Chronic diarrhea after kidney transplantation is a common complaint, often assumed by clinicians and patients to be an inevitable part of kidney transplantation. This is neglected despite its association with fatigue, increased hospitalizations and negative impacts on recipient quality of life graft survival and higher mortality.
Steatorrhea and malabsorption may result from severe and chronic posttransplant diarrhea and induce enteric hyperoxaluria
There was a resolution of diarrhea in approximately 50% of patients either by discontinuation of diarrhea-associated nonimmunosuppressive drugs or by the treatment of concurrent infections (most frequently Campylobacter or CMV). In the remainder of patients, changes in immunosuppressive therapy (most commonly MMF) led to remission of diarrhea in about twothirds of cases. Thus, considered together, the data from the DIDACT study indicate that an infectious cause of posttransplant diarrhea is present in approximately 50% of cases with CMV being the most common pathogen.
CAUSE OF DIARRHEA: IMMUNOSUPPRESSIVE DRUGS Noninfectious diarrhea is not uncommon among renal transplant recipients and has been reported to increase the risk of graft loss and mortality
Drug-induced diarrhea is a major problem as many of the immunosuppressive agents commonly used in transplantation may cause diarrhea, with the highest incidence associated with MMF.
CAUSE OF DIARRHEA: INFECTIONS
Diarrhea is commonly infectious [26] and the microbes usually responsible are CMV and C. difficile, but the literature describes a wide range of organisms in solid organ transplant (SOT) recipients
In the first month following transplant,
patients are not yet completely immunosuppressed and infection with opportunistic pathogens is relatively uncommon. After the first few months posttransplant, opportunist pathogens become more evident as a cause of infection. It is important to remember that the individual is also being exposed to common community-associated pathogens (e.g. norovirus and enteropathogenic bacteria). C. difficile, CMV and norovirus are important causes of diarrhea in this population, and management should be focused on these causes.
DIAGNOSIS AND THERAPEUTIC STRATEGY It is important to evaluate and attempt to diagnose the cause of diarrhea in a transplant recipient. It is imperative that the clinician makes a distinction between noninfectious and infectious causes of diarrhea.
The gold standard for C. difficile detection is the cell-based cytotoxicity assay. However, most laboratories use the easier, less expensive and more rapid fecal enzyme immunoassays or real-time PCR test. These tests have high sensitivity and specificity (90%) for the detection of CDI
Only about 70% of patients will respond
to treatment with metronidazole; persistent and more severe cases will require oral vancomycin. The greatest challenge for toxigenic Clostridium infections remains the prevention and treatment of relapsing and refractory forms. In transplant recipients, it has been estimated that up to 20% of cases will have at least one relapse
The diagnosis of tissue-invasive CMV disease is suggested by the presence of CMV viremia. Many patients with CMV colitis will have evidence of CMV replication in the blood via PCR, although approximately 15% will not
Optimal duration of antiviral therapy depends on the patient’s clinical and virologic responses, not on a fixed period. Before antiviral therapy is stopped, the following three criteria should be met: the treatment was given for at least 2 weeks, clinical symptoms have resolved and viral load is no longer detectable, if initially detected
In diagnosis of rotavirus, immune-based assays
are most routinely used to rapidly detect rotavirus antigens in stool samples Other diagnostic methods such as cell culture, real time-PCR and electron microscopy remain as reference methods because of their high specificity and sensitivity
Currently, no antirotaviral therapies are available, and the treatment of rotavirus infection in SOT patients is mainly supportive
Physicians should be familiar with common causes that result in posttransplant diarrhea. A directed approach to diagnosis and treatment will not only help to resolve diarrhea, but also prevent potentially life-threatening consequences such as loss of the graft. Prior to implicating an immunosuppressant medication as the culprit, a meticulous evaluation for other possible causes of diarrhea should always be conducted. Infectious agents and the concomitant use of other diarrhea genic medications such as proton-pump inhibitors, antibiotics and diuretics must first be excluded.
Introduction: Chronic diarrhoea post-renal transplant (RTx) is a major issue of poor quality life in the renal transplant recipient with frequent hospitalization. Post RTX incidence diarrhoea is around 11.2 ,17.5 and 22.6% in the 1 year,2 and 3 years, respectively. Causes of posttransplant diarrhoea include: infections, antibiotics, immunosuppressive drugs and other drugs A single-centre study in the US: most of the diarrhoeal episodes were self-limiting with no identifiable cause, 13% were due to C. difficile, 4% noro-virus, 3.5% CMV, 32% of the patients had modulation of their immunosuppressive medications. DIDACT study: – large prospective study done to identify causes of posttransplant diarrhoea – infection was the cause of diarrhoea in 50% of the cases; CMV and campylobacter-related infections were the most common. Causes of diarrhoea Infectious: – Bacterial – Clostridium defficile, Campylobacter, Salmonella – Viral – CMV, Noro-virus, Rotavirus, Adenovirus – Parasitic – giardia, entamoeba, cryptosporidium, microsporidia, isospora Non-infectious cause – Immunosuppressive drugs: MMF, Tacrolimus – Non-immunosuppressive drugs: Antibacterial DIAGNOSIS AND THERAPEUTIC STRATEGY. The development of an optimal diagnostic algorithm is extremely challenging due to the varying causes of post-transplant diarrhoea, but a thorough evaluation is crucial for effective treatment. To diagnose and treat diarrhoea in transplant recipients, clinicians must distinguish between non-infectious and infectious causes.
A cell-based cytotoxicity assay is the gold standard for detecting Clostridium difficile infections. Enzyme immunoassays or real-time PCR test on stool sample is easier, less expensive and more rapid. These tests have high sensitivity and specificity (90%) for the detection of CDI.
– Initial treatment of SOT includes fidaxomicin, metronidazole or vancomycin. There is a good effect for use of human monoclonal antibodies against C. difficile toxins A and B and new trend for fecal microbiota transplantation. 2. Cryptosporidiosis is generally diagnosed by visualization of oocysts in the stool. There is no specific treatment – no difference between nitazoxanide or paromomycin and placebo for immunosuppressed patients with cryptosporidiosis.
CMV colitis is confirmed through endoscopic biopsy, histoaptho+IHC, along with CMV-DNA PCR in blood (positive in 80%). Patients are managed with intravenous ganciclovir or oral valganciclovir.
Norovirus infection management includes reduction of immunosuppression. There is no specific treatment or vaccination for norovirus. live attenuated vaccine against rotavirus is available for use before transplantation.
Adenovirus can be diagnosed by viral culture, direct antigen detection, histopathology, and PCR. Adenovirus can be managed with supportive care and a reduced immunosuppressive regimen.
xTAG Gastrointestinal Pathogen Panel, which allows for simultaneous detection of three viruses (norovirus G-I /G-II, rotavirus A and Adenovirus AdV 40/41), nine bacteria and three parasites, mainly treatment is supportive for norovirus with oral or intravenous immunoglobulin, breast milk, ribavirin and nitazoxanide.
Finally, the approach will be consisting of bacterial culture, assessment for ova and parasites, PCR for CMV and C. difficile and stool lactoferrin. The next steps were breath test for bacterial overgrowth, reduction in immune suppression and colonoscopy. Treatment: First attempt should be isolation of infectious pathogen and administer appropriate antibacterial or antiviral therapy. Change in immunosuppression consists of MMF dose reduction or switching to EC-MPS, followed ultimately by MMF-EC-MPS withdrawal if symptoms persist. Level of evidence: V -narrative review article
Magnitude of the problem.
· Medicare claims state that the The cumulative incidence of diarrhea is 11.5%, 17.5%, and 22.6% at 1, 2, and 3 years after transplantation respectively.
· a survey of 4,232 Scandinavian renal transplant recipients found that 53% of participants experienced diarrhea, while their physicians estimated the incidence to be only 6.9%. This suggests that the posttransplant diarrhea is over looked.
· in one large retrospective study, posttransplant diarrhea of unknown origin (noninfectious) was associated with a two-fold increase in graft loss and risk of death.
CAUSE OF DIARRHEA: IMMUNOSUPPRESSIVE DRUGS Noninfectious diarrhea is not uncommon among renal transplant recipients
many of the immunosuppressive agents commonly used may cause diarrhea, MMF. highest incidence
dose reduction is followed by the decrease or the disappearance of diarrhea . 1-MMF and enteric-coated mycophenolate sodium (EC-MPS)
A recent meta-analysis identified that the relative risk of diarrhea associated with the use of MMF is 1.57 The mechanismof MMF-induced diarrhea remains unknown.
Þ possible mechanism is that gastrointestinal epithelial cells may be partially dependent on the de-novo pathway of purine synthesis for growth and proliferation, and are therefore vulnerable to Myco- phenolic acid (MPA) inhibition leading to diarrhea.
Þ Histologically,
· predominant crypt distortion. (inflammatory bowel disease- like MPA-associated toxicity )
· predominant apoptosis. (graft-versus host-like MPA- associated toxicity . )
Þ switch of from MMF to EC-MPS helps reduce diarrhea symptoms is a matter of debate. A recent randomized and controlled open study suggested that patients with MMF-related diarrhea who switch to EC-MPS may have a slightly, yet significant, greater chance of returning to a target MPA doses than those maintained on MMF .
the switch from MPA to azathioprine (AZA) is usually avoided reduced graft survival with AZA
is safe in the short term [16]. tacrolimus diarrhea in 29 – 64% of patients The mechanism unclear,
macrolide structure may result in stimulation of the intestinal motilin receptors. mild course and rarely require discontinuation
daily, extended release formulation of tacrolimus reported a decrease in the incidence of gastrointestinal symptoms
Sirolimus causes self-limiting diarrhea in 14 – 42% of treated patients. drug-induced jejunal villous atrophy and a structural homology with the promotility macrolide class of drugs is a possible explanations antithymocyte globulin (ATG) and anti – T cell antibody (OKT3)
· up to one-third of patients, lasts for 3 – 4 days and resolves sponta-neously
· mechanism activating T cells to release tumor necrosis factor which then interferes with sodium ion absorption and also disrupts the intestinal mucosal barrier.
CAUSE OF DIARRHEA: INFECTIONS Diarrhea is commonly infectious · Clostridium difficile, norovirus (NV), and cytomegalovirus (CMV) are the most common causes of infectious diarrhea,
· opportunistic and parasitic infections infrequently encountered In the firstfew month following transplant, After the first few months post- transplant, opportunist pathogens become more evident as a cause of infection
# Norovirus infection
· recently emerged as one of infectious causes
· 17 – 26% of severe posttransplant diarrhea
· This finding suggests that numerous cases of posttransplant diarrhea in the past may have been incorrectly solely ascribed to toxicity of immunosuppressive drugs,.
· course of norovirus infection tend to be more complex
· up to 94% having chronic diarrhea and
· 81% having episodes of diarrhea-induced acute renal failure
· a biphasic illness in the course of norovirus. acute phase, classical illness with nausea, vomiting, significant diarrhea (10 – 20 watery stools per day), abdominal pain and sometimes fever. chronic phase, period of relatively normal stools alternating with periods of more poorly formed stools [4]. no specific treatment exists beyond providing supportive care and reducing immunosuppressive therapy..
# CMV In a recent study of 1427 SOT patients, 7.2% developed CMV disease, of which approximately one-third had gastrointestinal involvement
The most significant risk factor for the development of CMV disease is seropositive donor/seronegative recipients
# rotavirus infection
In one study, rotavirus infection was diagnosed in 1.5% of SOT recipients, with most cases occurring in pediatric patients (63%)
# Adenovirus
The epidemiology of AdV is similar in the SOT popula- tion and in the general population.
# C. difficile
· is the most common cause of nosocomial diarrhea
· accounts for most infectious diarrhea within the first months after transplantation
· The reported incidence of Cdiff 3.5-4.5%
· . The single most important risk factor is recent anti-biotic use. Among antibacterials, the fluoroquinolones are associated with the highest risk
· CDI has a significant effect on mortality of SOT recipients, with mortality rates between 2.3 and 8.5%, and is an independent risk for death (adjusted odds ratio 2.48, 2.22–2.76)
# the protozoan or metazoan are most common Parasitic cause
Gastrointestinal infection due to microsporidia has been recorded in patients with SOT who experienced diarrhea and weight loss Enterocytozoon bieneusi is by far the most frequent strain found in kidney transplant recipients . Cryptosporidia (Cryptosporidia parvum and Cryptospo-ridia hominis)
are intracellular protozoans known to lead to severe acute diarrhea, chronic diarrheal illness and extraintestinal infection in transplanted patient
Diagnostic and therapeutic strategy for postrenal transplant diarrhea No evidence-based guidelines are available for the evaluation of diarrhea in SOT recipients.
management should be focused on these causes
Initially, all patients with diarrhea should have their medications reviewed for potential causes of diarrhea, and unnecessary agents should be stopped and followed by specific testing for different causes of the diarrhea The first-line microbiologic stool investigations
stool cultures for pathogenic bacteria, examinations for parasites and fungi, C. difficile toxin assay and quick tests for rotavirus, adenovirus and norovirus.
In case of fever, CMV Dþ/Rj serologic status, cytopenia, liver enzymes studies, and plasma CMV Q-PCR should be performed. (in our center we do it as a routine in any patient with chronic diarrhea Multiplex pcr based screening of chronic diarrhea for enteric pathogen
Campylobacter species, enteropathogenic and enterotoxigenic Escherichia coli, Shigella species, Salmonella species, Yersinia, Clostridium difficile, Cryptosporidium, Enterocytozoon bieneusi, Enteric viruses (rotavirus, adenovirus, norovirus and enterovirus).
The next steps were breath test for bacterial overgrowth, reduction in immune suppression and colonoscopy. If these tests are negative and the diarrhea persists, empiric antidiarrheal medications, probiotics and/or lac- tose-free diet should be tried.
performing esophagogastroduodenoscopy and colonoscopy with biopsies is necessary to investigate persistent diarrhea after kidney transplantation. This is because several conditions such as large bowel posttransplant lymphoproliferative disorder, CMV colitis, severe duodenal villous atrophy, and de-novo inflammatory bowel disease may be the underlying cause.
Chronic diarrhea following RTX is a significant cause of low quality of life and frequent hospitalization in renal transplant recipients.
The incidence of diarrhea following RTX is around 11.2, 17.5, and 22.6% in the first, second, and third years, respectively.
An American single-center research found that infections, antibiotics, immunosuppressive medications, and other treatments can all cause posttransplant diarrhea. Infection was the cause of diarrhoea in 50% of cases, with CMV and campylobacter-related infections being the most common. The majority of the diarrhoeal episodes were self-limiting with no apparent cause, 13% were due to C. difficile, 4% norovirus, 3.5% CMV, and 32% of the patients had modulation of their immunosuppressive medications.
The most frequent causes of post-transplant diarrhea are infections and drug usage, while there are many other potential reasons that might be difficult to identify. When treating patients with diarrhea, doctors should make every effort to distinguish between infectious and noninfectious causes.
To learn more about the prevalence, risk factors, and consequences of diarrhea in kidney transplant patients—particularly with regard to norovirus, rotavirus, and AdV infections—prospective studies are required.
The majority of IS agents that are often used in transplantation can induce diarrhea, with MMF having the greatest prevalence and an unknown primary reason. According to one idea, tacrolimus can also cause diarrhea in 29–64% of patients depending on the dosage and length of medication use. However, switching to tacrolimus’ extended release formulation has shown some relief.
Approximately 17–26% of severe post–transplant diarrhea is biphasic, consisting of an acute phase (characterized by 10–20 watery stools per day), abdominal pain, and occasionally fever, then a chronic phase, during which patients may alternate between cycles of relatively normal stools and periods of less-than-ideal stools.
Seropositive donors and seronegative recipients’ gastrointestinal involvement, which happens in up to 40% of patients, is the most important risk factor for the development of CMV illness. CMV is one of the most prevalent causes of diarrhea after kidney transplantation.
The incidence of C. difficile infection (CDI) in transplanted patients has been reported to be approximately 3.5–4.5% in adult renal transplantation patients.
Finally, the approach will be consisting of bacterial culture, assessment for ova and parasites, PCR for CMV and C. difficile and stool lactoferrin. The next steps were breath test for bacterial overgrowth, reduction in immune suppression and colonoscopy.
Chronic diarrhoea post-RTX is a major issue of poor quality of life in the renal transplant recipient with frequent hospitalization.
post RTX incidence diarrhoea is around 11.2 ,17.5 and 22.6% in the 1 year,2 and 3 years, respectively.
Causes of posttransplant diarrhoea include: infections, antibiotics, immunosuppressive drugs and other drugs
single-centre study in the US: most of the diarrhoeal episodes were self-limiting with no identifiable cause, 13% were due to C. difficile, 4% norovirus, 3.5% CMV, 32% of the patients had modulation of their immunosuppressive medications
– DIDACT study, large prospective study done to identify causes of posttransplant diarrhoea
– infection was the cause of diarrhoea in 50% of the cases, CMV and campylobacter-related infections were the most common Causes of diarrhoea
could be infectious and non-infectious
the infectious could be c. diff ,campylobacter, salmonella,
viral: CMV,norovirus,rotavirus, adenovirus
Parasitic: giardia, entamoeba, cryptosporidium, microsporidia, isospora
non-infectious cause
Immunosuppressive drugs: MMF, tacrolimus, cyclosporine, sirolimus
· Non-immunosuppressive drugs: antibacterial, antiarrhythmic, antidiabetic, laxatives. PPIs, protease inhibitors
this article level 5
Chronic diarrhea is a common complaint after kidney transplantation, with negative impacts on quality of life, graft survival, and mortality. Infectious and noninfectious causes of diarrhea can be difficult to distinguish, but infections and medication use are the most common causes.
Chronic diarrhea is often neglected by clinicians and patients, despite its significance. Chronic diarrhea can result in steatorrhea and malabsorption, which can induce enteric hyperoxaluria and lead to devastating effects on renal graft function.
The causes of post-transplant diarrhea are varied and can be challenging to diagnose, but infections and medication use are the most common culprits. Clinicians should make every effort to distinguish between infectious and noninfectious causes of diarrhea and provide appropriate treatment.
Prospective studies are needed to better understand the prevalence, risk factors, and complications of diarrhea in kidney transplant patients, particularly with respect to norovirus, rotavirus, and AdV infections.
The development of an optimal diagnostic algorithm is extremely challenging due to the varying causes of post-transplant diarrhea, but a thorough evaluation is crucial for effective treatment.
To diagnose and treat diarrhea in transplant recipients, clinicians must distinguish between noninfectious and infectious causes.
A cell-based cytotoxicity assay is the gold standard for detecting Clostridium difficile infections.
Cryptosporidiosis is generally diagnosed by visualization of oocysts in the stool.
CMV colitis is confirmed through endoscopic evidence of gastrointestinal involvement or histopathology, and patients can be managed with intravenous ganciclovir or oral valganciclovir.
Norovirus infection management includes reduction of immunosuppression. There is no specific treatment or vaccination for norovirus.
Adenovirus can be diagnosed by viral culture, direct antigen detection, histopathology, and PCR.
Adenovirus can be managed with supportive care and a reduced immunosuppressive regimen.
In most centers, the first change in immunosuppression consists of MMF dose reduction or switching to EC-MPS, followed ultimately by MMF-EC-MPS withdrawal if symptoms persist.
The cumulative incidence of diarrhea has been reported to be 11.5, 17.5 and 22.6% at 1, 2 and 3 years after renal transplantation, respectively.
In some studies, shown that diarrhoea was associated with a two-fold increase in graft loss and risk of death. Another study shown that the most common identifiable causes included Clostridium difficile infection, norovirus infection, and cytomegalovirus (CMV) gastrointestinal infection.
32% of individuals taking MMF or mycophenolic acid and diagnosed with diarrhoea had reductions or changes in their immune suppression.
DIDACT study shown that an infectious cause of post-transplant diarrhoea is present in approximately 50% of cases with CMV being the most common pathogen and the next most frequent cause is related to medication use.
IS
Most IS agents that commonly used in transplantation may cause diarrhea, with the highest incidence associated with MMF and still the main cause not well known. There has been theory mainly due to purine inhibition effect of KIT epithelial cells, tacrolimus also lead to diarrhea in 29–64% of patients depending upon the dose and duration of drug usage and shifting to extended release formulation of tacrolimus shown some improvement.
INFECTIONS
approximately 17–26% of severe post-transplant diarrhea
usually is biphasic which consist of the initial acute phase (10–20 watery stools per day), abdominal pain and sometimes fever then followed by a chronic phase, when patients can experience cycles of relatively normal stools followed by periods of more poorly formed stools.
CMV – one of the most common cause of diarrhea post kidney transplant and the most significant risk factor for the development of CMV disease is seropositive donor/seronegative recipients’ gastrointestinal involvement that occurs in up to 40% of patients.
The incidence of C. difficile infection (CDI) in transplanted patients has been reported to be approximately 3.5–4.5% in adult renal transplantation patients.
DIAGNOSIS AND THERAPEUTIC STRATEGY.
The gold standard for C. difficile detection is the cell-based cytotoxicity assay
easier, less expensive and more rapid fecal enzyme immunoassays or real-time PCR test.
These tests have high sensitivity and specificity (90%) for the detection of CDI and initial treatment of SOT includes fidaxomicin, metronidazole or vancomycin, with vancomycin, now there is a good effect for use of human monoclonal antibodies against C. difficile toxins A and B and new trend for fecal microbiota transplantation.
Cryptosporidiosis is generally diagnosed by visualization of oocysts in the stool, there is no specific TTT but studies shown that no difference between nitazoxanide or paromomycin and placebo for immunosuppressed patients with cryptosporidiosis.
CMV colitis will have evidence of CMV replication in the blood via PCR, although approximately 15% will not, so the gold standard for diagnosis histopathology by endoscopy and patientswith CMV colitis can be managed with intravenous ganciclovir or oral Valganciclovir.
xTAG Gastrointestinal Pathogen Panel, which allows for simultaneous detection of three viruses (norovirus G-I/G-II, rotavirus A and AdV 40/41), nine bacteria and three parasites, mainly treatment is supportive for norovirus with oral or intravenous immunoglobulin, breast milk, ribavirin and nitazoxanide.
We can use vaccine against rotavirus but before transplantation as there are live attenuated vaccine.
Finally, the approach will be consisting of bacterial culture, assessment for ova and parasites, PCR for CMV and C. difficile and stool lactoferrin. The next steps were breath test for bacterial overgrowth, reduction in immune suppression and colonoscopy.
Chronic diarrhoea post-RTX is a major issue of poor quality of life in the renal transplant recipient with frequent hospitalization.
post RTX incidence diarrhoea is around 11.2 ,17.5 and 22.6% in the 1 year,2 and 3 years, respectively. Causes of posttransplant diarrhoea include: infections, antibiotics, immunosuppressive drugs and other drugs
single-centre study in the US: most of the diarrhoeal episodes were self-limiting with no identifiable cause, 13% were due to C. difficile, 4% norovirus, 3.5% CMV, 32% of the patients had modulation of their immunosuppressive medications – DIDACT study, large prospective study done to identify causes of posttransplant diarrhoea – infection was the cause of diarrhoea in 50% of the cases, CMV and campylobacter-related infections were the most common Causes of diarrhoea could be infectious and non-infectious the infectious could be c. diff ,campylobacter, salmonella, viral: CMV,norovirus,rotavirus, adenovirus
Parasitic: giardia, entamoeba, cryptosporidium, microsporidia, isospora
II. Causes and management of postrenal transplant diarrhoea: an underappreciated cause of transplant-associated morbidity
Summarise this article
Introduction
– chronic diarrhoea is a common complaint though often under-estimated by practitioners
– it is associated with fatigue, increased hospitalization, negative impact on the recipients’ quality of life, graft survival, higher mortality
– severe and chronic diarrhoea can cause steatorrhea and malabsorption which can induce enteric hyperoxaluria
– oxalate nephropathy can cause inflammation and may have negative effects on the graft function
– risk factors for development of posttransplant diarrhoea include: immunosuppression, polypharmacy notably broad-spectrum antibiotics
– causes of posttransplant diarrhoea include: infections, antibiotics, immunosuppressive drugs and other drugs
– clinicians should attempt to distinguish between noninfectious and infectious causes of diarrhoea in KTRs
– due to the diverse causes of posttransplant diarrhoea, it is difficult to come up with a single optimal diagnostic algorithm
Epidemiologic impact
– the cumulative incidence of posttransplant diarrhoea has been reported as 11.5, 17.5 and 22.6% at 1, 2 and 3 years respectively
– posttransplant diarrhoea is often underreported and underrecognized by practitioners
– adverse GI symptoms adversely affect the quality of life, graft and patient survival
– single-center study in the US: most of the diarrhoeal episodes were self-limiting with no identifiable cause, 13% were due to C. difficile, 4% norovirus, 3.5% CMV, 32% of the patients had modulation of their immunosuppressive medications
– DIDACT study, large prospective study done to identify causes of posttransplant diarrhoea
– infection was the cause of diarrhoea in 50% of the cases, CMV and campylobacter-related infections were the most common
– medication use was the 2nd most common cause of diarrhoea
– 50% of patients had resolution of symptoms after withdrawal of offending non-immunosuppressive drugs or by treatment of infections (CMV, campylobacter)
– 2/3 of the cases had resolution of symptoms following adjustment in MMF dose
Causes of diarrhoea
– Causes of diarrhoea can be infectious or noninfectious
– Infectious causes of diarrhoea:
· Bacteria: C. difficile, campylobacter, salmonella, bacterial overgrowth, E. coli
· Viruses: CMV, norovirus, rotavirus, adenovirus, sapobavirus
· Parasitic: giardia, entamoeba, cryptosporidium, microsporidia, isospora
Causes of diarrhoea: Immunosuppressive drugs
– noninfectious diarrhoea increases graft loss and mortality
– most immunosuppressive agents cause diarrhoea but MMF is associated with the highest incidence
– a dose reduction in MMF results in a decrease or resolution of the diarrhoea
– postulated mechanism of MMF-induced diarrhoea: MPA inhibit purine synthesis – the GI epithelial cells are partially dependent on the de novo pathway of purine synthesis for growth and development, inhibition therefore leads to diarrhoea
– 2 different morphologic patterns have been described histologically:
· predominant crypt distortion a.k.a. IBD-like MPA-associated toxicity
· predominant apoptosis a.k.a. GVHD-like MPA toxicity
– whether switching from MMF to EC-MPS reduces diarrhoea symptoms remains debatable
– patients with MMF-related diarrhoea who switch to EC-MPS may have a slight but significant greater chance of returning to a target MPA dose than those who remain on MMF
– switch from MPA to AZA is safe in the short term but it is associated with reduced graft survival
– AZA has been associated with an increased risk of skin cancer especially SCC
– tacrolimus-related diarrhoea occurs in 29-64% of patients depending on the dose and duration of drug usage
– mechanism of CNI-related diarrhoea is still unclear with a hypothesis that the macrolide structure results in stimulation of the intestinal motilin receptors
– tacrolimus-related GI side effects have a mild course and rarely require drug discontinuation
– conversion to a daily, extended-release tacrolimus formulation may decrease the incidence of the GI symptoms
– sirolimus causes self-limiting diarrhoea in 14-42% of patients, the mechanism is unclear but is thought to be due to drug-induced jejunal villous atrophy and structural homology in this promotility macrolide class of drugs
– ATG and anti-T cell antibody (OKT3) are associated with diarrhoea in 1/3rd of patients
– the diarrhoea lasts 3-4 days and resolves spontaneously
– ATG and OKT3 activate T cells to release TNF which interferes with Na+ absorption and also disrupts the intestinal mucosal barrier
Causes of diarrhoea: Infections
– CMV, C. difficile, norovirus, enteropathogenic bacteria are common and important causes of diarrhoea although other organisms have been identified
– norovirus and enteropathogenic bacteria are common community acquired pathogens
– norovirus account for 17-26% of the cases of severe posttransplant diarrhoea and it has 2 phases:
·the initial acute phase where patients present with nausea, vomiting, diarrhoea, abdominal pain, fever
· chronic phase where patients experience relatively normal stools followed by periods of poorly formed stools
– risk factors for CMV infection:
· pretransplant CMV serostatus D+/R- (most important) and to a lesser degree, D-/R+
· lymphodepleting antibodies
· more potent immunosuppressive regimens
– there is a direct relationship between CMV infection and the level of posttransplant immunosuppression
– other viruses that have been identified include: rotavirus, adenovirus
– C. difficile infection (CDI):
· is the most common cause of nosocomial diarrhoea
· accounts for most infectious diarrhoea in the first months posttransplant
· risk factors include: recent antibiotic use (fluoroquinolones are associated with the highest risk), age >55 years, use of ATG, re-transplantation, organ type (highest rate among liver recipients)
· has a significant impact on mortality
– common parasitic infections include: enterocytozoon bieneusi, microsporidia, cryptosporidium
Diagnosis and therapeutic strategy
– it is prudent to distinguish between noninfectious and infectious diarrhoea
– avoid unnecessary reduction in immunosuppressive agents in a bid to try and manage diarrhoea since this has its own consequences including graft loss
– cell-based cytotoxicity assay is the gold standard for C. difficile detection
– most labs use the fecal enzyme immunoassays or real-time PCR tests since they are easier, less expensive and more rapid, have a high sensitivity and specificity (90%) for the detection of CDI
– transplant patients can have asymptomatic CDI but most present with diarrhoea, intestinal obstruction, abscess, toxic megacolon
– initial CDI treatment includes: fidaxomicin, metronidazole or vancomycin
– vancomycin is preferred for severe CDI cases
– only ~70% of patients respond to metronidazole
– the persistent and more sever cases require oral vancomycin
– prevention and treatment of the relapsing and refractory forms of toxigenic clostridium infections remains a big challenge
– up to 20% of transplant patients will have at least one relapse
– newer antibiotics used in the treatment of severe or recurrent disease include: fidaxomicin, ramoplanin, tigecycline
– human monoclonal antibodies against C. difficile toxins A and B have produced encouraging results
– use of fecal microbiota transplantation (FMT) is being studied, it involves instillation of processed donor faeces into the colon or duodenum of the recipient
– FMT has a high success rate as well as a high adverse effect rate warranting further study
– there is limited data on FMT among transplant patients
– fumagillin is used in the treatment of microsporidia-related diarrhoea, clears E. bieneusi with minimal reduction in immunosuppression
– unfortunately, fumagillin use is limited due to drug-induced thrombocytponeia
– Cryptosporidiosis is diagnosed by visualization of the oocysts in stool
– immunofluorescence assays and ELISA have a sensitivity and specificity of ~100%, this is far much better than the traditional modified acid-fast stains
– there are no existing specific therapies against cryptosporidium
– there was no difference between nitazoxanide or paromomycin and placebo among immunocompromised patients with cryptosporidiosis
– Diagnosis of CMV-associated colitis:
· presence of CMV viremia suggests a diagnosis of tissue-invasive CMV disease
· CMV serology is limited for determination of an active infection
· disadvantages of the conventional culture: has a lower sensitivity, longer incubation period, insufficient CMV virus quantity, high rate of false negatives
· shell vial assay – faster than the conventional culture but has a low sensitivity rate
· CMV pp65 Ag test – can be done on blood and CSF fluid
· CMV PCR – done on whole blood, plasma, leucocytes
· Endoscopy – is the definitive/ gold standard test for the diagnosis of CMV GI disease, confirmed on histopathology via the characteristic swollen cells containing “owl’s eye” intranuclear inclusions or IHC staining for pp65; however, viral inclusions are not easily seen
– Management of CMV colitis: IV ganciclovir (GCV) or oral valganciclovir (valGCV)
– IV GCV is preferred in cases where there is a likelihood of inadequate absorption of oral valGCV (e.g., patients with diarrhoea and vomiting) and early in the treatment of proven CMV colitis
– duration of treatment depends on the patient’s clinical and virological response
– criteria to be met before stopping antiviral therapy:
· been on treatment for at least 2 weeks
· resolution of clinical symptoms
· undetectable CMV viral load (if initially detected)
– 15-35% of SOT recipients with tissue invasive CMV disease develop recurrent CMV disease hence many experts recommend secondary prophylaxis with valGCV for 30-90 days following successful treatment
– Norovirus diagnosis: PCR run on stool, vomitus, foods, environmental specimens
– there is GI pathogen panel that detects 3 viruses (norovirus, rotavirus, adenovirus), 9 bacteria and 3 parasites – it is yet to be tested in the immunosuppressed population
– Norovirus management:
· supportive care i.e., fluid and electrolyte replacement
· reduction in immunosuppression – this is the most effective strategy
– norovirus is key in the induction of posttransplant diarrhoea
– MMF plays a significant role in the chronicity of symptoms – it prevents viral clearance and intestinal epithelium repair
– chronic norovirus-related diarrhoea is a major concern, often results in discontinuation of MMF and this is associated with increased risk of rejection
– no norovirus vaccine available as yet
– prevention of norovirus infection (i.e., hand washing, environmental sanitization) is key since there is no specific treatment or vaccination available
– Diagnosis of Rotavirus:
· immune-based assays – routinely used to rapidly detect rotavirus antigens in stool
· cell culture, real time-PCR and electron microscopy – have high sensitivity and specificity, remain as reference methods
– Management of Rotavirus:
· mainly supportive, there are no anti-rotaviral therapies available
· contact precautions to prevent viral transmission – disinfect contaminated surfaces with 95% ethanol or other alcohol-based disinfectants since the general disinfectants e.g., bleaches are ineffective
· there are two live attenuated oral vaccines available i.e., RotaTeq and Rotarix, however, transplant candidates can only be vaccinated pre-transplant (avoid live vaccines in the posttransplant period)
– Diagnosis of Adenovirus: direct antigen detection, viral culture, histopathology, PCR
– viral culture is the gold standard but can take up to 28 days to develop cytopathic effects and the serotypes associated with diarrhoea do not grow well in cell culture
– the clinical utility of direct antigen detection methods in immunocompromise patients remains unknown
– Management of Adenovirus – there is limited data:
· supportive care
· reduction in immunosuppression
· contact and droplet precautions to help prevent infections
– DIDACT study,
· large prospective study, which evaluated a stepwise prospective diagnostic and therapeutic flow chart
· the aim was to treat infectious causes and eliminate non-immunosuppressive drug toxicity causative factors before modifying the immunosuppressive regimen
· 28% patients had infectious causes of diarrhoea, with campylobacter jejuni enteritis and CMV colitis being the most common
· diarrhoea resolved in 50% of the patients without any change in immunosuppressive therapy
· 30% of the patients diagnosed with bacterial overgrowth responded to antibiotics
· review the patient’s medications for potential causes of diarrhoea, stop any unnecessary drugs
· test for the different causes of diarrhoea: assess for ova and parasites, bacterial culture, PCR for CMV and C. difficile and stool lactoferrin, breath test for bacterial overgrowth, reduction in immunosuppression and colonoscopy
· if the above are negative and diarrhoea persists, give a trial of anti-diarrhoeal medications, probiotics, lactose-free diet
· OGD, colonoscopy with biopsies
· treatment of diarrhoea with hydration, focused use of antimicrobials or modulation of immunosuppressive agents is crucial
· optimization and modulation of immunosuppression in patients with persistent posttransplant diarrhoea remains debatable and warrants prospective studies
· the first change in immunosuppression consists of reducing MMF dose or switching to EC-MPS
· if symptoms persist then withdraw MMF-EC-MPS
Conclusion
– clinicians should be familiar with the various causes of posttransplant diarrhoea
– a directed/ systematic approach to diagnosis and treatment of posttransplant diarrhoea helps resolve the diarrhoea as well prevent life-threatening consequences like graft loss
– evaluate thoroughly for other potential causes of diarrhoea before implicating an immunosuppressive agent
– exclude infectious agents, use of other drug-related diarrhoea e.g., antibiotics, PPIs, diuretics
– prospective studies are needed to evaluate the prevalence, risk factors, complications, diagnosis, management, prevention, vaccine development of diarrhoea caused by rotavirus, norovirus and adenovirus-related diarrhoea
– development of vaccines and antiviral therapies for these common viruses will greatly improve patient and graft survival
Level of evidence provided by this article
– Level 5
● Chronic diarrhea after kidney transplantation is a common complaint
● Steatorrhea and malabsorption may result from severe and chronic posttransplant diarrhea and induce enteric hyperoxaluria
● Oxalate nephropathy is associated with inflammation and may have devastating effects on renal graft function
● Causes of diarrhea after transplantation:
☆ Infections
☆ Immunosuppressive drugs
☆ Antibiotics and other drugs.
◇ EPIDEMIOLOGIC IMPACT
☆ The cumulative incidence of diarrhea is 11.5, 17.5 and 22.6% at 1, 2 and 3 years after renal transplantation
☆ posttransplant diarrhea of unknown origin was associated with a two-fold increase in graft loss and risk of death
☆ Majority of the diarrheal episodes had no identifiable cause and were self-limited.
☆ The most common causes included:
* Clostridium difficile infection
* Norovirus infection
* CMV
* Gastrointestinal infection
◇ CAUSES OF DIARRHEA: GENERAL:
● Changes in immunosuppressive therapy (most commonly MMF) led to remission of diarrhea in about two-thirds of cases.
● The infectious cause of posttransplant diarrhea is present in approximately 50% of cases with CMV being the most common pathogen.
● The next most frequent cause is related to medication use
1). IMMUNOSUPPRESSIVE DRUGS
☆ Many immunosuppressive agents used
in transplantation may cause diarrhea, especially MMF.
☆ Dose reduction is followed by the decrease or the disappearance of diarrhea
☆ MMF and enteric-coated mycophenolate sodium (EC-MPS) have long been implicated in posttransplant diarrhea.
☆ The relative risk of diarrhea associated with use of MMF is 1.57 and mechanism is that growth and proliferation of gastrointestinal epithelial cells depends on the de-novo pathway of purine synthesis which inhibits by MPA leading to diarrhea
● Histologically
* predominant crypt distortion, inflammatory bowel disease like MPA-associated toxicity
* predominant apoptosis:
graft-versus host-like MPA- associated toxicity
● switch from MPA to AZA is usually avoided because of reduced graft survival with AZA as compared to MMF besides a significantly increased risk of skin cancer in relation to AZA exposure
● Tacrolimus associated with diarrhea in 29–64% depending on dose and duration by stimulation intestinal motilin receptors.
