3. A 46-year-old CKD 5 on HD for the last 5 years due to IgA nephropathy has a kidney offer from his brother, 111 mismatch, no DSAs. The potential recipient has a history of TB during childhood, which was treated successfully. FCXM is negative.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
131 Comments
Elaf Amiri
#Any special consideration post transplantation?
*The incidence rate of TB markedly increases after solid organ transplantation (SOT), Reactivation of foci of latent TB infection (LTBI) is probably the main cause of posttransplant TB.
*Most of these cases were documented in patients who received a grant from a deceased donor with active TB infection, a situation that has been associated with a risk of transmission of approximately 30%.
*There is no diagnostic reference standard for f latent TB infection (LTBI). The tuberculin skin test (TST) remains the best studied test and, therefore, most current guidelines still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors. IFN-γ release assays (IGRAs) have emerged as new diagnostic tools in the last decade.
*Radiological work up
*The diagnosis of active TB infection relies on the detection of M. tuberculosis bacilli by direct observation, by culture, and nucleic acid testing, the availability of a rapid molecular test, such as the Xpert MTB/RIF assay, may have a major impact in the management of these patients[1]. #What is your induction immuneosuppression?
This patient with history of previous TB and immunologically showed negative DSA and FCXM, not need heavy induction therapy, so the patient can proceed with IL2-receptor antagonist (Basiliximab).
#Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
No, I will proceed with the same plan because it is a low level of DSA (weak to low level with phenotype panel MFI values from 1000 to 3000), however regular follow up for the DSA level Luminex-based SPIs and FCXM tests. is important[2].
[1] Guilherme Santoro-Lopes, Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors, Transplantation, February 2018, Volume 102, Number 2S-2
[2] Gladstone DE, Bettinotti MP. HLA donor-specific antibodies in allogeneic hematopoietic stem cell transplantation: challenges and opportunities. Hematology Am Soc Hematol Educ Program. 2017 Dec 8;2017(1):645-650. doi: 10.1182/asheducation-2017.1.645. PMID: 29222316; PMCID: PMC6142580.
Any special consideration post-transplantation?
The recipient and the donor both have to be screened using IGRA for latent TB and fully treated before proceeding to transplantation because immuno-suppression can cause flare of the dormant mycobacteria
What is your induction immunosuppression?
Basiliximab is enough for induction in this transplant pair with low immunological risk
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
MFI of 1500 will not change the management plan
References
Krishnamoorthy S, Kumaresan N, Zumla A. Latent tuberculosis infection and renal transplantation – Diagnosis and management. Int J Infect Dis. 2019 Mar;80S:S73-S76. doi: 10.1016/j.ijid.2019.01.049. Epub 2019 Feb 6. PMID: 30738187.
Abad CLR, Razonable RR. Donor derived Mycobacterium tuberculosis infection after solid-organ transplantation: A comprehensive review. Transpl Infect Dis. 2018 Oct;20(5):e12971. doi: 10.1111/tid.12971. Epub 2018 Aug 12. PMID: 30055041.
Sorohan BM, Ismail G, Tacu D, Obrișcă B, Ciolan G, Gîngu C, Sinescu I, Baston C. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens. 2022 Sep 13;11(9):1041. doi: 10.3390/pathogens11091041. PMID: 36145473; PMCID: PMC9505385.
· post-kidney transplantation TB is associated with high morbidity and mortality and can cause graft loss in 1/3 of cases. The reactivation of latent TB infection is probably the main cause of post-transplant TB.
· This recipient had a history of successful treatment of TB at childhood. However, he is at risk of having latent TB. Therefore, we need to ask about history of recent contact and perform both Tuberculin skin test and Interferon Gamma release assay(IGRA) to maximize the sensitivity of the screening. Any positive results should be considered evidence of LTBI and requires treatment. However, if the patient has symptoms of pulmonary or extra-pulmonary features of active TB, perform a chest X ray, sputum for Xpert, culture and AFB stain(recipient transplantation should be delayed till complete treatment of TB is done).
· It is preferred to start treatment for latent TB prior to transplantation a immunosuppression can result in TB flare. Treatment is with oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily(Better to avoid rifampicin post-transplant for its interaction with immunosuppression.).
· Moreover, the recipient should be counseled about the risks of primary GN recurrence(IgA) which may be clinical or histologic recurrence(around 30%) and need post-transplant monitoring of proteinuria, hematuria and graft functions
· What is your induction immunosuppression?
Avoid ATG that can cause TB flare and use Basiliximab during induction therapy(low immunogenic risk). Maintenance therapy with triple immunosuppression(still there is risk of recurrence of primary GN
· Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
· DSA is low and FCXM is negative. Therefore, we can still go with the same induction IS( Basiliximab) followed by triple maintenance therapy with close monitoring of DSA level.
References
1.José María Aguado, Julián Torre-Cisneros, Jesús Fortún, Natividad Benito, Yolanda Meije, Antonio Doblas, Patricia Muñoz, David R. Snydman, Tuberculosis in Solid-Organ Transplant Recipients: Consensus Statement of the Group for the Study of Infection in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology, Clinical Infectious Diseases, Volume 48, Issue 9, 1 May 2009, Pages 1276–1284.
2. Santoro-Lopes G, Subramanian AK, Molina I, Aguado JM, Rabagliatti R, Len O. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation. 2018 Feb;102(2S Suppl 2):S60-S65.
. Any special consideration post-transplantation? To exclude active tuberculosis with sputum AFB and chest x ray. To exclude Latent TBI by IGRA or Tuberculin skin test. If present – ATT 3months before transplant, as live related transplant can wait. Post transplant 6months INH-prophylaxis (+/- Moxifloxacin, if active TB+) 2. What is your induction immunosuppression? HLA haplo-match with negative FCXM and no DSA – confers low immunological risk. Either Induction with IL2RA (Basiliximab) or even no induction (just methyl-prednisone) should be adequate. Triple maintenance immunosuppression (TAC, MMF and steroids) regimen could be kept on higher level for 6months.
3. Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan? DSA positive, but low titre (1500) and thus FCXM negative – so, doesn’t require to change IS regimen. Need to follow DSA titre, RFT, Urine protein post transplantation – early biopsy on rising creatinine, proteinuria or high DSA – in such events, ABMR treatment may be required. Dear All The recipient had successful treatment for TB Also, his DSA is below the threshold of positive crossmatch (negative crossmatch). Will you give him aggressive induction that may cause flair of TB if there is a chance of latent TB?
Reply to Prof Ahmed Halawa No Infact, many large volume centres in India, never use induction for close related family live donors – just methyl prednisone is OK, or at best Basiliximab may be used. DSA 1500 MFI, is on lower side to cause to cause positive X match in vitro. But it can still excite immune response through memory B cells. In African patients, we had ABMR and graft loss in couple of cases with DSA 1200-1500. In view of this, some immuno-patho-lab recommend cut off 750MFI, for DSA to be positive. Our current practice in such cases, is to use IVIg 10gm (to bind existing DSA or nonspecific antibodies in plasma) in such cases; 1 plasma exchange + 5gm IVIg is safer alternative, to prevent accelerated ABMR.
Q1: This patient is at risk of reactivation of TB after TX due to immunosuppression therapy. In addition, his brother should be screen for LTBI carefully. So, the choice of immunosuppression should be done carefully.
Q2: Induction therapy with basiliximab and methylprednisolone pulse and then triple maintenance therapy is logical.
Q3: If the recipient has low level DSA with negative FCXM, there is no need to change induction therapy and basiliximab will be enough.
· Any special consideration post-transplantation?
Recipient has history of TB, igA nephropathy, so monitoring for flare of TB, and avoidance of aggressive immunosuppression as much possible.
· What is your induction immunosuppression?
Basiliximab induction is the drug of choice.
· Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
DSA of 1500, is not very high, below threshold for high sensitivity so need to change plan of induction, specially the recipient has history of TB before.
· Any special consideration post-transplantation?
Recipient had successful treatment for TB in childhood, with immunosuppression after TX there is risk of reactivation of latent TB infection,candidates should undergo evaluation for LTBI with either TST or IGRA.
If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction,a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
IFN-γ release assays (IGRAs) offer some advantages as compared with TST: avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and are probably more sensitive in candidates with chronic renal failure
both tests could be performed and any positive reaction considered an evidence of LTBI.
Living donors should undergo the same evaluation as candidates, with the exception that the cutoff for TST should be 10 mm or greater.
LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated
-patients at high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive, patients with history of active TB infection that was inadequately treated also should receive ttt.
– Chest imaging suggestive of previous untreated TB should receive therapy, especially in areas where endemic mycoses are uncommon.
-Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
For treatment of LTBI, oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily, patient should be monitored for hepatotoxicity ALT checked every 2 weeks for 6 weeks, then monthly thereafter. What is your induction immunosuppression Potential recipient with a living related donor, 111 miss-match, no DSA, FCXM is negative, history of TB that was successfully treated early in childhood. Induction therapy with basiliximab.
ATG is not preferred in this scenario as it may cause flare of latent TB infection.
· Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
No I will not change the plan, I will proceed with the same management with monitoring of DSA post transplantation especially if reduction of IS was planned at any time and I plan also for protocol biopsy.
DSA (A2 with MFI 1500) is below the cutoff of most centers which range from 2000-3000 and not sufficient to cause positive crossmatch .
Santoro-Lopes, Guilherme MD, PhD1,2; Subramanian, Aruna K. MD3; Molina, Israel MD4,5; Aguado, José María MD, PhD6; Rabagliatti, Ricardo MD, PhD7; Len, Oscar MD, PhD8. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation 102(2S):p S60-S65, February 2018.
· Any special consideration post-transplantation? In the post-transplantation period, some monitoring strategy should be created for the development of Tuberculosis in this patient. We have no evidence, but perhaps the serial use of a skin test for tuberculosis or IGRA, associated with screnning with imaging tests in all cases of persistent fever, especially in cases of respiratory symptoms.
· What is your induction immunosuppression? Low-risk patient would undergo induction with corticosteroid (methylprednisolone) and basiliximab. · Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
A low amount of DAS would not lead me to change the immunosuppression plan.
the potential recipient has had childhood history of TB which was treated and now is considered for renal transplant with donor as his brother…The recipient needs to be evaluated for latent TB before transplantation…TB could ger reactivated after transplant especially if the recipient has latent TB before transplant…there is no evidence of active TB in the recipient… Latent TB treatment is indicated if anyone of the following – positive TST or IGRA test, history of untreated TB, history of recent contact with an active TB patient, donor with untreated latent TB…in the kidney transplant setting ideal treatment will be isoniazid 5mg/kg/day with vit b6 for 9 months…. The treatment has to be given ideally pre transplant, but there are recommendations to start the treatment atleast 1 month before and continue it later in the post transplant period…3 – 4 months of rifamipicin and isoniazid…weekly rifapentine plus isoniazid are the other regimens tried in general populations..But renal transplant recipients have high chance of interaction with other immunosuppressive medications…
So this patient, I would rule out LTBI by mantoux or IGRA..If positive with no signs of active infection,I wil give INH prophylaxsis for LTBI…This is important as there should be no post transplant flare of TB…
Induction agent – I would prefer Basiliximab induction as ATG is not indicated as there is no DSA and this is a well matched transplant with no previous sensitization…
Even if the MFI 1500 to A2, which is low levels, I will go with basiliximab induction and monitor the serial DSA levels to decide on further action post transplant
Two issues must be clarified
First his primary cause of ESRD which is IgAN and the risk of coming back after transplantation, So monitoring of graft function and urinalysis for hematuria and proteinuria is of importance.
Second , as he had history of treated TB during childhood, there is chance of TB flare up after transplantation , so we should search for the presence of active or latent TB by taking good history and doing CXR, sputum for ZNS for AFB , culture and gene Xpert , CT chest ,abdomen and pelvis. If all negative so go for IGRA and TST if positive mean latent TB . And treat according to the results.
What is your induction immunosuppression?
As the patient has low immunological risk with the history of treated TB , so induction with Basiliximab will be enough in edition to the triple IS as maintenance,with regular DSA and graft function monitoring.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
No, the same induction choice , basiliximab , as the DSA level of 1500 is not high.
Any special consideration post-transplantation? Recipients has history of prior treatment for active TB with resolution and has been on HD for 5 years. We must to rule out latent TB in this recipient. We need to do IGRA which is more sensitive . Tuberculin skin test can also be done however there can be false positive results due to prior BCG immunisation. If the patient has latent TB then it is crucial to rule out active TB with CXR, sputum for ZN staining and Gene Xpert test. If we establish latent TB, treatment should be started and completed before transplantation, but in case of urgent transplantation then treatment can be initiated post-transplant. Treatment is either 3 months of rifampin and isoniazid or 6-9 months of isoniazid. Caution should be taken due to drug interactions with rifampin, rifabutin/rifapentine can be used instead. What is your induction immunosuppression? This patient has low immunological risk hence induction would be with basiliximab. Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan? No I will continue and monitoring the DSA. References Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors Guilherme Santoro-Lopes, MD, PhD,1,2 Aruna K. Subramanian, MD,3 Israel Molina, MD,4,5José María Aguado, MD, PhD,6 Ricardo Rabagliatti, MD, PhD,7 and Oscar Len, MD, PhD8
Adebiyi OO, Gralla J, Klem P, Freed B, Davis S, Wiseman AC, Cooper JE. Clinical Significance of Pretransplant Donor-Specific Antibodies in the Setting of Negative Cell-Based Flow Cytometry Crossmatching in Kidney Transplant Recipients. Am J Transplant. 2016 Dec;16(12):3458-3467. doi: 10.1111/ajt.13848. Epub 2016 Jun 15. PMID: 27140940.
Post-transplantation concerns?
TB history: This patient was successfully treated with TB, so immunosuppression following kidney transplantation may reactivate it.
The recipient had childhood treated TB (IGRA/TST for R/O LTBI), and any positive results should be deemed LTBI.
CXR, sputum for Xpert, culture, and AFB stain should screen his brother for LTBI or active TBI.
After excluding active TB, latent TB should be treated.
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 latent TB without chemoprophylaxis, untreated TB, or active TB require TB treatment.
Isoniazid 5 mg/kg/day (maximum 300 mg/day) for 9 months plus vitamin B6 is the best treatment for latent TB in KT.
LTBI treatment should begin before transplant and be finished while on the waiting list.
If an urgent transplant is needed, treatment can be paused perioperatively and resumed when medically possible to finish the course.
Avoid rifampicin post-transplant because it interacts with immunosuppressants.
Counsel the patient regarding the chance of recurrence of his main GN, which has ranged from 21 to 58%.
Hematuria, proteinuria, and increasing creatinine may occur.
-Graft function monitoring; urine analysis for proteinuria or hematuria.
2: What’s your induction immunosuppression?
low immunological risk and DSA titer in this case.
IL-2 receptor antagonist (Basiliximab) induction, triple maintenance immunosuppression, and DSA and proteinuria monitoring after transplantation
3-DSA (A2 with MFI 1500). Would this affect management?
This DSA level is low with negative FCXM; thus, the management plan will be the same: induction with basiliximab on D0 and D4, followed by triple I.S. as maintenance therapy.
-Close DSA level monitoring at 3 and 12 months.
What is your induction immunosuppression?This patient is considered as low immunological rsik with no DSA and mismatch of 111 so will proceed with simplest (BASILIXIMAB ).
In such patient with previous history of TB in the donor we need to consider that in the selection of the induction therapy ,even if the reciepient has DSA with MFI of 1500 it dosenot mean to be agressive iin our induction therapy ,but we need to have close observation for DSA level .
There are 2 issues which needs to be considered post transplantation-first is rhe recurrence of IgA Nephropathy and second is risk of reactivation of Tuberculosis as patient has been treated for T.B in childhood.For IgA nephropathy-close monitoring of graft function and proteinuria should be done and imaging like xray Chest followed by CT scan Chest ,Abdomen and pelvis,urine and sputum samples for afb and also for genexpert -rif resistance to rule out active infection as chances quite high after immunosuppression ..If no evidence of infection ,then whether treatment for latent tb needed or not can be considered if TST or IGRA assays are positive. Treatment regimens will b according to WHO guidelines.
The above recipient falls into low immunological risk as has no DSA,negative FCXM and 111 mismatch ,so no need to go for induction with ATG and basiliximab (IL-2 inhibitor )will be enough with triple based immunosuppression as maintenance therapy.However,if the above patient has DSA with A2 MFI 1500,still induction will be the same and needs close monitoring of DSA.
REFERENCE:
Sorohan BM, Ismail G, Tacu D, Obrișcă B, Ciolan G, Gîngu C, Sinescu I, Baston C. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens. 2022 Sep 13;11(9):1041.
Hand book of kidney transplanatation Nephrology and Hypertension .
3. A 46-year-old CKD 5 on HD for the last 5 years due to IgA nephropathy has a kidney offer from his brother, 111 mismatch, no DSAs. The potential recipient has a history of TB during childhood, which was treated successfully. FCXM is negative.
Issues/ concerns
– 46yo man, CKD5 due to IgA nephropathy, on HD for 5 years, hx of TB in childhood
– potential donor brother, 111 mismatch, no DSAs, FCXM negative
Any special consideration post-transplantation? (1-3)
– the risk of infection is high, this is determined by the patient’s epidemiologic exposure and the net state of immunosuppression
– determine the patient’s immunization history and risk of exposure
– screen for LTBI using TST, IGRA
– if IGRA is positive, evaluate for active TB, if positive treat for active TB, if negative treat for LTBI
– if IGRA is negative, consider the risk of LTBI and the risk of TB exposure, if high treat for LTBI, if low no further evaluation or treatment is required
– TST can also be done, if positive, evaluate for TB and manage accordingly
– if TST is negative, repeat in 2 weeks to evaluate for booster effect, if positive screen for active TB
– if TST remains negative after the two weeks, evaluate for risk of LTBI exposure, if high treat fr LTBI
Indications for treatment for LTBI (4)
· TST (initial or boosted) with induration ≥5mm and/ or a positive IGRA
· history of untreated latent TB
· history of contact with an active TB case
· receipt of an organ from a TST positive donor not treated for LTBI
– treat for LTBI in patients with high risk for primary TB even if TST and IGRA are negative
– for those with 2 indeterminate IGRAs, decision to treat LTBI depends on the patient’s characteristics i.e., consider presence of signs of prior infection (e.g., granulomas on chest imaging), history of contact with a positive case, other history of probable exposure, risk of drug toxicities
– LTBI treatment options: –
· rifampin daily for 4 months
· rifapentine plus isoniazid weekly for 12 weeks
· isoniazid plus rifampin for 3 months
· isoniazid daily for 6 months
– the recipient has a low immunologic risk – LRKT, no DSA, negative FCXM, 111 mismatch
– KDIGO (2009) recommends use of IL-2Ras i.e., basiliximab as first-line induction therapy in patients not at high immunologic risk
– in addition to IV methylprednisone
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan? (1)
– no, I would still maintain the same induction and maintenance regimen
– monitor DSA as well
References
1. KDIGO clinical practice guideline for the care of kidney transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009 Nov;9 Suppl 3:S1-155. PubMed PMID: 19845597. Epub 2009/10/23. eng.
2. Fishman JA. Infection in Organ Transplantation. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2017 Apr;17(4):856-79. PubMed PMID: 28117944. Epub 2017/01/25. eng.
3. Bumbacea D, Arend SM, Eyuboglu F, Fishman JA, Goletti D, Ison MG, et al. The risk of tuberculosis in transplant candidates and recipients: a TBNET consensus statement. The European respiratory journal. 2012 Oct;40(4):990-1013. PubMed PMID: 22496318. Epub 2012/04/13. eng.
4. Subramanian AK, Theodoropoulos NM. Mycobacterium tuberculosis infections in solid organ transplantation: Guidelines from the infectious diseases community of practice of the American Society of Transplantation. Clinical transplantation. 2019 Sep;33(9):e13513. PubMed PMID: 30817030. Epub 2019/03/01. eng.
A 46-year-old CKD 5 on HD for the last 5 years due to IgA nephropathy has a kidney offer from his brother, 111 mismatch, no DSAs. The potential recipient has a history of TB during childhood, which was treated successfully. FCXM is negative.
Any special consideration post-transplantation?
