid collections subsequently evaluated by smear and mycobacterium culture and histopathological evaluation) could represent diagnostic challenges .
Moreover, molecular tests based on rapid nucleic acid amplification techniques, such as mycobacterium tuberculosis complex and resistance to rifampin test (Xpert ® MTB/RIF, Cepheid, Sunnyvale, CA, USA), could provide false negative results when mycobacterial load is low .
Recognizing latent infection or undiagnosed active TB in the kidney donors is critical in preventing post-transplant infection [10]. As active disease in donors is a contraindication for donation, identification of latent TB in deceased donors remains a real challenge in KT, despite the current recommendation for screening [12,13]. Current guidelines (American Society of Transplantation Infectious Diseases Community of Practice and European Society of Clinical Microbiology and Infectious Diseases) recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors [12,13]. Nevertheless, in deceased donors, the patient’s medical history might be unobtainable, and the screening tests for latent TB (TST and IGRA) have low feasibility and accuracy .In these circumstances, details regarding donor history of previous active TB, specific treatment or exposure to active TB within the last 2 years should be obtained from the donor’s family or relatives .
Additionally, if an IGRA test is performed, a series of aspects should be considered—the result might not be available in time, the result could be false negative in donors with head injury due to depressed cell-mediated immunity and, in high-risk donors from low endemic areas with positive tests, the decision of donation should be correlated with personal history and chest imaging .
Latent Tuberculosis
Prevalence of latent TB after KT was reported in ~20% of recipients Current guidelines provide recommendations for latent TB screening in all KT candidates and donors before transplantation .
There are no gold standard tests for diagnosing latent TB accurately in KT candidates, but IGRA seems to present some advantages over TST in patients with ESRD.
IGRA tests have a good predictive potential for latent TB in KT recipient with negative TST
The importance of diagnosis is supported by the fact that undiagnosed and untreated latent TB after KT significantly increases the risk of active TB.
Treatment Challenges
Treatment of KT recipients with TB could be challenging due to drug–drug interactions, drug toxicity and treatment adherence. For this reason, it is recommended that the management of KT patients with TB be carried out by an experienced clinician and special attention must be paid to drug–drug interactions and potentially adverse events.
Active Tuberculosis
The treatment of active TB should be promptly started immediately after the diagnosis has been established. Additionally, the epidemiological features from the area of patient’s origin and drug resistance patterns should be assessed .
The optimal period of treatment could vary from 6 to 24 months and, in some cases, based on experts’ opinion, the duration of treatment is recommended to be at least 9–12 months
level of evidence V
Introduction
● Infection after KT is still an important limitation for graft and patient outcomes
● Active TB is higher in KT recipients than in general population . It could arise from:
☆ Reactivation of latent infection in the recipient
☆ Donor tissue
☆ can result from de novo infection after
transplantation.
● Endogenous reactivation after KT is the most common form of transmission
● KT candidates and recipients with TB are a real challenge in diagnosis and treatment due to:
☆ Atypical or diverse clinical presentation, ☆ Limitations of screening tests for latent infection
☆ Drug interactions and toxicities
● Factors associated with latent infection:
☆ Older age
☆ Absence of Bacillus Calmette–Guérin vaccine scars
☆ Presence of donor specific antibodies
● Positive latent infection conversion was found in ~20% of cases within the first 2 years after KT
Epidemiology of Tuberculosis in SOT Transplantation
● The prevalence of active TB in SOT is 0.3–6.4% with low TB endemicity and 15.2% in high endemic areas
● The incidence of active TB in SOT is
20–74 times more than in the general population
Epidemiology of Tuberculosis in Kidney Transplantation
● The prevalence of active TB in KT recipients varies from 0.3% to 15.2%
● Active TB incidence in KT recipients is lower than in lung transplant recipients
Risk Factors for Tuberculosis in Kidney Transplantation
● Recipient-associated :
* Older age
* Male gender
* Smoking
* Diabetes
* Malnutrition
* Latent TB before transplantation
* Chronic obstructive lung disease
* Hepatitis C virus infection
* Chronic liver disease
* Opportunistic co-infection : CMV , nocardia ,Pneumocystic
* Autoimmune disease
* Long term hemodialysis
● Donor associated :
☆ Donor type (cadaveric )
☆ Social risk factors ( homeless , alcohol abuse, incarceration , known TB contact , smoking )
☆ Medical risk factors : ( diabetes , history of untreated TB , BMI < 18.5 )
● Transplantation associated :
☆ Immunosuppression therapy
☆ Acute rejection episodes
☆ Chronic graft disfunction
● Others: TB burden of the country
Transmission and Pathogenesis of Tuberculosis in KT Recipients
● Aerosol droplets containing (MBT) are inhaled into the lungs, the evolution could be as follows:
☆ Clearance of MBT
☆ Development of primary disease which means an immediate onset of active disease
☆ Latent infection reactivation meaning a late onset of active disease many years following primary infection
● Transmission of TB in KT recipients:
☆ Reactivation of latent infection present in the recipient prior to transplantation prevalence of latent infection is higher in KT recipients than candidates
☆ Via kidney graft from an infected donor (4.8% of cases)
☆ A de novo infection after KT, in a recipient with exposure to a patient with active TB ( it is not common and associated with very high risk )
● The protection against MBT infection is mainly based on cellular immunity, more specifically, it depends on ( Th1) response
Diagnostic and Treatment Challenges
● active TB : Appears in the first year after KT in reactivation of latent infection and in first 3 months in donor-derived infection which associated with severe extrapulmonary manifestations and mortality
● KT recipients have atypical clinical presentations which reduce the suspicion of TB
● Co-infections and extrapulmonary localization in ~50% of cases
● (TST) and (IGRA) are not useful in the diagnosis of active TB
● Donor-derived TB is suspected in KT recipients with one of following features:
☆ Non-specific symptoms
☆ Frequent fever in first 3 months after KT
☆ Fluid collections
☆ Extrapulmonary manifestations or lack of response to antibiotic
● Current guidelines recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors
● IGRA test might not be available in time, and it could be false negative in donors with head injury
● In high-risk donors from low endemic areas with positive tests, the decision of donation should be correlated with personal history and chest imaging
Latent Tuberculosis
● IT is a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB
● Prevalence of latent TB after KT was reported in ~20% of recipients
● IGRA seems to present some advantages over TST in patients with ESRD
● The incidence and prevalence of latent TB in KT recipients is higher than in KT candidates and therefore KT recipients should be more frequently screened
Treatment of Active Tuberculosis
● In active uncomplicated pulmonary TB, treatment duration should be at least 6 M extended to 9 M in cavitary lesions and persistent culture-positive sputum after
2 M of therapy
● In severe disseminated disease or bone
and joint disease, treatment duration is at least 6–9 M
● Patients with central nervous system involvement should be treated 9–12 M
● The first-line treatment should be a four-drug regimen containing rifamycin and consists of a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin
● Second-line regimen without rifamycin the 2-month contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a phase of 12–18 months with isoniazid and ethambutol or pyrazinamide. Here a longer period of treatment is recommended
● One challenge is the drug interaction between rifampicin and IS drugs
☆ Rifampicin decrease the levels of CNi , mTORi and affects steroid metabolization,
which increases the risk of rejection
☆ Therefore calcineurin and mTOR inhibitors levels should be monitored and increased three- and five-fold and the glucocorticoid dose should be doubled
☆ An alternative to rifampicin is rifabutin, which is a weaker inducer of cytochrome P450 or fluoroquinolones
● Another challenge is AEs of TB therapy
☆ Hepatotoxicity (isoniazid, rifampicin,pyrazinamide, ethambutol)
☆ Neurotoxicity (isoniazid, ethambutol),
☆ Cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol)
☆ Visual disturbances (rifabutin, ethambutol)
☆ Skinlesions (rifampicin)
☆ Hyperuricemia (pyrazinamide)
☆ Interstitial nephritis (rifampicin , pyrazinamide)
☆ liver enzymes should be monitored with bi-weekly during intensive phase of treatment and monthly thereafter
● Another challenge is treatment adherence which can improve by directed observed therapy programs
● Reduction of immunosuppression in the case of severe TB or when a vital organ is involved should be considered.
Treatment of Latent Tuberculosis
● Considered only after active TB has been excluded.
● Treatment indicated in one of the following conditions:
☆ A positive TST or IGRA test
☆ A history of untreated TB
☆ A history of recent contact with an active TB patient
☆ When the kidney graft originates from a donor with known latent TB without chemoprophylaxis
☆ Known history of untreated TB or recent exposure to active TB
● The preferred treatment of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6
● An alternative regimen for KT recipients consists of ethambutol and levofloxacin or
moxifloxacin
Outcomes
● Rejection
☆ Can reach up to 55.6%
☆ Associated with reduced levels of IS secondary to CNi–rifampicin interaction and responsible for ~1/3 of graft losses
● Graft Loss
☆ Prevalence with active TB varies from 2.2% to 66.6%
☆ Due to infection especially in donor-derived TB
☆ Or through the sepsis produced by TB
☆ Or due to acute or chronic rejection
☆ Risk factors associated with non-recovery of graft function were :
*severe TB disease
*acute kidney injury stage 2 or 3
*acute rejection
*value of serum creatinine
● Mortality
☆ 0% to 60%
☆ 65% of KT recipients with active-TB who died had co-infections with fungi, CMV, nocardia, hepatotropic viral infections and chronic liver disease or received anti-rejection treatment before the TB development and had diabetes
Conclusions
● TB in KT is an opportunistic infection with higher incidence and prevalence and is associated with significant negative graft and patient outcomes.
● It requires close collaboration between kidney transplant and infectious disease
● Donor-derived TB and latent TB in KT are should be carefully evaluated.
● Newly discovered regimens could limit drug–drug interactions, improvement of treatment efficacy and reduction of adverse events.
● Level : 5
Summary:
Introduction :
The optimal treatment for ESRD is KT. Kidney transplant recipients have a higher incidence of tuberculosis than the overall population. Active TB in the recipient could be the result of reactivation of latent infection in recipient or donor tissue, or it could be the result of de novo infection in the recipient. The diagnosis and treatment of tuberculosis in recipients sometimes remains difficult.
Methodology :
This study performed an extensive literature review of articles published between 1 January 2000 and 15 June 2022 to provide an evidence-based review of epidemiology, pathogenesis, diagnosis, treatment and outcomes of TB in KT recipients. We included all studies which reported epidemiological and/or outcome data regarding active TB in KT, and we approached the diagnostic and treatment challenges according to the current guidelines.
Epidemiology:
Prevalence varies depending on geographic location; places with low endemicity vary from 0.3-6.4%, while those with high endemicity can reach 15%. The incidence of solid organ transplantation is between 20 and 74 times that of the general population. The prevalence is higher than in the general population but lower than in people who have had lung transplants.
Risk factors in kidney transplant recipients:
Recipients are more likely to develop TB than the general population due to several risk factors, such as immunosuppression therapy, acute rejection episodes and chronic graft dysfunction. Some immunosuppressive drugs or combinations increase the risk of TB development as it impairs T-cell-mediated immunity , such as T cell-depleting agents and cytotoxic T-lymphocyte-associated protein-4 (belatacept ) , calcineurin inhibitors, anti-metabolites, rejection, chronic graft dysfunction, and drug overdosing.
Transmission and pathogenesis in kidney transplant recipients:
There are three possible ways for TB to manifest in Kidney transplat recipient.
– Through reactivation of the latent infection (the most common).
– Through transmission from an infected donor kidney (4.6% of cases).
– Through de novo infections (rare, more common in endemic areas), which carry a high risk of progression.
Diagnostic Challenges:
Active tuberculosis
High index of suspicion is needed as unusual clinical presentations, and likelihood of co-infection make active TB diagnosis difficult. Mycobacterium tuberculosis complex and resistance to rifampin test may give false negative results when mycobacterial load is minimal.
Kidney transplant patients with vague symptoms, frequent fever, fluid accumulation, extra-pulmonary signs, or no response to empirical antibiotic therapy should be investigated.
Current guidelines demand a detailed epidemiological risk, personal medical history, physical exam, and chest radiography in all donors, although screening assays for latent TB (TST and IGRA) have low feasibility and accuracy.
Latent tuberculosis
Latent TB infection is an immunological response to MBT antigens without clinical symptoms.
Around 20% of KT recipients developed latent TB, and current recommendations urge screening all candidates and donors before transplantation.
In ESRD patients, IGRA may be better than TST for identifying latent TB in KT candidates.
In this group, TST and IGRA prediction findings are inconsistent.
Shu et al. recommend screening KT recipients more often than candidates since they have a higher latent TB rate.
Undiagnosed and untreated latent TB raises the likelihood of active TB, highlighting its relevance.
Treatment:
Active Tuberculosis:
The treatment of TB in transplant recipients may be complicated because to drug–drug interactions, drug toxicity, and treatment adherence.
The appropriate duration of treatment could range from six months to twenty-four months, and in some circumstances, according to the decision of specialists. The duration of treatment should be at least nine to twelve months. In cases of active, uncomplicated pulmonary tuberculosis, the American Society of Transplantation Infectious Diseases Community of Practice (AST-IDCOP) recommends a treatment duration of at least 6 months. However, if cavitary lesions are present or culture-positive sputum persists after 2 months of therapy, the treatment duration may be extended to 9 months. In cases of severe disseminated disease or bone and joint disease, at least 6–9 months of treatment is advised. Individuals with involvement of the central nervous system should be treated for at least 9–12 months.
A four-drug combination comprising rifamycin should be the first-line treatment for both severe and non-severe patients.
Latent tuberculosis:
Active TB should be excluded before treatment of latent TB is considered , which is isoniazid 5 mg/kg/day for 9 months, plus vitamin B6 supplement . Follow up of liver enzymes during treatment is recommended.
Conclusion:
Prevalence of active TB in KT recipients ranges between 0.3–15.2%. KT recipients with active TB could have a rejection rate up to 55.6%, a rate of graft loss that varies from 2.2% to 66.6% and a mortality rate up to 60%. Understanding the epidemiological risk, risk factors, transmission modalities, diagnosis and treatment challenges is critical for clinicians in providing an appropriate management for KT with TB.
Level of evidence: level V
MTB AFTER KIDNEY TRANSPLANTATION;A COMPREHENSIVE REVIEW.
Introduction.
-Covid aside, TB is the leading infection cause of death post transplant. Immunosuppression has made TB to be more prevalent in the transplant cohort compared to the general population.
-Active TB post transplant is from ; LTBI, donor tissue or de-novo infection post transplant.
-This article looks into updates on epidemiology, risk factors, pathophysiology. type of transmission, diagnostic challenges, infection challenges and TB impact on KTR.
Methods.
-Literature search on pubmed and embaca data bases was done using specific words to help the study.
-Inclusion criteria ;Studies wit epidemiological data or outcomes in TB in KTR
-Exclusion criteria ; Articles in non english, articles with inadequate information, Articles on non kidney transplants.
-All articles were reviewed by 2 reviewers and later cross checked by a 3rd reviewer.
Epidemiology and risk factors for TB in KT.
-Prevalence in SOT -Low endemic areas 0.3-6.4% vs 15.2% in high endemic areas. Incidence is x20-74 higher than the general population.
-Prevalence in KT -0.3-15.2% ,Higher than the general popn but lower than lung transplant recipients.
-Higher than in pts with ESRD pre dialysis but lower than those on PD and HD.
–Transplant associated risk factors; Immunosuppressive therapy, acute rejection and graft dysfunction all impair the immune system and favor TB infection.
-Recipient associated risk factors; old age, male ,smoking, DM,COPD,LTBI pre transplant, CLD, hep c infection, CMV,PCP and Norcardia infections ,Autoimmune dx and long term hemodialysis.
-Donor associated factors; cadaveric donor, homeless, smoking, alcohol use, DM. low BMI <18.5 and hx of untreated TB.
-Others ;TB burden in the country.
Transmission and pathogenesis of TB in KTR.
-Transmitted with aerosol spread into lungs where it is cleared by the immune response, develops into primary dx or LTBI.
-In KTR ,transmission occurs via; LTBI, donated kidney or de-novo infection post exposure to pt with active TB.
-Post transplant, immunosuppression destroys the immune system and leads to either reactivation or increased susceptibility to TB infection.
Diagnostic and treatment challenges.
>Active TB.
-Median time of 11.5monthd for LTBI while 3/12 for DDI for active TB to appear, Atypical presentation makes diagnosis challenging.
-TST and IGRA not useful in diagnosing active TB with the CXR being quite non specific.
-Donor derived TB has mostly extrapulmonary presentation.
-Invasive procedures might be needed to get samples for evaluation by smear and mycobacterial culture which could be a challenge in doing.
>Latent TB.
-All transplant pairs to be screened for LTBI pre-transplant. IGRA preferred to TST pre transplant.
.>Active TB.
-RIF is a cytochrome 450 +P glycoprotein inducer and thus decreases CNI and MTOR inhibitors and thus dose to be increased x3-5 while steroids dose doubles during treatment and readjusted thereafter. Readjust immunosuppression to pre treatment levels post TB tx with adequate trough levels to avert graft dysfunction.
-Other challenges include SE and Adherence to Tx, RIS to be considered in those with severe TB infection.
>LTBI.
-Tx once active TB has been excluded.
-Tx; INH -9/12+Pyridoxine.Rifampicin based regimens discouraged. Alternative; Ethambutol + levofloxacin or moxifloxacin.
TB Outcomes in KTR; Rejection, mortality or graft loss.
Conclusion.
TB in KTR is fatal with higher prevalence than the general popn. It has both diagnostic and treatment challenges and need careful consideration and approach.
LEVEL OF EVIDENCE; V
Introduction:
As KT is associated with an immunosuppression status, active TB is higher in KT recipients than in the general population.
Active TB after KT could arise from reactivation of latent infection in the recipient or donor tissue or can result from de novo infection after transplantation.
Endogenous reactivation after KT is the most common form of transmission.
In order to limit or prevent the occurrence of active TB post-KT, it is necessary to implement screening measures for both recipients and donors according to the current guidelines.
Methods:
A literature search on PubMed and Embase electronic databases was performed from 1 January 2000 to 15 June 202.
Epidemiology and Risk Factors for Tuberculosis in Kidney Transplantation:
Epidemiology of Tuberculosis in Solid Organ Transplantation:;
The prevalence of active TB among patients with solid organ transplantation is highly variable according to the geographic area.
In areas with low TB endemicity, the prevalence varies between 0.3–6.4%, compared to prevalence of TB in high, endemic areas which could rise to 15.2%.
Epidemiology of Tuberculosis in Kidney Transplantation:
The prevalence of active TB in KT recipients varies from 0.3% to 15.2%.
Risk Factors for Tuberculosis in Kidney Transplantation:
Transplant associated factors:
Immunosuppression therapy,
Presence of acute rejection episodes
Chronic graft dysfunction.
Donors and recipient related factors:
Type of donors ,medical conditions ,social factor’s ,smoking.
OLD MALE RECPIENT ,DIABETIC ,SMOKING ,MALNUTRTION ,LIVER DIASES ,COPD ,LONGTERM DIALYSIS ,LIVER DISAES ,LATENT INFECTION ,COINFECTION.
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients:
Aerosol droplets containing mycobacterium tuberculosis (MBT) are inhaled into the lungs,
Clearance of MBT by the organism
Development of primary disease.
Or latent infection reactivation meaning a late onset of active disease many years following primary infection.
Transmission of TB in KT recipients:
Reactivation of the latent infection. ~20% of cases.
Transmitted to KT recipients via kidney graft from an infected donors. 4.8% more risk of progression, and more frequent in endemic areas.
Diagnostic and Treatment Challenges:
Diagnostic Challenges :
Active Tuberculosis:
High index of suspicion:
Based on epidemiologic risk, personal history
Atypical clinical presentation.
Extra pulmonary localization in ~50%
And coinfection.
TST and iGRA are not useful in the diagnosis of active TB.
Various radiological manifestation, need of invasive test, Xpert® MTB/RIF, Cepheid, Sunnyvale, CA, USA), could provide false negative results when mycobacterial load is low.
Donor-derived TB, it is described in a minority of cases, it is associated with severe extra pulmonary manifestations and mortality.
Should be suspected in KT recipients with one of the following features:
non-specific symptoms, frequent fever in the first 3 months after KT, fluid collections, extra pulmonary manifestations or lack of response to empirical antibiotic therapy.
Current guidelines recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors.
For deceased donors:
Details regarding donor history of previous active TB, specific treatment or exposure to active TB within the last 2 years should be obtained from the donor’s family or relatives.
IGRA test is performed, false negative and false positive in donors .
Latent Tuberculosis :
According to WHO, latent TB infection is defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB.
The evaluation of latent TB in KT recipients is challenging because data regarding prediction capacity of TST and IGRA tests are discord.
Treatment Challenges Treatment of KT recipients with TB could be challenging due to drug–drug interactions, drug toxicity and treatment adherence.
Duration of treatment:
AST-IDCOP guidelines recommends
Case of active uncomplicated pulmonary TB ,6 months, but if Cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months.
In case of severe disseminated disease or bone and joint disease, is recommended for at least 6–9 months.
Patients with CNS should be treated for at least 9–12 month.
The European Society of Clinical Microbiology and Infectious Diseases suggests:
A standard regimen used for a period longer than 6 months, and, in cases of localized non-severe TB, a regimen without rifampicin could be used if no resistance to isoniazid is present.
If a regimen without rifamycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide
if second-line drugs are used, a longer period of treatment is recommended.
Drug interaction:
Rifampicin, a potent inducer of cytochrome P450 3A4 and P-glycoprotein, interferes decrease the levels
CNI
Mtor.
Calcineurin and mTor inhibitors levels should be closely monitored, the dose of calcineurin and mTOR inhibitor should be increased between three- and five-fold and the glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target.
Rifampicin is rifabutin, which is a weaker inducer of cytochrome P450 3A4 and P-glycoprotein but with similar efficacy. Follow and monitor IS.
Another safe and effective alternative to rifampicin in KT recipients is treatment with fluoroquinolones.
Adverse effects:
Hepatotoxicity (isoniazid, rifampicin, pyrazinamide, ethambutol).
Neurotoxicity (isoniazid, ethambutol).
Cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol),
Visual disturbances (rifabutin, ethambutol),
Skin lesions (rifampicin), hyperuricemia (pyrazinamide) or interstitial nephritis (rifampicin, pyrazinamide)
Creatinine clearance and adjust the doses for pyrazinamide and ethambutol
Reduction of immunosuppression in the case of severe TB or when a vital organ is involved should be considered.
Monitor LFT Biweekly, then monthly.
Latent Tuberculosis:
Suspect LTBI following conditions:
a positive TST or IGRA test, a history of untreated TB, a history of recent contact with an active TB patient and when the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB
The preferred treatment of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6.
Alternative regimen for KT recipients, mainly for those with high risk, consists of ethambutol and levofloxacin or moxifloxacin.
Outcomes:
Risk of rejection and graft loss.
The mortality:
patients with TB after KT has been reported to range from 0% to 60% .
Conclusions:
TB in KT is an important opportunistic infection with higher incidence and prevalence than in the general population and is associated with significant negative graft and patient outcome, high suspicion and early diagnosis reduce this risk, in collaboration with infectious disease specialist.
Level of evidence V
Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review
Introduction
· Although kidney transplantation is the best choice for patients with ESKD, infection, mainly TB still a main cause of poor outcomes of the graft.
· Active TB is higher in KT recipients than in the general population, mainly due to the reactivation of latent infection in the recipient or donor tissue.
· To prevent the activation of TB, it is crucial to screen both recipients and donors according to the current guidelines.
· This review provides a full revision of TB in KT recipients.
Inclusion Criteria
· All studies about epidemiological and/or outcomes data regarding TB in KT from 2000 to 2022
Exclusion Criteria
· Articles in languages other than English,
· articles that evaluated other types of transplantation than kidney only
· articles with inadequate information
Epidemiology and Risk Factors for Tuberculosis in Kidney Transplantation
· The incidence of active TB in solid organ transplantation is 20–74 times higher than in the general population
· The prevalence of active TB in KT recipients varies from 0.3% to 15.2% and is higher than in the general population but lower than in patients with lung transplantation.
· Risk Factors that predispose to TB in KT recipients: immunosuppression therapy, presence of acute rejection episodes, and chronic graft dysfunction.
· Immunosuppressive drugs that increase the risk of TB: ATG, belatacept, CNI, mycophenolate, azathioprine, and glucocorticoids.
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients
· Transmission of TB in KT recipients could be possible according to three scenarios
1) reactivation of the latent infection presents in the recipient prior to transplantation (the most common in all solid organ transplantation)
2) TB could be transmitted to KT recipients via kidney graft from an infected donor (only 4.8% of cases)
3) TB could occur as a de novo infection after KT, in a recipient with exposure to a patient with active TB (uncommon)
Diagnostic and Treatment Challenges
· The diagnosis of TB requires a high index of suspension, but KT recipients present with atypical manifestations, and tuberculin skin test and IGRA are not useful in the diagnosis of active TB.
· Diagnosis mostly needs invasive procedures (BAL, fluid collections drainage and then to be examined by smear and mycobacterium culture and histopathological evaluation)
· Donor-derived TB is considered an under-recognized condition with early onset after KT in the majority of cases.
· Donor-derived TB should be suspected in KT recipients with: non-specific symptoms, frequent fever in the first 3 months after KT, fluid collections, extrapulmonary manifestations, or lack of response to empirical antibiotic therapy
· Current guidelines recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam, and chest radiography in all donors
· In deceased donors details about a history of previous active TB, specific treatment or exposure to active TB within the last 2 years should be obtained from the donor’s family or relatives
Latent Tuberculosis
· Defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifested active TB
· Current guidelines recommend for latent TB screening in all KT candidates and donors before transplantation
· IGRA hasactive uncomplicated pul[1]monary TB, treatment duration should be at least 6 month some advantages over TST in the diagnosis of latent TB in patients with ESRD
Treatment Challenges
· due to drug–drug interactions, drug toxicity and treatment adherence.
Active Tuberculosis
· For active uncomplicated pulmonary TB, treatment duration should be at least 6 months
· If there is a cavitary lesion or there is a persistent positive sputum culture after 2 months of therapy, the duration of treatment may be extended to 9 months
· For severe disseminated disease or bone and joint disease, treatment duration is recommended for at least 6–9 months
· For CNS involvement, treatment for at least 9–12 months is required
· the first-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases
· The regimen consists of a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin
· in cases of localized non-severe TB, a regimen without rifampicin could be used if no resistance to isoniazid is present
· In rifamycin free regimen, the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide
· Rifampicin decreases the levels of CNI, the mTORi, and affects glucocorticoids metabolization, which increases the risk of rejection
Treatment of latent TB
· Indicated in one of the following conditions: positive TST or IGRA test, a history of untreated TB, a history of recent contact with an active TB patient and when the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB.