Most of these cases are mild course
● Conversion to a daily, extended release tacrolimus associated with a decrease in diarrhea
● Sirolimus causes diarrhea by jejunal villous atrophy with the promotility macrolide class of drugs
● ATG and OKT3 therapies are associated with diarrhea by releasing TNF which disrupts the intestinal mucosal barrier and resolves spontaneously
◇ CAUSE OF DIARRHEA: INFECTIONS
● After the first few months post-transplant, opportunist pathogens become more evident as a cause of infection.
● CMV and norovirus are important causes of diarrhea
● Chronic norovirus infection is one of the causes of post KTx with 94% of patients having chronic diarrhea and 81% having episodes of diarrhea-induced AKI with acute phase (nausea, vomiting, abdominal pain, fever,and 10-20 watery stools per day and a chronic phase ( cycles of normal stools followed by periods of poorly formed stools
● CMV is one of the most common infectious affecting SOT patients
● It’s most common target organ is the gastrointestinal tract
● 7.2% developed CMV disease, and of which one-third had GI involvement
● Risk factors for CMV disease include:
* (D+/R–) , (D–/R+)
* Lymphodepleting antibodies
● Rotavirus infections was diagnosed in 1.5% of SOT recipients especially in pediatric patients (63%) and liver transplant
● In adults, adenovirus (AdV) associated with GI symptoms in 10% of the cases.
● C. difficile is the most common cause of nosocomial diarrhea and accounts for most infectious diarrhea within the first months after transplantation
● The incidence of (CDI) is 3.5–4.5% in adult renal transplantation patients
● Risk factors include:
* Age above 55 years
* Use of ATG
* Retransplantation
* liver recipients
* Recent antibiotic use ( fluoroquinolones)
● CDI is an independent risk for death
● Among parasities, the protozoan are most common. Enterocytozoon bieneusi is the most frequent strain in KTRs
● Cryptosporidia are intracellular protozoans lead to diarrhea in KTRs
◇ DIAGNOSIS AND THERAPEUTIC
¤ Clostridium difficile
● Diagnosis by Real-time PCR with Sensitivity 85% and Specificity 77%
● 70% of patients will respond to metronidazole
● persistent and more severe cases will require oral vancomycin.
☆ First episode: metronidazole 500 mg three times per day for 10–14 days
☆ Severe disease:
* Vancomycin oral four times per day for 10–14 days
* Fidaxomicin 20 mg two times per day for 10 days
☆ First relapse: same for first episode
☆ Second relapse: vancomycin taper with pulse
☆ third relapse: consider fecal microbiota transplantation, prolonged oral vancomycin
● 20% of cases will have at least one relapse
● Fidaxomicin, ramoplanin and tigecycline are newer antibiotics that are effective for severe or recurrent disease
● New therapy :
☆ Human monoclonal antibodies against C. difficile toxins A and B
☆ Fecal microbiota transplantation (FMT) in the management of refractory CDI.
¤ Microsporidia-related diarrhea,
● Fumagilin may lead to sustained clearance of E. bieneusi but
thrombocytopenia limit it’s use
¤ Cryptosporidiosis
● Diagnosed by :
* visualization of oocysts in the stool.
* ELISA ( sensitivity and specificity 100%)
● No specific therapies directed toward cryptosporidium were exist.
¤ CMV disease
● The diagnosis
☆ PCR CMV in blood (sensitivity and specificity 91%)
☆ Serology (in new onset infections)
☆ Virus culture (lower sensitivity, long incubation period)
☆ Shell Vial Assay (low sensitivity)
☆ CMV pp65 Antigen Test in blood and CSF( sensitivity 83% and specificity 96%)
☆ Definitive diagnosis of CMV relies on endoscopic and histopathology (owl’s eye)
● Treatment :
Oral valganciclovir or IV ganciclovir in case of vomiting, diarrhea, or early CMV colitis
● Don’t stop CMV Treatment before :
☆ At least 2 weeks
☆ Resolved clinical symptoms
☆Undetectable viral load
☆ Because of recurrent CMV disease in SOT recipients secondary prophylaxis for 30–90 days with valGCV is recommended
¤ Norovirus
● Diagnosis by PCR on stool, vomitus, foods and environmental specimens
● Supportive care is the first treatment:
* Rehydration
*Antimotility drugs
* RI
* Replenishment of fluids and electrolytes
● Norovirus is the key factor in the induction of posttransplant diarrhea, whereas MMF plays a critical role in the chronicity of the symptoms
● No vaccines are available for norovirus
● prevention is essential by hand hygiene and environmental sanitization
¤ Rotavirus
● immune-based assay to detect antigens in stool is routinely used but culture, real time-PCR have high specificity and sensitivity
● Treatment is mainly supportive
● Prevention by contact precautions and disinfect surfaces by ethanol or alcohol
● Two live oral vaccines against rotavirus that should receive before transplantation
¤ Adeno Virus :
● Diagnosed by viral culture, direct antigen detection, histopathology and PCR
● Treatment
* Supportive care
* RI
● prevention by infectious control measures including contact and droplet precautions
● Treatment of diarrhea, with hydration and focused use of antimicrobials or changes in immune suppression, is of the
utmost importance.
● The first change in IS consists of :
* MMF dose reduction
* switching to EC-MPS
* MMF-EC-MPS with-drawal if symptoms persist
◇ CONCLUSION
● Common causes of posttransplant diarrhea should be familiar
● Diagnosis and treatment will prevent life-threatening consequences and loss of the
graft.
● Causes of diarrhea ( infections and non Immunosuppressive drug ) should be excluded before implicating IS drugs
● Development of effective vaccines and antiviral therapies will improve patient and graft survival.
Introduction:
Chronic diarrhea is common complain post renal transplantation and associated with fatigue, increased hospitalizations and negative impacts on recipient quality of life
It can also cause Steatorrhea and malabsorption which induce oxalate nephropathy that affect renal graft function.
The main causes of diarrhea after transplantation are infections, immunosuppressive drugs, antibiotics and other drugs EPIDEMIOLOGIC IMPACT:
The cumulative incidence of diarrhea has been reported to be 11.5, 17.5 and 22.6% at 1, 2 and3 years postrenal transplantation, respectively
causes of diarrhea:
There are relatively little data regarding the cause of posttransplant diarrhea.
(DIDACT) study – was conducted to identify the cause of posttransplant diarrhea in renal transplant recipients
There is 50% of diarrhea resolution by treatment of infection or by discontinuation of immunosuppressive drugs
Causes of postrenal transplant diarrhea infection (50%) and noninfectious:
Infectious causes: bacteria, viruses (CMV most), parasites
Noninfectious causes: immunosuppressive and non immunosuppressive medications and other causes Diagnosis and therapeutic strategies: It is imperative to distinguish between infectious and noninfectious cause of diarrhea and consider graft function in adjusting immunosuppressive medications. C.difficile: Detected by cell based cytotoxicity assay but it cost instead we use CDI PCR with a sensitivity and specificity of 90%. Treatment includes: Flagyl, fidaxomicin or vancomycin with vancomycin being preferred in severe cases. for refractory cases we use: fidaxomicin, ramoplanin and tigecycline. Novel therapies; Human monoclonal antibodies against C.Difficile toxin A and B,Fecal Microbiodata transplantation. Fumagilin has good outcomes in treatment of microsporidia but we need to look out for thrombocytopenia. Cryptosporidia: It is diagnosed via IF,ELISA and oocyst visualization. It has no specific treatment. CMV It is diagnosed via CMV viremia and PCR. Endoscopic confirmation of owls eye inclusion or IHC staining for PP65.Viral inclusion though sensitive and gold standard is rare. Treatment either IV GCV or PO ValGCV. Treatment stopped if ;1- given for weeks 2-Resolution of clinical symptoms 3-viral load undetectable. ValGCV is recommended for secondary prophylaxis for 30 to 90 days post-transplant. Norovirus Itis detected by PCR from stool, vomitus, foods and environmental specimens Treated by rehydration, electrolyte correction and reduction in immunosuppressive therapy. Prevention is key in managing norovirus. Rotavirus: It is diagnosed via immune based assays, cell culture and real time PCR. It is treated by supportive care with emphasis on preventive protocols. Vaccines available are; Rota teq and Rotarix which should be given pre transplant as they are live. Adenovirus is detected by viral culture, direct antigen detection, histopathology and PCR. It is treated with supportive measures and reduction in immunosuppressive medications. Indications for esophagogastroduodenoscopy + colonoscopy with biopsy in persistent diarrhea: 1. Intestinal ulceration from large bowel PTLD may have exudative enteropathy and chronic diarrhea. 2. CMV colitis with simultaneous Neg CMV PCR has been reported. 3. Severe duodenal villous atrophy may cause some medics to adjust immunosuppressive meds regardless of cause. 4. Post KTR de novo IBD occurs x10 in transplant population than the general population Conclusion: Physicians should be familiar with common causes that result in posttransplant diarrhea. A directed approach to diagnosis and treatment will not only help to resolve diarrhea, but also prevent potentially life-threatening consequences such as loss of the graft. Infectious agents and the concomitant use of other diarrhea genic medications such as proton-pump inhibitors, antibiotics and diuretics must first be excluded. Prospective studies are needed to better assess in kidney transplant patients the true prevalence, risk factors and complications of diarrhea by norovirus, rotavirus and AdV. Development of effective vaccines and antiviral therapies for these common viruses will likely improve patient and graft survival This a narrative review level of evidence: 5
Causes and management of postrenal transplant diarrhea: an underappreciated cause of transplant-associated morbidity Overall incidence: The cumulative incidence of diarrhoea has been reported to be 11.5, 17.5 and 22.6% at 1, 2 and 3 years post renal Tx. Half of diarrheal episodes results from infection with CMV being one of the common causes
MMF related: Relative risk of diarrhea associated with the use of MMF is 1.57 mechanism GI epi cells may be partially dependent on the de-novo pathway of purine synthesis for growth and proliferation, therefore vulnerable to Mycophenolic acid (MPA) inhibition leading to diarrhea Types: a) IBD like MPA-associated toxicity: predominant crypt distortion b) GVH like MPA-associated toxicity: predominant apoptosis Management: Decrease MMF dose by 50% Shifting from MMF to enteric coated mycophenolate (debatable) Shifting from MMF to azathioprine (not preferable due to reduced graft survival and higher skin cancer incidence) TAC realted: Incidence: 30-60 % of cases depending upon the dose and duration of drug usage Mechanism: it may stimulate intestinal motilin receptors, but it is usually mild, self-limited, and not require drug discontinuation. Management: Shift to extended release (advagraf) or switch to ciclosporin Close follow up of CN level as there may be an increase in tacrolimus level with diarrhea due to disruption of P-glycoprotein efflux pump in the damaged enterocytes. mTOR: Incidence: 14-40 % of cases Mechanism: jejunal villous atrophy Management: self-limited or switch to CNI ATG: Incidence: 1/3 patients Mechanism: ATG can activate T cells to release TNF which then interferes with Na ion absorption and disrupts the intestinal mucosal barrier. Management: self-limiting lasts 3 days Management. self limited, supportive care If non infection cause and last more than 2 weeks, can give loperamide
Clostridium difficile First episode: Metronidazole 500mg TDS for 14 days Severe disease: Vancomycin PO QID for 14 days or Fidaxomicin 20mg BID for 10 days. First relapse: same for 1st episode Second relapse: Vancomycin taper with pulse Third relapse: Consider fecal microbiota TX (FMT), prolonged oral vancomycin. CMV: Oral valganciclovir, IV ganciclovir (if decreased absorption) Microsporidia-related diarrhea:: Fumagillin may lead to sustained clearance with minimal IS reduction. Norovirus,Adenovirus, cryptosporadium: supportive
Post-renal transplant diarrhea have worse serious effects on renal transplant recipient starting from fatigue, increased hospitalizations, bad quality of life, less graft survival and higher mortality.
Certain predisposing features for the development of post-transplant diarrhea in this population as generalized immunosuppressed state besides the exposure to polypharmacy commonly broad-spectrum antimicrobial therapy.
Aetiology of post renal transplant diarrhea could be infections, immunosuppressive drugs, antibiotics and other drugs. The cumulative incidence of diarrhea was estimated by 11.5, 17.5 and 22.6% at 1, 2 and 3 years after renal transplantation.
One large retrospective study, posttransplant diarrhea of unknown origin (noninfectious) was strongly linked to a two-fold increase in graft loss and risk of death.
CAUSES OF DIARRHEA:
A large famous prospective study recognized as the Diarrhea Diagnosis Aid and Clinical Treatment (DIDACT) study concerned by identification of the cause of posttransplant diarrhea in renal transplant recipients. The most important data revealed by this study are two constant points; first the commonly encountered infectious cause of posttransplant diarrhea in about 50% of cases was CMV while the second culprit was related to medication use the highest incidence was associated with MMF.
The mechanism of MMF-induced diarrhea remains unknown. Postulations included defective purine synthesis within the gastrointestinal epithelial cells that may be partially dependent on the de-novo pathway for growth and proliferation. The need to switch of immunosuppression from MMF to EC-MPS to aid reducing diarrhea symptoms is still debatable.
Furthermore, a short-term approach adopted in some situations involved the switch from MPA to azathioprine (AZA) keeping in mind the reported data concerned by the reduced graft survival with AZA when compared to MMF.
The fact proved by the U.S. Renal Transplant Scientific Registry that MMF reduced the relative risk of graft loss by 27% (P<0.001) and the improvement of recorded Death-censored graft survival at 4 years was significantly better among MMF-treated versus AZA-treated patients.
Tacrolimus also may be associated with diarrhea in 29–64% of patients depending upon the dose and duration of drug usage. The proposed theory that its macrolide structure may result in stimulation of the intestinal motilin receptors. The incidence of diarrhea already declined with the conversion to a daily, extended release formulation of tacrolimus.
Sirolimus causes self-limiting diarrhea in 14–42% of treated patients. The drug-induced jejunal villous atrophy and a structural homology with the promotility macrolide class of drugs have been suggested.
Also, up to one-third of patients when antithymocyte globulin (ATG) and anti–T cell antibody (OKT3) were administered both have been associated with diarrhea characterized by spontaneous resolution after 3–4 days. The possible mechanism was attributed to the T cells activation followed by release of tumor necrosis factor that interferes with sodium ion absorption subsequently with further disruption of the intestinal mucosal barrier.
Regarding the infectious causes of diarrhea in SOT worldwide, the literature describes a wide range of organisms as norovirus, enteropathogenic bacteria C. difficile and CMV. Chronic norovirus infection was found to be responsible for 17–26% of severe post-transplant diarrhea. The course of norovirus infection becomes even more complicated with up to 94% having chronic diarrhea besides 81% having episodes of diarrhea-induced acute renal failure.
The initial acute phase presentation in the form of classic illness with nausea, vomiting, significant diarrhea (10–20 watery stools per day), with abdominal pain and sometimes fever then followed by chronic diarrhea.
CMV is one of the most common infectious complications affecting SOT patients especially the CMV gastrointestinal disease. A famous recent study of 1427 SOT patients documented the development of CMV disease in 7.2%; approximately one-third of the population had gastrointestinal involvement. Risk factors for CMV disease are known to be higher in seronegative recipients of seropositive organs (D+/R–), lymphodepleting antibodies and more potent immunosuppressive protocols.
The rotavirus infections is recently more recognized in both pediatric and adult SOT patients with more severe course documented in 1.5% higher in liver transplant pediatric patients about (63%).
C. difficile is the most common cause of nosocomial diarrhea particularly within the first months post transplantation of prevalence 3.5–4.5%. Risk factors included age above 55 years, along with the use of ATG, retransplantation and the type of organ transplanted (more in the liver recipients).
CDI has a significant effect on mortality of SOT recipients, of reported mortality rates between 2.3 and 8.5% counted then as an independent risk for death (adjusted odds ratio 2.48, 2.22–2.76).
Parasitic infestations as microsporidia, Enterocytozoon bieneusi and Cryptosporidium (Cryptosporidia parvum and Cryptosporidia hominis) are the most encountered ones.
DIAGNOSIS AND THERAPEUTIC STRATEGY
C. difficile detection can be done by fecal enzyme immunoassays or real-time PCR test being more sensitive and specific in 90% CDI cases. About 70% of patients will respond to metronidazole while persistent severe cases will require oral vancomycin. It is to be considered that 20% of cases will experience at least one relapse in which the next lines as Fidaxomicin, ramoplanin and tigecycline are known to be effective for the treatment of severe recurrent cases. The use of human monoclonal antibodies against C. difficile toxins A and B as fecal microbiota transplantation (FMT) in the management of refractory CDI has started a new era, yet the data is still limited.
Cryptosporidiosis is diagnosed by visualization of oocysts in the stool until the development of immunofluorescent assays and ELISA which was proved to of higher sensitivity and specificity almost 100%. Nitazoxanide and paromomycin are the lines of treatment. While cases of microsporidia-related diarrhea, treatment is via fumagilin.
Tissue invasive CMV disease is considered after the detection of CMV viremia based on blood PCR. CMV is confirmed on histopathology with characteristically swollen cells containing ‘owl’s eye’ intranuclear inclusions, or by immunohistochemical staining for pp65 antigen.
Despite it is the ‘gold standard’ for the diagnosis of CMV active disease, viral inclusions cannot be easily seen as they are very rare. Management of these cases is primarily by intravenous ganciclovir or oral valganciclovir. Optimal duration of antiviral therapy is mainly according to the patient’s clinical and virologic responses for at least 2 weeks after clinical symptoms have resolved and viral load is no longer detected. CMV disease has been documented to be recurrent in 15–35% of SOT recipients with tissue-invasive CMV disease that led to the recommendation of secondary prophylaxis for 30–90 days after successful treatment.
Supportive care is the first line of treatment with higher priority directed to replenish fluids and electrolytes. The most adopted effective strategy is to reduce immunosuppression as MMF has a crucial role in the chronicity of the symptoms by preventing both the clearance of the virus and the repair of intestinal epithelium.
Currently no vaccines are available for viral pathogens apart from two live oral vaccines against rotavirus which are live attenuated vaccines that must be administered prior to transplantation.
The need to perform esophagogastroduodenoscopy and colonoscopy with biopsies to investigate persistent diarrhea post transplantation are rendered to severe undiagnosed nonresponsive cases. Situations of intestinal ulcerations owing to large bowel post-transplant lymphoproliferative disorder may be the aetiology presented by exudative enteropathy and chronic diarrhea. Patients suspected to have severe duodenal villous atrophy may prompt clinicians to change the immunosuppressive regimen. Post transplantation de-novo inflammatory bowel disease occurs up to 10 folds more frequently than general population.
CONCLUSION
Prospective studies are more required to assess in kidney transplant patients in terms of the true prevalence as well as risk factors to provide the best preventative plans for SOT population.
Development of effective vaccines and antiviral therapies for these common viruses will provide better patient and graft survival.
II. Causes and management of postrenal transplant diarrhoea: an underappreciated cause of transplant-associated morbidity
Please summarise this article.
Chronic diarrhea after kidney transplantation is a common presenting problem .
This diarrhea is usually associated with fatigue, high rate of hospitalizations and poor quality of life.
And may lead to malabsorption .
In kidney transplantation there are many risk factors predisposing to this complication which include a 1- generalized immunosuppression.
2- polypharmacy, most notably broad-spectrum antimicrobial therapy.
The main causes are
1- Infections.
2- immunosuppressive drugs.
3- antibiotics and other drugs. Epidemiology
The cumulative incidence of diarrhea is 11.5, 17.5, & 22.6% at 1, 2, & 3 years post-KTX, respectively (UNOS registry).
Participant based data report incidence as much as 53% in kidney transplant . but the doctors’ based data shows the prevalence of about 6.9%. this show large percent of missed attacks of post transplant diarrhea.
Most of the diarrheal events are self-limited & lack a known cause. The most frequent causes were CMV GI infection, norovirus infection, & Clostridium difficile infection. Causes
50% of diarrhea result from infection with CMV being one of the common causes.
Immunosuppressive medications which is common with MMF which resolves with dose reduction or stopping it completely.
CNI, MTORs and ATG have also been associated with diarrhea with unclear mechanisms. Infection;
Common infections are :
CMV
Norovirus
C.difficile
Mostly occurs after 1st few months when they are immunosuppressed.
Chronic norovirus has emerged as a common cause of diarrhea that was initially underestimated with a biphasic illness- acute and chronic.
CMV is common but with a predilection to GI involvement, risk factors; D+/R- pair, D-/R+ pair, lymphocyte depleting agents and more potent immunosuppressive medications.
Recent antibiotic use is strongest risk factor for CDI with fluoroquinolones being associated with highest risk.
Rotavirus infections:
occur in 1.5% of SOT recipients.
Adenovirus:
is common in early posttransplant course (isolated in 6.5–22.5% of cases).
Viremia in the 1st few months post-TX (6.5–22.5%), & GI symptoms occur in 10%.
Microsporidia
Cryptosporidium (Cryptosporidium parvum & Cryptosporidium hominis). Diagnosis
C. difficile detection is the cell-based cytotoxicity assay.
most laboratories use the easier, less expensive and more rapid fecal enzyme immunoassays or real-time PCR test.
These tests have high sensitivity and specificity (90%) for the detection of CDI.
Transplanted patients can be asymptomatic carriers of C. difficile, but most often they develop diarrhea, intestinal obstruction, abscesses or toxic megacolon.
Treatment of SOT includes fidaxomicin, metronidazole 70% respond to treatment or vancomycin,
vancomycin better for more severe infection.
-The greatest challenge for toxigenic Clostridium infections remains the prevention and treatment of relapsing and refractory forms.
In transplant recipients, it has been estimated that up to 20% of cases will have at least one relapse.
-Fidaxomicin, ramoplanin and tigecycline are newer antibiotics that are effective for the treatment of severe or recurrent disease.
A newer area of interest is the use of fecal microbiota transplantation (FMT) in the management of refractory CDI.
The recent availability of fumagilin has been a major breakthrough in the treatment of microsporidia-related diarrhea, treatment that may lead to sustained clearance of E. bieneusi, with minimal reduction in immunosuppression. CMV disease:
The diagnosis of tissue-invasive CMV disease is suggested by the presence of CMV viremia. Many patients with CMV colitis will have evidence of CMV replication in the blood via PCR, although approximately 15% will not.
Management with intravenous ganciclovir (GCV) or oral valganciclovir (valGCV).
Optimal duration of antiviral therapy depends on the patient’s clinical and virologic responses, not on a fixed period.
Before antiviral therapy is stopped, the following three criteria should be met: the treatment was given for at least 2 weeks, clinical symptoms have resolved and viral load is no longer detectable, if initially detected.
Because recurrent CMV disease has been reported in 15–35% of SOT recipients with tissue-invasive CMV disease, many experts recommend the use of valGCV for secondary prophylaxis for 30–90 days after successful treatment. Norovirus:
Diagnosis of norovirus by PCR can be run on stool, vomitus, foods and environmental specimens.
Supportive care is the first line with IV fluids and correction of electrolytes.
The most effective management of norovirus infection is to reduce immunosuppression.
It is important to know that norovirus is the key factor in the induction of posttransplant diarrhea, whereas MMF plays a critical role in the chronicity of the symptoms by preventing both the clearance of the virus and the repair of intestinal epithelium.
Till now no vaccines are available for norovirus, although several candidate vaccines are under investigation.
Because of the lack of specific treatment or vaccination, prevention plays an especially important role in norovirus infection control, especially hand hygiene and environmental sanitization. Rotavirus:
Immune-based assays is most use in diagnosis of rotavirus, used to rapidly detect rotavirus antigens in stool samples.
Other diagnostic methods such as cell culture, real time-PCR and electron microscopy remain as reference methods because of their high specificity and sensitivity.
Currently, no anti-rotaviral therapies are available, and the treatment of rotavirus infection in SOT patients is mainly supportive.
Contact precautions are recommended to prevent viral transmission.
Contaminated surfaces should be disinfected by 95% ethanol or other alcohol-containing disinfectant, because general disinfectants (e.g. bleach) are ineffective.
In the United States, two live oral vaccines against rotavirus currently are licensed for use: RotaTeq (RV5) and Rotarix (RV1).
Because both vaccines are live attenuated vaccines, transplant candidates should receive the vaccines before transplantation; their use posttransplant is contraindicated. Adenovirus:
Adenovirus can be diagnosed by viral culture, direct antigen detection, histopathology and PCR.
Although culture has traditionally been considered the gold standard for diagnosing AdV, it may take up to 28 days to develop cytopathic effects, and serotypes associated with diarrhea do not grow well in cell culture.
Limited data are available on the optimal treatment of AdV infections.
-Generally, diarrhea caused by AdV can be managed with supportive care and a reduced immunosuppressive regimen.
Diligent infectious control measures, including contact and droplet precautions, can help prevent infections in the SOT population. Conclusion;
A directed approach to diagnosis and treatment will not only help to resolve diarrhea, but also prevent potentially life-threatening consequences such as loss of the graft.
Meticulous evaluation for possible causes of diarrhea Prior to implicating an immunosuppressant medication as the culprit.
Infectious agents and the concomitant use of other diarrhea genic medications such as proton-pump inhibitors, antibiotics and diuretics must first be excluded .
Prospective studies are needed to better assess in kidney transplant patients the true prevalence, risk factors and complications of diarrhea by norovirus, rotavirus and AdV.
Development of effective vaccines and antiviral therapies for these common viruses will likely improve patient and graft survival. What is the level of evidence provided by this article?
This review highlights the current literature on both infectious and noninfectious diarrhea in renal transplant recipients and provides a diagnostic algorithm for the evaluation of posttransplant diarrhea.
The main causes of diarrhea after transplantation are infections, immunosuppressive drugs, antibiotics and other drugs.
Renal transplant recipients share certain predisposing characteristics, such as a generalized immunosuppressed state and exposure to polypharmacy, most notably broad-spectrum antimicrobial therapy.
Prospective studies are needed to better assess true prevalence, risk factors and complications of diarrhea by norovirus, rotavirus and adenovirus in kidney transplant patients.
This article discusses the extent to which posttransplant diarrhea is often under-recognized by practitioners.
It found that 53% of participants reported diarrhea, whereas the incidence estimated by their physicians was only 6.9%.
A recent study from a single transplant center in the United States reviewed the diagnostic yield of tests for diarrhea among hospitalized transplant recipients over a period of 18 months and found that the majority of the diarrheal episodes had no identifiable cause and were self-limited.
Chronic diarrhea after kidney transplantation has negative impacts on the recipient’s quality of life, graft survival and mortality.
Noninfectious diarrhea is a major problem as many immunosuppressive agents commonly used in transplantation may cause diarrhea, with the highest incidence associated with MMF.
It is important to diagnose the cause of diarrhea and make a distinction between noninfectious and infectious causes of diarrhea in kidney transplant recipients.
Antithymocyteocyteglobulin (ATG) and anti-T cell antibody (OKT3) therapies are both associated with diarrhea, which lasts for 3-4 days and resolves spontaneously.
Posttransplant diarrhea is a common infectious complication affecting SOT patients, with up to 94% having chronic diarrhea and 81% having episodes of diarrhea-induced acute renal failure.
Risk factors for CMV disease include seronegative recipients of seropositive organs (D+/R–), lymph depleting antibodies and more potent immunosuppressive regimens.
The incidence of C.difficile infection (CDI) in transplanted patients has been reported to be 3.5-4.5% in adult renal transplantation patients.
Risk factors include age above 55 years, use of ATG, retransplantation and the type of organ transplanted.
Recent anti-biotic use is the single most important risk factor for CDI, with fluoroquinolones being associated with the highest risk.
metronidazole & oral vancomycin is the 1st lines of management.
supportive management , good hydration & reduction of immunosuppression is the most importatnt
CMV associted colitis , diagnosed by CMV PCR with findings in endoscope , ttt by IV gancyclovir for at least 2 weeks , followed by oral valgancyclovir prophylaxis for 3 months.
reduction of immunosuppression include :
1-reduction of the dose of MMF or shift to enteric coated MFS or switch to AZA if reduction of MMF >50 %.
2- tacrolimus dose reduction or switch to cyclo , monitor drug trough level (5-8)
3-switch between mTORi & cyclo.
Prospective studies are
needed to better assess in kidney transplant patients
the true prevalence, risk factors and complications
of diarrhea by norovirus, rotavirus and AdV. Such
studies will help guide the care of these patients and
provide appropriate prevention and prompt management. level of evidence :
level 5 , a narrative review
Diarrhoea leads to fatigue, increased hospitalisation, increased morbidity (Poor graft survival as a result of hyperoxaluria) and mortality
Causes of diarrhoea Non-infectious
1) Immunosuppression: most commonly with MMF, others are Tac, CSA and sirolimus
2) Non-immunosuppression medications:antibacterial, antiarrythmias, antidiabetic, laxatives, PPI
3) Others: Primary GI diagnosis (IBD, malabsorption), malignancy (colon ca, PTLD)
Introduction
Chronic diarrhea after kidney transplantation is a common presenting problem .
This complication usually associated with fatigue, high rate of hospitalizations and poor quality of life.
In kidney transplantation there are many risk factors predisposing to this complication which include a 1- generalized immunosuppressed state
2- polypharmacy, most notably broad-spectrum antimicrobial therapy.
The main causes are
1- Infections.
2- immunosuppressive drugs.
3- antibiotics and other drugs.
This study review the current literature regarding both infectious and noninfectious diarrhea in renal transplant recipients and provide a diagnostic algorithm for the evaluation of posttransplant diarrhea
Epidemiology
The cumulative incidence of diarrhea is 11.5, 17.5, & 22.6% at 1, 2, & 3 years post-KTX, respectively (UNOS registry).
Participant based data report incidence as much as 53% in kidney transplant . but the doctors’ based data shows the prevalence of about 6.9%. this show large percent of missed attacks of post transplant diarrhea.
Most of the diarrheal events are self-limited & lack a known cause. The most frequent causes were CMV GI infection, norovirus infection, & Clostridium difficile infection.
Important points :
· Chronic diarrhea after kidney transplantation has negative impacts on the recipient’s quality of life, graft survival and mortality.
· It is important that clinicians evaluate and attempt to diagnose the cause of diarrhea and make a distinction between noninfectious and infectious causes of diarrhea in kidney transplant recipients.
· Prospective studies are needed to better assess the true prevalence, risk factors and complications of diarrhea by norovirus, rotavirus and AdV in kidney transplant patients.
Causes:
Simply classified in to two group :
either infectious or none infectious .
1- Infectious etiology : ( common cause are CMV and Clostridium difficile)
b- Other disorders:
GVHD, IBD, PTLD, cancer colon, malabsorption and microscopic colitis .
The important step is is to determine the cause , as reduction of IS when drug induced diarrhea is suspected. May end by AR and graft loss and also the delay in diagnosing the microbial cause of infectious diarrhea can lead to poor patient and graft outcome.
The mechanism of MMF-induced diarrhea remains unknown. One possible mechanism is that gastrointestinal epithelial cells may be partially dependent on the de-novo pathway of purine synthesis for growth and proliferation, and are therefore vulnerable to Mycophenolic acid (MPA) inhibition leading to diarrhea.
The use of tacrolimus may be associated with diarrhea in 29–64% of patients depending upon the
dose and duration of drug usage . The mechanism by which calcineurin inhibitors cause diarrhea
remains unclear, although it is hypothesized that a macrolide structure may result in stimulation
of the intestinal motilin receptors. Most of the tacrolimus-associated gastrointestinal side-effects
have a mild course and rarely require drug discontinuation
Sirolimus causes self-limiting diarrhea in 14 – 42% of treated patients. The mechanism by which sirolimus causes diarrhea is poorly understood, although drug-induced jejunal villous atrophy and a structural homology with the pro motility macrolide class of drugs have been proposed as possible explanations.
In up to one-third of patients, antithymocyte globulin (ATG) and anti–T cell antibody (OKT3)
therapies are both associated with diarrhea, which predictably lasts for 3–4 days and resolves spontaneously.
Diagnosis and therapeutic strategy :
It is important to differentiate between the infectious and non-infectious etiology to avoid unnecessary immunosuppressive drug dose reductions.
C.difficile – cell based cytotoxicity assay, fecal enzyme based immunoassay and real time PCR . Treatment is with
First episode: metronidazole 500mg three times per day for 10–14 days
Severe disease : vancomycin oral four times per day for 10–14 days
fidaxomicin 20mg two times per day for 10 days
First relapse: same for first episode
Second relapse: vancomycin taper with pulse
third relapse: consider fecal microbiota transplantation, prolonged oral vancomycin
CMV-
Diagnosis : endoscopic evidence of GIT involvement- Owl eye intranuclear inclusions and IHC staining for pp65.
Treatment :
Cytomegalovirus Oral valganciclovir
IV ganciclovir (if any concern for decreased absorption)
Optimal duration is dependent on patient’s clinical and virological response :
1- at least 2 weeks .
2- Become a symptoms .
3- The viral load should not be detectable – negative PCR .
Because of risk of recurrence, CMV prophylaxis for 30-90 days after treatment of tissue invasive disease is recommended.
Noravirus – It is the key factor in the induction of post transplant diarrhea.
Diagnosis: PCR ( stool, food and vomitus) .
Treatment:
1- supportive care with fluid and electrolyte replacement.
2- immunosuppressive reduction.
Prevention : hand hygiene and environmental sanitization.
Rotavirus-
Diagnosed : immune assay.
Treatment : mainly supportive.
Prevention : live attenuated, contraindicated in post-transplant period.
Adenovirus-
diagnosed ; culture, antigen detection, PCR and histopathology.
Management :
1- supportive
2- reduction of immunosuppression
CONCLUSION
Physicians should be familiar with common causes that result in posttransplant diarrhea. A directed approach to diagnosis and treatment will not only help to resolve diarrhea, but also prevent potentially life-threatening consequences such as loss of the graft. Prior to implicating an immunosuppressant medication as the culprit, a meticulous evaluation for other possible causes of diarrhea should always
be conducted. Infectious agents and the concomitant use of other diarrhea genic medications such as
proton-pump inhibitors, antibiotics and diuretics must first be excluded. Prospective studies are
needed to better assess in kidney transplant patients the true prevalence, risk factors and complications
of diarrhea by norovirus, rotavirus and AdV. Such studies will help guide the care of these patients and provide appropriate prevention and prompt diagnosis.
Development of effective vaccines and antiviral therapies for these common viruses will likely improve patient and graft survival.
Causes and management of postrenal transplant diarrhoea: an underappreciated cause of transplant-associated morbidity Summarise.
Introduction.
Chronic diarrhea post transplant has negative impact and needs to be promptly addressed. Main causes; infection, immunosuppressive meds, antibiotic use etc.
Epidemiologic Impact.
Cumulative incidence ; 11.5,17.5 and 22.6% at 1.2 and 3 yrs post KTR based on one study. Post transplant diarrhea is grossly under reported and careful hx is important.
Causes.
General ;50% of diarrhea result from infection with CMV being one of the common causes.
Immunosuppressive meds; Higher incidences with MMF which resolves with dose reduction or stopping it completely. CNI, MTORi and ATG have also been associated with diarrhea with unclear mechanisms.
Infection; CMV, norovirus and C.difficile are the commonest cause. Mostly occurs after 1st few months when they are immunosuppressed. Chronic norovirus has emerged as a common cause of diarrhea that was initially underestimated with a biphasic illness- acute and chronic. CMV is common but with a predilection to GI involvement, risk factors; D+/R- pair, D-/R+ pair, lymphocyte depleting agents and more potent immunosuppressive meds. Recent antibiotic use is strongest risk factor for CDI with fluoroquinolones being associated with highest risk.
Diagnosis and therapeutic strategies.
Always strive to distinguish infectious from non infectious causes and consider graft function in adjusting immunosuppressive meds.
C.difficile; Gold standard is cell based cytotoxicity assay but it is costly. CDI PCR with a sensitivity and specificity of 90% is commonly used. Tx includes ;Flagyl, fidaxomicin or vancomycin with vancomycin being preferred in severe cases. Other options for refractory cases are- fidaxomicin, ramoplanin and tigecycline. Novel therapies; Human monoclonal antibodies against C.Difficile toxin A and B,Fecal Microbiodata transplantation. Fumagilin has good outcomes in tx of microsporidia but we need to look out for thrombocytopenia.
Cryptosporidia is diagnosed via IF,ELISA and oocyst visualization. It has no specific treatment.
CMV is diagnosed via CMV viremia and PCR. Endoscopic confirmation of owls eye inclusion or IHC staining for PP65.Viral inclusion though sensitive and gold standard is rare. Tx involves IV GCV or PO ValGCV. Tx is stopped if ;Tx is given for 2/52,Resolution of clinical symptoms and VL undetectable. For recurrent dx, ValGCV is recommended for secondary prophylaxis for 30-90/7 post transplant.
Norovirus is detected via PCR. Tx is via rehydration, electrolyte correction and RIS. Prevention is key in managing norovirus.
Rotavirus is diagnosed via immune based assays ,cell culture and real time PCR. It is mostly tx via supportive tx with emphasis on preventive protocols. Vaccines availabe are; Rota teq and Rotarix which should be given pre transplant as they are live.
Adenovirus is detected by viral culture, direct antigen detection, histopathology and PCR. It is treated with supportive measures and RIS.
Reasons for esophagogastroduodenoscopy + colonoscopy with biopsy in persisitent diarrhea;
Intestinal ulceration from large bowel PTLD may have exudative enteropathy and chronic diarrhea.
CMV colitis with simultaneous Neg CMV PCR has been reported.
Severe duodenal villous atrophy may cause some medics to adjust immunosuppressive meds regardless of cause.
Post KTR de novo IBD occurs x10 in transplant popn than the general popn.
Tx generally involves; Preventive therapy, hydration, antimicrobials for infective causes and RIS(MMF dose reduction or switch to EC-MPS then later MMF,EC-MPS withdrawal if symptoms persist).
Please summarise this article? Introduction
Post-transplant diarrhea is common affecting nearly one fourth of transplant recipients.
Chronic diarrhea after transplantation is common and associated with increased morbidity, hospitalization, allograft loss and poor quality of life.
Steatorrhea and malabsorption can lead to secondary enteric hyperoxaluria with subsequent oxalate nephropathy (intense inflammation of allograft). Diarrhea is defined as > 3 loose stool/day. Persistent (>2 weeks) and chronic (> 1month)
The Quality of life, graft survival and mortality are all negatively impacted by chronic diarrhea post-transplant. Transplant physician must assess the diarrhea in Transplant recipients, try to determine its source and differentiate between infectious and non-infectious causes of diarrhea.
Epidemiology.