Screen for latent TB and treat pre pre – transplant ; IGRA/MANTOUX test, CXR, Abd pelvic ultrasound. If positive we treat i.e High and low TB endemic area ;INH – 6/12/rifampicin +INH OD 3/12/Rifapentin +INH weekly 3/12 .
Counsel on recurrence of IGA nephropathy which is estimated to be between 21-58%.Post transplant to regularly monitor graft function with UECS and urinalysis for new onset proteinuria and hematuria +/- worsening renal function.
Induction suppression‘
Negative FCXM,No DSA – low rejection risk ;Basiliximab + IV methylprednisone then maintain with triple immunosuppressive therapy.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
Negative FCXM, still low risk, I would not change the management. We induce and monitor DSA.
Ref;
Abad CLR et al; Donor derived MTB infection after SOT;A comprehensive review.Transp infec dis.2018 oct ;20(5);e1297.
Liu Y .Zhou P et al; Basiliximab or ATG for induction therapy in kidney transplants .A meta analysis.
Any special consideration post-transplantation?
· Before transplant he should be screened for latent TB with IGRA, as TST have lower sensitivity in candidates with ESKD.
· For treatment of latent TB, if the transplant is unlikely to occur within the following 4 to 6 months, rifampin for 4 months is prescribed.
· Other options for pretransplant are isoniazid plus rifapentine for 12 weeks, or isoniazid plus rifampin for 3 months.
· If the treatment course will start, or continue, after transplant, oral isoniazid 5 mg/kg (maximum dose 300 mg) daily for adults (for nine months) with oral pyridoxine 25 to 50 mg daily should be given.
· TB occurs most commonly in transplant recipients as a result of reactivation of latent infection in the recipient, which occurred a median of 183 days after transplantation.
· If he is planning to move to a highly endemic area post transplantation, INH preventive therapy should be considered during the first posttransplant year.
· Post-transplant, the recipient should be asked about fever, night sweats, and weight loss.
· IgA nephropathy also should be investigated post-transplant for possible recurrence. Monitoring for haematuria, proteinuria, and HTN is recommended.
What is your induction immunosuppression?
· As the patient has no DSA, no need for ATG as it may increase the risk of TB activation, so I think that Basiliximab is the best option.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
· DSA-SPA are clinically significant even in the absence of FCXM, so he should be monitored closely for development of early AMR.
· But as MFI not so high I still will use Basiliximab, since the possibility of flaring up the fatal disseminated TB.
· Any special consideration post-transplantation?– Evaluation for latent TB before transplantation: cbc, sputum culture & microscopy for AFB , tuberculin skin test or preferably IGRA (more sensitive & specific esp. in CKD & immunocompromised pt) , CXR , CT or MRI as indicated by the case.- Consider treatment if positive for latent TB, partially treated or hx of TB in the donor – Keep high level of suspicion post transplantation including pt education & consider prophylaxis with rifampicin free regimen , observe for drug-drug interaction.- Regarding IgA , counselling about recurrence risk. · What is your induction immunosuppression?– Induction with basiliximab (low immunological risk , avoid aggressive immunosuppression for the hx of TB)· Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?– No , the same plan with follow up of DSA levels regularly ( MFI is considered significant if >3000)
will avoid ATG being close relation donor , absent DSA
Basiliximab as induction
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?no
still low risk
monitor DSA
consider early graft biopsy if creatinine is rising
He needs to continue on rifampicin free regimen (prophylactic therapy INH for 6-9m with frequent monitoring of liver enzymes)
No need to do TST and IGRA
Active TB should be carefully evaluated clinically, radiological and laboratory
Reactivation of TB can occur post transplantation with atypical presentation and high so diagnosis will rely mainly on high suspicious.
What is your induction immunosuppression?
Because of history of TB and also this patient is considered low immunological risk so, I will go with induction non depleting basiliximab and maintenance tac, MMF and steroids
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
Low MFI detected by Luminex with negative FCXM still I will not change my induction therapy but I will keep maintenance medications on the higher side with follow up of DSA post-transplant or I will consider paired kidney exchange
Any special consideration post-transplantation?
Recipients has history of prior treatment for active TB with resolution and has been on HD for 5 years.
We must to rule out latent TB in this recipient.
We need to do IGRA which is more sensitive . Tuberculin skin test can also be done however there can be false positive results due to prior BCG immunisation.
If the patient has latent TB then it is crucial to rule out active TB with CXR, sputum for ZN staining and Gene Xpert test.
If we establish latent TB, treatment should be started and completed before transplantation, but in case of urgent transplantation then treatment can be initiated post-transplant.
Treatment is either 3 months of rifampin and isoniazid or 6-9 months of isoniazid. Caution should be taken due to drug interactions with rifampin, rifabutin/rifapentine can be used instead. What is your induction immunosuppression?
This patient has low immunological risk hence induction would be with basiliximab.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
No I will continue and monitoring the DSA. References
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
Guilherme Santoro-Lopes, MD, PhD,1,2 Aruna K. Subramanian, MD,3 Israel Molina, MD,4,5José María Aguado, MD, PhD,6 Ricardo Rabagliatti, MD, PhD,7 and Oscar Len, MD, PhD8
Adebiyi OO, Gralla J, Klem P, Freed B, Davis S, Wiseman AC, Cooper JE. Clinical Significance of Pretransplant Donor-Specific Antibodies in the Setting of Negative Cell-Based Flow Cytometry Crossmatching in Kidney Transplant Recipients. Am J Transplant. 2016 Dec;16(12):3458-3467. doi: 10.1111/ajt.13848. Epub 2016 Jun 15. PMID: 27140940.
Prevalence TB in endemic area around 10-15% & in developed countries ~12%-6.4%.
Post transplant TB infection (reactivation or de novo) associated with poor graft outcome.
Post transplant reactivation of LTBI can occur in first 12 months & its diagnosis usually challenging which often delayed, so pre-transplant screening is crucial & prophylaxis is essential.
NICE recommend preventive treatment for all immunocompromised patients regardless negative result of IGRA & TST.
So this patient with history of treated TB infection need post transplant prophylaxis
Induction immunosuppression:
111HLA mismatch, negative FXCM consider as low immunological risk & induction with basiliximab & maintenance on triple immunosuppression enough.
If DSA against A2 1500:
The cut off of DSA differ according center policy but in general cut off >3000 considered as significant, because this patient had low DSA (below significant level) the induction will be the same with close monitoring of DSA post transplantation.
References:
Anada M., Nayyar E., Concepcion B., Salani M. and Schaefer H. Tuberculosis in kidney transplant recipients: A case series. WorldJTransplant,2017;7(3):213-221.
Meiner G., Silva C., Dorsdt D., Adames J., Andrade J., et al. Latent tuberculosis screening before kidney transplantation in the south of Brazil. Brazil.J.Nephrol,2021;43(4):520-529.
Sorohan B., Ismail G., Tac D., Obrisca B., Ciolan G., et al. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review.Pathogens,2022.
Any special consideration post-transplantation?Recipients has history of prior treatment for active TB with resolution and has been on HD for 5 days.
There is need to rule out latent TB in this recipient.
IGRA is more sensitive since the results are not affected by prior BCG immunisation status.
Tuberculin skin test can also be done however there can be false positive results due to prior BCG immunisation.
If the patient has latent TB then it is crucial to rule out active TB with CXR, sputum for ZN staining and Gene Xpert.
Ideally treatment for latent TB should be started and completed before transplantation, but in case of urgent transplantation then treatment can be initiated post-transplant.
Treatment is either 3 months of rifampin and isoniazid or 6-9 months of isoniazid. Caution should be taken due to drug interactions with rifampin, rifabutin/rifapentine can be used instead.
What is your induction immunosuppression?This patient has low immunological risk hence induction would be with IV methylprednisolone and basiliximab.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management planNo I will continue with the same plan and monitor the DSA.
References Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors Guilherme Santoro-Lopes, MD, PhD,1,2 Aruna K. Subramanian, MD,3 Israel Molina, MD,4,5José María Aguado, MD, PhD,6 Ricardo Rabagliatti, MD, PhD,7 and Oscar Len, MD, PhD8
Adebiyi OO, Gralla J, Klem P, Freed B, Davis S, Wiseman AC, Cooper JE. Clinical Significance of Pretransplant Donor-Specific Antibodies in the Setting of Negative Cell-Based Flow Cytometry Crossmatching in Kidney Transplant Recipients. Am J Transplant. 2016 Dec;16(12):3458-3467. doi: 10.1111/ajt.13848. Epub 2016 Jun 15. PMID: 27140940.
The potential KTR with history of TB is at high risk for reactivation of TB.
Treatment of latent TB should be considered only after active TB has been excluded:
Treatment 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
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.
preferred treatment of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with pyridoxine
Treatment of latent TB in donor and recipient
The WHO 2018 guidelines outline the following treatment options for latent TB.
INH monotherapy for 6 months is recommended.
Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy:
9 months of isoniazid
3-month regimen of weekly rifapentine plus isoniazid
3–4 months of isoniazid plus rifampicin
3–4 months of rifampicin alone
What is your induction immunosuppression?
Basiliximab is as effective as ATG for induction therapy in kidney transplantation and less incidence of infection. The patient has negative FXM and low titre of A2 DSA, I would consider induction with Basiliximab and monitor DSA.
References:
Krishnamoorthy S, Kumaresan N, Zumla A. Latent tuberculosis infection and renal transplantation – Diagnosis and management. Int J Infect Dis. 2019 Mar;80S:S73-S76.
Sorohan BM, Ismail G, Tacu D, Obrișcă B, Ciolan G, Gîngu C, Sinescu I, Baston C. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens. 2022 Sep 13;11(9):1041.
Santoro-Lopes, Guilherme; Subramanian, Aruna K.; Molina, Israel; Aguado, José María; Rabagliatti, Ricardo; Len, Oscar. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation 102(2S):p S60-S65, February 2018.
1-Any special consideration post-transplantation? Regarding TB history;
–This recipient had previous exposure to TB and was treated successfully,so consider the risk of reactivation after kidney transplantation with the use of immunosuppression. -Recipient had history of treated TB during childhood : investigations R/O LTBI should be done as such; (IGRA/TST) and any positive results should be considered evidence of LTBI. -His brother should be screened for LTBI or active TBI; CXR and Sputum for Xpert , culture , AFB stain. -Treatment of latent TB should be considered only after active TB has been excluded. -Treatment of 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. -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. -When possible, treatment for LTBI should be started before transplant, and can often be completed while the patient is on the waiting-list. -If urgent transplant is indicated, the treatment can be held perioperatively and resumed when medically possible post transplant to complete the planned course. -Avoid rifampicin post-transplant because of its interaction with immunosuppression medications. Regarding his original disease (IgA nephropathy); -Counsel patient about the risk of recurrence of his primary GN, the recurrence of IgAN has ranged from 21 to 58 %. -Patient may present with active urine sediment (hematuria , proteinuria) with or with out rising creatinine. -Close monitoring of graft function, urine analysis for newly onset of proteinuria or hematuria. 2-What is your induction immunosuppression? -This current patient with low immunological risk with low DSA titer. -So my induction go with IL-2 receptors antagonist (Basiliximab) , followed by triple maintenance immunosuppression with close monitoring after transplantation with DSA level and proteinuria. 3-Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan? -This level of DSA is low with negative FCXM so the management plan will be the same and the induction with Basiliximab on (D0& D4),followed by triple I.S. as maintenance therapy. -Close monitoring of DSA level at 3 months and 12 months.
References; -Krishnamoorthy S, Kumaresan N, Zumla A. Latent tuberculosis infection and renal transplantation – Diagnosis and management. Int J Infect Dis. 2019 Mar;80S:S73-S76. -Sorohan BM, Ismail G, Tacu D, Obrișcă B, Ciolan G, Gîngu C, Sinescu I, Baston C. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens. 2022 Sep 13;11(9):1041. -Santoro-Lopes, Guilherme; Subramanian, Aruna K.; Molina, Israel; Aguado, José María; Rabagliatti, Ricardo; Len, Oscar. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation 102(2S):p S60-S65, February 2018.
A 46-year-old CKD 5 on HD for the last 5 years due to IgA nephropathy has a kidney offer from his brother, 111 mismatch, no DSAs. The potential recipient has a history of TB during childhood, which was treated successfully. FCXM is negative.
Special consideration post-transplantation?
Latent tuberculosis infection (LTBI) is defined by the World Health Organisation as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifest active TB disease’.
Up to 10% of people with LTBI will progress to developing active TB disease during their lifetime.
The highest risk for developing TB disease occurs when a range of 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 transplantpatients (Hasan et al., 2018). WHO recommends three tests for screening for LTBI:
Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs). IGRAs are more specific to Mycobacterium tuberculosis antigens and offer high specificity in detecting LTBI in immunosuppressed patients.
A systematic review and meta-analysis found that IGRAs are more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation. Post-transplant TB is more common in renal recipients than in liver transplant patients. Chest Xray TREATMENT OF LTBI IN DONOR AND RECIPIENT:
The WHO 2018 guidelines outline the following treatment options for LTBI:
Isoniazid mono-therapy 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 mono-therapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid mono-therapy as preventive treatment for both adults and children in countries with a high TB incidence.
The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid mono-therapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone(2).
What is your induction immunosuppression?
As The recipient had successful treatment for TB and his DSA is below the threshold of positive crossmatch (negative crossmatch), Low immunological risk with 111 mismatches.
I will give Basiliximab and Pulse Methylprednisone for induction.
Standard maintenance immunosuppression was triple therapy with calcineurin inhibitors to maintain target levels.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
No Change,
The recipient had successful treatment for TB and his DSA is below the threshold of positive crossmatch (negative crossmatch).
I will not give him aggressive induction that may cause flare of TB if there is a chance of latent TB?
MFI of 1500 is a low level and will not change the management plan. Basiliximab will be choice for induction therapy.Still the recipient low immunological risk (low DSA)
Post-transplant patient follow-up outpatient clinic, with medical consultations every week in the first three months, then biweekly until six months, monthly until one year, and then every two months.
Reference
UpToDate
Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020
Saudi guidelines for testing and treatment of latent tuberculosis infection Hamdan H. Al Jahdali, Salim Baharoon, and Dick Menzies2010
Any special consideration post-transplantation?For SOT candidates with end-stage kidney disease use the IGRA to screen for latent TB.
For those with a negative IGRA, we consider the risk of latent TB and treat those at high risk
Regimen selection — For treatment of latent TB, we follow national guidelines while taking into account issues of drug interactions and organ failure encountered in transplant patients.
When the transplant is unlikely to occur within the following 4 to 6 months, we typically prescribe rifampin for 4 months Other options pretransplant are isoniazid plus rifapentine for 12 weeks, or isoniazid plus rifampin for 3 months.
Timing of treatment — When possible, we treat transplant candidates with latent TB prior to transplantation, although it is also acceptable to treat following transplantation
Patients may proceed to transplant before the full course of therapy for latent TB has been given. In these cases, therapy is typically continued post-transplant, but the regimen sometimes needs to be modified to minimize toxicities and drug-drug interactions
What is your induction immunosuppression?either an IL-2 receptor antagonist (basiliximab) or rATG-Thymoglobulin is a reasonable induction therapy agent
ASSESSMENT OF IMMUNOLOGIC RISK
An important element of some approaches to induction protocols involves the attempt to identify patients at high risk of acute rejection. With this view, more aggressive immunosuppression is justified in patients at significantly increased risk of rejection
Risk factors for acute rejection include the following
●One or more human leukocyte antigen (HLA) mismatches
●Younger recipient and older donor age
●Calculated panel reactive antibody (cPRA) greater than 20 percent
●Presence of a donor-specific antibody (DSA)
●Blood group incompatibility
●Delayed onset of graft function
●Cold ischemia time greater than 24 hours
Patients with one or more of the above risk factors are considered to be at high immunologic risk for acute rejection. Those who have none of the above risk factors are considered to be at low immunologic risk.
For patients at high immunologic risk of acute rejection we recommend induction therapy with rATG-Thymoglobulin rather than an interleukin (IL) 2 receptor antagonist (basiliximab)
For patients who are at low immunologic risk of acute rejection either an IL-2 receptor antagonist (basiliximab) or rATG-Thymoglobulin is a reasonable induction therapy agent
Some experts prefer rATG-Thymoglobulin based upon data showing lower rates of biopsy-proven acute rejection at one year with rATG-Thymoglobulin Other experts prefer basiliximab based upon studies that have shown similar rates of acute rejection, patient and graft survival, and infection with rATG-Thymoglobulin and IL-2 receptor antibodies in low-risk patients. The 2009 KDIGO clinical practice guidelines recommend the use of IL-2 receptor antibodies as first-line induction therapy in patients not at high immunologic risk . Dosing and administration of these agents are discussed below.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
YES OUR PATIENT WILL BE RISKY AND NEED INDUCATION THERAPY WITH rATG-Thymoglobulin
In December 2007, UNOS mandated that calculated PRA (cPRA) provide a more uniform and accountable method for assessing sensitization
. The cPRA calculates the likelihood of transplantation by using results of the SAB assay to identify the specificity of the anti-HLA antibodies, in combination with the known frequencies of HLA antigens within the donor population.
As an example, if the patient has an antibody against the HLA-A2 antigen, which is present in 48 percent of the United States donor population (phenotypic frequency of the A2 antigen), their cPRA level would be 48 percent, and they would be ineligible to receive 48 percent of the kidneys on the basis of having DSA against the A2 antigen
Clinical significance of MFI values of pretransplant DSA — Median fluorescence intensity (MFI) values of pretransplant donor-specific anti-HLA antibody (DSA) do not appear to consistently predict graft outcomes.
In one study, higher rates of ABMR and graft loss were seen when pretransplant DSA had MFI values >10,000 but were comparable between all other groups (moderate MFI [5000 to 10,000] versus low MFI [1000 to 5000]) Another study found that differences in graft survival were dependent upon identifying the presence of DSA (MFI >1500) but not upon the actual level of MFI
. Failure to discern differences between these groups of patients may reflect technical limitations of the assay (with MFI values themselves being a poor predictor of amount/strength of antibody as well as our inability to predict whether low-level DSA will remain low or rapidly increase posttransplantation upon repeat exposure to the antigen
.
Absence of pretransplant DSA on outcome — Even in the absence of donor-specific anti-HLA antibody (DSA), some studies have shown that sensitized recipients (with non-DSA alloantibody) are at higher risk for graft failure However, this remains controversial, as other studies have shown no impact of having non-DSA on graft outcome These disparate findings may depend upon whether more or less aggressive immunosuppression is used or could also reflect incomplete identification of DSA depending upon whether antibodies against all loci (including class II alpha chain) are accounted for.
Any special consideration post-transplantation? Need To exclude latent TB by IGRA test or Tuberculin skin test. To exclude active tuberculosis with sputum AFB and chest x ray. What is your induction immunosuppression?
Induction with basiliximab is sufficient followed by triple maintenance immunosuppression (TAC, MMF and steroids) Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
DSA is positive with low titer (1500) so, doesn’t require to change IS regimen but need to follow up of DSA Titre post transplantation.
This is a low immunologic risk case, but we need to check for TB (latent) in both donor and recipient (monitor recipient later); PPD test, and or quantifereon.
We need induction because of the 111 mismatch to avoid acute rejection, but this can be done with anti IL2, basiliximab rather than ATG, not to increase the risk of opportunistic infections as well as activation of probable TB.
Any special consideration post-transplantation?
Past history with TB(site and duration of ATT not mentioned) treated successfully so if living in endemic area will have to assess for active TB and TBI(latent TB)
In case of
Active TB (positive IGRA/TST plus radiological evidence and symptoms will have to treat with ATT upto nine month if Live related transplant or post transplant ATT upto 18 month if transplant occurred) OR In case of TBI (NO symptoms but positive IGRA and TST ) will have to treat with 3HR regimen INH 5mg/kg and Rifa 10mg/kg daily for 3 months.In endemic area will prefer to have INH prophylaxis for 6 months post transplantWhat is your induction immunosuppression?
Methylpred and IL2 antagonists
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
No but will have to observe for Graft function, DSAs and Donor derived cell free DNA where avilable.
Any special consideration post-transplantation?Will use INH for atleast six months or INH and Rifampin for three months.
What is your induction immunosuppression?As recipient has been treated for TB in the past there remains a risk of deactivation in post transplant period.