· In the KT setting, the preferred treatment of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6
· An alternative regimen for KT recipients, mainly for those with high risk, consists of ethambutol and levofloxacin or moxifloxacin
Outcomes
· immunosuppression associated with morbidity and mortality, and increased extrapulmonary disease
· Graft rejection in KT recipients with TB can reach up to 55.6%, mostly due to CNI–rifampicin interaction
· graft loss in KT patients with TB can be due to infection of the graft, or sepsis from TB
· Graft loss can be due to acute or chronic rejection post-reduction or withdrawal of immunosuppression
· mortality in SOT recipients about 20%, and of patients with TB after KT from 0-60%
Conclusions
· TB in KT has a higher incidence and prevalence than in the general population and has bad graft and patient outcomes
· Transplant physicians should be oriented about the diagnosis and management of TB after KT.
· physicians should be alert about donor-derived TB and latent TB in KT.
· New diagnostic tools and new regimens without drug-drug interaction are needed.
This is a narrative review with evidence 5
II. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review
Summarise the article
Introduction
– kidney transplantation is the preferred treatment among ESKD patients
– TB is an important opportunistic infection in kidney transplant recipients (KTRs)
– the incidence and prevalence of TB is higher among KTRs compared to the general population due to the state of immunosuppression
– it is also associated with significant morbidity and mortality
– active TB infection in KTRs can be as a result of reactivation of LTBI in the recipient or the donor tissue or de novo infection post-transplantation
– endogenous reactivation of LTBI is the most common mode of transmission
– screening measures for both recipients and the donor should be implemented to limit/ prevent occurrence of active TB post-kidney transplantation
Methods
– literature search on PubMed and Embase electronic databases for articles published between 1 January 2000 and 15 June 2022
– inclusion criteria – all studies that reported epidemiological and/ or outcome data regarding active TB in KTRs
– exclusion criteria – articles in other languages apart from English, articles evaluating non-kidney transplantation, articles with missing information
– the investigators looked at the diagnostic and treatment challenges according to the current guidelines
Epidemiology and risk factors for TB in kidney transplantation
– prevalence of active TB among SOTs varies from 0.3 – 15% depending on the geographical area
– incidence of active TB in SOT is 20 – 74times higher than in the general population
– prevalence of TB in KTRs varies from 0.3 – 15%, it is higher than in the general population but lower than in lung transplant recipients
– the risk for developing TB is mostly influenced by endemicity of TB in the population
– risk factors for TB development in KTRs include: –
– Acute rejection increases risk of TB by 7.6 times and the number of rejections is an independent risk factor for TB development
– Immunosuppression impairs T-cell immunity which is involved in TB control and favours LTBI reactivation
– Immunosuppressive agents which increase the risk of TB development include ATG, Belatecept, CNIs, antimetabolites, glucocorticoids
– Chronic graft dysfunction amplifies the immunosuppression state on its own
Transmission and pathogenesis of TB in kidney transplant recipients
– there are 3 possible outcomes following inhalation of the aerosol droplets i.e.,
– transmission of TB in KTRs can occur in three modes i.e.,
Diagnostic challenges
o Active TB
– prognosis depends on early diagnosis and appropriate treatment
– diagnosis requires a high index of suspicion
– diagnostic challenges include atypical or diverse clinical presentation, co-infections, extrapulmonary localization, diverse radiological manifestations, decreased predictive values of screening tests, false negative results, limitations of screening, need for invasive procedures like bronchoscopy
– donor-derived TB is associated with severe extrapulmonary manifestations and mortality
– active TB in the donor is a contraindication to donation
– identification of LTBI in deceased donors remains a challenge
– treatment challenges include drug interactions and toxicities
– these diagnostic and treatment challenges may result in delayed management which can lead to graft rejection, graft loss and increased mortality
o Latent TB (LTBI)
– LTBI is defined as persistent immune response to stimulation by mycobacterium antigens without any evidence of active TB clinically
– evaluation of LTBI in KTRs remains a challenge
– there are no gold standard tests for diagnosing LTBI accurately in KTRs
– IGRA seems to be advantageous than TST in ESKD patients
– undiagnosed and untreated LTBI following kidney transplantation increases the risk of active TB significantly
Treatment challenges
– challenges encountered in treatment of TB in KTRs are due to drug-drug interactions, drug toxicity/ adverse events and treatment adherence
o Active TB
– duration of treatment varies: –
– 1st line treatment is a four-drug regimen containing rifamycin, this is used for both severe and non-severe cases
– rifamycin is recommended due to its sterilization capacity and efficiency, it also reduces the risk of resistance
– standard regimen entails 2-month intensive phase of RHZE followed by a 4-month continuation phase of RH
– Rifampicin (R), Isoniazid (H), Pyrazinamide (Z), Ethambutol (E)
– the main challenge in treatment of active TB in KTRs is the drug interactions between rifampicin and the immunosuppressive agents
– rifampicin is a potent inducer of cytochrome P450 3A4 and P-glycoprotein hence it decreases the levels of CNIs, mTORi, and affects metabolization of glucocorticoids; this in effect increases the risk of rejection
– it is advised that the CNI and mTORi dose be increased by 3- to 5-fold and the glucocorticoid dose doubled during treatment with a rifampicin-based regimen, and the trough levels should be closely monitored
– once rifampicin is stopped, the immunosuppression dose should be reduced to the pre-rifampicin treatment level and dose adjusted accordingly depending on the trough level
– rifabutin is an alternative to rifampicin, it is a weaker inducer of cytochrome P450 3A4 and P-glycoprotein but with similar efficacy
– fluoroquinolones are another safe and effective alternative to rifampicin in KTRs
– the 2nd challenge is adverse effects of anti-TBs which are more frequent among KTRs than in the general population
– these adverse effects include: –
– the 3rd challenge is treatment adherence but this has improved with DOTs (direct observed therapy) programs
– adjust dose of pyrazinamide and ethambutol based on the kidney function
– immunosuppression modulation should be considered in cases of severe TB or when there is involvement of a vital organ
– IRIS can occur with use of rifampicin and reduction in immunosuppression
o Latent TB
– LTBI treatment is only considered after ruling out active TB
– LTBI treatment in KTRs prevent risk of reactivation
– indications for LTBI treatment among KTRs include: – a positive TST or IGRA test, history of untreated TB, history of recent active TB contact, graft kidney from a donor with untreated LTBI, untreated TB or recent exposure to active TB
– the preferred treatment of LTBI in KTRs is 9 months of isoniazid and pyridoxine, closely monitor the LFTs
– a rifampicin-based regimen is not recommended in KTRs
– an alternative regimen is ethambutol and levofloxacin or moxifloxacin especially for those at high risk
Outcomes – graft rejection, graft loss, mortality
– among KTRs, TB is associated with significant morbidity and mortality due to the state of immunosuppression, increased extrapulmonary disease and challenges in diagnosis which result in delayed treatment
-the risk of graft rejection in KTRs with TB can reach 55% and is mainly due to low levels of immunosuppression as a result of the interaction between CNIs and rifampicin; this can also account for 1/3rd of the graft losses
– graft loss among KTRs with TB can reach 66%, it occurs: –
– mortality of KTRs with TB ranges from 0-60% with most cases being associated with coinfections (fungi, CMV, HCV), diabetes, anti-rejection treatment
Conclusions
– incidence and prevalence of TB in KTRs is higher than that in the general population and is associated with significant negative patient and graft outcomes
– preventive measures should be implemented by careful identification of the risk factors
– there are diagnostic and treatment challenges encountered hence a multidisciplinary approach is advocated for
– donor derived TB and LTBI should be carefully evaluated in KTRs
– graft and patient outcomes can be improved by development of tests with better predictive values, drug regimens with less drug-drug interactions, adverse effects and improved efficacy
Level of evidence provided by this article
– Level V
This review by Bogdan Marian Sorohan and collaegues did an extensive literature review of articles published between 1 January 2000 and 15 June 2022 to provide an evidence-based review of epidemiology,pathogenesis,diagnosis,treatyand outcome of TB in KT recipients.
According to World Health Organization (WHO),
~10 million cases of TB (were reported in 2020 worldwide, corresponding to an incidence rate of 127 cases per 100,000 people per year .This shows that TB is quite prevalent all over the world and the risk of infection increases markedly in SOT patients.
Epidemiology of Tuberculosis in Solid Organ Transplantation
The prevalence of active TB among patients with solid organ transplantation is highly variable according to the geographic area. In areas with low TB endemicity, the prevalence varies between 0.3–6.4%, compared to prevalence of TB in high, endemic areas which could rise to 15.2% .The incidence of active TB in solid organ transplantation is 20–74 times higher than in the general population.
Epidemiology of Tuberculosis in Kidney Transplantation.
The prevalence of active TB in KT recipients varies from 0.3% to 15.2% and is higher than in the general population but lower than in patients with lung transplantation.
Risk Factors for Tuberculosis in Kidney Transplantation.
The risk factors are
Recipient associated like older age, Malnutrition, Diabetes, COPD, CLD, latent TB , opportunistic infections, autoimmune disease.
Donor associated
Donor type ( Cadaveric)
Homeless
DM , BMI less than 18.5
History of untreated TB
Transplant associated
Immunosupression
Acute rejection
chronic graft dysfunction
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients
According to the natural history of infection, after the aerosol droplets containing mycobacterium tuberculosis (MBT) are inhaled into the lungs, the evolution could be as follows: clearance of MBT by the organism either due to innate immune response or acquired T cell immunity, development of primary disease which means an immediate onset of active disease (first 24 months after primary infection) or latent infection reactivation meaning a late onset of active disease many years following primary infection.
Diagnostic Challenges
Active Tuberculosis. A high index of suspicion is needed to diagnose active TB in this group of patients as at times the clinical picture is not classical and labs tests might not support the diagnosis.
Latent Tuberculosis
According to WHO, latent TB infection is defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB. The epidemiology and survey of latent TB after KT remain scarce. Prevalence of latent TB after KT was reported in ~20% of recipients. TST and IGRA should be used appropriately to diagnose latent TB.
Treatment Challenges
Treatment of KT recipients with TB could be challenging due to drug–drug interac- tions, drug toxicity and treatment adherence. For this reason, it is recommended that the management of KT patients with TB be carried out by an experienced clinician and special attention must be paid to drug–drug interactions and potentially adverse events.
Latent Tuberculosis
Treatment of latent TB should be considered only after active TB has been excluded. Treatment of KT recipients with latent TB is important for preventing the risk of reactivation. Treatment in this category of patients is indicated in one of the following conditions: a positive TST or IGRA test, a history of untreated TB, a history of recent contact with an active TB patient and when the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB.
Outcomes
TB in KT is associated with important morbidity and mortality due to immunosup- pression status, increased extrapulmonary disease and challenges in diagnosis that delay the initiation of treatment.
Rejection
Graft rejection in KT recipients with TB can reach up to 55.6%, often being associated with reduced levels of immunosuppression secondary to calcineurin inhibitors–rifampicin interaction and could be responsible for ~1/3 of graft losses
Graft Loss
The causes of graft loss among KT patients with TB can be directly due to infection, especially in the case of donor-derived TB, or indirectly through the sepsis produced by sepsis.
Mortality
The mortality of patients with TB after KT has been reported to range from 0% to 60%
CONCLUSION
This article has again reiterated the importance of vigilance in diagnosing TB in post kidney transplant patients and prompt treatment as otherwise it can lead to mortality and graft loss far more than General population.
Mycobacterium Tuberculosis Infection after Kidney
Transplantation: A Comprehensive Review.
Introduction.
TB infection is more common in post kidney transplant recipients than general population due to immunosuppressed status, mainly it is due to reactivation of latent TB in recipient or in donor tissue but might be de novo infection after transplantation, hence, TB screening and treatment for donor and recipient is such important to avoid the negative impact on graft and recipient survival.
Aim of the work and Methods.
Trying to provide an evidence-based update regarding epidemiology, risk factors, pathophysiology, type of transmission, diagnostic challenges, treatment challenges and the impact of TB in KT recipients by collecting data from published studies from 1 January 2000 to 15 June 2022 after review.
Epidemiology and Risk Factors for Tuberculosis in Kidney Transplantation.
The incidence of active TB in solid organ transplantation is 20–74 times higher than in the general population and the incidence varies according to low versus high endemic areas.
The prevalence of active TB in KT recipients varies from0.3% to 15.2% and is higher than in the general population but lower than in patients with lung transplantation and one study shown that the pooled incidence of active TB in KT recipients was higher than in patients with ESRD in pre-dialysis but lower than in those on peritoneal dialysis and hemodialysis.
Many risk factors such as (endemicity of TB in the population, immunosuppression therapy, presence of acute rejection episodes and chronic graft dysfunction, latent TB, DM, malnutrition, smoking, CLD and others).
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients.
The most common scenario is reactivation of the latent infection in the recipient prior to transplantation, second scenario, TB could be transmitted to KT recipients via kidney graft from an infected donor, finally, TB could occur as a de novo infection after KT, in a recipient with exposure to a patient with active TB.
Diagnostic challenges of active Tuberculosis.
Many conditions make TB diagnosis in PKX is a challenge such as atypical clinical presentations, probability of association with other co-infections and extra pulmonary localization in ~50%of cases also low sensitivity of diagnostic tests such as mycobacterium tuberculosis complex and resistance to rifampin test could provide false negative results when mycobacterial load is low.
Many guidelines recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors, and in deceased donor, donor history of previous active TB, specific treatment or exposure to active TB within the last 2 years should be obtained from the donor’s family or relatives.
Latent Tuberculosis.
A state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB, IGRA seems to present some advantages over TST in patients with ESRD but still no gold standard test for diagnosis.
Treatment Challenges/ Active Tuberculosis.
Treatment should start immediately after diagnosis and the most important challenges during treatment are drug–drug interactions, drug toxicity and treatment adherence, the optimal period of treatment could vary from 6 to 24 months and (AST-IDCOP) guidelines recommends that in case of active uncomplicated pulmonary TB, treatment duration should be at least 6 months, but if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months. Rifampicin is recommended for its sterilization capacity and efficiency but also to reduce the risk of resistance, but once started, calcineurin and mTOR inhibitors levels should be closely monitored to avoid risk of rejection and graft loss, also another important point is to follow drugs side effects and the most common adverse event associated with anti-TB therapy is hepatotoxicity; therefore, liver enzymes should be closely monitored with bi-weekly.
Treatment of latent Tuberculosis.
The preferred treatment of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6 and treatment should be for patients with one of the following conditions: a positive TST or IGRA test, a history of untreated TB, a history of recent contact with an active TB patient and when the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB.
Outcomes.
1-Graft rejection in KT recipients with TB can reach up to 55.6%, often due to calcineurin inhibitors–rifampicin interaction and could be responsible for ~1/3 of graft losses.
2-A study from France with a long follow-up period, graft survival rates in KT patients with TB at 1 year, 5 years and 10 years after KT were 97%, 85% and 67%, respectively and mainly due to sepsis, acute rejection, interstitial fibrosis and tubular atrophy were causes of graft loss.
3-The mortality of patients with TB after KT has been reported to range from0% to 60%, and More than half of patients who died received anti-rejection treatment before the TB development and had diabetes, hepatitis C virus infection or fungal infection.
Conclusion:
TB post kidney transplant is one of the common infection that occurred more than general population, it is diagnosis and treatment is still challenging and need high suspicion and still new tools for diagnosis with high sensitivity is required and treatment plan with high efficacy and short time plan is required with low drug- drug interaction.
Level of evidence: (v).
Mycobacterium Tuberculosis Infection after Kidney Transplantation:
A Comprehensive Review:
It’s literature research done in 1 January 2000 to 15 June 2022 from Pubmed.
Epidemiology of Tuberculosis in Solid Organ Transplantation:
The prevalence of active TB among patients with solid organ transplant is generally high and depend on geographical areas.
In low endemic area is 0.3% to 4%. in high endemic area reach to 15%.
The incidence of active TB in solid organ transplantation is 20–74 times higher than in the general population.
Epidemiology of Tuberculosis in Kidney Transplantation:
Many retrospective cohort studies shows Prevalence of active TB in kidney transplant is higher than in general population but lower in comparison with lung transplant.
In a recent meta analysis studies shows prevalence and incidence of active TB in recipient of kidney transplant is more in patients previously known case of ESRD and on haemodialysis in comparison to peritoneal dialysis .
Risk Factors for Tuberculosis in Kidney Transplantation:
Recipient factors:
Donor factors:
Transplant factors:
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients
According to the natural history of infection:
Mode of transmission is aerosol droplets, reactivation of latent TB, donor derived tuberculosis or de novo infection.
Diagnosis and treatment :
It’s by clinical suspicion and radiological manifestations while tuberculin skin test (TST) and interferon gamma release assay (IGRA) are not helpful in the diagnosis of active TB.
Donor derived tuberculosis is suspected when there is extra pulmonary manifestations.
Symptoms of tuberculosis appear early after kidney transplant and radiological manifestation of activation of latent tuberculosis.
The current screening and guidelines (American Society of Transplantation Infectious Diseases Community of Practice and European Society of Clinical Microbiology and Infectious Diseases) recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors; However still activation of latent infection higher in appearance.
The prevalence of latent TB 20% in all kidney transplant patients and There are no gold standard tests for diagnosing latent TB.
The under diagnosis and untreated latent tuberculosis increase risk of active tuberculosis and mortality after kidney transplant.
Treatment:
Treatment of active tuberculosis need multidisciplinary team and infectious specialist regarding drug drug interaction and drug toxicity.Treatment is indicated if TST or IGRA test are positive or presence history of untreated TB, or history of recent contact with an active TB patient and when the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB. The drugs recommended in kidney transplant is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6. A regimen based on rifampicin is not recommended. Other regimen is ethambutol and levofloxacin or moxifloxacin. The main adverse event associated to isoniazid is hepatotoxicity, so evaluation of liver enzymes during treatment is recommended initially biweekly for 6 weeks and then monthly.
Outcomes:
TB in KT is associated with high risk of morbidity and mortality due to immunosuppression status and increase extra-pulmonary disease.
Level 5
Summary of Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Reviewintroduction
Active TB is higher in KR recipient than in the general population and active TB after KT result from reactivation in the recipient or donor tissue or can result from de novo infection after transplantation.
This review aimed to provide evidence Based on updates regarding epidemiology risk factors, pathophysiology, type of transmission, diagnostic challenge treatment challenges, and the impact of TB in KT recipient
methods:-
A literature search or PubMed and Embrace electronic database was performed from I January 2000 to 15 Jan 2022.
Epidemiology and risk factors for tuberculosis in Kidney Transplantation.
Epidemiology of TB in SOT:-
The prevention of active TB among patients with SOT in the area with low endemicity is between 0.3-6.4% but in high T.B endemic areas 15.2%
Risk Factors For TB in Kidney Transplantation:-
Risk Factors that predispose KT recipients to develop TB more frequently than general population
. endemicity of TB in the population.
. Immunosuppression therapy
. acute rejection episodes
. chronic graft dysfunction
. any immunosuppression used in KT impaired T-cell mediated immunity involved in TB control and favor latent infection reactivation such as ATG, abatacept CNI, antimetabolite, and glucocorticoids.
Transmission and pathogenesis of TB in Kidney Transplant recipients:-
1- The reactivation of latent TB in the recipient prior to transplantation (20%).
2- TB could be transmitted to KT recipient via Kidney graft from or infected donor at 4.8%
3- TB can occur as de novo infection after KT uncommon, has a very high risk of progression, and it more frequent in an endemic area.
Diagnostic and treatment challenges
Diagnostic challenges
Active TB
If from reactivation of later TB in the first year of KT (11.5 months).
In the case of the donor derived infection (in the first 3 months).
The diagnosis of TB based on epidemiology risks personal History, manifestation, and imagistic lesions.
KT has a typical chemical presentation and the probability of association with other co-infections and extrapulmonary realization in the 50% of cases adds a supplementary confusing element to the clinical pictures and donor-devised TB should be suspected in KT recipients with one of the following features:-
. non-specific symptoms
. frequent fever in the first 3 months after KT.
. fluid collection
. extrapulmonary manifestation
. lack of response to empirical antibiotics therapy.
Current guidelines recommend a careful evaluation of the epidemiological risk, personal medical history physical exam, and chest radiography in all donors.
In the deceased donor, the details negativity donor history of previous active TB-specific treatment or exposure to active TB within the last 2 years should be obtained from the donor family or relatives.
Laten TB
Guidelines recommended screening for laten TB in all KT candidates and donors before transplantation.
No gold standard test to diagnose latent TB accurately in KT candidates by IGRA has some advantages are TST in patients with ESRD.
Treatment challenges Active TB
Duration of treatment is recommended to at least 9-12 months.
American Society of TX infection disease community of practice guidelines recommend in case of active uncomplicated pulmonary TB duration should be at least 6 months.
If a cavity exists or persistence is culture-positive after 2 months of therapy duration should be 9 months.
->CNS infection 19-18 months
-> according to AST- IDCOP
-> four-drug regimen contains rifampicin
->2 months of INH, rifampicin pyrazinamide, and ethambutol forward by 4 months of INH and rifampicin
->ESCMID European suggests standard therapy longer than 6 months.
-> rifampicin-free region if looked no severe TB regimen includes INH, ethambutol, and pyrazinamide or levofloxacin following 12 -18 months with INH and ethambutol or pyrazinamide.
If the second line of drug use longer period of treatment is recommended.
Rifampicin enzyme inducer of cytochrome p45 decrease the level of CNI and mTOR and also affect glucocorticoid metabolism and causes acute rejection
CNI and mTOR monitoring and increase 3-5 fold should be increased and glucocorticoid dose should be doubled the dose.
Rifabutin is alternative to rifampicin and is a weaker enzyme inducer of cytochrome p45 but even in a rifabutin based regimen is dose could be modified and level closely monitored.
Also fluoroquinolone is a safe and effective alternative to rifampicin, patients should be monitored for side effects of anti T.B medication
Treatment adherence is crucial with KT if not offer DOT.
Sever T.B can reduce IS therapy however the possible occurrence of immune reconstitution inflammatory syndrome which is associated with the reduction of IS therapy and use of rifampicin
Laten T.B
First exclude active T.B and treatment indicated of LTBI when positive TST or IGRA test a history of untreated T,B ,history of recent contact with active T. B patent and when the graft with donor known LTBI without chemoprophylaxis.
Treated by INH 5mg/kg /day(300mg od) for 9 months plus vit B6.
Alternative regimen with high-risk ethambutol and levofloxacin or moxifloxacin .
Follow up liver enzyme weekly for 6 months and then monthly
Outcomes
T.B in KT associated with morbidity and mortality .
Rejection
Graft rejection in KT recipients with T.B can reach up to 55.6% due to decrease level of IS.
Mortality
The mortality of patients with T.B after KT ranges 0-60%.
Conclusion
T.B in KT is associated with significant negative graft and patient outcome.
Donor-derived T.B and laten T.B in KT are under-recognized conditions that should be evaluated carefully.
Newly discovered regimens of drugs in the future limit the drug-drug interaction and reduce the side effects
level of evidence is 5
Introduction:
TB is one of the most important opportunistic infections in post kidney transplant, causing morbidity & mortality. TB infection can occur as reactivation of latent TB in the recipient or derived from the donor or de-novo.
This review aimed to provide an evidence-based update regarding epidemiology, risk
factors, pathophysiology, type of transmission, diagnostic challenges, treatment challenges
and the impact of TB in KT recipients.
Review was done by Searching the literatures on PubMed and Embase electronic databases from
1 January 2000 to 15 June 2022.
Epidemiology of Tuberculosis in Solid Organ Transplantation:
Active TB in solid organ transplant recipients varies by region. TB prevalence ranges from 0.3–6.4% in low-endemic areas to 15.2% in high-endemic areas.
Active TB in solid organ transplant recipients was 3%.
Active TB is 20–74 times more common in solid organ donation.
In a study of 4388 solid organ transplant recipients in 16 Spanish transplant facilities, TB incidence was 512 cases per 100,000 patients per year, 26.6 times higher than in the general population. In 1989 solid organ transplantation recipients in a low-TB country, the incidence of active TB was 41 cases per 100,000 patients per year, 8.5 times higher than the general population.
Epidemiology of Tuberculosis in Kidney Transplantation:
Active TB in KT recipients range from 0.3% to 15.2%, higher than in the general population but lower than in lung transplant recipients. In a case-control analysis of 12,820 KT recipients from 12 main Iranian KT centers, Basiri et al. found 0.3% prevalence. Two comprehensive reviews and meta-analyses found 2.51% and 3% prevalence of active TB following KT. In another meta-analysis, Al-Efraiji et al. showed an uncorrected TB risk ratio of 11.36 times higher among KT recipients compared to the general population and an adjusted risk ratio for dialysis patients of 3.62 times higher.
In a recent meta-analysis, Alemu et al. found that KT patients had a pooled incidence of active TB of 2700 per 100,000 patient-years, ranging from 340 in low-TB burden countries to 14,680 in high-endemic countries. In the same study, the pooled incidence of active TB in KT recipients was higher than in patients with ESRD in pre-dialysis (2700 vs. 913 per 100,000 person-years) but lower than in those on peritoneal dialysis and haemodialysis (2700 vs. 3533 and 5611 per 100,000 person-years, respectively). KT recipients have a lower active TB rate than lung transplant recipients.
Risk Factors for Tuberculosis in Kidney Transplantation: figure 1
Types of transmission:
1- Reactivation of latent TB after transplantation
2- Transmission via infected graft
3- De-novo infection
Diagnosis:
1- Active TB:
– Needs high level of suspicion based on risk factors.
– Presentation &X-ray findings may be atypical
– Tuberculin test &IGRA test are not useful
– Molecular test may be false negative if low bacterial load
– frequent need for invasive procedures (bronchoscopy with bronchoalveolar lavage, derange of fluid collections subsequently evaluated by smear and mycobacterium culture and histopathological evaluation)
– should be suspected one of the following features: non-specific symptoms, frequent fever in the first 3 months after KT, fluid collections, extrapulmonary manifestations or lack of response to empirical antibiotic therapy
– important to consider in deceased donor the detailed history of previous TB & that IGRA results may be not available yet or falsely negative & correlate this with imaging before decision of donation
2- latent TB:
– Current guidelines provide recommendations for latent TB screening in all KT candidates and donors before transplantation
– Kim et al. showed that IGRA tests have a good predictive potential for latent TB in KT recipient with negative TST however, Hadaya and colleagues observed that IGRA tests had a low sensitivity in KT recipients and cannot be used to exclude latent TB.