The cumulative incidence of diarrhea is 11.5, 17.5, and 22.6% at 1-, 2-, and 3-years post-Kidney transplant, respectively (UNOS registry). Yet, 53% of participants in a large survey of Kidney transplant recipients reported having diarrhea, despite their doctors’ estimates of the prevalence being only 6.9%. This finding shows how frequently post-TX diarrhea goes undiagnosed by healthcare professionals. Most of the diarrheal events are self-limited & lack a known cause. The most frequent causes were CMV GI infection, norovirus infection, & Clostridium difficile infection.
Causes of post-transplant diarrhea. Data from the DIDACT study; Diarrhea resolved in 50% of patients either by cessation of diarrhea associated non-IS drugs or by the treatment of concurrent infections (mostly Campylobacter or CMV). In the remainders, changes in IS therapy (mostly MMF) led to remission in 2/3 of cases. CMV was the most prevalent infection\ etiology of post-TX diarrhea was found in 50% of cases. Medication use is the 2nd most common reason.
Causes Of Infectious Diarrhea Post-Kidney transplant.
The most common identifiable causes include clostridium difficile infection, norovirus infection, CMV infection and drug induced.
Viral: CMV most common, Norovirus, Rotavirus, Adenovirus, Sapobavirus
Bacterial: Clostridium difficile, Campylobacter, Salmonella, E coli, Bacterial overgrowth.
Parasitic: Cryptosporidium, Giardia, Isosopora Cyclospora, Microsporidium and Entamoeba.
Bacteria such as clostridium deficile is the most common cause of nosocomial diarrhea and accounts for most infectious diarrhea in the 1st months post-Transplant,
Clostridium deficile infection occurs in 3.5–4.5%, most common nosocomial infection in 1st month posttransplant, more common in age > 55 years, use of ATG, re-TX, liver transplant and with use of broad-spectrum antibiotics as quinolones, it is associated with 2.3-8.5% risk of mortality. It can lead to diarrhea, intestinal obstruction, abscesses, or toxic megacolon.
CMV is the most important risk factor for CMV disease is D+/R– GI involvement (40% of patients). Other risk factors are D+/R–status, lymphodepleting antibodies & more potent IS regimens. Viruses such as CMV, adenovirus, norovirus, rotavirus, and sapovirus. Norovirus: Has 2 phases: acute phase; presented with nausea, vomiting, significant diarrhea (10–20 watery stools per day), abdominal pain and sometimes fever. Then followed by a chronic phase; (cycles of relatively normal stools followed by periods of poorly formed stools). Lately, chronic norovirus infection has become one of the most common infectious causes (17–26% of cases). This suggests that many infectious causes of diarrhea may have previously been misdiagnosed as being caused by IS medications, resulting in inappropriate diagnostic & treatment approaches. Rotavirus infections:
occur in 1.5% of SOT recipients. Adenovirus:
is common in early posttransplant course (isolated in 6.5–22.5% of cases).
Viremia in the 1st few months post-TX (6.5–22.5%), & GI symptoms occur in 10%. Microsporidia
Cryptosporidium(Cryptosporidium parvum & Cryptosporidium hominis).
Diagnostic work up should include;
Review all medications and stop unnecessary ones. A- Routine investigations;
Renal function tests and electrolytes
Complete blood count, c reactive protein
Stool analysis B- Searching for the cause;
CNI level, CMV PCR, Stool culture and CD toxin in stool, and parasitic infection (Cryptosporidium, Entamoeba histolytica, Giardia lamblia, Campylobacter, Shigella, Salmonella, Vibrio, Yersinia enterocolitica, adenovirus and sapovirus), enzyme immunoassay for giardia and cryptosporidium and breath test for bacterial overgrowth.
Clostridium diff. infection:
Cell-based cytotoxicity assay is the gold standard test
Real-time PCR tests or fecal enzyme immunoassays (simpler, less expensive, & faster) are commonly used. Tissue-invasive CMV disease:
CMV viremia is suggestive of the diagnosis.
Laboratory tests include biopsy, CMV IgM & or elevation in IgG, conventional culture, Shell Vial assay, CMV pp65 Ag, PCR, & Real-time PCR. Norovirus:
Diagnosed by PCR run on stool, vomitus, foods & environmental specimens. Rotavirus:
Immune-based assays rapidly detect rotavirus antigens in stool. Adenovirus:
Diagnosed by viral culture, direct antigen detection, histopathology & PCR. Cryptosporidiosis:
Oocysts in the stool
Modified acid-fast stains.
IF assays&ELISA (100% sensitivity & specificity)
Imaging, Colonoscopy and Biopsy:
may be needed if there is suspicious of malignancy, IBD or CMV colitis with negative PCR (15% of cases will have CMV PCR negative
If these tests are negative & the diarrhea persists, empiric anti-diarrheal medications, probiotics &/or lactose-free diet tried.
Non-infectious causes of diarrhea
Drug induced:
Immunosuppression drugs (MMF mainly, CNI and mTORi). Others as (laxatives, anti-diabetics, PPI, anti-arrhythmic drugs).
Mechanism of MMF induced diarrhea: It inhibits de-novo pathway of purine synthesis essential for growth, Proliferation, and generation of enterocytes.
IBD-like toxicity (predominant crypt distortion).
GVHD associated toxicity (predominant apoptosis).
Treatment of MMF induced or associated diarrhea requires either:
Shift from MMF to EC-MPS that may be beneficial, or Short-term conversion to AZA (while long term graft outcome is lower with AZA than MMF in addition to higher risk of skin cancer).
MMF has the highest prevalence (RR 1.57), & numerous IS medications frequently used in TX may cause diarrhea. Dose reduction is generally followed by a decline or cessation of diarrhea. It is unclear how MMF causes diarrhea.
It’s debatable whether switching from MMF to EC-MPS helps lessen symptoms of diarrhea. According to a recent RCT, patients who switch from MMF to EC-MPS may have a marginally but significantly higher likelihood of returning to the target MPA levels than those who stay on MMF.
Switch from MPA to AZA is usually avoided because of risk of reduced graft survival with AZA versus MMF.
Mechanism of TAC induced diarrhea:
It occurs in 30-60 % of cases, it may stimulate intestinal motilin receptors, but it is usually mild, self-limited, and not require drug discontinuation. Shift to extended release (advagraf) may be beneficial.
mTORi induced diarrhea:
It occurs in 14-40 % of cases, it is related to jejunal villous atrophy, it is usually self-limited.
ATG induced diarrhea:
Use of ATG can activate T cells to release TNF which then interferes with Na ion absorption and disrupts the intestinal mucosal barrier.
Both ATG & OKT3 can cause diarrhea in 1/3 of patients; this diarrhea is self-limiting (lasts 3–4 d).
Others including, GVHD (graft versus host disease), IBD, malabsorption, and microscopic colitis).
Malignancy such as cancer colon, PTLD Management.
In most cases, the cause is not identified, and diarrhea is self-limited. Supportive therapyincluding intravenous fluids for treatment of dehydration. Symptomatic therapyincluding loperamide to decrease bowel motions which is indicated in persistent (> 2 weeks) or chronic diarrhea (> 1 month)
Modulation and monitoring of immunosuppression.
Reduction of immunosuppression in the form of reducing the dose of MMF by 50% after estimation of the rejection risk and keeping low target trough for CNI (5-8 ng/ml)
Shifting from MMF to enteric coated mycophenolate (debatable)
Shifting from MMF to azathioprine (not preferred due to reduced graft survival, increased risk of rejection and increased risk of skin cancer associated with azathioprine use)
Switching from tacrolimus to extended released formulation or to cyclosporine.
Switching from sirolimus to CNI since around 14-41 % of cases taking sirolimus experienced diarrhia. Close follow up of CN level as there may be an increase in tacrolimus level with diarrhea due to disruption of P-glycoprotein efflux pump in the damaged enterocytes.
Treatment of the cause;
Treatment of major infectious causes Clostridium difficile
First episode: Metronidazole 500mg TDS for 14 days
Severe disease: Vancomycin PO QID for 14 days or Fidaxomicin 20mg BID for 10 days.
First relapse: same for 1st episode
Second relapse: Vancomycin taper with pulse
Third relapse: Consider fecal microbiota TX (FMT), prolonged oral vancomycin. CMV:
Oral valganciclovir, IV ganciclovir (if decreased absorption) Norovirus: Rehydration, Antimotility drugs, Reduction in IS drugs. Adenovirus:
Supportive care and IS reduction. Microsporidia-related diarrhea:
Fumagillin may lead to sustained clearance with minimal IS reduction.
Drug-induced thrombocytopenialimits its use. Cryptosporidium:
No specific therapy
No difference between therapy with nitazoxanide or paromomycin and placebo.
Conclusions;
First; Other possible causes should be evaluated.
Very carefully assess other potential causes of diarrhea before accusing an IS drug of being the culprit.
it is necessary to rule out infectious agents and the other diarrhea-causing drugs such PPIs, antibiotics, and diuretics.
Prospective studies are required to determine the true prevalence more accurately, complications, and risk factors of diarrhea caused by norovirus, rotavirus and Adv in KTX recipients.
Improved patient and transplant survival is predicted to result from the development of potent vaccinations and antiviral treatments for these widespread viruses. What is the level of evidence provided by this article?
Narrative review ==> Level V
SUMMARY Causes and management of postrenal transplant diarrhea: an underappreciated cause of transplant-associated morbidity
Introduction
The main causes of diarrhea after transplantation are infections, immunosuppressive drugs, antibiotics and other drugs. The cumulative incidence of diarrhea has been reported to be 11.5, 17.5 and 22.6% at 1, 2 and 3 years after renal transplantation, respectively. In one large retrospective study, posttransplant diarrhea of unknown origin (noninfectious) was associated with a two-fold increase in graft loss and risk of death.
This review elaborates the current literature on both infectious and noninfectious diarrhea in renal transplant recipients and provides a diagnostic algorithm for the evaluation of posttransplant diarrhea.
CAUSES OF DIARRHEA
DIDACT study indicate that an infectious cause of posttransplant diarrhea is present in approximately 50% of cases with CMV being the most common pathogen.
C. difficile
The gold standard for C. difficile detection is the cell-based cytotoxicity assay.
Initial treatment of SOT includes fidaxomicin, metronidazole or vancomycin, with vancomycin preferred for cases of more severe infection
Fidaxomicin, ramoplanin and tigecycline are newer antibiotics that are effective for the treatment of severe or recurrent disease
A newer area of interest is the use of fecal microbiota transplantation (FMT) in the management of refractory CDI.
CMV
Cmv pcr, serology, for invasive disease- endoscopy and biopsy- CMV is confirmed on histopathology with characteristically swollen cells containing ‘owl’s eye’ intranuclear inclusions, or by immunohistochemical staining for pp65.- treatment includes -oral vangancyclovir/iv gancyclovir
Multiplex pcr-based screening for enteric pathogen
EGD Colonoscopy, capsule endoscopy- biopsy- to rule out IBD, PTLD
Breath test- to see bacterial overgrowth.- treatment with antimicrobial
Microsporidia : Fumagilin has been a major breakthrough in the treatment and may lead to sustained clearance of E. bieneusi, with minimal reduction in immunosuppression
Cryptosporidiosis -diagnosed by visualization of oocysts in the stool, modified acid-fast stains, Immunofluorescent assays and ELISA (sensitivity and specificity approaching 100%). In meta-analysis, there was no observed difference between therapy with nitazoxanide or paromomycin and placebo for immunosuppressed patients with cryptosporidiosis.
Norovirus diagnosis by PCR (stool, vomitus, foods and environmental specimens) treatment -reduction of immunospuression
Rotavirus -diagnosis- immune-based assays to detect rotavirus antigens in stool samples. Other diagnostic methods such as cell culture, real time-PCR and electron microscopy remain as reference methods because of their high specificity and sensitivity. Currently, no antirotaviral therapy, treatment of rotavirus infection is mainly supportive. In the United States, two live oral vaccines against rotavirus currently are licensed for use: RotaTeq (RV5) and Rotarix (RV1) . Because both vaccines are live attenuated vaccines, transplant candidates should receive the vaccines before transplantation; their use posttransplant is contraindicated
Adenovirus can be diagnosed by viral culture, direct antigen detection, histopathology and PCR .Generally, diarrhea caused by AdV can be managed with supportive care and a reduced immunosuppressive regimen.
For noninfectious diarrhea
Withdrawal of non-immunosuppressive causing diarrhea then
The first change in immunosuppression consists of MMF dose reduction or switching to EC-MPS, followed ultimately by MMF-EC-MPS withdrawal if symptoms persist.
Conclusion
A directed approach to diagnosis and treatment will not only help to resolve diarrhea, but also prevent potentially life threatening consequences, such as loss of graft.
Causes and management of post-renal transplant diarrhea: Introduction;
-Chronic diarrhea after kidney transplantation is a common complaint.
-The main causes of diarrhea after transplantation are infections, immunosuppressive drugs, antibiotics and other drugs.
-The cumulative incidence of diarrhea has been reported to be 11.5 % (at 1 year) & 17.5 % (at 2 years) and 22.6% (at 3 years) after renal transplantation. Causes of Diarrhea; Immunosuppressive Drugs:
-Drug-induced diarrhea is a major problem as many of the immunosuppressive agents commonly used in transplantation may cause diarrhea, with the highest incidence associated with MMF, and enteric-coated mycophenolate sodium (EC-MPS).
-The mechanism of MMF-induced diarrhea remains unknown.
-One possible mechanism is that gastrointestinal epithelial cells may be partially dependent on the de-novo pathway of purine synthesis for growth and proliferation, and are therefore vulnerable to Mycophenolic acid (MPA) inhibition leading to diarrhea.
-The use of tacrolimus may be associated with diarrhea in 29–64% of patients depending upon the dose and duration of drug usage.
-The mechanism by which calcineurin inhibitors cause diarrhea remains unclear, it may affect in stimulation of the intestinal motilin receptors.
-A decrease in the incidence of gastrointestinal symptoms, including diarrhea, after conversion to a daily, extended release formulation of tacrolimus was reported in a recent study in renal transplant recipients.
-Sirolimus causes self-limiting diarrhea in 14– 42% of treated patients.
-The mechanism by which sirolimus causes diarrhea is poorly understood, although drug-induced jejunal villous atrophy and the promotility macrolide class of drugs have been proposed as possible explanations.
-In up to one-third of patients, antithymocyte globulin (ATG) and anti–T cell antibody (OKT3) therapies are both associated with diarrhea, which predictably lasts for 3–4 days and resolves spontaneously.
-Activating T cells to release tumor necrosis factor which then interferes with sodium ion absorption and also disrupts the intestinal mucosal barrier is one mechanism by which these antibodies may cause diarrhea. Infections:
-After the first few months post-transplant, opportunist pathogens become more evident as a cause of infection, C. difficile, CMV and norovirus are important causes of diarrhea in this population.
-Chronic norovirus infection has only recently emerged as one of the leading infectious causes (approximately 17–26% of severe post-transplant diarrhea) of post-transplant diarrhea in kidney transplant recipients.
-In these patients, the course of norovirus infection tends to be more complicated, with up to 94% having chronic diarrhea and 81% having episodes of diarrhea-induced acute renal failure.
-CMV is one of the most common infectious complications affecting SOT patients and is associated with significant morbidity and occasional mortality, the most common target organ is the gastrointestinal tract, causing CMV gastrointestinal disease.
-In one study, rotavirus infection was diagnosed in 1.5% of SOT recipients, with most cases occurring in pediatric patients (63%) and in those who received a liver transplant.
-In adults, adenovirus (AdV) viremia is commonly observed in the early post-transplant course (6.5-22.5%), and may be associated with gastrointestinal symptoms in 10% of the cases.
-C. difficile is the most common cause of nosocomial diarrhea and accounts for most infectious diarrhea within the first months after transplantation.
-The incidence of C. difficile infection (CDI) in transplanted patients has been reported to be approximately 3.5–4.5% in adult renal transplantation patients.
-Risk factors that are specific to the SOT population include age above 55 years, use of ATG, retransplantation and the type of organ transplanted, with the highest rate among liver recipients.
-The single most important risk factor for the development of CDI is recent antibiotic use.
-Among antibacterials, the fluoroquinolones are associated with the highest risk.
-CDI has a significant effect on mortality of SOT recipients, with mortality rates between 2.3 and 8.5%, and is an independent risk for death.
-Among parasities, the protozoan or metazoan are most common.
-Gastrointestinal infection due to microsporidia has been recorded in patients with SOT who experienced diarrhea and weight loss.
-Enterocytozoon bieneusi is by far the most frequent strain found in kidney transplant recipients.
-Cryptosporidia (Cryptosporidia parvum and Cryptosporidia hominis) are intracellular protozoans known to lead to severe acute diarrhea, chronic diarrheal illness and extraintestinal infection in transplanted patients. Diagnosis and Therapeutic Strategy; C. difficile:
-The gold standard for C. difficile detection is the cell-based cytotoxicity assay.
-However, most laboratories use the easier, less expensive and more rapid fecal enzyme immunoassays or real-time PCR test.
-These tests have high sensitivity and specificity (90%) for the detection of CDI.
-Transplanted patients can be asymptomatic carriers of C. difficile, but most often they develop diarrhea, intestinal obstruction, abscesses or toxic megacolon.
-Initial treatment of SOT includes fidaxomicin, metronidazole or vancomycin, with vancomycin preferred for cases of more severe infection.
-Only about 70% of patients will respond to treatment with metronidazole; persistent and more severe cases will require oral vancomycin.
-The greatest challenge for toxigenic Clostridium infections remains the prevention and treatment of relapsing and refractory forms.
-In transplant recipients, it has been estimated that up to 20% of cases will have at least one relapse.
-Fidaxomicin, ramoplanin and tigecycline are newer antibiotics that are effective for the treatment of severe or recurrent disease.
-A newer area of interest is the use of fecal microbiota transplantation (FMT) in the management of refractory CDI.
-The recent availability of fumagilin has been a major breakthrough in the treatment of microsporidia-related diarrhea, treatment that may lead to sustained clearance of E. bieneusi, with minimal reduction in immunosuppression. CMV disease:
-The diagnosis of tissue-invasive CMV disease is suggested by the presence of CMV viremia. Many patients with CMV colitis will have evidence of CMV replication in the blood via PCR, although approximately 15% will not.
-In general, patients with CMV colitis can be managed with intravenous ganciclovir (GCV) or oral valganciclovir (valGCV).
-Intravenous GCV is often used if there is concern for inadequate absorption of oral valGCV (e.g. in patients with vomiting and diarrhea) or early in the treatment of proven CMV colitis.
-Optimal duration of antiviral therapy depends on the patient’s clinical and virologic responses, not on a fixed period.
-Before antiviral therapy is stopped, the following three criteria should be met: the treatment was given for at least 2 weeks, clinical symptoms have resolved and viral load is no longer detectable, if initially detected.
-Because recurrent CMV disease has been reported in 15–35% of SOT recipients with tissue-invasive CMV disease, many experts recommend the use of valGCV for secondary prophylaxis for 30–90 days after successful treatment. Norovirus:
-Diagnosis of norovirus by PCR can be run on stool, vomitus, foods and environmental specimens.
-Supportive care is the first line of treatment with an emphasis on replenishment of fluids and electrolytes.
-At present, the most effective strategy to manage norovirus infection is the reduction of immunosuppression.
-It is important to know that norovirus is the key factor in the induction of posttransplant diarrhea, whereas MMF plays a critical role in the chronicity of the symptoms by preventing both the clearance of the virus and the repair of intestinal epithelium.
-At present, no vaccines are available for norovirus, although several candidate vaccines are under investigation.
-Because of the lack of specific treatment or vaccination, prevention plays an especially important role in norovirus infection control, especially hand hygiene and environmental sanitization. Rotavirus:
-In diagnosis of rotavirus, immune-based assays are most routinely used to rapidly detect rotavirus antigens in stool samples.
-Other diagnostic methods such as cell culture, real time-PCR and electron microscopy remain as reference methods because of their high specificity and sensitivity.
-Currently, no anti-rotaviral therapies are available, and the treatment of rotavirus infection in SOT patients is mainly supportive.
-Contact precautions are recommended to prevent viral transmission.
-Contaminated surfaces should be disinfected by 95% ethanol or other alcohol-containing disinfectant, because general disinfectants (e.g. bleach) are ineffective.
-In the United States, two live oral vaccines against rotavirus currently are licensed for use: RotaTeq (RV5) and Rotarix (RV1).
-Because both vaccines are live attenuated vaccines, transplant candidates should receive the vaccines before transplantation; their use posttransplant is contraindicated. Adenovirus:
-AdV can be diagnosed by viral culture, direct antigen detection, histopathology and PCR.
-Although culture has traditionally been considered the gold standard for diagnosing AdV, it may take up to 28 days to develop cytopathic effects, and serotypes associated with diarrhea do not grow well in cell culture.
-Limited data are available on the optimal treatment of AdV infections.
-Generally, diarrhea caused by AdV can be managed with supportive care and a reduced immunosuppressive regimen.
-Diligent infectious control measures, including contact and droplet precautions, can help prevent infections in the SOT population. Conclusion;
-A directed approach to diagnosis and treatment will not only help to resolve diarrhea, but also prevent potentially life-threatening consequences such as loss of the graft.
-Meticulous evaluation for possible causes of diarrhea Prior to implicating an immunosuppressant medication as the culprit.
-Infectious agents and the concomitant use of other diarrhea genic medications such as proton-pump inhibitors, antibiotics and diuretics must first be excluded .
-Prospective studies are needed to better assess in kidney transplant patients the true prevalence, risk factors and complications of diarrhea by norovirus, rotavirus and AdV.
-Development of effective vaccines and antiviral therapies for these common viruses will likely improve patient and graft survival. What is the level of evidence provided by this article? -This is Narrative review (LOE V)
Introduction
Chronic diarrhea after kidney transplantation is associated with fatigue, increased hospitalization, and has a negative impact on the patient’s quality of life, graft survival and mortality.
It may also lead to steatorrhea and malabsorption. Oxalate nephropathy is associated with inflammation which can have detrimental effects on graft survival. Some of the risk factors that kidney transplant recipients have include immune suppression and exposure to broad spectrum antimicrobial therapy.
The main causes of diarrhea after transplantation are
Infections
Immunosuppressive drugs
Antibiotics and other drugs.
This article reviewed current literature regarding infectious and non-infectious diarrhea and renal transplant recipients to provide a diagnostic algorithm for the evaluation post transplant diarrhea.
Epidemiologic impact
53% of 4232 Scandinavian renal transplant recipients reported diarrhea, but the incidence estimated by their physicians was only 6.9%. This showed that the physicians greatly under-reported diarrhea.
One study noted that chronic diarrhea results in poor quality of life, graft loss and risk of death.
A study in the US noted that the majority of the diarrheal episodes had no identifiable cause and were self-limited. The most common identifiable causes included Clostridium difficile infection (13.1% patients), norovirus infection (3.9% patients) and cytomegalovirus (CMV) gastrointestinal infection (3.5% patients).
Causes of diarrhea
Noninfectious diarrhea is common among renal transplant recipients. It leads to increased risk of graft loss and mortality.
The highest incidence is associated with MMF. The mechanism of MMF-induced diarrhea remains unknown. The enterocytes are dependent on the de novo pathways of purine synthesis for growth and these are inhibited the MMF. Histologically, 2 different morphologic patterns of mycophenolate-induced diarrhea can be identified:
Predominant crypt distortion also called inflammatory bowel disease-like MPA-associated toxicity
Predominant apoptosis, also called graft versus host-like MPA-associated toxicity
The use of tacrolimus may be associated with diarrhea in 29–64% of patients depending upon the dose and duration of drug usage. It is thought that a macrolide structure may result in stimulation of the intestinal motilin receptors.
Sirolimus causes self-limiting diarrhea in 14-42% of treated patients due to drug-induced jejunal villous atrophy.
Infectious diarrhea is more common. The pathogens commonly involved are CMV and C. difficile. After the first month of transplantation, when the patients are more immune suppressed, opportunist pathogens become more evident. Chronic Noro virus infection has emerged as one of the leading infectious causes of posttransplant diarrhea in kidney transplant recipients.
CMV is associated with significant morbidity and sometimes mortality. Risk factors for CMV disease include seronegative recipients of seropositive organs (D þ /R–) and, to a lesser extent, seropositive recipients (D–/R þ ), lymphodepleting antibodies and more potent immunosuppressive regimens. Adenovirus viremia is observed in early post transplant phase.
C. difficile is a common cause of nosocomial diarrhea. Risk factors include age above 55 years, use of ATG, retransplantation and the type of organ transplanted. Gastrointestinal infection due to microsporidia has been recorded in patients with SOT who experienced diarrhea and weight loss. Cryptosporidia have been implicated to cause severe acute diarrhea, chronic diarrheal illness and extraintestinal infection in transplanted patients.
Diagnosis and therapeutic strategy
It is important to evaluate and diagnose the cause of the diarrhea in a transplant recipient, especially between infectious and noninfectious causes.
The gold standard for C. difficile detection is the cell-based cytotoxicity assay, but a PCR is cheaper and more accessible to most labs. Both tests, have high sensitivity and specificity. Transplant recipient may develop diarrhea, intestinal obstruction, abscesses or toxic megacolon due to C. difficile. Only about 70% of patients respond to treatment with metronidazole. Persistent and more severe cases require oral vancomycin. Fecal microbiota transplantation (FMT) is a new option for refractory C. difficile infection (CDI), but further studies are required as current data is limited. Fumagilin treatment may also lead to sustained clearance of E. bieneusi. But it may cause drug induced thrombocytopenia.
Tissue invasive CMV infection is diagnosed by the presence of CMV viremia. CMV can be confirmed with PCR and histopathology. Histopathology shows, characteristically swollen cells containing ‘owl’s eye’ intranuclear inclusions. In general, patients with CMV colitis can be managed with intravenous ganciclovir (GCV) or oral valganciclovir (valGCV). The optimal duration of the therapy depends on the patient’s response.
Norovirus can be diagnosed by PCR on samples of stool, vomitus, food and environmental specimen. Currently, the most effective strategy to manage norovirus infection is the reduction of immunosuppression. It may lead to MMF discontinuation, which has been associated with an increased risk of rejection.
Rotavirus can be detected by PCR of stool samples, and treatment is mainly supportive. Prevention is key, and contaminated surfaces should be disinfected. Transplant candidates should receive the vaccines before transplantation. The vaccines are live attenuated vaccine, and hence cannot be used post transplant. For some patients an endoscopy or colonoscopy with biopsy may be required after transplantation.
This may be due to:
Intestinal ulcerations because of large bowel posttransplant lymphoproliferative disorder which may be accompanied by exudative enteropathy and chronic diarrhea
Cases of CMV colitis with concurrent negative CMV plasma PCR have been reported
The presence of severe duodenal villous atrophy may prompt clinicians to change more rapidly the immunosuppressive regimen, regardless of the cause
Post transplantation de-novo inflammatory bowel disease occurs more common in the transplant population.
Treatment of diarrhea, with hydration and focused use of antimicrobials or changes in immune suppression is important in its management.
Conclusion
The transplant team should be familiar with the common causes that result in post transplant diarrhea. A more direct approach to diagnosis and treatment will help prevent potentially life-threatening consequences. Further studies are required to better assist the true prevalence, risk factors, causative agent and complications of specific pathogens in kidney transplant recipients. Further studies will assist in the development of appropriate management and effective prevention mechanisms, which will consequently improve patient and graft survival.
Level of evidence:
This is a narrative review: LOE V
Causes and management of transplant diarrhoea: an cause of transplant-associated morbidity
Please summarise this article?
Introduction
Post-transplant diarrhea is common affecting nearly one fourth of transplant recipients at three years after transplantation. Chronic diarrhea after transplantation is common and associated with increased morbidity, hospitalization, allograft loss and poor quality of life. Steatorrhea and malabsorption can lead to secondary enteric hyperoxaluria with subsequent oxalate nephropathy (intense inflammation of allograft). Diarrhea is defined as > 3 loose stool/day.
Persistent (>2 weeks) and chronic (> 1month) The Quality of life, graft survival and mortality are all negatively impacted by chronic diarrhea post-transplant.
Transplant physician must assess the diarrhea in Kidney Transplant recipients, try to determine its source and differentiate between infectious and non-infectious causes of diarrhea.
Epidemiology.
The cumulative incidence of diarrhea is 11.5, 17.5, and 22.6% at 1-, 2-, and 3-years post-Kidney transplant, respectively (UNOS registry).
Yet, 53% of participants in a large survey of Kidney transplant recipients reported having diarrhea, despite their doctors’ estimates of the prevalence being only 6.9%. This finding shows how frequently post-TX diarrhea goes undiagnosed by healthcare professionals.
Most of the diarrheal events are self-limited & lack a known cause. The most frequent causes were CMV GI infection, norovirus infection, & Clostridium difficile infection. Causes of post-transplant diarrhea; Data from the DIDACT study;
Diarrhea resolved in 50% of patients either by cessation of diarrhea associated non-IS drugs or by the treatment of concurrent infections (mostly Campylobacter or CMV).
In the remainders, changes in IS therapy (mostly MMF) led to remission in 2/3 of cases.
CMV was the most prevalent infection\ etiology of post-TX diarrhea was found in 50% of cases. Medication use is the 2nd most common reason. Causes Of Infectious Diarrhea Post-Kidney transplant;
The most common identifiable causes include clostridium difficile infection, norovirus infection, CMV infection and drug induced. Viral: CMV most common, Norovirus, Rotavirus, Adenovirus, Sapobavirus
Bacterial: Clostridium difficile, Campylobacter, Salmonella, E coli, Bacterial overgrowth.
Parasitic: Cryptosporidium, Giardia, Isosopora Cyclospora, Microsporidium and Entamoeba.
CMV is the most important risk factor for CMV disease is D+/R– GI involvement (40% of patients). Other risk factors are D+/R–status, lymphodepleting antibodies & more potent IS regimens. Bacteria such as clostridium deficile is the most common cause of nosocomial diarrhea and accounts for most infectious diarrhea in the 1st months post-Transplant,
Clostridium deficile infection occurs in 3.5–4.5%, most common nosocomial infection in 1st month posttransplant, more common in age > 55 years, use of ATG, re-TX, liver transplant and with use of broad-spectrum antibiotics as quinolones, it is associated with 2.3-8.5% risk of mortality. It can lead to diarrhea, intestinal obstruction, abscesses, or toxic megacolon. Viruses such as CMV, adenovirus, norovirus, rotavirus, and sapovirus Parasites such as giardiasis, entamoeba histolotica, cryptosporidium salmonella, shigella, E coli, and bacterial overgrowth
Norovirus:
Has 2 phases: acute phase; presented with nausea, vomiting, significant diarrhea (10–20 watery stools per day), abdominal pain and sometimes fever. Then followed by a chronic phase; (cycles of relatively normal stools followed by periods of poorly formed stools).
Lately, chronic norovirus infection has become one of the most common infectious causes (17–26% of cases). This suggests that many infectious causes of diarrhea may have previously been misdiagnosed as being caused by IS medications, resulting in inappropriate diagnostic & treatment approaches.
Rotavirus infections:
occur in 1.5% of SOT recipients.
Adenovirus: is common in early posttransplant course (isolated in 6.5–22.5% of cases).
Viremia in the 1st few months post-TX (6.5–22.5%), & GI symptoms occur in 10%.
CNI level, CMV PCR, Stool culture and CD toxin in stool, and parasitic infection (Cryptosporidium, Entamoeba histolytica, Giardia lamblia, Campylobacter, Shigella, Salmonella, Vibrio, Yersinia enterocolitica, adenovirus and sapovirus), enzyme immunoassay for giardia and cryptosporidium and breath test for bacterial overgrowth. Clostridium diff. infection:
Cell-based cytotoxicity assay is the gold standard test Real-time PCR tests or fecal enzyme immunoassays (simpler, less expensive, & faster) are commonly used.
Tissue-invasive CMV disease:
CMV viremia is suggestive of the diagnosis. Laboratory tests include biopsy, CMV IgM & or elevation in IgG, conventional culture, Shell Vial assay, CMV pp65 Ag, PCR, & Real-time PCR.
Norovirus:
Diagnosed by PCR run on stool, vomitus, foods & environmental specimens.
Rotavirus:
Immune-based assays rapidly detect rotavirus antigens in stool.
Adenovirus:
Diagnosed by viral culture, direct antigen detection, histopathology & PCR.
Cryptosporidiosis:
Oocysts in the stool Modified acid-fast stains. IF assays&ELISA (100% sensitivity & specificity) Imaging, Colonoscopy and Biopsy:
may be needed if there is suspicious of malignancy, IBD or CMV colitis with negative PCR (15% of cases will have CMV PCR negative If these tests are negative & the diarrhea persists, empiric anti-diarrheal medications, probiotics &/or lactose-free diet tried.
Non-infectious causes of diarrhea Drug induced: Immunosuppression drugs (MMF mainly, CNI and MTORi). Others as (laxatives, anti-diabetics, PPI, anti-arrhythmic drugs).
Mechanism of MMF induced diarrhea: It inhibits de-novo pathway of purine synthesis essential for growth, Proliferation, and generation of enterocytes. IBD-like toxicity (predominant crypt distortion). GVHD associated toxicity (predominant apoptosis).
Treatment of MMF induced or associated diarrhea requires either:
Shift from MMF to EC-MPS that may be beneficial, or Short-term conversion to AZA (while long term graft outcome is lower with AZA than MMF in addition to higher risk of skin cancer).
MMF has the highest prevalence (RR 1.57), & numerous IS medications frequently used in TX may cause diarrhea.
Dose reduction is generally followed by a decline or cessation of diarrhea. It is unclear how MMF causes diarrhea. Two distinct histological patterns are seen: (i) IBD-like MPA-associated toxicity with predominant crypt distortion, & (ii) GVHD like type with predominant apoptosis.
It’s debatable whether switching from MMF to EC-MPS helps lessen symptoms of diarrhea. According to a recent RCT, patients who switch from MMF to EC-MPS may have a marginally but significantly higher likelihood of returning to the target MPA levels than those who stay on MMF.
Switch from MPA to AZA is usually avoided because of risk of reduced graft survival with AZA versus MMF.
Mechanism of TAC induced diarrhea:
It occurs in 30-60 % of cases, it may stimulate intestinal motilin receptors, but it is usually mild, self-limited, and not require drug discontinuation. Shift to extended release (advagraf) may be beneficial. MTORi induced diarrhea:
It occurs in 14-40 % of cases, it is related to jejunal villous atrophy, it is usually self-limited. ATG induced diarrhea:
Use of ATG can activate T cells to release TNF which then interferes with Na ion absorption and disrupts the intestinal mucosal barrier. Both ATG & OKT3 can cause diarrhea in 1/3 of patients; this diarrhea is self-limiting (lasts 3–4 d). Others including, GVHD (graft versus host disease), IBD, malabsorption, and microscopic colitis). Malignancy such as cancer colon, PTLD
Management;
In most cases, the cause is not identified, and diarrhea is self-limited. Supportive therapyincluding intravenous fluids for treatment of dehydration. Symptomatic therapyincluding loperamide to decrease bowel motions which is indicated in persistent (> 2 weeks) or chronic diarrhea (> 1 month) Modulation and monitoring of immunosuppression;
Reduction of immunosuppression in the form of reducing the dose of MMF by 50% after estimation of the rejection risk and keeping low target trough for CNI (5-8 ng/ml) Shifting from MMF to enteric coated mycophenolate (debatable)
Shifting from MMF to azathioprine (not preferred due to reduced graft survival, increased risk of rejection and increased risk of skin cancer associated with azathioprine use) Switching from tacrolimus to extended released formulation or to cyclosporine.
Switching from sirolimus to CNI since around 14-41 % of cases taking sirolimus experienced diarrhia.
Close follow up of CN level as there may be an increase in tacrolimus level with diarrhea due to disruption of P-glycoprotein efflux pump in the damaged enterocytes. Treatment of the cause;
For clostridium deficille infection: treatment lines include metronidazole 500 mg 3 times daily for 10–14 days, vancomycin 125 mg oral four times per day for 10–14 days, fidaxomicin 20 mg two times per day for 10 days, fecal microbiota transplantation, prolonged oral vancomycin.
Antibiotics for bacterial diarrhea and bacterial overgrowth
Anti-parasitic for parasites
Ganciclovir for CMV colitis for the first 2 weeks and shift to valganciclovir provided that the patient can tolerate oral, till 2 successive PCR samples are negative, then start secondary prophylaxis using valganciclovir for 1-3 month.
Specific treatment in case of cancer colon or PTLD
Treatment of major infectious causes
Clostridium difficile
First episode: Metronidazole 500mg TDS for 14 days
Severe disease: Vancomycin PO QID for 14 days or Fidaxomicin 20mg BID for 10 days.
First relapse: same for 1st episode
Second relapse: Vancomycin taper with pulse
Third relapse: Consider fecal microbiota TX (FMT), prolonged oral vancomycin.
CMV:
Oral valganciclovir, IV ganciclovir (if decreased absorption)
Norovirus: Rehydration, Antimotility drugs, Reduction in IS drugs.
Adenovirus:
Supportive care and IS reduction.
Microsporidia-related diarrhea:
Fumagillin may lead to sustained clearance with minimal IS reduction. Drug-induced thrombocytopenialimits its use.
Cryptosporidium:
No specific therapy
No difference between therapy with nitazoxanide or paromomycin and placebo.
Conclusions;
First; Other possible causes should be evaluated.
Very carefully assess other potential causes of diarrhea before accusing an IS drug of being the culprit.
it is necessary to rule out infectious agents and the other diarrhea-causing drugs such PPIs, antibiotics, and diuretics.
Prospective studies are required to determine the true prevalence more accurately, complications, and risk factors of diarrhea caused by norovirus, rotavirus and Adv in KTX recipients.
Improved patient and transplant survival is predicted to result from the development of potent vaccinations and antiviral treatments for these widespread viruses.
What is the level of evidence provided by this article?
Chronic diarrhea after kidney transplantation is a common complaint, associated with fatigue, increased hospitalizations and negative impacts on recipient quality of life.
EPIDEMIOLOGIC IMPACT:
Posttransplant diarrhea is often underrecognized by practitioners, and is associated with a two-fold increase in graft loss and risk of death. Common causes include Clostridium difficile, norovirus, and cytomegalovirus. 32% of those diagnosed with diarrhea had reductions or changes in their immune suppression.