Basiliximab would be a better induction option as there is low immunological risk being No DSA and negative flow cross match.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?No
Because cross match is still negative
As this is a related LD s there is the privilege to wait and investigate the TB status ie. to exclude a latent TB infection by IGRA and radiology work up which can not be conclusive post TX due to IS, then proceed with the needed regimen.
This patient was successfully treated for TB during childhood but he was on dialysis for 5 yeast which increased the risk of latent TB and reactivation after kidney transplantation so we need to do IGRA and skin test sputum PCR and CXR if positive for anti tuberculosis treatment before transplantation .
What is your induction immunosuppression?
This patient has low immunological risk with negative FCXM and no DSA so induction is by basiliximab and IV methylprednisolone.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
Antibodies are considered to have weak to low level with phenotype panel MFI values from 1000 to 3000; moderate from 3000 to 5000; and strong when >5000 this patient MFI is 1500 which is considered weak so I will proceed for transplantation with the same plan of management and follow the DSA level .
Reference :
HLA donor-specific antibodies in allogeneic hematopoietic stem cell transplantation: challenges and opportunities Hematology Am Soc Hematol Educ Program. 2017 Dec 8; 2017(1): 645–650. doi: 10.1182/asheducation-2017.1.645
2. Transplant Direct. 2018 Sep; 4(9): e385. Published online 2018 Aug 22. doi: 10.1097/TXD.0000000000000823
3. PLoS One. 2020; 15(10): e0240929. Published online 2020 Oct 22. doi: 10.1371/journal.pone.0240929
PMCID: PMC7580969PMID: 33091057
⭐Special consideration in such recipient with prior history of TB treatment, is to exclude latent TB by Tuberculin skin test or IGRA test.
_ if postive …use of chemoprophylaxis aganist TB including monotherapy with INH for 6 months or 3 months of combined (INH and rifampin with close monitoring of TAC trough level as rifampin is an enzyme inducer.
⭐The patient has one haplotype mismatch, with negative FCXM and no DSA …so induction with basiliximab is quite sufficient followed by TAC based triple miantenance therapy with MMF and steroids.
⭐If DSA postive with low titer (1500), no change of IS regimen, but just follow up of DSA titre post transplantation.
Recipient criteria; The recipient is considered a low risk
Living donation.
111 MM.
No DSA.
Negative FXCM.
Consideration
History of successfully treated TB in childhood.
IgA nephropathy as is a primary disease.
Approach
Reduce the incidence or existence of TB infection.
Reduce the recurrence of the primary disease.
Workup;
Chest x-ray.
TST and IGRA (IGRA is more sensitive in advanced CKD and ESKD).
If both are negative the recipient is excluded as having LTB, and can proceed with transplantation without prophylactic therapy. Induction therapy
Balanced induction (between TB reactivation and IgA recurrence), IL-6 inhibitor (Basiliximab) (as the patient’s the primary disease is IgAN) although prove by many study that ATG is superior to IL-6 antagonist.
MFI1500 will not change the plan as no DSA and negative FXCM References
Hariharan S, Peddi VR, Savin VJ, et al. Recurrent and de novo renal diseases after renal transplantation: A report from the renal allograft disease registry. Am J Kidney Dis 1998; 31: 928.
2.Berger J, Yaneva H, Crosnier J. Mesangial IgA glomerulonephritis: A frequent cause of terminal renal failure. Nouv Presse Med 1980; 9: 219.
Patel R, Terasaki PI. Significance of the positive crossmatch test in kidney transplantation. N Engl J Med 1969; 280: 735.
2. Johnson AH, Rossen RD, Butler WT. Detection of alloantibodies using a sensitive antiglobulin microcytotoxicity test: Identification of low levels of pre-formed antibodies in accelerated allograft rejection. Tissue Antigens 1972; 2: 215.
before transplantation (for both donor & recipient ) and post transplantation (for recipient ) should workup for LTBI via tuberculin skin test and IGRA which more sensitive and specific.
if positive tests ….require either pre or post transplantation anti TB treatment
What is your induction immunosuppression?because of low immunological risk and risk of reactivation of TB…..Better to not doing aggressive induction , so better to use basiliximab as induction agent.
this is related LD so they can wait to investigate a LTBI and even if proved a safer situation than after TX (if accepted by the R ) with precautions of the drug inter action.
1-initial active TB should be excluded
2-IF patient has a positive TST or IGRA test treatment as latent TB (isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6. ) 3- patient has standard immunological risk so induction with Basilliximab
The WHO 2018 guidelines outline the following treatment options for LTBI (WHO, 2018b).
1- Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
2- Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
3- Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
4- The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy:
a- 9 months of isoniazid,
b-or a 3-month regimen of weekly rifapentine plus isoniazid,
c-or 3–4 months of isoniazid plus rifampicin,
d-or 3–4 months of rifampicin alone.
Patients may find completing the long course of LTBI treatment difficult due to adverse effects and the interactions with immunosuppressive drugs, hence shorter courses of treatment are recommended.
Any special consideration post-transplantation?
This potential KTR with PH of TB is at high risk for reactivation and post-transplant TB infection. In this potential KTR, I need to rule out disease activity and to consider prophylaxis at time of transplant.
Treatment of latent TB should be considered only after active TB has been excluded(1): a) Treatment of 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. 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. Treatment of LTBI in donor and recipient
The WHO 2018 guidelines outline the following treatment options for LTBI (WHO, 2018b).
a) Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
b) Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
c) Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
d) The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone(2). What is your induction immunosuppression?
1. 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.
2. Basiliximab is as effective as ATG for induction therapy in kidney transplantation, whereas basiliximab has a lower incidence of infection(4).
3. In this case with undetectable DSA level and a history of TB, I will consider Basiliximab for induction.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
MFI of 1500 is a low level and will not change the management plan. Basiliximab will be choice for induction therapy.
References 1. Abad CLR, Razonable RR. Donor derived Mycobacterium tuberculosis infection after solid-organ transplantation: A comprehensive review. Transpl Infect Dis. 2018 Oct;20(5):e12971. doi: 10.1111/tid.12971. Epub 2018 Aug 12. PMID: 30055041. 2. Krishnamoorthy S, Kumaresan N, Zumla A. Latent tuberculosis infection and renal transplantation – Diagnosis and management. Int J Infect Dis. 2019 Mar;80S:S73-S76. doi: 10.1016/j.ijid.2019.01.049. Epub 2019 Feb 6. PMID: 30738187. 3. Sorohan BM, Ismail G, Tacu D, Obrișcă B, Ciolan G, Gîngu C, Sinescu I, Baston C. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens. 2022 Sep 13;11(9):1041. doi: 10.3390/pathogens11091041. PMID: 36145473; PMCID: PMC9505385. 4. Liu Y, Zhou P, Han M, Xue CB, Hu XP, Li C. Basiliximab or antithymocyte globulin for induction therapy in kidney transplantation: a meta-analysis. Transplant Proc. 2010 Jun;42(5):1667-70. doi: 10.1016/j.transproceed.2010.02.088. PMID: 20620496.
Any special consideration post-transplantation?
This recipient had previous exposure to TB and was treated successfully, we should consider the risk of reactivation after kidney transplantation, with the use of immunosuppression also need to ask about the treatment course and type of ATT that he received any recent exposure or contact with active TB cases, his brother should be screened for LTBI, also ask about the type and duration of ATT, did he completed the course of ATT, do CXR and send for urine and blood sample for AFB staining and cultures, and should be careful in the choice of immunosuppression, as he is at risk of endogenous reactivation with immunosuppression.
TB post-kidney transplantation is associated with high morbidity and mortality and in 1/3 of cases can lead to graft loss also the diagnosis will be challenging as they usually have a nonspecific clinical presentation and after SOT there is a risk of extrapulmonary TB or disseminated TB, also the treatment of active TB after transplantation consider another challenge due to the drug-drug interaction and hepatotoxicity, neurotoxicity so in such case, will be careful in handling his immunosuppression induction type and also keep a high index of clinical suspicion of reactivation after transplantation. What is your induction immunosuppression?
Still, this patient can go with basiliximab as induction IS along with PMP and followed by triple IS including tacrolimus, MMF and steroid as his primary disease was IgA nephropathy so preferred to be on triple maintenance IS Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
This level of DSA is low with negative FCXM so still can go with the same induction IS, basiliximab, and PMP followed by triple maintenance therapy with close monitoring of DSA level in 3 months and 12 months
References
1.José María Aguado, Julián Torre-Cisneros, Jesús Fortún, Natividad Benito, Yolanda Meije, Antonio Doblas, Patricia Muñoz, David R. Snydman, Tuberculosis in Solid-Organ Transplant Recipients: Consensus Statement of the Group for the Study of Infection in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology, Clinical Infectious Diseases, Volume 48, Issue 9, 1 May 2009, Pages 1276–1284, https://doi.org/10.1086/597590
Any special consideration post-transplantation?
-History of clinical or radiological TB and the treatment taken have to be evaluated
-Tuberculin skin test and gammainterferon test to exclude latent TB infection
– Active TB infection must be excluded in cases with positive result in any of these tests.
– checking for the presence of symptoms and signs suggestive of TB, chest Xray
If any evidence of active infection is noticed, suitable clinical specimens need to be obtained for microbiological confirmation .
If active TB infection was diagnosed, transplantation should have been postponed till TB is cured with adequate treatment and smears are negative.
IF Latent TB was discovered treatd with oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
For prophylaxis isoniazid (300 mg daily or 25 mg/kg twice weekly) administered for six to nine months with special couscous for drug interaction with immunosuppressives .
MDR TB have to be excluded
-Regarding Ig A nephropathy recurrence the recipient has to be counselled for that asIgA nephropathy recurrence post kidney transplantation occurs in about 30% of cases. The relevance of recurrence for the long-term graft survival is expected to increase, since graft survival continues to improve. What is your induction immunosuppression?
Basiliximab and steroids in the presence of the current crossmatching with no DSA rendering the case of low immunogenic risk also in order not to provoke activation of latent TB Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
MFI threshold for unacceptable antigens in most centers are between 3000–5000.Therefore MFI1500 and A2 is of low risk.
So the same management will be carried on with induction using basilismab and triple maintenance therapy
Yoo PS et al demonstrated that a weakly positive DSA of less than 3000 MFI by SAB assays combined with a negative flow cytomatric crossmatch have no adverse effect on short-term renal function or rates of early graft rejection Reference
-Santoro-Lopes G et al ,Tuberculosis Recommendations for Solid OrganTransplant Recipients and Donors. Transplantation 2018 ,Volume 102,Number 2S-2
-Yoo PS, Bonnel A, Kamoun M, Levine MH. Clinical outcomes among renal transplant recipients with pre-transplant weakly reactive donor-specific antibodies. Clin Transplant. 2014;28(1):127-133.
– Jäger, C., Stampf, S., Molyneux, K. et al. Recurrence of IgA nephropathy after kidney transplantation: experience from the Swiss transplant cohort study. BMC Nephrol 23, 178 (2022)
Any special consideration post-transplantation? A-TB –The incidence rate of TB markedly increases after SOT, reactivation of latent TB infection (LTBI) is probably the main cause of posttransplant TB and primary TB is less frequent.
-Recipient had history of treated TB during childhood. Therefore, we need to rule out LTBI by doing IGRA/TST in high-risk patients, both tests could be performed, and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening.
– Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started, CXR and if there is any symptoms sputum for Xpert, culture, AFB stain.
– Treatment for LTBI if had history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
– When possible, treatment for LTBI should be started before transplant, and can often be completed while the patient is on the waitlist.
-If urgent transplant is indicated, the treatment can be held perioperatively and resumed when medically possible until completion of the originally planned course
– Better to avoid rifampicin post-transplant for its interaction with immunosuppression.
B– IgA nephropathy.
-The candidate need to be aware about the risk of recurrence, the recurrence of IgAN has ranged from 21 to 58 %.
-TANGO study reported the cumulative incidence of recurrence was 19 % at 10 years and 23 % at 15 years. -Histologic recurrence, with or without evidence of clinical disease, may occur. – Present with hematuria, new or worsening proteinuria, or an increased creatinine.
– Monitor graft function, urine for new onset proteinuria and hematuria.
What is your induction immunosuppression? Despite HLA mismatch, no DSA and FCXM is negative, low immunological risk induction with steroid and basilliximab. Given the previous history of TB better to avoid aggressive induction therapy. Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
-I will proceed with the same plane with careful and frequent DSA monitoring, as DSA MFI is low and negative FXCM.
-One study showed pre-transplant DSA with a negative FCXM did not significantly impact AR rates, graft function (GFR or proteinuria) or intermediate-term graft survival, in the setting of low MFI< 3000.(2)
-While a recent meta-analysis showed pretransplant DSA and reported an increased incidence of AMR (25% vs. 11%) and a significant increases the risk for graft failure by 76% and decrease in graft survival in the presence of pretransplant DSA versus those without.(3)
References: · -Santoro-Lopes G, Subramanian AK, Molina I, Aguado JM, Rabagliatti R, Len O. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation. 2018 Feb;102(2S Suppl 2):S60-S65. doi: 10.1097/TP.0000000000002014. PMID: 29381579. · Adebiyi OO, Gralla J, Klem P, Freed B, Davis S, Wiseman AC, Cooper JE. Clinical Significance of Pretransplant Donor-Specific Antibodies in the Setting of Negative Cell-Based Flow Cytometry Crossmatching in Kidney Transplant Recipients. Am J Transplant. 2016 Dec;16(12):3458-3467. doi: 10.1111/ajt.13848. Epub 2016 Jun 15. PMID: 27140940.
· Mohan S, Palanisamy A, Tsapepas D, Tanriover B, Crew RJ, Dube G, Ratner LE, Cohen DJ, Radhakrishnan J. Donor-specific antibodies adversely affect kidney allograft outcomes. J Am Soc Nephrol. 2012 Dec;23(12):2061-71. doi: 10.1681/ASN.2012070664. Epub 2012 Nov 15. PMID: 23160511; PMCID: PMC3507372.
This patient has a very remote history of successfully treated TB; however, no detailed information is provided regarding the site of infection (pulmonary or extra-pulmonary), duration of therapy, sensitivity results, adverse effects of treatment, etc.
Recent history of contact with a case of TB?
Exclude active or latent TB in the potential donor.
Pre-transplant workup to exclude active, or LTBI (CXR, TST, IGRAS, NAT, etc).
If the workup reveals active TB, I will treat him before transplantation; however, this shouldn’t be an absolute contraindication if the transplantation is needed urgently.
After excluding active TB, I will treat for LBTI post-transplantation. Drug interactions and possibility of MDR TB should also be considered.
I will also counsel this patient about the risk of recurrence his primary GN.
====================== What is your induction immunosuppression?
The HLA is 111 mismatches, FCXM is negative, & there is no DSA. Therefore, I will consider this a low-risk transplant & will not use only methylprednisolone for induction.
The use of ATG or Alemtuzumab in such patient may cause reactivation of TB infection.
====================== Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
No, I will not change my management plan:
Pre-transplant DSA (by SAB) have been associated with inferior graft outcomes.
However, studies reported similar 1-year AR rates in DSA-positive versus DSA-negative patients.
However, rejection rates were higher in those with DSA MFI =/> 3000.
References
Santoro-Lopes, Guilherme; Subramanian, Aruna K.; Molina, Israel; Aguado, José María; Rabagliatti, Ricardo; Len, Oscar. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation 102(2S):p S60-S65, February 2018. | DOI: 10.1097/TP.0000000000002014
Adebiyi OO, Gralla J, Klem P, Freed B, Davis S, Wiseman AC, Cooper JE. Clinical Significance of Pretransplant Donor-Specific Antibodies in the Setting of Negative Cell-Based Flow Cytometry Crossmatching in Kidney Transplant Recipients. Am J Transplant. 2016 Dec;16(12):3458-3467. doi: 10.1111/ajt.13848. Epub 2016 Jun 15. PMID: 27140940.
3. A 46-year-old CKD 5 on HD for the last 5 years due to IgA nephropathy has a kidney offer from his brother, 111 mismatch, no DSAs. The potential recipient has a history of TB during childhood, which was treated successfully. FCXM is negative.
Latent tuberculosis infection is defined by the World Health Organisation (WHO) as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis (M.tb) antigens with no evidence of clinically manifest active TB disease’ (WHO, 2018b).
Up to 10% of people with LTBI will progress to developing active TB disease during their lifetime.
The highest risk for developing TB disease occurs when a range of 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 (Hasan et al., 2018).
WHO recommends three tests for screening for LTBI:
Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs).
IGRAs are more specific to M.tb antigens and offer high specificity in detecting LTBI in immunosuppressed patients.
A systematic review and meta-analysis found that IGRAs are more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation.
Posttransplant TB is more common in renal recipients than in liver transplant patients.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
NO
Still the recipent low immunological risk(low DSA )
IV methylprednisone and basiliximab will be used for induction.
Post transplant patient follow-up outpatient clinic, with medical consultations every week in the first three months, then biweekly until six months, monthly until one year, and then every two months.
Ram R, Swarnalatha G, Prasad N, Dakshinamurty KV. Tuberculosis in renal transplant recipients. Transpl Infect Dis. 2007 Jun;9(2):97-101.
Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020
Al Jahdali HH, Baharoon S, Abba AA, et al. Saudi guidelines for testing and treatment of latent tuberculosis infection. Ann Saudi Med. 2010;30(1):38-49. doi:10.4103/0256-4947.59373
Saudi guidelines for testing and treatment of latent tuberculosis infection Hamdan H. Al Jahdali, Salim Baharoon, […], and Dick Menzies2010
Prophylactic treatments for TB reactivation after kidney transplantation include antibiotics such as isoniazid, rifampin and pyrazinamide, which can help to prevent the reactivation of TB in patients who have a history of being infected with the disease. Oral corticosteroid therapy may also be recommended for patients at risk of TB reactivation to reduce the risk of complications. Additionally, it is important for patients to receive regular TB screenings, in order to quickly identify any TB infections post-transplantation.
most guideline recommend inh with pyrodxine for 9 moth.
i will go for smilucet
low levels DSA will not change my paln , just to keep an eye on his kidney panel and his acr with follow up regulary , any signs of rejection ,i will send DSA with biobsy to confirm.
ATT should be given if IGRA and TST are positive, inadequately treated TB, history of untreated TB in donor.
What is your induction immunosuppression?
There HLA 111 mismatch, No DSA
Induction with Basiliximab and TAC based maintenance therapy
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
I will proceed with transplantation. Induction with Basiliximab, with DSA moniroring. pretransplant DSA in the setting of a negative FCXM confers minimal immunologic risk in the intermediate term, does not necessitate desensitization therapy and should not represent a barrier to renal transplant.
Adebiyi OO, Gralla J, Klem P, Freed B, Davis S, Wiseman AC, Cooper JE. Clinical Significance of Pretransplant Donor-Specific Antibodies in the Setting of Negative Cell-Based Flow Cytometry Crossmatching in Kidney Transplant Recipients. Am J Transplant. 2016 Dec;16(12):3458-3467.
Risk of latent TB;
Long duration on dialysis.
Immunosuppressive medicine
Prior TB infection
I presume that the patient would have undergone a complete evaluation for latent TB, including an IGRA, sputum cultures, and chest imaging.(before to the transplant). If every all test are normal than there is no need for ATT, better to proceed for transplantation.
Treatment of latent TB is recommended for 9 months in case of positive test for latent TB .
Post transplantation,
there is a higher risk of tuberculosis (TB) reactivation and infection.
Patient should be monitor for ;
Respiratory sign and symptom, night sweat, weight loss, loss of appetite, close contacts with TB patients. Induction
Due to the fact that this is a first transplant, there is no history of sensitization, no DSA, a negative FCMXM, and a prior history of TB, the immunologic risk is most likely low.
My induction would therefore consist of basiliximab and IV methyl prednisone.
Although there is a lot of difference between laboratories and various laboratories may have a different cut-off, UNOS states that the cut-off is MFI > 3000.
DSA alone should not preclude the transplant process
Any special consideration post-transplantation?