– Screening should be more frequent
Treatment:
1- Active TB:
The American Society of Transplantation Infectious Diseases Community of Practice (AST-IDCOP) recommends at least 6 months of treatment for active uncomplicated pulmonary TB, but 9 months if cavitary lesions present or if culture-positive sputum persists after 2 months. In severe disseminated or bone and joint disease, treatment should last 6–9 months. Treat central nervous system patients for 9–12 months.
AST-IDCOP recommends a four-drug regimen with rifamycin as first-line treatment for severe and non-severe patients. Rifamycin is suggested for sterilizing and resistance reduction. A 2-month intense phase of isoniazid, rifampicin, pyrazinamide, and ethambutol is followed by a 4-month continuation phase.
the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) recommends a conventional regimen for longer than 6 months and a regimen without rifampicin for localized non-severe TB if isoniazid resistance is absent. If rifamycin is not used, the 2-month intensive phase should include isoniazid, ethambutol, and pyrazinamide or levofloxacin, followed by a 12- to 18-month continuation phase. Second-line medicines require lengthier treatment.
Drug drug interaction between rifampicin & immunosuppression:
– Rifampicin is potent enzyme inducer to Cyp450 , leading to decrease level of CNIs , MTORi , glucocorticoid& increase risk of rejection
– If rifampicin used, increase dose of CNIs & MTORi to 3-5 times & double the glucocorticoid dose with frequent monitoring of drug levels & graft function
– Alternatives is rifabutin which has weaker enzyme inducer effect with same efficacy or fluroquinolones
Ø S/E of the ttt:
Hepatotoxicity, neurotoxicity(INhðambutol), cytopenia, visual abnormalities(rifabutin ðambutol), skin lesions(riafmpoicin), hyperuricemia(pyrizinamide), and interstitial nephritis(rifampicin&pyrizinamide) should be watched in patients on anti-TB medicines. Hepatotoxicity, the most prevalent side effect of anti-TB therapy, should be examined bi-weekly during rigorous treatment and regularly thereafter.
– Adjust dose of pyrazinamide & ethambutol to eGFR
– Consider to Reduce immunosuppression if vital organs affected
2- Latent TB:
– consider latent TB treatment After excluding active TB only.
– Treating latent TB in KT patients prevents reactivation.
– treatment is suggested if the patient has a positive TST or IGRA test, a history of untreated TB, recent contact with an active TB patient, or a kidney graft from a donor with known latent TB without chemoprophylaxis.
– treatment is suggested if the patient has a positive TST or IGRA test, a history of untreated TB, recent contact with an active TB patient, or a kidney graft from a donor with known latent TB without chemoprophylaxis.
– Isoniazid 5 mg/kg/day (maximum 300 mg/day) for 9 months with vitamin B6 is the optimal treatment for latent TB in KT. Rifampicin is not advised . Ethambutol plus levofloxacin or moxifloxacin are a high-risk KT regimen.
Outcomes:
– Graft rejection in KT recipients with TB can reach up to 55.6%
– f graft loss in KT patients with active TB varies from 2.2% to 66.6%
– The mortality of patients with TB after KT has been reported to range from 0% to 60%
risk factors
Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review
A Summary-of this article:
Kidney transplantation is the best modality of renal replacement therapy in individuals with end stage kidney disease. However, infections is one the important cause of morbidity and mortality among these patients. One example of an infection is tuberculosis which occurs due to immune suppression with higher rates in transplant recipients compared to the general populations.
Active tuberculosis developed due to reactivation of latent infection(most common) in recipient or donor tissue or de novo after transplantation.
Diagnosis and management of tuberculosis is difficult because of atypical presentation, problems with screening for latent TB, drug interactions and side effects.
Late diagnosis is associated with risk of rejection, graft loss, and even death.
Method: This article reviewed many articles published between 1 January 2000 and 15 June 2022 regarding epidemiology, pathogenesis, diagnosis, treatment and outcomes of active TB in kidney transplant recipients
Excluded articles: studies in language other than English, studies include other organ
transplant other than kidney only & studies with inadequate information.
The prevalence of active TB is significantly higher in KTx than general population; around 20-74 times higher than general population. It differ according to geographic area, it ranges from 0.3–6.4%, in developed countries and in up to 15% in endemic regions
Aim of the study:
Provide evidence-based update of epidemiology, risk factor, pathophysiology of transmission, diagnostic challenge, treatment challenge and impact of TB infection in Solid organ kidney transplant recipient.
Mode of transmission:
Activation of latent TB (the most common)
Acquiring the disease from the graft (DD)
Acquiring new infection through air born transmission (not common, associated with
aggressive disease and is more commonly seen in endemic areas)
Risk factors for TB in Kidney Transplantation:
Recipient related:
Older age
Male gender
Smoking
Other Comorbidities including DM, COPD, chronic liver disease, malnutrition
HCV infection and opportunistic co-infection such as CMV, PCJ and nocardia
Prolonged hemodialysis before renal transplantation
Latent TB before transplantation
Use of aggressive immunosuppressive therapy
Acute rejection (increase the risk of TB 7.6 times) and chronic allograft dysfunction
Donor related:
Deceased donor transplantation
High Risk DD TB: Social risk factors including homeless patients, smoking, alcohol abuse and contact to TB case
Medical risk factors including the presence of DM, history of previous TB or underweight
Community Related Factors:
TB burden in the community
Pathogenesis of TB in KTx. recipients:
After inhalation of the organism, the patient deal in one of 3 ways : Complete clearance of the organism, primary disease (active TB) or latent TB which may be reactivated later
Recipients with latent TB are at high risk of conversion to active TB after transplantation, it was estimated that around 1/5th of patients with latent TB develop active disease 2 years after transplantation
On the other hand, If the donor has latent TB and did not receive treatment it carry a risk of transmission to the recipient and if that happen the recipient should be treated for latent TB before possible progression to active disease
So all recipients and donors should both be undergo careful evaluation of the risk, history, examination and CXR, together with test for latent TB
Diagnosis of Latent TB:
Latent TB is estimated to involve 20% of transplant recipients
In general, all transplant recipients and donors should be evaluated for the presence of latent TB and once detected treatment should be given.
Two test are used to detect latent TB, tuberculin skin test (TST) and IGRA, both are usually negative in immunosuppressed patients due to their dependence on the host immune response which is impaired in these sets of patients
Which test to use:
In SOT candidates with ESRD, it is preferred to use IGRA over TST due to its higher sensitivity in these sets of patients
In SOT candidates without ESRD, either TST or IGRA can be used.
Patients who have received BCG vaccination in early life can have false positive TST, so they should be evaluated by IGRA
If TST is negative it is better to do IGRA if the patient is living in country with high TB prevalence or if the patient has TB risk factors.
Indications of treatment of latent TB in transplant recipient and donor:
Positive TST or a positive IGRA
History of positive TST or pervious history of TB
Negative TST and/or IGRA in a patient with close contact to an active TB case
If the donor has latent TB and did not receive treatment (treat the recipient), but if the
donor received treatment there is no need to treat the recipient
Protocol for treatment of latent TB:
INH in a dose of 5 mg/kg (maximum dose 300 mg) together with oral pyridoxine 25 to 50 mg daily for 9 months.(The preferred regimen)
Patient should be monitored for liver enzymes and bilirubin at baseline then monthly
Rifampicin containing regimen are not preferred after renal transplantation due to several drug drug interactions
Timing of active TB after transplantation:
Most of cases occur at a median of 11.5 months after tranplantation. Donor-derived TB usually occur earlier within the first 3 months
The diagnosis is challenging (needs high index of suspicion) due to the following:
Atypical clinical presentation is more common in immunocompromised compared to immunocompetent patients
The presence of co-infections which may delay the diagnosis
Around 50% of cases presents with extra pulmonary or disseminated TB (much higher than immunocompetent hosts)
Tuberculin test and IGRA are usually negative
Sputum smear for TB is usually negative despite active TB.
PCR from specimen can be falsely negative if the TB load is low
It is uncommon for the transplant recipients to have the classic picture of TB
To reach diagnosis invasive procedure is usually required including bronchoscopy and BAL or lung biopsy
The treatment of TB in SOT is challenging due to the following
Drug-drug interaction between Rifampicin =The corner stone of TB treatment and immunosuppressive medications used in transplantation
Loss of host immune response to TB due to the use of immunosuppressive drugs
Toxicity of anti-TB medications including hepatotoxicity (the most common side efcect) and cytopenia (isoniazid, rifampicin,pyrazinamide, ethambutol), neurotoxicity (isoniazid, ethambutol), visual disturbances (rifabutin, ethambutol), skin lesions (rifampicin), hyperuricemia (pyrazinamide) and interstitial nephritis (rifampicin,pyrazinamide)
Adherence to the treatment may be a problem in multi-medicated patients like transplant recipients
Protocols used in treatment of TB:
1) Rifampicin containing regimen:
Regimen A– 4-drug regimen of Rifampicin+ INH+ ethambutol + pyrazinamide for 2
months, followed by a 2-drug regimen of Rifampicin + INH for 4 months
It is recommended to increase the duration of treatment to at least 9-12 months if one of
the following is present
-Disseminated disease
-Cavitary disease with positive sputum culture after 2 months of treatment
-Bone and joint disease
-CNS disease.
-Some recommends extending the duration of treatment to 9-12 months in all SOT
recipients since there is improvement in the mortality when using extended duration
2) Rifampicin free regimen:
Regimen A – 3-drug regimen of INH+ ethambutol + pyrazinamide or levofloxacin are used for 2 months, followed by a 2-drug regimen of INH + either ethambutol or pyrazinamide for 12 to 18 months
Regimen B – 3 drugs (INH+ ethambutol + pyrazinamide or levofloxacin are used for 12 months
Regimen C – Rifabutiun can be used instead of rifampicin due to its lesser effect on cytochrome p450, so minimal drug-drug interactions but experience is little when using this drug in transplantation, although it seems effective in HIV TB patients.
It is strongly recommended to use Rifampicin containing regimen especially in patients with severe (cavitary or multilobar) or disseminated disease or if there is an evidence of INH resistance.
In non-severe cases with no evidence of INH resistance, Rifampicin is usually avoided due to its intense drug-drug interactions with immunosuppressive drug (Induction of CYP3A4) with subsequent increase in the risk of rejections so it is better to use rifampicin free protocols
Once rifampin is used, it is recommended to increase the dose of CNI or rapamycin 3-5 folds, with close follow up of serum level and corticosteroid dose should be doubled.
In SOT it is recommended to save Rifampicin for severe and resistant cases , and avoid streptomycin due to its nephrotoxicity
Avoid extreme reduction of the immunosuppressive agents to decrease the possibility of anti-tuberculous therapy – induced immune reconstitution inflammatory syndrome (IRIS). So mild to moderate reduction is advised
Prognosis:
Up to half of the renal transplant recipients with active TB may develop rejection
Graft loss occur in 2.2% to 66.6%
Mortality occur in up to 60 % of patients
What is the level of evidence provided by this article?
A-narrative review =====> level of evidence is (V)
DIAGNOSIS AND TREATMENT CHALLANGES IN TB IN KT RECEPIENTS
Diagnosis is challenging
· Tuberculin skin test (TST) and interferon- gamma release assay (IGRA) are not useful in the diagnosis of active TB .
· the wide range of radiographic manifestations in pulmonary TB and the frequent need for invasive procedures (bronchoscopy with bronchoalveolar lavage, derange of fluid collections subsequently evaluated by smear and mycobacterium culture and histopathological evaluation) could represent diagnostic challenges
· molecular tests based on rapid nucleic acid amplification techniques, such as mycobacterium tuberculosis complex and resistance to rifampin test could provide false negative results when mycobacterial load is low
Latent Tuberculosis
· latent TB infection is defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB
· There are no gold standard tests for diagnosing latent TB accurately in KT candidates,
· IGRA seems to present some advantages over TST in patients with ESRD ,IGRA tests have a good predictive potential for latent TB in KT recipient with negative TST
· The importance of diagnosis is supported by the fact that undiagnosed and untreated latent TB after KT significantly increases the risk of active TB
Treatment Challenges in KT recepients
1- the drug interaction between rifampicin and transplant-associated immunosuppression .Rifampicin, a potent inducer of cytochrome P450 3A4 and P-glycoprotein, interferes with immuno- suppression metabolization . it decrease the levels of calcineurin inhibitors (cyclosporine, tacrolimus), mTOR) inhibitors (sirolimus, everolimus), and affects glucocorticoids metabolization, calcineurin and mTOR inhibitors levels should be closely monitored, and the glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target.
2- TB drugs should be closely monitored for
· hepatotoxicity (isoniazid, rifampicin, pyrazinamide, ethambutol),
· neurotoxicity (isoniazid, ethambutol),
· cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol),
· visual disturbances (rifabutin, ethambutol),
· skin lesions (rifampicin), hyperuricemia (pyrazinamide)
· interstitial nephritis (rifampicin, pyrazinamide) .
· The most common adverse event associated with anti-TB therapy is hepatotoxicity; therefore, liver enzymes should be closely monitored with bi-weekly evaluation during the intensive phase of treatment and monthly thereafter
3- Treatment adherence could also be an issue in KT recipients.
4-The patients with KT could have different degrees of graft function it is very important to evaluate creatinine clearance and adjust the doses for pyrazinamide and ethambutol .
5-Reduction of immunosuppression in the case of severe TB or when a vital organ is involved should be considered.
6- there are some concerns regarding the possible occurrence of immune reconstitution inflammatory syndrome, which is associated with the reduction of immunosuppression and the use of rifampicin
Treatment of latent TB in KT recipient
· Treatment of latent TB should be considered only after exclusion of active TB
· Treatment of KT recipients with latent TB is important for preventing the risk of reactivation.
· Treatment is indicated in one of the following conditions:
1- a positive TST or IGRA test,
2- a history of untreated TB,
3- a history of recent contact with an active TB patient
4- when the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB
5- the preferred treatment of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6. A regimen based on rifampicin is not recommended .
6- An alternative regimen for KT recipients, mainly for those with high risk, consists of ethambutol and levofloxacin or moxifloxacin
Treatment of active TB
the first-line treatment
· a four-drug regimen containing rifamycin used both in severe and non-severe cases the same as regimen for general population
· consists of a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin .
· if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treat- ment may be extended to 9 months
· severe disseminated disease or bone and joint disease, treatment duration is recommended for at least 6–9 months .
· Patients with central nervous system involvement should be treated for at least 9–12 months .
the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) suggests
· a standard regimen used for a period longer than 6 months,
· and, in cases of localized non-severe TB, a regimen without rifampicin could be used if no resistance to isoniazid is present.
· If a regimen without rifamycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide.
Outcomes
Rejection
Graft rejection in KT recipients with TB can reach up to 55.6%, often being associated with reduced levels of immunosuppression secondary to calcineurin inhibitors–rifampicin interaction
Graft Loss
The causes of graft loss among KT patients with TB can be directly due to infection, especially in the case of donor-derived TB, or indirectly through the sepsis produced by TBand due to the acute or chronic rejection that occurred after minimization or withdrawal of immunosuppression.
Mortality
The mortality of patients with TB after KT has been reported to range from 0% to 60% .
Summary
This is a review of articles published between 1 January 2000 and 15 June 2022 to provide an evidence-based review of epidemiology, pathogenesis, diagnosis, treatment and outcomes of TB in KT recipients. TB is one of the most common infections. The delay in diagnosis and treatment could determine negative consequences, such as graft rejection, graft loss and increased mortality rate.
Active TB after KT could arise from reactivation of latent infection in the recipient or donor tissue or can result from de novo infection after transplantation. In order to limit or prevent the occurrence of active TB post-KT, it is necessary to implement screening measures for both recipients and donors according to the current guidelines. In this review all studies that provided epidemiological and/or outcomes data regarding TB in KT were included.
Epidemiology and Risk Factors for Tuberculosis in Kidney Transplantation
A recent systematic review and meta-analysis including 60 studies analyzed the prevalence of active TB in solid organ transplant recipients and showed a pooled prevalence of 3%. The incidence of active TB in solid organ transplantation is 20–74 times higher than in the general population. In a study performed in 16 transplant centers from Spain, which included 4388 solid organ transplantation recipients, the incidence of TB was 512 cases per 100,000 patients per year (95% CI: 317–783), which was 26.6 times higher than in the general population.The prevalence of active TB in KT recipients varies from 0.3% to 15.2%
Risk Factors for Tuberculosis in Kidney Transplantation
Transplant-associated risk factors- immunosuppression therapy, presence of acute rejection episodes and chronic graft disfunction.
Recipient associated- old age, malnutrition, diabetes, COPD, Latent tb, CLD, Long term HD
Donor associate- cadaveric, homeless, incarceration, smoking, alcohol abuse, diabetes, BMI<18.5
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients
After the aerosol droplets containing mycobacterium tuberculosis (MBT) are inhaled into the lungs, the evolution could be as follows: clearance of MBT by the organism either due to innate immune response or acquired T cell immunity, development of primary disease which means an immediate onset of active disease (first 24 months after primary infection) or latent infection reactivation meaning a late onset of active disease many years following primary infection.
Diagnostic Challenges
High index of suspicion based on epidemiological risk, personal history manifestation and imagistic lesion. Kt recipient may have atypical presentation.
Tuberculin skin test (TST) and interferon gamma release assay (IGRA) are not useful in the diagnosis of active TB.
Bronchoscopy with bronchoalveolar lavage, fluid collections subsequently evaluated by smear and mycobacterium culture and histopathological evaluation could represent diagnostic challenges.
Molecular tests based on rapid nucleic acid amplification techniques, such as mycobacterium tuberculosis complex and resistance to rifampin test could provide false negative results when mycobacterial load is low.
Recognizing latent infection or undiagnosed active TB in the kidney donors is critical in preventing post-transplant infection.
Current guidelines (American Society of Transplantation Infectious Diseases Community of Practice and European Society of Clinical Microbiology and Infectious Diseases) recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors.
Kim et al. showed that IGRA tests have a good predictive potential for latent TB in KT recipient with negative TST
Treatment Challenges
Treatment of KT recipients with TB could be challenging due to drug–drug interactions, drug toxicity and treatment adherence.
American Society of Transplantation Infectious Diseases Community of Practice (AST-IDCOP) guidelines recommends that in case of active uncomplicated pulmonary TB, treatment duration should be at least 6 months.
If cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months.
In case of severe disseminated disease or bone and joint disease, treatment duration is recommended for at least 6–9 months.
Patients with central nervous system involvement should be treated for at least 9–12 months.
This standard regimen consists of a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin
In cases of localized non-severe TB, a regimen without rifampicin could be used if there is no resistance to isoniazid. If a regimen without rifamycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide. Additionally, if second-line drugs are used, a longer period of treatment is recommended.
Interation
Rifampicin, a potent inducer of cytochrome P450 3A4 and P-glycoprotein, interferes with immunosuppression metabolization.
It decrease the levels of calcineurin inhibitors (cyclosporine, tacrolimus), the mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus), and affects glucocorticoids metabolization, which increases the risk of rejection.
When a rifampicin-based regimen is used, calcineurin and mTOR inhibitors levels should be closely monitored, the dose of calcineurin and mTOR inhibitor should be increased between three- and five-fold and the glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target.
After the rifampicin is stopped, the immunosuppression doses should be reduced to the value before the start of rifampicin and then adjusted to obtain the therapeutic target.
An alternative to rifampicin is rifabutin, which is a weaker inducer of cytochrome P450 3A4 and P-glycoprotein but with similar efficacy.
Another safe and effective alternative to rifampicin in KT recipients is treatment with fluoroquinolones
Adverse effect
Patients should be closely monitored for hepatotoxicity (isoniazid, rifampicin, pyrazinamide, ethambutol), neurotoxicity (isoniazid, ethambutol), cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol), visual disturbances (rifabutin, ethambutol), skin lesions (rifampicin), hyperuricemia (pyrazinamide) or interstitial nephritis (rifampicin, pyrazinamide)
Reduction of immunosuppression in the case of severe TB or when a vital organ is involved should be considered but there are some concerns regarding the possible occurrence of immune reconstitution inflammatory syndrome.
Latent TB treatment
In the KT setting, the preferred treatment of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6. A regimen based on rifampicin is not recommended. An alternative regimen for KT recipients, mainly for those with high risk, consists of ethambutol and levofloxacin or moxifloxacin
Outcomes
Rejection
Graft rejection in KT recipients with TB can reach up to 55.6%, often being associated with reduced levels of immunosuppression secondary to calcineurin inhibitors–rifampicin interaction and could be responsible for approx. 1/3 of graft losses.
Graft Loss
The causes of graft loss among KT patients with TB can be directly due to infection, especially in the case of donor-derived TB, or indirectly through the sepsis produced TB and due to the acute or chronic rejection that occurred after minimization or withdrawal of immunosuppression.
One study that analyzed graft function and survival in KT recipients with active TB showed a prevalence of graft loss of 14.7% and an association of TB with acute kidney injury and incomplete recovery of graft function after treatment
Mortality
In a recent meta-analysis, Mamishi et al. found that mortality rate in solid organ transplantation recipients was 20% . The mortality of patients with TB after KT has been reported to range from 0% to 60% .
Conclusions
TB in KT is an important opportunistic infection with higher incidence and prevalence than in the general population and is associated with significant negative graft and patient outcomes.
Level of evidence -is level 5 for Narrative review.
Summarize this articleIntroduction :
The optimal treatment for ESRD is KT , but infections like TB post-transplantation can have a negative impact on graft and patient outcomes, so screening measures and evidence-based updates are needed to reduce or prevent TB post-KT.
Methodology :
A literature search on PubMed and Embase was conducted from 1 January 2000 to 15 June 2022 to identify studies that provided epidemiological and/or outcomes data related to TB in kidney transplantation (KT).All articles were analyzed by two reviewers for inclusion/exclusion criteria, and the process was checked by a third reviewer.
Epidemiology and Risk Factors for Tuberculosis in Kidney Transplantation :
The prevalence of active TB among patients with solid organ transplantation is highly variable according to the geographic area . The incidence of active TB in solid organ transplantation is 20–74 times higher than in the general population but lower than in patients with lung transplantation .
A recent meta-analysis found that patients with KT had a pooled incidence of active TB of 2700 per 100,000 patient-years, which ranged from 340-14,680 in low TB burden countries to 14,680 in countries with high endemicity.
Risk Factors for Tuberculosis in Kidney Transplantation:
T recipients are more likely to develop TB than the general population due to several risk factors, such as immunosuppression therapy, acute rejection episodes and chronic graft dysfunction. Some immunosuppressive drugs or combinations increase the risk of TB development as it impairs T-cell-mediated immunity , such as T cell-depleting agents and cytotoxic T-lymphocyte-associated protein-4 (belatacept ) , calcineurin inhibitors, anti-metabolites, rejection, chronic graft dysfunction, and drug overdosing.Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients
Transmission and pathogenesis of tuberculosis in kidney transplant recipients (KT) is possible according to three scenarios:
Clearance of MBT, Development of primary diseaseLatent infection reactivation. KT is a risk factor for TB reactivation in candidates with latent infection due to initiation of induction and maintenance specific immunosuppression. This could disrupt the protection against TB and increase the risk of reactivation through multiple mechanisms, such as depletion of all types of T cells, decrease in activation and proliferation, decrease in IL-2 synthesis, and decrease in production of Th-1 type cytokines.
Diagnosis and treatment challenges :
Diagnosis and treatment of TB can be challenging due to the particularities associated with KT which should be addressed because the patients’ prognosis depends on the early diagnosis and the appropriate therapeutic approach , but atypical clinical presentations or diverse manifestations can reduce clinical suspicion. Donor-derived TB is an under-recognized condition with early onset after KT, and should be suspected in KT recipients with non-specific symptoms, frequent fever, fluid collections, extrapulmonary manifestations or lack of response to empirical antibiotic therapy.
Latent TB :
Latent TB infection is defined as a persistent immune response to stimulation by MBT antigens with no evidence of active TB. The reported prevalence of latent TB after KT is in ~20% of recipients, and current guidelines recommend screening in all KT candidates and donors before transplantation. IGRA test is better than TST in patients with ESRD,however, data regarding prediction capacity of TST and IGRA tests are discordant. The incidence and prevalence of latent TB in KT recipients is higher than in KT candidates and should be more frequently screened. Undiagnosed and untreated latent TB after KT significantly increases the risk of active TB.
Treatment Challenges: Management of KT patients with TB should be carried out by an experienced clinician because it is challenging due to drug–drug interactions, drug toxicity and treatment adherence. Also special attention must be paid to drug–drug interactions and potentially adverse events .
Active Tuberculosis:
The treatment of active TB in KT recipients is complex and challenging. AST-IDCOP recommends a four-drug regimen containing rifamycin, followed by a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol.
The duration of treatment ranges from 6-12 and may extend to 24 months according to severity and site of involvement .
Adverse effects such as hepatotoxicity, neurotoxicity, cytopenia, visual disturbances, skin lesions, hyperuricemia, and interstitial nephritis are common. Drug interaction is common , especially rifampicin which is a potent enzyme inducer that reduces the level of immunosuppressant and increases the risk of rejection .
Reduction of immunosuppression in severe TB or when a vital organ is involved should be considered, but there are concerns about immune reconstitution inflammatory syndrome.
Latent TB: Active TB should be excluded before treatment of latent TB is considered , which is isoniazid 5 mg/kg/day for 9 months, plus vitamin B6 supplement . Follow up of liver enzymes during treatment is recommended.
Outcomes : There is increased morbidity and mortality in KT when developed TB due to immunosuppression status, increased extrapulmonary disease and challenges in diagnosis that delay the initiation of treatment .
Rejection : The commonest cause of graft rejection in KT recipients with TB is reduced levels of immunosuppression secondary to calcineurin inhibitors–rifampicin interaction and could be responsible for ~1/3 of graft losses .
Graft Loss: Graft loss among KT patients with active TB is caused by infection, sepsis, acute rejection, interstitial fibrosis, tubular atrophy, and suboptimal levels of immunosuppression. It varies from 2.2% to 66.6%, with the highest rate reported in a study by Vandermarliere et al. (66.6%) with active TB.
Mortality:
Mortality rates in solid organ transplantation recipients have been reported to range from 0% to 60% . Active TB after 2 years post-KT is an independent risk factor. 65% of KT recipients with active-TB who died had co-infections with fungi, cytomegalovirus, nocardia, hepatotropic viruses, and chronic liver disease.
Conclusion :
TB in KT has higher incidence and prevalence than in the general population, requiring close collaboration between kidney transplant and infectious disease physicians.
level of evidence : Level V
I like your summary, level of evidence, analysis and take home messages.