CAUSES OF DIARRHEA: GENERAL:
The DIDACT study found that an infectious cause of posttransplant diarrhea is present in approximately 50% of cases, with CMV being the most common pathogen.
CAUSE OF DIARRHEA: IMMUNOSUPPRESSIVE DRUGS:
Drug-induced diarrhea is a major problem in transplantation, with the highest incidence associated with Mycophenolic acid (MPA) inhibition. MMF reduced graft loss by 27%, increased skin cancer risk, and caused diarrhea in 29-64% of patients.
CAUSE OF DIARRHEA: INFECTIONS
Diarrhea is commonly caused by CMV and C. difficile in solid organ transplant (SOT) recipients, but it is important to remember that the individual is also being exposed to common community-associated pathogens (e.g. norovirus and enteropathogenic bacteria). Chronic norovirus infection is the leading infectious cause of posttransplant diarrhea in kidney transplant recipients, with up to 94% having chronic diarrhea and 81% having episodes of diarrhea-induced acute renal failure. CMV is one of the most common infectious complications affecting SOT patients and is associated with significant morbidity and occasional mortality. CMV is the most common target organ for SOT patients, with 7.2% developing CMV disease.
DIAGNOSIS AND THERAPEUTIC STRATEGY:
The gold standard for C. difficile detection is the cell-based cytotoxicity assay, but most laboratories use fecal enzyme immunoassays or real-time PCR tests. Fecal microbiota transplantation (FMT) is promising, but its high adverse effect rate warrants further study. The most accurate means to diagnose CMV-associated colitis is endoscopic evidence of gastrointestinal involvement and immunohistochemical staining for pp65.Antiviral therapy can be managed with intravenous GCV or oral valganciclovir. Before antiviral therapy is stopped, three criteria must be met: treatment was given for at least 2 weeks, clinical symptoms have resolved and viral load is no longer detectable. Diagnosis of norovirus by PCR can be run on stool, vomitus, foods and environmental specimens .The most effective strategy to manage norovirus infection is the reduction of immunosuppression, and prevention is important. Perform esophagogastroduodenoscopy and colonoscopy with biopsies to investigate persistent diarrhea after kidney transplantation due to intestinal ulcerations, CMV colitis, duodenal villous atrophy, and post-transplantation de-novo inflammatory bowel disease. Treatment is of utmost importance.
CONCLUSION:
Physicians should be familiar with common causes of posttransplant diarrhea and take a directed approach to diagnosis and treatment to prevent potentially life-threatening consequences. Prospective studies are needed to better assess the prevalence, risk factors and complications of diarrhea by norovirus, rotavirus and AdV.
What is the level of evidence provided by this article?
This narrative review, published in 2017, provides an overview of an important clinical topic: diarrhoea occurring in solid-organ transplant (SOT) recipients. The authors highlight that incidence of diarrhoea in SOT recipients may be grossly underestimated: for example a Scandinavian study identified a huge discrepancy in reported incidence rates of post-transplant diarrhoea between clinicians and patients: 6.9% versus 53% respectively. Post-transplant diarrhoea can be a significant cause of morbidity as well as having potential impact on graft and patient survival.
Issues related to diarrhoea in renal transplant recipients: Impact on patient:
· Increased hospitalisation
· Reduced patient quality of life Impact on graft function/survival:
· Acute kidney injury associated with gastrointestinal losses
· Steatorrhoea/malabsorption hyperoxaluria with associated risk of oxalate nephropathy and reduced graft function
· Potential need to reduce immunosuppression with risk of rejection
· Poor absorption of crucial immunosuppression medications
· Overall reduced allograft and patient survival
The key diagnostic dilemma regarding post-transplant diarrhoea in SOT recipients is determining whether it is an infectious aetiology or a side-effect of medication: the treatment approaches for both are very different and erroneous treatment could lead to further harm.
Infectious causes of post-transplant diarrhoea:
An infectious aetiology is thought to be responsible for approximately 50% of cases of post-transplant diarrhoea.
Common infectious causes:
1. Cytomegalovirus (CMV) = commonest cause, highest risk patients are D+/R-
2. clostridium difficile (commonest hospital-acquired cause) – recent broad-spectrum antibiotic use often plays a role
3. bacterial overgrowth
4. norovirus – beware of chronic norovirus infection in SOT recipients who have a biphasic illness with the first phase being similar to that seen in non-immunosuppressed patients but the more chronic phase being different and sometimes mis-diagnosed
Other infectious causes:
5. rotavirus- limited data, further studies would aid knowledge in this area
6. adenovirus (AdV) – seen in early post-transplant period, 10% cases have GI symptoms
7. other bacterial causes: campylobacter, salmonella, aeromonous, E. coli
8. parasitic causes: giardia, cryptosporidium, isopopora Cyclospora, Microsporidium, Entameoba
Non-infectious causes of post-transplant diarrhoea
Commonly this is medication-related with the most common cause being:
· mycophenolate (MMF)
Other (less common) medication causes include:
· tacrolimus, ciclosporin
· sirolimus
· broad-spectrum antibiotics
· proton pump inhibitors
· laxatives
More rarely, a non-medication cause may be responsible such as:
· post-transplant lymphoproliferative disorder
· malabsorption
· inflammatory bowel disease
The authors summarise what is currently understood about MMF-induced diarrhoea. The exact mechanism remains unclear but there are 2 histological types: inflammatory bowel disease-like MPA toxicity which shows predominantly crypts being affected and graft-versus host-like MPA associated toxicity which demonstrates mainly cell apoptosis. The evidence that a switch to enteric coated mycophenolate sodium can alleviate post-transplant diarrhoea is mixed. However, a switch to azathioprine is generally not recommended as it is associated with poorer graft outcomes.
The authors have provided their own flow diagram for the management of post-transplant diarrhoea. They emphasise that the importance lies in correctly identifying the aetiology of the diarrhoea. Each patient’s experience is likely to be very different and this makes constructing a universal diagnosis/treatment algorithm very difficult. However, perhaps the most important take-home message from the paper is to clearly ask the patient about any symptoms of diarrhoea at each review in order to avoid the large discrepancy in patient-reported versus physician-reported incidence of post-transplant diarrhoea.
Level of evidence
This narrative review provides a succinct summary of post-transplant diarrhoea causes, diagnosis and management and is a useful introductory guide. However, the review methods are not discussed and there could be bias in the papers the authors have focussed upon. As such it provides level 5 evidence.
I like your well-structured summary, level of evidence, analysis and take home messages typed as conclusion. I like your step-wise approach. Please change to azathioprine or to a smaller dose sirolimus as an adjunct if that patient can not be give azathioprine to avoid interaction with allopurinol.
· Chronic diarrhea after kidney transplantation is a common complaint, but it can have negative impacts on the recipient’s quality of life, graft survival, and mortality. · Predisposing characteristics include immunosuppression and exposure to polypharmacy. · The main causes of posttransplant diarrhea are infections, immunosuppressive drugs, antibiotics, and other drugs.
· A diagnostic algorithm is needed to evaluate posttransplant diarrhea.
EPIDEMIOLOGIC IMPACT
· The DIDACT study found that an infectious cause of posttransplant diarrhea is present in approximately 50% of cases, with CMV being the most common pathogen.
· Changes in immunosuppressive therapy (most commonly MMF) led to remission of diarrhea in about two-thirds of cases.
· A survey of 4232 Scandinavian renal transplant recipients found that 53% reported diarrhea, whereas the incidence estimated by their physicians was only 6.9%.
· A recent study from a single transplant center in the United States reviewed the diagnostic yield of tests for diarrhea among hospitalized transplant recipients over a period of 18 months.
CAUSES OF DIARRHEA: GENERAL
· The DIDACT study identified an infectious cause of posttransplant diarrhea in approximately 50% of cases, with CMV being the most common pathogen.
· Changes in immunosuppressive therapy led to remission in two-thirds of cases.
CAUSE OF DIARRHEA: IMMUNOSUPPRESSIVE DRUGS
· Noninfectious diarrhea is a major problem among renal transplant recipients, with the highest incidence associated with MMF.
· A recent meta-analysis identified the relative risk of diarrhea associated with the use of MMF at 1.57.
· The mechanism of MMF-induced diarrhea remains unknown, but two morphologic patterns can be distinguished: crypt distortion and graft-versus host-like MPA-associated toxicity.
· Switching from MPA to EC-MPS may help reduce diarrhea symptoms, but is usually avoided due to reduced graft survival.
· The U.S. Renal Transplant Scientific Registry showed that MMF reduced the relative risk of graft loss by 27%, and death-censored graft survival was significantly better among MMF-treated versus AZA-treated patients.
CAUSE OF DIARRHEA: INFECTIONS
· Diarrhea in SOT recipients is often caused by opportunistic pathogens, including CMV and C. difficile. Chronic norovirus infection is one of the leading causes of posttransplant diarrhea, with up to 94% having chronic diarrhea and 81% having episodes of diarrhea-induced acute renal failure.
· Risk factors for CMV disease include seronegative recipients, lymphodepletion antibodies, and more potent immunosuppressive regimens.
· The most important risk factors for the development of CMV disease in SOT patients are seropositive donor/seronegative recipients’ gastrointestinal involvement, rotavirus infection, adenovirus viremia, C. difficile infection, recent antibiotic use, protozoan or metazoan infection, and extraintestinal infection.
DIAGNOSIS AND THERAPEUTIC STRATEGY
· Diagnosis of diarrhea in transplant recipients is important, and fecal enzyme immunoassays and real-time PCR tests are used to detect C. difficile.
· Treatment includes fidaxomicin, metronidazole, or vancomycin, and newer antibiotics such as fidaxomicin, ramoplanin and tigecycline.
· Fecal microbiota transplantation (FMT) is promising, but limited due to drug-induced thrombocytopenia. Cryptosporidiosis is diagnosed by visualization of oocysts in the stool, with immunofluorescent assays and ELISA having a sensitivity and specificity approaching 100%.
· CMV-associated colitis is diagnosed by endoscopic evidence of gastrointestinal involvement and can be managed with intravenous ganciclovir or oral valganciclovir.
· The most effective strategy to manage norovirus infection is to reduce immunosuppression, as norovirus is the key factor in posttransplant diarrhea.
· Prevention plays an important role in norovirus infection control, including hand hygiene and environmental sanitization.
· Contact precautions are recommended to prevent viral transmission, and two live oral vaccines against rotavirus are licensed for use.
· AdV can be diagnosed by viral culture, direct antigen detection, histopathology, and PCR.
· Treatment should include supportive care and a reduced immunosuppressive regimen.
· Treatment of persistent posttransplant diarrhea with hydration and focused use of antimicrobials or changes in immunosuppression is essential.
CONCLUSION
· Physicians should be aware of common causes of posttransplant diarrhea and use a directed approach to diagnosis and treatment.
· Prospective studies are needed to better assess the true prevalence, risk factors, and complications of diarrhea by norovirus, rotavirus, and AdV.
· Development of effective vaccines and antiviral therapies for these common viruses will improve patient and graft survival.
Thanks, Dear Professor for the concern,
In the United States, two live oral vaccines against rotavirus currently are licensed to use, but as they are live attenuated vaccines, transplant candidates should receive the vaccines before transplantation; their use post-transplant is contraindicated.
Please summarise this article.This narrative review addresses the post-transplant diarrhea epidemiology, causes, and algorithm for the diagnosis Introduction
Post-transplant chronic diarrhea is a common problem and considered an ignored condition that can affect a patient’s quality of life, increase the rate of hospitalization, generally unwell, increase morbidity, and impact graft survival, the main risk factors that can be shared among SOT includes the immunosuppression and polypharmacy including immunosuppression medications broad-spectrum antibiotics, and infections. it’s important to identify the underlying causes of chronic diarrhea and differentiate between infectious and non-infectious causes, improve the diagnostic tools this review study address the current evidence in regard f of infectious and noninfectious causes of chronic diarrhea after transplantation and share diagnostic algorithm with emphases of the need for more studies to address the real incidence of post-transplant chronic diarrhea, risk factors, and the impact of certain viral infections like norovirus, adenovirus, and rotavirus. Causes of diarrhea Infectious bacterial infection
Clostridium(CDI), Campylobacter spp. Salmonella spp. Bacterial overgrowth Aeromonous spp. Escherichia coli
C. difficile is the most common cause of nosocomial diarrhea and accounts for most infectious diarrhea within the first months after transplantation
The incidence of C. difficile infection (CDI) is between 3.5–4.5%, specific risk factors for CDI include age > 55, recent AB use includes ciprofloxacin group, use of ATG induction, retransplantation, and more after liver transplantation. CDI is associated with increased mortality rates between 2.3 and 8.5% and is an independent risk for death.
Viral infection, most common, CMV colitis, norovirus, rotavirus, adenovirus
Chronic norovirus infection has only recently emerged as one of the leading infectious causes
(Approximately 17–26% of severe posttransplant diarrhea) with the biphasic course ( acute and chronic form of diarrhea )
CMV colitis very common cause of diarrhea with tissue-invasive colitis
Parasitic infections
Giardia
Cryptosporidium
Isosopora Cyclospora
Microsporidium
Entameoba
microsporidia have been recorded in patients with SOT who experienced diarrhea and weight loss.
Noninfectious Drug-induced
MMF (most common, mechanism not clear)
Tacrolimus, cyclosporine, sirolimus Nonimmunosuppressive medications like broad-spectrum antibiotics and most common include ciprofloxacin with risk of clostridium defficilea, others like antiarrhythmics drugs, PPI , protease inhibitors, laxative
Other causes of chronic diarrhea after transplantations include PTLD, GVHD, denovo IBS, malignancies, microscopic colitis A diagnostic approach for chronic diarrhea after transplantation
Stool culture and parasitology, viral screen panel includes, CMV PCR, adenovirus PCR, Rotavirus, norovirus, and other gastroenteritis viral screen by Rapid antigen test (RAT) in the stool, immunoassay, cell Viral cultures, CDI toxin A, B antigens cell-based cytotoxicity assay. fecal enzyme immunoassays or real-time PCR tests with 90% sensitivity.
Cryptosporidiosis is mostly diagnosed by visualization of oocysts in the stool. Immunofluorescent assays and ELISA tests have 100% sensitivity and specificity and are better than modified ACID-FAST staining
In the case of tissue-invasive CMV disease, the best in addition to the presence of CMV viremia is to confirm by tissue biopsy by looking for typical owl eye viral inclusion bodies
Around 15% of patients with CMV colitis will have negative CMV PCR with low specificity only 77%, while tissue biopsy is found 100% specific for the diagnoses of CMV disease
Treatment
Depending on the underlying pathology, and by principles all patients with diarrhea should have their medications reviewed for potential causes of diarrhea, and unnecessary agents should be stopped and followed by specific testing for different causes of diarrhea, stepwise approach before reduction of immunosuppression
1. CDI treatment depends on the severity and the frequency of infection, mild to moderate CDI need isolation and in addition to supportive medical care need medical therapy with oral AB, like metronidazole for 10-12 days fidaxomicin, metronidazole, or vancomycin, with vancomycin preferred for cases of more severe infection
about 70% of patients will respond to treatment with metronidazole; persistent and
more severe cases will require oral vancomycin. in combination with oral vancomycin main challenges with the management of CDI, is the risk of relapse and failure for medical treatment ( refractory CDI ) leading to Complicated severe CDI with toxic megacolon, which might need surgical intervention including hemicolectomy ileostomy and broad-spectrum AB
Fidaxomicin, ramoplanin, and tigecycline are newer antibiotics that are effective for the treatment of severe or recurrent disease also new monoclonal AB and microbiota fecal transplantation are still in clinical research
2. rotaviral infection is mainly supportive therapy
Prevention by contact precaution and use 95% alcohol disinfection to the surfaces, two vaccination available for rotavirus infection RotaTeq (RV5) and Rotarix (RV1), both live attenuated and should be given before the transplantation
3.CMV colitis can be managed with intravenous ganciclovir (GCV) or oral valganciclovir (valGCV) duration of antiviral therapy depends on
the patient’s clinical and virologic responses should be at least for 2-3 weeks provided that patient symptoms are resolved and repeated CMV PCR is no more detected at least for two consecutive cmv pcr tests.
What is the level of evidence provided by this article? narrative review level 5
I like your well-structured rather extensive summary, level of evidence, analysis and take home messages typed as conclusion.
I like your step-wise diagnostic approach.
Posttransplant diarrhea is one of the commonest complications that negatively impact the graft and patient survival in organ transplant recipients (OTRs), it is usually underestimated by physician that is why its incidence is incorrect but in general, its incidence is cumulative; increased in the third year more than second year which is more than first year posttransplant.
Graft loss and death are two fold increased if compared with OTRs without diarrhea especially non infectious diarrhea.
Several risk factors are present in all OTRs like hospitalization, susceptibility to infection by various organisms, immunosuppressive medications like mycophenolate mofetil (MMF), other drugs like antibiotics.
Definition of chronic diarrhea post solid organ transplant:
It is three or more times of motion of unformed stool per day for at least one month, and is associated with weight loss.
Causes of diarrhea:
Posttransplant diarrhea may be infectious or noninfectious, the commonest cause of infectious is cytomegalovirus (CMV) which is responsible for fifty percent of the cases, and the commonest cause of noninfectious diarrhea which is drug related is immunosuppressive medication which is MMF.
1- Infectious causes of diarrhea:
a- Bacterial causes like clostridium difficile and bacterial overgrowth which are the commonest bacterial causes, other bacteria can cause diarrhea like campylobacter spp., salmonella spp., and Escherichia coli (E-coli).
b- Viral causes like CMV which is the commonest viral infection, other viruses like Noroviruses, Rotavirus, and Adenovirus.
c- Parasitic causes like Giardia, Entamoeba, Cryptosporidium and Microsporidium.
2- Non-infectious causes: mostly done after six months of transplantation.
a- Immunosuppressive medications like MMF which is the commonest, others like cyclosporin, sirolimus and tacrolimus.
b- Non-immunosuppressive medications like antibiotics, laxatives, proton pump inhibitors, antidiabetics, protease inhibitors.
3- Other causes:
a- Malabsorption
b- Cancer colon
c- Inflammatory bowel disease (IBD)
d- Rare causes like posttransplant lymphoproliferative disease (PTLD), graft versus host disease (GVHD).
Non-infectious diarrhea:
1- The commonest cause of non-infectious diarrhea is MMF which represents twelve to thirty percent of the cases, its mechanism is unknown, but may be related to partial dependance of gastrointestinal epithelial cells on de novo purine synthesis for growth and proliferation so become vulnerable to mycophenolic acid (MPA) inhibition, duodenal villous atrophy (DVA), crypt distortion (IBD like disease), apoptosis (GVHD like disease), direct intestinal cell injury, imbalance between tolerance and immunity, defect in regeneration of intestinal cells, infection may be associated.
DVA is present in the most of cases of MPA associated diarrhea, and it improved after its dose reduction and resolves completely after its cessation.
GIT symptoms associated with MMF is dyspepsia, epigastric pain and diarrhea which are associated with poor quality of life.
Its management:
a- It responds to dose reduction.
b- Shift to enteric coated mycophenolate sodium EC-MPS, which is associated with improvement in gastrointestinal symptoms.
c- Shift to azathioprine, this may have negative impact on graft survival on long term and it increased risk of skin cancer especially squamous cell carcinoma, hence, has negative impact on patient survival on long term, but can save the situation on short term follow up.
d- It is usually associated with poor graft outcome, because of full MPA exposure is associated with less biopsy proven acute rejection.
e- When facing considerable GIT symptoms, therapeutic dose monitoring of MPA should be implemented to control dose reduction.
2- Calcineurin inhibitors (CNI) like cyclosporin and tacrolimus result in mild diarrhea, its mechanism is related to stimulation of intestinal motilin receptors, no need for dose reduction or change medication, but gastrointestinal symptoms are increased when shifting from cyclosporin to tacrolimus in the presence of MPA, as it increases the level of MPA.
3- Sirolimus can induce mild self limited diarrhea, of unknown mechanism, and may be related to jejunal villous atrophy and stimulation of motilin receptors like CNI.
Double Hit theory
Means mixed infective organism with MPA toxicity, like cryptosporidium especially within tacrolimus.
Norovirus: has biphasic illness in immunocompromised patients, acute phase which includes fever, nausea, vomiting, abdominal pain, watery diarrhea ten to twenty times per day , and can induce acute kidney injury, then chronic phase which involves episodes of diarrhea alternating with normal stool.
Clostridium difficile infection (CDI): it is the commonest hospital acquired infection causing diarrhea especially in the first month post renal transplant, has several risk factors like age more than fifty five years, heavy immunosuppression by antithymocyte globulin (ATG), retransplantation, type of transplanted organ; highest risk among liver transplant recipients, also recent antibiotic use with special attention to fluoroquinolones which remains the single most common risk factor, may present asymptomatic, diarrhea, intestinal obstruction, or toxic megacolon.
CMV infection which is the commonest viral infection and is related to the degree of immunosuppression, the seropositive donor to seronegative recipient remains the single commonest risk factor, the target organ of CMV is GIT.
Management (diagnosis and treatment):
1- CDI
a- diagnosed by real time PCR or fecal enzyme immunoassay which is easy, less expensive, and has high sensitivity and specificity.
b- Treated by metronidazole 500 mg three times daily for two weeks, but in severe cases oral vancomycin should be given for two weeks.
c- Tigecycline, and ramoplanin restored to severe or recurrent cases.
d- Human monoclonal antibodies against C. difficile toxin A and B is introduced recently.
e- Fecal microbiota transplantation (FMT) ; installation of processed feces donor into the colon or duodenum of the recipient.
2- Cryptosporidium diagnosed by immunofluorescence assay, ELISA which has 100% sensitivity and specificity, and has no specific treatment.
3- CMV gastrointestinal disease associated
a- can be diagnosed by endoscopic biopsy for histopathological diagnosis which revealed swollen cells with intranuclear viral inclusions giving owl eye appearance or can diagnosed by immunohistochemistry staining for PP65, both are gold standard methods to diagnose CMV colitis , this regardless CMV PCR.
b- Can be treated by intravenous ganciclovir or oral valganciclovir if there is no risk of malabsorption due to vomiting and diarrhea (may be early in disease), this for at least two weeks and can be extended according to the clinical situation, and should not be stopped except after the following: at least two weeks duration of treatment, no clinical symptoms present, no detectable viremia if initially present.
Oral valganciclovir should be given as secondary prophylaxis for 1-3 months.
4- Norovirus diagnosed by PCR of stool or vomits, and treated by rehydration, antimotility drugs, and supportive treatment.
It is the important cause of posttransplant diarrhea, and its chronicity leads to holding of MPA which expose to rejection.
No specific treatment or vaccine , so, implementation of hand hygiene instructions and environmental sanitation are the key for prevention.
5- Rota virus diagnosed by PCR, no specific treatment and can be prevented by live attenuated rota vaccine which should be given pretransplant only and is contraindicated posttransplant.
6- Adenovirus diagnosed by viral culture and PCR, has no specific treatment.
Conclusions and take home message:
1- Posttransplant diarrhea should taken into consideration and not to be neglected.
2- Medical team should be aware by all causes of diarrhea and its management.
3- Drug induced diarrhea rather than MPA should be kept in the mind.
1.Please summarise this article. Introduction
The recipient’s quality of life, graft survival, & mortality are all negatively impacted by chronic diarrhea pos-KTX.
Clinicians must assess diarrhea in KTX recipients, try to determine its source, & distinguish between infectious & noninfectious causes of diarrhea. Epidemiology
The cumulative incidence of diarrhea is 11.5, 17.5, & 22.6% at 1, 2, & 3 years post-KTX, respectively (UNOS registry).
Yet, 53% of participants in a large survey of KTX recipients reported having diarrhea, despite their doctors’ estimates of the prevalence being only 6.9%. This finding shows how frequently post-TX diarrhea goes undiagnosed by healthcare professionals.
Most of the diarrheal events are self-limited & lack a known cause. The most frequent causes were CMV GI infection, norovirus infection, & Clostridium difficile infection. Causes of post-transplant diarrhea Data from the DIDACT study
Diarrhea resolved in 50% of patients either by cessation of diarrhea-associated non-IS drugs or by the treatment of concurrent infections (mostly Campylobacter or CMV).
In the remainders, changes in IS therapy (mostly MMF) led to remission in 2/3 of cases.
CMV was the most prevalent infection, & an infectious etiology of post-TX diarrhea was found in 50% of cases. Medication use is the 2nd most common reason. Noninfectious causes of diarrhea
MMF has the highest prevalence (RR 1.57), & numerous IS medications frequently used in TX may cause diarrhea.
Dose reduction is generally followed by a decline or cessation of diarrhea.
It is unclear how MMF causes diarrhea. Two distinct histological patterns are seen: (i) IBD-like MPA-associated toxicity with predominant crypt distortion, & (ii) GVHD like type with predominant apoptosis.
It’s debatable whether switching from MMF to EC-MPS helps lessen symptoms of diarrhea. According to a recent RCT, patients who switch from MMF to EC-MPS may have a marginally but significantly higher likelihood of returning to the target MPA levels than those who stay on MMF.
Switch from MPA to AZA is usually avoided because of risk of reduced graft survival with AZA versus MMF.
Depending on the dosage & length of treatment, 29–64% of patients on tacrolimus may experience diarrhea.
SIR causes self-limiting diarrhea in 14–42% of patients.
Both ATG & OKT3 can cause diarrhea in 1/3 of patients; this diarrhea is self-limiting (lasts 3–4 d). Infectious causes of post-KTX diarrhea CMV & C. difficile (CDI):
The most important risk factor for CMV disease is D+/R– GI involvement (40% of patients). Other risk factors are D+/R–status, lymphodepleting antibodies & more potent IS regimens.
CDI is the most common cause of nosocomial diarrhea & accounts for most infectious diarrhea in the 1st months post-TX. The incidence of CDI is 3.5–4.5% in adult KTX patients. Risk factors include age > 55 years, use of ATG, re-TX & the type of organ TX (highest in liver TX). Recent antibiotic use, particularly fluoroquinolone, is the single biggest risk factor. Mortality rate from CDI is 2.3 to 8.5%. Norovirus:
Lately, chronic norovirus infection has become one of the most common infectious causes (17–26% of cases). This suggests that many infectious causes of diarrhea may have previously been misdiagnosed as being caused by IS medications, resulting in inappropriate diagnostic & treatment approaches. Rotavirus infections:
occur in 1.5% of SOT recipients. AdV:
Viremia in the 1st few months post-TX (6.5–22.5%), & GI symptoms occur in 10%. Microsporidia Cryptosporidia (Cryptosporidia parvum & Cryptosporidia hominis). Diagnosis CDI:
Cell-based cytotoxicity assay is the gold standard test
Real-time PCR tests or fecal enzyme immunoassays (simpler, less expensive, & faster) are commonly used. Tissue-invasive CMV disease:
CMV viremia is suggestive of the diagnosis.
Laboratory tests include biopsy, CMV IgM & or elevation in IgG, conventional culture, Shell Vial assay, CMV pp65 Ag, PCR, & Real-time PCR. Norovirus:
Diagnosed by PCR run on stool, vomitus, foods & environmental specimens. Rotavirus:
Immune-based assays rapidly detect rotavirus antigens in stool. AdV:
Diagnosed by viral culture, direct antigen detection, histopathology & PCR. Cryptosporidiosis:
Oocysts in the stool
Modified acid-fast stains.
IF assays&ELISA (100% sensitivity & specificity) Diagnostic approach from DIDACT study
1. Review all medications & stop unnecessary ones.
2. Specific testing for different causes of the diarrhea, including bacterial culture, assessment for ova & parasites, PCR for CMV & C. difficile & stool lactoferrin.
3. Breath test for bacterial overgrowth
4. Reduction in immune suppression
5. Colonoscopy.
6. If these tests are negative & the diarrhea persists, empiric anti-diarrheal medications, probiotics &/or lactose-free diet tried. Treatment of major infectious causes Clostridium difficile
First episode:
Metronidazole 500mg TDS/10–14 days
Severe disease:
Vancomycin PO QID/10–14 days
Fidaxomicin 20mg BID/10 days
First relapse: same for 1stepisode
Second relapse:
Vancomycin taper with pulse
Third relapse:
Consider fecal microbiota TX (FMT), prolonged oral vancomycin. CMV:
Oral valganciclovir
IV ganciclovir (if decreased absorption) Norovirus:
Rehydration
Antimotility drugs
Reduction in IS drugs. AdV:
Supportive care & IS reduction. Microsporidia-related diarrhea:
Fumagilin may lead to sustained clearance with minimal IS reduction.
Drug-induced thrombocytopenialimits its use. Cryptosporidium:
No specific therapy
No difference between therapy with nitazoxanide or paromomycin & placebo. Conclusions
A targeted diagnostic & therapeutic approach will help to resolve diarrhea & prevent potentially harmful effects like graft loss.
Very carefully assess other potential causes of diarrhea before accusing an IS drug of being the culprit.
First, it is necessary to rule out infectious agents & the other diarrhea-causing drugs such PPIs, antibiotics, & diuretics.
Prospective studies are required to more accurately determine the true prevalence, complications, & risk factors of diarrhea caused by norovirus, rotavirus, & AdV in KTX recipients.
Improved patient & transplant survival is predicted to result from the development of potent vaccinations & antiviral treatments for these widespread viruses.
========================= 2.What is the level of evidence provided by this article?
Level V
I like your well-structured rather extensive summary, level of evidence, analysis and take home messages typed as conclusion. I like your step-wise approach.
Causes and management of postrenal transplant diarrhea: an underappreciated cause of transplant-associated morbidity
Please summaries this article.
Diarrhea is one of the most common complaints in post-transplant. Almost 25% of recipients develop diarrhea which disturbs their quality of life.
Causes of post-transplant diarrhea
A- Infectious diarrhea
Bacteria such as clostridium deficile, salmonella, shigella, E coli, and bacterial overgrowth
Viruses such as SARS-cove 2, CMV, adenovirus, norovirus, rotavirus
Parasites such as giardiasis, entamoeba histolotica, cryptosporidium
B-Non-infectious diarrhea
· Drug induced: MMF, CNI, sirolimus, antibiotics, proton pump inhibitors
· Malignancy such as cancer colon, PTLD How to approach:
The main important issue is to differentiate between infectious causes from noninfectious causes
v detailed history should be taken about onset, course and durations of diarrhea and if there is any symptoms of infection like fever, upper GIT manifestations and any other family member developed same picture.
v Examination: looking for any signs of infection or malignancy
v Investigations include:
· Basic investigations include: UE1, electrolytes including magnesium, Complete blood count, c reactive protein, Stool analysis and culture, CL.deficiel toxin, CMV PCR, tacrolimus level
· stool multiplex PCR for viral if available which include screening for three viruses, nine bacteria and three parasites.
· colonoscopy, and biopsy may be needed because CMV colitis with negative PCR occurs in 15% of cases. Management
1. Supportive therapy including intravenous fluids for treatment of dehydration
2. Immunosuppression
a. Shifting from MMF to enteric coated mycophenolate maybe of benefit.
b. To keep tacrolimus level on the lower side
3. Treatment of the cause What is the level of evidence provided by this article?
I like your well-structured rather extensive summary, level of evidence, analysis and take home messages typed as conclusion.
I like your step-wise approach.
Caution: Not many patient benefit from conversion conversion of MMF to myfortic. Please change to azathioprine or to a smaller dose sirolimus as an adjunct if that patient can not be give azathioprine to avoid interaction with allopurinol.
Week 10, Causes and management of postrenal transplant diarrhea:
Summary
· Chromic diarrhea after transplantation is common and associated with increased morbidity, hospitalization, allograft loss and poor quality of life.
· Steatorrhea and malabsorption can lead to secondary enteric hyperoxaluria with subsequent oxalate nephropathy (intense inflammation of allograft).
· Diarrhea is defined as > 3 loose stool/day.
· Persistent (>2 weeks) and chronic (> 1month).
· Causes: either infectious or none infectious, as exposure to polypharmacy as immunosuppressive drugs, antibiotics and other drugs.
· Infectious causes as: (most common are CMV and Clostridium difficile)
o Viral: CMV (most common), Norovirus, Rotavirus, Adenovirus, Sapobavirus
o Bacterial: Clostridium difficile, Campylobacter, Salmonella, E coli, Bacterial overgrowth.
o Parasitic: Cryptosporidium, Giardia, Isosopora Cyclospora, Microsporidium and Entameoba.
· None infectious causes:
o Drug induced:
§ IS drugs (MMF mainly, CNI and MTORi).
§ Others as (laxatives, anti-diabetics, PPI, anti arrhthmic drugs).
o Other disorders:GVHD, IBD, PTLD, cancer colon, malabsorption and microscopic colitis).
· Identification of the cause is crucial, as reduction of IS in case of suspected drug induced diarrhea can lead to AR and graft loss and in addition the delay in identification of microbial cause of infectious diarrhea can lead to poor patient and graft outcome.
· Mechanism of MMF induced diarrhea:
o It inhibits de-novo pathway of purine synthesis essential for growth, Proliferation and generation of enterocytes.
o IBD-like toxicity (predominant crypt distortion).
o GVHD associated toxicity (predominant apoptosis).
o Ttt of MMF induced or associated diarrhea requires either: Shift from MMF to EC-MPS that may be beneficial, or short-term conversion to AZA (while long term graft outcome is lower with AZA than MMF in addition to higher risk of skin cancer).
· Mechanism of TAC induced diarrhea:
o It occurs in 30-60 % of cases, it may stimulate intestinal motilin receptors, but it is usually mild, self-limited and not require drug discontinuation.
o Shift to extended release (advagraf) may be beneficial.
· MTORi induced diarrhea:
o It occurs in 14-40 % of cases, it is related to jejunal villous atrophy, it is usually self-limited.
· ATG induced diarrhea:
o Use of ATG can activate T cells to release TNF which then interferes with Na ion absorption and disrupts the intestinal mucosal barrier.
· Infectious diarrhea:
o Norovirus: has 2 phaseshttps://s.w.org/images/core/emoji/14.0.0/svg/2639.svg acute phase; presented with nausea, vomiting, significant diarrhea (10–20 watery stools per day), abdominal pain and sometimes fever. Then followed by a chronic phase (cycles of relatively normal stools followed by periods of poorly formed stools).
o CMV infection: occurs in 7 % of KTRs, most common site involved is GIT (occurs in 1/3 patents,risk factors (strong IS as ATG induction, D+/R-).
o Rotavirus, limited data, but more common in children and in liver transplantation.
o Adenovirus: is common in early posttransplant course (isolated in 6.5–22.5% of cases).
o C. difficile infection occurs in 3.5–4.5%, most common nosocomial infection in 1st month posttransplant, more common in liver transplant and with use of broad-spectrum antibiotics as quinolones, it is associated with 2.3-8.5% risk of mortality. It can lead to diarrhea, intestinal obstruction, abscesses or toxic megacolon.
· Protozoa: microsporidia (severe diarrhea and weight loss) and Cryptosporidia (severe acute diarrhea, chronic diarrheal illness + extraintestinal infection.
· Diagnosis:
o The first-line microbiologic stool investigations is standard stool cultures for pathogenic bacteria, examinations for parasites and fungi, C. difficile toxin assay and quick tests for rotavirus, adenovirus and norovirus.
o In case of fever, CMV D+/R-, cytopenia, liver enzymes studies, and plasma CMV Q-PCR is indicated.
o CMV tissue invasive disease (+VE PCR (viremia, but -ve in 15 % of cases) + PCR can be performed on whole blood, plasma and leukocytes. Definitive diagnosis of CMV depends on endoscopy and biopsy (characteristic owl eye appearance, swollen cells with intranuclear inclusions, or by immunohistochemical staining for pp65.
o Norovirus: diagnosed by PCR can be run on stool or vomitus.
o Rotavirus: ELISA, cell culture, real time-PCR and electron microscopy.
o Adenovirus: viral culture, direct antigen detection, histopathology and PCR, clinical manifestations and biopsy help to differentiate infection from carrier stae.
o Clostridium is diagnosed by fecal enzyme immunoassays or real-time PCR test (easier than standard cell-based cytotoxicity assay).
o Cryptosporidium is diagnosed by oocyst visualization in the stool and Immunofluorescent assays as ELISA.
o Breath test is used for diagnosis of bacterial overgrowth
· Treatment= treatment of the cause.
o Clostridium difficile is treated by 10-14 days of metronidazole or oral vancomycin for severe cases. Fidaxomicin, ramoplanin and tigecycline are newer antibiotics that can be use in severe or recurrent disease. In addition, human monoclonal antibodies against C. difficile toxins A and B and fecal microbiota transplantation (FMT) in refractory cases (however FMT is debatable and may lead to adverse effect in transplant population).
o Protozoa: No specific treatment against cryptosporidium and neither nitazoxanide or paromomycin had beneficial effect over placebo while fumagilin is very effective in treatment of microsporidia.
o CMV colitis: IV ganciclovir (GCV) or oral valganciclovir (valGCV). IV is used in patients with vomiting and diarrhea). Optimal duration is based on patient’s clinical and virologic responses, stop treatment at least 2 weeks after clinical resolution of symptoms and negative PCR. Recurrent CMV disease is reported in 15–35% of SOT recipients with tissue-invasive CMV disease, so oral valganciclovir may be recommended for 30–90 days after successful treatment.
o Norovirus (ttt is mainly supportive with fluids and anti-motility+ reduction of IS). No available vaccine and many suggested treatment lines as oral or IV immunoglobulin, breast milk, ribavirin and nitazoxanide seem ineffective. So, hand hygiene is the most important strategy to prevent infection.
o Rotavirus (ttt is supportive), prevention (hygiene+ 2 licensed oral vaccine (RotaTeq and Rotarix), but they are live attenuated (used only pretransplant, and contraindicated after transplant)).
o Adenovirus (ttt is mainly supportive with fluids and anti-motility+ reduction of IS).
· If all diagnostic tests are negative and the diarrhea persists, empiric antidiarrheal medications, probiotics and/or lactose-free diet should be tried.
· Esophagogastroduodenoscopy and colonoscopy with biopsies to investigate persistent diarrhea in KTR is still debatable. However, it may be of value in the following situations, intestinal ulcers in PTLD, CMV colitiswith concurrent -ve plasma CMV PCR, severe duodenal villous atrophythat indicates change MMF and post transplantation de-novo IBDthat is 10 times more common than the general population.