I want to believe the detailed history of how TB was diagnosed in childhood, a combination of drugs used, the duration of treatment, and evidence of cure would have been established before proceeding with the transplant
Also, investigations like TST, IGRA, and TB culture can be done if is not an emergency transplantation
Imaging tests like CXR for old healed focus on the lung parenchyma
Post-transplantation, I will do the following
Sputum and urine culture for TB
IGRA
CXR
TST, may not have any role because of past history of treatment for TB
However, with past history of TB, and for those patients living in the endemic areas I will start the patient on Tab INH 300mg daily for 6-9 months
What is your induction immunosuppression?
This is an immunologically low-risk recipient with HLA haplotype, no DSA, and negative crossmatch. The induction therapy will be Basiliximab 20mg on days 0 and 4 post-transplantation
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
The patient still has a good HLA match with a negative crossmatch, but the DSA MFI is now 1500. Although DSA-level treatment is mostly centre specific, however, 1500 is still low to warrant desensitization in the index patient. Thus, I will still use the same induction regimen earlier stated.
References
Guilherme Santoro-Lopes, Aruna K. Subramanian, Israel Molina,José María Aguado, Ricardo Rabagliatti, Oscar Len. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation. 2018; 102: s60-s65
Gabriel M. Danovitch. Handbook of Kidney Transplantation. Six Edition.
The potential recipient has had TB treated successfully in childhood. However, he can still be having latent TB
The pre-transplant work up should assess for latent TB. There are 2 methods of diagnosing latent TB:
The tuberculin skin test
Interferon gamma release assay (IGRA):
TB Gold quantiferon
T spot TB test
If the recipient is diagnosed to have latent TB, active TB needs to be ruled out
If the potential recipient is diagnosed to have latent TB, it is important to treat it before the transplant as there is a risk of TB flare due to the immunosuppression
If the recipient does not have latent TB then he can be safely transplanted
Post Transplant:
Monitor for any symptoms of occult infection which could signify a reactivation or re-infection
Monitor for recurrence of IgA nephropathy – the rate of recurrence is 19%-23%
Induction Immunosuppression:
The induction immunosuppression will be basiliximab as the risk of reactivation of TB with ATG is very high
DSA A2 with MFI of 1500 with a negative FCXM:
The induction will still be basiliximab as the FCXM is negative and his DSAs are still low
Any special consideration post-transplantation? Screening and diagnosis of LTBI and active TB before transplantation: History:previous TB infection, contact with active TB patient Symptoms:chronic cough, weight loss, night sweats, and anorexia Clinical examination:examine for active pulmonary tuberculosis, exclude extra pulmonary TB Investigations: CBC, CRP, RFT, LFT, microscopy for AFB and culture, biopsy or aspirate histology (AFB or granuloma), and genXpert MTB/Ris Assay (on sputum, urine or biopsy) Tests for LTBI:
1. Tuberculin skin test (TST): unreliable in advanced CKD/immunosuppressive patients
2. IGRA test (TSPOT.TB or QuantiFeron): more sensitive and specific for diagnosing LTBI Imaging:chest x ray, renal ultrasound, MRI or CT scan (where indicated), and PET/CT scan (where indicated)
This patient had successful treatment of TB but the risk of infection is still high, so to decrease the risk of infection:
1. Avoid aggressive induction therapy with ATG
2. Avoid contact with TB patients
3. TB prophylaxis
4. Low threshold of suspicion of the infection
5. Contact the transplant team if developed fever, cough or night sweating
In case of TB therapy tries to give rifampicin-free regimen (interaction)
What is your induction immunosuppression?This patient with living related donor, 111 mismatch, no DSA, negative crossmatch is low immunological risk. Induction therapy with steroids and basiliximab
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
No, I will proceed with the same management with monitoring of DSA. Patient with DSA but negative FCXM is a low risk of AMR. DSA (A2 with MFI 1500) is a weak positive and most centers use 3000 MFI as a cut off for significant DSAs
References
1. Santoro-Lopes, Guilherme, Subramanian, Aruna, Molina, Israel, Aguado, José María, Rabagliatti, Ricardo, Len, Osca. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation 102(2S):p S60-S65, February 2018.
2. Sundaram M, Adhikary SD, John GT, Kekre NS. Tuberculosis in renal transplant recipients. Indian J Urol. 2008 Jul;24(3):396-400. doi: 10.4103/0970-1591.42625. PMID: 19468476; PMCID: PMC2684355.
Dear All The recipient had successful treatment for TB Also, his DSA is below the threshold of positive crossmatch (negative crossmatch). Will you give him aggressive induction that may cause flair of TB if there is a chance of latent TB?
The presence of DSA is one criteria of high inmunologic risk transplantation, 2 options are avilable for induction, ATG or basiliximab with preferance of ATG
But in the current sensrio, we can give basiliximab induction with close follow up of the DSA titer post transplantation
What is your induction immunosuppression?
Living related (brother) donor, 111 mismatch, negative cross match, and No DSA- very low immunological risk. I would not give an induction therapy but IV methylprednisolone, or use induction with basiliximab.
This would also minimize the risk of TB reactivation.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
In this case living related donor (brother) with 111 mismatch, negative crossmatch, but DSA (A2 with MFI 1500), still with negative cross match and low A2 titer DSA < 3000. It is low risk to have ABMR. I would consider induction with basiliximab and iv methylprednisolone.
Given the history of TB and the risk of reactivation, as the FCXM is negative and DSA is low basilliximab is preferred with close monitoring of DSA level.
This is probably low immunologic risk; first transplant, we are not given history of sensitization, no DSA, negative FCMXM & had past history of TB. Therefore, my induction would be the form of IV methyl prednisone, and basiliximab
provided the past history of TB which may may be latent and tend to reactivate in the post-transplant period as a sequelae of intense immunosuppression.
the patient is not highly sensitized to consider aggressive induction therapy.
this patient still can go with basiliximab induction followed by triple maintenance immunosuppression taking into consideration his primary disease IgA nephropathy
with close monitoring after transplnation with DSA level and protienuria
No .This patient MFI is 1500 which is considered weak so I will proceed for transplantation with the Basiliximab and IV methyleprednisolone induction and follow the DSA level .
In general, all transplant recipients and donors should be evaluated for the presence of latent TB, by careful evaluation of the risk, history, examination and CXR, together with test for latent TB
Recipients with latent TB are at high risk of conversion to active TB after transplantation
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 (1)
In low risk transplant recipients with ESRD, it is it is preferred to use IGRA over TST due to its higher sensitivity in these sets of patients (2), while in high risk transplant recipients (patient who are living in country with high TB prevalence , contacts of active TB infection, and those who work or live in correctional facilities or homeless shelters), it is better to do both tests to maximize sensitivity, at that time IGRA should be done either at the same time of before TST to avoid TST-mediated IGRA response.
Diagnosis of latent TB in the recipient is settled if :
One of the following is present
History of pervious TB
History of positive TST
Positive TST (> 5mm in recipient) or a positive IGRA
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
And all of the followings are fulfilled
Patient has no symptoms of active TB
CXR should be normal
No evidence of exra-pulmonary TB
So in the current patient there is no need to do the test and I have to consider the diagnosis based on the previous history of TB if there are no symptoms, CXR is normal and no evidence of extrapulmonary TB
If radiology is suspicious for TB (apical fibronodular lesions, calcified solitary nodule, calcified lymph nodes, or pleural thickening) thorough evaluation including microbiological assessment is indicated to exclude TB as a cause
If TB diagnosed in the recipient transplantation should be delayed till complete treatment of TB
Protocol for treatment of latent TB
INH in a dose of 5 mg/kg (maximum dose 300 mg) together with oral pyridoxine 50 mg daily for 9 months
Rifampin in a dose of 600 mg for 4 months
INH + rifampin for 3 months
INH+ weekly rifapentine for 3 months
Ideally, regimen for recipient should be started before transplantation if the donor can wait as for the current case, but if transplantation cannot be postponed, at that time treatment can be given after transplantation.
Rifampicin containing regimen is preferred in patients unlikely to be transplanted within the next 4-6 months due to drug-drug interactions with CNI
Patient should be monitored for liver enzymes and bilirubin at baseline, every 2 weeks for 6 weeks then monthly, if there is 3 fold rises of liver enzymes with symptoms or 5 fold rise without symptoms, INH should be stopped
Any special consideration post-transplantation?
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
Reactivation of latent TB is common if no treatment given and around 95% of cases occur at 1 mouth to 1 year after transplantation (3).
High index of suspicion should be present in interpretation of any symptoms the recipient suffer, putting in mind that the presentation differ from immunocompetent patients in the following
Atypical presentation is more common (pyomyositis, , tenosynovitis , skin ulcers or abscess)
Around 30-50% of cases presents with extra pulmonary or disseminated TB (much higher than immunocompetent hosts) (4).
Tuberculin test and IGRA are usually negative
Sputum smear for TB is usually negative despite active TB (5).
Less than 5% of transplant patients have the classic cavitary changes seen in immunocompetent patients , on the other hand focal infiltrate is seen in 40%, military pattern in 22%, nodyules in 15%, pleural effusion in 13%, and diffuse interstitial infiltrates in 5%
So … if the transplant recipient presents with any skin or pulmonary lesions, unexplained fevers, night sweats, and weight loss the diagnosis of TB should be suspected
To reach diagnosis invasive procedure is usually required including bronchoscopy and BAL or lung biopsy, and any specimen collected (sputum, abscess fluid, lung tissue) should be stained and cultured for AFP, tested for PCR (rapid diagnosis) together with with histopathological examination of tissue taken if available
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
Nephrotoxicity and other side effects related to the use of anti –TB medications
So … post transplantation, high index of suspicion is needed, avoid intensification of immunosuppression and treatment of latent TB should be given before and if not after transplantation (rifampicin free regimen).
What is your induction immunosuppression?
I will use basiliximab induction since this is low risk transplantation
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
Risk factors for reactivation of TB are multiple, the most important are
The presence of latent TB before transplantation.
Use of aggressive immunosuppressive therapy
Acute rejection (increase the risk of TB 7.6 times) and chronic allograft dysfunction
And once TB develop there are the following risks
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
The presence of DSA increases the risk of transplantation and makes the patient of high immunologic risk, which requires induction with ATG, and increase the risk of rejection post transplantation.
So I will recommend paired kidney exchange in order to have a more compatible donor, but if not available I will transplant the patient after education of the risk of active TB and also high index of suspicion is needed, and treatment of latent TB should be given before and if not after transplantation (rifampicin free regimen).
References
1. Pai M, Denkinger CM, Kik SV, et al. Gamma interferon release assays for detection of Mycobacterium tuberculosis infection. Clin Microbiol Rev 2014; 27:3.
2. Subramanian AK. Tuberculosis in solid organ transplant candidates and recipients: current and future challenges. Curr Opin Infect Dis 2014; 27:316.
3. Torre-Cisneros J, Doblas A, Aguado JM, et al. Tuberculosis after solid-organ transplant: incidence, risk factors, and clinical characteristics in the RESITRA (Spanish Network of Infection in Transplantation) cohort. Clin Infect Dis 2009; 48:1657.
4. Fiske CT, Griffin MR, Erin H, et al. Black race, sex, and extrapulmonary tuberculosis risk: an observational study. BMC Infect Dis 2010; 10:16.
5. Subramanian AK, Theodoropoulos NM, Infectious Diseases Community of Practice of the American Society of Transplantation. Mycobacterium tuberculosis infections in solid organ transplantation: Guidelines from the infectious diseases community of practice of the American Society of Transplantation. Clin Transplant 2019; 33:e13513.
The recipient had successful treatment for TB Also, his DSA is below the threshold of positive crossmatch (negative crossmatch). Will you give him aggressive induction that may cause flair of TB if there is a chance of latent TB?
A 46-year-old CKD 5 on HD for the last 5 years due to IgA nephropathy has a kidney offer from his brother, 111 mismatch, no DSAs. The potential recipient has a history of TB during childhood, which was treated successfully. FCXM is negative.
Any special consideration post-transplantation? The patient risk of having latent TB are: 5 years on HD, immunosuppression to be used post transplantation, previous TB infection. I assume that the patient would has been fully evaluated for latent TB, by doing chest imaging, IGRA, and sputum cultures. (before the transplantation). If it was clear, then would not keep him on anti TB medication and proceed with transplant as soon. If latent TB is positive, then I would recommend treatment for 9 months before the transplant. After transplantation, there is increased risk of TB reactivation, and getting infection from an affected people if he is living in an endemic area, education and preventive measures to be taken, and the patient should be aware of any new respiratory or fever night sweets and weight loss, and to be in close contact with the transplant physician. If after transplantation Latent TB is diagnosed then treatment should be started with concern of drug drug interactions, and side effects.
What is your induction immunosuppression? Living related (brother) donor, 111 mismatch, negative cross match, and No DSA- very low immunological risk. I would not give an induction therapy but IV methylprednisolone, or use induction with basiliximab. This would also minimize the risk of TB reactivation.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan? In this case living related donor (brother) with 111 mismatch, negative crossmatch, but DSA (A2 with MFI 1500), still with negative cross match and low A2 titer DSA < 3000. It is low risk to have ABMR. I would consider induction with basiliximab and iv methylprednisolone.
References: (1) José María Aguado, Julián Torre-Cisneros, Jesús Fortún, Natividad Benito, Yolanda Meije, Antonio Doblas, Patricia Muñoz, David R. Snydman, Tuberculosis in Solid-Organ Transplant Recipients: Consensus Statement of the Group for the Study of Infection in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology, Clinical Infectious Diseases, Volume 48, Issue 9, 1 May 2009, Pages 1276–1284, https://doi.org/10.1086/597590. (2) Adebiyi OO, Gralla J, Klem P, et al. Clinical Significance of Pretransplant Donor-Specific Antibodies in the Setting of Negative Cell-Based Flow Cytometry Crossmatching in Kidney Transplant Recipients. Am J Transplant. 2016;16(12):3458-3467. doi:10.1111/ajt.13848.
Any special consideration post-transplantation?
close monitoring of urine analysis and Alb/creatinine. CXR. close monitoring of any symptoms of fever of unknown origin, night sweats, and loss of weight. IGRA.
IgA-GN is a common disease in most countries, accounting for a relatively high proportion of end-stage renal failure.
Recurrence rates are high, especially if sought in renal biopsies after transplantation using specific identification of IgA deposits in the glomeruli.
IgA is thus among the most common recurrent diseases but is generally slow to cause renal impairment and graft loss.It is more common after living-related donor grafts, but recurrence does not seem to affect early or medium-term graft survival, though the use of steroid-free regimens may increase recurrence rates.
The assessment of the family donor, however, needs to include consideration of the possibility that IgA may be a familial disease and thus also affect the potential donor.
What is your induction immunosuppression?
Induction :Basiliximab
Maintenance: Tacrolimus, MMF, and prednisolone(avoid steroid-free regimen)
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
Pretransplant DSA in the presence of a negative FCXM does not need desensitization treatment, and should not constitute a barrier to renal transplantation.
the same treatment with close observation of DSA post-transplantation.
Some centers proceed with the protocol biopsy.
Clayton P, McDonald S, Chadban S. Steroids and recurrent IgA nephropathy after kidney transplantation. Am J Transplant 2011;11(8):1645–9.
One study found that differences in graft survival were dependent upon identifying the presence of DSA (MFI > 1500) but not upon the actual level of MFI. Failure to discern differences between these groups of patients may reflect the technical limitations of the assay, (with MFI values themselves being a poor predictor of the amount and strength of antibodies.
Although the A2 antigen is not strongly immunological,
Still, the patient is at risk for rejection in comparison to a negative DSA.
Explain the image findingMRI shows two round lesions with central low intensity, surrounding enhancement (ring) and edema. The left ventricular is compressed.
What is the difference between T1 and T2-weighted images? T1-weighted images
are produced by using short TE and TR times.
It inhances the signal of the fatty tissue
It suppresses the signal of the water
T2-weighted images are produced by using longer TE and TR times.
It enhances the signal of the water
In general, T1- and T2-weighted images can be easily differentiated by looking the CSF.
CSF is dark on T1-weighted imaging and bright on T2-weighted imaging
about this case
MRI
T1: iso- to hypointense to cortexT1 C+ (Gd): vivid contrast enhancementT2variablemajority are iso to hypointensehyperintense is more common when necrosis is presentsurrounding vasogenic edemaWhat is your differential diagnosis?
●PTLD
●Tuberculoma
●Abscess (bacterial- fungus)
●Brain toxaplasmosis
●Criptococosis
●Neurosarcoid
●Metastasis
How would manage this case?
□We should ask about the EBV test in donor and recipient before transplantation
□Also the TB evaluation in donor and recipient before transplantation
A- Primary CNS PTLD is uncommon and the diagnosis and treatment are difficult
□The diagnosis should be suspected in transplant recipients with mental status changes or new neurologic findings.
□Diagnostic tests include (MRI) of the head;
□analysis of (CSF) by cytology, flow cytometry, and for EBV genes by (PCR);
□ PCR (EBV) clear positive
□Sometimes, the diagnosis should be confirmed either by the presence of malignant lymphocytes in the CSF or by direct biopsy of the lesion
□Neurologist consultation for controlling seizures
□CBC – LDH – UA- CA
□CXR – CT (chest- abdomin)
□ the best management iniate with the reduction of immunosuppression agents with close monitoring (clinically and laboratory ) for rejection.
□Rituximab (anti CD20) is the treatment of choice for PTLD
□chemotherapy in addition to Rituximab, cyclophosphamide- doxorubicin- vincristine- prednisolone
□radiation therapy
□ Adoptive immunotherapy — Adoptive immunotherapy uses EBV-specific cytotoxic T lymphocytes (EBV-CTLs) or donor lymphocyte infusion (DLI) in an attempt to kill dividing B cells in EBV-associated PTLD.
This therapy needs more evidence.
B- The wide spectrum antibiotics and anti fungal treatment may consider if the diagnosis is not clear
C- evaluation of tuberculosis is essential notably when the recipient or donor has been treated previously. In addition to the recipient in endemic regions or patient with HIV
♡CXR – CT chest
♤IGRA- BAL sputum samples
♡CSF examination and culture- blood culture.
♤Depending an the BTS RECOMMENDATIONS
Rifampicin can interact with IS regimens, Increasing the chance ofgraft rejection, and doses of MMF, TAC and ciclosporin may need adjustment. Corticosteroid doses should be doubled in patients receiving rifampicin. (B)
♤the treatment consists of 4 drugs for two months then 2 drugs for two months
REFERENCES
1- Central nervous system tuberculosis (UpToDate)
2- Prevention and treatment of Post-transplant lymphoproliferative disorders (UpToDate)
3- Intracranial tuberculous granuloma.Last revised by Travis Fahrenhorst-Jones on 21 Aug 2022
4- phoproliferative disorder. Last revised by Frank Gaillard on 15 Mar 2023
Any special consideration post-transplantation?
TST or IGRA tests could be performed and any positive reaction considered an evidence of LTBI. Criteria to Start Treatment.
LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated.
Those with history of active TB infection that was inadequately treated.
Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB.
-we should exclude active and LTBI in donor and recipient and if they clear can proceed for transplantation. What is your induction immunosuppression?
Living related with low immunological risk with 111 mismatch, no DSAs.
Induction therapy by steroid and basiliximab with tacrolimus based therapy . Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
Pretransplant DSA in the setting of a negative FCXM confers minimal immunologic risk in the intermediate term, does not necessitate desensitization therapy and should not represent a barrier to renal transplant (2).
DSA A2 with low MFI 1500 .