Introduction
A common infection after kidney transplant is tuberculosis (TB), and it is associated with a negative impact on the patient. Due to the immune suppression after kidney transplant, the cases of TB are higher in kidney transplant recipients than the general population. There are also other risk factors favoring the development of TB present in the transplant recipients, apart from the immune suppression. After kidney transplantation, active TB could arise from reactivation of a latent infection in the recipient or donor tissue, or can occur de novo after transplantation. Endogenous reactivation of TB is the most common form of transmission. Screening measures are required for both the donor and recipients according to the current guidelines. Diagnosis and treatment of TB among kidney transplant recipients is challenging because of the atypical or diverse clinical presentation, the limitations of screening tests to detect latent infection, drug interactions and drug toxicities. These reasons can cause delays in treatment and diagnosis of the infection, hence lead to complications such as graft rejection, graft loss and an increased mortality rate. The aim of this review was to provide an evidence-based update regarding epidemiology, risk factors, pathophysiology, type of transmission, diagnostic challenges, treatment challenges and the impact of TB in kidney transplant recipients.
Methodology
A literature search was performed from 1st January 2000 to 15th June 2022, on PubMed and Embase databases. All studies that provided epidemiological and/or outcomes data regarding tuberculosis in kidney transplant were included.
Epidemiology and risk factors for TB in Kidney transplantation
Epidemiology of TB in solid organ transplantation In low TB endemic areas, the prevalence of TB among patients with sold organ transplantation was 0.3 to 6.4% compared to up to 15.2% in high TB endemic areas. The incidence of active TB in solid organ transplant recipients is 20-74 times higher than in the general population, approximately 512 cases per 100,000 patients per year.
Epidemiology of TB in kidney transplantation The prevalence of TB in kidney transplant recipients can vary from 0.3 to 15.2%. It has a higher prevalence than the general population, but lower than lung transplant recipients. The highest prevalence of active TB in kidney transplant recipients was reported from Pakistan, a country with high rates of TB. Another study showed that the prevalence was also higher among patients on dialysis.
Risk factors of TB in kidney transplantation Recipient-associated risk factors
Older age, male gender, history of cigarette smoking, malnutrition, diabetes, chronic obstructive pulmonary disease, latent TB (pre-transplant), chronic liver disease, Hepatitis C virus infection, opportunistic co-infections (e.g. CMV, pneumocystis, nocardia), autoimmune disease, long-term hemodialysis.
Donor-associated risk factors
Donor type (cadaveric), social risk factors (homeless, incarceration, smoking, alcohol abuse, known TB contact), medical risk factors (diabetes, BMI > 18.5kg/m2, history of untreated TB).
Transplant-associated risk factors
Immune suppression, acute rejection, chronic graft dysfunction.
Others
TB burden of the country.
Transmission and pathogenesis of TB in kidney transplant recipients
The natural history of the infection begins with inhalation of the aerosol droplets containing mycobacterium tuberculosis (MTB). The infection may be cleared by the innate immune system or acquired T-cell immunity, development of primary disease leading to an immediately active (first 24 months after the primary infection) or latent infection reactivation.
Transmission of TB in kidney transplant recipients can occur by:
The protection against MTB infection is mainly based on cellular immunity. The use of immune suppression medications after kidney transplants disrupts the protection against TB and increases the risk of reactivation through many mechanisms, such as, depletion of all types of T cells, decrease in activation and proliferation of T cells, decrease in IL-2 synthesis, decrease in the production of Th-1 type of cytokines or impairment of cellular immunity.
Diagnostic challenges
Active TB The diagnosis of TB requires a high index of suspicion, based on the epidemiological risk, personal history, manifestations and lesions on imaging. Kidney transplant recipients have atypical clinical presentations. Co-infections and extra-pulmonary localizations may add to the confusion. These reasons may delay the diagnosis of TB in kidney transplant recipients. Tuberculin skin test (TST) and interferon-gamma release assay (IGRA) are not useful in the diagnosis of active TB. TB also has a wide range of radiologic manifestations, and it may require invasive procedures to obtain samples. Some molecular tests may provide false negatives when the mycobacterial load is low.
Donor-derived TB should be suspected in kidney transplant recipients with non-specific symptoms, frequent fevers in the first 3 months after transplantation, fluid collections, extra-pulmonary manifestations or lack of response to empirical antibiotic therapy. All donors should undergo a careful evaluation of epidemiological risk, personal medical history physical exam and chest radiography.
Latent TBLatent TB is a state of persistent immune response to stimulation by MTB antigens with no evidence of clinically manifested active TB. There are no gold standards for diagnosing latent TB accurately in kidney transplant recipients. It has been shown that IGRA has advantages over TST. It is important to diagnoses latent TB in kidney transplant recipients, as undiagnosed and untreated latent TB after kidney transplant significantly increases the risk of active TB.
Treatment challenges
Active TBThe treatment of active TB should be promptly initiated after the diagnosis has been established. Guidelines recommend that in the case of uncomplicated active pulmonary TB, treatment should be for 6 months. If there are cavitary lesions or persistence of culture-positive sputum after two months of treatment initiation, treatment should extend for 9 months. In the case of severe disseminated disease or bone and joint disease, treatment duration is recommended for 6-9 months. Patients with central nervous system involvement should undergo treatment at least 9-12 months.
First line treatment should include rifamycin. The 2 month intensive phase includes isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4 month continuation phase with isoniazid and rifampicin.
Rifampicin is a potent inducer of cytochrome P450 3A4 and P-glycoprotein, and so it interferes with immune suppression metabolism. It decreases the levels of CNIs, mTORIs and affects glucocorticoid metabolism. Therefore, the immune suppression levels require monitoring and their levels adjusted accordingly during treatment. An alternative for rifampicin in kidney transplant recipients is treatment with fluoroquinolones. The adverse effects include hepatotoxicity, nephrotoxicity, cytopenia, visual disturbances, skin lesions, hyperuricemia or interstitial nephritis.
Latent TBTreatment of latent TB should be considered only after active TB has been excluded. Treatment of kidney transplant recipients with latent TB is important for preventing the risk of reactivation. Treatment in indicated if there is a positive TST or IGRA test, a history of untreated TB, a history of recent contact with an active TB patient and when the graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB. The preferred treatment of latent TB is isoniazid 5mg/kg/day (maximum dose of 300mg/day) for 9 months, supplemented with vitamin B6. The main adverse effect associated with isoniazid is hepatotoxicity.
Outcomes
It has been noted that graft rejection in kidney transplant recipients is approximately 55.6%. The losses were due to acute rejection. Graft loss can be due to the infection, or the acute and chronic rejection. The mortality of patients with TB after kidney transplant has been reported between 0 and 60%.
Conclusions
For kidney transplant recipients, TB is an important opportunistic infection with a higher incidence and prevalence than in the general population. It is associated with negative graft and patient outcomes.
It is important for clinicians to recognize the diagnostic and treatment challenges of TB in kidney transplant recipients. It will assist in better management of the patients, and therefore better outcomes.
In endemic areas, it would be important to offer prophylaxis with INH after ruling out latent TB
This is a systematic review article: LOE I
Since there is no clearly defined question, and there is no PICO format, I would not call it a systematic review article with LOE I.
It is a narrative review, hence level 5 of evidence.
Thank you Professor Sharma for the clarification. It was a bit confusing for me as the authors had included studies with some criteria
Summarise this article
Introduction:
Tuberculosis (TB) in kidney transplant (KT) recipients is an important opportunistic in[1]fection with higher incidence and prevalence than in the general population and is associated with important morbidity and mortality.
TB is the thirteenth-most common cause of death and the leading infectious cause of death, excluding coronavirus disease 2019 (COVID-19), worldwide.
The incidence rate of 127 cases per 100,000 people per year, according WHO 2000 report.
This article performed an extensive literature review of articles published between 1 January 2000 and 15 June 2022 to provide an evidence-based review of epidemiology, pathogenesis, diagnosis, treatment and outcomes of TB in KT recipients.
Epidemiology of Tuberculosis in Solid Organ Transplantation:
The prevalence of disease is related to endmecity of the disease, 0.3-6.4% in low endemic areas, to 15% in high endemic areas.
The incidence of active TB in solid organ transplantation is 20–74 times higher than in the general population.
Risk Factors for Tuberculosis in Kidney Transplantation:
Recipient associated risk factors are: older age, male gender, smoking, malnutrition, diabetes mellitus, chronic obstructive lung disease, latent TB, chronic liver disease, hepatitis c virus infection, co-infection with CMV,PCP, and Nocardia, autoimmune diseases, long time on HD.
Donor associated risk factors are: cadaveric donors, social risk factors (homeless, iv drug abuse, alcohol, smoking, known TB contact, and incarcination), medical riks factors (diabetes, BMI<18, history of untreated TB).
Transplant associated risk factors are: immunosuppression, acute rejection, chronic allograft dysfunction).
TB burden of the country.
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients:
Reactivation of latent TB.
Donor derived TB infection.
Post transplantation exposure to infected TB patient.
Use of immunosuppression in Kidney transplnatation could disrupt the T cell mediated(CD4+/CD8+) immune system.
Diagnostic Challenges:
1- Active Tuberculosis:
Active TB post-transplant usually occur at the first year after transplantation, in case of latent TB reactivation, and within 3 months in case of donor derived TB.
The diagnosis of TB requires a high index of suspicion based on the epidemiological risk, personal history, manifestations and imagistic lesions (non-specific) , co-infections, extra-pulmonary manifestations.
Tuberculin skin test (TST) and interferon gamma release assay (IGRA) are not useful in the diagnosis of active TB infection.
Bronchoscopy with bronchoalveolar lavage, derange of fluid collections subsequently evaluated by smear and mycobacterium culture and histopathological evaluation, may require weeks to months.
Molecular tests based on rapid nucleic acid amplification techniques, such as mycobacterium tuberculosis complex and resistance to rifampin test, could provide false negative results when mycobacterial load is low.
Donor-derived TB is suspected with early onset after KT presents with one of the following features: non-specific symptoms, frequent fever in the first 3 months after KT, fluid collections, extrapulmonary manifestations or lack of response to empirical antibiotic therapy.
The American Society of Transplantation Infectious Diseases Community of Practice(AST-IDCOP) and European Society of Clinical Microbiology and Infectious Diseases(ESCMID) recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors.
2- Latent TB:
Latent TB infection (WHO) is defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB.
Prevalence of latent TB after KT was reported in ~20% of recipients, so current guidelines recommend latent TB screening in all KT candidates and donors before transplantation.
Both TST and IGRA are not sensitive, so frequent monitoring and screening of post transplant recipient should be carried out.
Treatment Challenges
1- Treatment of active disease:
(AST-IDCOP) guidelines recommends that in case of active uncomplicated pulmonary TB, treatment duration should be at least 6 months.
If cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, severe disseminated disease, and bone/ joint disease, the duration of treatment may be extended to 9 months.
Patients with central nervous system involvement should be treated for at least 9–12 months.
Rafamycin based regimen: 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin.
(ESCMID) suggests treatment more than 6 months:
Rifampicin, a potent inducer of cytochrome P450 3A4 and P-glycoprotein, interferes with immunosuppression metabolization. Specifically, rifampicin usage decreases the levels of calcineurin inhibitors (cyclosporine, tacrolimus), the mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus) the dose should be increased 3-5 times the used dose, and affects glucocorticoids metabolization, which increases the risk of rejection, mandates frequent monitoring of drug level as well as monitor for drug toxicity (hepatotoxicity).
Rifamycin free regimen: 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide.
Directed observed therapy programs has improved the adherence of patients to anti-TB therapy and their outcomes.
Reduction of immunosuppression in the case of severe TB or when a vital organ is involved should be considered.
2- Latent Tuberculosis:
Treatment of KT recipients with latent TB is indicated in one of the following conditions: a positive TST or IGRA test, a history of untreated TB, a history of recent contact with an active TB patient and when the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB.
Treatment regimen of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6, or ethambutol and levofloxacin or moxifloxacin in isoniazid resistant and toxicity.
Outcomes:
1- Rejection:
Graft rejection in KT recipients with TB can reach up to 55.6%, often being associated with reduced levels of immunosuppression secondary to calcineurin inhibitors–rifampicin interaction and could be responsible for ~1/3 of graft losses.
2- Graft Loss:
The causes of graft loss among KT patients with TB can be directly due to donor-derived TB infection, or through the sepsis/ disseminated infection and due to the acute or chronic rejection that occurred after minimization or withdrawal of immunosuppression.
Rejection could be precipitated by suboptimal levels of immunosuppression in the context of rifampicin-based regimen use.
The prevalence of graft loss in KT patients with active TB varies from 2.2% to 66.6%.
3- Mortality:
Mortality rate in solid organ transplantation recipients was 20%, ranging from 0-60% in kidney transplants, increased when anti-rejection used, diabetic recipient, and co- infection with hepatitis c or fungal infections.
Conclusion:
TB post transplantation is a challenging infection in diagnosis and treatment, requiring high index of suspicion, early detection and treatment in order to reduce the bad disease outcomes.
Multidisciplinary team work (infectious, nephrologist, microbiologist and pathologist) are required for better outcome with understanding the drug-drug interaction, and side effects.
What is the level of evidence provided by this article?
Level of evidence is V- erratic review.
What is your suggestion regarding MDTs.
I like your summary, level of evidence, analysis and take home messages.
Introduction
For people with ESKD, the optimum treatment is a kidney transplant. Infections, however, limit graft efficacy and patient outcomes. TB remains the biggest infectious cause of death worldwide. Kidney transplant recipients have a higher incidence of tuberculosis than the overall population. Active TB in the recipient could be the result of reactivation of latent infection in recipient or donor tissue, or it could be the result of de novo infection in the recipient. The diagnosis and treatment of tuberculosis in recipients remains difficult.
Epidemiology in solid organ transplantation
Prevalence varies depending on geographic location; places with low endemicity vary from 0.3-6.4%, while those with high endemicity can reach 15%. The incidence of solid organ transplantation is between 20 and 74 times that of the general population.
Epidemiology in kidney transplant recipients
The prevalence is higher than in the general population but lower than in people who have had lung transplants.
Risk factors in kidney transplant recipients
TB endemicity affects recipient, donor, and transplant factors. Immunosuppressive drugs, acute rejection, and chronic graft malfunction are transplant-related. Immunosuppressive drugs decrease T cell-mediated immunity, reactivating latent TB infection. Immunosuppressive drugs used to treat rejection may reactivate TB and cause rejection episodes. Overdosing on immunosuppressive drugs also causes chronic graft malfunction. Older age, male gender, smokers, COPD, DM, longer dialysis, opportunistic infection, and latent TB are recipient-related variables.
Transmission and pathogenesis in kidney transplant recipients
Aerosol droplets can be cleared from the body by inherent or acquired immunity, or the disease can become active during the first 24 months after exposure or stay latent.
Consequently, there are three possible ways for TB to manifest in KTX: through reactivation of the latent infection (the most common), through transmission from an infected donor kidney (4.6% of cases), or through de novo infections (rare, more common in endemic areas), which carry a high risk of progression.
Cellular immunity, specifically T helper cells, interferon beta, and interleukin-2, is what protects against MTB.
Immunosuppressive drugs used during induction and maintenance phases of treatment have been linked to a reduction in T-cells, a drop in IL-2 production, and overall cellular immunity impairment.
Diagnostic Challenges
Active tuberculosis
Kidney transplant patients’ high index of suspicion, unusual clinical presentations, and likelihood of coinfection make active TB diagnosis difficult.
Paraclinical difficulties can delay diagnosis, and TST and IGRA are useless.
Mycobacterium tuberculosis complex and resistance to rifampin test may give false negative results when mycobacterial load is minimal.
Early-onset donor-derived TB following kidney donation is underdiagnosed.
Kidney transplant patients with vague symptoms, frequent fever, fluid accumulation, extrapulmonary signs, or no response to empirical antibiotic therapy should be investigated.
Current guidelines demand a detailed epidemiological risk, personal medical history, physical exam, and chest radiography in all donors, although screening assays for latent TB (TST and IGRA) have low feasibility and accuracy.
Personal history and chest imaging should influence donation.
Latent tuberculosis
Latent TB infection is an immunological response to MBT antigens without clinical symptoms.
Around 20% of KT recipients developed latent TB, and current recommendations urge screening all candidates and donors before transplantation.
In ESRD patients, IGRA may be better than TST for identifying latent TB in KT candidates.
In this group, TST and IGRA prediction findings are inconsistent.
Shu et al. recommend screening KT recipients more often than candidates since they have a higher latent TB rate.
Undiagnosed and untreated latent TB raises the likelihood of active TB, highlighting its relevance.
Active Tuberculosis treatment
The treatment of TB in transplant recipients may be complicated because to drug–drug interactions, drug toxicity, and treatment adherence.
The appropriate duration of treatment could range from six to twenty-four months, and in some circumstances, according to the advice of specialists, the duration of treatment should be at least nine to twelve months. In cases of active, uncomplicated pulmonary tuberculosis, the American Society of Transplantation Infectious Diseases Community of Practice (AST-IDCOP) recommends a treatment duration of at least 6 months. However, if cavitary lesions are present or culture-positive sputum persists after 2 months of therapy, the treatment duration may be extended to 9 months. In cases of severe disseminated disease or bone and joint disease, at least 6–9 months of treatment is advised. Individuals with involvement of the central nervous system should be treated for at least 9–12 months.
A four-drug combination comprising rifamycin should be the first-line treatment for both severe and non-severe patients.
Treatment of latent tuberculosis
After excluding active TB, treat latent TB. In this category of individuals, treatment is suggested if the patient has a positive TST or IGRA test, a history of untreated TB, recent contact with an active TB patient, or a kidney graft from a donor with known latent TB without chemoprophylaxis. Isoniazid 5 mg/kg/day (maximum 300 mg/day) for 9 months plus vitamin B6 is the recommended treatment for latent TB in KT. Avoid rifampicin-based treatment. Ethambutol with levofloxacin or moxifloxacin are a high-risk KT regimen. Hepatotoxicity is the major side effect of isoniazid, but KT individuals may have a lower risk. Nonetheless, liver enzymes should be checked bi-weekly for 6 weeks and then monthly during treatment.
Outcomes of Tb in kidney transplant recipients
The possibility of graft rejection in KT patients with TB is up to 55.6%. This is brought on by inadequate IS levels in the setting of rifampicin-based therapy. Infection can cause graft loss directly, especially when the infection comes from the donor. Graft loss occurs in 2.2% to 66.6% of KT patients with active TB. SOT recipients have a death risk of 20%. After KT, TB patients can experience mortality ranging from 0% to 60%.
What is the level of evidence provided by this article?
Level V
I like your excellent summary, level of evidence, and analysis.
Review Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review
1. Epidemiology of Tuberculosis in Kidney Transplantation
· The prevalence of active TB in KT recipients varies from 0.3%to15.2%, which is higher than the general population.
2. Risk Factors for Tuberculosis in Kidney Transplantation
3. Transmission and Pathogenesis of TB in Kidney Transplant Recipients
4. Diagnostic Challenges
a. Active Tuberculosis
b. Latent Tuberculosis
5. Treatment Challenges
a. Active Tuberculosis
b. Latent Tuberculosis
6. Outcomes
TB in KT is associated with important morbidity and mortality due to immunosuppression status, increased extrapulmonary disease and challenges in diagnosis that delay the initiation of treatment.
a. Rejection
· Graft rejection in KT recipients with TB can reach up to 55.6%, often being associated with calcineurin inhibitors–rifampicin interaction and could be responsible for ~1/3 of graft losses.
b. Graft Loss
· The prevalence of graft loss in KT patients with active TB varies from 2.2% to 66.6%.
· The graft loss could be directly due to TB infection, especially in the case of donor-derived TB, or indirectly through the sepsis produced by TB and due to the acute or chronic rejection that occurred after minimization or withdrawal of immunosuppression.
7. Mortality
Conclusions
Level of evidence : V
SUMMARY
Introduction
The burden of TB in the Latin has reduced in the Latin American continent in the last decades, although according to WHO classification, Bazil still remains one of the countries with the highest burden of the disease with 110,000 prevalence disease and 7700 TB death. Moreso, the national incidence varies from as low as 11 cases per 100000 in the capital city to as high as 300 per 100000 in underprivileged communities. A more challenging situation is the emergence of MDR which is known to be quite common among those previously treated with TB
TB after solid organ transplantation
Diagnosis of Latent TB
Advantages of IGRA over TST
Limitation of IGRA
The advice given by some specialists is to use IGRA in low-risk patients and in those with high risk for TB
Diagnosis of active TB
It relies on the detection of M. Tuberculosis in samples via tests like
Risk assessment of transplant patient-recipients
Risk assessment of transplant patient-donors and diseased donor
Lungs with residual TB lesions should not be used for donation
Treatment for LTBI in transplant and recipient patient
Treatment of active infection
The general local guideline of the country or region be followed based on the endemicity of TB in the area and it has been advised that the treatment should be at least 9 months. The treatment comprises the intensive phase (INH+RIF+ PYRAZINAMIDE + EHTAMBUTO), for 2 months then followed by 6-9 months of the maintenance phase of INH + RIF.
The major challenge is a rifampicin drug interaction with CNIs, mTORs, and corticosteroids by reducing their trough level and this could result in allograft rejection or loss.
Other toxicities of concern are neurotoxicity, hepatotoxicity, and nephrotoxicity
Sorry, meant for week three pls!!!
I like your detailed summary.
Mycobacterium Tuberculosis Infection after Kidney
Transplantation
Type of article: A Comprehensive Review with evidence V
Date :27 August 2022
Journal: MDPI /pathogens with impact factor 4.6 in 2021
Summarize this article
The prevalence of active TB in transplanted patients is significantly higher than general population 20-74 times. It differs according to geographic area ranging from 0.3–6.4%, in developed countries and in up to 15% in endemic regions
Mode of transmission
Risk factors for TB in Kidney Transplantation
Recipient related
Donor related
Diagnosis of latent TB
There is clear specific test for diagnosis and diagnosis is based on high clinical suspicious as tuberculin skin test (TST) and IGRA which usually used in diagnosis can be negative in immunosuppressed patients due to absence of immune response.
Indications of treatment of latent TB in transplant recipient and donor
Protocol for treatment of latent TB
The diagnosis of active TB is challenging
The treatment of active TB in SOT is challenging due to the following
Protocols used in treatment of TB
I- Rifampicin containing regimen
Rifampicin+ INH+ ethambutol + pyrazinamide for 2 months, followed by a 2-drug regimen of Rifampicin + INH for 4 months
It is recommended to increase the duration of treatment to at least 9-12 months if there is disseminated disease, cavitary disease with positive sputum culture after 2 months of treatment, bone and joint disease, CNS disease.
II- Rifampicin free regimen
In which levofloxacin and rifabutiun can replace rifampicin due to its lesser effect on cytochrome p450, so minimal drug-drug interactions but experience is little when using this drug in transplantation, although it seems effective in HIV TB patients.
Prognosis
Mortality occurs in up to 60 % of patients
I like your summary, level of evidence, analysis and take home messages.
Stating that, “Mortality occurs in up to 60 % of patients” is a NOT correct reflection in some studies but it may be as little as zero in some reports.
Summary
Introduction
Kidney transplantation is the optimal treatment in patients with ESKD.
However infections limits graft function and patient outcomes.
TB remains to be a leading cause of infectious death worldwide.
Incidence of TB in kidney transplant recipients is higher than the general population.
Active TB in the recipient could be due; to reactivation of latent infection in recipient or donor tissue or due to de novo infection in the recipient.
Diagnosis and treatment of TB in recipients remains to be challenging.
Epidemiology in SOT
Prevalence is variable depending with the geographical area; areas with low endemicity ranges between 0.3-6.4% while high endemic areas could be as high as 15%.
Incidence in SOT is 20-74 times higher that of general population.
Epidemiology in kidney transplant recipients
Prevalence ranges between 0.3-15%; its is higher than the general population but lower than lung transplant recipients.
Risk factors in kidney transplant recipients
There are recipient, donor and transplant related factors which are all influenced by the endemicity of TB in the area.
Transplant related factors include the use of immunosuppressive agents, presence of acute rejection episode and chronic graft dysfunction.
Immunosuppressive agents impair the T cell mediated immunity that controls TB infection hence reactivation of latent infection.
Rejection episodes and TB could be explained by the use of immunosuppressive agents to treat rejection that leads to TB reactivation.
Similarly chronic graft dysfunction is associated with amplification or overdosing of immunosuppressive agents.
Recipients related factors include:older age, male gender, smokers, COPD, DM, longer dialysis duration, presence of opportunistic infection, presence of latent TB.
Donor related factors include:donor type-cadaveric, social risk factors- homeless, incarcerated and medical risk factors-DM, untreated TB.
Transmission and pathogenesis in kidney transplant recipients
After inhalation of aerosol droplets the body can either; clear it through innate or acquired immunity, or active disease can occur within the first 24 months, or remains latent.
Thus TB can occur in KTX in 3 scenarios: through reactivation of the latent infection this is the most common form, or transmitted from infected donor kidney that accounts for 4.6% of cases, or de novo infections that is rare, more frequent in endemic areas and has a high risk of progression.
Protection against MTB is through cellular immunity- T helper cells , IFN γ and IL2.
Some immunosuppressive agents used in induction and maintenance may deplete T cells, decreases synthesis of IL2 or impair the whole cellular immunity.
Diagnostic challenges
Active TB
The diagnosis of TB requires high index of suspicion, however KTX have atypical presentation which lowers the clinical suspicion.
TST and IGRA have no role in the diagnosis of active TB.
Donor derived TB should be suspected in KTX who presents with: unexplained fever, fluid collections, extra-pulmonary manifestation and lack of response to empirical antibiotics therapy.
Latent TB
Prevalence of LTBI is reported to be 20% in kidney transplant recipients.
There is no gold standard test.
Data on capacity of TST and IGRA are contraindicating.
Treatment challenges
Active TB
Treatment follows the principles of immunocompetent individuals and should be began promptly.
Optimal treatment period varies between 6-24 months.
The AST-IDCOP recommends the following:
However the ESCMID recommends in cases of non-severe localised disease with no rifampicin resistance, then a non-rifampicin based regimen can be used for 2 months followed by an intensive phase of 12-18 months.
Rifampicin is a potent cytochrome P 450 inducer hence interferes with the metabolisation of immunosuppressive agents.
Thus CNI and MTOR inhibitors should be increased to 3 and 5 fold and steroids doubled during treatment and doses adjusted to pretreatment doses after discontinuation.
Rifabutin is a weaker inducer of cytochrome P 450 and hence an alternative to rifampicin with similar efficacy.
Another alternative to rifampicin is fluoroquinolones.
Adverse events to monitor for include:
Most common adverse event is hepatotoxicity thus liver enzymes should be monitored bi-weekly in the intensive phase and there after monthly.