· Prior to implicating IS medication as the culprit, a meticulous evaluation for other possible causes of diarrhea should be conducted. Infectious agents and the concomitant use of other diarrhea genic medications such as PPI, antibiotics and diuretics must first be excluded.
Summary Introduction
Chronic diarrhoea is a common complaint in the post-transplant period that is overlooked by both the clinician and recipient.
Though overlooked, chronic and severe diarrhoea may lead to steatorrhea and malabsorption.
Enteric hyoeroxaluria may occur leading to oxalate nephropathy.
Thus chronic diarrhoea affects the recipient’s quality of life, graft survival and mortality.
Poly-pharmacy and an immunosuppressed state and the most significant risk factors.
Causes of diarrhoea
There is limited data on the causes of diarrhoea in kidney transplant recipients.
The DIDACT study the most common cause of diarrhoea was infections- CMV and drug related.
Immunosuppressive drugs
Most immunosuppressive medications cause diarrhoea with the highest incidence with MMF.
Diarrhoea caused by MMF disappears with dose reductions.
MMF and EC-MPS both have been implicated to cause diarrhoea; and whether switching MMF to EC-MPS helps alleviate symptoms is a matter of debate.
Two histological morphological types have been identified: Inflammatory bowel disease like MPA associated toxicity where there is disruption of crypt and graft versus host like MPA associated toxicity-there is predominant apoptosis.
Tacrolimus may also cause diarrhoea though it depends with the dose and the duration, however unlike MMF induced diarrhoea, it has a mild course and doesn’t require dose reduction.
Sirolimus has also been implicated to cause diarrhoea though it is self-limiting lasting for approximately 2 weeks.
Lymphocyte depleting agents-ATG and OKT3 also cause diarrhoea which resolves spontaneously in 3-4 days.
Infections C.difficile, noravirus and CMV are the most common causes.
Noravirus- biphasic illness in the immunocompromised. Acute phase characterised by fever, vomiting, nausea, abdominal pain and diarrhoea. Chronic phase where there are cyclical phases of well formed stools alternating with periods of poorly formed stools.
CMV- Risk factors include CMV seropositivity status pre-transplantation D+/R-, use of lymphocyte depleting agents and more potent immunosuppressive regimens. C.difficile- accounts for most cases of infectious diarrhoea in the firsts months post-transplant. Most significant risk factor is recent antibiotic use with fluoroquinolones associated with the highest risk.
Diagnosis and therapeutic strategy
It is imperative to differentiate infectious and non-infectious causes to avoid unnecessary dose reductions.
C.difficile – gold standard for diagnosis is cell based cytotoxicity assay, fecal enzyme based immunoassay and real time PCR can be used. Treatment is with either metronidazole or vancomycin or fidaxomicin.
There is limited data on the use of FMT in the transplant population.
CMV- definitive diagnosis relies on endoscopic evidence of GIT involvement- Owl eye intranuclear inclusions and IHC staining for pp65. Treatment is with IV ganciclovir or oral valganciclovir.
Optimal duration is dependent on patient’s clinical and virological response.
Before discontinuation of treatment the following criteria must be meant:
Patient must have been on treatment for at least 2 weeks
The clinical symptoms should have resolved
The viral load should not be detectable.
Because of risk of recurrence, CMV prophylaxis for 30-90 days after treatment of tissue invasive disease is recommended.
Noravirus – It is the key factor in the induction of post transplant diarrhoea, while MMF plays a critical role in the chronicity of the virus by impairing the clearance of the virus and repair of the intestinal epithelium.
PCR on stool, food and vomitus can be done for diagnosis.
First line in management is supportive with fluid and electrolyte replacement.
Second is immunosuppressive reduction.
Currently there are no vaccines available, prevention is thus by proper hand hygiene and environmental sanitisation.
Rotavirus- diagnosed via immune based assay.
Management is mainly supportive.
Currently there are 2 vaccines available which are live attenuated, hence should be given prior to transplantation and contraindicated in the post-transplant period.
Adenovirus- can be diagnosed via culture, antigen detection, PCR and histopathology. Detection in patient’s sample should be correlated with clinical and histopathology to distinguish asymptomatic infection.
Management is supportive and reduction of immunosuppression.
DIDACT study.
Large prospective study that was done to identify the cause of diarrhoea post renal transplantation.
Most common cause was CMV and campylobacter jejunii.
50% diarrhoea resolved without change of immunosuppressive therapy.
A third of patients diagnosed with bacterial overgrowth responded to antibiotics.
Stepwise approach
First step of evaluation of diarrhoea is drug evaluation and stopping any medication that are not immunosuppressive that could be associated with the diarrhoea.
Next is evaluation of the diarrhoea with culture, PCR, evaluate for parasites, C.Difficile, adenovirus, rotavirus and noravirus.
If negative empirical antidiarrhoeal treatment, lactulose free diet and probiotics should be tried.
If diarrhoea persists then reduction of immunosuppression should be considered.
MMF should be switched to EC-MPS, if diarrhoea still persists then both should be withdrawn.
Endoscopy and colonoscopy with biopsy should be considered to investigate persistent diarrhoea.
Conclusion
Prior to implicating immunosuppressive agents a meticulous evaluation of other possible causes should be evaluated.
Other non-immunosuppressive medications and infections should be ruled out.
Further studies are required to evaluate the true prevalence, risk factors, and complications of diarrhoea caused by noravirus,rotavirus and adenovirus.
I like your well-structured rather extensive summary, level of evidence, analysis and take home messages typed as conclusion.
I like your step-wise approach.
Caution: Pleas change to azathioprine or to a smaller dose sirolimus as an adjunct if that patient can not be give azathioprine to avoid interaction with allopurinol.
Causes and management of post-renal transplant diarrhea: an underappreciated cause of transplant-associated morbidity. INTRODUCTION.
One of most common complications in post kidney transplant recipients is chronic diarrhea which is mainly due to common sharing risk factors such as immunocompromised status which lead to infectious diarrhea as a common cause of diarrhea , drugs induced diarrhea due to immunosuppressive medications and others, as there are variety of causes so single standard approach is difficult and not clear so far. EPIDEMIOLOGIC IMPACT
The cumulative incidence of diarrhea has been reported to be 11.5, 17.5 and 22.6% at 1, 2 and 3 years after renal transplantation, respectively, chronic diarrhea is some studies shown that it was associated with a two-fold increase in graft loss and risk of death. Other study shown that the most common identifiable causes included Clostridium difficile
infection, norovirus infection, and cytomegalovirus (CMV) gastrointestinal infection.
About 32% of individuals taking Mycophenolate mofetil (MMF) or mycophenolic acid and diagnosed with diarrhea had reductions or changes in their immune suppression. CAUSES OF DIARRHEA: GENERAL.
DIDACT study shown that an infectious cause of post-transplant diarrhea is present in approximately 50% of cases with CMV being the most common pathogen and the next most frequent cause is related to medication use. CAUSE OF DIARRHEA: IMMUNOSUPPRESSIVE DRUGS.
Unfortunately many of the immunosuppressive agents commonly used in transplantation may cause diarrhea, with the highest incidence associated with MMF and still the main cause not well known but the theory mainly due to purine inhibition effect of KIT epithelial cells, tacrolimus also lead to diarrhea in 29–64% of patients depending upon the dose and duration of drug usage and shifting to extended release formulation of tacrolimus shown some improvement. CAUSE OF DIARRHEA: INFECTIONS.
Chronic norovirus infection has only recently emerged as one of the leading infectious causes (approximately 17–26% of severe post-transplant diarrhea), usually is biphasic which consist of the initial acute phase (10–20 watery stools per day), abdominal pain and sometimes fever then followed by a chronic phase, when patients can experience cycles of relatively normal stools followed by periods of more poorly formed stools.
CMV also one of the most common cause of diarrhea post kidney transplant and the most significant risk factor for the development of CMV disease is seropositive donor/seronegative recipients gastrointestinal involvement that occurs in up to 40% of patients.
The incidence of C. difficile infection (CDI) in transplanted patients has been reported to be approximately 3.5–4.5% in adult renal transplantation patients. DIAGNOSIS AND THERAPEUTIC STRATEGY.
1-The gold standard for C. difficile detection is the cell-based cytotoxicity assay. However, most laboratories use the easier, less expensive and more rapid fecal enzyme immunoassays or real-time PCR test. These tests have high sensitivity and specificity (90%) for the detection of CDI and initial treatment of SOT includes fidaxomicin, metronidazole or vancomycin, with vancomycin, now there is a good effect for use of human monoclonal antibodies against C. difficile toxins A and B and new trend for fecal microbiota transplantation (FMT).
2-Cryptosporidiosis is generally diagnosed by visualization of oocysts in the stool, there is no specific TTT but studies shown that no difference between nitazoxanide or paromomycin and placebo for immunosuppressed
patients with cryptosporidiosis.
3-CMV colitis will have evidence of CMV replication in the blood via PCR, although approximately 15% will not, so the gold standard for diagnosis histopathology by endoscopy and patients
with CMV colitis can be managed with intravenous ganciclovir (GCV) or oral Val ganciclovir .
4-xTAG Gastrointestinal Pathogen Panel (Luminex Corp., Austin, Texas, USA), which allows for simultaneous detection of three viruses (norovirus G-I/G-II, rotavirus A and AdV 40/41), nine bacteria and three parasites, mainly treatment is supportive for norovirus with oral or intravenous immunoglobulin, breast milk, ribavirin and nitazoxanide.
5-We can use vaccine against rotavirus but before transplantation as there are live attenuated vaccine.
Finally, the approach will be consisting of bacterial culture, assessment for ova and parasites, PCR for CMV
and C. difficile and stool lactoferrin. The next steps were breath test for bacterial overgrowth, reduction in immune suppression and colonoscopy. CONCLUSION.
Diarrhea post kidney transplant has deleterious effect on graft and recipient survival and we need to be more systematic and approached when dealing with this issue and not starting our approach by blaming the immunosuppression and should be familiar with other infections causes and still need more studies to assess the prevalence of the causes and looking for new vaccination and anti-viral therapy. Level of evidence: V (a narrative review article).
Introduction
Chronic diarrhea after kidney transplantation is a common complaint, often assumed by clinicians and patients to be an inevitable part of kidney transplantation.
This is neglected despite its association with fatigue, increased hospitalizations and negative impacts on recipient quality of life.
Renal transplant recipients share certain predisposing characteristics for the development of posttransplant diarrhea, among the more significant of which include a generalized immunosuppressed state and exposure to polypharmacy, most notably broad-spectrum antimicrobial therapy.
The main causes of diarrhea after transplantation are infections, immunosuppressive drugs, antibiotics and other drugs.
We review the current literature regarding both infectious and noninfectious diarrhea in renal transplant recipients and provide a diagnostic algorithm for the evaluation of posttransplant diarrhea Epidemiology
The cumulative incidence of diarrhea has been reported to be 11.5, 17.5 and 22.6% at 1, 2 and a Renal Division, Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
In a survey of 4232 Scandinavian renal transplant recipients, 53% of participants reported diarrhea, whereas the incidence estimated by their physicians was only 6.9% [1&.
The burden of adverse gastrointestinal symptoms inversely correlates with indicators of life quality in kidney transplant recipients.
A recent study from a single transplant center in the United States reviewed the diagnostic yield of tests for diarrhea among hospitalized transplant recipients over a period of 18 months.
The majority of the diarrheal episodes had no identifiable cause and were self-limited.
About 32% of individuals taking mycophenolate mofetil or mycofenolic acid and diagnosed with diarrhea had reductions or changes in their immune suppression General causes of diarrhea
There are relatively little data regarding the cause of posttransplant diarrhea.
A large, prospective study – the Diarrhea Diagnosis Aid and Clinical Treatment (DIDACT) study – was conducted to identify the cause of posttransplant diarrhea in renal transplant recipients .
. There was a resolution of diarrhea in approximately 50% of patients either by discontinuation of diarrhea-associated nonimmunosuppressive drugs or by the treatment of concurrent infections.
In the remainder of patients, changes in immunosuppressive therapy led to remission of diarrhea in about twothirds of cases.
Considered together, the data from the DIDACT study indicate that an infectious cause of posttransplant diarrhea is present in approximately 50% of cases with CMV being the most common pathogen.
The most frequent cause is related to medication use. Causes of diarrhea ; immunosuppressive drugs
Noninfectious diarrhea is not uncommon among renal transplant recipients and has been reported to increase the risk of graft loss and mortality.
Drug-induced diarrhea is a major problem as many of the immunosuppressive agents commonly used in transplantation may cause diarrhea, with the highest incidence associated with MMF.
Chronic diarrhea after kidney transplantation has negative impacts on the recipient’s quality of life, graft survival and mortality.
It is important that clinicians evaluate and attempt to diagnose the cause of diarrhea and make a distinction between noninfectious and infectious causes of diarrhea in kidney transplant recipients.
Prospective studies are needed to better assess the true prevalence, risk factors and complications of diarrhea by norovirus, rotavirus and AdV in kidney transplant patients Dialysis and transplantation
Dose reduction is followed by the decrease or the disappearance of diarrhea ,MMF and enteric-coated mycophenolate sodium (EC-MPS) have long been implicated in posttransplant diarrhea.
A recent meta-analysis identified that the relative risk of diarrhea associated with the use of MMF is 1.57.
One possible mechanism is that gastrointestinal epithelial cells may be partially dependent on the de-novo pathway of purine synthesis for growth and proliferation, and are vulnerable to mycophenolic acid inhibition leading to diarrhea.
Whether switch of immunosuppression from MMF to EC-MPS helps reduce diarrhea symptoms is a matter of debate.
A recent randomized and controlled open study suggested that patients with MMF -related diarrhea who switch to EC-MPS may have a slightly, yet significant, greater chance of returning to a target MPA doses than those maintained on MMF. Renal transplant scientific registyry showed that
The use of tacrolimus may be associated with diarrhea in 29–64% of patients depending upon the dose and duration of drug usage.
The mechanism by which calcineurin inhibitors cause diarrhea remains unclear, it is hypothesized that a macrolide structure may result in stimulation of the intestinal motilin receptors.
Most of the tacrolimus-associated gastrointestinal side-effects have a mild course and rarely require drug discontinuation.
A recent study in renal transplant recipients has reported a decrease in the incidence of gastrointestinal symptoms, including diarrhea, after conversion to a daily, extended release formulation of tacrolimus.
One mechanism by which these antibodies may cause diarrhea is by activating T cells to release tumor necrosis factor which interferes with sodium ion absorption and disrupts the intestinal mucosal barrier.
Causes of diarrhea ; infection
Diarrhea is commonly infectious ,and the microbes usually responsible are CMV andC.defficile , but the literature describes a wide range of organisms in solid organ transplant (SOT) recipients .
Chronic norovirus infection has only recently emerged as one of the leading infectious This finding suggests that numerous cases of posttransplant diarrhea in the past may have been incorrectly solely ascribed to toxicity of immunosuppressive drugs, leading to diagnostic misconceptions and inappropriate treatments.
In these patients, the course of norovirus infection tends to be more complicated, with up to.
This acute phase is frequently followed by a chronic phase, when patients can experience cycles of relatively normal stools followed by periods of more poorly formed stools. Causes and management of postrenal transplant diarrhea shin and chandraker
CMV is one of the most common infectious complications affecting SOT patients and is associated with significant morbidity and occasional mortality.
The most significant risk factors for the development of CMV disease is seropositive donor/seronegative recipients gastrointestinal involvement that occurs in up to 40% of patients.
Rotavirus infection was diagnosed in 1.5% of SOT recipients, with most cases occurring in pediatric patients (63%) and in those who received a liver transplant.
A wide range of clinical syndromes associated with AdV in SOT recipients has been described, with the most clinically severe infections involving the transplanted organ or disseminated disease.
Risk factors that are specific to the SOT population include age above 55 years, use of ATG, retransplantation and the type of organ transplanted, with the highest rate among liver recipients.
Cryptosporidia (Cryptosporidia parvum and Cryptosporidia hominis) are intracellular protozoans known to lead to severe acute diarrhea, chronic diarrheal illness and extraintestinal infection in transplanted patients. Diagnostic and therapeutic
It is important to evaluate and attempt to diagnose the cause of diarrhea in a transplant recipient.
It is imperative that the clinician makes a distinction between noninfectious and infectious causes of diarrhea
Another important factor to consider in the SOT recipient is the consequence of unnecessary reduction in immune-suppressive medications to try and manage diarrhea.
Most laboratories use the easier, less expensive and more rapid fecal enzyme immunoassays or real-time PCR test
These tests have high sensitivity and specificity (90%) for the detection of CDI.
A newer area of interest is the use of fecal microbiota transplantation (FMT) in the management of refractory CDI.
Patients with CMV colitis can be managed with intravenous ganciclovir (GCV) or oral valganciclovir.
. Because recurrent CMV disease has been reported in 15–35% of SOT recipients with tissue-invasive CMV disease, many experts recommend the use of valGCV for secondary prophylaxis for 30–90 days after successful treatment.
Consider reduction in immuniosuppressive drugs
A commercially available assay is the U.S Food and Drug Administration-approved xTAG Gastrointestinal Pathogen Panel (Luminex Corp., Austin, Texas, USA), which allows for simultaneous detection of three viruses, nine bacteria and three parasites
This assay has not yet been systematically tested in the immunocompromised population.
Immune-based assays are most routinely used to rapidly detect rotavirus antigens in stool samples.
Other diagnostic methods such as cell culture, real time-PCR and electron microscopy remain as reference methods because of their high specificity and sensitivity.
The optimization and adjustment of the immunosuppression in patients with persistent posttransplant diarrhea is an unresolved issue that warrants prospective studies.
The first change in immunosuppression consists of MMF dose reduction or switching to EC-MPS, followed by MMF-EC-MPS withdrawal,if symptoms persist Findings
MMFreduced the relative risk of graft loss by 27%.
The most significant risk factors for the development of CMV disease is seropositive donor/seronegative recipients gastrointestinal involvement that occurs in up to 40% of patients.
It has been estimated that up to 20% of cases will have at least one relapse.
Conclusion
Physicians should be familiar with common cause that result in posttransplant diarrhea.
A directed approach to diagnosis and treatment will help to resolve diarrhea, and prevent potentially life-threatening consequences such as loss of the graft.
Prior to implicating an immunosuppressant medication as the culprit, a meticulous evaluation for other possible causes of diarrhea should always be conducted.
Prospective studies are needed to better assess in kidney transplant patients the true prevalence, risk factors and complications of diarrhea by norovirus, rotavirus and AdV.
Such studies will help guide the care of these patients and provide appropriate prevention and prompt diagnosis.
Development of effective vaccines and antiviral therapies for these common viruses will likely improve patient and graft survival Level of evidence is 5
Post transpant diarrhea is common affecting nearly one forth of transplant recipients at 3 years after transplantation
Causes of post-transplant diarrhia
A- Infectious diarrhea
Bacteria such as clostridium deficile (due to recent antibiotic use especially fluoroquinolones), salmonella, shigella, E coli, and bacterial overgrowth
Viruses such as CMV, adenovirus, norovirus, rotavirus, and sapovirus
Parasites such as giardiasis, entamoeba histolotica, cryptosporidium
D- Others including graft versus host disease, IBD (denovo IBD occurs 10 times more frequent than in general population), malabsorption
In the majority of cases, the cause is not identified and diarrhea is self-limited
The most common identifiable causes include clostridium difficile infection, norovirus infection , CMV infection and drug induced
Diagnostic work up should include
A- Routine investigations
Renal function tests and electrolytes
Complete blood count, c reactive protein
Stool analysis
B- Searching for the cause
–
Primary investigations including CNI level, CMV PCR, Stool culture and CD toxin in stool
Secondary investigations (if primary investigations were not conclusive) including stool multiplex PCR for viral, bacterial and parasitic infection (Cryptosporidium, Entamoeba histolytica, Giardia lamblia, Campylobacter, Shigella, Salmonella, Vibrio, Yersinia enterocolitica, adenovirus and sapovirus), enzyme immunoassay for giardia and cryptosporidium and breath test for bacterial overgrowth
Imaging, colonoscopy, and biopsy may be needed if there is suspicious of malignancy, IBD or CMV colitis with negative PCR (15% of cases will have CMV PCR negative)
Management
1- Supportive therapy including intravenous fluids for treatment of dehydration
2- Symptomatic therapy including lopramide to decrease bowel motions which is indicated in persistant (> 2 weeks) or chronic diarrhea (> 1 month)
3- Modulation and monitoring of immunosuppression
–
Reduction of immunosuppression in the form of reducing the dose of MMF by 50% after estimation of the rejection risk and keeping low target trough for CNI (5-8 ng/ml)
Shifting from MMF to enteric coated mycophenolate (debatable)
Shifting from MMF to azathioprine (not preferred due to reduced graft survival, increased risk of rejection and increased risk of skin cancer associated with azathioprine use)
Switching from tacrolimus to extended released formulation or to cyclosporine
Switching from sirolimus to CNI since around 14-41 % of cases taking sirolimus experienced diarrhia.
Close follow up of CN level as there may be an increase in tacrolimus level with diarrhea due to disruption of P-glycoprotein efflux pump in the damaged enterocytes
4- Treatment of the cause
For clostridium deficille infection: treatment lines include metronidazole 500 mg 3 times daily for 10–14 days, vancomycin 125 mg oral four times per day for 10–14 days, fidaxomicin 20 mg two times per day for 10 days, fecal microbiota transplantation, prolonged oral vancomycin
Antibiotics for bacterial diarrhea and bacterial overgrowth
Anti-parasetic for parasites
Ganciclovir for CMV colitis for the first 2 weeks and shift to valgancyclovir provided that the patient can tolerate oral, till 2 successive PCR samples are negative, then start secondary prophylaxis using valgancyclovir for 1-3 month
Specific treatment in case of cancer colon or PTLD
What is the level of evidence provided by this article?
I like your well-structured rather extensive summary, level of evidence, analysis and take home messages typed as conclusion.Typing whole sentence in bold amounts to shouting.
Clinicians and patients expect chronic diarrhea following kidney donation. Despite its link with fatigue, more hospitalizations, worse quality of life for recipients, lower graft survival, and higher death, this is ignored. Chronic posttransplant diarrhea may cause enteric hyperoxaluria and steatorrhea. Inflammatory oxalate nephropathy may damage renal transplant function.
Epidemic impact:
Based on Medicare claims in the United Network for Organ Sharing registry, diarrhea was 11.5%, 17.5%, and 22.6% at 1, 2, and 3 years following kidney donation.
DIARRHOEA CAUSES:
nonimmunosuppressive medications linked to diarrhea (antibiotics, laxatives, anti-diabetics, PPIs, and protease inhibitors).
managing many illnesses at once (Campylobacter or CMV).
MMF, cyclosporine, sirolimus, anti-T cell antibody (ATG), and tacrolimus are examples of immunosuppressive drugs.
Infection caused by bacteria
Clostridium difficile (the reported incidence of C. difficile infection (CDI) in transplanted patients is 3.5% to 4.5% among adults who have had renal transplantation.
Bacteria: Campylobacter spp, Salmonella spp. Cyclosporine Bacterial overgrowths Sirolimus Aeromonas spp. Escherichia coli
Viruses Nonimmunosuppressive medications CMV, Norovirus, Sapobavirus, Rotavirus, and Adenovirus
Parasitic Other Giardia, Cryptosporidium, Isosopora Cyclospora, Microsporidium, Entamoeba.
DIAGNOSIS AND THERAPEUTIC STRATEGY:
Cell-based cytotoxicity assays identify C. difficile best. Most labs utilize fecal enzyme immunoassays or real-time PCR, which are simpler, cheaper, and faster.
These CDI tests are 90% sensitive and specific.
Transplanted individuals may carry C. difficile asymptomatically, but most develop diarrhea, intestinal blockage, abscesses, or toxic megacolon. SOT is first treated with fidaxomicin, metronidazole, or vancomycin, with vancomycin recommended for severe infections.
Viremia suggests a tissue-invasive CMV illness. PCR shows CMV replication in blood in most CMV colitis patients, while 15% do not. Serology may help diagnose new-onset infections but not current illnesses in adults.
The PCR test for the diagnosis of norovirus can be run on a stool, vomitus, food, and environmental specimens.
Immunosuppression is the best norovirus treatment. MMF prevents viral clearance and intestinal epithelial healing, which prolongs posttransplant diarrhea. Norovirus causes it.
Immune-based assays are most often employed to quickly identify rotavirus antigens in stool samples.
Epidemiologic research has linked diarrhea to numerous infections. The prospective Diarrhea Diagnosis Aid and Clinical Treatment research used a stepwise diagnostic and treatment flow chart to remove nonimmunosuppressive medication toxicity and address infectious causes before modifying the immunosuppressive regimen.
Esophagogastroduodenoscopy and colonoscopy with biopsies may explore chronic diarrhea following kidney transplantation. First, large bowel posttransplant lymphoproliferative disease may induce intestinal ulcerations, exudative enteropathy, and persistent diarrhea.
Second, CMV colitis with negative plasma PCR is described. Finally, significant duodenal villous atrophy may induce doctors to modify the immunosuppressive regimen faster, whether drug-related or infectious. Lastly, post-transplantation de-novo inflammatory bowel illness is up to 10 times more common. Diarrhea must be treated with fluids, antimicrobials, and immune suppression.
Prospective studies are needed to optimize immunosuppression in posttransplant diarrhea patients.
What is the level of evidence provided by this article?level 5, narrative review
I like your well-structured rather extensive summary, level of evidence, analysis and take home messages typed as conclusion.Typing whole sentence in bold amounts to shouting.
This article a narrative review that focusses on the discussion of both infectious and non-infectious diarrhea post kidney transplant and the evaluation or diagnosis of the same. The study is based on current available literature and outlines the consideration that a targeted approach to post transplant diarrhea is crucial to achieve effective treatment of diarrhea in the patient, protect the allograft, and prevent fatal complications that could be potentially irreversible.
Discussion
Chronic diarrhea, although a relatively common complaint among transplant recipients, is often overlooked by the transplant team as inevitable. However this condition can have serious consequences on the welfare of the graft and the patient. It causes fatigue in the patient, and possible increased period of hospitalization and negative impact on quality of life for the recipient.
Complications that can occur from untreated chronic diarrhea include steatorrhea and malabsorption, leading to enteric hyperoxaluria. Oxalate nephropathy can occur in association with inflammation and negatively impact kidney function of the graft.
In order to treat post transplant diarrhea, it is imperative to first identify the cause of the diarrhea episode in the patient, and to group it under one of two categories, namely, infectious cause and non-infectious cause.This will help the transplant team to treat the diarrhea quickly and effectively.
Infectious causes of diarrhea include the following :
bacteria such as E.coli and salmonella, campylobacter, aeromonous spp.
Viruses such as CMV, noravirus, sapobavirus, rotavirus, adenovirus
Parasites such as Giardia, cryptosporidium, isosopora cyclosporine, microsporidium, and entamoeba.
Non-infectious causes of post transplant diarrhea include the following
Immunosuppressive drugs such as MMF, tacrolimus, cyclosporine, and sirolimus. ATG and anti-T cell antibody can also be associated with diarrhoea post transplant, and usually resolve within 4 days of onset spontaneously. Activation of T cells to release TNF can be a causative mechanism for diarrhea in this case. The released tumor necrosis factor interferes with sodium ion absorption and disrupts the intestinal mucosal barrier.
Non-immunosuppressive medications such as antibacterials, antiarrhythmics, anti diabetics, laxatives, proton pump inhibitors, and protease inhibitors
Other causes under this category include graft vs host disease, PTLD, inflammatory bowel disease, colon cancer, malabsorption, microscopic colitis, malakoplakia
Diagnosis of the cause is dependent on the cause. However, identification needs to be done as rapidly as possible to avoid damage or loss of allograft.
Infectious causes such as Clostridium difficile can be diagnosed by doing cell based cytotoxicity assay, which is the gold standard for detection of this infection. Real time PCR can also be done for diagnosis. Initial treatment in this case will include fidaxomicin, metronidazole or vancomycin. Vancomycin is used for severe or resistant cases. It is administered orally to the patient. Most cases will, however, respond adequately to metronidazole. Recurrent disease can be treated with fidaxomicin or other newer antibiotics such as ramoplanin and tigecycline.
A newer treatment for refractory CDI includes fecal microbiota transplantation (FMT). Donor feces is processed into the colon of the recipient. The results are still being studied, and appear promising, but are associated with high adverse effects.
CMV is diagnosed through PCR, and endocopic evidence of GI involvement. Histopathology reveals owl’s eye intranuclear inclusions. Treatment includes IV ganciclovir or oral valganciclovir.
Conclusion
Chronic diarrhea is common in the post transplant period following kidney transplant, but it cannot be taken lightly due to the potential for serious complications affecting both the allograft and the recipient’s quality of life. Treatment is based on accurate diagnosis of whether the diarrhea is due to an infectious or non-infectious cause. Different causes have been listed under both these categories in this article, and relevant diagnostic methods as well as treatment strategies have been discussed.
Further studies are needed to speeden the process of identification of cause, as well as prevent the occurrence of post transplant diarrhea in these patients. Effective vaccines and antivirals need to be developed to this regard in order to safely improve both graft as well as patient survival.
Level of evidence
This article is a narrative review with level of evidence 5.
Post-kidney transplant chronic diarrhea is common, have a negative effect on the quality of life of the recipient, and graft outcome through enteric hyperoxaluria, and mortality.
Immunosuppressive medications, antibiotics, and other medications, as well as infections, are the causes. In addition to providing a diagnostic algorithm for assessing post-transplant diarrhea, this article reviews the most recent research in the field.
Epidemiology:
The cumulative incidence of diarrhea post-transplant is 11.5, 17.5 and 22.6% at 1, 2 and 3 years, respectively. Posttransplant diarrhea of unknown origin increases graft loss and risk of death by two folds.
Infectious causes of diarrhea post-transplant:
The DIDACT study found that an infectious cause of posttransplant diarrhea is present in approximately 50% of cases, with CMV being the most common pathogen.
CMV and C. difficile, as well as opportunist pathogens, are the main causes of diarrhea in SOT recipients. On these causes, management should concentrate.
Chronic norovirus infection is a leading cause of post-transplant diarrhea in kidney transplant recipients, with up to 94% having chronic diarrhea and 81% having episodes of diarrhea-induced acute renal failure.
CMV is common, mostly affect the gastrointestinal tract. Risk factors include seronegative recipients of seropositive organs, lymphodepleting antibodies, and more potent immunosuppressive regimens.
Rotavirus infection is mostly occurring in pediatric and liver transplants. Adenovirus viremia is more common in adults early post-trasnplant (6.5–22.5%), involving the transplanted organ or disseminated disease.
The most frequent cause of nosocomial diarrhea in transplant recipients is C. difficile infection (CDI), with recent antibiotic use posing the greatest risk. Mortality rates range from 2.3 to 8.5%, indicating a significant impact. Microsporidia and Cryptosporidia are the most common parasities in kidney transplant recipients, leading to severe diarrhea, chronic diarrheal illness, and extraintestinal infection.
Immunosuppressive related diarrhea:
Higher incidence with MMF associated diarrhea, with two morphologic patterns: predominant crypt distortion and predominant apoptosis. It resolves by reducing the dose or changing the drug. Tacrolimus may cause diarrhea in 29-64% of patients, but most side-effects are mild and rarely require drug discontinuation. Sirolimus causes self-limiting diarrhea due to jejunal villous atrophy and structural homology with promotility macrolide. ATG and OKT3 therapies can cause diarrhea by activating T cells to release tumor necrosis factor, disrupting sodium ion absorption and mucosal barrier. Diagnosis and therapeutic strategy:
– The cell-based cytotoxicity assay is the gold standard for C. difficile detection, but most laboratories opt for the simpler, faster, and less expensive fecal enzyme immunoassays or real-time PCR tests. Fidaxomicin, metronidazole, or vancomycin are some first-line treatment. FMT (fecal microbiota transplant), donor feces are injected into the recipient’s colon or duodenum, has a high success rate, but it also has a high rate of negative effects. – IS reduction and Fumagilin is the treatment of microsporidia (diagnosed by IF assay (100% sensitive and specific), but its use is limited due to drug-induced thrombocytopenia. – The diagnosis of tissue-invasive CMV disease is suggested by the presence of CMV viremia in the blood. PCR is the most accurate means to diagnose CMV-associated colitis, but it has disadvantages such as lower sensitivity, long incubation period, insufficient virus quantity and the high rate of false negativity. Endoscopic evidence of gastrointestinal involvement is used to confirm CMV, and IV antiviral therapy (GCV or oral valganciclovir). Before stopping antiviral, three criteria must be met: the treatment was given for at least 2 weeks, clinical symptoms have resolved and viral load is no longer detectable. – Norovirus infectiontreated by reduction of immunosuppression, supportive care is the first line of treatment with correction of fluids and electrolytes, and oral or intravenous immunoglobulin, breast milk, ribavirin and nitazoxanide have been tried in limited numbers of patients. No vaccines are available for norovirus, Prevention is important, especially hand hygiene and environmental sanitization. – Real time PCR and stool electronmicroscopy used to detect rotavirus in stool samples, and no antirotaviral therapies are available. Contact precautions are recommended to prevent viral transmission, and two live oral vaccines against rotavirus are licensed for use: RotaTeq (RV5) and Rotarix (RV1). – Adenovirus can be treated with supportive care and a reduced immunosuppressive regimen, and it can be diagnosed using viral culture, direct antigen detection, histopathology, and PCR. Infections can be avoided in the SOT population with the use of diligent control measures.
Before modifying the immunosuppressive regimen, a stepwise prospectived diagnostic and therapeutic flow chart that aimed to eliminate non-immunosuppressive drug toxicity causative factors and treat infectious causes was used. Bacterial culture, examination for parasites and ova, PCR for CMV and C. difficile, and stool lactoferrin were all part of the testing.Probiotics, a lactose-free diet, and/or empiric antidiarrheal medications should be tried if the tests are negative. Conclusion: The study identify the differential diagnosis of post-transpalnt diarrhea, a stepwise prospective diagnostic and therapeutic flow chart can eliminate non-immunosuppressive drug causative factors and treat infectious causes. Further studies needed to assess prevalence, risk factors and complication of norovirus, rotavirus and AdV, and development of effective vaccines and antiviral therapies to improve patient and graft survival.
What is the level of evidence provided by this article? Level of evidence V- review article.
I like your well-structured rather extensive summary, level of evidence, analysis and take home messages typed as conclusion.Typing whole sentence in bold or typing in capitals amounts to shouting.
Causes and management of postrenal transplant diarrhoea: an underappreciated cause of transplant-associated morbidity
1. The main causes of diarrhea after transplantation are infections, immunosuppressive drugs, antibiotics and other drugs.
2. The cumulative incidence of diarrhea has been reported to be 11.5, 17.5 and 22.6% at 1, 2 and 3 years after renal transplantation.
3. The most common identifiable causes included Clostridium difficile infection(13.1%), norovirus infection(3.9%) and cytomegalovirus (CMV) gastrointestinal infection.
CAUSES OF DIARRHEA:
1. GENERAL
a) diarrhea-associated nonimmunosuppressive drugs(antibiotics, laxatives, anti-diabetic, PPI and protease inhibitor).
b) treatment of concurrent infections (Campylobacter or CMV).
· Clostridium difficile: (the incidence of C. difficile infection (CDI) in transplanted patients has been reported to be approximately 3.5 – 4.5% in adult renal transplantation patients.
b) Parasitic: Giardia, Cryptosporidium, Isosopora Cyclospora, Microsporidium and Entameoba.
c) Viruses:
· CMV (40%).
· Norovirus(17-26% of severe posttransplant diarrhea).
· Sapobavirus & Rotavirus.
· Adenoviruses(AdV) viremia is commonly observed in the early posttransplant course (6.5 – 22.5%), and may be associated with gastrointestinal symptoms in 10% of the cases.
4. Other causes: GVHD, PTLD, IBD, Colon cancer, Malabsorption, Microscopic colitis and Malakoplakia.
DIAGNOSIS AND THERAPEUTIC STRATEGY
1. C. difficile:
a) The gold standard for C. difficile detection is the cell-based cytotoxicity assay.
b) fecal enzyme immunoassays or real-time PCR test are mostly used by many laboratories.
c) In general, initial treatment of SOT includes fidaxomicin, metronidazole or vancomycin, with vancomycin preferred for cases of more severe infection.
· First episode: metronidazole 500mg three times per day for 10–14 days.
· Severe disease: vancomycin oral four times per day for 10–14 days fidaxomicin 20 mg two times per day for 10 days.
· First relapse: same for first episode.
· Second relapse: vancomycin taper with pulse.
· third relapse: consider fecal microbiota transplantation, prolonged oral vancomycin.
2. CMV:
· diagnosed by the presence of CMV viremia,CMV pp65 Antigen and CMV PCR.
· For treatment: Oral valganciclovir or IV ganciclovir (if any concern for decreased absorption).
3. Cryptosporidiosis is generally diagnosed by visualization of oocysts in the stool.
4. Rotavirus:
· In diagnosis of rotavirus, immune-based assays are most routinely used to rapidly detect rotavirus antigens in stool samples.
· Cell culture, real time-PCR and electron microscopy remain as reference methods because of their high specificity and sensitivity.
· The treatment of rotavirus infection in SOT patients is mainly supportive.
· Contact precautions are recommended for prevention beside pre-transplant life attenuated vaccine of rotavirus(RotaTeq (RV5) and Rotarix (RV1)).
5. Adenovirus(AdV):
· can be diagnosed by viral culture, direct antigen detection, histopathology and PCR.
· AdV can be managed with supportive care and a reduced immunosup- pressive regimen.
6. Norovirus:
· Diagnosis of norovirus by PCR can be run on stool, vomitus, foods and environmental specimens.
· For treatment, the followings to be considered: Rehydration, Antimotility drugs and reduction in immunosuppressive drugs.
· Chronic norovirus-related diarrhea remains a major concern often leading to MMF discontinuation, which has been associated with an increased risk of rejection.
7. Persistent chronic diarrhoea: OGD with colonoscopy and biopsies +/- capsular endoscopy.
· To look for intestinal ulcerations because of large bowel post-transplant lymphoproliferative disorder, that may be accompanied by exudative enteropathy and chronic diarrhea.
· CMV colitis with concurrent negative CMV plasma PCR has been reported.
· The presence of severe duodenal villous atrophy may prompt clinicians to change more rapidly the immunosuppressive regimen, regardless of the cause (drug-related or infectious).
· Post-transplantation de-novo inflammatory bowel disease occurs up to 10 times more frequently than in the general population.