I will proceed with the same induction therapy with DSA monitoring. References:
1- Santoro-Lopes G, Subramanian AK, Molina I, Aguado JM, Rabagliatti R, Len O. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation. 2018;102(2S Suppl 2):S60-S65. doi:10.1097/TP.0000000000002014
2- Adebiyi OO, Gralla J, Klem P, et al. Clinical Significance of Pretransplant Donor-Specific Antibodies in the Setting of Negative Cell-Based Flow Cytometry Crossmatching in Kidney Transplant Recipients. Am J Transplant. 2016;16(12):3458-3467. doi:10.1111/ajt.13848
1.Any special consideration post-transplantation?-Two key issues in this case;
Recipient had previous history of TB: after transplantation and with immune-suppression he may be at risk of reactivation or even de novo TB infection. We to counsel him and discuss these facts. He need to be given TB prophylaxis in form of INH for a period of 9 months and advised to inform the transplant team as early as possible should he developed any unusual symptoms such as cough fever, weight loss, night sweats
IgA nephropathy: counseling about this disease is also important as it may recur in up to 30% of patients. Risk factors for recurrence are pre-transplant high levels of galactose-deficient IgA1,steroid-free regimen, earlier age of disease onset, and cresentic IgA nephropathy. However, allograft loss is low in the range of 3 to 4%
2.What is your induction immuno suppression
This is probably low immunologic risk; first transplant, we are not given history of sensitization, no DSA, negative FCMXM & had past history of TB. Therefore, my induction would be the form of IV methyl prednisone, and basiliximab
3.Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
Pre-transplant DSA is important, mostly type and may be associated with early ABMR and therefore posttransplant monitoring is essential
DSA may wave & wane
According UNOS the cut off is MFI > 3000 but there is a lot of variation between laboratories and many laboratories may have a different cut off
The presence of DSA alone should not preclude the transplant process
The management will not change and I will just add DSA monitoring for the plan
Yes the same management, monitor, wait and see
Source
Pocket nephrology by Wooin Ahin & Jai Radhakarishnan
Pre-transplant assessment: and exclusion of active tuberculosis is first step in management of post-transplant tuberculosis, which includes testing with TST and IGTB.
When pre-transplant tests are negative for both donor and recipients, kidney transplantation can be performed safely. However, keeping high index of suspicion in the follow up of patients post transplantation is crucial, with monitoring of clinical features for active renal tuberculosis such as pyuria, hematuria and perinephric collection by US exam. Risk of recurrence is maximum in the first 9 months post transplantation. Induction Immune suppression:
Owing to high HLA mismatch of III [ high immunologic risk], I would advocate ATG induction, which is a polyclonal antibody targeting T lymphocytes. Dosing is 1.5 mg/kg for 4-7 days with accumulative dose of 6-10 mg /kg, with first dose given prior to transplantation. Alternatively, Alemtuzumab can be administered. If DSAs is of :1500 MFI: It is considered weak positive, as most of the centers recognized DSAs of more than 3000 MFI as the cut off for significant DSAs. As a general role level of DSAs is not correlated with its significance to a certain extent .
#Any special consideration post transplantation?
*The incidence rate of TB markedly increases after solid organ transplantation (SOT), Reactivation of foci of latent TB infection (LTBI) is probably the main cause of posttransplant TB.
*Most of these cases were documented in patients who received a grant from a deceased donor with active TB infection, a situation that has been associated with a risk of transmission of approximately 30%.
*There is no diagnostic reference standard for f latent TB infection (LTBI). The tuberculin skin test (TST) remains the best studied test and, therefore, most current guidelines still recommend its use for the screening of LTBI in solid organ candidates/recipients and living donors. IFN-γ release assays (IGRAs) have emerged as new diagnostic tools in the last decade.
*Radiological work up
*The diagnosis of active TB infection relies on the detection of M. tuberculosis bacilli by direct observation, by culture, and nucleic acid testing, the availability of a rapid molecular test, such as the Xpert MTB/RIF assay, may have a major impact in the management of these patients[1].
#What is your induction immuneosuppression?
This patient with history of previous TB and immunologically showed negative DSA and FCXM, not need heavy induction therapy, so the patient can proceed with IL2-receptor antagonist (Basiliximab).
#Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
No, I will proceed with the same plan because it is a low level of DSA (weak to low level with phenotype panel MFI values from 1000 to 3000), however regular follow up for the DSA level Luminex-based SPIs and FCXM tests. is important[2].
[1] Guilherme Santoro-Lopes, Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors, Transplantation, February 2018, Volume 102, Number 2S-2
[2] Gladstone DE, Bettinotti MP. HLA donor-specific antibodies in allogeneic hematopoietic stem cell transplantation: challenges and opportunities. Hematology Am Soc Hematol Educ Program. 2017 Dec 8;2017(1):645-650. doi: 10.1182/asheducation-2017.1.645. PMID: 29222316; PMCID: PMC6142580.
> recipient has low immunological risk. Induction therapy with basiliximab with close monitoring of DSA.
>no change of management plan.
Any special consideration post-transplantation?
The recipient and the donor both have to be screened using IGRA for latent TB and fully treated before proceeding to transplantation because immuno-suppression can cause flare of the dormant mycobacteria
What is your induction immunosuppression?
Basiliximab is enough for induction in this transplant pair with low immunological risk
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
MFI of 1500 will not change the management plan
References
Krishnamoorthy S, Kumaresan N, Zumla A. Latent tuberculosis infection and renal transplantation – Diagnosis and management. Int J Infect Dis. 2019 Mar;80S:S73-S76. doi: 10.1016/j.ijid.2019.01.049. Epub 2019 Feb 6. PMID: 30738187.
Abad CLR, Razonable RR. Donor derived Mycobacterium tuberculosis infection after solid-organ transplantation: A comprehensive review. Transpl Infect Dis. 2018 Oct;20(5):e12971. doi: 10.1111/tid.12971. Epub 2018 Aug 12. PMID: 30055041.
Sorohan BM, Ismail G, Tacu D, Obrișcă B, Ciolan G, Gîngu C, Sinescu I, Baston C. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens. 2022 Sep 13;11(9):1041. doi: 10.3390/pathogens11091041. PMID: 36145473; PMCID: PMC9505385.
I will go for Basiliximab (no DSA)
and id DSA with 1500 MFI >Basiliximab also
Any special consideration post-transplantation?
· post-kidney transplantation TB is associated with high morbidity and mortality and can cause graft loss in 1/3 of cases. The reactivation of latent TB infection is probably the main cause of post-transplant TB.
· This recipient had a history of successful treatment of TB at childhood. However, he is at risk of having latent TB. Therefore, we need to ask about history of recent contact and perform both Tuberculin skin test and Interferon Gamma release assay(IGRA) to maximize the sensitivity of the screening. Any positive results should be considered evidence of LTBI and requires treatment. However, if the patient has symptoms of pulmonary or extra-pulmonary features of active TB, perform a chest X ray, sputum for Xpert, culture and AFB stain(recipient transplantation should be delayed till complete treatment of TB is done).
· It is preferred to start treatment for latent TB prior to transplantation a immunosuppression can result in TB flare. Treatment is with oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily(Better to avoid rifampicin post-transplant for its interaction with immunosuppression.).
· Moreover, the recipient should be counseled about the risks of primary GN recurrence(IgA) which may be clinical or histologic recurrence(around 30%) and need post-transplant monitoring of proteinuria, hematuria and graft functions
· What is your induction immunosuppression?
Avoid ATG that can cause TB flare and use Basiliximab during induction therapy(low immunogenic risk). Maintenance therapy with triple immunosuppression(still there is risk of recurrence of primary GN
· Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
· DSA is low and FCXM is negative. Therefore, we can still go with the same induction IS( Basiliximab) followed by triple maintenance therapy with close monitoring of DSA level.
References
1.José María Aguado, Julián Torre-Cisneros, Jesús Fortún, Natividad Benito, Yolanda Meije, Antonio Doblas, Patricia Muñoz, David R. Snydman, Tuberculosis in Solid-Organ Transplant Recipients: Consensus Statement of the Group for the Study of Infection in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology, Clinical Infectious Diseases, Volume 48, Issue 9, 1 May 2009, Pages 1276–1284.
2. Santoro-Lopes G, Subramanian AK, Molina I, Aguado JM, Rabagliatti R, Len O. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation. 2018 Feb;102(2S Suppl 2):S60-S65.
. Any special consideration post-transplantation?
To exclude active tuberculosis with sputum AFB and chest x ray.
To exclude Latent TBI by IGRA or Tuberculin skin test.
If present – ATT 3months before transplant, as live related transplant can wait.
Post transplant 6months INH-prophylaxis (+/- Moxifloxacin, if active TB+)
2. What is your induction immunosuppression?
HLA haplo-match with negative FCXM and no DSA – confers low immunological risk.
Either Induction with IL2RA (Basiliximab) or even no induction (just methyl-prednisone) should be adequate. Triple maintenance immunosuppression (TAC, MMF and steroids) regimen could be kept on higher level for 6months.
3. Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
DSA positive, but low titre (1500) and thus FCXM negative – so, doesn’t require to change IS regimen.
Need to follow DSA titre, RFT, Urine protein post transplantation – early biopsy on rising creatinine, proteinuria or high DSA – in such events, ABMR treatment may be required.
Dear All
The recipient had successful treatment for TB
Also, his DSA is below the threshold of positive crossmatch (negative crossmatch). Will you give him aggressive induction that may cause flair of TB if there is a chance of latent TB?
Reply to Prof Ahmed Halawa
No
Infact, many large volume centres in India, never use induction for close related family live donors – just methyl prednisone is OK, or at best Basiliximab may be used.
DSA 1500 MFI, is on lower side to cause to cause positive X match in vitro. But it can still excite immune response through memory B cells.
In African patients, we had ABMR and graft loss in couple of cases with DSA 1200-1500.
In view of this, some immuno-patho-lab recommend cut off 750MFI, for DSA to be positive.
Our current practice in such cases, is to use IVIg 10gm (to bind existing DSA or nonspecific antibodies in plasma) in such cases; 1 plasma exchange + 5gm IVIg is safer alternative, to prevent accelerated ABMR.
Q1: This patient is at risk of reactivation of TB after TX due to immunosuppression therapy. In addition, his brother should be screen for LTBI carefully. So, the choice of immunosuppression should be done carefully.
Q2: Induction therapy with basiliximab and methylprednisolone pulse and then triple maintenance therapy is logical.
Q3: If the recipient has low level DSA with negative FCXM, there is no need to change induction therapy and basiliximab will be enough.
· Any special consideration post-transplantation?
Recipient has history of TB, igA nephropathy, so monitoring for flare of TB, and avoidance of aggressive immunosuppression as much possible.
· What is your induction immunosuppression?
Basiliximab induction is the drug of choice.
· Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
DSA of 1500, is not very high, below threshold for high sensitivity so need to change plan of induction, specially the recipient has history of TB before.
induction with IL2 recepter basileximab as the DSA below the threshold of positive crossmatch, with close monitoring
· Any special consideration post-transplantation?
Recipient had successful treatment for TB in childhood, with immunosuppression after TX there is risk of reactivation of latent TB infection,candidates should undergo evaluation for LTBI with either TST or IGRA.
If TST is selected as the screening test, an induration of 5 mm or greater at 48 to 72 hours should be considered a positive reaction,a second TST should be performed 7 to 10 days after the first TST to evaluate a boosted-related skin conversion.
IFN-γ release assays (IGRAs) offer some advantages as compared with TST: avoid interpreting bias, reduce false-positive results related to previous exposure to nontuberculous mycobacteria or BCG vaccination, and are probably more sensitive in candidates with chronic renal failure
both tests could be performed and any positive reaction considered an evidence of LTBI.
Living donors should undergo the same evaluation as candidates, with the exception that the cutoff for TST should be 10 mm or greater.
LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated
-patients at high-risk pretransplant TB exposure should be considered for therapy even if the TST or IGRA is not positive, patients with history of active TB infection that was inadequately treated also should receive ttt.
– Chest imaging suggestive of previous untreated TB should receive therapy, especially in areas where endemic mycoses are uncommon.
-Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
For treatment of LTBI, oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily, patient should be monitored for hepatotoxicity ALT checked every 2 weeks for 6 weeks, then monthly thereafter.
What is your induction immunosuppression
Potential recipient with a living related donor, 111 miss-match, no DSA, FCXM is negative, history of TB that was successfully treated early in childhood. Induction therapy with basiliximab.
ATG is not preferred in this scenario as it may cause flare of latent TB infection.
· Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
No I will not change the plan, I will proceed with the same management with monitoring of DSA post transplantation especially if reduction of IS was planned at any time and I plan also for protocol biopsy.
DSA (A2 with MFI 1500) is below the cutoff of most centers which range from 2000-3000 and not sufficient to cause positive crossmatch .
Santoro-Lopes, Guilherme MD, PhD1,2; Subramanian, Aruna K. MD3; Molina, Israel MD4,5; Aguado, José María MD, PhD6; Rabagliatti, Ricardo MD, PhD7; Len, Oscar MD, PhD8. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation 102(2S):p S60-S65, February 2018.
· Any special consideration post-transplantation? In the post-transplantation period, some monitoring strategy should be created for the development of Tuberculosis in this patient. We have no evidence, but perhaps the serial use of a skin test for tuberculosis or IGRA, associated with screnning with imaging tests in all cases of persistent fever, especially in cases of respiratory symptoms.
· What is your induction immunosuppression? Low-risk patient would undergo induction with corticosteroid (methylprednisolone) and basiliximab. · Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
A low amount of DAS would not lead me to change the immunosuppression plan.
Any special consideration post-transplantation?
Regular TB screening, Chest CT Scan and abdomen pelvic ultrasound
What is your induction immunosuppression?
Immunosuppression induction with Basiliximab followed by immunosuppression with MMF, Tacrolimus and steroid.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
No, the management will remain same.
the potential recipient has had childhood history of TB which was treated and now is considered for renal transplant with donor as his brother…The recipient needs to be evaluated for latent TB before transplantation…TB could ger reactivated after transplant especially if the recipient has latent TB before transplant…there is no evidence of active TB in the recipient… Latent TB treatment is indicated if anyone of the following – positive TST or IGRA test, history of untreated TB, history of recent contact with an active TB patient, donor with untreated latent TB…in the kidney transplant setting ideal treatment will be isoniazid 5mg/kg/day with vit b6 for 9 months…. The treatment has to be given ideally pre transplant, but there are recommendations to start the treatment atleast 1 month before and continue it later in the post transplant period…3 – 4 months of rifamipicin and isoniazid…weekly rifapentine plus isoniazid are the other regimens tried in general populations..But renal transplant recipients have high chance of interaction with other immunosuppressive medications…
So this patient, I would rule out LTBI by mantoux or IGRA..If positive with no signs of active infection,I wil give INH prophylaxsis for LTBI…This is important as there should be no post transplant flare of TB…
Induction agent – I would prefer Basiliximab induction as ATG is not indicated as there is no DSA and this is a well matched transplant with no previous sensitization…
Even if the MFI 1500 to A2, which is low levels, I will go with basiliximab induction and monitor the serial DSA levels to decide on further action post transplant
Two issues must be clarified
First his primary cause of ESRD which is IgAN and the risk of coming back after transplantation, So monitoring of graft function and urinalysis for hematuria and proteinuria is of importance.
Second , as he had history of treated TB during childhood, there is chance of TB flare up after transplantation , so we should search for the presence of active or latent TB by taking good history and doing CXR, sputum for ZNS for AFB , culture and gene Xpert , CT chest ,abdomen and pelvis. If all negative so go for IGRA and TST if positive mean latent TB . And treat according to the results.
As the patient has low immunological risk with the history of treated TB , so induction with Basiliximab will be enough in edition to the triple IS as maintenance,with regular DSA and graft function monitoring.
No, the same induction choice , basiliximab , as the DSA level of 1500 is not high.
Any special consideration post-transplantation?
Recipients has history of prior treatment for active TB with resolution and has been on HD for 5 years.
We must to rule out latent TB in this recipient.
We need to do IGRA which is more sensitive .
Tuberculin skin test can also be done however there can be false positive results due to prior BCG immunisation.
If the patient has latent TB then it is crucial to rule out active TB with CXR, sputum for ZN staining and Gene Xpert test.
If we establish latent TB, treatment should be started and completed before transplantation, but in case of urgent transplantation then treatment can be initiated post-transplant.
Treatment is either 3 months of rifampin and isoniazid or 6-9 months of isoniazid. Caution should be taken due to drug interactions with rifampin, rifabutin/rifapentine can be used instead.
What is your induction immunosuppression?
This patient has low immunological risk hence induction would be with basiliximab.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
No I will continue and monitoring the DSA.
References
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
Guilherme Santoro-Lopes, MD, PhD,1,2 Aruna K. Subramanian, MD,3 Israel Molina, MD,4,5José María Aguado, MD, PhD,6 Ricardo Rabagliatti, MD, PhD,7 and Oscar Len, MD, PhD8
Adebiyi OO, Gralla J, Klem P, Freed B, Davis S, Wiseman AC, Cooper JE. Clinical Significance of Pretransplant Donor-Specific Antibodies in the Setting of Negative Cell-Based Flow Cytometry Crossmatching in Kidney Transplant Recipients. Am J Transplant. 2016 Dec;16(12):3458-3467. doi: 10.1111/ajt.13848. Epub 2016 Jun 15. PMID: 27140940.
Post-transplantation concerns?
TB history: This patient was successfully treated with TB, so immunosuppression following kidney transplantation may reactivate it.
The recipient had childhood treated TB (IGRA/TST for R/O LTBI), and any positive results should be deemed LTBI.
CXR, sputum for Xpert, culture, and AFB stain should screen his brother for LTBI or active TBI.
After excluding active TB, latent TB should be treated.
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 latent TB without chemoprophylaxis, untreated TB, or active TB require TB treatment.
Isoniazid 5 mg/kg/day (maximum 300 mg/day) for 9 months plus vitamin B6 is the best treatment for latent TB in KT.
LTBI treatment should begin before transplant and be finished while on the waiting list.
If an urgent transplant is needed, treatment can be paused perioperatively and resumed when medically possible to finish the course.
Avoid rifampicin post-transplant because it interacts with immunosuppressants.
Counsel the patient regarding the chance of recurrence of his main GN, which has ranged from 21 to 58%.
Hematuria, proteinuria, and increasing creatinine may occur.
-Graft function monitoring; urine analysis for proteinuria or hematuria.
2: What’s your induction immunosuppression?
low immunological risk and DSA titer in this case.
IL-2 receptor antagonist (Basiliximab) induction, triple maintenance immunosuppression, and DSA and proteinuria monitoring after transplantation
3-DSA (A2 with MFI 1500). Would this affect management?
This DSA level is low with negative FCXM; thus, the management plan will be the same: induction with basiliximab on D0 and D4, followed by triple I.S. as maintenance therapy.
-Close DSA level monitoring at 3 and 12 months.
What is your induction immunosuppression?This patient is considered as low immunological rsik with no DSA and mismatch of 111 so will proceed with simplest (BASILIXIMAB ).
In such patient with previous history of TB in the donor we need to consider that in the selection of the induction therapy ,even if the reciepient has DSA with MFI of 1500 it dosenot mean to be agressive iin our induction therapy ,but we need to have close observation for DSA level .
There are 2 issues which needs to be considered post transplantation-first is rhe recurrence of IgA Nephropathy and second is risk of reactivation of Tuberculosis as patient has been treated for T.B in childhood.For IgA nephropathy-close monitoring of graft function and proteinuria should be done and imaging like xray Chest followed by CT scan Chest ,Abdomen and pelvis,urine and sputum samples for afb and also for genexpert -rif resistance to rule out active infection as chances quite high after immunosuppression ..If no evidence of infection ,then whether treatment for latent tb needed or not can be considered if TST or IGRA assays are positive. Treatment regimens will b according to WHO guidelines.
The above recipient falls into low immunological risk as has no DSA,negative FCXM and 111 mismatch ,so no need to go for induction with ATG and basiliximab (IL-2 inhibitor )will be enough with triple based immunosuppression as maintenance therapy.However,if the above patient has DSA with A2 MFI 1500,still induction will be the same and needs close monitoring of DSA.
REFERENCE:
Sorohan BM, Ismail G, Tacu D, Obrișcă B, Ciolan G, Gîngu C, Sinescu I, Baston C. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens. 2022 Sep 13;11(9):1041.
Hand book of kidney transplanatation Nephrology and Hypertension .
3. A 46-year-old CKD 5 on HD for the last 5 years due to IgA nephropathy has a kidney offer from his brother, 111 mismatch, no DSAs. The potential recipient has a history of TB during childhood, which was treated successfully. FCXM is negative.