Latent TB
Treatment indicated if:
Preferred drug is Isoniazid 5mg/kg/day with maximum 300mg/day for 9 months with vitamin B6 supplementation.
Rifampicin based regimen is not recommended
Other alternative is ethambutol with levofloxacin or moxifloxacin.
Outcomes
Incidence of rejection in KTX with TB is high, could be due to interactions of rifampicin with the immunosuppressants leading to 1/3 of graft losses.
There is also increased mortality in KTX with TB.
Conclusion
TB is an opportunistic infection with increased prevalence in KTX than general population and associated with negative graft and patient outcomes.
Due to the diagnostic and treatment challenges, collaboration between the transplant physicians and infectious disease specialist is required.
Donor derived TB and latent TB are under recognised conditions that should be evaluated.
Development of new test and treatment regimens is required.
Level of evidence V
I like your summary, level of evidence, analysis and conclusions.
Summary
Introduction
best therapy for ESRD is kidney transplantation (KT)
Tuberculosis (TB) is a major post-transplant infection.
It is the thirteenth-highest cause of mortality globally and the top infectious cause in Post Tx period.
Method
A search on PubMed and Embase electronic databases performed from 1 January 2000 to 15 June 2022. All studies that provided epidemiological and/or outcome data regarding TB in KT were included.
Tuberculosis in SOT
Active TB in solid organ transplantation varies in different regions but TB prevalence ranges from 0.3–6.4% in low-endemic regions to 15.2% in high-endemic areas.
Risk Factors
Post transplant cases are more likely to acquire TB. High prevalence in community along with donor, and transplantation variables like immunosuppression medication, rejection episodes, and chronic graft dysfunction.
Immunosuppression inhibits T-cell-mediated TB control and promotes latent infection reactivation. T-cell-depleting medications, calcineurin inhibitors, anti-metabolites, and glucocorticoids all enhance the risk of TB. Each rejection episodes increases TB risk 7.6 times.
Transmission and Pathogenesis
Active TB could result due to reactivation. TB could also be transmitted to KT recipients via kidney graft from an infected donor or TB could occur as a de novo infection after KT or exposure to active TB patients.
Diagnostic and Treatment
Active TB; Treatment lasts 6–24 months, but at least 9–12.
American Society of Transplantation IDCOP recommends 6 months for active uncomplicated pulmonary TB and 9 months for cavity lesion.
AST-IDCOP recommends a 4-drug regimen for first-line treatment:
Latent TB
It has also should be treated to stop it from becoming active. Positive TST or IGRA test, a history of treated tuberculosis, a history of recent contact with an active TB patient, donor-derived latent TB in an infected graft, a history of untreated tuberculosis, or recent exposure to active tuberculosis, makes a person venerable to tuberculosis.
INH combined with vitamin B6 is used to treat latent tuberculosis for a period of nine months. Ethambutol with either levofloxacin or moxifloxacin is another treatment option for those at high risk.
Conclusions
TB is a common opportunistic infection in KT patients.
It has negative impact on graft and patient survival.
Preventive strategies include TB risk stratification and monitoring.
Donor-derived TB and latent TB in KT are underdiagnosed.
In KT recipients, non-T cell immunity-based assays with good predictive values might enhance latent TB diagnosis in future.
level of evidence
The level of evidence is V
I like your summary, level of evidence, analysis and take home messages.
1- Renal transplantation is only hope to ESRD receiving regular dialysis.
2- Infections is common complication among SOT patients.
3- TB prevalence in SOT is varied from 0.3-15% according to endemic area or not.
4- There are risk factors related to increase incidence of TB among SOT than general population.
5- TB infection in SOT can happen either primary infection (new infection ) or reactivation of latent infection in the recipient which is the most common type of infection or reactivation from the side of the donor so can be donor-derived which constitute 4.8% of the infected cases.
6- Proper screening of the donor and recipient pre-transplantation is very important to discover latent infection and manage it before transplantation, but there is a limitation of the screening tests.
7- The story of TB in SOT remains challenging because of limited screening tests to diagnose latent infection, confusing clinical picture, treatment carries a possibility of drug-drug interaction with multiple toxicity, with risk of graft rejection.
8- Remains undiagnosed and untreated carries high morbidity and mortality.
9- Risk factors related to recipient: old age, male gender, chronic liver disease, HCV, smoking, malnutrition, DM, COPD, associated co-infection like CMV and PCP, pre-transplant latent TB, autoimmune disease, long time on hemodialysis
10- Risk factors related to the donor; donor type (cadaveric), social risk (homeless, known TB contact, smoking, alcohol abuse), medical risk (DM, obesity, history of untreated TB)
11- Risk factors related to transplantation; immunosuppression, graft rejection either acute or chronic
12- Other risk factors like TB country burden
13- reactivation of latent infection occurs through multiple mechanisms, such as: depletion of all types of T cells, decrease in activation and proliferation of T cells, decrease in IL-2 synthesis, decrease in the production of Th-1 type cytokines or impairment of cellular immunity almost completely.
14- Diagnosis:
a- TB occurs in the first year post-transplant in cases of reactivation of latent infection in the recipient , but occurs in the first three months in cases of reactivation of latent infection from the infected graft (donor derived).
b- Diagnosis can be initiated by high index of suspicion because of atypical clinical picture in immunosuppressed patients and confusing manifestations because of associated co-infections.
c- tuberculin skin test (TST) and interferongamma release assay (IGRA) are not useful in the diagnosis of active TB.
d- molecular tests based on rapid nucleic acid amplification techniques, such as mycobacterium tuberculosis complex and resistance to rifampin test (Xpert® MTB/RIF, Cepheid, Sunnyvale, CA, USA), could provide false negative results when mycobacterial load is low.
e- Radiological diagnosis either CXR or CT can be confused with other pathological diagnosis.
f- Donor-derived TB is considered an under-recognized condition with early onset after KT in the majority of cases and should be suspected in KT recipients with one of the following features: non-specific symptoms, frequent fever in the first 3 months after KT, fluid collections, extrapulmonary manifestations or lack of response to empirical antibiotic therapy.
g- Current guidelines (American Society of Transplantation Infectious Diseases Community of Practice and European Society of Clinical Microbiology and Infectious Diseases) recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors.
h- In cadaveric donor, donor history of previous active TB, specific treatment or exposure to active TB within the last 2 years should be obtained from the donor’s family or relatives.
i- IGRA test if performed, a series of aspects should be considered—the result might not be available in time, the result could be false negative in donors with head injury due to depressed cell-mediated immunity and, in high-risk donors from low endemic areas with positive tests, the decision of donation should be correlated with personal history and chest imaging.
j- latent TB infection is defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB . it constitute 20% of cases of TB in the recipients.
k- no gold standard tests for diagnosing latent TB accurately in KT candidates, but IGRA seems to present some advantages over TST in patients with ESRD.
15- Treatment remains challenging because of drug interaction, toxicity and risk of rejection.
a- In active TB ; duration of treatment 6-24 months , in some recommendations at least 9-12 months
1- In active uncomplicated pulmonary TB should be 6 months
2- but if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months
3- severe disseminated disease or bone and joint disease, treatment duration is recommended for at least 6–9 months
4- Patients with central nervous system involvement should be treated for at least 9–12 months
5- first-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases
6- Rifamycin is recommended for its sterilization capacity and efficiency but also to reduce the risk of resistance
7- Protocol is 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin as general population.
8- In localized non-severe TB, a regimen without rifampicin could be used if no resistance to isoniazid is present
9- If a regimen without rifamycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide.
10- if second-line drugs are used, a longer period of treatment is recommended.
11- Rifampicin, a potent inducer of cytochrome P450 3A4 and P-glycoprotein, interferes with immunosuppression metabolization.
12- It decreases the trough level of CNI so the dose of CNI should be increased 3- f times so the toxicity and the cost also will increase
13- Rifampicin also decrease the trough level of mTORI and affect steroid metabolism hence increase risk of rejection
14- Dose of steroid should be doubled during treatment with rifampicin
15- after the rifampicin is stopped, the immunosuppression doses should be reduced to the value before the start of rifampicin and then adjusted to obtain the therapeutic target.
16- Rifabutin is alternative to rifampicin, which is a weaker inducer of cytochrome P450 3A4 and P-glycoprotein but with similar efficacy and less drug interaction
17- safe and effective alternative to rifampicin in KT recipients is treatment with fluoroquinolones
18- Patients treated with anti-TB drugs should be closely monitored for hepatotoxicity (isoniazid, rifampicin, pyrazinamide, ethambutol), neurotoxicity (isoniazid, ethambutol), cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol), visual disturbances (rifabutin, ethambutol), skin lesions (rifampicin), hyperuricemia (pyrazinamide) or interstitial nephritis (rifampicin, pyrazinamide) same as general population
19- The most common adverse event associated with anti-TB therapy is hepatotoxicity; therefore, liver enzymes should be closely monitored with bi-weekly evaluation during the intensive phase of treatment and monthly thereafter
20- adjust the doses for pyrazinamide and ethambutol according to renal function
21- RIS should be implemented in severe cases when vital organ involved
b- In latent TB its criteria to be diagnosed:
1- Exclusion of active TB
2- positive TST or IGRA test,
3- history of untreated TB
4- history of recent contact with an active TB patient
5- kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB
preferred treatment of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6.
alternative regimen for KT recipients, mainly for those with high risk, consists of ethambutol and levofloxacin or moxifloxacin
monitor liver enzymes during treatment, initially bi-weekly for 6 weeks and monthly thereafter.
Use of rifampicin is not recommended
16- outcome: there is increase risk o morbidity and mortality in immunosuppressed patient with TB as we deal with pulmonary and extra pulmonary complications , and its treatment is challenging with drug interaction and risk of rejection and graft loss and the toxicity of the drugs itself, another issue is the compliance to treatment, and of course the mortality is high when left untreated or late in diagnosis or development of co-infection or died from the toxicity of the drugs itself.
level of evidence 1
Please use headings and sub-headings to make easier to read your write-up. Please use bold or underline to highlight headings and sub-headings.
I like your detailed summary.
This review of TBC in kidney transplantation recipients encompasses literature between January 2000- June 2022. The level of evidence is 5
TBC in Kidney transplant recipients has a higher incidence and prevalence than the general population. Excluding covid 19, TBC was reported as the 13th and leading cause of death in general. İncidence was reported 127/100.000/year. The source of infection in Kidney recipients can be de novo or donor-derived. Depending on geographical area, there is a numerical variance of numbers but the prevalence and incidence, but it was reported to be eight times more prevalent in solid organ recipients.
TBC risk factors in KT recipients can be related to transplant and immunosuppression but can be either recipient-associated or donor-related.
Donor-associated factors include donor type, social status (higher with low), medical situation and immune status. Recipients’ related factors include diabetes, smoking, COPD, latent tbc and long-term dialysis. Acute rejection was reported to have an increased risk of 7.6 (Thitisuriyarax et al.). Immunosuppression potency seems to have an important role. As shown in figure 2, the source of infection could be the reactivation of latent TBc, Denovo infection or donor-derived.
Diagnosis may be challenging. Although more prevalent in the first year, high suspicion is needed to diagnose. Nonspecific symptoms and coinfections may withdraw attention apart from TBC and contribute to the delay in diagnosis. In addition, TST and IGRA are not useful in active TBC definite diagnosis. IGRA may be false negative in some cases with T cell depression, like in head injury cases. Even TST may be unattainable and overlocked.
Donor-derived infections are expected to have been reported more, especially in poor emigration areas.
Regarding Latent infection, both TST and IGRA can be utilized, with IGRA being more sensitive and predictive, according to some reports.
Treatment of TBC may be challenging because of toxicity and drug interactions. The length of treatment may vary from 6-24 months. Rifampicin usage entails close monitoring of Calcinurine/mTOR levels, as lowering the effect may put the patient in risk of rejection. Although lower cytochrome P450 3A4 induction of Refabutine, caution and monitoring are still needed.
The risk of graft rejection can reach up to 55.6%. Mortality doubles in the case of active TBC. HR was found to be 1.8. Usually, patients have co-infections, either bacterial or fungal. Collaboration between infectious diseases and transplant follow-up teams is essential.
Please use headings and sub-headings to make easier to read your write-up. Please use bold or underline to highlight headings and sub-headings.
II. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review
====================================================================
====================================================================
Summarise this article
Introduction
====================================================================
Methods
====================================================================
Epidemiology and Risk Factors for Tuberculosis in Kidney Transplantation
1. Epidemiology of Tuberculosis in Solid Organ Transplantation
2. Epidemiology of Tuberculosis in Kidney Transplantation
3. Risk Factors for Tuberculosis in Kidney Transplantation
===================================================================
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients
====================================================================
Diagnostic and Treatment Challenges
1. Diagnostic Challenges
1.1. Active Tuberculosis
1.2. Latent Tuberculosis
===================================================================
2. Treatment Challenges
2.1. Active Tuberculosis
2.2. Latent Tuberculosis
====================================================================
Outcomes
1. Rejection
2. Graft Loss
3. Mortality
===================================================================
Conclusions
====================================================================
What is the level of evidence provided by this article?
The level of evidence is 5
======================
Typing whole sentence in bold amounts to shouting.
I like your summary, level of evidence, analysis and conclusions.
SUMMARY
Introduction
Kidney transplantation remains the best option of renal replacement therapy for those with end-stage kidney disease, but one of its downsides is the occurrence of infection post-transplant due to a reduced immune system.
One such common infection is tuberculosis, which could either be reactivated in the recipient or even be transmitted from the donor despite adequate screening pre-transplantation
Aim of the study
Methods
Epidemiology
Risk factor for TB in kidney transplant patient
This could be broadly divided into :
Transmission and pathogenesis
Diagnosis
The diagnosis is generally challenging and it requires a high index of suspicion not to lose the patient eventually
Active TB treatment
The optimal treatment period could vary from 6- 24 months depending on the sites and severity. Treatment is usually in two phases comprising intensive and maintenance.
Latent TB treatment
Challenges with drug therapy
Conclusion
The impact of TB infection on the kidney transplant recipient could be fatal if early diagnosis and prompt treatment are not administered on time. The development of better diagnostic tools will help more in the accurate diagnosis of latent TB infection plus medication with less drug interaction
I like your summary, level of evidence, analysis and take home messages.
What is your suggestion regarding communication gap?
What is IRIS?
Summarise this articleSummarise this article
TB is common cause of death and the leading infectious cause of death worldwide (exclude covid 19).because of immunosuppression in transplantation ,active TB is higher than general population..
Proper assessment for donor and recipient is limited occurrence of the disease.
Methods
A literature search on PubMed and Embase electronic databases was performed from 1 January 2000 to 15 June 2022.
All studies that provided epidemiological and/or outcomes data regarding TB in KT were included.
Epidemiology and Risk Factors for Tuberculosis in Kidney Transplantation
The prevalence of active TB among patients with solid organ transplantation is highly variable according to the geographic area.
The incidence of active TB in solid organ transplantation is 20–74 times higher than in the general population,but differ upon the area which endemic or not.
Epidemiology of Tuberculosis in Kidney Transplantation
The prevalence of active TB in kidney transplantation recipients varies from 0.3%to15.2%,and is higher than in the general population.
Risk Factors for Tuberculosis in Kidney Transplantation
main cause of TB in kidney transplant is:
1. reactivation of latent disease .
2.donor tissue .
3. Denovo infection.
Transplant-associated risk factors, such as immunosuppression therapy, presence of acute rejection episodes and chronic graft disfunction.
But generally the risk factor depending on recipient and donor:
Recipient :
Old age
Male
Smoking
Malnutrition
DM
COPD
Latent tuberculosis
HCV
CMV
Pneumocystis
Auto immune disease
Donor risk factor
Donor type (cadaveric )
Smoking
Alchol
DM
BMI(more than 18.5kg/m)
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients
Transmission of TB in KT recipients depend on:
Reactivation of latent TB.
Positive latent infection conversion was found in ~20% of cases within the first 2 years after kidney transplant.
Diagnostic Challenges
Active TB usually appears in the first year after kidney transplantation.
Diagnosis of TB need :
The diagnosis requires a high index of suspicion but kidney transplant recipients have atypical clinical presentations which reduce the clinical suspicion of TB,
Is it associated with other co-infections,
TST and IGRA are not useful in the diagnosis of active TB .
Latent Tuberculosis.
Prevalence of latent TB after KT was reported in ~20% of recipients.
latent TB must be screening in all KT candidates and donors before transplantation.
IGRA is superior to TST in patient with ESRD.
IGRA tests have a good predictive potential for latent TB in KT recipient with negative TST.
IGRA tests had a low sensitivity in KT recipients .
IGRA test cannot be used to exclude latent TB.
Kidney transplant recipients should be more frequently screened.
Treatment Challenges:
Treatment of KT recipients with TB should carried out by an experienced clinician due to adverse events and drug –drug iteractions ,drug toxicity and treatment adherents .
Active Tuberculosis:
Once diagnosis of active TB established ,treatment must be start. treatment period from 6 to 24 months.
According to AST-IDCOP, the first-line treatment should be a four-drug regimen.
Standard regimen consists of a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed bya4-month continuation phase of isoniazid and rifampicin as in general. Rifamycin is recommended for its sterilization capacity and efficiency but also to reduce the risk of resistance. If a regimen without rifamycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide.Rifampicin, a potent inducer of cytochrome P450 3A4 and P-glycoprotein that interfere with CNI (cyclosporin and tacrolimus).
That must be monitoring the CNI when use rifampicin.also monitoring for hepatotoxicity ,neurotoxicity ,cytopenia ,visual disturbances ,skin lesions,hyperuricaemia,and interstitial nephritis.
Another safe and effective alternative to rifampicin in KT recipients is treatment with fluoroquinolones.
Outcomes
Graft rejection in KT recipients with TB can reach up to 55.6%. The prevalence of graft loss in KT patients with active TB varies from 2.2% to 66.6% ,mortality was described in 41.4% of patients with active TB after KT and in 14.4% of cases mortality was associated with anti-TB therapy.
Conclusions
Tuberculosis in kidney transplantation is associated with significant negative graft and patient outcome .
clinicians should recognize the diagnostic and treatment challenges of TB after KT.
optimal management approach should be done by experience clinician .
Donor-derived TB and latent TB in KT are under recognized conditions that should be carefully evaluated.
Development of tests with helpful predictive values.
Newly discovered regimens or could have an important contribution in the future limitation of drug–drug interactions, improvement of treatment efficacy and reduction of
adverse events.
What is the level of evidence provided by this article?
Level V.
I like your detailed summary, level of evidence, analysis and conclusions. I appreciate your debate regarding the uncertainty on optimal duration of therapy
Summary of the article
Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review
Epidemiology of TB in SOT
· The prevalence varies between 0.3–6.4% in low TB endemicity to 15.2% in high endemic areas.
· The incidence of active TB in SOT is 20–74 times higher than in the general population.
· Latent TB infection: according to WHO is defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB. Prevalence of latent TB after KT was reported in ~20% of recipients.
Epidemiology of TB in Kidney Transplantation
· The prevalence of active TB in KT recipients varies from 0.3% to 15.2%.
· The prevalence is higher than in the general population but lower than in patients with lung transplantation.
· The pooled incidence of active TB in KT recipients was higher than in patients with ESRD in pre-dialysis but lower than in those on peritoneal dialysis and hemodialysis.
Risk Factors for TB in Kidney Transplantation
· Endemicity of TB in the population.
· Transplant-associated risk factors: immunosuppression therapy, presence of acute rejection episodes and chronic graft disfunction.
· Recipient-associated risk factors: older age, male gender, smoking, malnutrition, DM, COPD, latent TB (pre-transplant), CLD &HCV, opportunistic co-infection(CMV, PJP & Nocardia), auto-immune disease and long-term HD.
· Donor-associated risk factors: donor type(cadaveric), social risk factors(homeless, incarceration, smoking, alcohol abuse and known TB contact) and medical risk factors(DM, BMI< 18.5 Kg/m2, history of untreated TB).
Transmission of TB in KTRs
There are three possible scenarios for transmission of TB in KTRs:
1. Reactivation of the latent infection that occurred in the pre-transplant period. This is the most common form in all solid organ transplantation, including KT.
2. Via kidney graft from an infected donor, this type of transmission is responsible for only 4.8% of cases.
3. A de novo infection after KT.
· in a recipient with exposure to a patient with active TB and is more frequent in endemic areas.
· This type of transmission is not common.
· It is associated with very high risk of progression.
Pathogenesis of TB in KTRs:
1. The protection against MBT infection is mainly based on cellular immunity, and, more specifically, it depends on T helper 1 (Th1) response. Th1-type CD4+ T cells and type-1 cytokines are crucial for protection against MBT.
2. Proliferative capacities of CD4+ and CD8+ T cells and interferon gamma (IFN-γ) and interleuqin-2 (IL-2) production are essential effectors in the protective response.
3. Using immunosuppression in the setting of KT could disrupt the protection against TB and increase the risk of reactivation through multiple mechanisms:
a) depletion of all types of T cells.
b) decrease in activation and proliferation of T cells.
c) decrease in IL-2 synthesis.
d) decrease in the production of Th-1 type cytokines.
e) impairment of cellular immunity almost completely.
Diagnosis of TB in KTRs and diagnostic challenges:
a) The diagnosis of TB requires a high index of suspicion based on the epidemiological risk, personal history, manifestations and imagistic lesions.
· Atypical clinical presentations or diverse manifestations reduce the linical suspicion of TB.
· Donor-derived TB should be suspected in KTR with one of the following features: non-specific symptoms, frequent fever in the first 3 months after KT, fluid collections, extrapulmonary manifestations or lack of response to empirical antibiotic therapy.
b) Tuberculin skin test (TST) and interferon- gamma release assay (IGRA) are not useful in the diagnosis of active TB.
c) Molecular tests based on rapid nucleic acid amplification techniques, such as mycobacterium tuberculosis complex and resistance to rifampin test (Xpert® MTB/RIF, Cepheid, Sunnyvale, CA, USA), could provide false negative results when mycobacterial load is low.
d) Screening tests for latent TB (TST and IGRA) have low feasibility and accuracy.
e) Data regarding prediction capacity of TST and IGRA tests are discordant in category of patients with latent TB.
Treatment of KT recipients with TB
1. Treatment Challenges: drug–drug interactions, drug toxicity and treatment adherence.
2. Active Tuberculosis:
a) The optimal period of treatment could vary from 6 to 24 months. Recommended to be at least 9–12 months.
b) According to AST-IDCOP, the first-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases.
c) The standard regimen is similar to that used for the general population and consists of a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin.
d) Adjustment of immunosuppression as Rifampicin reduces the level of CNIs and mTORi:
· the dose of CNIs and mTORi should be increased between three- and five-fold and the glucocorticoid dose should be doubled during treatment and adjusted thereafter to obtain the therapeutic target.
3. Treatment of latent TB should be considered only after active TB has been excluded.
a) Treatment in this category of patients is indicated in one of the following conditions: a positive TST or IGRA test, a history of untreated TB, a history of recent contact with an active TB patient and when the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB.
b) In the KT setting, the preferred treatment of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6.
c) An alternative regimen for KT recipients, mainly for those with high risk, consists of ethambutol and levofloxacin or moxifloxacin.
Outcomes of TB in KT:
1. TB in KT is associated with important morbidity and mortality due to:
· immunosuppression status.
· increased extrapulmonary disease.
· challenges in diagnosis that delay the initiation of treatment.
2. Rejection:
· Graft rejection in KT recipients with TB can reach up to 55.6% and could be responsible for ~1/3 of graft losses.
3. Graft Loss: The prevalence of graft loss in KT patients with active TB varies from 2.2% to 66.6%.
· Sepsis, acute rejection, interstitial fibrosis and tubular atrophy were causes of graft loss.
4. Mortality:
· The mortality of patients with TB after KT has been reported to range from 0% to 60%.
· Active TB after 2 years post-KT is an independent risk factor for mortality.
The level of evidence provided by this article:
This is an extensive literature review of articles published between 1 January 2000 and 15 June 2022. It is a retrospective study with level of evidence grade 3.
What is your suggestion regarding communication gap in regards to MDT approach and to discuss reports when offer is made often in the middle of night?
I like your summary, level of evidence, and analysis.
Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review
Bogdan MS and colleagues in this review article aimed to provide an evidence-based update regarding epidemiology, risk factors, pathophysiology, type of transmission, diagnostic challenges, treatment challenges and the impact of TB in KT recipients.
Methods
All studies that provided epidemiological and/or outcomes data regarding TB in KT from PubMed and Embase electronic databases from 1 January 2000 to 15 June 2022 were included except those in other languages or without complete information.
Epidemiology and Risk Factors for Tuberculosis in Kidney Transplantation
The prevalence of active TB in KT recipients varies from 0.3% to 15.2% and is higher than in the general population but lower than in patients with lung transplantation.
Transplant-associated risk factors for TB in KT includes immunosuppression therapy, presence of acute rejection episodes and chronic graft dysfunction. Immunosuppression used in KT impairs T-cell-mediated immunity involved in TB control and favors latent infection reactivation. T cell-depleting agents (anti-thymocyte globulin), cytotoxic T-lymphocyte-associated protein-4 inhibitors (belatacept), calcineurin inhibitors (tacrolimus, cyclosporine), anti-metabolites (mycophenolate, azathioprine) and glucocorticoids all increase the risk of development of TB.
Recipient risk factors for TB in KT includes older age, male sex, smoking, malnutrition, diabetes mellitus, malnutrition, COPD, latent TB before transplant, CLD, HCV infection, opportunistic infection (such as CMV, norcardia), autoimmune disease, long dialysis vintage.
Donor associated risk factors includes cadaveric donors, social risks (homelessness, incarceration, smoking, alcohol,), medical risk (DM, BMI<18.5, history of untreated TB).
Others are burden of TB and its endemicity.
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipient
Transmission is via aerosol droplets containing mycobacterium tuberculosis (MBT) that are inhaled into the lungs. The outcome of exposure could be as follows: clearance of MBT by the organism either due to innate immune response or acquired T cell immunity, development of primary disease which means an immediate onset of active disease (first 24 months after primary infection) or latent infection reactivation meaning a late onset of active disease many years following primary infection.
The most common mode of disease transmission in KTP is through activation of latent infection acquired prior to transplantation. In 4.8% of cases, TB could be transmitted to KT recipients via kidney graft from an infected donor. Lastly, though very uncommon, TB could occur as a de novo infection after KT in a recipient with exposure to a patient with active TB. This mode of transmission associated with very high risk of progression, and it is more frequent in endemic areas.