8. Breath test(14c-glycocholic acid or D-xylose) to diagnose bacterial over-growth. Anti-microbial agents are the treatment of choice.
9. Diarrhoea due to malabsorption gives a suspicion of PTLD, IBD when there is grossly bloody diarrhoea and/or a FH of IBD.
The level of evidence provided by this article:
This is a narrative review article with level of evidence grade 5.
II. Causes and management of postrenal transplant diarrhoea: an underappreciated cause of transplant-associated morbidity
Please summarise this article.
INTRODUCTION
Chronic diarrhea after kidney transplantation is a common complaint, often neglected due to its negative impacts on recipient quality of life, graft survival and mortality.
Predisposing characteristics include immunosuppression and exposure to polypharmacy.
The main causes of posttransplant diarrhea areinfections, immunosuppressive drugs, antibiotics and other drugs.
EPIDEMIOLOGIC IMPACT
Posttransplant diarrhea has a significant impact on life quality and risk of death inkidney transplant recipients.
A survey of 4232 Scandinavian renal transplant recipients found 53%reported diarrhea, while the incidence estimated by physicians was 6.9%.
The most common causes were Clostridium difficile infection, norovirus infection, and CMV gastrointestinal infection.
32% of individuals taking MMF or mycofenolic acid had reduced immune suppression.
CAUSES OF DIARRHEA:
The Diarrhea Diagnosis Aid and Clinical Treatment (DIDACT) study found that an infectious cause of posttransplant diarrhea is present in approximately 50% of cases, with CMV being the most common pathogen.
Immunosuppressive drugs are also a major cause, with the highest incidence associated with MMF.
MMF and enteric-coated mycophenolate sodium (EC-MPS) have long been implicated in posttransplant diarrhea.
A recent meta-analysis identified the relative risk of diarrhea associated with the use of MMF is 1.57.
The mechanism of MMF-induced diarrhea remains unknown.
Switching from MPA to EC-MPS may help reduce diarrhea symptoms.
MMF-treated versus AZA-treated patients have a significantly increased risk of skin cancer, tacrolimus may be associated with diarrhea, sirolimus causes self-limiting diarrhea, and antithymocyte globulin (ATG) and anti-T cell antibody (OKT3) therapies are both associated with diarrhea.
The mechanism by which these therapies cause diarrhea is unclear, but may involve activating T cells to release tumor necrosis factor.
==================================================================== CAUSE OF DIARRHEA: INFECTIONS
Diarrhea is commonly infectious and can be caused by CMV, C. difficile, or norovirus.
Chronic norovirus infection is one of the leading infectious causes of posttransplant diarrhea in kidney transplant recipients, with up to 94% having chronic diarrhea and 81% having episodes of diarrhea-induced acute renal failure.
Immunocompromised patients typically have a biphasic illness in the course of norovirus, with nausea, vomiting, diarrhea, abdominal pain, and fever.
CMV is one of the most common infectious complications affecting SOT patients and is associated with significant morbidity and mortality.
Risk factors for CMV include seronegative recipients of seropositive organs, lymphodepleting antibodies and more potent immunosuppression regimens.
Rotavirus infection is becoming increasingly recognized in both pediatric and adult SOT patients.
Adenovirus (ADV) viremia is commonly observed in the early posttransplant course and may be associated with gastric symptoms.
C. difficile infection (CDI) is the most common cause of nosocomial diarrhea and accounts for most infectious diarrhea within the first months after transplantation.
Risk factors for CDI include age above 55 years, use of ATG, retransplantation and the type of organ transplant.
Protozoans and metazoans are the most common parasites in transplant recipients, leading to diarrhea and weight loss.
=================================================================== DIAGNOSIS AND THERAPEUTIC STRATEGY
The most important details in this text are the diagnosis and therapeutic strategies for diarrhea in a transplant recipient.
The gold standard for C. difficile detection is the cell-based cytotoxicity assay, but most laboratories use fecal enzyme immunoassays or real-time PCR tests.
Initial treatment of SOT includes fidaxomicin, metronidazole or vancomycin, with vancomycin preferred for cases of more severe infection.
The greatest challenge for toxigenic Clostridium infections remains the prevention and treatment of relapsing and refractory forms.
Fecal microbiota transplantation (FMT) is a procedure that involves the instillation of donor feces into the colon or duodenum of the recipient.
Fumagilin has been a major breakthrough in the treatment of microsporidia-related diarrhea, but its use may be limited due to drug-induced thrombocytopenia.
Cryptosporidiosis is generally diagnosed by visualization of oocysts in the stool.
Specific therapies directed toward cryptosporidiosis do not exist.
The diagnosis of tissue-invasive CMV disease is suggested by the presence of CMV viremia.
A systematic review analyzed 18 studies to determine the most accurate means to diagnose CMV-associated colitis.
Shell Vial Assay, CMV pp65 Antigen Test, and CMV pp65 Antigen Test are all used to diagnose CMV-associated colitis.
Endoscopeic evidence of gastrointestinal involvement is the definitive diagnosis of CMV active disease.
Patients with CMV colitis can be managed with intravenous ganciclovir (GCV) or oral valganciclovir (valGCV).
Optimal duration of antiviral therapy depends on the patient’s clinical and virologic responses, not on a fixed period.
Diagnosis of norovirus by PCR can be run on stool, vomitus, foods and environmental specimens.
The most effective strategy to manage norovirus infection is the reduction of immunosuppression.
Prevention plays an important role in norovirus infection control, especially hand hygiene and environmental sanitization.
Immunebased assays are used to rapidly detect rotavirus antigens in stool samples.
Contact precautions are recommended to prevent viral transmission.
Two live oral vaccines against rotavirus are licensed for use.
AdV can be diagnosed by viral culture, direct antigen detection, histopathology and PCR.
Diarrhea Diagnosis Aid and Clinical Treatment study identified a specific infectious cause in 30 of 108 patients, with Campylobacter jejuni enteritis and CMV colitis being the most common.
The most striking finding was that 50% of the patients resolved without any change in immunosuppressive therapy and only one-third of the 39 patients diagnosed with bacterial overgrowth responded to antibiotics.
Patients with diarrhea should have their medications reviewed and tested for potential causes.
If tests are negative and the diarrhea persists, empiric antidiarrheal medications, probiotics and/or lactose-free diet should be tried.
There are several arguments in support of esophagogastroduodenoscopy and colonoscopy with biopsies to investigate persistent diarrhea after kidney transplantation.
Treatment with hydration and focused use of antibiotics or changes in immunosuppression is essential.
I like your well-structured rather extensive summary, level of evidence, analysis and take home messages typed as conclusion.Typing whole sentence in bold or typing in capitals amounts to shouting.
Post transplant diarrhea associated with fatigue, increase hospitalization rate & negative impact on recipient QoL & graft survival with higher mortality.
Malabsorption & steatorrhea can occur due to severe chronic post transplant diarrhea which can induce enteric hyperoxaluria causing devastated effect on graft function.
Most common cause of post transplant diarrhea are infection & immunosuppression & antibacterials.
Epidemiology:
Cumulative incidence at 1,2 &3 years post transplant is 11.5,17.5 & 22.6% according UNOS.
Post transplant diarrhea often under recognized by practitioners
Causes of diarrhea:
50% of cases resolved by discontinuation of non immunosuppression drugs or by treatment of infection.
Change in MMF can cause remission of diarrhea in 2/3 of cases.
CMV infection is the most common cause of infectious diarrhea (50%)
Causes of post transplant diarrhea :
infection: bacterial, viral, parasite
Non infectious: immunosuppression, non immunosuppression drugs, PTLD, GVHD, IBD, colon cancer, malabsorption, microscopic colitis & malakoplakia.
Immunosuppression drugs:
Non infectious diarrhea in KTR associated with increase risk of graft loss & mortality.
Immunosuppression especially MMF can cause post transplant diarrhea & reduce dose can reduce or disappear of diarrhea.
The exact mechanism of MMF induce diarrhea is unclear, but it may explained by partial dependance of GI epithelial cells on de novo pathway of purine synthesis for growth & proliferation, therefore it is vulnerable to MPA inhibition.
MMF switch to EC-MPS if reduce diarrhea is debate, but study show that patients with MMF related diarrhea switch to EC-MPS have slight but but significant reduction in diarrhea with greater chance of returning to target MPS doses.
Usually switch from MPA to AZA avoided because of reduce graft survival with AZA as compared to MMF.
Tacrolimus associated diarrhea occurs in 29-64% of patients, & it depends on dose & duration of drug use.
Mechanism of Tac-related diarrhea may be related to macrolide structure of Tac result in stimulation of motilin receptors.
Tac associated GI side-effects usually mils & rarely need stop the drug, & diarrhea reduced after conversion to daily extended release formulation of Tac.
Sirolimus cause self-limited diarrhea in 14-42% of patients & it may result from drug induced jejunely villous atrophy & structural homology with promotability macrolide class of the drug.
1/3 of patients, ATG & OKT3 can cause self limited diarrhea due to TNF that interfere with sodium ion absorption, & disruption of intestinal mucosal barrier.
Infections:
Most common infectious pathogen are CMV & C. difficile.
After few months post transplant opportunistic pathogen become more evident cause of infection.
CMV, C. difficile & norovirus are an important cause of diarrhea in SOT recipients.
Chronic norovirus:
It cause 17-26% of severe post transplant diarrhea.
In past patients diagnosed with immunosuppression toxicity were actually norovirus infection.
2phase of norovirus infection: acute phase with classical symptoms (nausea, vomiting, abdominal pain & diarrhea) & chronic phase which characterized by cycles of normal stool alternated with periods of poorly formed stool.
CMV:
Associated with significant morbidity & occasional mortality.
Most common target organ is GIT
7.2% of patients develop CMV disease.
Risk factors: D+/R-, use of ATG, & more potent immunosuppression
Rotavirus:
Occurs in 1.5% of SOT recipients.
Commonly occurs in pediatric(63%) & in liver transplant recipients.
Adenovirus:
Adenovirus viremia commonly occur in early post transplant period(6.5-22.5%).
Associated with GI symptoms in 10% of patients.
May present as severe infection involve graft or disseminated disease.
C. difficile:
Occurs in first month post transplant.
3.5-4.5% in adult renal transplant recipients.
Risk factors: age>55, ATG use, re-transplant, type of organ(higher in liver), antibiotic(fluoroquinolone associated with higher risk).
Mortality rate 2.3-8.5%.
Parasites:
GI infection with microsporidia occur in SOT cause diarrhea & weight loss.
E. beineusi most common strain found in KTR.
Cryptosporidia: chronic diarrhea & extra intestinal infection occur in transplant patients.
Diagnosis & treatment:
During evaluation of diagnosis, it is important to distinguish between infection & non infectious cause.
Reduction in immunosuppression carry a risk of graft loss.
Diagnosis & treatment of C difficile:
Cell base cytotoxicity is the gold standard test.
Fecal enzyme immunoassay & real-time PCR are easier, less expensive & more rapid with high sensitivity & specificity(90%).
Treatment: fidaxomicin, metronidazole & vancomycin(preferred for severe cases).
70% of cases responding to metronidazole.
20% of cases will have relapse.
Fidaxomicin, ramoplamin & tigecycline are effective treatment for severe & recurrent disease.
Human monoclonal Abs against C. difficile toxin A & B useful.
FMT used for refractory CDI(limited data in transplant recipients).
Furriagilin used successfully in treatment of microsporidia related diarrhea with minimal reduction in immunosuppression , but its used limited by drug-induced thrombocytopnea.
Cryptosporidiosis diagnosis & treatment:
Diagnosis by identification of oocytes in stool.
IF & ELISA sensitivity & specificity 100%.
No specific effective drug.
CMV diagnosis & treatment:
CMV viremia suggest presence of CMV disease.
Serology test role in diagnosis limited.
Culture had low sensitivity, long duration, insufficient virus quantity & high rate of false negative.
Sell Viral Assay is a quick method but low sensitivity.
PCR in whole blood, plasma & leucocytes
CMV pp65 Ag test used in blood & CSF.
Gold standard method of CMV active disease is histopathological changes.
Treatment of CMV colitis by IV GCV or oral valGCV & duration depend on clinical & virological response.
Recurrence occur in 15-35%, so valGCV as prophylaxis for 30-90 days is recommended.
Norovirus diagnosis & treatment:
Diagnosis by PCR on stool, vomitus, food & environmental specimens.
Treatment is supportive (control of fluid status & electrolytes balance), reduction of immunosuppression especially MMF.
Oral or IV Ig, breast milk, ribavirine & nitazoxanide( not proved to be effective).
Prevention very important (hand hygiene & environmental sanitization.
Rotavirus diagnosis & management:
immune-based assay for rapid detection of Ag in stool.
Cell culture, real-time PCR & EM have high sensitivity & specificity.
No treatment available , in SOT recipients is supportive
Contact precaution recommended for prevention.
In USA, 2 live oral vaccine available, so it should be received before transplantation.
Adenovirus diagnosis & treatment:
Diagnosis by viral culture, direct Ag detection, histopathology & PCR.
Limited data about best treatment.
Treatment is supportive care & reduction of immunosuppression
Contact & droplets precaution can prevent infection in SOT.
The prospective Diarrhea Diagnosis Aid & Clinical Treatment study show:
28% of cases are due to infection & Compylobacter jijunmi enteritis & CMV colitis were the most common infectious cause.
50% of diarrhea resolved without change in immunosuppression
1/3 of cases diagnosed with bacterial overgrowth respond to antibiotics.
All patients with diarrhea should be reviewed their drug & unnecessary drugs should be stopped. Investigation for specific cause as bacterial culture, ova & parasites, CMV PCR & C. difficile PCR & stool lactoferrin.
Next step include breath test, reduction of immunosuppression & colonoscopy if negative & diarrhea persist, imperial antidiarrheal, probiotic &/or lactose free diet should be tried.
Please summarise this article. INTRODUCTION
o Chronic diarrhea after kidney transplantation is a common complaint, may be associated with fatigue, increased hospitalizations and negative impacts on recipient quality of life, graft survival and higher mortality
o Steatorrhea and malabsorption may result from severe and chronic posttransplant diarrhea and induce enteric hyperoxaluria and Oxalate nephropathy
o The main causes of diarrhea after transplantation are infections, immuno-suppressive drugs, antibiotics and other drugs Aim of the study: review both infectious and noninfectious diarrhea in renal transplant recipients and provide a diagnostic algorithm for the evaluation of posttransplant diarrhea
EPIDEMIOLOGIC IMPACT
The cumulative incidence of diarrhea is 11.5, 17.5 and 22.6% at 1, 2 and 3 years after renal transplantation, respectively
Post transplant diarrhea is often under-recognized by practitioners
CAUSES OF DIARRHEA
The data from the Diarrhea Diagnosis Aid and Clinical Treatment (DIDACT) study indicate that an infectious cause of posttransplant diarrhea is present inapproximately 50% of cases with (CMV is the most common pathogen). The next most frequent cause is related to medication use
Immunosuppressive drugs
o The highest incidence associated with MMF (the relative risk is 1.57)
o Dose reduction is usually followed by the decrease or the disappearance of diarrhea
o Switch of immunosuppression from MMF to EC-MPS is a matter of debate
o Tacrolimus may be associated with diarrhea in 29–64% of patients depending upon the dose and duration of drug usage (mild course and rarely require drug discontinuation)
o Sirolimus causes self-limiting diarrhea in 14–42% of patients
o In up to one-third of patients, ATG and OKT3 therapies are both associated with diarrhea, which lasts for 3–4 days and resolves spontaneously
Infections
o Diarrhea is commonly infectious usually CMV and C. difficile
o Chronic norovirus infection causes 17–26% of severe posttransplant diarrhea in kidney transplant recipients (biphasic illness-acute and chronic phase)
o CMV: The most common target organ is the GIT
o Rotavirus: can cause severe course in both pediatric and adult SOT patients
o Adenovirus: may be associated with gastrointestinal symptoms in 10% of the cases
o C. difficile: the most common cause of nosocomial diarrhea and accounts for most infectious diarrhea within the first months after transplantation. The incidence is 3.5–4.5%. The single most important risk
factor for the development of CDI is recent antibiotic use. The mortality rate is 2.3-8.5%
DIAGNOSIS AND THERAPEUTIC STRATEGY
o Make a distinction between noninfectious and infectious causes of diarrhea and avoid unnecessary
reduction in immune-suppressive medications
Clostridium difficile: First episode: metronidazole 500 mg three times per day for 10–14 days Severe disease: vancomycin oral four times per day for 10–14 days or fidaxomicin 20 mg two times per day for 10 days First relapse: same for first episode Second relapse: vancomycin taper with pulse Third relapse or more: consider fecal microbiota transplantation, prolonged oral vancomycin
o Cryptosporidiosis: diagnosed by visualization of oocysts in the stool mmunofluorescent assays and ELISA have a sensitivity and specificity approaching 100%, which is significantly better than the traditional modified acid-fast stains
o Noroviru: diagnosis by PCR can be run on stool, vomitus, foods and environmental specimens. Management is rehydration, antimotility drugs and reduction in immunosuppressive drug
o Rotavirus: immune-based assays to rapidly detect rotavirus antigens in stool samples. Other diagnostic
methods are cell culture, real time-PCR and electron microscopy. Treatment is mainly supportive
o Adenovirus: can be diagnosed by viral culture, direct antigen detection, histopathology and PCR
CONCLUSION
o Physicians should be familiar with common causes that result in posttransplant diarrhea
o A directed approach to diagnosis and treatment will help to resolve diarrhea and prevent potentially life- threatening consequences, such as loss of the graft
o Prospective studies are needed to better assess prevalence, risk factors and complications of diarrhea by norovirus, rotavirus and adenovirus in kidney transplant patients.
What is the level of evidence provided by this article?Level V
Chronic diarrhea after a kidney transplant is quite common though usually neglected particularly by the physician despite patient complaints and the possibility of having a negative impact on the quality of life of the patient. The level of immunosuppression and the inevitable polypharmacy after kidney transplant are the two common similarities among the patients that can be linked to a contributory factor to the aetiology of the disease. Among the many causes of chronic diarrhea after kidney transplantation, this article reviewed the infectious and noninfectious causes, and also try to provide a diagnostic pathway for them
Epidemiologic impact
The cumulative incidence of diarrhea has been reported to be 11.5, 17.5, and 22.6% at 1, 2, and 3 following kidney transplantation.
A study reported a two-fold increase in graft loss and death
A study reported that the majority of diarrhea had no identifiable causes and they are self-limiting
Causes of Diarrhea
a) Immunosuppressive drugs: this is a common non-infectious cause that has been known with morbidity and mortality among transplant patients as these drugs are a must to be taken to sustain the graft. The commonly implicated drugs are:
MMF- the most common, causes intestinal crypt distortion
EC-MPS
Tacrolimus – implicated in stimulating intestinal motilin, and seen in 29-64% patients depending on the dose
Sirolimus – causes diarrhea in 14 -42% of patients via drug-induced jejunal villous atrophy
The two most important factors during diagnosis are to be able to distinguish between infection and non – infectious causes of diarrhea and also to pay close attention to graft function when reducing the immunosuppressive drugs. The following investigation can be requested based on the frequency and epidemiology
PCR test for CMV, Clostridium Defficile, and fecal Multiplex test
EGD Colonoscopy and biopsy could be taken if CMV colitis is suspected
A capsule endoscope is indicated if the above test could not view some parts of the GIT
If the above investigation comes back negative, then proceed to do
Stool PCR for a viral pathogen, ova, and parasite evaluation
Giardia and cryptosporidium enzyme immunoassay
Breath test for bacterial overgrowth
Treatment
If non-infection, an initial reduction of MMF. but not resolved, it can be changed to lower doses of EC-MPS
Reduction of Tacrolimus to achieve trough level between 5-8ng/ml
A switch from Tacrolimus to cyclosporin can be tried if the above failed
mTOR can be use to replaced CNIs completely
Good hand hygiene should be encouraged with fluid replacement either oral or I.V
Infectious causes
Clostridium Defficile- stop the use of offending antibiotics, metronidazole and oral Vancomycin can be used
CMV virus- oral Valganciclovir or I.V Gancyclovir if absorption is impaired
Other viruses- Rehydration, use of antimotility drugs, and reduce immunosuppressive drugs
Conclusion
Post-kidney transplant diarrhea is a common presentation, and it is very important for physician to be equipped with good knowledge in identifying common causes and how to make a definitive diagnosis. Further landscape studies is required to be able to provide specific therapy to common causes of chronic diarrhea following transplantation.
Introduction;
– Diarrhea is a common complaint in KTR, it lead to significant morbidity and negatively affect quality of life, graft and patient survival.
– Predisposing factors in KTR includes; the overall immunosuppressed state and exposure to polypharmacy. Epidemiology:
– The cumulative incidence;11.5, 17.5 and 22.6% at 1, 2 and 3 years post-Tx.
– The problem is under-recognized by practitioners.
– It increase the risk of graft loss and death by two-folds.
– The majority had no identifiable cause and were self-limited.
*Data from the Diarrhea Diagnosis Aid and Clinical Treatment (DIDACT) study indicate that:
– Infectious cause is present in 50% of cases with CMV being the most common pathogen.
– The next most frequent cause is related to medication use with the highest incidence associated with MMF.
Diarrhea 2ry to Immunosuppressive drugs:
– Multiple IS drugs can cause post-transplant diarrhea, MMF being the most frequent.
– The relative risk of diarrhea associated with the use of MMF is 1.57.
– MMF-inhibit purine synthesis, which is needed for growth and proliferation of epithelial cells.
– Histologically many patterns; if mainly crypt distortion, called IBD-like MPA-associated toxicity and if predominant apoptosis, also called GVHD-like MPA-associated toxicity
– Dose reduction lead to decrease or the disappearance of diarrhea.
– Switching from MMF to EC-MPS helps reduce diarrhea symptoms is a matter of debate.
– Switch from MPA to azathioprine is usually avoided because of reported reduced graft survival with AZA.
– Tacrolimus use may lead to diarrhea in 29–64%, by stimulating intestinal motilin receptors, usually mild course and rarely require drug discontinuation.
– Sirolimus causes self-limiting diarrhea in 14–42% of treated patients, by causing jejunal villous atrophy
– ATG and OKT3 are both associated with self-limited diarrhea, by interfere with sodium absorption and disrupts the intestinal barrier
Infectious diarrhea:
-Usually CMV and C. difficile are responsible. –In the first month post-Tx opportunistic pathogen is uncommon, it become more common after few months postTx.
-Norovirus infection; recently emerged as one of the leading infectious causes (in 17–26% of severe cases).
– 94% chronic diarrhea and 81% with episodes of diarrhea-induced AKI.
–CMV gastrointestinal disease is common among SOT 7.2% developed CMV disease, of which approximately
one-third had gastrointestinal involvement
-Risk factors include (D+/R–) in 40 % and, (D–/R+), lymphodepleting antibodies and intensity of IS.
– Rotavirus infection, data are limited. diagnosed in 1.5% of SOT, sever course reported in pediatric and liver transplant recipient.
–Adenovirus (AdV) may be associated with gastrointestinal symptoms in 10% of the cases, wide range of clinical syndrome reported in SOT.
-C. difficile
-It is the most common cause of nosocomial diarrhea and accounts for most infectious diarrhea within the first months after transplantation, reported in 3.5–4.5% in KTR, mortality in SOT is reported 2.3 – 8.5%
– The single most important risk factor for the development of CDI is recent antibiotic use, with fluoroquinolones.
– Cryptosporidia lead to severe acute & chronic diarrhea and extra-intestinal infection.
-Microsporidia in SOT lead to diarrhea and weight loss.
– Enterocytozoon bieneusi is by far the most frequent strain found in KTR.
Diagnosis and therapeutic strategy:
– It is important to differentiate between noninfectious and infectious causes of diarrhea.
– Reduction of immunosuppression to manage diarrhea should be never taken lightly as it carries risk of graft loss.
C. difficile
– The gold standard cell-based cytotoxicity assay or fecal enzyme assay or real-time PCR.
– Patients can be asymptomatic carriers, and may develop diarrhea, intestinal obstruction, abscesses or toxic megacolon.
– Initial treatment of SOT includes fidaxomicin, metronidazole or vancomycin ( for persistent severe infection)
– The prevention treatment of relapsing and refractory forms is challenging.
– Encouraging results from using human monoclonal antibodies against C. difficile toxins A and B.
– Fidaxomicin, ramoplanin and tigecycline are effective for the treatment of severe or recurrent disease.
– A newer area of interest is the use of fecal microbiota transplantation (FMT) in the management of refractory CDI.
Cryptosporidiosis
– Diagnosed by visualization of oocysts in the stool.
– Immunofluorescent assays and ELISA higher sensitivity and specificity.
– Treatment; nitazoxanide or paromomycin
Tissue-invasive CMV
-CMV viremia is suggestive, however, it is negative in 15%
Endoscopy / biopsy for histopathology for definitive diagnosis ‘gold standard’; IHC staining for pp65 and pathognomic cells owl’s eye’ intranuclear inclusions.
-Treated with IV ganciclovir or oral valganciclovir (valGCV) followed by valGCV prophylaxis for 30–90 days to decrease the risk of recurrence.
Norovirus
Diagnosis PCR on stool, vomitus, foods and environmental specimens. Treated supportively, immunosuppression reduction as MMF plays role in its chronicity. The use of IVIG, ribavirin and nitazoxanide (selected cases). No available vaccine.
Prevention by strict infection control measures (hand hygiene and environmental sanitization).
Rotavirus
Diagnosis by stool immune-based assays, culture, real time-PCR. No available anti-viral therapies and the treatment of is mainly supportive and infection control measures to reduce transmission. Live attenuated vaccination is available and should be give pre-transplantation
Adenovirus:
diagnosis by viral culture, direct antigen detection, histopathology and PCR. Management by supportive care and a reduced immunosuppressive and strict infectious control measures to prevent transmission.
The DIDACT Study:
– Evaluated a stepwise prospective diagnostic and therapeutic flow chart
– Aimed to diagnose and treat infectious causes and exclude other causes before adjusting the IS.
– They found Campylobacter jejuni enteritis and CMV colitis being the most common in 28%
– Diarrhea resolved without any change in IS in 50%.
– 1/3 had bacterial overgrowth responded to antibiotics.
-For all patient to review medications for potential causes of diarrhea, and to stopped unnecessary one.
– Specific testing; bacterial culture, ova and parasites, PCR for CMV and C. difficile and stool lactoferrin.
-Test for bacterial overgrowth; breath test.
– Reduction of IS.
– if all test are negative consider empiric antidiarrheal, probiotics, and lactose- free diet should be tried.
– Colonoscopy: PTLD; exudative enteropathy, CMV colitis with negative viral load, duodenal villous atrophy; drug toxicity, de-novo IBD.
-Treatment: with hydration and specific antimicrobials or modification in IS by reduce MMF dose/ or switching to
EC-MPS, if no improvement complete withdrawal.
Conclusion:
-Physicians should be aware about post-transplant diarrhea.
– Meticulous evaluation and stepwise approach for diagnose and treatment will help to resolve diarrhea, and prevent potentially life-threatening consequences as graft loss.
Diarrhea is a common complaint post-transplantation.
It is associated with fatigue, frequent hospitalization, quality of life, and a negative impact on patent and graft survival.
Causes may include; immunosuppressants, polypharmacy, and infection.
Causes of diarrhea after transplantation 1.Immunosuppressants
Non-infectious D.
Highest incidence associated with MMF.
MMF dose reduction is associated with a reduction of diarrhea or disappearance.
A recent meta-analysis study identified that the relative risk of diarrhea associated with MMF is 1.57.
The mechanism is unknown, but it may be because of a de novo pathway of purine synthesis for growth and proliferation, and they’re vulnerable to MPA inhibition and diarrhea.
There are two histomorphological patterns;
a) Predominant crypt distribution, other names ; b) IBD-like MPA-associated toxicity and predominant apoptosis. c) graft-versus host-like MPA- associated toxicity.
A recent RCT suggests that switching from MMF to EC-MPS has a higher chance of returning to target MPA doses than those remaining on MMF.
Switch from MMF to AZA is associated with reduced graft survival as compared to MMF, although safe in a short time.
US-RTSR showed that MMF reduces the relative risk of graft loss to 27%.
Death-censored graft survival at 4 years was better among MMF vs AZA treated patients.
TAC can cause diarrhea in 29-64% of patients, hypothesized that the macrolide structure may results in stimulation intestinal motility, usually mild and does not required dose reduction or discontinuation, and a recent study reported a decrease incidence of diarrhea after conversion to a daily, extended release formulation of TAC.
Sirolimus cause a self-limiting diarrhea in 14-42% of treated patients, proposed to be due to jijunal villous atrophy and a structural homology wit the promotility macrolide class of drugs.
ATG and OKT3 are both associated with diarrhea lasts for 3-4 days and resolved spontaneously.
2.Infection associated diarrhea
CMV and C.difficile, but other (E.coli, rotavirus, giardia, and entameba and others).
Diarrhae is uncommon in the early postoperative time.
After few months, patient become completely suppressed and pathogens develops.
More common cause of sever diarrhea recently reported is the chronic norovirus infection, (17-26%), a biphasic illness; acute phase with more classical as a nausea, vomiting and diarrhea (10-20 watery diarrhea
/day), abdominal pain +/- fever, followed by chronic phase with cycles of normal stools and poorly formed stools.
CMV-GIT infection (1/3rd of the CMV infected patient have GIT affection).
Rotavirus infection, (limited data in SOT), diagnosed in 1.5% of SOT by one study mostly n paediatric patients
Adenovirus viremia, commonly observed in early Tx period with GIT occur in 10% of patients.
C.difficile is a common nosocomial and infectious diarrhea in early post Tx (3.5-4.5% in SOT recipients), with the significant effect on mortality and is an independent risk factor of death, the followings are the risk factors
a) Older recipients. b) Use of ATG. c) Retransplantation and higher incidence among liver Tx. d) Recent antibiotic use (higher with fluoroquinolones).
Parasites (protozoan or metazoan).
Diagnosis
A fecal enzyme immunoassay or real-time PCR or a cell-based cytotoxicity assay for C.dificile, all are highly sensitive and specific.
C.dificile treatment includes; fidaxomicin, metronidazole (70% response) and vancomycin in sever cases.
Fidaxomicin, ramoplanin and tigecycline are effective of traeting sever or recurrent disease.
Human monoclonal antibody has encouraging result against C.dificile toxins A and B.
Immunofluorescent assays and ELISA with high sensitivity and specificity 100% for diagnosis of cryptosporidiosis, and treated with nitazoxanide or paromomycin.
CMV IgG, IgM, PCR, immunohistochemical staining and biopsy (owls eye) for CMV diagnosis, CMV cloitis treated by gancilclovir (better option to avoid inadequate oral absorption) or valganciclovir and continue prophylaxis after complete cure of CMV colitis for 30-90 days.
Norovirus; PCR stool or vomitus, and treated with supportive managementwith reduction of immunosuppressants, IVIG in selected cases, ribavirin and nitazoxanide, ( no available vaccine), so hand hygiene and sanitization is vital in prevention of norovirus infection.
Rotavirus; stool-immunoassay, culture, and PCR, with supportive tratemnet is the main treatment approach, with advice disinfectants and sensitizers as a preventive measures, with liscened 2 oral rota vaccines (Rota Teg and Rotarix) which should be provided preTx as it is a life attenuated vaccines.
Adenovirus (AdV) diagnosed by viral culture (gold standard), direct antigen detection (specific for serotypes) histopathology and PCR, treatment based on supportive Rx and IS reduction, with advice procausion as a protective plan.
DDACT study;
a) A stepwise protective approach for identification of pathogens and therapeutic flow chart. b) Aimed to eliminate causative factors, infectious and non-infectious cause of diarrhea in SOT recipients. c) 30 of 108 recipietns diagnose with infectious diarrhea (Compylobacter jejuni enteritis, and CMV colitis the most common pathogens). d) 50% of patients diarrhea resolved without IS reduction. e) Only 39 patients diagnose with bacterial overgrowth were respond to antibiotics. f) All patient should have medication review for possible medication related diarrhea and stop unnecessary medications. g) Specific tests; cultures, PCRs and ova and parasite assessment. h) IS reduction. i) +/- colonoscopy (intestinal ulceration due to PTLD, CMV colitis, villoud atrophy, and de novo IBD) j) If all -ve and diarhae persist, empric antidiarrheal medications, probiotics and/or lactose free diet, should be tried. k) Hydration, IS reduction, specific antimicrobials therapy. Conclusion
Physician should be aware with diarrhea post Tx.
Stepwise approach help not only treat the infection but to avoid associated complication, graft loss and mortality risk.
Introduction
It is supposed that chronic diarrhea post transplantation is inevitable along with it’s drawbacks on recipient’s quality of life ,graft survival and mortality..
It can lead to steatorrhea ,malabsorption ,enteric hyperoxaluria and oxalate nephropathy
Immunosuppression, broad spectrum antimicrobial treatment ,other treatment and infectious causes can predispose to post transplant diarrhea.
The current review assess Infectious and non infectious diarrhea post renal transplantation. Epidemiology
The cumulative incidence of diarrhea increase with time post transplantation meanwhile it is underestimated.
The diarrheal episodes were self-limited, the most common cause was Clostridium difficile infection norovirus infection and cytomegalovirus (CMV) gastrointestinal infection .
Immune suppression were reduced in some cases with diarrhea on MMF or Mycofenolic acid. Causes of diarrhea
A prospective study –the Diarrhea Diagnosis Aid and Clinical Treatment (DIDACT) study was carried out to detect the causes ,demonstrating that 50% of cases were due to CMV being the most common etiology.
Infectious causes of diarrhea include
· bacterial as campylobacter,C.difficle ,Ecoli and bacterial overgrowth.
Non infectious causes of diarrhea
· viral as CMV ,Norovirus ,Rotavirus ,adenovirus
· parasitic as Giardia and entameba
Non infectious causes
Immunosuppressives as MMF ,Tac ,Cyclosporine ,Sirolimus
Non immunosuppressives as antibacterial ,antidiabetic ,antiarrhythmic
Others as GVHD ,PTLD ,IBD ,Cancer colon ,malabsorption.
Diarrhea subsided in half the cases due to stopping of diarrhea-associated nonimmune suppressive drugs or due to treatment of concurrent infection. Cause of diarrhea immunosuppressive drugs
Many immunosuppressives can cause diarrhea particularly MMF ,which lead to increased risk of graft loss and mortality but the mechanism is unknown a supposed mechanism was that gastrointestinal epithelial cells depend partially on the de-novo pathway of purine synthesis for growth and proliferation, rendering it vulnerable to Mycophenolic acid causing diarrhea.
Dose reduction can treat diarrhea ;regarding switching from MMF to enteric coated mycophenolate sodium to decrease diarrhea is controversial.
Shifting from MPA to azathioprine is not recommended due to high graft loss risk.
A study revealed that Azathioprine significantly increase skin cancer risk .
Inflammatory bowel disease like MPA-associated toxicity and graft-versus host-like MPA -associated toxicity are 2 histological types.
Tacrolimus dose and drug duration can affect diarrhea risk.
The mechanism of CNI induced diarrhea is unknown but supposed to be due to the macrolide structure that can stimulate intestinal motilin receptors.
Tac induced diarrhea is mild and usually doesnot require stopping of the drug
Dailt extended release formula of Tac can reduce diarrhea.
Sirolimus can cause self limiting diarrhea in some cases,the mechanism is unknown but could be due to induced jejunal atrophy.
In some cases , ATG and anti–T cell antibody (OKT3) can lead to self limited diarrhea ,through activating T cells to produce TNF that prevent sodium ion absorption and disrupts the intestinal mucosal barrier. Infectious cause of diarrhea
Infection is a common cause of diarrhea as CMV and C difficle in SOT .
After the first few months, opportunistic infection can be the leading cause of diarrhea due to the complete immunosuppression state .
Also community-associated organisms as norovirus are implicated Chronic norovirus is one of the recently detected causes of post transplant diarrhea in SOT raising the possibility of previous misdiagnosis.
It can be complicated by chronic diarrhea or acute attacks of diarrhea induced AKI.
Chronic norovirus diarrhea has 2 phases the first acute phase presents with extensive diarrhea and chronic phase of normal formed stool. CMV gastroenteritis is one of the most common causes of diarrhea in SOT.
Risk factors are D+/R- and after that comes D-/R+, lymphodepleting antibodies and more potent immunosuppressives .
For Rota virus induced diarrhea there isnot much data ,in fact it was detected in adult and pediatric SOT espeically pediatrics with liver transplant Adenovirus diarrhea can occur early post transplant in 10% of SOT cases. There are severe infection forms involving the transplanted organ or disseminated disease was described. C. difficile is the most common cause of nosocomial diarrhea and common to occur within the first months post transplantation.
Risk factor include recent antibiotic use particularly fluoroquinolones ,age >55 years, ATG use, re transplantation and type of organ transplanted, as much prevalent among liver recipients
CDI is accompanied by high mortality rate .
The metazoan infection is most common parasite.
SOT with diarrhea and weight loss due to microsporidia infection
Enterocytozoon bieneusi is common in kidney transplant recipients .
Cryptosporidia (Cryptosporidia parvum and Cryptosporidia homini) can lead acute ,chronic infection with extraintestinal spread. Diagnosis and treatment
Distinguishing between infectious and non infectious causes is essential to avoid unnecessary reduction of immunosuppression and graft loss For C. difficle diagnosis
,cell-based cytotoxicity assay is the standard , but fecal enzyme immunoassays or real-time PCR test are more practical.
C. difficile is usually asymptomatic in transplant recipient but when activated can lead to diarrhea, intestinal obstruction, abscesses or toxic megacolon.
C.difficle treatment in SOT includes fidaxomicin, metronidazole or vancomycin for severe infection
prevention and treatment of relapsing and refractory forms of C. difficle is difficult .
Fidaxomicin, ramoplanin and tigecycline are effective for the treatment of severe or recurrent disease.
Human monoclonal antibodies against C. difficile toxins A and toxin B.
Fecal microbiota transplantation (FMT) for treatment of refractory CDI Microsporidia-related diarrhea
can be treated by fumagilin with favourable outcomes but associated thrombocytopenia limited it’s use. Cryptosporidiosis
diagnosed by oocysts detection in stool, Immunofluorescent assays and ELISA having high sensitivity and specificity . Tissue-invasive CMV disease is
diagnosed by CMV viremia detection in most cases.