Issues/ concerns
– 46yo man, CKD5 due to IgA nephropathy, on HD for 5 years, hx of TB in childhood
– potential donor brother, 111 mismatch, no DSAs, FCXM negative
Any special consideration post-transplantation? (1-3)
– the risk of infection is high, this is determined by the patient’s epidemiologic exposure and the net state of immunosuppression
– determine the patient’s immunization history and risk of exposure
– screen for LTBI using TST, IGRA
– if IGRA is positive, evaluate for active TB, if positive treat for active TB, if negative treat for LTBI
– if IGRA is negative, consider the risk of LTBI and the risk of TB exposure, if high treat for LTBI, if low no further evaluation or treatment is required
– TST can also be done, if positive, evaluate for TB and manage accordingly
– if TST is negative, repeat in 2 weeks to evaluate for booster effect, if positive screen for active TB
– if TST remains negative after the two weeks, evaluate for risk of LTBI exposure, if high treat fr LTBI
Indications for treatment for LTBI (4)
· TST (initial or boosted) with induration ≥5mm and/ or a positive IGRA
· history of untreated latent TB
· history of contact with an active TB case
· receipt of an organ from a TST positive donor not treated for LTBI
– treat for LTBI in patients with high risk for primary TB even if TST and IGRA are negative
– for those with 2 indeterminate IGRAs, decision to treat LTBI depends on the patient’s characteristics i.e., consider presence of signs of prior infection (e.g., granulomas on chest imaging), history of contact with a positive case, other history of probable exposure, risk of drug toxicities
– LTBI treatment options: –
· rifampin daily for 4 months
· rifapentine plus isoniazid weekly for 12 weeks
· isoniazid plus rifampin for 3 months
· isoniazid daily for 6 months
– monitor LFTs in patients on isoniazid
What is your induction immunosuppression? (1)
– the recipient has a low immunologic risk – LRKT, no DSA, negative FCXM, 111 mismatch
– KDIGO (2009) recommends use of IL-2Ras i.e., basiliximab as first-line induction therapy in patients not at high immunologic risk
– in addition to IV methylprednisone
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan? (1)
– no, I would still maintain the same induction and maintenance regimen
– monitor DSA as well
References
1. KDIGO clinical practice guideline for the care of kidney transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009 Nov;9 Suppl 3:S1-155. PubMed PMID: 19845597. Epub 2009/10/23. eng.
2. Fishman JA. Infection in Organ Transplantation. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2017 Apr;17(4):856-79. PubMed PMID: 28117944. Epub 2017/01/25. eng.
3. Bumbacea D, Arend SM, Eyuboglu F, Fishman JA, Goletti D, Ison MG, et al. The risk of tuberculosis in transplant candidates and recipients: a TBNET consensus statement. The European respiratory journal. 2012 Oct;40(4):990-1013. PubMed PMID: 22496318. Epub 2012/04/13. eng.
4. Subramanian AK, Theodoropoulos NM. Mycobacterium tuberculosis infections in solid organ transplantation: Guidelines from the infectious diseases community of practice of the American Society of Transplantation. Clinical transplantation. 2019 Sep;33(9):e13513. PubMed PMID: 30817030. Epub 2019/03/01. eng.
A 46-year-old CKD 5 on HD for the last 5 years due to IgA nephropathy has a kidney offer from his brother, 111 mismatch, no DSAs. The potential recipient has a history of TB during childhood, which was treated successfully. FCXM is negative.
Any special consideration post-transplantation?
Induction suppression‘
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
Ref;
–
Any special consideration post-transplantation?
· Before transplant he should be screened for latent TB with IGRA, as TST have lower sensitivity in candidates with ESKD.
· For treatment of latent TB, if the transplant is unlikely to occur within the following 4 to 6 months, rifampin for 4 months is prescribed.
· Other options for pretransplant are isoniazid plus rifapentine for 12 weeks, or isoniazid plus rifampin for 3 months.
· If the treatment course will start, or continue, after transplant, oral isoniazid 5 mg/kg (maximum dose 300 mg) daily for adults (for nine months) with oral pyridoxine 25 to 50 mg daily should be given.
· TB occurs most commonly in transplant recipients as a result of reactivation of latent infection in the recipient, which occurred a median of 183 days after transplantation.
· If he is planning to move to a highly endemic area post transplantation, INH preventive therapy should be considered during the first posttransplant year.
· Post-transplant, the recipient should be asked about fever, night sweats, and weight loss.
· IgA nephropathy also should be investigated post-transplant for possible recurrence. Monitoring for haematuria, proteinuria, and HTN is recommended.
What is your induction immunosuppression?
· As the patient has no DSA, no need for ATG as it may increase the risk of TB activation, so I think that Basiliximab is the best option.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
· DSA-SPA are clinically significant even in the absence of FCXM, so he should be monitored closely for development of early AMR.
· But as MFI not so high I still will use Basiliximab, since the possibility of flaring up the fatal disseminated TB.
1) https://www.uptodate.com/contents/tuberculosis-in-solid-organ-transplant-candidates-and-recipients?source=autocomplete&index=0~1&search=Latent%20TB%20in%20tra#:~:text=Back-,Tuberculosis%20in%20solid%20organ%20transplant%20candidates%20and%20recipients,-Topic
2) https://academic.oup.com/cid/article/48/9/1276/409456#:~:text=Tuberculosis%20in%20Solid%2DOrgan%20Transplant%20Recipients%3A%20Consensus%20Statement%20of%20the%20Group%20for%20the%20Study%20of%20Infection%20in%20Transplant%20Recipients%20(GESITRA)%20of%20the%20Spanish%20Society%20of%20Infectious%20Diseases%20and%20Clinical%20Microbiology
3) https://journals.lww.com/transplantjournal/Fulltext/2018/02002/Tuberculosis_Recommendations_for_Solid_Organ.8.aspx#:~:text=Outline,MD%2C%20PhD8
4) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3507372/#:~:text=Donor%2DSpecific%20Antibodies,Jai%20Radhakrishnan*
· Any special consideration post-transplantation?– Evaluation for latent TB before transplantation: cbc, sputum culture & microscopy for AFB , tuberculin skin test or preferably IGRA (more sensitive & specific esp. in CKD & immunocompromised pt) , CXR , CT or MRI as indicated by the case.- Consider treatment if positive for latent TB, partially treated or hx of TB in the donor – Keep high level of suspicion post transplantation including pt education & consider prophylaxis with rifampicin free regimen , observe for drug-drug interaction.- Regarding IgA , counselling about recurrence risk.
· What is your induction immunosuppression?– Induction with basiliximab (low immunological risk , avoid aggressive immunosuppression for the hx of TB)· Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?– No , the same plan with follow up of DSA levels regularly ( MFI is considered significant if >3000)
will avoid ATG being close relation donor , absent DSA
Basiliximab as induction
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?no
still low risk
monitor DSA
consider early graft biopsy if creatinine is rising
This patient is considered latent TB patient So,
Because of history of TB and also this patient is considered low immunological risk so, I will go with induction non depleting basiliximab and maintenance tac, MMF and steroids
Low MFI detected by Luminex with negative FCXM still I will not change my induction therapy but I will keep maintenance medications on the higher side with follow up of DSA post-transplant or I will consider paired kidney exchange
Any special consideration post-transplantation?
Recipients has history of prior treatment for active TB with resolution and has been on HD for 5 years.
We must to rule out latent TB in this recipient.
We need to do IGRA which is more sensitive .
Tuberculin skin test can also be done however there can be false positive results due to prior BCG immunisation.
If the patient has latent TB then it is crucial to rule out active TB with CXR, sputum for ZN staining and Gene Xpert test.
If we establish latent TB, treatment should be started and completed before transplantation, but in case of urgent transplantation then treatment can be initiated post-transplant.
Treatment is either 3 months of rifampin and isoniazid or 6-9 months of isoniazid. Caution should be taken due to drug interactions with rifampin, rifabutin/rifapentine can be used instead.
What is your induction immunosuppression?
This patient has low immunological risk hence induction would be with basiliximab.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
No I will continue and monitoring the DSA.
References
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
Guilherme Santoro-Lopes, MD, PhD,1,2 Aruna K. Subramanian, MD,3 Israel Molina, MD,4,5José María Aguado, MD, PhD,6 Ricardo Rabagliatti, MD, PhD,7 and Oscar Len, MD, PhD8
Adebiyi OO, Gralla J, Klem P, Freed B, Davis S, Wiseman AC, Cooper JE. Clinical Significance of Pretransplant Donor-Specific Antibodies in the Setting of Negative Cell-Based Flow Cytometry Crossmatching in Kidney Transplant Recipients. Am J Transplant. 2016 Dec;16(12):3458-3467. doi: 10.1111/ajt.13848. Epub 2016 Jun 15. PMID: 27140940.
Any special consideration post-transplantation?Latent TB or reactivation of TB post-transplantation
I will put on this patient for lifelong anti-TB
What is your induction immunosuppression?Basiliximab
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?Basiliximab
Any consideration post transplantation:
Induction immunosuppression:
If DSA against A2 1500:
References:
Any special consideration post-transplantation?Recipients has history of prior treatment for active TB with resolution and has been on HD for 5 days.
There is need to rule out latent TB in this recipient.
IGRA is more sensitive since the results are not affected by prior BCG immunisation status.
Tuberculin skin test can also be done however there can be false positive results due to prior BCG immunisation.
If the patient has latent TB then it is crucial to rule out active TB with CXR, sputum for ZN staining and Gene Xpert.
Ideally treatment for latent TB should be started and completed before transplantation, but in case of urgent transplantation then treatment can be initiated post-transplant.
Treatment is either 3 months of rifampin and isoniazid or 6-9 months of isoniazid. Caution should be taken due to drug interactions with rifampin, rifabutin/rifapentine can be used instead.
What is your induction immunosuppression?This patient has low immunological risk hence induction would be with IV methylprednisolone and basiliximab.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management planNo I will continue with the same plan and monitor the DSA.
References
Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors
Guilherme Santoro-Lopes, MD, PhD,1,2 Aruna K. Subramanian, MD,3 Israel Molina, MD,4,5José María Aguado, MD, PhD,6 Ricardo Rabagliatti, MD, PhD,7 and Oscar Len, MD, PhD8
Adebiyi OO, Gralla J, Klem P, Freed B, Davis S, Wiseman AC, Cooper JE. Clinical Significance of Pretransplant Donor-Specific Antibodies in the Setting of Negative Cell-Based Flow Cytometry Crossmatching in Kidney Transplant Recipients. Am J Transplant. 2016 Dec;16(12):3458-3467. doi: 10.1111/ajt.13848. Epub 2016 Jun 15. PMID: 27140940.
special consideration post-transplantation?
The potential KTR with history of TB is at high risk for reactivation of TB.
Treatment of latent TB should be considered only after active TB has been excluded:
Treatment is indicated in one of the following conditions:
preferred treatment of latent TB is isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with pyridoxine
Treatment of latent TB in donor and recipient
The WHO 2018 guidelines outline the following treatment options for latent TB.
INH monotherapy for 6 months is recommended.
Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy:
What is your induction immunosuppression?
Basiliximab is as effective as ATG for induction therapy in kidney transplantation and less incidence of infection. The patient has negative FXM and low titre of A2 DSA, I would consider induction with Basiliximab and monitor DSA.
References:
1-Any special consideration post-transplantation?
Regarding TB history;
–This recipient had previous exposure to TB and was treated successfully,so consider the risk of reactivation after kidney transplantation with the use of immunosuppression.
-Recipient had history of treated TB during childhood : investigations R/O LTBI should be done as such; (IGRA/TST) and any positive results should be considered evidence of LTBI.
-His brother should be screened for LTBI or active TBI; CXR and Sputum for Xpert , culture , AFB stain.
-Treatment of latent TB should be considered only after active TB has been excluded.
-Treatment of 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.
-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.
-When possible, treatment for LTBI should be started before transplant, and can often be completed while the patient is on the waiting-list.
-If urgent transplant is indicated, the treatment can be held perioperatively and resumed when medically possible post transplant to complete the planned course.
-Avoid rifampicin post-transplant because of its interaction with immunosuppression medications.
Regarding his original disease (IgA nephropathy);
-Counsel patient about the risk of recurrence of his primary GN, the recurrence of IgAN has ranged from 21 to 58 %.
-Patient may present with active urine sediment (hematuria , proteinuria) with or with out rising creatinine.
-Close monitoring of graft function, urine analysis for newly onset of proteinuria or hematuria.
2-What is your induction immunosuppression?
-This current patient with low immunological risk with low DSA titer.
-So my induction go with IL-2 receptors antagonist (Basiliximab) , followed by triple maintenance immunosuppression with close monitoring after transplantation with DSA level and proteinuria.
3-Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
-This level of DSA is low with negative FCXM so the management plan will be the same and the induction with Basiliximab on (D0& D4),followed by triple I.S. as maintenance therapy.
-Close monitoring of DSA level at 3 months and 12 months.
References;
-Krishnamoorthy S, Kumaresan N, Zumla A. Latent tuberculosis infection and renal transplantation – Diagnosis and management. Int J Infect Dis. 2019 Mar;80S:S73-S76.
-Sorohan BM, Ismail G, Tacu D, Obrișcă B, Ciolan G, Gîngu C, Sinescu I, Baston C. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens. 2022 Sep 13;11(9):1041.
-Santoro-Lopes, Guilherme; Subramanian, Aruna K.; Molina, Israel; Aguado, José María; Rabagliatti, Ricardo; Len, Oscar. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation 102(2S):p S60-S65, February 2018.
A 46-year-old CKD 5 on HD for the last 5 years due to IgA nephropathy has a kidney offer from his brother, 111 mismatch, no DSAs. The potential recipient has a history of TB during childhood, which was treated successfully. FCXM is negative.
Special consideration post-transplantation?
Latent tuberculosis infection (LTBI) is defined by the World Health Organisation as ‘a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifest active TB disease’.
Up to 10% of people with LTBI will progress to developing active TB disease during their lifetime.
The highest risk for developing TB disease occurs when a range of 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 (Hasan et al., 2018).
WHO recommends three tests for screening for LTBI:
Tuberculin skin test (TST) and two interferon gamma release assays (IGRAs).
IGRAs are more specific to Mycobacterium tuberculosis antigens and offer high specificity in detecting LTBI in immunosuppressed patients.
A systematic review and meta-analysis found that IGRAs are more sensitive than the TST for the diagnosis of LTBI in patients requiring renal transplantation.
Post-transplant TB is more common in renal recipients than in liver transplant patients.
Chest Xray
TREATMENT OF LTBI IN DONOR AND RECIPIENT:
The WHO 2018 guidelines outline the following treatment options for LTBI:
Isoniazid mono-therapy 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 mono-therapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid mono-therapy as preventive treatment for both adults and children in countries with a high TB incidence.
The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid mono-therapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone(2).
What is your induction immunosuppression?
As The recipient had successful treatment for TB and his DSA is below the threshold of positive crossmatch (negative crossmatch), Low immunological risk with 111 mismatches.
I will give Basiliximab and Pulse Methylprednisone for induction.
Standard maintenance immunosuppression was triple therapy with calcineurin inhibitors to maintain target levels.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
No Change,
The recipient had successful treatment for TB and his DSA is below the threshold of positive crossmatch (negative crossmatch).
I will not give him aggressive induction that may cause flare of TB if there is a chance of latent TB?
MFI of 1500 is a low level and will not change the management plan. Basiliximab will be choice for induction therapy.Still the recipient low immunological risk (low DSA)
Post-transplant patient follow-up outpatient clinic, with medical consultations every week in the first three months, then biweekly until six months, monthly until one year, and then every two months.
Reference
UpToDate
Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020
Saudi guidelines for testing and treatment of latent tuberculosis infection Hamdan H. Al Jahdali, Salim Baharoon, and Dick Menzies2010
Any special consideration post-transplantation?For SOT candidates with end-stage kidney disease use the IGRA to screen for latent TB.
For those with a negative IGRA, we consider the risk of latent TB and treat those at high risk
Regimen selection — For treatment of latent TB, we follow national guidelines while taking into account issues of drug interactions and organ failure encountered in transplant patients.
When the transplant is unlikely to occur within the following 4 to 6 months, we typically prescribe rifampin for 4 months Other options pretransplant are isoniazid plus rifapentine for 12 weeks, or isoniazid plus rifampin for 3 months.
Timing of treatment — When possible, we treat transplant candidates with latent TB prior to transplantation, although it is also acceptable to treat following transplantation
Patients may proceed to transplant before the full course of therapy for latent TB has been given. In these cases, therapy is typically continued post-transplant, but the regimen sometimes needs to be modified to minimize toxicities and drug-drug interactions
What is your induction immunosuppression?either an IL-2 receptor antagonist (basiliximab) or rATG-Thymoglobulin is a reasonable induction therapy agent
ASSESSMENT OF IMMUNOLOGIC RISK
An important element of some approaches to induction protocols involves the attempt to identify patients at high risk of acute rejection. With this view, more aggressive immunosuppression is justified in patients at significantly increased risk of rejection
Risk factors for acute rejection include the following
●One or more human leukocyte antigen (HLA) mismatches
●Younger recipient and older donor age
●Calculated panel reactive antibody (cPRA) greater than 20 percent
●Presence of a donor-specific antibody (DSA)
●Blood group incompatibility
●Delayed onset of graft function
●Cold ischemia time greater than 24 hours
Patients with one or more of the above risk factors are considered to be at high immunologic risk for acute rejection. Those who have none of the above risk factors are considered to be at low immunologic risk.
For patients at high immunologic risk of acute rejection we recommend induction therapy with rATG-Thymoglobulin rather than an interleukin (IL) 2 receptor antagonist (basiliximab)
For patients who are at low immunologic risk of acute rejection either an IL-2 receptor antagonist (basiliximab) or rATG-Thymoglobulin is a reasonable induction therapy agent
Some experts prefer rATG-Thymoglobulin based upon data showing lower rates of biopsy-proven acute rejection at one year with rATG-Thymoglobulin Other experts prefer basiliximab based upon studies that have shown similar rates of acute rejection, patient and graft survival, and infection with rATG-Thymoglobulin and IL-2 receptor antibodies in low-risk patients. The 2009 KDIGO clinical practice guidelines recommend the use of IL-2 receptor antibodies as first-line induction therapy in patients not at high immunologic risk . Dosing and administration of these agents are discussed below.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
YES OUR PATIENT WILL BE RISKY AND NEED INDUCATION THERAPY WITH rATG-Thymoglobulin
In December 2007, UNOS mandated that calculated PRA (cPRA) provide a more uniform and accountable method for assessing sensitization
. The cPRA calculates the likelihood of transplantation by using results of the SAB assay to identify the specificity of the anti-HLA antibodies, in combination with the known frequencies of HLA antigens within the donor population.
As an example, if the patient has an antibody against the HLA-A2 antigen, which is present in 48 percent of the United States donor population (phenotypic frequency of the A2 antigen), their cPRA level would be 48 percent, and they would be ineligible to receive 48 percent of the kidneys on the basis of having DSA against the A2 antigen
Clinical significance of MFI values of pretransplant DSA — Median fluorescence intensity (MFI) values of pretransplant donor-specific anti-HLA antibody (DSA) do not appear to consistently predict graft outcomes.
In one study, higher rates of ABMR and graft loss were seen when pretransplant DSA had MFI values >10,000 but were comparable between all other groups (moderate MFI [5000 to 10,000] versus low MFI [1000 to 5000]) Another study found that differences in graft survival were dependent upon identifying the presence of DSA (MFI >1500) but not upon the actual level of MFI
. Failure to discern differences between these groups of patients may reflect technical limitations of the assay (with MFI values themselves being a poor predictor of amount/strength of antibody as well as our inability to predict whether low-level DSA will remain low or rapidly increase posttransplantation upon repeat exposure to the antigen
.
Absence of pretransplant DSA on outcome — Even in the absence of donor-specific anti-HLA antibody (DSA), some studies have shown that sensitized recipients (with non-DSA alloantibody) are at higher risk for graft failure However, this remains controversial, as other studies have shown no impact of having non-DSA on graft outcome These disparate findings may depend upon whether more or less aggressive immunosuppression is used or could also reflect incomplete identification of DSA depending upon whether antibodies against all loci (including class II alpha chain) are accounted for.
Any special consideration post-transplantation?
Need
To exclude latent TB by IGRA test or Tuberculin skin test.
To exclude active tuberculosis with sputum AFB and chest x ray.
What is your induction immunosuppression?
Induction with basiliximab is sufficient followed by triple maintenance immunosuppression (TAC, MMF and steroids)
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
DSA is positive with low titer (1500) so, doesn’t require to change IS regimen but need to follow up of DSA Titre post transplantation.
This is a low immunologic risk case, but we need to check for TB (latent) in both donor and recipient (monitor recipient later); PPD test, and or quantifereon.