The protection against MBT infection is mainly based on T helper 1 (Th1) response. Th1-type CD4+ T cells and type-1 cytokines are crucial for protection against MBT. In addition, proliferative capacities of CD4+ and CD8+ T cells and interferon gamma (IFN-γ) and interleukin-2 (IL-2) production are essential effectors in the protective response. Using immunosuppression in the setting of KT could disrupt the protection against TB and increase the risk of reactivation through multiple mechanisms, such as: depletion of all types of T cells, decrease in activation and proliferation of T cells, decrease in IL-2 synthesis, decrease in the production of Th-1 type cytokines or impairment of cellular immunity almost completely.
Diagnostic and Treatment Challenges
Active tuberculosis
The diagnosis of TB requires a high index of suspicion based on the epidemiological risk, personal history, manifestations and imagistic lesions. Delay in diagnosis could result from atypical presentations which could occur in KT recipients. Additionally, the probability of association with other co-infections and extrapulmonary localization in ~50% of cases add a supplementary confusing element to the clinical picture. Paraclinical issues such as poor utility of IGRA and tuberculin skin testing in diagnosis. The need for invasive procedures such as bronchoalveolar lavage for diagnosis could also represent a diagnostic challenge sometimes. False negative test can occur with molecular tests when mycobacterial load is low, and this can be challenging.
Latent tuberculosis
According to WHO, latent TB infection is defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB. There are no gold standard tests for diagnosing latent TB accurately in KT candidates, but IGRA seems to present some advantages over TST in patients with ESRD. Even so, the evaluation of latent TB in KT recipients is challenging because data regarding prediction capacity of TST and IGRA tests are discordant in this category of patients.
Treatment Challenges
Active Tuberculosis
Treatment of KT recipients with TB could be challenging due to drug–drug interactions, drug toxicity and treatment adherence.
The optimal period of treatment could vary from 6 to 24 months and, in some cases, based on experts’ opinion, the duration of treatment is recommended to be at least 9–12 months. American Society of Transplantation Infectious Diseases Community of Practice (AST-IDCOP) guidelines recommends that in case of active uncomplicated pulmonary TB, treatment duration should be at least 6 months, but if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months. In case of severe disseminated disease or bone and joint disease, treatment duration is recommended for at least 6–9 months. Patients with central nervous system involvement should be treated for at least 9–12 months.
The first-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases.
Latent Tuberculosis
Treatment of latent TB should be considered only after active TB has been excluded. Treatment in this category of patients is indicated in one of the following conditions: a positive TST or IGRA test, a history of untreated TB, a history of recent contact with an active TB patient and when the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB [13]. In the KT setting, the preferred treatment of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6. A regimen based on rifampicin is not recommended. An alternative regimen for KT recipients, mainly for those with high risk, consists of ethambutol and levofloxacin or moxifloxacin. The main adverse event associated to isoniazid is hepatotoxicity, but the risk of liver damage seems to be reduced in KT patients. Nonetheless, evaluation of liver enzymes during treatment, initially bi-weekly for 6 weeks and monthly thereafter, is recommended.
Outcomes
TB in KT is associated with important morbidity and mortality due to immunosuppression status, increased extrapulmonary disease and challenges in diagnosis that delay the initiation of treatment.
Rejection
Graft rejection in KT recipients with TB can reach up to 55.6%, often being associated with reduced levels of immunosuppression secondary to calcineurin inhibitors–rifampicin interaction and could be responsible for ~1/3 of graft losses.
Graft Loss
Increased risk of graft loss from rejection sepsis and donor derived TB and varies between 2.2 and 66%.
Conclusions
TB in KT is an important opportunistic infection with higher incidence and prevalence than in the general population and is associated with significant negative graft and patient outcomes.
Level of evidence – Level V
I like your detailed summary. I appreciate your debate regarding the uncertainty on optimal duration of therapy
1. Summarise this article
Introduction
Epidemiology & Risk Factors for TB
Risk Factors for TB in KTX
Transplant-associated risk factors:
Recipient-associated risk factors:
Donor-associated risk factors:
Pathogenesis
Types of TB transmission
Diagnostic Challenges of active TB in KTX recipients:
Diagnostic Challenges of LTBI in KTX recipients:
Treatment challenges of active TB
Outcomes of TB in KT
Future
======================
2. What is the level of evidence provided by this article?
Level V
Do you think you would like to use a test or battery of tests with good likelihood ratio of >10, rather than those with high predictive value, of diagnosing TB in an immuno-suppressed patients?
I like your projection for future.
Summarise this article
Introduction
· Kidney transplantation is the optimal treatment for end-stage renal disease, but infection post-transplantation is an important limitation.
· TB is the leading cause of death post-transplantation, with an incidence rate of 127 cases per 100,000 people.
· Kidney transplantation is linked to an immunosuppressive condition, which can cause patients to have greater rates of active TB than the general population.
· To reduce or eliminate the occurrence of active TB following transplantation, screening procedures should be put into place.
· Kidney transplantation candidates and recipients with TB are a major challenge for diagnosis and management, with potential adverse effects such as transplant rejection, graft loss, and death.
Methods
· An evidence-based review of TB in kidney transplantation recipients.
· Current guidelines used to diagnose and treat active TB in kidney transplantation.
· Epidemiology and Risk Factors for Tuberculosis in Kidney Transplantation
Epidemiology of Tuberculosis in Kidney Transplantation
· The prevalence of active TB in kidney transplantation recipients varies from 0.3% to 15.2% and is higher than in the general population but lower than in patients with lung transplantation.
· Two systematic reviews and meta-analyses found similar results, with an unadjusted TB risk ratio of 11.36 times higher and an adjusted risk ratio for dialysis of 3.62 times higher than those from the general population.
· Kidney transplantation recipients had a pooled incidence of active TB of 2700-14,680 per 100,000 patient-years, higher than ESRD in pre-dialysis and lower than those on peritoneal dialysis and hemodialysis.
Risk Factors for Tuberculosis in Kidney Transplantation
· Immunosuppressive medication, (T-cell depleting medicines, cytotoxic T-lymphocyte-associated protein-4 inhibitors, calcineurin inhibitors, anti-metabolites, and glucocorticoids)
· Acute rejection episodes,
· Chronic graft malfunction,
· Chronic graft dysfunction,
· Quantity of rejections following a transplant is a separate risk factor for the development of TB.
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients
· The natural history of infection involves clearance of MBT, development of primary disease, or latent infection reactivation.
· Transmission of TB in kidney transplantation recipients could occur in three scenarios: reactivation of latent infection, transmission via kidney graft, or de novo infection.
· In a prospective study, latent infection was found to be higher in recipients than candidates, and older age, absence of Bacillus Calmette–Guérin vaccine scars, and donor-specific antibodies were associated with latent infection. A strategy for post-transplantation latent infection evaluation could be helpful in addition to pre-transplant screening.
· Kidney transplantation generates a favorable path for TB reactivation in candidates with latent infection due to initiation of induction and maintenance-specific immunosuppression.
· This could disrupt the protection against TB and increase the risk of reactivation through depletion of all types of T cells, decrease in activation and proliferation, decrease in IL-2 synthesis, decrease in the production of Th-1 type cytokines, or impairment of cellular immunity.
Diagnostic and Treatment Challenges
· Patients’ prognosis depends on the early diagnosis and the appropriate therapeutic approach.
Diagnostic Challenges
Active Tuberculosis
· The diagnosis of active TB in kidney transplantation patients is challenging due to the high index of suspicion, atypical clinical presentations, and the probability of association with other co-infections.
· Diagnostic challenges such as tuberculin skin test (TST) and interferon-gamma release assay (IGRA) are not useful, and molecular tests based on rapid nucleic acid amplification techniques may provide false negative results when the mycobacterial load is low.
· Donor-derived TB is an under-recognized condition with early onset after kidney transplantation and should be suspected in recipients with:
o Non-specific symptoms.
o Frequent fever.
o Fluid collections,
o Extrapulmonary manifestations.
o Lack of response to empirical antibiotic therapy.
o Screening tests for latent TB have low feasibility and accuracy.
o Donor history, treatment, and exposure to active TB should be obtained from family or relatives.
Latent Tuberculosis
· Latent TB infection is defined as a persistent immune response to stimulation by MBT antigens with no evidence of clinically manifested active TB.
· Prevalence of latent TB after kidney transplantation was reported in ~20% of recipients, and current guidelines recommend screening before transplantation.
· There are no gold standard tests for diagnosing latent TB accurately, but IGRA seems to present some advantages over TST in patients with ESRD.
· However, data regarding the prediction capacity of TST and IGRA tests are discordant in this category of patients.
· The importance of diagnosis is supported by the fact that undiagnosed and untreated latent TB significantly increases the risk of active TB.
Treatment Challenges
· Treatment of kidney transplantation patients with TB should be managed by an experienced clinician with special attention to drug-drug interactions and adverse events.
Active Tuberculosis
· Treatment of active TB in kidney transplantation recipients should be promptly started and assessed for epidemiological features and drug resistance patterns.
· The optimal period of treatment for active uncomplicated pulmonary TB is recommended to be at least 6 months, but if cavitary lesions exist or there is a persistent culture-positive sputum, it may be extended to 9 months.
· The first-line treatment should be a four-drug regimen containing rifamycin, which is recommended for its sterilization capacity and efficiency but also to reduce the risk of resistance.
· Rifampicin is a potent inducer of cytochrome P450 3A4 and P-glycoprotein that interferes with immuno- suppression metabolization, increasing the risk of rejection and graft loss in kidney transplantation recipients with active TB.
· To manage this, calcineurin and mTOR inhibitor levels should be increased, and immunosuppression doses should be reduced or adjusted to obtain the therapeutic target. Rifabutin and fluoroquinolones are safe and effective alternatives.
· The most common adverse effects of TB therapy are hepatotoxicity, neurotoxicity, cytopenia, visual disturbances, skin lesions, hyperuricemia, and interstitial nephritis.
· Treatment adherence is an issue in kidney transplantation recipients, but the implementation of directed observed therapy programs has improved adherence.
· Reduction of immunosuppression in severe TB or when a vital organ is involved should be considered, but there are concerns about immune reconstitution inflammatory syndrome.
Latent Tuberculosis
· Treatment of kidney transplantation recipients with latent TB is important for preventing reactivation and is indicated in one of the following conditions:
o Positive TST or IGRA test,
o History of untreated TB,
o Recent contact with an active TB patient,
o Kidney graft originates from a donor with known latent TB,
· Isoniazid 5 mg/kg/day for 9 months, supplemented with vitamin B6.
· Evaluation of liver enzymes during treatment is recommended.
Outcomes
· TB in kidney transplantation is associated with increased morbidity and mortality.
Rejection
· Graft rejection in kidney transplantation recipients with TB can be associated with reduced levels of immunosuppression, with acute rejection being responsible for ~1/3 of graft losses.
Graft Loss
· Graft loss among kidney transplantation patients with active TB can be caused by infection, sepsis, acute rejection, interstitial fibrosis, and tubular atrophy, and can be precipitated by suboptimal levels of immunosuppression.
· The prevalence of graft loss varies from 2.2% to 66.6%.
Mortality
· Mortality rates for patients with active TB have been reported to range from 0-60%. 65% of participants with active TB who died had co-infections with fungi, cytomegalovirus, Nocardia, hepatotropic viral infections, and chronic liver disease.
· Mortality was also associated with anti-TB therapy in 14.4% of cases.
· More than half of patients who died received anti-rejection treatment before the TB development and had diabetes, hepatitis C virus infection, or fungal infection.
Conclusions
· A serious opportunistic infection that affects patients and grafts adversely after kidney transplantation, TB has a greater incidence and prevalence than in the general population.
· Medical professionals who specialize in kidney transplantation and infectious diseases must work closely together to eliminate the risk factors for both the development of TB and its harmful effects.
· Latent TB and donor-derived TB should be thoroughly assessed and tested with useful predictive values.
· Newly developed regimens or medications in the pipeline may have a significant role in limiting drug-drug interactions, increasing treatment effectiveness, and lowering adverse effects in the future.
====================================================
What is the level of evidence provided by this article?
Level V
I like your summary, level of evidence, analysis and take home messages.
I like that you state, “Medical professionals who specialise in kidney transplantation and infectious diseases must work closely together.”
Introduction:
Epidemiology of Tuberculosis in Solid Organ Transplantation
Epidemiology of Tuberculosis in Kidney Transplantation
Risk Factors for Tuberculosis in Kidney Transplantation
Transmission of TB in KT recipients
Diagnosis
Management
Level of evidence : Level V (Narrative review)
Typing whole sentence in bold or typing in capitals amounts to shouting.
I like your very detailed summary, level of evidence, analysis and take home messages.
I appreciate your debate regarding the uncertainty on optimal duration of therapy
Introduction:
Kidney transplantation (KT) remains the optimal treatment for patients with end-stage renal disease (ESRD) One of the most common infections with negative impact post-transplantation is tuberculosis (TB) According to World Health Organization (WHO), >10 million cases of TB (were reported in 2020 worldwide, corresponding to an incidence rate of 127 cases per 100,000 people per year Active
TB after KT could arise from reactivation of latent infection in the recipient or donor tissue or can result from de novo infection after transplantation. Endogenous reactivation after KT is the most common form of transmission
KT candidates and recipients with TB represent a real challenge regarding the diagnosis and treatment due to atypical or diverse clinical presentation, limitations of screening tests for latent infection, drug interactions and toxicities . The delay in diagnosis and treatment could determine negative consequences, such as graft rejection, graft loss and increased mortality rate
objective :
to provide an evidence-based update regarding epidemiology, risk
factors, pathophysiology, type of transmission, diagnostic challenges, treatment challenges and the impact of TB in KT recipients
Methods:
literature review of articles published between 1 January 2000 and 15 June 2022 to provide an evidence-based review of epidemiology, pathogenesis, diagnosis, treatment and outcomes of TB in KT recipients. And included all studies which reported epidemiological and/or outcome data regarding active TB in KT, and we approached the diagnostic and treatment challenges according to the current guidelines
Epidemiology and Risk Factors for Tuberculosis in Kidney Transplantation:
The prevalence of active TB among patients with solid organ transplantation is highly variable according to the geographic area. In areas with low TB endemicity, the prevalence varies between 0. 3 to 6.4%, while the prevalence of tuberculosis can reach 15.2% in highly endemic areas. KT recipients ranged from 0.3% to 15.2% Prevalence of tuberculosis in the population.
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipient
1-active TB could arise after KT as a result of reactivation of the latent infection present in the recipient prior to transplantation
2-donor -derived infection.
3-De novo infection after KT. TB—tuberculosis
Diagnostic and Treatment Challenges:
High index of susciption based on : Epidemiological risk Personal history Imaging lesion
(bronchoscopy with bronchoalveolar lavage, derange of fluid collections
subsequently evaluated by smear andmycobacteriumculture and histopathological evaluation
Donor-derived TB is considered an under-recognized condition:
non-specific symptoms, frequent fever in the first 3 months after KT, fluid collections, extrapulmonary manifestations or lack of response to empirical antibiotic therapy active disease in donors is a contraindication for donation, identification of latent TB in deceased donors remains a real challenge in KT, despite the current recommendation for screenin
Current guidelines (American Society of Transplantation Infectious
Diseases Community of Practice and European Society of Clinical Microbiology and Infectious Diseases) recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors
in deceased donors, the patient’s medical history might be unobtainable, and the screening tests for latent TB (TST and IGRA) have low feasibility and accuracy , In these circumstances, details regarding donor history of previous active TB, specific treatment or exposure to active TB within the last 2 years should be obtained from the donor’s family or relatives
Latent Tuberculosis
According to WHO, latent TB infection is defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB
Treatment Challenges:
Treatment of KT recipients with TB could be challenging due to drug–drug interactions, drug toxicity and treatment adherence Active Tuberculosis
The optimal period of treatment could vary from 6 to 24 months and, in some
cases, based on experts’ opinion, the duration of treatment is recommended to be at least 9–12 months
American Society of Transplantation Infectious Diseases Community
of Practice (AST-IDCOP) guidelines recommends that in case of active uncomplicated pulmonary TB, treatment duration should be at least 6 months, but if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months
challenge in the treatment of KT recipients with active TB is the drug interaction between rifampicin and transplant-associated immunosuppression
Outcomes
Rejection
Graft Loss
Mortality
Please use headings and sub-headings to make easier to read your write-up. Please use bold or underline to highlight headings and sub-headings.
Summarise this article
Tuberculosis (TB) in kidney transplant (KT) recipients is an important opportunistic infection with higher incidence and prevalence than in the general population and is associated with important morbidity and mortality. Active TB after KT could arise from reactivation of latent infection in the recipient or donor tissue or can result from de novo infection after transplantation.
Methodology
Search was done for articles published between 1 January 2000 and 15 June 2022 to provide an evidence-based review of epidemiology, pathogenesis, diagnosis, treatment and outcomes of TB in KT recipients.
Epidemiology of Tuberculosis in Solid Organ Transplantation
Prevalence of active TB in KT recipients ranges between 0.3–15.2%. KT recipients with active TB could have a rejection rate up to 55.6%, a rate of graft loss that varies from 2.2% to 66.6% and a mortality rate up to 60%. A recent systematic review and meta-analysis including 60 studies analyzed the prevalence of active TB in solid organ transplant recipients and showed a pooled prevalence of 3%.
Risk Factors for Tuberculosis in Kidney Transplantation
Important risk factors include:
Immunosuppression therapy, presence of acute rejection episodes and chronic graft dysfunction.
Immune suppression can lead to impairs T-cell-mediated immunity involved in TB control and favors latent infection reactivation.
Drugs- anti-thymocyte globulin, cytotoxic T-lymphocyte-associated protein-4 inhibitors (belatacept), calcineurin inhibitors (tacrolimus, cyclosporine), anti-metabolites (mycophenolate, azathioprine) and glucocorticoids increase risk of TB.
Acute rejection significantly increases the risk of TB by 7.6 times
Chronic graft dysfunction, can increase the risk of TB development by amplifying the immunosuppression status.
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients
Active TB could arise after KT as a result of reactivation of the latent infection present in the recipient prior to transplantation
Transmission by infected graft
Denovo development of TB after exposure
Diagnostic and Treatment Challenges
Active Tuberculosis
Diagnosis of TB requires high index of suspicion
KT recipients have atypical clinical presentations
Tuberculin skin test (TST) and interferongamma release assay (IGRA) are not useful in the diagnosis of active TB
Molecular tests
Bronchoscopy with bronchoalveolar lavage–Fluid for smear and mycobacterium culture
Bronchoscopy and biopsy
Latent Tuberculosis
Current guidelines provide recommendations for latent TB screening in all KT candidates and donors before transplantation
IGRA seems to present some advantages over TST in patients with ESRD
Untreated latent TB after KT significantly increases the risk of active
Treatment of Active TB
The optimal period of treatment could vary from 6 to 24 months
American Society of Transplantation Infectious Diseases Community of Practice (AST-IDCOP) guidelines recommends-
– Treatment for 6 months, but if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy, the duration of treatment may be extended to 9 months
– severe disseminated disease or bone and joint disease, treatment duration is recommended for at least 6–9 month
-CNS involvement- 12 months
Recommendations-2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin
ESCMID suggests a standard regimen used for a period longer than 6 months
If Regimen without rifamycin is used, then the 2-month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide.
Latent TB
Isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6
Another regimen consists of ethambutol and levofloxacin or moxifloxacin
Conclusions
· TB in KT is an important opportunistic infection with higher incidence and prevalence than in the general population
· Clinicians should recognize the diagnostic and treatment challenges of TB after KT for an optimal management approach
· Close collaboration between kidney transplant and infectious disease physicians is mandatory
· More diagnostic test which are not based on T cell immunity are required
· Newly discovered regimens or pipeline drugs could have an important contribution in the future management
What is the level of evidence provided by this article?
Level V
Which ‘pipeline’ drugs are you mentioning?
Bedaquiline , Nitroimidazoles and oxazolidinones
1-Summarise this article;
Introduction;
-Tuberculosis (TB) in kidney transplant (KT) recipients is an important opportunistic infection with higher incidence and prevalence than in the general population and is associated with important morbidity and mortality.
-Active TB after KT could arise from reactivation of latent infection in the recipient or donor tissue or can result from de novo infection after transplantation.
-Endogenous reactivation after KT is the most common form of transmission.
Aim;
-Provide an evidence-based update regarding epidemiology, risk factors, pathophysiology, type of transmission, diagnostic challenges, treatment challenges and the impact of TB in KT recipients.
Methodology;
-An extensive literature review of articles were performed and published between 1 January 2000 and 15 June 2022 to provide an evidence-based review of epidemiology, pathogenesis, diagnosis, treatment and outcomes of TB in KT recipients.
-They included all studies which reported epidemiological and/or outcome data regarding active TB in KT, and they approached the diagnostic and treatment challenges according to the current guidelines.
Risk factors for re-activation LTBI;
-Occur when conditions of immunosuppression are present such as diabetes, malnutrition, HIV, and prescription of biologics and immunosuppressive agents including anti-rejection therapies in transplant patients.
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients;
-Transmission of TB in KT recipients could be possible according to three scenarios.
*Active TB could arise after KT as a result of reactivation of the latent infection present in the recipient prior to transplantation,
*TB could be transmitted to KT recipients via kidney graft from an infected donor,
*TB could occur as a de novo infection after KT, in a recipient with exposure to a patient with active TB.
Diagnostic challenges;
Screening and diagnosis of LTBI;
-There is no gold standard test for diagnosing LTBI accurately.
-WHO recommends three tests for screening for LTBI: Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs); (QFT & T-SPOT).
-The TST may be unreliable in patients with advanced chronic kidney disease and in those on immunosuppressive agents.
-IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients & more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation.
-British Thoracic Society guidelines suggest screening for LTBI where tuberculosis incidence rates are high or in patients with risk factors for developing tuberculosis in low incidence areas: need to be evaluated with chest radiography and other screening tests as part of the screening for latent tuberculosis.
Active Tuberculosis;
-Occurs in the first year after KT (a median time of 11.5 months) in the case of reactivation and earlier in the case of donor-derived infection (in the first 3 months)
-The diagnosis requires a high index of suspicion but KT recipients have atypical clinical presentations which reduce the clinical suspicion of TB,
-Probability of association with other co-infections,
-TST and IGRA are not useful in the diagnosis of active TB,
-Molecular tests based on rapid nucleic acid amplification techniques could provide false negative results when mycobacterial load is low.
Treatment challenges;
-Regarding treatment challenges in KT recipients with TB, drug interactions, drug toxicities and therapeutical adherence must be considered.
Treatment of LTBI in donor and recipient;
-The WHO 2018 guidelines for treatment options for LTBI;
-Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
-Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy.
-Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy.
Active Tuberculosis;
Duration of treatment is recommended to be at least 9–12 months.
AST-IDCOP guidelines treatment:
-First-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases (2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-months of isoniazid and rifampicin)
Challenge in the treatment of KT recipients:
-Rifampicin is a potent inducer of cytochrome P450 3A4 and P-glycoprotein.
-Rifampicin decrease the levels of CNIs, mTOR inhibitors, and affects glucocorticoids.
-The dose of CNIs and mTOR inhibitor should be increased between 3-5 folds and the glucocorticoid dose should be doubled during treatment.
-Rifabutin (alternative to rifampicin):weaker inducer of cytochrome P450 3A4 and P-glycoprotein but with similar efficacy.
-Immunosuppression doses could be modified, and levels should be closely monitored.
-Fluoroquinolones: it is safe alternative to rifampicin
-The most common adverse event is hepatotoxicity (liver enzymes should be closely monitored with bi-weekly evaluation during the intensive phase of treatment and monthly thereafter)
Outcome;
–KT recipients with active TB could have a rejection rate up to 55.6%, a rate of graft loss that varies from 2.2% to 66.6% and a mortality rate up to 60%.
Conclusions;
-Prevalence of active TB in KT recipients ranges between 0.3–15.2%.
-Clinicians should recognize the diagnostic and treatment challenges of TB after KT for an optimal management approach.
-This requires close collaboration between kidney transplant and infectious disease physicians.
-Donor-derived TB and latent TB in KT are under recognized conditions that should be carefully evaluated.
-Development of tests with helpful predictive values, which are not based on T cell immunity, could bring important improvement in the diagnosis of latent TB in KT recipients.
2-What is the level of evidence provided by this article?
This is a comprehensive Review with (LOE V).
I like your summary, level of evidence, and analysis.
You mention 3 possible options for prophylaxis against latent TB in recipients. Which one would you choose for your patients?
Thanks our Prof;
We follow 1st option for our patients:
(INH 300 mg od + Pyridoxin 40 mg od / 6 months)
1- Summary:
Epidemiology among KT:
The prevalence of active TB in KT recipients varies from0.3% to 15.2% and is higher than in the general population but lower than in patients with lung transplantation and more than those on dialysis.
Risk factors:
1- TB endemicity in the population
2- Recipient-associated factors:
Old age, male, malnutrition, DM, long dialysis duration, latent T.B, chronic obstructive pulmonary disease, chronic liver disease, opportunistic co-infections.
3- Donor related factors:
Cadaveric donor, homeless, alcoholic, drug abuse, latent T.B, DM
4- Transplant-associated factors:
Immunosuppression, acute rejection, chronic allograft dysfunction
Transmission of T.B:
1- Reactivation of the latent infection present in the recipient. The most common form among KT.
2- Donor-derived infection: 4.8% of cases
3- Do-Novo infection: This type of transmission is not common; it is associated with very high risk of progression, and it is more frequent in endemic areas.
Pathogenesis among KT:
Using immunosuppression disrupt the protection against TB and increase the risk of reactivation through multiple mechanisms, such as: depletion of all types of T cells, decrease in activation and proliferation of T cells, decrease in IL-2 synthesis, decrease in the production of Th-1 type cytokines or impairment of cellular immunity almost completely.
Diagnostic challenges:
1- Active T.B:
Active TB usually appears in the first year after KT, at a median time of 11.5months in the case of reactivation after latent infection and earlier in the case of donor-derived infection (in the first 3months)
Challenges:
– KT recipients have atypical clinical presentations or diverse manifestations
– The probability of association with other co-infections and extrapulmonary localization in ~50%
– Paraclinical issues. For example, tuberculin skin test (TST) and interferon gamma release assay (IGRA) are not useful in the diagnosis of active TB. Additionally, the wide range of radiographic manifestations in pulmonary TB and the frequent need for invasive procedures.
Current guidelines recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors
The diagnosis requires high suspicious index.
2- Latent T.B:
– According to WHO, latent TB infection is defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB.
– Current guidelines recommend latent TB screening in all KT candidates and donors before transplantation. There are no gold standard tests for diagnosing latent TB accurately in KT candidates, but IGRA seems to present some advantages over TST in patients with ESRD.
Treatment challenges:
Active T.B:
– The optimal period of treatment 6-24 months (not less than 6-9 months)
– The first-line treatment should be a four-drug regimen containing rifampicin used both in severe and non-severe cases.