CMV colitis diagnosis by
· serology is usefull for diagnosis of new disease onset
· conventional culture has lower sensitivity ,long incubation period and the high rate of false negativity.
· Shell Vial Assay is a rapid test but has a low sensitivityrate.
· CMV pp65 Antigen Test can be used for blood and cerebrospinal fluid.
· PCR method can be done with whole blood, plasma and leukocytes.
· the definitive diagnosis is by endoscopic evidence of gastrointestinal involvement.
· Pathological specimen revealing owl’s eye’ intranuclear inclusions, or b.y immunohistochemical staining for pp65 which is the standard test for diagnosis but viral inclusions are rarely detected
Treatment with intravenous ganciclovir or oral valganciclovir ,treatment can be stopped if given for at least 2 weeks, clinical symptoms subsided and viral load is undetectable .
For tissue-invasive CMV disease,it is recommended to use valGCV for secondary prophylaxis for 30–90 days after successful treatment Norovirus
Diagnosed by PCR in stool, vomitus, foods and environmental specimens.
FDA approved xTAG Gastrointestinal Pathogen Panel for simultaneous detection of 3 viruses (norovirus G-I/G-II, rotavirus A and AdV 40/41), 9 bacteria and 3parasites but not tested in immunocompromised cases.
Treatment include supportive therapy ,immunosuppression reduction.
Chronic norovirus-related diarrhea mandates MMF discontinuation
Prevention through hand hygiene and sanitation is the main method as no vaccines are available . Rotavirus
Diagnosed by immune-based assays for rapid detection in stool.
Other tests are cell culture, real time-PCR and electron microscopy with high specificity and sensitivity .
Treatment is supportive as no antirotaviral therapies are available.
Prevention through contact precautions , in USA there are 2 live attenuated vaccines that can be given before transplant. Adenovirus
diagnosed by viral culture which is the gold standard but takes a long time , direct
antigen detection utility in immunocompromised is unknown, histopathology and PCR.
Treated with supportive care and a reduced immunosuppressive regimen.
Prevention by contact and droplet infection.
A study on SOT cases with CMV colitis and campylobacter jejuni enteritis showed that 50% of the patients, diarrhea resolved without immunosuppressive therapy change and only third of the cases had bacterial overgrowth that responded to antibiotics.
An algorithm was introduced to evaluate the case before manipulating immunosuppressives including bacterial culture, ova and parasites testing, PCR for CMVand C. difficile and stool lactoferrin. Then excluding bacterial overgrowth by breath test , afterwards reduction
in immune suppression and colonoscopy. If results are negative and the diarrhea persists, empiric
antidiarrheal medications, probiotics and/or lactose-free diet can be given .
Esophagogastroduodenoscopy and colonoscopy with biopsies to investigate persistent diarrhea after kidney transplantation to exclude IBD ,CMV coloitis , large bowel posttransplant lymphoproliferative disorder.
Treatment of diarrhea, with proper hydration and antimicrobials or reduction of immune suppression, is the main therapy. Conclusion
A directed algorithm to diagnose and treat post transplant diarrhea will help cure it diarrhea, also will prevent potentially drastic outcomes as graft loss .
Article-2
Q1. Introduction
· Kidney transplantation is a risk factors for posttransplant diarrhea due to the immune suppression, infections and drugs such as immune suppressive medications, antibiotics, and other drugs as well Epidemiology
· According to UNOS, the cumulative incidence was confirmed to be 11.5, 17.5 and 22.6% at 1, 2-, and 3-years following kidney transplantation Causes of diarrhea
· The DIDACT study (the Diarrhea Diagnosis Aid and Clinical Treatment study) revealed that, infection (mainly CMV) is responsible for 50% of causes of posttransplant diarrhea. This is followed by immune suppressive drugs (mainly MMF) in two-third of the remaining cases Drug-induced diarrhea/ immune suppression
· MMF (high incidence), tacrolimus, cyclosporin, & sirolimus Major infectious causes of posttransplant diarrhea A. Bacteria * Clostridium difficile
· Most common nosocomial infection
· Incidence is between 3.4 to 4.5%
· Risk factors are; Age >55, ATG induction, re-transplantation, liver transplantation, and recent antibiotic exposure particularly fluoroquinolones (single important risk factor)
· High mortality between up to 8.5%
· Clinical presentation; May be asymptomatic carrier, diarrhea, intestinal obstruction, abscesses or toxic mega colon
· Diagnosis; cell-based cytotoxic assay (gold standard), fecal immune assays, or real time PCR
· Treatment; First episode metronidazole, severe disease vancomycin or fidaxomicin, first relapse treated the same as first episodes.
· Second relapse consider vancomycin taper with pulse
· >= 3 relapse consider fecal microbiota transplantation, or prolonged oral vancomycin
· Surgery may be considered for surgical issues such as a toxic mega colon, abscesses or obstruction B. Viruses * CMV
· CMV colitis or tissue-invasive CMV is diagnosis can be suggested by PCR in up to 85% of case (may be negative in 15%). How ever, the gold standard is histopathology with the presence of viral inclusion bodies ‘owl eye appearance’ or immune histochemical staining of the tissue for CMV pp 65 antigens. The challenge is that, the inclusion bodies are very rare and you cannot easily see them.
· Treatment is by oral valganciclovir or IV ganciclovir in cases of malabsorption
· The treatment should not be stopped unless, the patient is treated for at least two weeks, the symptoms has resolved, and the viral load is undetectable in at least one occasion
· CMV relapse is common in 15 to 35% of patients and therefore, the treatment should be followed by a prolonged course of oral valganciclovir up to 3 months * Norovirus
· Member of enteric virus and diagnosed mainly by PCR of any specimen including stool, vomitus, and food
· Interactions between Norovirus and MMF; Norovirus initiate the diarrhea in renal recipient and MFF play a key role in chronicity by preventing viral clearance as well as the repair of the intestinal epithelium
· Chronic norovirus diarrhea is major concern because it is a common cause of MMF discontinuation and increased risk of rejection
· Treatment; Supportive, rehydration, anti-motility agents, and reduction of immune suppression
· Prevention; No vaccine, hand washing for 20 s with optional use of hand sanitizers but not substitute
Other differential diagnosis of posttransplant diarrhea:
A. Infection
· Bacterial; Campylobacer ssp, salmonella ssp, bacterial overgrowth, aeromomous spp, E. coli
· Viruses; Rotavirus, adenovirus, sapovirus
· Parasites; Giardia, cryptosporidium, isosopora Cyclospora, Microsporidium, Entameoba
B. Non-infection
· Non-immune suppressive drugs e.g antibiotics, PPI, antidiabetic
· Others e.g., GVHD, PTLD, IBD, colon cancer Conclusion
· Posttransplant diarrhea may be associated with poor quality of life and may increase risk of allograft dysfunction. The transplant clinician must evaluate and attempt to diagnose the cause of diarrhea and differentiate between infectious and non-infectious causes of posttransplant diarrhea. Future prospective studies to guide better understanding of this issue is highly needed.
Anti-motilityto be given only after ruling out infective causes. I like your well-structured detailed summary, level of evidence, analysis and take home messages typed as conclusion.
Chronic diarrhea after kidney transplantation is a common complaint, often assumed by clinicians and patients to be an inevitable part of kidney transplantation. This is neglected despite its association with fatigue, increased hospitalizations and negative impacts on recipient quality of life graft survival and higher mortality.
Steatorrhea and malabsorption may result from severe and chronic posttransplant diarrhea and induce enteric hyperoxaluria
There was a resolution of diarrhea in approximately 50% of patients either by discontinuation of diarrhea-associated nonimmunosuppressive drugs or by the treatment of concurrent infections (most frequently Campylobacter or CMV). In the remainder of patients, changes in immunosuppressive therapy (most commonly MMF) led to remission of diarrhea in about twothirds of cases. Thus, considered together, the data from the DIDACT study indicate that an infectious cause of posttransplant diarrhea is present in approximately 50% of cases with CMV being the most common pathogen.
CAUSE OF DIARRHEA: IMMUNOSUPPRESSIVE DRUGS Noninfectious diarrhea is not uncommon among renal transplant recipients and has been reported to increase the risk of graft loss and mortality
Drug-induced diarrhea is a major problem as many of the immunosuppressive agents commonly used in transplantation may cause diarrhea, with the highest incidence associated with MMF.
CAUSE OF DIARRHEA: INFECTIONS
Diarrhea is commonly infectious [26] and the microbes usually responsible are CMV and C. difficile, but the literature describes a wide range of organisms in solid organ transplant (SOT) recipients
In the first month following transplant,
patients are not yet completely immunosuppressed and infection with opportunistic pathogens is relatively uncommon. After the first few months posttransplant, opportunist pathogens become more evident as a cause of infection. It is important to remember that the individual is also being exposed to common community-associated pathogens (e.g. norovirus and enteropathogenic bacteria). C. difficile, CMV and norovirus are important causes of diarrhea in this population, and management should be focused on these causes.
DIAGNOSIS AND THERAPEUTIC STRATEGY It is important to evaluate and attempt to diagnose the cause of diarrhea in a transplant recipient. It is imperative that the clinician makes a distinction between noninfectious and infectious causes of diarrhea.
The gold standard for C. difficile detection is the cell-based cytotoxicity assay. However, most laboratories use the easier, less expensive and more rapid fecal enzyme immunoassays or real-time PCR test. These tests have high sensitivity and specificity (90%) for the detection of CDI
Only about 70% of patients will respond
to treatment with metronidazole; persistent and more severe cases will require oral vancomycin. The greatest challenge for toxigenic Clostridium infections remains the prevention and treatment of relapsing and refractory forms. In transplant recipients, it has been estimated that up to 20% of cases will have at least one relapse
The diagnosis of tissue-invasive CMV disease is suggested by the presence of CMV viremia. Many patients with CMV colitis will have evidence of CMV replication in the blood via PCR, although approximately 15% will not
Optimal duration of antiviral therapy depends on the patient’s clinical and virologic responses, not on a fixed period. Before antiviral therapy is stopped, the following three criteria should be met: the treatment was given for at least 2 weeks, clinical symptoms have resolved and viral load is no longer detectable, if initially detected
In diagnosis of rotavirus, immune-based assays
are most routinely used to rapidly detect rotavirus antigens in stool samples Other diagnostic methods such as cell culture, real time-PCR and electron microscopy remain as reference methods because of their high specificity and sensitivity
Currently, no antirotaviral therapies are available, and the treatment of rotavirus infection in SOT patients is mainly supportive
Physicians should be familiar with common causes that result in posttransplant diarrhea. A directed approach to diagnosis and treatment will not only help to resolve diarrhea, but also prevent potentially life-threatening consequences such as loss of the graft. Prior to implicating an immunosuppressant medication as the culprit, a meticulous evaluation for other possible causes of diarrhea should always be conducted. Infectious agents and the concomitant use of other diarrhea genic medications such as proton-pump inhibitors, antibiotics and diuretics must first be excluded.
Introduction:
Chronic diarrhoea post-renal transplant (RTx) is a major issue of poor quality life in the renal transplant recipient with frequent hospitalization.
Post RTX incidence diarrhoea is around 11.2 ,17.5 and 22.6% in the 1 year,2 and 3 years, respectively.
Causes of posttransplant diarrhoea include: infections, antibiotics, immunosuppressive drugs and other drugs
A single-centre study in the US: most of the diarrhoeal episodes were self-limiting with no identifiable cause, 13% were due to C. difficile, 4% noro-virus, 3.5% CMV, 32% of the patients had modulation of their immunosuppressive medications.
DIDACT study:
– large prospective study done to identify causes of posttransplant diarrhoea
– infection was the cause of diarrhoea in 50% of the cases; CMV and campylobacter-related infections were the most common.
Causes of diarrhoea
Infectious:
– Bacterial – Clostridium defficile, Campylobacter, Salmonella
– Viral – CMV, Noro-virus, Rotavirus, Adenovirus
– Parasitic – giardia, entamoeba, cryptosporidium, microsporidia, isospora
Non-infectious cause
– Immunosuppressive drugs: MMF, Tacrolimus
– Non-immunosuppressive drugs: Antibacterial
DIAGNOSIS AND THERAPEUTIC STRATEGY.
The development of an optimal diagnostic algorithm is extremely challenging due to the varying causes of post-transplant diarrhoea, but a thorough evaluation is crucial for effective treatment.
To diagnose and treat diarrhoea in transplant recipients, clinicians must distinguish between non-infectious and infectious causes.
– Initial treatment of SOT includes fidaxomicin, metronidazole or vancomycin. There is a good effect for use of human monoclonal antibodies against C. difficile toxins A and B and new trend for fecal microbiota transplantation.
2. Cryptosporidiosis is generally diagnosed by visualization of oocysts in the stool. There is no specific treatment – no difference between nitazoxanide or paromomycin and placebo for immunosuppressed patients with cryptosporidiosis.
Finally, the approach will be consisting of bacterial culture, assessment for ova and parasites, PCR for CMV and C. difficile and stool lactoferrin. The next steps were breath test for bacterial overgrowth, reduction in immune suppression and colonoscopy.
Treatment:
First attempt should be isolation of infectious pathogen and administer appropriate antibacterial or antiviral therapy.
Change in immunosuppression consists of MMF dose reduction or switching to EC-MPS, followed ultimately by MMF-EC-MPS withdrawal if symptoms persist.
Level of evidence: V -narrative review article
Magnitude of the problem.
· Medicare claims state that the The cumulative incidence of diarrhea is 11.5%, 17.5%, and 22.6% at 1, 2, and 3 years after transplantation respectively.
· a survey of 4,232 Scandinavian renal transplant recipients found that 53% of participants experienced diarrhea, while their physicians estimated the incidence to be only 6.9%.
This suggests that the posttransplant diarrhea is over looked.
· in one large retrospective study, posttransplant diarrhea of unknown origin (noninfectious) was associated with a two-fold increase in graft loss and risk of death.
CAUSE OF DIARRHEA: IMMUNOSUPPRESSIVE DRUGS
Noninfectious diarrhea is not uncommon among renal transplant recipients
many of the immunosuppressive agents commonly used may cause diarrhea,
MMF. highest incidence
dose reduction is followed by the decrease or the disappearance of diarrhea .
1-MMF and enteric-coated mycophenolate sodium (EC-MPS)
A recent meta-analysis identified that the relative risk of diarrhea associated with the use of MMF is 1.57
The mechanism of MMF-induced diarrhea remains unknown.
Þ possible mechanism is that gastrointestinal epithelial cells may be partially dependent on the de-novo pathway of purine synthesis for growth and proliferation, and are therefore vulnerable to Myco- phenolic acid (MPA) inhibition leading to diarrhea.
Þ Histologically,
· predominant crypt distortion. (inflammatory bowel disease- like MPA-associated toxicity )
· predominant apoptosis. (graft-versus host-like MPA- associated toxicity . )
Þ switch of from MMF to EC-MPS helps reduce diarrhea symptoms is a matter of debate. A recent randomized and controlled open study suggested that patients with MMF-related diarrhea who switch to EC-MPS may have a slightly, yet significant, greater chance of returning to a target MPA doses than those maintained on MMF .
the switch from MPA to azathioprine (AZA)
is usually avoided reduced graft survival with AZA
is safe in the short term [16].
tacrolimus diarrhea in 29 – 64% of patients
The mechanism unclear,
macrolide structure may result in stimulation of the intestinal motilin receptors.
mild course and rarely require discontinuation
daily, extended release formulation of tacrolimus reported a decrease in the incidence of gastrointestinal symptoms
Sirolimus causes self-limiting diarrhea in 14 – 42% of treated patients.
drug-induced jejunal villous atrophy and a structural homology with the promotility macrolide class of drugs is a possible explanations
antithymocyte globulin (ATG) and anti – T cell antibody (OKT3)
· up to one-third of patients, lasts for 3 – 4 days and resolves sponta-neously
· mechanism activating T cells to release tumor necrosis factor which then interferes with sodium ion absorption and also disrupts the intestinal mucosal barrier.
CAUSE OF DIARRHEA: INFECTIONS
Diarrhea is commonly infectious
· Clostridium difficile, norovirus (NV), and cytomegalovirus (CMV) are the most common causes of infectious diarrhea,
· opportunistic and parasitic infections infrequently encountered In the firstfew month following transplant, After the first few months post- transplant, opportunist pathogens become more evident as a cause of infection
# Norovirus infection
· recently emerged as one of infectious causes
· 17 – 26% of severe posttransplant diarrhea
· This finding suggests that numerous cases of posttransplant diarrhea in the past may have been incorrectly solely ascribed to toxicity of immunosuppressive drugs,.
· course of norovirus infection tend to be more complex
· up to 94% having chronic diarrhea and
· 81% having episodes of diarrhea-induced acute renal failure
· a biphasic illness in the course of norovirus.
acute phase, classical illness with nausea, vomiting, significant diarrhea (10 – 20 watery stools per day), abdominal pain and sometimes fever.
chronic phase, period of relatively normal stools alternating with periods of more poorly formed stools [4].
no specific treatment exists beyond providing supportive care and reducing immunosuppressive therapy..
# CMV
In a recent study of 1427 SOT patients, 7.2% developed CMV disease, of which approximately one-third had gastrointestinal involvement
The most significant risk factor for the development of CMV disease is seropositive donor/seronegative recipients
# rotavirus infection
In one study, rotavirus infection was diagnosed in 1.5% of SOT recipients, with most cases occurring in pediatric patients (63%)
# Adenovirus
The epidemiology of AdV is similar in the SOT popula- tion and in the general population.
# C. difficile
· is the most common cause of nosocomial diarrhea
· accounts for most infectious diarrhea within the first months after transplantation
· The reported incidence of Cdiff 3.5-4.5%
· . The single most important risk factor is recent anti-biotic use. Among antibacterials, the fluoroquinolones are associated with the highest risk
· CDI has a significant effect on mortality of SOT recipients, with mortality rates between 2.3 and 8.5%, and is an independent risk for death (adjusted odds ratio 2.48, 2.22–2.76)
# the protozoan or metazoan are most common Parasitic cause
Gastrointestinal infection due to microsporidia has been recorded in patients with SOT who experienced diarrhea and weight loss Enterocytozoon bieneusi is by far the most frequent strain found in kidney transplant recipients .
Cryptosporidia (Cryptosporidia parvum and Cryptospo-ridia hominis)
are intracellular protozoans known to lead to severe acute diarrhea, chronic diarrheal illness and extraintestinal infection in transplanted patient
Diagnostic and therapeutic strategy for postrenal transplant diarrhea
No evidence-based guidelines are available for the evaluation of diarrhea in SOT recipients.
management should be focused on these causes
Initially, all patients with diarrhea should have their medications reviewed for potential causes of diarrhea, and unnecessary agents should be stopped and followed by specific testing for different causes of the diarrhea
The first-line microbiologic stool investigations
stool cultures for pathogenic bacteria, examinations for parasites and fungi, C. difficile toxin assay and quick tests for rotavirus, adenovirus and norovirus.
In case of fever, CMV Dþ/Rj serologic status, cytopenia, liver enzymes studies, and plasma CMV Q-PCR should be performed. (in our center we do it as a routine in any patient with chronic diarrhea
Multiplex pcr based screening of chronic diarrhea for enteric pathogen
Campylobacter species, enteropathogenic and enterotoxigenic Escherichia coli, Shigella species, Salmonella species, Yersinia, Clostridium difficile, Cryptosporidium, Enterocytozoon bieneusi, Enteric viruses (rotavirus, adenovirus, norovirus and enterovirus).
The next steps were breath test for bacterial overgrowth, reduction in immune suppression and colonoscopy. If these tests are negative and the diarrhea persists, empiric antidiarrheal medications, probiotics and/or lac- tose-free diet should be tried.
performing esophagogastroduodenoscopy and colonoscopy with biopsies is necessary to investigate persistent diarrhea after kidney transplantation. This is because several conditions such as large bowel posttransplant lymphoproliferative disorder, CMV colitis, severe duodenal villous atrophy, and de-novo inflammatory bowel disease may be the underlying cause.
Chronic diarrhea following RTX is a significant cause of low quality of life and frequent hospitalization in renal transplant recipients.
The incidence of diarrhea following RTX is around 11.2, 17.5, and 22.6% in the first, second, and third years, respectively.
An American single-center research found that infections, antibiotics, immunosuppressive medications, and other treatments can all cause posttransplant diarrhea. Infection was the cause of diarrhoea in 50% of cases, with CMV and campylobacter-related infections being the most common. The majority of the diarrhoeal episodes were self-limiting with no apparent cause, 13% were due to C. difficile, 4% norovirus, 3.5% CMV, and 32% of the patients had modulation of their immunosuppressive medications.
The most frequent causes of post-transplant diarrhea are infections and drug usage, while there are many other potential reasons that might be difficult to identify. When treating patients with diarrhea, doctors should make every effort to distinguish between infectious and noninfectious causes.
To learn more about the prevalence, risk factors, and consequences of diarrhea in kidney transplant patients—particularly with regard to norovirus, rotavirus, and AdV infections—prospective studies are required.
The majority of IS agents that are often used in transplantation can induce diarrhea, with MMF having the greatest prevalence and an unknown primary reason. According to one idea, tacrolimus can also cause diarrhea in 29–64% of patients depending on the dosage and length of medication use. However, switching to tacrolimus’ extended release formulation has shown some relief.
Approximately 17–26% of severe post–transplant diarrhea is biphasic, consisting of an acute phase (characterized by 10–20 watery stools per day), abdominal pain, and occasionally fever, then a chronic phase, during which patients may alternate between cycles of relatively normal stools and periods of less-than-ideal stools.
Seropositive donors and seronegative recipients’ gastrointestinal involvement, which happens in up to 40% of patients, is the most important risk factor for the development of CMV illness. CMV is one of the most prevalent causes of diarrhea after kidney transplantation.
Finally, the approach will be consisting of bacterial culture, assessment for ova and parasites, PCR for CMV and C. difficile and stool lactoferrin. The next steps were breath test for bacterial overgrowth, reduction in immune suppression and colonoscopy.
Chronic diarrhoea post-RTX is a major issue of poor quality of life in the renal transplant recipient with frequent hospitalization.
post RTX incidence diarrhoea is around 11.2 ,17.5 and 22.6% in the 1 year,2 and 3 years, respectively.
Causes of posttransplant diarrhoea include: infections, antibiotics, immunosuppressive drugs and other drugs
single-centre study in the US: most of the diarrhoeal episodes were self-limiting with no identifiable cause, 13% were due to C. difficile, 4% norovirus, 3.5% CMV, 32% of the patients had modulation of their immunosuppressive medications
– DIDACT study, large prospective study done to identify causes of posttransplant diarrhoea
– infection was the cause of diarrhoea in 50% of the cases, CMV and campylobacter-related infections were the most common
Causes of diarrhoea
could be infectious and non-infectious
the infectious could be c. diff ,campylobacter, salmonella,
viral: CMV,norovirus,rotavirus, adenovirus
Parasitic: giardia, entamoeba, cryptosporidium, microsporidia, isospora
non-infectious cause
Immunosuppressive drugs: MMF, tacrolimus, cyclosporine, sirolimus
· Non-immunosuppressive drugs: antibacterial, antiarrhythmic, antidiabetic, laxatives. PPIs, protease inhibitors
this article level 5
Chronic diarrhea is a common complaint after kidney transplantation, with negative impacts on quality of life, graft survival, and mortality.
Infectious and noninfectious causes of diarrhea can be difficult to distinguish, but infections and medication use are the most common causes.
Chronic diarrhea is often neglected by clinicians and patients, despite its significance. Chronic diarrhea can result in steatorrhea and malabsorption, which can induce enteric hyperoxaluria and lead to devastating effects on renal graft function.
The causes of post-transplant diarrhea are varied and can be challenging to diagnose, but infections and medication use are the most common culprits. Clinicians should make every effort to distinguish between infectious and noninfectious causes of diarrhea and provide appropriate treatment.
Prospective studies are needed to better understand the prevalence, risk factors, and complications of diarrhea in kidney transplant patients, particularly with respect to norovirus, rotavirus, and AdV infections.
The development of an optimal diagnostic algorithm is extremely challenging due to the varying causes of post-transplant diarrhea, but a thorough evaluation is crucial for effective treatment.
To diagnose and treat diarrhea in transplant recipients, clinicians must distinguish between noninfectious and infectious causes.
In most centers, the first change in immunosuppression consists of MMF dose reduction or switching to EC-MPS, followed ultimately by MMF-EC-MPS withdrawal if symptoms persist.
The cumulative incidence of diarrhea has been reported to be 11.5, 17.5 and 22.6% at 1, 2 and 3 years after renal transplantation, respectively.
In some studies, shown that diarrhoea was associated with a two-fold increase in graft loss and risk of death. Another study shown that the most common identifiable causes included Clostridium difficile infection, norovirus infection, and cytomegalovirus (CMV) gastrointestinal infection.
32% of individuals taking MMF or mycophenolic acid and diagnosed with diarrhoea had reductions or changes in their immune suppression.
DIDACT study shown that an infectious cause of post-transplant diarrhoea is present in approximately 50% of cases with CMV being the most common pathogen and the next most frequent cause is related to medication use.
IS
INFECTIONS
DIAGNOSIS AND THERAPEUTIC STRATEGY.
Finally, the approach will be consisting of bacterial culture, assessment for ova and parasites, PCR for CMV and C. difficile and stool lactoferrin. The next steps were breath test for bacterial overgrowth, reduction in immune suppression and colonoscopy.
Level of evidence: V -narrative review article
Chronic diarrhoea post-RTX is a major issue of poor quality of life in the renal transplant recipient with frequent hospitalization.
post RTX incidence diarrhoea is around 11.2 ,17.5 and 22.6% in the 1 year,2 and 3 years, respectively.
Causes of posttransplant diarrhoea include: infections, antibiotics, immunosuppressive drugs and other drugs
single-centre study in the US: most of the diarrhoeal episodes were self-limiting with no identifiable cause, 13% were due to C. difficile, 4% norovirus, 3.5% CMV, 32% of the patients had modulation of their immunosuppressive medications
– DIDACT study, large prospective study done to identify causes of posttransplant diarrhoea
– infection was the cause of diarrhoea in 50% of the cases, CMV and campylobacter-related infections were the most common
Causes of diarrhoea
could be infectious and non-infectious
the infectious could be c. diff ,campylobacter, salmonella,
viral: CMV,norovirus,rotavirus, adenovirus
Parasitic: giardia, entamoeba, cryptosporidium, microsporidia, isospora
non-infectious cause
Immunosuppressive drugs: MMF, tacrolimus, cyclosporine, sirolimus
· Non-immunosuppressive drugs: antibacterial, antiarrhythmic, antidiabetic, laxatives. PPIs, protease inhibitors
this article level 5
II. Causes and management of postrenal transplant diarrhoea: an underappreciated cause of transplant-associated morbidity
Summarise this article
Introduction
– chronic diarrhoea is a common complaint though often under-estimated by practitioners
– it is associated with fatigue, increased hospitalization, negative impact on the recipients’ quality of life, graft survival, higher mortality
– severe and chronic diarrhoea can cause steatorrhea and malabsorption which can induce enteric hyperoxaluria
– oxalate nephropathy can cause inflammation and may have negative effects on the graft function
– risk factors for development of posttransplant diarrhoea include: immunosuppression, polypharmacy notably broad-spectrum antibiotics
– causes of posttransplant diarrhoea include: infections, antibiotics, immunosuppressive drugs and other drugs
– clinicians should attempt to distinguish between noninfectious and infectious causes of diarrhoea in KTRs
– due to the diverse causes of posttransplant diarrhoea, it is difficult to come up with a single optimal diagnostic algorithm
Epidemiologic impact
– the cumulative incidence of posttransplant diarrhoea has been reported as 11.5, 17.5 and 22.6% at 1, 2 and 3 years respectively
– posttransplant diarrhoea is often underreported and underrecognized by practitioners
– adverse GI symptoms adversely affect the quality of life, graft and patient survival
– single-center study in the US: most of the diarrhoeal episodes were self-limiting with no identifiable cause, 13% were due to C. difficile, 4% norovirus, 3.5% CMV, 32% of the patients had modulation of their immunosuppressive medications
– DIDACT study, large prospective study done to identify causes of posttransplant diarrhoea
– infection was the cause of diarrhoea in 50% of the cases, CMV and campylobacter-related infections were the most common
– medication use was the 2nd most common cause of diarrhoea
– 50% of patients had resolution of symptoms after withdrawal of offending non-immunosuppressive drugs or by treatment of infections (CMV, campylobacter)
– 2/3 of the cases had resolution of symptoms following adjustment in MMF dose
Causes of diarrhoea
– Causes of diarrhoea can be infectious or noninfectious
– Infectious causes of diarrhoea:
· Bacteria: C. difficile, campylobacter, salmonella, bacterial overgrowth, E. coli
· Viruses: CMV, norovirus, rotavirus, adenovirus, sapobavirus
· Parasitic: giardia, entamoeba, cryptosporidium, microsporidia, isospora
– Noninfectious causes of diarrhoea:
· Immunosuppressive drugs: MMF, tacrolimus, cyclosporine, sirolimus
· Non-immunosuppressive drugs: antibacterial, antiarrhythmic, antidiabetic, laxatives. PPIs, protease inhibitors
Others causes:
· PTLD, colon cancer, IBD, malabsorption, malakoplakia, microscopic colitis, GVHD
Causes of diarrhoea: Immunosuppressive drugs
– noninfectious diarrhoea increases graft loss and mortality
– most immunosuppressive agents cause diarrhoea but MMF is associated with the highest incidence
– a dose reduction in MMF results in a decrease or resolution of the diarrhoea
– postulated mechanism of MMF-induced diarrhoea: MPA inhibit purine synthesis – the GI epithelial cells are partially dependent on the de novo pathway of purine synthesis for growth and development, inhibition therefore leads to diarrhoea
– 2 different morphologic patterns have been described histologically:
· predominant crypt distortion a.k.a. IBD-like MPA-associated toxicity
· predominant apoptosis a.k.a. GVHD-like MPA toxicity
– whether switching from MMF to EC-MPS reduces diarrhoea symptoms remains debatable
– patients with MMF-related diarrhoea who switch to EC-MPS may have a slight but significant greater chance of returning to a target MPA dose than those who remain on MMF
– switch from MPA to AZA is safe in the short term but it is associated with reduced graft survival
– AZA has been associated with an increased risk of skin cancer especially SCC
– tacrolimus-related diarrhoea occurs in 29-64% of patients depending on the dose and duration of drug usage
– mechanism of CNI-related diarrhoea is still unclear with a hypothesis that the macrolide structure results in stimulation of the intestinal motilin receptors
– tacrolimus-related GI side effects have a mild course and rarely require drug discontinuation
– conversion to a daily, extended-release tacrolimus formulation may decrease the incidence of the GI symptoms
– sirolimus causes self-limiting diarrhoea in 14-42% of patients, the mechanism is unclear but is thought to be due to drug-induced jejunal villous atrophy and structural homology in this promotility macrolide class of drugs
– ATG and anti-T cell antibody (OKT3) are associated with diarrhoea in 1/3rd of patients
– the diarrhoea lasts 3-4 days and resolves spontaneously
– ATG and OKT3 activate T cells to release TNF which interferes with Na+ absorption and also disrupts the intestinal mucosal barrier
Causes of diarrhoea: Infections
– CMV, C. difficile, norovirus, enteropathogenic bacteria are common and important causes of diarrhoea although other organisms have been identified
– norovirus and enteropathogenic bacteria are common community acquired pathogens
– norovirus account for 17-26% of the cases of severe posttransplant diarrhoea and it has 2 phases:
·the initial acute phase where patients present with nausea, vomiting, diarrhoea, abdominal pain, fever
· chronic phase where patients experience relatively normal stools followed by periods of poorly formed stools
– risk factors for CMV infection:
· pretransplant CMV serostatus D+/R- (most important) and to a lesser degree, D-/R+
· lymphodepleting antibodies
· more potent immunosuppressive regimens
– there is a direct relationship between CMV infection and the level of posttransplant immunosuppression
– other viruses that have been identified include: rotavirus, adenovirus
– C. difficile infection (CDI):
· is the most common cause of nosocomial diarrhoea
· accounts for most infectious diarrhoea in the first months posttransplant
· risk factors include: recent antibiotic use (fluoroquinolones are associated with the highest risk), age >55 years, use of ATG, re-transplantation, organ type (highest rate among liver recipients)
· has a significant impact on mortality
– common parasitic infections include: enterocytozoon bieneusi, microsporidia, cryptosporidium
Diagnosis and therapeutic strategy
– it is prudent to distinguish between noninfectious and infectious diarrhoea
– avoid unnecessary reduction in immunosuppressive agents in a bid to try and manage diarrhoea since this has its own consequences including graft loss
– cell-based cytotoxicity assay is the gold standard for C. difficile detection
– most labs use the fecal enzyme immunoassays or real-time PCR tests since they are easier, less expensive and more rapid, have a high sensitivity and specificity (90%) for the detection of CDI
– transplant patients can have asymptomatic CDI but most present with diarrhoea, intestinal obstruction, abscess, toxic megacolon
– initial CDI treatment includes: fidaxomicin, metronidazole or vancomycin
– vancomycin is preferred for severe CDI cases
– only ~70% of patients respond to metronidazole
– the persistent and more sever cases require oral vancomycin
– prevention and treatment of the relapsing and refractory forms of toxigenic clostridium infections remains a big challenge
– up to 20% of transplant patients will have at least one relapse
– newer antibiotics used in the treatment of severe or recurrent disease include: fidaxomicin, ramoplanin, tigecycline
– human monoclonal antibodies against C. difficile toxins A and B have produced encouraging results
– use of fecal microbiota transplantation (FMT) is being studied, it involves instillation of processed donor faeces into the colon or duodenum of the recipient
– FMT has a high success rate as well as a high adverse effect rate warranting further study
– there is limited data on FMT among transplant patients
– fumagillin is used in the treatment of microsporidia-related diarrhoea, clears E. bieneusi with minimal reduction in immunosuppression
– unfortunately, fumagillin use is limited due to drug-induced thrombocytponeia
– Cryptosporidiosis is diagnosed by visualization of the oocysts in stool
– immunofluorescence assays and ELISA have a sensitivity and specificity of ~100%, this is far much better than the traditional modified acid-fast stains
– there are no existing specific therapies against cryptosporidium
– there was no difference between nitazoxanide or paromomycin and placebo among immunocompromised patients with cryptosporidiosis
– Diagnosis of CMV-associated colitis:
· presence of CMV viremia suggests a diagnosis of tissue-invasive CMV disease
· CMV serology is limited for determination of an active infection
· disadvantages of the conventional culture: has a lower sensitivity, longer incubation period, insufficient CMV virus quantity, high rate of false negatives
· shell vial assay – faster than the conventional culture but has a low sensitivity rate
· CMV pp65 Ag test – can be done on blood and CSF fluid
· CMV PCR – done on whole blood, plasma, leucocytes
· Endoscopy – is the definitive/ gold standard test for the diagnosis of CMV GI disease, confirmed on histopathology via the characteristic swollen cells containing “owl’s eye” intranuclear inclusions or IHC staining for pp65; however, viral inclusions are not easily seen
– Management of CMV colitis: IV ganciclovir (GCV) or oral valganciclovir (valGCV)
– IV GCV is preferred in cases where there is a likelihood of inadequate absorption of oral valGCV (e.g., patients with diarrhoea and vomiting) and early in the treatment of proven CMV colitis
– duration of treatment depends on the patient’s clinical and virological response
– criteria to be met before stopping antiviral therapy:
· been on treatment for at least 2 weeks
· resolution of clinical symptoms
· undetectable CMV viral load (if initially detected)
– 15-35% of SOT recipients with tissue invasive CMV disease develop recurrent CMV disease hence many experts recommend secondary prophylaxis with valGCV for 30-90 days following successful treatment
– Norovirus diagnosis: PCR run on stool, vomitus, foods, environmental specimens
– there is GI pathogen panel that detects 3 viruses (norovirus, rotavirus, adenovirus), 9 bacteria and 3 parasites – it is yet to be tested in the immunosuppressed population
– Norovirus management:
· supportive care i.e., fluid and electrolyte replacement
· reduction in immunosuppression – this is the most effective strategy
– norovirus is key in the induction of posttransplant diarrhoea
– MMF plays a significant role in the chronicity of symptoms – it prevents viral clearance and intestinal epithelium repair
– chronic norovirus-related diarrhoea is a major concern, often results in discontinuation of MMF and this is associated with increased risk of rejection
– no norovirus vaccine available as yet
– prevention of norovirus infection (i.e., hand washing, environmental sanitization) is key since there is no specific treatment or vaccination available
– Diagnosis of Rotavirus:
· immune-based assays – routinely used to rapidly detect rotavirus antigens in stool
· cell culture, real time-PCR and electron microscopy – have high sensitivity and specificity, remain as reference methods
– Management of Rotavirus:
· mainly supportive, there are no anti-rotaviral therapies available
· contact precautions to prevent viral transmission – disinfect contaminated surfaces with 95% ethanol or other alcohol-based disinfectants since the general disinfectants e.g., bleaches are ineffective
· there are two live attenuated oral vaccines available i.e., RotaTeq and Rotarix, however, transplant candidates can only be vaccinated pre-transplant (avoid live vaccines in the posttransplant period)
– Diagnosis of Adenovirus: direct antigen detection, viral culture, histopathology, PCR
– viral culture is the gold standard but can take up to 28 days to develop cytopathic effects and the serotypes associated with diarrhoea do not grow well in cell culture
– the clinical utility of direct antigen detection methods in immunocompromise patients remains unknown
– Management of Adenovirus – there is limited data:
· supportive care
· reduction in immunosuppression
· contact and droplet precautions to help prevent infections
– DIDACT study,
· large prospective study, which evaluated a stepwise prospective diagnostic and therapeutic flow chart
· the aim was to treat infectious causes and eliminate non-immunosuppressive drug toxicity causative factors before modifying the immunosuppressive regimen
· 28% patients had infectious causes of diarrhoea, with campylobacter jejuni enteritis and CMV colitis being the most common
· diarrhoea resolved in 50% of the patients without any change in immunosuppressive therapy
· 30% of the patients diagnosed with bacterial overgrowth responded to antibiotics
· review the patient’s medications for potential causes of diarrhoea, stop any unnecessary drugs
· test for the different causes of diarrhoea: assess for ova and parasites, bacterial culture, PCR for CMV and C. difficile and stool lactoferrin, breath test for bacterial overgrowth, reduction in immunosuppression and colonoscopy
· if the above are negative and diarrhoea persists, give a trial of anti-diarrhoeal medications, probiotics, lactose-free diet
· OGD, colonoscopy with biopsies
· treatment of diarrhoea with hydration, focused use of antimicrobials or modulation of immunosuppressive agents is crucial
· optimization and modulation of immunosuppression in patients with persistent posttransplant diarrhoea remains debatable and warrants prospective studies
· the first change in immunosuppression consists of reducing MMF dose or switching to EC-MPS
· if symptoms persist then withdraw MMF-EC-MPS
Conclusion
– clinicians should be familiar with the various causes of posttransplant diarrhoea
– a directed/ systematic approach to diagnosis and treatment of posttransplant diarrhoea helps resolve the diarrhoea as well prevent life-threatening consequences like graft loss
– evaluate thoroughly for other potential causes of diarrhoea before implicating an immunosuppressive agent
– exclude infectious agents, use of other drug-related diarrhoea e.g., antibiotics, PPIs, diuretics
– prospective studies are needed to evaluate the prevalence, risk factors, complications, diagnosis, management, prevention, vaccine development of diarrhoea caused by rotavirus, norovirus and adenovirus-related diarrhoea
– development of vaccines and antiviral therapies for these common viruses will greatly improve patient and graft survival
Level of evidence provided by this article
– Level 5
◇ INTRODUCTION
● Chronic diarrhea after kidney transplantation is a common complaint
● Steatorrhea and malabsorption may result from severe and chronic posttransplant diarrhea and induce enteric hyperoxaluria
● Oxalate nephropathy is associated with inflammation and may have devastating effects on renal graft function
● Causes of diarrhea after transplantation:
☆ Infections
☆ Immunosuppressive drugs
☆ Antibiotics and other drugs.