We need induction because of the 111 mismatch to avoid acute rejection, but this can be done with anti IL2, basiliximab rather than ATG, not to increase the risk of opportunistic infections as well as activation of probable TB.
Any special consideration post-transplantation?
Past history with TB(site and duration of ATT not mentioned) treated successfully so if living in endemic area will have to assess for active TB and TBI(latent TB)
In case of
Active TB (positive IGRA/TST plus radiological evidence and symptoms will have to treat with ATT upto nine month if Live related transplant or post transplant ATT upto 18 month if transplant occurred) OR In case of TBI (NO symptoms but positive IGRA and TST ) will have to treat with 3HR regimen INH 5mg/kg and Rifa 10mg/kg daily for 3 months.In endemic area will prefer to have INH prophylaxis for 6 months post transplantWhat is your induction immunosuppression?
Methylpred and IL2 antagonists
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
No but will have to observe for Graft function, DSAs and Donor derived cell free DNA where avilable.
References UpToDate
Thankyou but can you explain ( cell free donor derived DNA)!
Thank you, You should give basiliximab induction and monitor the DSA in in case of DSA (Anti-HLA 2 with negative crossmatch) .
Any special consideration post-transplantation?Will use INH for atleast six months or INH and Rifampin for three months.
What is your induction immunosuppression?As recipient has been treated for TB in the past there remains a risk of deactivation in post transplant period.
Basiliximab would be a better induction option as there is low immunological risk being No DSA and negative flow cross match.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?No
Because cross match is still negative
As this is a related LD s there is the privilege to wait and investigate the TB status ie. to exclude a latent TB infection by IGRA and radiology work up which can not be conclusive post TX due to IS, then proceed with the needed regimen.
Any special consideration post-transplantation?
This patient was successfully treated for TB during childhood but he was on dialysis for 5 yeast which increased the risk of latent TB and reactivation after kidney transplantation so we need to do IGRA and skin test sputum PCR and CXR if positive for anti tuberculosis treatment before transplantation .
What is your induction immunosuppression?
This patient has low immunological risk with negative FCXM and no DSA so induction is by basiliximab and IV methylprednisolone.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
Antibodies are considered to have weak to low level with phenotype panel MFI values from 1000 to 3000; moderate from 3000 to 5000; and strong when >5000 this patient MFI is 1500 which is considered weak so I will proceed for transplantation with the same plan of management and follow the DSA level .
Reference :
2. Transplant Direct. 2018 Sep; 4(9): e385. Published online 2018 Aug 22. doi: 10.1097/TXD.0000000000000823
3. PLoS One. 2020; 15(10): e0240929. Published online 2020 Oct 22. doi: 10.1371/journal.pone.0240929
PMCID: PMC7580969PMID: 33091057
Well done, considering the time spent on HD to be taken seriously as regards to the TB history.
,
Thank you prof Dawlat .
⭐Special consideration in such recipient with prior history of TB treatment, is to exclude latent TB by Tuberculin skin test or IGRA test.
_ if postive …use of chemoprophylaxis aganist TB including monotherapy with INH for 6 months or 3 months of combined (INH and rifampin with close monitoring of TAC trough level as rifampin is an enzyme inducer.
⭐The patient has one haplotype mismatch, with negative FCXM and no DSA …so induction with basiliximab is quite sufficient followed by TAC based triple miantenance therapy with MMF and steroids.
⭐If DSA postive with low titer (1500), no change of IS regimen, but just follow up of DSA titre post transplantation.
Well done.
Recipient criteria;
The recipient is considered a low risk
Consideration
Approach
Workup;
If both are negative the recipient is excluded as having LTB, and can proceed with transplantation without prophylactic therapy.
Induction therapy
MFI 1500 will not change the plan as no DSA and negative FXCM
References
Hariharan S, Peddi VR, Savin VJ, et al. Recurrent and de novo renal diseases after renal transplantation: A report from the renal allograft disease registry. Am J Kidney Dis 1998; 31: 928.
2.Berger J, Yaneva H, Crosnier J. Mesangial IgA glomerulonephritis: A frequent cause of terminal renal failure. Nouv Presse Med 1980; 9: 219.
Patel R, Terasaki PI. Significance of the positive crossmatch test in kidney transplantation. N Engl J Med 1969; 280: 735.
2. Johnson AH, Rossen RD, Butler WT. Detection of alloantibodies using a sensitive antiglobulin microcytotoxicity test: Identification of low levels of pre-formed antibodies in accelerated allograft rejection. Tissue Antigens 1972; 2: 215.
Basiliximab is an interlukin 2 antagonist not 6 please revise
Any special consideration post-transplantation?
What is your induction immunosuppression?because of low immunological risk and risk of reactivation of TB…..Better to not doing aggressive induction , so better to use basiliximab as induction agent.
this is related LD so they can wait to investigate a LTBI and even if proved a safer situation than after TX (if accepted by the R ) with precautions of the drug inter action.
1-initial active TB should be excluded
2-IF patient has a positive TST or IGRA test treatment as latent TB (isoniazid 5 mg/kg/day (maximum dose 300 mg/day) for 9 months, supplemented with vitamin B6. )
3- patient has standard immunological risk so induction with Basilliximab
Thankyou.
1- special consideration post transplant for early diagnosis and treatment of TB reactivation if happen.
follow up by CXR, CT chest , abdomen and pelvis
2- induction by basiliximab
3- no change in management
The WHO 2018 guidelines outline the following treatment options for LTBI (WHO, 2018b).
1- Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
2- Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
3- Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
4- The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy:
a- 9 months of isoniazid,
b-or a 3-month regimen of weekly rifapentine plus isoniazid,
c-or 3–4 months of isoniazid plus rifampicin,
d-or 3–4 months of rifampicin alone.
Patients may find completing the long course of LTBI treatment difficult due to adverse effects and the interactions with immunosuppressive drugs, hence shorter courses of treatment are recommended.
Sriram Krishnamoorthya, Natarajan Kumaresana , Alimuddin Zumla. Latent tuberculosis infection and renal transplantation – Diagnosis and management. International Journal of Infectious Diseases 80 (2019) S73–S76
How about exclusion of LTBI before deciding to treat
Try to rule out LTBI before you proceed and not wait for a possible reactivation.!
Any special consideration post-transplantation?
This potential KTR with PH of TB is at high risk for reactivation and post-transplant TB infection. In this potential KTR, I need to rule out disease activity and to consider prophylaxis at time of transplant.
Treatment of latent TB should be considered only after active TB has been excluded(1):
a) Treatment of 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.
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.
Treatment of LTBI in donor and recipient
The WHO 2018 guidelines outline the following treatment options for LTBI (WHO, 2018b).
a) Isoniazid monotherapy for 6 months is recommended for treatment of LTBI in both adults and children in countries with high and low TB incidence.
b) Rifampicin plus Isoniazid daily for 3 months should be offered as an alternative to 6 months of isoniazid monotherapy as preventive treatment for children and adolescents aged <15 years in countries with a high TB incidence.
c) Rifapentine and Isoniazid weekly for 3 months may be offered as an alternative to 6 months of Isoniazid monotherapy as preventive treatment for both adults and children in countries with a high TB incidence.
d) The following options are recommended for treatment of LTBI in countries with a low TB incidence as alternatives to 6 months of isoniazid monotherapy: 9 months of isoniazid, or a 3-month regimen of weekly rifapentine plus isoniazid, or 3–4 months of isoniazid plus rifampicin, or 3–4 months of rifampicin alone(2).
What is your induction immunosuppression?
1. 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.
2. Basiliximab is as effective as ATG for induction therapy in kidney transplantation, whereas basiliximab has a lower incidence of infection(4).
3. In this case with undetectable DSA level and a history of TB, I will consider Basiliximab for induction.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
MFI of 1500 is a low level and will not change the management plan. Basiliximab will be choice for induction therapy.
References
1. Abad CLR, Razonable RR. Donor derived Mycobacterium tuberculosis infection after solid-organ transplantation: A comprehensive review. Transpl Infect Dis. 2018 Oct;20(5):e12971. doi: 10.1111/tid.12971. Epub 2018 Aug 12. PMID: 30055041.
2. Krishnamoorthy S, Kumaresan N, Zumla A. Latent tuberculosis infection and renal transplantation – Diagnosis and management. Int J Infect Dis. 2019 Mar;80S:S73-S76. doi: 10.1016/j.ijid.2019.01.049. Epub 2019 Feb 6. PMID: 30738187.
3. Sorohan BM, Ismail G, Tacu D, Obrișcă B, Ciolan G, Gîngu C, Sinescu I, Baston C. Mycobacterium Tuberculosis Infection after Kidney Transplantation: A Comprehensive Review. Pathogens. 2022 Sep 13;11(9):1041. doi: 10.3390/pathogens11091041. PMID: 36145473; PMCID: PMC9505385.
4. Liu Y, Zhou P, Han M, Xue CB, Hu XP, Li C. Basiliximab or antithymocyte globulin for induction therapy in kidney transplantation: a meta-analysis. Transplant Proc. 2010 Jun;42(5):1667-70. doi: 10.1016/j.transproceed.2010.02.088. PMID: 20620496.
Well done.
Any special consideration post-transplantation?
This recipient had previous exposure to TB and was treated successfully, we should consider the risk of reactivation after kidney transplantation, with the use of immunosuppression also need to ask about the treatment course and type of ATT that he received any recent exposure or contact with active TB cases, his brother should be screened for LTBI, also ask about the type and duration of ATT, did he completed the course of ATT, do CXR and send for urine and blood sample for AFB staining and cultures, and should be careful in the choice of immunosuppression, as he is at risk of endogenous reactivation with immunosuppression.
TB post-kidney transplantation is associated with high morbidity and mortality and in 1/3 of cases can lead to graft loss also the diagnosis will be challenging as they usually have a nonspecific clinical presentation and after SOT there is a risk of extrapulmonary TB or disseminated TB, also the treatment of active TB after transplantation consider another challenge due to the drug-drug interaction and hepatotoxicity, neurotoxicity so in such case, will be careful in handling his immunosuppression induction type and also keep a high index of clinical suspicion of reactivation after transplantation.
What is your induction immunosuppression?
Still, this patient can go with basiliximab as induction IS along with PMP and followed by triple IS including tacrolimus, MMF and steroid as his primary disease was IgA nephropathy so preferred to be on triple maintenance IS
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
This level of DSA is low with negative FCXM so still can go with the same induction IS, basiliximab, and PMP followed by triple maintenance therapy with close monitoring of DSA level in 3 months and 12 months
References
1.José María Aguado, Julián Torre-Cisneros, Jesús Fortún, Natividad Benito, Yolanda Meije, Antonio Doblas, Patricia Muñoz, David R. Snydman, Tuberculosis in Solid-Organ Transplant Recipients: Consensus Statement of the Group for the Study of Infection in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology, Clinical Infectious Diseases, Volume 48, Issue 9, 1 May 2009, Pages 1276–1284, https://doi.org/10.1086/597590
This is an exellent answer ,taking his brother and family seriously with regard to TB.
Any special consideration post-transplantation?
-History of clinical or radiological TB and the treatment taken have to be evaluated
-Tuberculin skin test and gammainterferon test to exclude latent TB infection
– Active TB infection must be excluded in cases with positive result in any of these tests.
– checking for the presence of symptoms and signs suggestive of TB, chest Xray
If any evidence of active infection is noticed, suitable clinical specimens need to be obtained for microbiological confirmation .
If active TB infection was diagnosed, transplantation should have been postponed till TB is cured with adequate treatment and smears are negative.
IF Latent TB was discovered treatd with oral INH 300 mg/d for 9 months, along with oral pyridoxine 25 to 50 mg daily.
For prophylaxis isoniazid (300 mg daily or 25 mg/kg twice weekly) administered for six to nine months with special couscous for drug interaction with immunosuppressives .
MDR TB have to be excluded
-Regarding Ig A nephropathy recurrence the recipient has to be counselled for that asIgA nephropathy recurrence post kidney transplantation occurs in about 30% of cases. The relevance of recurrence for the long-term graft survival is expected to increase, since graft survival continues to improve.
What is your induction immunosuppression?
Basiliximab and steroids in the presence of the current crossmatching with no DSA rendering the case of low immunogenic risk also in order not to provoke activation of latent TB
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
MFI threshold for unacceptable antigens in most centers are between 3000–5000.Therefore MFI1500 and A2 is of low risk.
So the same management will be carried on with induction using basilismab and triple maintenance therapy
Yoo PS et al demonstrated that a weakly positive DSA of less than 3000 MFI by SAB assays combined with a negative flow cytomatric crossmatch have no adverse effect on short-term renal function or rates of early graft rejection
Reference
-Santoro-Lopes G et al ,Tuberculosis Recommendations for Solid OrganTransplant Recipients and Donors. Transplantation 2018 ,Volume 102,Number 2S-2
-Yoo PS, Bonnel A, Kamoun M, Levine MH. Clinical outcomes among renal transplant recipients with pre-transplant weakly reactive donor-specific antibodies. Clin Transplant. 2014;28(1):127-133.
– Jäger, C., Stampf, S., Molyneux, K. et al. Recurrence of IgA nephropathy after kidney transplantation: experience from the Swiss transplant cohort study. BMC Nephrol 23, 178 (2022)
Thankyou you plan to manage according to whether LTBI or ACTIVE TB.
What do you mean by prophylactic treatment.
Any special consideration post-transplantation?
A-TB
–The incidence rate of TB markedly increases after SOT, reactivation of latent TB infection (LTBI) is probably the main cause of posttransplant TB and primary TB is less frequent.
-Recipient had history of treated TB during childhood. Therefore, we need to rule out LTBI by doing IGRA/TST in high-risk patients, both tests could be performed, and any positive result should be considered evidence of LTBI, to maximize the sensitivity of screening.
– Active TB infection must be excluded in all candidates with a positive result in any of these tests before LTBI treatment is started, CXR and if there is any symptoms sputum for Xpert, culture, AFB stain.
– Treatment for LTBI if had history of untreated or incompletely treated LTBI or TB, or if the recipient is exposed to TB after transplantation.
– When possible, treatment for LTBI should be started before transplant, and can often be completed while the patient is on the waitlist.
-If urgent transplant is indicated, the treatment can be held perioperatively and resumed when medically possible until completion of the originally planned course
– Better to avoid rifampicin post-transplant for its interaction with immunosuppression.
B– IgA nephropathy.
-The candidate need to be aware about the risk of recurrence, the recurrence of IgAN has ranged from 21 to 58 %.
-TANGO study reported the cumulative incidence of recurrence was 19 % at 10 years and 23 % at 15 years.
-Histologic recurrence, with or without evidence of clinical disease, may occur.
– Present with hematuria, new or worsening proteinuria, or an increased creatinine.
– Monitor graft function, urine for new onset proteinuria and hematuria.
What is your induction immunosuppression?
Despite HLA mismatch, no DSA and FCXM is negative, low immunological risk induction with steroid and basilliximab. Given the previous history of TB better to avoid aggressive induction therapy.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
-I will proceed with the same plane with careful and frequent DSA monitoring, as DSA MFI is low and negative FXCM.
-One study showed pre-transplant DSA with a negative FCXM did not significantly impact AR rates, graft function (GFR or proteinuria) or intermediate-term graft survival, in the setting of low MFI< 3000.(2)
-While a recent meta-analysis showed pretransplant DSA and reported an increased incidence of AMR (25% vs. 11%) and a significant increases the risk for graft failure by 76% and decrease in graft survival in the presence of pretransplant DSA versus those without.(3)
References:
· -Santoro-Lopes G, Subramanian AK, Molina I, Aguado JM, Rabagliatti R, Len O. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation. 2018 Feb;102(2S Suppl 2):S60-S65. doi: 10.1097/TP.0000000000002014. PMID: 29381579.
· Adebiyi OO, Gralla J, Klem P, Freed B, Davis S, Wiseman AC, Cooper JE. Clinical Significance of Pretransplant Donor-Specific Antibodies in the Setting of Negative Cell-Based Flow Cytometry Crossmatching in Kidney Transplant Recipients. Am J Transplant. 2016 Dec;16(12):3458-3467. doi: 10.1111/ajt.13848. Epub 2016 Jun 15. PMID: 27140940.
· Mohan S, Palanisamy A, Tsapepas D, Tanriover B, Crew RJ, Dube G, Ratner LE, Cohen DJ, Radhakrishnan J. Donor-specific antibodies adversely affect kidney allograft outcomes. J Am Soc Nephrol. 2012 Dec;23(12):2061-71. doi: 10.1681/ASN.2012070664. Epub 2012 Nov 15. PMID: 23160511; PMCID: PMC3507372.
Thank ,exellent well justified plan.,you are one of the few who addressed the IgA issue.
Thank you prof.
Any special consideration post-transplantation?
======================
What is your induction immunosuppression?
======================
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
References
3. A 46-year-old CKD 5 on HD for the last 5 years due to IgA nephropathy has a kidney offer from his brother, 111 mismatch, no DSAs. The potential recipient has a history of TB during childhood, which was treated successfully. FCXM is negative.
====================================================================
Any special consideration post-transplantation?
WHO recommends three tests for screening for LTBI:
====================================================================
What is your induction immunosuppression?
===================================================================
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
NO
====================================================================
Reference
Any special consideration post-transplantation?
IGRA and TST to rule out latent tuberculosis
ATT should be given if IGRA and TST are positive, inadequately treated TB, history of untreated TB in donor.
What is your induction immunosuppression?
There HLA 111 mismatch, No DSA
Induction with Basiliximab and TAC based maintenance therapy
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
I will proceed with transplantation. Induction with Basiliximab, with DSA moniroring. pretransplant DSA in the setting of a negative FCXM confers minimal immunologic risk in the intermediate term, does not necessitate desensitization therapy and should not represent a barrier to renal transplant.
Adebiyi OO, Gralla J, Klem P, Freed B, Davis S, Wiseman AC, Cooper JE. Clinical Significance of Pretransplant Donor-Specific Antibodies in the Setting of Negative Cell-Based Flow Cytometry Crossmatching in Kidney Transplant Recipients. Am J Transplant. 2016 Dec;16(12):3458-3467.
Thankyou.
Risk of latent TB;
Long duration on dialysis.
Immunosuppressive medicine
Prior TB infection
I presume that the patient would have undergone a complete evaluation for latent TB, including an IGRA, sputum cultures, and chest imaging.(before to the transplant). If every all test are normal than there is no need for ATT, better to proceed for transplantation.
Treatment of latent TB is recommended for 9 months in case of positive test for latent TB .
Post transplantation,
there is a higher risk of tuberculosis (TB) reactivation and infection.
Patient should be monitor for ;
Respiratory sign and symptom, night sweat, weight loss, loss of appetite, close contacts with TB patients.
Induction
Due to the fact that this is a first transplant, there is no history of sensitization, no DSA, a negative FCMXM, and a prior history of TB, the immunologic risk is most likely low.
My induction would therefore consist of basiliximab and IV methyl prednisone.
Although there is a lot of difference between laboratories and various laboratories may have a different cut-off, UNOS states that the cut-off is MFI > 3000.
DSA alone should not preclude the transplant process
1-Tuberculosis in Solid Organ Transplantation
Afshin Mohammad Alizadeh, Majid Marjani, Afshin Moniri, Parvaneh Baghaei, Sayena Jabbehdari,Pedram Javanmard, and Payam Tabarsi
2-Nephrology and Hypertension Board Review
Phuong-Chi T. Pham, MD, FASN
3-Hand book of kidney transplanatation
Nephrology and Hypertension Board
Thankyou for highlighting the reasons to consider Latent TB in this case.
Any special consideration post-transplantation?
I want to believe the detailed history of how TB was diagnosed in childhood, a combination of drugs used, the duration of treatment, and evidence of cure would have been established before proceeding with the transplant
Also, investigations like TST, IGRA, and TB culture can be done if is not an emergency transplantation
Imaging tests like CXR for old healed focus on the lung parenchyma
Post-transplantation, I will do the following
However, with past history of TB, and for those patients living in the endemic areas I will start the patient on Tab INH 300mg daily for 6-9 months
What is your induction immunosuppression?