– Consists of a 2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampicin
Challenges:
1- Drug interaction between rifampicin and IS:
Rifampicin is an inducer of cytochrome P 450 and P glycoprotein, so enhance the metabolism of IS drugs and decreases the doses of CNI, -TOR inhibitors and glucocorticoids. So the drug dose should be increased.
2- Adverse effect of the drugs:
– Hepatotoxicity (isoniazid, rifampicin, pyrazinamide, ethambutol): most common
– Neurotoxicity (isoniazid, ethambutol)
– Cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol),
– Visual disturbances (rifabutin, ethambutol)
– Skin lesions (rifampicin), hyperuricemia (pyrazinamide) or interstitial nephritis (rifampicin, pyrazinamide)
3- Drug adherence
4- Associated graft dysfunction require dose modification
5- Reduction of IS in severe cases
Latent T.B
Indication of treatment:
– positive TST or IGRA test, a history of untreated TB, a history of recent contact with an active TB patient
– When the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active.
The preferred treatment of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6.
Outcome:
1- Rejection:
Graft rejection in KT recipients with TB can reach up to 55.6%
2- Graft loss:
It varies from 2.2-66.6%
Causes: infection especially in donor-derived infection, impact of sepsis, acute and chronic rejection from reduction of IS.
3- Mortality:
The mortality of patients with TB after KT has been reported to range from0% to 60%
2- Level of evidence: V
I like your detailed summary. I appreciate your debate regarding the uncertainty on optimal duration of therapy
Summarise this article
o TB is the thirteenth-most common cause of death and the leading infectious cause of death (excluding COVID-19) worldwide
o ~10 million cases of TB in 2020 worldwide with an incidence rate of 127 cases per 100,000 people per year (WHO)
o Active TB is higher in KT recipients than in the general population
o Reactivation of LTBI after KT is the most common form of transmission
Aim of this review: update of epidemiology, risk factors, pathophysiology, type of transmission, diagnostic challenges, treatment challenges and the impact of TB in KT recipients
Methods
Literature review of articles published between 2000-2022 to provide an evidence-based review of epidemiology, pathogenesis, diagnosis, treatment and outcomes of TB in KT recipients
Epidemiology of Tuberculosis
Epidemiology of Tuberculosis in SOT
o Prevalence of active TB in KT recipients ranges between 0.3–15.2% (0.3–6.4% in areas with low TB endemicity and up to 15.2% in high TB endemic areas)
o The incidence of active TB in SOT is 20–74 times higher than in the general population (26.6 times in a study from Spain)
Epidemiology of Tuberculosis in Kidney Transplantation
o The prevalence of active TB in KT recipients varies from 0.3%-15.2% (higher than in the general population but lower than in patients with lung transplantation)
Risk Factors for Tuberculosis in Kidney Transplantation
The risk is mainly influenced by endemicity of TB
Recipient-associated causes:
1. Older age
2. Male gender
3. Smoking
4. Malnutrition
5. Diabetes
6. Chronic obstructive pulmonary disease
7. Latent TB (pre-transplant)
8. Chronic liver disease
9. HCV
10. Opportunistic infections (CMP, PJP, nocardia)
11. Autoimmune disease
12. Long-term haemodialysis
Donor causes:
1. Donor type (cadaveric)
2. Social risk factors (homeless, incarceration, smoking, alcohol abuse, known TB contact)
3. Medical risk factors (diabetes, BMI<18, history of untreated TB)
Transplant-associated:
1. Immunosuppression
2. Acute rejection (increases the risk of TB by 7.6 times)
3. Chronic graft dysfunction
Others: TB burden
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients
After inhalation of mycobacterium tuberculosis (MBT) into the lungs, the fate could be:
1. Clearance of MBT by the organism either due to innate immune response or acquired T cell immunity
2. Development of primary disease with immediate onset of active disease (first 24 months after primary infection)
3. Latent infection with reactivation many years latter
Types of TB transmission in KT recipients:
1. Reactivation after KT of a latent infection (the most common and occurs in ~20% of cases within the first 2 years after)
2. Donor-derived infection (responsible for only 4.8% of cases)
3. De novo infection after KT (exposure in patient with active TB): it is not common, associated with very high risk of progression, and more frequent in endemic areas
Immunosuppression mechanisms increasing the risk of reactivation:
1. Depletion of all types of T cells
2. Decrease in activation and proliferation of T cells
3. Decrease in IL-2 synthesis
4. Decrease in the production of Th-1 type cytokines
5. Impairment of cellular immunity completely
Diagnostic challenges
Active Tuberculosis
Usually occurs in the first year after KT (a median time of 11.5 months) in the case of reactivation and earlier in the case of donor-derived infection (in the first 3 months)
Why diagnosis is challenging?
1. The diagnosis requires a high index of suspicion but KT recipients have atypical clinical presentations which reduce the clinical suspicion of TB
2. Probability of association with other co-infections
3. Extra pulmonary localization (in 50%)
4. TST and IGRA are not useful in the diagnosis of active TB
5. wide range of radiographic manifestations in pulmonary TB and the frequent need for invasive procedures
6. Molecular tests based on rapid nucleic acid amplification techniques could provide false negative results when mycobacterial load is low
Donor-derived TB:
Associated with severe extrapulmonary manifestations and mortality
Under-recognized with early onset after KT in the majority of cases
Suspected in KT recipients with one of the following features:
1. Non-specific symptoms
2. Frequent fever in the first 3 months after KT
3. Fluid collections
4. Extrapulmonary manifestations
5. Lack of response to empirical antibiotic therapy
Current guidelines recommend a careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors
Latent Tuberculosis
o Defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB (WHO)
o Prevalence after KT was reported in ~20% of recipients
o Current guidelines recommend screening for latent TB in all KT candidates and donors before transplantation
o IGRA has some advantages over TST in patients with ESRD
o IGRA tests have a good predictive potential for latent TB in KT recipient with negative TST (in another study it has sensitivity and cannot be used to exclude latent TB)
Treatment challenges
Active Tuberculosis
Duration of treatment is recommended to be at least 9–12 months
AST-IDCOP guidelines recommend:
1. active uncomplicated pulmonary TB (treatment duration should be at least 6 months)
2. if cavitary lesions exist or there is a persistent culture-positive sputum after 2 months of therapy (9 months)
3. Severe disseminated disease or bone and joint disease (at least 6–9 months)
4. CNS involvement (at least 9–12 months)
AST-IDCOP guidelines treatment:
First-line treatment should be a four-drug regimen containing rifamycin used both in severe and non-severe cases (2-month intensive phase of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-months of isoniazid and rifampicin)
ESCMID guidelines treatment:
A standard regimen used for a period longer than 6 months
In cases of localized non-severe TB, a regimen without rifampicin could be used if no resistance to isoniazid (the 2-month intensive phase contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid ande thambutol or pyrazinamide)
Challenge in the treatment of KT recipients:
o Rifampicin and transplant-associated immunosuppression interaction
o Rifampicin is a potent inducer of cytochrome P450 3A4 and P-glycoprotein
o Rifampicin decrease the levels of CNIs, mTOR inhibitors, and affects glucocorticoids
o CNIs and mTOR inhibitors levels should be closely monitored during rifampicin-based regimen
o The dose of CNIs and mTOR inhibitor should be increased between 3-5 folds and the glucocorticoid dose should be doubled during treatment
Rifabutin (alternative to rifampicin):
o Weaker inducer of cytochrome P450 3A4 and P-glycoprotein but with similar efficacy
o Immunosuppression doses could be modified, and levels should be closely monitored
Fluoroquinolones: it is safe alternative to rifampicin
Another challenge is the adverse effects of TB therapy:
The most common adverse event is hepatotoxicity (liver enzymes should be closely monitored with bi-weekly evaluation during the intensive phase of treatment and monthly thereafter)
1. Hepatotoxicity (isoniazid, rifampicin, pyrazinamide, ethambutol)
2. Neurotoxicity (isoniazid, ethambutol)
3. Cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol)
4. Visual disturbances (rifabutin, ethambutol)
5. Skin lesions (rifampicin)
6. Hyperuricemia (pyrazinamide)
7. Interstitial nephritis (rifampicin, pyrazinamide)
Severe TB or when a vital organ is involved:
Reduce immunosuppression (risk of immune reconstitution inflammatory syndrome, which is associated with the reduction of immunosuppression and the use of rifampicin)
Latent Tuberculosis
Should be considered only after exclusion of active TB
Treatment indicated in one of:
1. A positive TST or IGRA test
2. A history of untreated TB
3. A history of recent contact with an active TB patient
4. When the kidney graft originates from a donor with known latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB
In the KT recipients:
o The preferred treatment is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6
o Rifampicin is not recommended
o Ethambutol and levofloxacin or moxifloxacin is an alternative regimen mainly for those with high risk
o The main adverse event of isoniazid is hepatotoxicity (but the risk of liver damage seems to be reduced in KT patients)
o Evaluate for liver enzymes during treatment (initially bi-weekly for 6 weeks and monthly thereafter)
Outcomes
Rejection
o Graft rejection in KT recipients with TB can occur in up to 55.6% (often associated with reduced levels of immunosuppression secondary to CNIs–rifampicin interaction and responsible for ~1/3 of graft losses
o Treatment of acute rejection before TB significantly increased the risk of graft loss 2.5 times
Graft Loss
Causes of graft loss KT patients:
1. Directly due to infection (donor-derived TB)
2. Indirectly through the sepsis produced by TB
3. Acute or chronic rejection after minimization or withdrawal of immunosuppression or rifampicin-based regimen use
The prevalence of graft loss in KT patients with active TB varies from 2.2-66.6%
Mortality
o Mortality rate in SOT is 20%
o Mortality of patients with TB after KT range from 0%-60%
Conclusions
o TB in KT has a higher incidence and prevalence than in the general population and is associated with morbidity and mortality
o Diagnostic and treatment challenges of TB after KT should be recognized for an optimal management approach
o Donor-derived TB and latent TB in KT should be carefully evaluated
o Tests that are not based on T cell immunity could improve the diagnosis of latent TB in KT recipients
o New drugs with low drug–drug interactions and adverse effects could have an important contribution in the future management
What is the level of evidence provided by this article?
Level V (narrative review)
I like your summary, level of evidence, analysis and conclusions.
Thank you prof.
Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review
Summary
· TB in KT has an incidence of 0.3–15.2% and it represents a great cause of morbidity and mortality.
· It increased risk of acute allograft rejection rate up to 55.6%, graft loss 2.2% to 66.6% and a mortality rate up to 60%.
· Source of infection is either reactivation of latent infection either from the donor or recipient source, or denovo infection acquired after transplantation (due to immunosuppressed status after transplantation).
1. Reactivation of latent infection (recipient source) is the most common form in KT and other SOT, mostly presented with reactivation and active disease 2 years after transplantation.
2. Donor derived infection occurs only in 4.8 % of KT, characterized by early onset around 2-3 months post-transplant, rapid progressive course and mainly extra-pulmonary and atypical presentation.
3. denovo infection (due to exposure to open TB cases in high endemic area, rare but progressive course).
· Hence, TB screening is a must for both recipient and potential donors in every case.
· Diverse clinical presentation, atypical presentation and inaccurate screening tests represent a challenge to diagnose latent TB infection.
· Incidence of TB in kidney transplantation:
o Differs according to the geographical area (low or high endemicity of the disease).
o It is lower in kidney than heart and lung transplantation.
o it is higher in KT than in HD and PD patients.
· Additional risk factors for TB in KT as use of potent immunosuppressive drugs as depleting antibodies as ATG and use of belatacept and CNI, MMF and steroids as all impair T cell mediated immunity and increase risk of reactivation of latent TB. In addition, repeated episodes of rejection with their subsequent treatment and chronic graft dysfunction also increase risk of TB activation and progression from latent to active TB disease.
· older age recipient, male gender, smoking and presence of comorbidities as HCV, diabetes, other nosocomial infections as CMV and PCP all increase risk of TB reactivation.
· As regard donor related risk factors, deceased donor with drug and alcohol abuse, low BMI and low socioeconomic state all increase risk of donor derived TB.
· In all cases, pulmonary manifestations present in about half of KT cases.
· mode of transmission: air droplet.
· Natural history:
o 1ry disease (clinical presentation within 1 st year after infection)
o latent disease (organism remains dormant and become reactivated and symptoms of the disease appear after years from infection).
· Diagnosis of TB:
o High index of suspicion.
o Challenge is that difficult suspicion in case of extra-pulmonary and disseminated disease.
o Take care of epidemiological history and prior history of exposure.
o Specific bacteriological investigations:
§ Smear with special stain for acid fast bacilli (AFB) by ziel nelseen stain (ZN stain).
§ Culture on special L J (lowenstien Jenseen) media is more sensitive, but takes 4-6 weeks so rapid culture technique using BACTEC system is helpful (result within 10 days) , but obtaining sputum specimen may need invasive bronchoscopy and BAL to get it.
o Molecular tests based on rapid nucleic acid amplification techniques can give false negative results when low load of the organism.
o Tuberculin skin test and quantiferron or TB blood tests are negative in active TB cases (only useful in diagnosis of latent TB).
· DD-TB should be suspected in unexplained fever, in 1st 3 months post transplantation, with peri-graft collection and unresponsive to empirical antibiotics.
· Latent TB is defined as state of persistent immune response to MBT antigens with no evidence of any clinical manifestations of active TB.
· The problem is that latent tuberculosis is difficult to diagnose especially in deceased donor and contributes to DD TB in spite of careful evaluation of the epidemiological risk, personal medical history, physical exam and chest radiography in all donors.
· The screening tests for latent TB (TST and IGRA) have very low sensitivity, so obtaining history of previous TB disease in donor or family is crucial, but sometimes it is difficult and unfeasible.
· IGRA may give false negative results in any case with depressed cell mediated immunity as severe head trauma and false positive if living in high endemic area.
· Screening for latent TB is essential in both kidney transplant potential and actual recipients. IGRA has better sensitivity than TST. It is essential to do screening and give prophylactic therapy to prevent progression to active TB disease.
· Treatment of active TB;
o Start immediately after diagnosis.
o Consider epidemiological criteria of the disease and drug resistant strains.
o Duration of therapy ranges from 6-24 months, at least 6 months,
§ If cavitary lesions exist or there is a persistent positive sputum culture after 2 months of therapy, the duration may be extended to 9 months.
§ In case of severe disseminated disease or bone and joint disease, treatment duration is recommended for at least 6–9 months.
§ Patients with CNS involvement should be treated for at least 9–12 months
· Regimen:
1. Rifampin containing regimen:
· Intensive therapy for 2 months with 4 drugs (isoniazid, rifampicin, pyrazinamide and ethambutol) followed by continuation phase of 2 drugs (isoniazid and rifampicin) for 4 months.
· Rifampin is enzyme inducer and lower trough level of CNI and mTORi so increase their dose 3-5 folds and double dose of steroids to avoid risk of rejection.
· After stoppage of rifampin, decrease dose according to the trough level is essential.
· Rifabutin is an alternative, less enzyme inducer but not well-studied in transplant cases. While fluoroquinolones are another safe and effective alternative in transplant cases.
2. Rifampin free regimen (2nd line regimen):
· Intensive phase of 2-month of 3 drugs (should contain isoniazid, ethambutol and pyrazinamide or levofloxacin), followed by a continuation phase of 12–18 months with 2 drugs (isoniazid and ethambutol or pyrazinamide). Longer period of treatment is recommend.
· Monitoring of adverse effects as hepatotoxicity and cytopenias in all drugs (isoniazid, rifampicin, pyrazinamide, ethambutol), neurotoxicity (isoniazid, ethambutol), visual disturbances (rifabutin, ethambutol), skin lesions (rifampicin), hyperuricemia (pyrazinamide) or interstitial nephritis (rifampicin, pyrazinamide).
· Hepatotoxicity is The most common adverse event associated with anti-TB therapy; therefore, liver enzymes should be closely monitored with bi-weekly evaluation during the intensive phase of treatment and monthly thereafter.
· Ensure adherence to treatment, and adjust doses according to EGFR.
· IRIS (immune reconstitution inflammatory syndrome) in anti tuberculous especially rifampin.
· Treatment of latent TB in KT recipients:
o Indications:
§ +ve TST or IGRA test
§ History of untreated TB, a history of recent contact with an active TB patient and when the kidney graft originates from a donor with known latent TB without chemoprophylaxis
§ known history of untreated TB or recent exposure to active TB.
· Regimen either INH alone for 9 months or combined (ethambutol and levofloxacin or moxifloxacin) in high risk recipinets. Level of evidence.
· Prognosis: TB increase risk of graft rejection, graft loss, also sepsis that can leads to loss of the graft and patient life. In addition, co-infections with fungi, CMV, nocardia, HCV and chronic liver disease increased risk of mortality.
· Future perspectives:
o New diagnostic modalities of latent TB not depending on cell mediated immunity that are impaired in such immunocompromised SOT recipients.
o Drugs with minimal drug-drug interactions.
· Level of evidence: narrative review (level V)
I like your detailed summary, level of evidence, analysis and conclusions. I appreciate your debate regarding the uncertainty of the value of IGRA in head trauma cadaveric donors.
Thanks dear professor
Introduction
ESRD patients’ best therapy is kidney transplantation (KT) [1]. Nevertheless, post-KT infection limits transplant and patient outcomes. Tuberculosis (TB) is a major post-transplant infection [5]. It is the thirteenth-highest cause of mortality globally and the top infectious cause, excluding COVID-19.
Methods
A literature search on PubMed and Embase electronic databases was performed from 1 January 2000 to 15 June 2022. . All studies that provided epidemiological and/or outcome data regarding TB in KT were included.
Solid Organ Transplantation Tuberculosis Epidemiology
Active TB in solid organ transplant recipients varies by region. TB prevalence ranges from 0.3–6.4% in low-endemic regions to 15.2% in high-endemic areas. A 60-study systematic review and meta-analysis found 3% of solid organ transplant patients had active TB.
Kidney Transplant Tuberculosis Risk Factors
KT recipients are more likely to acquire TB. TB endemicity in the community and recipient, donor, and transplantation variables enhance risk. Immunosuppression medication, acute rejection episodes, and chronic graft dysfunction are important transplant-related risk factors. KT immunosuppression inhibits T-cell-mediated TB control and promotes latent infection reactivation. T-cell-depleting medications, cytotoxic T-lymphocyte-associated protein-4 inhibitors, calcineurin inhibitors, anti-metabolites, and glucocorticoids all enhance the risk of TB. Acute rejection increases TB risk 7.6 times. It was found that post-transplant rejections independently increase TB risk.
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients
-Active TB could arise after KT as a result of reactivation of the latent infection present in the recipient prior to transplantation.
-TB could be transmitted to KT recipients via kidney graft from an infected donor
-TB could occur as a de novo infection after KT, in a recipient with exposure to a patient with active TB
Diagnostic and Treatment Challenges
Active TB; Start soon after diagnosis.
Treatment lasts 6–24 months, but at least 9–12.
American Society of Transplantation IDCOP recommends 6 months for active uncomplicated pulmonary TB and 9 months for cavity lesion or persistent culture-positive after 2 months of treatment.
AST-IDCOP recommends a 4-drug regimen for first-line treatment: intense dosage for 2 months (Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol) and 4 months of Isoniazid and Rifampicin.
ESCMID; regular regiment greater than 6 months, and in localized non-severe TB, rifampicin-free regiment, so intense phase should contain (Iso, Eth, Pyr, or levofloxacin), followed by 12-18 months of Iso and Eth or Pyr.
Latent TB
It has to be treated to stop it from becoming active again.
If you have a positive TST or IGRA test, a history of untreated tuberculosis, a history of recent contact with an active TB patient, donor-derived latent TB in an infected graft, a history of untreated tuberculosis, or recent exposure to active tuberculosis, you may have tuberculosis.
INH combined with vitamin B6 is used to treat latent tuberculosis for a period of nine months.
Ethambutol with either levofloxacin or moxifloxacin is another treatment option for those at high risk.
Conclusions
TB is a common opportunistic infection in KT that negatively impacts graft and patient outcomes. Preventive strategies should be based on TB risk factors and KT results. For optimum therapy, doctors should know TB’s diagnostic and therapeutic problems following KT. Kidney transplant and infectious disease doctors must work together. Donor-derived TB and latent TB in KT are underdiagnosed and should be examined. In KT recipients, non-T cell immunity-based assays with good predictive values might enhance latent TB diagnosis. Novel regimens or pipeline medications may help reduce drug–drug interactions, therapeutic effectiveness, and side effects.
What is the level of evidence provided by this article?
The level of evidence is V
I like your detailed summary, level of evidence, analysis and conclusions. I appreciate your debate regarding the uncertainty on optimal duration of therapy.
Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review
7 August 2022
***Summary****
TB is more prevalent in kidney transplant than the general population but less common post lung Tx.
Risk factors are nicely written in the diagram from donor to recipient specific to the immunosuppression state.
Natural history of infection: After the aerosol droplets containing mycobacterium tuberculosis (MBT) are inhaled into the lungs
Kidney Tx can got infected either by
****Active infection:
Diagnosis:
It is challenging due to a wide range of radiographic manifestations and need for invasive procedures. Molecular tests like (Xpert® MTB/RIF, Cepheid) could provide false negative results when mycobacterial load is low
Donor-derived TB should be suspected in KT recipients: non-specific symptoms, frequent fever in the first 3 months after KT, fluid collections, extrapulmonary manifestations or lack of response to empirical antibiotic therapy
Treatment
Treatment of KT recipients with TB could be challenging due to drug–drug interactions, drug toxicity and treatment adherence.
American Society of Transplantation Infectious Diseases Community of Practice (AST-IDCOP) guidelines recommends: 2-month intensive phase of RIPE (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol) followed by a 4-month continuation phase of RI.
Duration varies:
European Society of Clinical Microbiology and Infectious Diseases (ESCMID) suggests a standard regimen used for a period longer than 6 months, and, in cases of localised non-severe TB, a regimen without rifampicin. Two month intensive phase should contain isoniazid, ethambutol and pyrazinamide or levofloxacin, followed by a continuation phase of 12–18 months with isoniazid and ethambutol or pyrazinamide.
***Latent infection:
Diagnosis
latent TB infection is defined as a state of persistent immune response to stimulation by MBT antigens with no evidence of clinically manifest active TB. The epidemiology and survey of latent TB after KT remain scarce. Prevalence of latent TB after KT was reported in ~20% of recipients.
Treatment:
It is Considered if; +ve TST, or IGRA test, a history of untreatd TB, history of recent contact, or donated kidney from donor with latent TB, untreated TB or recent exposure.
Rejection: can reach up to 50 % of cases and caused by reduced levels of immunosuppression secondary to CNI–rifampicin interaction and could be responsible for ~1/3 of graft losses.
*********** Level of evidence
systematic review
I like your detailed summary, level of evidence, analysis and conclusions. I appreciate your debate regarding the uncertainty on optimal duration of therapy.
Rather than “Kidney Tx can got infected either by…”, you should type “Kidney Transplant recipient can got infected either by…”
‘Donor’ is mistyped as ‘Donner’ !
Summarise this article
This is an article that review many articles published between 1 January 2000 and 15 June 2022 regarding epidemiology, pathogenesis, diagnosis, treatment and outcomes of active TB in kidney transplant recipients
The prevalence of active TB is significantly higher than general population; around 20-74 times higher than general population. It differ according to geographic area, it ranges from 0.3–6.4%, in developed countries and in up to 15% in endemic regions
Mode of transmission
Risk factors for TB in Kidney Transplantation
Recipient related
Donor related
Community related factors
Pathogenesis and natural history of TB in kidney transplant recipients
Diagnosis of latent TB
Which test to use?
Indications of treatment of latent TB in transplant recipient and donor
Protocol for treatment of latent TB
Timing of active TB after transplantation
The diagnosis is challenging (needs high index of suspicion) due to the following
The treatment of TB in SOT is challenging due to the following
Protocols used in treatment of TB
I- Rifampicin containing regimen
Regimen A– 4-drug regimen of Rifampicin+ INH+ ethambutol + pyrazinamide for 2 months, followed by a 2-drug regimen of Rifampicin + INH for 4 months
It is recommended to increase the duration of treatment to at least 9-12 months if one of the following is present
II- Rifampicin free regimen
Regimen A – 3-drug regimen of INH+ ethambutol + pyrazinamide or levofloxacin are used for 2 months, followed by a 2-drug regimen of INH + either ethambutol or pyrazinamide for 12 to 18 months
Regimen B – 3 drugs (INH+ ethambutol + pyrazinamide or levofloxacin are used for 12 months
Regimen C – Rifabutiun can be used instead of rifampicin due to its lesser effect on cytochrome p450, so minimal drug-drug interactions but experience is little when using this drug in transplantation, although it seems effective in HIV TB patients.
Prognosis
What is the level of evidence provided by this article?
I like your detailed summary, level of evidence, analysis and conclusions. I appreciate your debate regarding the uncertainty on optimal duration of therapy
Mycobacterium Tuberculosis following kidney transplantation
Summary of the Article
Introduction
Post-transplant infection is a risk for graft loss and affects recipient survival.
TB infection is highest among transplant recipient as they receive immunosuppressants medications.
Source of TB infection post-trasnplantation
A screening strategy and protocols to prevent occurence of reactivation of latent or active disease is to be applied.
Challenges
Epimeilogy of TB in SOT;
Epedimiology of TB in kidney transplantation
Risk factors of TB in kidney transplantation
2.Donor associated;
3.Transplan associated;
4.Others;
Transmission and pathogenesis;
Diagnostic challenges;
2.DD-TB;
3.Latent TB;
Treatment challenges;
2.Latent TB;
Drug interaction and side effects;
Outcomes;
Upto 55% aossicaiated with immunosuppressants reduced level in rifampicin regiment.
Related to infection, or indirectly to sepsis, rejection.
Range from 0-60% by many studies.
Conclusion
Level of evidence
level ((V))
Review
The are some unacceptable mistypes: ‘drug’ been typed as ‘drud’.
‘Associated’ has been mistyped as ‘Associtaed’.
However, I like your summary, level of evidence, analysis and conclusions.
Thank you Prof for your comment
Sorry for my mistakes
I will try to avoid this
Thanks
This is a narrative review study, whose level of evidence is V, on tuberculosis after kidney transplantation.
Introduction
The consequences of renal transplantation of a late diagnosis of tuberculosis in the context of this patient’s immunosuppression lead to a significant increase in graft loss and death. Treatment, prophylaxis and its context in the interaction with immunosuppressants.
Methods
Studies from January 2000 to June 2022
Epidemiology
The incidence varies depending on the geographic area. with an increased risk of disease when compared to patients in the general population.
Risk factors such as immunosuppression, graft dysfunction, use of antimetabolites, and T-cell depleting drugs.
Donor
– corpse
– Homeless
– Deprived of liberty
– Smoker
– alcohol abuse
– Contact with tuberculosis
– Malnourished, diabetes, abandonment of TB treatment
Recipient
– Elderly
– Male
– Smoking
– Malnutrition
– diabetes
– COPD
– latent tuberculosis
– DHC
– Opportunistic coinfection
– autoimmune disease
– Prolonged hemodialysis
Associated with transplantation
– Immunosuppression
– acute rejection
– Chronic graft dysfunction
– Prevalence of tuberculosis in the country
Brazil, Turkey, and India are the countries with the highest prevalence, both due to their sociocultural aspects and also limitations in diagnosis, leading to late treatment (either due to inadequate screening or diagnosis when there is disseminated disease). Another form of transmission is contact with a patient infected by the mycobacteria and the patient in the context of immunosuppression.
Diagnosis
TST and IGRA do not seem to be suitable for diagnosis. The Xpert gene can help in the pre-emptive diagnosis, but the culture is the gold standard, however, limited by the delay in making the test positive.
The risk of reactivating latent TB is extremely high in this group of patients and adequate chemoprophylaxis should be carried out.
Treatment in immunosuppressed patients can be extended from 9 to 24 months depending on the immunosuppression and the extent of the disease.
The lack of exams to control the disease and the classic scheme with high drug interaction, mainly Rifampicin. It is necessary to replace this scheme with Rifabutin and to measure serum levels of immunosuppressants.
Outcomes
HR 2.5 rejection, graft loss, and mortality are higher in this group. The risk of death is 20%.
Conclusions
Tuberculosis has a high incidence and prevalence, especially in developing countries. The lack of adequate tests for screening and diagnosis increases the risk of the disease being reactivated or passed on by the donor.
New treatment regimens that minimize drug interactions may help improve efficacy and reduce adverse effects.
In you conclusions, yo have suggestion ‘the lack of adequate tests’.
Do you mean specifically at your workplace or in general ?
What is your suggestion regarding availability of newer diagnostic tests and promptness of action on these reports?
Yes, in general, we use 19th-century diagnosis methods
Baciloscopy with Koch and Leweenhok at 1870
Skin tests with CG in early 1900
X rays with Roentgen at 1896
We need PCR and molecular methods with good sensibility and specificity
For an endemic country, the challenge is even higher, because exposure is very common.
Introduction
TB is the thirteenth-most common cause of death and the leading infectious cause of death, apart from coronavirus disease 2019 (COVID-19) all over the world.
Kidney transplant (KT) recipients are at risk of developing TB due to immunocompromising status and due to donor recipient risk factors.
Active TB in KT can occur either due to reactivation of latent infection which is the most common forum or due to denovo infection
Current guidelines recommend that screening for the donor and the recipient is mandatory.
In fact diagnosing and treating TB is challenging in those group of patients .
This review covers multiple updated aspects of TB for KT recipients
Methods
A literature review of articles published nearly within the last 22 years was done to provide an evidence-based review of epidemiology, pathogenesis, diagnosis, treatment and outcomes of TB in KT recipients according to latest guidelines.
Epidemiology and Risk Factors for TB in KT
Active TB prevalence in SOT is variable according to geographical area.
A recent metanalysis revealed that it’s pooled prevalence could be 3%
Incidence of active TB in SOT is 20–74 times higher than in general population
Prevalence of active TB in KT recipients ranges 0.3% -15.2% but it is higher compared to the general population and lower than in lung transplantation recipients.
Another study showed that the pooled incidence of active TB in KT recipients was higher than in ESRD in pre-dialysis but lower than in those on peritoneal dialysis and hemodialysis.
Risk factors for TB development in KT recipients are related to endemicity ,donor ,recipient and transplantation factors.
Transplantation risk factors include immunosuppressive therapy, acute rejection attacks and chronic graft dysfunction.
Donor factors involve medical risk factors, his type and social risk factors.
Recipient factors include age ,gender ,age ,COPD ,and DM
Transmission and Pathogenesis of TB in KT Recipients
It occurs through aerosol droplet infection, then mycobacterium T cell is manged by either innate immunity or acquired T cell immunity leading to either active disease occurrence or reactivation .
In KT transmission occurs due to either reactivation of latent infection in the recipient that was already present before transplantation which is a common scenario, therefore post-transplantation latent infection assessment is needed with pre-transplant screening .
Or it can be transmitted through an infected renal graft from the donor.
Or another method common in endemic area is de novo infection of the recipient after transplantation due to exposure to activeTB case.
T helper 1 response is the main response in front of TB infection and immunosuppressive therapy disrupts T cell and cellular mediated immunity response.
Diagnostic and treatment challenges
Active TB usually occur in the first year post transplant.
TB diagnosis needs high suspicion index because the clinical picture and diagnosis are diverse.
As Tuberculin skin test (TST) and interferon gamma release assay (IGRA) are not conclusive for active TB diagnosis also radiological findings in pulmonary TB is variable necessitating invasive procedures also molecular tests have false negative results .
Donor derived TB infection has an early onset post transplant leading to extrapulmonary manifestations and high mortality rate.
Detecting latent or undiagnosed active TB in the donor is challenging but crucial.
Current recommendations include evaluation of the epidemiological risk, personal
medical history, physical exam and chest radiography in all donors but for deceased donor it is difficult therefore extra care need to be done to take history from the deceased donor’s family and If IGRA test was done need to be followed and raise suspicion for further evaluation .
Prevalence of latent TB after KT recipients is 20% .
There is no gold standard test for latent TB but IGRA test have a good predictive potential for latent TB in KT recipient with negative TST on the other hand it has a low sensitivity in KT recipients and cannot be used to exclude latent TB.
KT recipients are more liable to reactivation of latent TB more than KT candidates so more frequent screening is needed in the KT recipients.
Treatment
Drug–drug interactions, drug toxicity and treatment adherence render therapy difficult.
Active TB treatment
Diagnosing active TB in KT recipients necessitate immediate treatment considering epidemiological and drug resistance aspects.
The optimum treatment period ranges 6-24 months according to case severity if uncomplicated 6 months is recommended but in CNS affection at least 9-12 months are adviced.
4drug regimen including rifamycin is the main treatment used both in severe and non severe cases.
2-month isoniazid, rifampicin, pyrazinamide and ethambutol, followed by a 4-month continuation of isoniazid and rifampicin.
There is interaction between rifampicin as enzyme inducer and immunosuppressives therefore m TORI , CNI and glucocorticoids doses need to be increased and after finishing rifampicin course the immunosuppressives dose have to be reduced and adjusted to avoid the risk of rejection and graft loss.
Rifabutin and fluoroqiunolones are alternatives to rifampicin.
If second line treatment is used long treatment duration will be needed.
Another aspect is the anti TB drugs side effects including hepatotoxicity therefore monitoring liver functions is mandatory, neurotoxicity, cytopenia and visual disturbances .
Anti TB drug therapy adherence is challenging.
In case of severe TB immunosuppression need to be reduced.
Latent TB
It has to be treated to prevent reactivation.
Positive TST or IGRA test, history of untreated TB, history of recent contact with active TB patient ,donor derived latent TB in infected graft,history of untreated TB or recent exposure to active TB.
Latent TB is treated by INH with vitamin B6 for 9months
Another regimen for high risk is ethambutol and levofloxacin or moxifloxacin
Outcomes
Graft rejection
Graft rejection in KT recipients having TB can reach 55.6% due to decreased levels of immunosuppression because of CNI–rifampicin interaction leading to graft loss.
Graft Loss
Due to donor-derived TB or indirectly through sepsis caused by acute or chronic rejection
It’s prevalence with active TB ranges from 2.2% to 66.6%
A study demonstrated that severe TB disease, AKI stage 2 or 3, acute rejection and value of serum creatinine were risk factors leading to graft loss.
Mortality
Mamishi et al. showed that mortality rate in SOT recipients was 20% .
Another study published that active TB after 2 years post-KT is an independent risk
factor for mortality
Conclusion
KT recipients are at high risk of developing TB compared to general population leading to graft loss and mortality ,therefore preventive measures should be applied and early detection and treatment will be crucial.
-Level of evidence is V
I like your summary, level of evidence, analysis and conclusions.
What is your suggestion regarding communication gap between availability of newer diagnostic tests and promptness of action on these reports?
I think following up the results and maintaining direct communication methods between institutes where diagnostic tests are done and transplant centers are essential
Introduction:
Aim of the study:
Method:
Epidemiology of TB in SOT:
Epidemiology of TB in kidney transplantation:
Risk factors of TB:
Transmission & pathogenesis:
Challenges of active TB diagnosis:
Diagnosis of latent TB infection:
Treatment of active TB:
Treatment of LTB:
Outcome:
Level of evidence is 5
Which kind of recipients would you keep on INH prophylaxis for 6 months after renal transplant?
I like your summary, level of evidence, analysis and take home messages.
6 months INH regime highly recommended in high risk recipients who can’t use 9 months INH regime (6 months associated with less adverse events).
Introduction
Kidney transplantation (KT)remains the optimal treatment for patients with end stage renal disease.
Infection after KT is still an important limitation for graft and patient outcomes.
One of the most common infections with negative impact post-transplantation is tuberculosis (TB).
It is considered the thirteenth-most common cause of death and the leading infectious cause of death, excluding coronavirus disease 2019 (COVID-19), worldwide.
As KT is associated with an immunosuppression status, active TB is higher in KT recipients than in the general papulation.
Active TB after KT could arise from reactivation of latent infection in the recipient or donor tissue or can result from de novo infection after transplantation.
In order to limit or prevent the occurrence of active TB post-KT, it is necessary
Objectives
This review aimed to provide an evidence-based update regarding epidemiology, risk factors pathophysiology, type of transmission, diagnostic challenges, treatment challenges and the impact of TB in KT recipients
Methods
A literature search on PubMed and Embase electronic databases was performed from 1 January 2000 to 15 June 2022.
We used a combination of the following words: “tunerculosis “mycobacterium tuberculosis “kidney transplant”, “prevalence”, “incidence”, “frequency”, “graft”, “loss”, “failure”, “rejection”, “survival”, “mortality”, “death”, “donorderived” and “latent”.
All studies that provided epidemiological and/or outcomes data regarding TB inKT were included.
Articles in languages other than English, articles that evaluated other types of transplantation than kidney only and articles with inadequate information were excluded.
All articles were analyzed by two reviewers for inclusion/exclusion criteria, and the process was checked by a third reviewer.
Epidemiology and risk factors for tuberculosis in kidney transplantation.
Findings
In areas with low TB endemicity, the prevalence varies between 0.3–6.4%, compared to prevalence of TB in high, endemic areas which could rise to 15.2%.
The pooled prevalence of active TB after KT was analyzed in two systematic reviews and meta-analyses, and the results were relatively similar: 2.51% and 3%.
In another meta-analysis, Al-Efraiji et al found an unadjusted TB risk ratio of 11.36 times higher in KT recipients, compared to the general papulation and an adjusted risk ratio for patients on dialysis of 3.62 times higher than those from the general papulation.
In a recent meta-analysis, Alemu et al reported that patients with KT had a pooled incidence of active TB of 2700 per 100,000 patient-years, which ranged from 340 per 100,000 patient-years in low TB burden countries to 14,680 per 100,000 patientyears in countries with high endemicity.
Viana et al showed that treatment of acute rejection before TB significantly increased the risk of graft loss 2.5 times (HR = 2.51, 95%CI: 1.17–5.39, p = 0.01).
An increased rate of mortality (50%) was reported in a cohort of 545 KTrecipients from Mexico
conclusion
TB in KT is an important opportunistic infection with higher incidence and prevalence than in the general papulation and is associated with significant negative graft and patient outcomes.
Pinpointing the risk factors for both TB development and negative outcomes after KT should be the basis for successful implementation of preventive measures.
Clinicians should recognize the diagnostic and treatment challenges of TB after KT for an optimal management approach.
This requires close collaboration between kidney transplant and infectious disease physicians.
Development of tests with helpful predictive values, which are not based on T cell immunity, could bring important improvement in the diagnosis of latent TB inKT recipients.
Discovered regimens or pipeline drugs could have an important contribution in the future limitation of drug–drug interactions, improvement of treatment efficacy and reduction of adverse events
level of evidence is 5
Do you think you would like to use a test or battery of tests with good likelihood ratio of diagnosing TB in an immuno-suppresed patients?
Do you think you would like to use a test or battery of tests with good likelihood ratio, rather than those with high predictive value, of diagnosing TB in an immuno-suppresed patients?
The most typical recommendation for LTBI screening in immunosuppressed people included a combination of TST and/or IGRA tests, chest X-ray, full background history (including prior exposure to people with TB), and risk factor assessment (travel or migration from endemic areas).
The available and affordable test options affected the suggested selection of screening modalities and their frequency.The TST is reasonably priced and widely accessible.
TST and IGRA were recommended for screening in guidelines for medical immunosuppression, although there were significant differences between the two.
Screening and prevention for latent tuberculosis in immunosuppressed patients at risk for tuberculosis: a systematic review of clinical practice guidelines
Tasnim Hasan,1 Eric Au,2 Sharon Chen,1,3 Allison Tong,4,5 and Germaine Wong2,5
Introduction
Pulmonary tuberculosis (TB) is considered one of the most important serious infections after kidney transplantation (KT) and is associated with increased frequency compared to the general population and carries a high risk of morbidity and mortality. The prevalence of active TB after KTX was in the range of 0.5-15.2 %, with an increased risk of rejection up to 55% and risk of graft loss in the range of 2.2-66%, with a high risk of death up to 60%. many challenges should be taken into consideration while treating active TB in immunocompromised patients like kidney transplant recipients the diagnostic challenges, atypical presentations co-infections with reduced prognostic values of some laboratory tests, and a variety of radiological findings, which can delay the diagnosis and management, also challenges regarding the interaction of the drug with immunosuppression and drug intolerance, toxicity, and non-adherence, all these factors should be taken into consideration while dealing with active TB infection after KTX. This study reviewed in depth the diagnostic and management challenges of active TB after kidney transplantation through an extensive review of the available epidemiological and interventional statistics from different studies between 2000-2022.
The aim of the study is to keep us informed with the best available evidence regarding the epidemiology, diagnosis, and management challenges of this devastating opportunistic infection post-KTX.
The source of Active TB post-KT, risk factors
1. Donor source, reactivation of latent TB from donor tissues
2. Recipient source (latent TB reactivation) with IS
3. Denovo infection
4. Endogenous reactivation (most common form)
The best preventive strategy is to screen both donor and recipient as per current guidelines especially those from an endemic area
Methods
They review all studies that address the epidemiology or intervention outcome by reviewing the database from Embase and MEDLINE with search keywords including epidemiology, prevalence, incidence, diagnosis, and intervention by reviewing the electronic data by two reviewers, they exclude articles with inadequate information over 22years (2000-2022.
Epidemiology and Risk Factors for Tuberculosis in Kidney Transplantation
The overall prevalence of active TB post-transplantation is higher compared to the general population and the prevalence is quite variable based on geographical distribution with a higher rate of infection in the endemic area. In a recent meta-analysis, Alemu et al. reported that patients with KT had a collective
incidence of active TB of 2700 (95% CI: 1878–3522) per 100,000 patient-years, which ranged from 340 per 100,000 patient-years in low TB burden countries to 14,680 per 100,000 patient-years in countries with high endemicity. The table1 summarizes all the studies between 2000-2022 which show diverse results in the prevalence of TB based on geographical distribution, more extrapulmonary TB was reported from donor-derived Its associated with severe extrapulmonary manifestations and mortality in India, Egypt, Turkey, and Brazil with even longer time for the diagnosis in the range between 40-60 months ( this can be explained by the extrapulmonary or atypical presentation c compared to pulmonary TB which can be diagnosed even earlier 6 months or even less, some reports missing data about death as an outcome and the mortality also varies.
Active TB is higher in PKTX compared to hemodialysis or PD patients, but a lower incidence is reported in KTX recipients compared to lung transplantation recipients.
Risk Factors for Tuberculosis in Kidney Transplantation
Recipient factors
Age (older)
Gender (male)
Comorbid (DM, Liver disease, COPD, malnutrition)
Chronic HCV infection
Smoking history
Reactivation of latent TB
Co-infections (CMV, Nocardia, PJP)
Autoimmune disease
Duration of dialysis
Donor Factors
Donor type (DD), social background (homeless, sick contact, smoking history, Alcoholic abuse)
Medical risk factors Like DM, BMI < 18, Reactivation of latent TB, History of previous exposure, untreated TB
Transplantation related factors
Immunosuppression, rejections, chronic allograft dysfunction
Community burden and endemicity
Transmission and Pathogenesis of Tuberculosis in Kidney Transplant Recipients
Prevalence reactivation of latent TB is higher after KTX and the main risk factors include old age, absence of BCG scar, and the formation of DSA
Positive latent infection conversion was found in ~20% of cases within the first 2 years after KT as per one prospective study. The protection against MBT is through the activation and proliferation of the Th1 c4d cellular immunity and type 1cytokine protection in addition to the proliferative bulks of CD4+ and CD8+ T cells and interferon-gamma (IFN-γ) and interleukin-2 (IL-2) production are vital effectors in the defensive response. So use of induction and maintenance IS leads to impaired cellular immune response via T-cell depletion and deactivation and increased risk of denovo TB or reactivation of latent TB in previously exposed recipients.
Diagnostic and Treatment Challenges
The key to a better outcome after MBT infection after KT is early diagnosis and effective treatment, so the diagnosis of MTB should keep a high index of clinical suspicion, especially in early MBT, which is likely of donor source (DD, endemic area)so personal and social history important, while late after 1 year should consider denovo or reactivation of latent TB. Limitations of diagnostic tests like both tuberculin skin test (TST) and interferon-gamma release assay (IGRA) are not useful in the diagnosis of active TB.
Additional diagnostic challenges include the diverse radiological manifestation, limitations with sputum culture, and BAL fluid assay, even molecular testing by using gene experts can give false negative results in case of low mycobacterial load.
Identifying latent infection or undiagnosed active TB in kidney donors is serious in preventing post-transplant infection. as we know active TB is a contraindication for donation but latent TB or reactivation of latent TB remained a big challenge in KTX, both TB (TST and IGRA) have low feasibility and accuracy as a screening test for TB, so the donor history including previous history of the active TB or previous exposure or treated case of MBT, social history, from the DD family, friends including ethnicity ( endemic area) is very important in addition to IGRA Test and chest radiology.
Current guidelines recommend for latent TB screening should include all KT candidates and donors before transplantation.
treatment challenges include drug-drug interactions especially in rifampicin-based anti-TB ( with CNI reduction risk and might trigger rejection ), drug side effects, non-compliance, and anti-TB resistance, especially in an endemic area.
level 5 narrative review ( review of non homogenous studies with diverse epidemiology and intervention outcome , small sample size )
I like your summary, level of evidence, analysis, limitations of this article and key messages.
Do you think you would like to use a test or battery of tests with good likelihood ratio of diagnosing TB in an immuno-suppresed patients?
Molecular genetic testing by using gene experts is preferred and gives faster results compared to culture , tissue biops,y especially for extrapulmonary TB and other radiological imaging
Introduction
– Tuberculosis (TB) is one of the most common infections in KTRs that has negative consequences, such as graft rejection, graft loss and increased mortality rate
– It can result from reactivation of latent infection or de novo infection, several risk factors that favor the development of TB in KTRs.
– The diagnosis and treatment is challenging, and implement screening measures is necessary to limit and prevent occurrence of active TB.
Epidemiology:
-The prevalence and incidence of active TB is higher than general population(GP) and varies according to geographic area.
SOT recipients: The prevalence 0.3–6.4% in low TB endemicity and 15.2% in endemic areas. The incidence is 20–74 times higher than in GP.
KTRs: The prevalence is lower than lung transplantation and varies from 0.3% to 15.2%.The incidence in KTRs was higher than in patients with ESRD in pre-dialysis but lower than dialysis population.
Risk Factors
–Endemicity of TB is the main influence risk.
–Transplant-associated risk factors;
Immunosuppression therapy; impairs T-cell-mediated immunity which control TB replication.
Acute rejection episodes: increases the risk of TB by 7.6 times
Chronic graft disfunction: by amplifying the immunosuppression status
-Donor- related risks; cadaveric donor, social risks; homeless donor, incarceration, smoking, alcohol abuse, TB contact, diabetes, low BMI, & previous history of untreated TB.
-Recipients- related risks; old age, mal gender, smoking, malnutrition, COBD, DM, chronic liver disease, HCV infection, other infection CMV, PCP, nocardia, autoimmune disease, latent TB and long term HD.
Transmission and Pathogenesis
Natural after inhalation of droplets containing the organism, then it will evolute as follows:
-Clearance of MBT by immune response
-Development of primary disease ( active disease ), in the first 24 months after primary infection
-Latent infection might reactivate many years following primary infection
Transmission of TB in KT recipients
– Reactivation of the latent infection present in the recipient prior to transplantation. (the most common), Latent TB conversion was found in 20% of cases within the first 2 years after KT.
– Donor-derived TB infection, responsible for only 4.8% of cases
– De novo infection after KT, mainly in endemic areas.
Diagnostic Challenges
Active Tuberculosis
-The diagnosis require high index of suspicion.
-KTRs have atypical clinical presentations or diverse manifestations, which reduce the suspicion of TB.
-The probability of other co-infections and extrapulmonary localization in ~50% of cases is another challenge.
-Tuberculin skin test (TST) and interferon gamma release assay (IGRA) are not useful in the diagnosis of active TB.
-Wide range of radiographic manifestations in pulmonary TB
-The need for invasive procedures BLA/ bronchoscopy is another diagnostic challenge.
– PCR could provide false negative results when mycobacterial load is low.
Donor-derived TB
-It is associated with severe extrapulmonary manifestations and mortality
– It is an under-recognized condition with early onset after KT.
– It should be suspected in KTRs with one of the following features: non-specific symptoms, frequent fever in the first 3 months after KT, fluid collections, extrapulmonary manifestations or lack of response to empirical antibiotic therapy
– Donors screening is highly recommended; reviewing medical and social data, CXR.
– IGRA result might not be available in time.
– IGRA could be false negative in donors with head injury.
Latent Tuberculosis
-There are no gold standard tests for diagnosing latent TB accurately in KT candidates.
-The prediction capacity of TST and IGRA tests are discordant in KTRs.
– IGRA has a low sensitivity in KTRs and cannot be used to exclude latent TB
– IGRA has some advantages over TST in patients with ESRD
– Undiagnosed and untreated latent TB after KT significantly increases the risk of active TB, therefore , screening and diagnosis is essential.
Treatment Challenges
Active Tuberculosis
-The duration of treatment is vary from 6 to 24 months.
* Active uncomplicated pulmonary TB, treatment; at least 6 months,
* Cavitary lesions or persistent positive culture; treatment may be extended to 9 months
* Disseminated disease or bone and joint disease; least 6–9 months.
*CNS involvement ; at least 9–12 months
– First-line treatment should be a four-drug regimen, follows the principles of treatment for immunocompetent patients
Drug-Drug interaction:
– Rifampicin potent enzyme inducer, its usage decrease the levels of CNI, mTORi and affects glucocorticoids metabolization, which increases the risk of rejection.
-Therefore, levels should be closely monitored, and doses should be adjusted to obtain the therapeutic target.
– Rifabutin; is a weaker enzyme inducer with similar efficacy to rifampicin.
– Fluoroquinolones is another safe and effective alternative to rifampicin.
Adverse effects of TB therapy
– More frequent than GP.
– Hepatotoxicity (isoniazid, rifampicin, pyrazinamide, ethambutol). The most common
– Neurotoxicity (isoniazid, ethambutol).
– Cytopenia (isoniazid, rifampicin, pyrazinamide, ethambutol)
– Visual disturbances (rifabutin, ethambutol)
– Skin lesions (rifampicin)
– Hyperuricemia (pyrazinamide)
– Interstitial nephritis (rifampicin, pyrazinamide)
Treatment adherence directed observed therapy programs has improved the adherence
Different degrees of graft function; evaluate creatinine clearance and adjust the doses.
Reduction of immunosuppression
The possible occurrence of immune reconstitution inflammatory syndrome, which is associated with the
reduction of immunosuppression and the use of rifampicin
Latent Tuberculosis
-To preventing the risk of reactivation, should be after exclusion of active TB
-Indications:
– Positive TST or IGRA test
– History of untreated TB, or recent contact with an active TB patient
– Graft from a donor with latent TB without chemoprophylaxis, known history of untreated TB or recent exposure to active TB
-Regimen: isoniazid for 9 months with vitamin B6. An alternative ethambutol and levofloxacin or Moxifloxacin.
Outcomes;
Rejection
-Reach up to 55.6%,
-Associated with reduced levels of immunosuppression secondary to rifampicin.
– 50% of graft failure cases were 2ry to acute rejection.
Graft Loss
– Graft loss in KTRs with active TB varies from 2.2% to 66.6%
– Can be directly due to infection or through the sepsis, AKI, acute or chronic rejection that occurred after reduction of IS.
Mortality
-The mortality rate in SOT was 20% while in KTRs ranging from 0% to 60%
– Cases of mortality was associated with anti-TB therapy, active TB, and other co-infections (virus, fungal), rejection episode.
Conclusions
-TB in KT is a highly prevalent opportunistic infection in KTRs and is associated with significant negative graft and patient outcomes.
– The diagnosis and treatment is challenging, and implement screening measures is necessary to limit and prevent occurrence of active TB.
Level of evidence; 5 narrative review.
I like your summary, and level of evidence. What kind of screening program would you suggest that all those clinicians (stakeholders) can be informed well in time?
Thank you prof.
-Screening fro both donor and recipient should be screened.
-Results should be reported directly to transplant centers to guide managing patients.
-At the time being using both TST and IGRA together to have better result.
–National screening program, initiation of central registry and enhance public health reporting.
-looking for newer screening method with better sensitivity and specificity.
Q1
Introduction
Epidemiology
Risk Factors
Recipient-related
Donor-related
Transplant-related
Others: TB burden of the country
Transmission: Aerosol droplets, latent infection, infected donor organ
Pathogenesis: The fate of inhaled TB in the droplets is either;
Other important mode of transmission in transplant recipients are;
Diagnosis challenges:
1.Active tuberculosis
2.Donor-derived
3.Latent TB
Treatment challenges
1.Active tuberculosis
2.Latent tuberculosis
Outcomes
Conclusion
Q2.
I like your summary, level of evidence, analysis and take home messages. What kind of network would you suggest?
What is your suggestion regarding communication gap between availability of newer diagnostic tests and promptness of action on these reports?
Thnxs prof