This is an immunologically low-risk recipient with HLA haplotype, no DSA, and negative crossmatch. The induction therapy will be Basiliximab 20mg on days 0 and 4 post-transplantation
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
The patient still has a good HLA match with a negative crossmatch, but the DSA MFI is now 1500. Although DSA-level treatment is mostly centre specific, however, 1500 is still low to warrant desensitization in the index patient. Thus, I will still use the same induction regimen earlier stated.
References
So you decided he is a latent TB case with possible confusing TST(past infection) and start INH for 9 momths
What are your strong reasons to consider him a iatent TB case?
The potential recipient has had TB treated successfully in childhood. However, he can still be having latent TB
The pre-transplant work up should assess for latent TB. There are 2 methods of diagnosing latent TB:
If the recipient is diagnosed to have latent TB, active TB needs to be ruled out
If the potential recipient is diagnosed to have latent TB, it is important to treat it before the transplant as there is a risk of TB flare due to the immunosuppression
If the recipient does not have latent TB then he can be safely transplanted
Post Transplant:
Induction Immunosuppression:
DSA A2 with MFI of 1500 with a negative FCXM:
Along with follow up of DSA ,wisely consider IgA as a possible recurrence.
Any special consideration post-transplantation?
Screening and diagnosis of LTBI and active TB before transplantation:
History: previous TB infection, contact with active TB patient
Symptoms: chronic cough, weight loss, night sweats, and anorexia
Clinical examination: examine for active pulmonary tuberculosis, exclude extra pulmonary TB
Investigations: CBC, CRP, RFT, LFT, microscopy for AFB and culture, biopsy or aspirate histology (AFB or granuloma), and genXpert MTB/Ris Assay (on sputum, urine or biopsy)
Tests for LTBI:
1. Tuberculin skin test (TST): unreliable in advanced CKD/immunosuppressive patients
2. IGRA test (TSPOT.TB or QuantiFeron): more sensitive and specific for diagnosing LTBI
Imaging: chest x ray, renal ultrasound, MRI or CT scan (where indicated), and PET/CT scan (where indicated)
This patient had successful treatment of TB but the risk of infection is still high, so to decrease the risk of infection:
1. Avoid aggressive induction therapy with ATG
2. Avoid contact with TB patients
3. TB prophylaxis
4. Low threshold of suspicion of the infection
5. Contact the transplant team if developed fever, cough or night sweating
In case of TB therapy tries to give rifampicin-free regimen (interaction)
What is your induction immunosuppression?This patient with living related donor, 111 mismatch, no DSA, negative crossmatch is low immunological risk. Induction therapy with steroids and basiliximab
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
No, I will proceed with the same management with monitoring of DSA. Patient with DSA but negative FCXM is a low risk of AMR. DSA (A2 with MFI 1500) is a weak positive and most centers use 3000 MFI as a cut off for significant DSAs
References
1. Santoro-Lopes, Guilherme, Subramanian, Aruna, Molina, Israel, Aguado, José María, Rabagliatti, Ricardo, Len, Osca. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation 102(2S):p S60-S65, February 2018.
2. Sundaram M, Adhikary SD, John GT, Kekre NS. Tuberculosis in renal transplant recipients. Indian J Urol. 2008 Jul;24(3):396-400. doi: 10.4103/0970-1591.42625. PMID: 19468476; PMCID: PMC2684355.
Clever policy to follow post TX DSA at regular intervals.
Dear All
The recipient had successful treatment for TB
Also, his DSA is below the threshold of positive crossmatch (negative crossmatch). Will you give him aggressive induction that may cause flair of TB if there is a chance of latent TB?
No
I would use basiliximab for induction
Thank you, yes basiliximab and monitoring the DSA.
Absolutely not.
Low immunological recipient with low DSA titer.
IL-2 receptors antagonist (Basiliximab)
Thank you, yes basiliximab and monitoring the DSA.
NO, there is no place for an aggressive immunosuppressive.
Basiliximab is fine
Yes, Basiliximab (or simulect) in addition to careful close monitoring of DSA.
The presence of DSA is one criteria of high inmunologic risk transplantation, 2 options are avilable for induction, ATG or basiliximab with preferance of ATG
But in the current sensrio, we can give basiliximab induction with close follow up of the DSA titer post transplantation
Thank you, yes basiliximab and monitoring the DSA.
Thank you Prof. Ahmad
What is your induction immunosuppression?
Living related (brother) donor, 111 mismatch, negative cross match, and No DSA- very low immunological risk.
I would not give an induction therapy but IV methylprednisolone, or use induction with basiliximab.
This would also minimize the risk of TB reactivation.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
In this case living related donor (brother) with 111 mismatch, negative crossmatch, but DSA (A2 with MFI 1500), still with negative cross match and low A2 titer DSA < 3000. It is low risk to have ABMR.
I would consider induction with basiliximab and iv methylprednisolone.
Thank you, yes basiliximab and monitoring the DSA.
What is your induction immunosuppression?
===================================================================
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
NO
Thank you, yes basiliximab and monitoring the DSA.
I will Use Simulect Induction 20 mg D0 & D4 because ;
LRKTx, 111 MM,-ve XM & No DSA (Low immunological risk)
-Low risk of TB reactivation.
Thank you, yes basiliximab and monitoring the DSA.
Given the history of TB and the risk of reactivation, as the FCXM is negative and DSA is low basilliximab is preferred with close monitoring of DSA level.
Thank you, yes basiliximab and monitoring the DSA.
Thnxs prof, my approach to this here.
This recipient considered as low immunological risk patient so induction with basiliximab is enough
No,I wouldn’t go to aggressive induction:
no need for aggressive induction
basiliximab can be used
this patient still can go with basiliximab induction followed by triple maintenance immunosuppression taking into consideration his primary disease IgA nephropathy
with close monitoring after transplnation with DSA level and protienuria
Obviously No aggressive induction would prefer to have IL2 receptor antagonist
In such scenario Basiliximab is a better option. We had few similar patients and successfully used basiliximab.
No, Prof
He falls on slandered risk so will give him basiliximab for induction.
sorry for spelling, stander risk
No. But he should be monitored closely for possible development of early AMR.
Maintain basiliximab and monitor DSA.
No, I would still maintain the same induction and maintenance regimen. In addition to monitoring the DSA.
THANKS PROF
I would use Basiliximab and monitor DSA
Silmulect is the most reasonable choice for this recipient
No, only use basiliximab and DSA monitoring.
Diagnosis of latent TB in the recipient is settled if :
One of the following is present
And all of the followings are fulfilled
So in the current patient there is no need to do the test and I have to consider the diagnosis based on the previous history of TB if there are no symptoms, CXR is normal and no evidence of extrapulmonary TB
Protocol for treatment of latent TB
Ideally, regimen for recipient should be started before transplantation if the donor can wait as for the current case, but if transplantation cannot be postponed, at that time treatment can be given after transplantation.
Rifampicin containing regimen is preferred in patients unlikely to be transplanted within the next 4-6 months due to drug-drug interactions with CNI
Patient should be monitored for liver enzymes and bilirubin at baseline, every 2 weeks for 6 weeks then monthly, if there is 3 fold rises of liver enzymes with symptoms or 5 fold rise without symptoms, INH should be stopped
Any special consideration post-transplantation?
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
Reactivation of latent TB is common if no treatment given and around 95% of cases occur at 1 mouth to 1 year after transplantation (3).
High index of suspicion should be present in interpretation of any symptoms the recipient suffer, putting in mind that the presentation differ from immunocompetent patients in the following
So … if the transplant recipient presents with any skin or pulmonary lesions, unexplained fevers, night sweats, and weight loss the diagnosis of TB should be suspected
To reach diagnosis invasive procedure is usually required including bronchoscopy and BAL or lung biopsy, and any specimen collected (sputum, abscess fluid, lung tissue) should be stained and cultured for AFP, tested for PCR (rapid diagnosis) together with with histopathological examination of tissue taken if available
The treatment of TB in SOT is challenging due to the following
So … post transplantation, high index of suspicion is needed, avoid intensification of immunosuppression and treatment of latent TB should be given before and if not after transplantation (rifampicin free regimen).
What is your induction immunosuppression?
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
Risk factors for reactivation of TB are multiple, the most important are
And once TB develop there are the following risks
The presence of DSA increases the risk of transplantation and makes the patient of high immunologic risk, which requires induction with ATG, and increase the risk of rejection post transplantation.
So I will recommend paired kidney exchange in order to have a more compatible donor, but if not available I will transplant the patient after education of the risk of active TB and also high index of suspicion is needed, and treatment of latent TB should be given before and if not after transplantation (rifampicin free regimen).
References
1. Pai M, Denkinger CM, Kik SV, et al. Gamma interferon release assays for detection of Mycobacterium tuberculosis infection. Clin Microbiol Rev 2014; 27:3.
2. Subramanian AK. Tuberculosis in solid organ transplant candidates and recipients: current and future challenges. Curr Opin Infect Dis 2014; 27:316.
3. Torre-Cisneros J, Doblas A, Aguado JM, et al. Tuberculosis after solid-organ transplant: incidence, risk factors, and clinical characteristics in the RESITRA (Spanish Network of Infection in Transplantation) cohort. Clin Infect Dis 2009; 48:1657.
4. Fiske CT, Griffin MR, Erin H, et al. Black race, sex, and extrapulmonary tuberculosis risk: an observational study. BMC Infect Dis 2010; 10:16.
5. Subramanian AK, Theodoropoulos NM, Infectious Diseases Community of Practice of the American Society of Transplantation. Mycobacterium tuberculosis infections in solid organ transplantation: Guidelines from the infectious diseases community of practice of the American Society of Transplantation. Clin Transplant 2019; 33:e13513.
The recipient had successful treatment for TB
Also, his DSA is below the threshold of positive crossmatch (negative crossmatch). Will you give him aggressive induction that may cause flair of TB if there is a chance of latent TB?
A 46-year-old CKD 5 on HD for the last 5 years due to IgA nephropathy has a kidney offer from his brother, 111 mismatch, no DSAs. The potential recipient has a history of TB during childhood, which was treated successfully. FCXM is negative.
Any special consideration post-transplantation?
The patient risk of having latent TB are: 5 years on HD, immunosuppression to be used post transplantation, previous TB infection.
I assume that the patient would has been fully evaluated for latent TB, by doing chest imaging, IGRA, and sputum cultures. (before the transplantation).
If it was clear, then would not keep him on anti TB medication and proceed with transplant as soon.
If latent TB is positive, then I would recommend treatment for 9 months before the transplant.
After transplantation, there is increased risk of TB reactivation, and getting infection from an affected people if he is living in an endemic area, education and preventive measures to be taken, and the patient should be aware of any new respiratory or fever night sweets and weight loss, and to be in close contact with the transplant physician.
If after transplantation Latent TB is diagnosed then treatment should be started with concern of drug drug interactions, and side effects.
What is your induction immunosuppression?
Living related (brother) donor, 111 mismatch, negative cross match, and No DSA- very low immunological risk.
I would not give an induction therapy but IV methylprednisolone, or use induction with basiliximab.
This would also minimize the risk of TB reactivation.
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
In this case living related donor (brother) with 111 mismatch, negative crossmatch, but DSA (A2 with MFI 1500), still with negative cross match and low A2 titer DSA < 3000. It is low risk to have ABMR.
I would consider induction with basiliximab and iv methylprednisolone.
References:
(1) José María Aguado, Julián Torre-Cisneros, Jesús Fortún, Natividad Benito, Yolanda Meije, Antonio Doblas, Patricia Muñoz, David R. Snydman, Tuberculosis in Solid-Organ Transplant Recipients: Consensus Statement of the Group for the Study of Infection in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology, Clinical Infectious Diseases, Volume 48, Issue 9, 1 May 2009, Pages 1276–1284, https://doi.org/10.1086/597590.
(2) Adebiyi OO, Gralla J, Klem P, et al. Clinical Significance of Pretransplant Donor-Specific Antibodies in the Setting of Negative Cell-Based Flow Cytometry Crossmatching in Kidney Transplant Recipients. Am J Transplant. 2016;16(12):3458-3467. doi:10.1111/ajt.13848.
Your induction decision is fine but remember to follow up with DSA levels.
If you start anti TB therapy post TX better use a Rifampicin free regimen.
Thank you Prof. Dawlat
Any special consideration post-transplantation?
close monitoring of urine analysis and Alb/creatinine.
CXR.
close monitoring of any symptoms of fever of unknown origin, night sweats, and loss of weight.
IGRA.
IgA-GN is a common disease in most countries, accounting for a relatively high proportion of end-stage renal failure.
Recurrence rates are high, especially if sought in renal biopsies after transplantation using specific identification of IgA deposits in the glomeruli.
IgA is thus among the most common recurrent diseases but is generally slow to cause renal impairment and graft loss. It is more common after living-related donor grafts, but recurrence does not seem to affect early or medium-term graft survival, though the use of steroid-free regimens may increase recurrence rates.
The assessment of the family donor, however, needs to include consideration of the possibility that IgA may be a familial disease and thus also affect the potential donor.
What is your induction immunosuppression?
Induction :Basiliximab
Maintenance: Tacrolimus, MMF, and prednisolone(avoid steroid-free regimen)
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
Pretransplant DSA in the presence of a negative FCXM does not need desensitization treatment, and should not constitute a barrier to renal transplantation.
the same treatment with close observation of DSA post-transplantation.
Some centers proceed with the protocol biopsy.
Do you think this patient is at higher risk of AMR if the recipient has DSA (A2 with MFI 1500)?
One study found that differences in graft survival were dependent upon identifying the presence of DSA (MFI > 1500) but not upon the actual level of MFI. Failure to discern differences between these groups of patients may reflect the technical limitations of the assay, (with MFI values themselves being a poor predictor of the amount and strength of antibodies.
Although the A2 antigen is not strongly immunological,
Still, the patient is at risk for rejection in comparison to a negative DSA.
.
Explain the image findingMRI shows two round lesions with central low intensity, surrounding enhancement (ring) and edema. The left ventricular is compressed.
What is the difference between T1 and T2-weighted images?
T1-weighted images
are produced by using short TE and TR times.
It inhances the signal of the fatty tissue
It suppresses the signal of the water
T2-weighted images
are produced by using longer TE and TR times.
It enhances the signal of the water
In general, T1- and T2-weighted images can be easily differentiated by looking the CSF.
CSF is dark on T1-weighted imaging and bright on T2-weighted imaging
about this case
MRI
T1: iso- to hypointense to cortexT1 C+ (Gd): vivid contrast enhancementT2variablemajority are iso to hypointensehyperintense is more common when necrosis is presentsurrounding vasogenic edemaWhat is your differential diagnosis?
●PTLD
●Tuberculoma
●Abscess (bacterial- fungus)
●Brain toxaplasmosis
●Criptococosis
●Neurosarcoid
●Metastasis
How would manage this case?
□We should ask about the EBV test in donor and recipient before transplantation
□Also the TB evaluation in donor and recipient before transplantation
A- Primary CNS PTLD is uncommon and the diagnosis and treatment are difficult
□The diagnosis should be suspected in transplant recipients with mental status changes or new neurologic findings.
□Diagnostic tests include (MRI) of the head;
□analysis of (CSF) by cytology, flow cytometry, and for EBV genes by (PCR);
□ PCR (EBV) clear positive
□Sometimes, the diagnosis should be confirmed either by the presence of malignant lymphocytes in the CSF or by direct biopsy of the lesion
□Neurologist consultation for controlling seizures
□CBC – LDH – UA- CA
□CXR – CT (chest- abdomin)
□ the best management iniate with the reduction of immunosuppression agents with close monitoring (clinically and laboratory ) for rejection.
□Rituximab (anti CD20) is the treatment of choice for PTLD
□chemotherapy in addition to Rituximab, cyclophosphamide- doxorubicin- vincristine- prednisolone
□radiation therapy
□ Adoptive immunotherapy — Adoptive immunotherapy uses EBV-specific cytotoxic T lymphocytes (EBV-CTLs) or donor lymphocyte infusion (DLI) in an attempt to kill dividing B cells in EBV-associated PTLD.
This therapy needs more evidence.
B- The wide spectrum antibiotics and anti fungal treatment may consider if the diagnosis is not clear
C- evaluation of tuberculosis is essential notably when the recipient or donor has been treated previously. In addition to the recipient in endemic regions or patient with HIV
♡CXR – CT chest
♤IGRA- BAL sputum samples
♡CSF examination and culture- blood culture.
♤Depending an the BTS RECOMMENDATIONS
Rifampicin can interact with IS regimens, Increasing the chance ofgraft rejection, and doses of MMF, TAC and ciclosporin may need adjustment. Corticosteroid doses should be doubled in patients receiving rifampicin. (B)
♤the treatment consists of 4 drugs for two months then 2 drugs for two months
REFERENCES
1- Central nervous system tuberculosis (UpToDate)
2- Prevention and treatment of Post-transplant lymphoproliferative disorders (UpToDate)
3- Intracranial tuberculous granuloma.Last revised by Travis Fahrenhorst-Jones on 21 Aug 2022
4- phoproliferative disorder. Last revised by Frank Gaillard on 15 Mar 2023
Sorry. This was my answer for scenario 2.
I accidentally wrote it here.
I will answer this scenario later.
No problem, Dr Ghalia.
Any special consideration post-transplantation?
TST or IGRA tests could be performed and any positive reaction considered an evidence of LTBI.
Criteria to Start Treatment.
LTBI therapy is recommended for transplant candidates with positive TST or IGRA who have not been previously treated.
Those with history of active TB infection that was inadequately treated.
Therapy is recommended for transplant recipients whose donor has a history of untreated or incompletely treated LTBI or TB.
-we should exclude active and LTBI in donor and recipient and if they clear can proceed for transplantation.
What is your induction immunosuppression?
Living related with low immunological risk with 111 mismatch, no DSAs.
Induction therapy by steroid and basiliximab with tacrolimus based therapy .
Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
Pretransplant DSA in the setting of a negative FCXM confers minimal immunologic risk in the intermediate term, does not necessitate desensitization therapy and should not represent a barrier to renal transplant (2).
DSA A2 with low MFI 1500 .
I will proceed with the same induction therapy with DSA monitoring.
References:
1- Santoro-Lopes G, Subramanian AK, Molina I, Aguado JM, Rabagliatti R, Len O. Tuberculosis Recommendations for Solid Organ Transplant Recipients and Donors. Transplantation. 2018;102(2S Suppl 2):S60-S65. doi:10.1097/TP.0000000000002014
2- Adebiyi OO, Gralla J, Klem P, et al. Clinical Significance of Pretransplant Donor-Specific Antibodies in the Setting of Negative Cell-Based Flow Cytometry Crossmatching in Kidney Transplant Recipients. Am J Transplant. 2016;16(12):3458-3467. doi:10.1111/ajt.13848
That is a very pragmatic and scientific approach, and is well-referenced
I do appreciate
1.Any special consideration post-transplantation?-Two key issues in this case;
2.What is your induction immuno suppression
3.Presume the recipient has DSA (A2 with MFI 1500). Would this change your management plan?
Source
That is a very pragmatic and scientific approach.
Pre-transplant assessment: and exclusion of active tuberculosis is first step in management of post-transplant tuberculosis, which includes testing with TST and IGTB.
When pre-transplant tests are negative for both donor and recipients, kidney transplantation can be performed safely. However, keeping high index of suspicion in the follow up of patients post transplantation is crucial, with monitoring of clinical features for active renal tuberculosis such as pyuria, hematuria and perinephric collection by US exam. Risk of recurrence is maximum in the first 9 months post transplantation.
Induction Immune suppression:
Owing to high HLA mismatch of III [ high immunologic risk], I would advocate ATG induction, which is a polyclonal antibody targeting T lymphocytes. Dosing is 1.5 mg/kg for 4-7 days with accumulative dose of 6-10 mg /kg, with first dose given prior to transplantation. Alternatively, Alemtuzumab can be administered.
If DSAs is of :1500 MFI: It is considered weak positive, as most of the centers recognized DSAs of more than 3000 MFI as the cut off for significant DSAs. As a general role level of DSAs is not correlated with its significance to a certain extent .
references
1] Kamila Bednarova et al.Tuberculosis dissemination in kidney transplant recipient treated with anti-CD40 monoclonal antibody: a case report.BMC Nephrology volume
23, Article number: 290 (2022) .
That is a well-referenced and logical approach that you have demonstrated in your reply.