◇ EPIDEMIOLOGIC IMPACT
☆ The cumulative incidence of diarrhea is 11.5, 17.5 and 22.6% at 1, 2 and 3 years after renal transplantation
☆ posttransplant diarrhea of unknown origin was associated with a two-fold increase in graft loss and risk of death
☆ Majority of the diarrheal episodes had no identifiable cause and were self-limited.
☆ The most common causes included:
* Clostridium difficile infection
* Norovirus infection
* CMV
* Gastrointestinal infection
◇ CAUSES OF DIARRHEA: GENERAL:
● Changes in immunosuppressive therapy (most commonly MMF) led to remission of diarrhea in about two-thirds of cases.
● The infectious cause of posttransplant diarrhea is present in approximately 50% of cases with CMV being the most common pathogen.
● The next most frequent cause is related to medication use
1). IMMUNOSUPPRESSIVE DRUGS
☆ Many immunosuppressive agents used
in transplantation may cause diarrhea, especially MMF.
☆ Dose reduction is followed by the decrease or the disappearance of diarrhea
☆ MMF and enteric-coated mycophenolate sodium (EC-MPS) have long been implicated in posttransplant diarrhea.
☆ The relative risk of diarrhea associated with use of MMF is 1.57 and mechanism is that growth and proliferation of gastrointestinal epithelial cells depends on the de-novo pathway of purine synthesis which inhibits by MPA leading to diarrhea
● Histologically
* predominant crypt distortion, inflammatory bowel disease like MPA-associated toxicity
* predominant apoptosis:
graft-versus host-like MPA- associated toxicity
● switch from MPA to AZA is usually avoided because of reduced graft survival with AZA as compared to MMF besides a significantly increased risk of skin cancer in relation to AZA exposure
● Tacrolimus associated with diarrhea in 29–64% depending on dose and duration by stimulation intestinal motilin receptors.
Most of these cases are mild course
● Conversion to a daily, extended release tacrolimus associated with a decrease in diarrhea
● Sirolimus causes diarrhea by jejunal villous atrophy with the promotility macrolide class of drugs
● ATG and OKT3 therapies are associated with diarrhea by releasing TNF which disrupts the intestinal mucosal barrier and resolves spontaneously
◇ CAUSE OF DIARRHEA: INFECTIONS
● After the first few months post-transplant, opportunist pathogens become more evident as a cause of infection.
● CMV and norovirus are important causes of diarrhea
● Chronic norovirus infection is one of the causes of post KTx with 94% of patients having chronic diarrhea and 81% having episodes of diarrhea-induced AKI with acute phase (nausea, vomiting, abdominal pain, fever,and 10-20 watery stools per day and a chronic phase ( cycles of normal stools followed by periods of poorly formed stools
● CMV is one of the most common infectious affecting SOT patients
● It’s most common target organ is the gastrointestinal tract
● 7.2% developed CMV disease, and of which one-third had GI involvement
● Risk factors for CMV disease include:
* (D+/R–) , (D–/R+)
* Lymphodepleting antibodies
● Rotavirus infections was diagnosed in 1.5% of SOT recipients especially in pediatric patients (63%) and liver transplant
● In adults, adenovirus (AdV) associated with GI symptoms in 10% of the cases.
● C. difficile is the most common cause of nosocomial diarrhea and accounts for most infectious diarrhea within the first months after transplantation
● The incidence of (CDI) is 3.5–4.5% in adult renal transplantation patients
● Risk factors include:
* Age above 55 years
* Use of ATG
* Retransplantation
* liver recipients
* Recent antibiotic use ( fluoroquinolones)
● CDI is an independent risk for death
● Among parasities, the protozoan are most common. Enterocytozoon bieneusi is the most frequent strain in KTRs
● Cryptosporidia are intracellular protozoans lead to diarrhea in KTRs
◇ DIAGNOSIS AND THERAPEUTIC
¤ Clostridium difficile
● Diagnosis by Real-time PCR with Sensitivity 85% and Specificity 77%
● 70% of patients will respond to metronidazole
● persistent and more severe cases will require oral vancomycin.
☆ First episode: metronidazole 500 mg three times per day for 10–14 days
☆ Severe disease:
* Vancomycin oral four times per day for 10–14 days
* Fidaxomicin 20 mg two times per day for 10 days
☆ First relapse: same for first episode
☆ Second relapse: vancomycin taper with pulse
☆ third relapse: consider fecal microbiota transplantation, prolonged oral vancomycin
● 20% of cases will have at least one relapse
● Fidaxomicin, ramoplanin and tigecycline are newer antibiotics that are effective for severe or recurrent disease
● New therapy :
☆ Human monoclonal antibodies against C. difficile toxins A and B
☆ Fecal microbiota transplantation (FMT) in the management of refractory CDI.
¤ Microsporidia-related diarrhea,
● Fumagilin may lead to sustained clearance of E. bieneusi but
thrombocytopenia limit it’s use
¤ Cryptosporidiosis
● Diagnosed by :
* visualization of oocysts in the stool.
* ELISA ( sensitivity and specificity 100%)
● No specific therapies directed toward cryptosporidium were exist.
¤ CMV disease
● The diagnosis
☆ PCR CMV in blood (sensitivity and specificity 91%)
☆ Serology (in new onset infections)
☆ Virus culture (lower sensitivity, long incubation period)
☆ Shell Vial Assay (low sensitivity)
☆ CMV pp65 Antigen Test in blood and CSF( sensitivity 83% and specificity 96%)
☆ Definitive diagnosis of CMV relies on endoscopic and histopathology (owl’s eye)
● Treatment :
Oral valganciclovir or IV ganciclovir in case of vomiting, diarrhea, or early CMV colitis
● Don’t stop CMV Treatment before :
☆ At least 2 weeks
☆ Resolved clinical symptoms
☆Undetectable viral load
☆ Because of recurrent CMV disease in SOT recipients secondary prophylaxis for 30–90 days with valGCV is recommended
¤ Norovirus
● Diagnosis by PCR on stool, vomitus, foods and environmental specimens
● Supportive care is the first treatment:
* Rehydration
*Antimotility drugs
* RI
* Replenishment of fluids and electrolytes
● Norovirus is the key factor in the induction of posttransplant diarrhea, whereas MMF plays a critical role in the chronicity of the symptoms
● No vaccines are available for norovirus
● prevention is essential by hand hygiene and environmental sanitization
¤ Rotavirus
● immune-based assay to detect antigens in stool is routinely used but culture, real time-PCR have high specificity and sensitivity
● Treatment is mainly supportive
● Prevention by contact precautions and disinfect surfaces by ethanol or alcohol
● Two live oral vaccines against rotavirus that should receive before transplantation
¤ Adeno Virus :
● Diagnosed by viral culture, direct antigen detection, histopathology and PCR
● Treatment
* Supportive care
* RI
● prevention by infectious control measures including contact and droplet precautions
● Treatment of diarrhea, with hydration and focused use of antimicrobials or changes in immune suppression, is of the
utmost importance.
● The first change in IS consists of :
* MMF dose reduction
* switching to EC-MPS
* MMF-EC-MPS with-drawal if symptoms persist
◇ CONCLUSION
● Common causes of posttransplant diarrhea should be familiar
● Diagnosis and treatment will prevent life-threatening consequences and loss of the
graft.
● Causes of diarrhea ( infections and non Immunosuppressive drug ) should be excluded before implicating IS drugs
● Development of effective vaccines and antiviral therapies will improve patient and graft survival.
◇ Level 5
Introduction:
Chronic diarrhea is common complain post renal transplantation and associated with fatigue, increased hospitalizations and negative impacts on recipient quality of life
It can also cause Steatorrhea and malabsorption which induce oxalate nephropathy that affect renal graft function.
The main causes of diarrhea after transplantation are infections, immunosuppressive drugs, antibiotics and other drugs
EPIDEMIOLOGIC IMPACT:
The cumulative incidence of diarrhea has been reported to be 11.5, 17.5 and 22.6% at 1, 2 and3 years postrenal transplantation, respectively
causes of diarrhea:
There are relatively little data regarding the cause of posttransplant diarrhea.
(DIDACT) study – was conducted to identify the cause of posttransplant diarrhea in renal transplant recipients
There is 50% of diarrhea resolution by treatment of infection or by discontinuation of immunosuppressive drugs
Causes of postrenal transplant diarrhea infection (50%) and noninfectious:
Infectious causes: bacteria, viruses (CMV most), parasites
Noninfectious causes: immunosuppressive and non immunosuppressive medications and other causes
Diagnosis and therapeutic strategies:
It is imperative to distinguish between infectious and noninfectious cause of diarrhea and consider graft function in adjusting immunosuppressive medications.
C.difficile:
Detected by cell based cytotoxicity assay but it cost instead we use CDI PCR with a sensitivity and specificity of 90%. Treatment includes: Flagyl, fidaxomicin or vancomycin with vancomycin being preferred in severe cases. for refractory cases we use: fidaxomicin, ramoplanin and tigecycline. Novel therapies; Human monoclonal antibodies against C.Difficile toxin A and B,Fecal Microbiodata transplantation. Fumagilin has good outcomes in treatment of microsporidia but we need to look out for thrombocytopenia.
Cryptosporidia:
It is diagnosed via IF,ELISA and oocyst visualization. It has no specific treatment.
CMV
It is diagnosed via CMV viremia and PCR. Endoscopic confirmation of owls eye inclusion or IHC staining for PP65.Viral inclusion though sensitive and gold standard is rare. Treatment either IV GCV or PO ValGCV. Treatment stopped if ;1- given for weeks 2-Resolution of clinical symptoms 3-viral load undetectable. ValGCV is recommended for secondary prophylaxis for 30 to 90 days post-transplant.
Norovirus
It is detected by PCR from stool, vomitus, foods and environmental specimens Treated by rehydration, electrolyte correction and reduction in immunosuppressive therapy. Prevention is key in managing norovirus.
Rotavirus:
It is diagnosed via immune based assays, cell culture and real time PCR. It is treated by supportive care with emphasis on preventive protocols. Vaccines available are; Rota teq and Rotarix which should be given pre transplant as they are live.
Adenovirus is detected by viral culture, direct antigen detection, histopathology and PCR. It is treated with supportive measures and reduction in immunosuppressive medications.
Indications for esophagogastroduodenoscopy + colonoscopy with biopsy in persistent diarrhea:
1. Intestinal ulceration from large bowel PTLD may have exudative enteropathy and chronic diarrhea.
2. CMV colitis with simultaneous Neg CMV PCR has been reported.
3. Severe duodenal villous atrophy may cause some medics to adjust immunosuppressive meds regardless of cause.
4. Post KTR de novo IBD occurs x10 in transplant population than the general population
Conclusion:
Physicians should be familiar with common causes that result in posttransplant diarrhea. A directed approach to diagnosis and treatment will not only help to resolve diarrhea, but also prevent potentially life-threatening consequences such as loss of the graft. Infectious agents and the concomitant use of other diarrhea genic medications such as proton-pump inhibitors, antibiotics and diuretics must first be excluded. Prospective studies are needed to better assess in kidney transplant patients the true prevalence, risk factors and complications of diarrhea by norovirus, rotavirus and AdV. Development of effective vaccines and antiviral therapies for these common viruses will likely improve patient and graft survival
This a narrative review level of evidence: 5
Causes and management of postrenal transplant diarrhea: an underappreciated cause of transplant-associated morbidity
Overall incidence:
The cumulative incidence of diarrhoea has been reported to be 11.5, 17.5 and 22.6% at 1, 2 and 3 years post renal Tx. Half of diarrheal episodes results from infection with CMV being one of the common causes
CAUSES OF DIARRHEA:
Non infections:
INFECTIONS
MMF related:
Relative risk of diarrhea associated with the use of MMF is 1.57
mechanism GI epi cells may be partially dependent on the de-novo pathway of purine synthesis for growth and proliferation, therefore vulnerable to Mycophenolic acid (MPA) inhibition leading to diarrhea
Types:
a) IBD like MPA-associated toxicity: predominant crypt distortion
b) GVH like MPA-associated toxicity: predominant apoptosis
Management:
Decrease MMF dose by 50%
Shifting from MMF to enteric coated mycophenolate (debatable)
Shifting from MMF to azathioprine (not preferable due to reduced graft survival and higher skin cancer incidence)
TAC realted:
Incidence: 30-60 % of cases depending upon the dose and duration of drug usage
Mechanism: it may stimulate intestinal motilin receptors, but it is usually mild, self-limited, and not require drug discontinuation.
Management: Shift to extended release (advagraf) or switch to ciclosporin
Close follow up of CN level as there may be an increase in tacrolimus level with diarrhea due to disruption of P-glycoprotein efflux pump in the damaged enterocytes.
mTOR:
Incidence: 14-40 % of cases
Mechanism: jejunal villous atrophy
Management: self-limited or switch to CNI
ATG:
Incidence: 1/3 patients
Mechanism: ATG can activate T cells to release TNF which then interferes with Na ion absorption and disrupts the intestinal mucosal barrier.
Management: self-limiting lasts 3 days
Management.
self limited, supportive care
If non infection cause and last more than 2 weeks, can give loperamide
Clostridium difficile
First episode: Metronidazole 500mg TDS for 14 days
Severe disease: Vancomycin PO QID for 14 days or Fidaxomicin 20mg BID for 10 days.
First relapse: same for 1st episode
Second relapse: Vancomycin taper with pulse
Third relapse: Consider fecal microbiota TX (FMT), prolonged oral vancomycin.
CMV: Oral valganciclovir, IV ganciclovir (if decreased absorption)
Microsporidia-related diarrhea:: Fumagillin may lead to sustained clearance with minimal IS reduction.
Norovirus, Adenovirus, cryptosporadium: supportive
INTRODUCTION
Post-renal transplant diarrhea have worse serious effects on renal transplant recipient starting from fatigue, increased hospitalizations, bad quality of life, less graft survival and higher mortality.
Certain predisposing features for the development of post-transplant diarrhea in this population as generalized immunosuppressed state besides the exposure to polypharmacy commonly broad-spectrum antimicrobial therapy.
Aetiology of post renal transplant diarrhea could be infections, immunosuppressive drugs, antibiotics and other drugs. The cumulative incidence of diarrhea was estimated by 11.5, 17.5 and 22.6% at 1, 2 and 3 years after renal transplantation.
One large retrospective study, posttransplant diarrhea of unknown origin (noninfectious) was strongly linked to a two-fold increase in graft loss and risk of death.
CAUSES OF DIARRHEA:
A large famous prospective study recognized as the Diarrhea Diagnosis Aid and Clinical Treatment (DIDACT) study concerned by identification of the cause of posttransplant diarrhea in renal transplant recipients. The most important data revealed by this study are two constant points; first the commonly encountered infectious cause of posttransplant diarrhea in about 50% of cases was CMV while the second culprit was related to medication use the highest incidence was associated with MMF.
The mechanism of MMF-induced diarrhea remains unknown. Postulations included defective purine synthesis within the gastrointestinal epithelial cells that may be partially dependent on the de-novo pathway for growth and proliferation. The need to switch of immunosuppression from MMF to EC-MPS to aid reducing diarrhea symptoms is still debatable.
Furthermore, a short-term approach adopted in some situations involved the switch from MPA to azathioprine (AZA) keeping in mind the reported data concerned by the reduced graft survival with AZA when compared to MMF.
The fact proved by the U.S. Renal Transplant Scientific Registry that MMF reduced the relative risk of graft loss by 27% (P<0.001) and the improvement of recorded Death-censored graft survival at 4 years was significantly better among MMF-treated versus AZA-treated patients.
Tacrolimus also may be associated with diarrhea in 29–64% of patients depending upon the dose and duration of drug usage. The proposed theory that its macrolide structure may result in stimulation of the intestinal motilin receptors. The incidence of diarrhea already declined with the conversion to a daily, extended release formulation of tacrolimus.
Sirolimus causes self-limiting diarrhea in 14–42% of treated patients. The drug-induced jejunal villous atrophy and a structural homology with the promotility macrolide class of drugs have been suggested.
Also, up to one-third of patients when antithymocyte globulin (ATG) and anti–T cell antibody (OKT3) were administered both have been associated with diarrhea characterized by spontaneous resolution after 3–4 days. The possible mechanism was attributed to the T cells activation followed by release of tumor necrosis factor that interferes with sodium ion absorption subsequently with further disruption of the intestinal mucosal barrier.
Regarding the infectious causes of diarrhea in SOT worldwide, the literature describes a wide range of organisms as norovirus, enteropathogenic bacteria C. difficile and CMV. Chronic norovirus infection was found to be responsible for 17–26% of severe post-transplant diarrhea. The course of norovirus infection becomes even more complicated with up to 94% having chronic diarrhea besides 81% having episodes of diarrhea-induced acute renal failure.
The initial acute phase presentation in the form of classic illness with nausea, vomiting, significant diarrhea (10–20 watery stools per day), with abdominal pain and sometimes fever then followed by chronic diarrhea.
CMV is one of the most common infectious complications affecting SOT patients especially the CMV gastrointestinal disease. A famous recent study of 1427 SOT patients documented the development of CMV disease in 7.2%; approximately one-third of the population had gastrointestinal involvement. Risk factors for CMV disease are known to be higher in seronegative recipients of seropositive organs (D+/R–), lymphodepleting antibodies and more potent immunosuppressive protocols.
The rotavirus infections is recently more recognized in both pediatric and adult SOT patients with more severe course documented in 1.5% higher in liver transplant pediatric patients about (63%).
C. difficile is the most common cause of nosocomial diarrhea particularly within the first months post transplantation of prevalence 3.5–4.5%. Risk factors included age above 55 years, along with the use of ATG, retransplantation and the type of organ transplanted (more in the liver recipients).
CDI has a significant effect on mortality of SOT recipients, of reported mortality rates between 2.3 and 8.5% counted then as an independent risk for death (adjusted odds ratio 2.48, 2.22–2.76).
Parasitic infestations as microsporidia, Enterocytozoon bieneusi and Cryptosporidium (Cryptosporidia parvum and Cryptosporidia hominis) are the most encountered ones.
DIAGNOSIS AND THERAPEUTIC STRATEGY
C. difficile detection can be done by fecal enzyme immunoassays or real-time PCR test being more sensitive and specific in 90% CDI cases. About 70% of patients will respond to metronidazole while persistent severe cases will require oral vancomycin. It is to be considered that 20% of cases will experience at least one relapse in which the next lines as Fidaxomicin, ramoplanin and tigecycline are known to be effective for the treatment of severe recurrent cases. The use of human monoclonal antibodies against C. difficile toxins A and B as fecal microbiota transplantation (FMT) in the management of refractory CDI has started a new era, yet the data is still limited.
Cryptosporidiosis is diagnosed by visualization of oocysts in the stool until the development of immunofluorescent assays and ELISA which was proved to of higher sensitivity and specificity almost 100%. Nitazoxanide and paromomycin are the lines of treatment. While cases of microsporidia-related diarrhea, treatment is via fumagilin.
Tissue invasive CMV disease is considered after the detection of CMV viremia based on blood PCR. CMV is confirmed on histopathology with characteristically swollen cells containing ‘owl’s eye’ intranuclear inclusions, or by immunohistochemical staining for pp65 antigen.
Despite it is the ‘gold standard’ for the diagnosis of CMV active disease, viral inclusions cannot be easily seen as they are very rare. Management of these cases is primarily by intravenous ganciclovir or oral valganciclovir. Optimal duration of antiviral therapy is mainly according to the patient’s clinical and virologic responses for at least 2 weeks after clinical symptoms have resolved and viral load is no longer detected. CMV disease has been documented to be recurrent in 15–35% of SOT recipients with tissue-invasive CMV disease that led to the recommendation of secondary prophylaxis for 30–90 days after successful treatment.
Supportive care is the first line of treatment with higher priority directed to replenish fluids and electrolytes. The most adopted effective strategy is to reduce immunosuppression as MMF has a crucial role in the chronicity of the symptoms by preventing both the clearance of the virus and the repair of intestinal epithelium.
Currently no vaccines are available for viral pathogens apart from two live oral vaccines against rotavirus which are live attenuated vaccines that must be administered prior to transplantation.
The need to perform esophagogastroduodenoscopy and colonoscopy with biopsies to investigate persistent diarrhea post transplantation are rendered to severe undiagnosed nonresponsive cases. Situations of intestinal ulcerations owing to large bowel post-transplant lymphoproliferative disorder may be the aetiology presented by exudative enteropathy and chronic diarrhea. Patients suspected to have severe duodenal villous atrophy may prompt clinicians to change the immunosuppressive regimen. Post transplantation de-novo inflammatory bowel disease occurs up to 10 folds more frequently than general population.
CONCLUSION
Prospective studies are more required to assess in kidney transplant patients in terms of the true prevalence as well as risk factors to provide the best preventative plans for SOT population.
Development of effective vaccines and antiviral therapies for these common viruses will provide better patient and graft survival.
Level of evidence is V.
II. Causes and management of postrenal transplant diarrhoea: an underappreciated cause of transplant-associated morbidity
Please summarise this article.
Chronic diarrhea after kidney transplantation is a common presenting problem .
This diarrhea is usually associated with fatigue, high rate of hospitalizations and poor quality of life.
And may lead to malabsorption .
In kidney transplantation there are many risk factors predisposing to this complication which include a 1- generalized immunosuppression.
2- polypharmacy, most notably broad-spectrum antimicrobial therapy.
The main causes are
1- Infections.
2- immunosuppressive drugs.
3- antibiotics and other drugs.
Epidemiology
The cumulative incidence of diarrhea is 11.5, 17.5, & 22.6% at 1, 2, & 3 years post-KTX, respectively (UNOS registry).
Participant based data report incidence as much as 53% in kidney transplant . but the doctors’ based data shows the prevalence of about 6.9%. this show large percent of missed attacks of post transplant diarrhea.
Most of the diarrheal events are self-limited & lack a known cause. The most frequent causes were CMV GI infection, norovirus infection, & Clostridium difficile infection.
Causes
50% of diarrhea result from infection with CMV being one of the common causes.
Immunosuppressive medications which is common with MMF which resolves with dose reduction or stopping it completely.
CNI, MTORs and ATG have also been associated with diarrhea with unclear mechanisms.
Infection;
Common infections are :
CMV
Norovirus
C.difficile
Mostly occurs after 1st few months when they are immunosuppressed.
Chronic norovirus has emerged as a common cause of diarrhea that was initially underestimated with a biphasic illness- acute and chronic.
CMV is common but with a predilection to GI involvement, risk factors; D+/R- pair, D-/R+ pair, lymphocyte depleting agents and more potent immunosuppressive medications.
Recent antibiotic use is strongest risk factor for CDI with fluoroquinolones being associated with highest risk.
Rotavirus infections:
occur in 1.5% of SOT recipients.
Adenovirus:
is common in early posttransplant course (isolated in 6.5–22.5% of cases).
Viremia in the 1st few months post-TX (6.5–22.5%), & GI symptoms occur in 10%.
Microsporidia
Cryptosporidium (Cryptosporidium parvum & Cryptosporidium hominis).
Diagnosis
C. difficile detection is the cell-based cytotoxicity assay.
most laboratories use the easier, less expensive and more rapid fecal enzyme immunoassays or real-time PCR test.
These tests have high sensitivity and specificity (90%) for the detection of CDI.
Transplanted patients can be asymptomatic carriers of C. difficile, but most often they develop diarrhea, intestinal obstruction, abscesses or toxic megacolon.
Treatment of SOT includes fidaxomicin, metronidazole 70% respond to treatment or vancomycin,
vancomycin better for more severe infection.
-The greatest challenge for toxigenic Clostridium infections remains the prevention and treatment of relapsing and refractory forms.
In transplant recipients, it has been estimated that up to 20% of cases will have at least one relapse.
-Fidaxomicin, ramoplanin and tigecycline are newer antibiotics that are effective for the treatment of severe or recurrent disease.
A newer area of interest is the use of fecal microbiota transplantation (FMT) in the management of refractory CDI.
The recent availability of fumagilin has been a major breakthrough in the treatment of microsporidia-related diarrhea, treatment that may lead to sustained clearance of E. bieneusi, with minimal reduction in immunosuppression.
CMV disease:
The diagnosis of tissue-invasive CMV disease is suggested by the presence of CMV viremia. Many patients with CMV colitis will have evidence of CMV replication in the blood via PCR, although approximately 15% will not.
Management with intravenous ganciclovir (GCV) or oral valganciclovir (valGCV).
Optimal duration of antiviral therapy depends on the patient’s clinical and virologic responses, not on a fixed period.
Before antiviral therapy is stopped, the following three criteria should be met: the treatment was given for at least 2 weeks, clinical symptoms have resolved and viral load is no longer detectable, if initially detected.
Because recurrent CMV disease has been reported in 15–35% of SOT recipients with tissue-invasive CMV disease, many experts recommend the use of valGCV for secondary prophylaxis for 30–90 days after successful treatment.
Norovirus:
Diagnosis of norovirus by PCR can be run on stool, vomitus, foods and environmental specimens.
Supportive care is the first line with IV fluids and correction of electrolytes.
The most effective management of norovirus infection is to reduce immunosuppression.
It is important to know that norovirus is the key factor in the induction of posttransplant diarrhea, whereas MMF plays a critical role in the chronicity of the symptoms by preventing both the clearance of the virus and the repair of intestinal epithelium.
Till now no vaccines are available for norovirus, although several candidate vaccines are under investigation.
Because of the lack of specific treatment or vaccination, prevention plays an especially important role in norovirus infection control, especially hand hygiene and environmental sanitization.
Rotavirus:
Immune-based assays is most use in diagnosis of rotavirus, used to rapidly detect rotavirus antigens in stool samples.
Other diagnostic methods such as cell culture, real time-PCR and electron microscopy remain as reference methods because of their high specificity and sensitivity.
Currently, no anti-rotaviral therapies are available, and the treatment of rotavirus infection in SOT patients is mainly supportive.
Contact precautions are recommended to prevent viral transmission.
Contaminated surfaces should be disinfected by 95% ethanol or other alcohol-containing disinfectant, because general disinfectants (e.g. bleach) are ineffective.
In the United States, two live oral vaccines against rotavirus currently are licensed for use: RotaTeq (RV5) and Rotarix (RV1).
Because both vaccines are live attenuated vaccines, transplant candidates should receive the vaccines before transplantation; their use posttransplant is contraindicated.
Adenovirus:
Adenovirus can be diagnosed by viral culture, direct antigen detection, histopathology and PCR.
Although culture has traditionally been considered the gold standard for diagnosing AdV, it may take up to 28 days to develop cytopathic effects, and serotypes associated with diarrhea do not grow well in cell culture.
Limited data are available on the optimal treatment of AdV infections.
-Generally, diarrhea caused by AdV can be managed with supportive care and a reduced immunosuppressive regimen.
Diligent infectious control measures, including contact and droplet precautions, can help prevent infections in the SOT population.
Conclusion;
A directed approach to diagnosis and treatment will not only help to resolve diarrhea, but also prevent potentially life-threatening consequences such as loss of the graft.
Meticulous evaluation for possible causes of diarrhea Prior to implicating an immunosuppressant medication as the culprit.
Infectious agents and the concomitant use of other diarrhea genic medications such as proton-pump inhibitors, antibiotics and diuretics must first be excluded .
Prospective studies are needed to better assess in kidney transplant patients the true prevalence, risk factors and complications of diarrhea by norovirus, rotavirus and AdV.
Development of effective vaccines and antiviral therapies for these common viruses will likely improve patient and graft survival.
What is the level of evidence provided by this article?
Level V.
This review highlights the current literature on both infectious and noninfectious diarrhea in renal transplant recipients and provides a diagnostic algorithm for the evaluation of posttransplant diarrhea.
The main causes of diarrhea after transplantation are infections, immunosuppressive drugs, antibiotics and other drugs.
Renal transplant recipients share certain predisposing characteristics, such as a generalized immunosuppressed state and exposure to polypharmacy, most notably broad-spectrum antimicrobial therapy.
Prospective studies are needed to better assess true prevalence, risk factors and complications of diarrhea by norovirus, rotavirus and adenovirus in kidney transplant patients.
This article discusses the extent to which posttransplant diarrhea is often under-recognized by practitioners.
It found that 53% of participants reported diarrhea, whereas the incidence estimated by their physicians was only 6.9%.
A recent study from a single transplant center in the United States reviewed the diagnostic yield of tests for diarrhea among hospitalized transplant recipients over a period of 18 months and found that the majority of the diarrheal episodes had no identifiable cause and were self-limited.
Chronic diarrhea after kidney transplantation has negative impacts on the recipient’s quality of life, graft survival and mortality.
Noninfectious diarrhea is a major problem as many immunosuppressive agents commonly used in transplantation may cause diarrhea, with the highest incidence associated with MMF.
It is important to diagnose the cause of diarrhea and make a distinction between noninfectious and infectious causes of diarrhea in kidney transplant recipients.
Antithymocyteocyteglobulin (ATG) and anti-T cell antibody (OKT3) therapies are both associated with diarrhea, which lasts for 3-4 days and resolves spontaneously.
Posttransplant diarrhea is a common infectious complication affecting SOT patients, with up to 94% having chronic diarrhea and 81% having episodes of diarrhea-induced acute renal failure.
Risk factors for CMV disease include seronegative recipients of seropositive organs (D+/R–), lymph depleting antibodies and more potent immunosuppressive regimens.
The incidence of C.difficile infection (CDI) in transplanted patients has been reported to be 3.5-4.5% in adult renal transplantation patients.
Risk factors include age above 55 years, use of ATG, retransplantation and the type of organ transplanted.
Recent anti-biotic use is the single most important risk factor for CDI, with fluoroquinolones being associated with the highest risk.
metronidazole & oral vancomycin is the 1st lines of management.
supportive management , good hydration & reduction of immunosuppression is the most importatnt
CMV associted colitis , diagnosed by CMV PCR with findings in endoscope , ttt by IV gancyclovir for at least 2 weeks , followed by oral valgancyclovir prophylaxis for 3 months.
reduction of immunosuppression include :
1-reduction of the dose of MMF or shift to enteric coated MFS or switch to AZA if reduction of MMF >50 %.
2- tacrolimus dose reduction or switch to cyclo , monitor drug trough level (5-8)
3-switch between mTORi & cyclo.
Prospective studies are
needed to better assess in kidney transplant patients
the true prevalence, risk factors and complications
of diarrhea by norovirus, rotavirus and AdV. Such
studies will help guide the care of these patients and
provide appropriate prevention and prompt management.
level of evidence :
level 5 , a narrative review
Epidemiology
Causes of diarrhoea
Non-infectious
1) Immunosuppression: most commonly with MMF, others are Tac, CSA and sirolimus
2) Non-immunosuppression medications:antibacterial, antiarrythmias, antidiabetic, laxatives, PPI
3) Others: Primary GI diagnosis (IBD, malabsorption), malignancy (colon ca, PTLD)
Infectious
1) Bacterial (C.diff, Compylobacter, Salmonella, E.Coli, Aeromonas and bacterial overgrowth)
2) Viruses (CMV, Norvovirus, Sapovirus, Rotavirus, Adenovirus)
3) Parasite (Giadia, entameoba, Crytosporadium, Isospora, Microsporadium)
Diagnosis
1) Detection of Clostridium difficile- fecal enzyme immunoassays or real-time PCR
2) Stool culture (isolated bacterial agents)
3) Stool ova and cyst (parasitic infection- cryptosporidiosis)
4) CMV PCR, tissue culture/colonoscopy
5) Stool PCR for norovirus
6) Multiplex PCR-based screening for enteric pathogen
Management
Immunosuppression reduction, switch MMF to EC MPS, switch MMF to Aza
Treat conservatively- hydration
Treat according to causative agents
1) Clostridium difficile- metronidazole, vancomycin, others-fidaxomicin, ramoplanin, tigecycline, fecal microbiota transplantation
2) Microsporadia – fumagilin
3) CMV- Intravenous ganciclovir/ oral valganciclovir
Introduction
Chronic diarrhea after kidney transplantation is a common presenting problem .
This complication usually associated with fatigue, high rate of hospitalizations and poor quality of life.
In kidney transplantation there are many risk factors predisposing to this complication which include a 1- generalized immunosuppressed state
2- polypharmacy, most notably broad-spectrum antimicrobial therapy.
The main causes are
1- Infections.
2- immunosuppressive drugs.
3- antibiotics and other drugs.
This study review the current literature regarding both infectious and noninfectious diarrhea in renal transplant recipients and provide a diagnostic algorithm for the evaluation of posttransplant diarrhea
Epidemiology
The cumulative incidence of diarrhea is 11.5, 17.5, & 22.6% at 1, 2, & 3 years post-KTX, respectively (UNOS registry).
Participant based data report incidence as much as 53% in kidney transplant . but the doctors’ based data shows the prevalence of about 6.9%. this show large percent of missed attacks of post transplant diarrhea.
Most of the diarrheal events are self-limited & lack a known cause. The most frequent causes were CMV GI infection, norovirus infection, & Clostridium difficile infection.
Important points :
· Chronic diarrhea after kidney transplantation has negative impacts on the recipient’s quality of life, graft survival and mortality.
· It is important that clinicians evaluate and attempt to diagnose the cause of diarrhea and make a distinction between noninfectious and infectious causes of diarrhea in kidney transplant recipients.
· Prospective studies are needed to better assess the true prevalence, risk factors and complications of diarrhea by norovirus, rotavirus and AdV in kidney transplant patients.
Causes of posttransplant diarrhea
Infection Noninfection
Bacteria Immunosurpressive medications
Clostridium difficilea MMFa
Campylobacter spp. Tacrolimus
Salmonella spp. Cyclosporine
Bacterial overgrowtha Sirolimus
Aeromonous spp.
Escherichia coli
Viruses Nonimmunosuppressive medications
CMVa Antibacterial
Norovirus Antiarrhythmic
Sapobavirus Antidiabetic
Rotavirus Laxatives
Adenovirus Proton pump inhibitors
Protease inhibitors
Parasitic Other
Giardia GVHD
Cryptosporidium PTLD
Isosopora Cyclospora IBD
Microsporidium Colon cancer
Entameoba Malabsorption
Microscopic colitis
Malakoplakia
Causes:
Simply classified in to two group :
either infectious or none infectious .
1- Infectious etiology : ( common cause are CMV and Clostridium difficile)
Ø Viral: CMV (most common), Norovirus, Rotavirus, Adenovirus, Sapobavirus
Ø Bacterial: Clostridium difficile, Campylobacter, Salmonella, E coli, Bacterial overgrowth.
Ø Parasitic: Cryptosporidium, Giardia, Isosopora Cyclospora, Microsporidium and Entameoba.
2- None infectious etiology :
a- Drug induced:
Immunosuppressive drugs (MMF mainly, CNI and MTORi).
Others (laxatives, anti-diabetics, PPI, antiarrhythmic drugs).
b- Other disorders:
GVHD, IBD, PTLD, cancer colon, malabsorption and microscopic colitis .
The important step is is to determine the cause , as reduction of IS when drug induced diarrhea is suspected. May end by AR and graft loss and also the delay in diagnosing the microbial cause of infectious diarrhea can lead to poor patient and graft outcome.
The mechanism of MMF-induced diarrhea remains unknown. One possible mechanism is that gastrointestinal epithelial cells may be partially dependent on the de-novo pathway of purine synthesis for growth and proliferation, and are therefore vulnerable to Mycophenolic acid (MPA) inhibition leading to diarrhea.
The use of tacrolimus may be associated with diarrhea in 29–64% of patients depending upon the
dose and duration of drug usage . The mechanism by which calcineurin inhibitors cause diarrhea
remains unclear, although it is hypothesized that a macrolide structure may result in stimulation
of the intestinal motilin receptors. Most of the tacrolimus-associated gastrointestinal side-effects
have a mild course and rarely require drug discontinuation
Sirolimus causes self-limiting diarrhea in 14 – 42% of treated patients. The mechanism by which sirolimus causes diarrhea is poorly understood, although drug-induced jejunal villous atrophy and a structural homology with the pro motility macrolide class of drugs have been proposed as possible explanations.
In up to one-third of patients, antithymocyte globulin (ATG) and anti–T cell antibody (OKT3)
therapies are both associated with diarrhea, which predictably lasts for 3–4 days and resolves spontaneously.
Diagnosis and therapeutic strategy :
It is important to differentiate between the infectious and non-infectious etiology to avoid unnecessary immunosuppressive drug dose reductions.
C.difficile – cell based cytotoxicity assay, fecal enzyme based immunoassay and real time PCR . Treatment is with
First episode: metronidazole 500mg three times per day for 10–14 days
Severe disease : vancomycin oral four times per day for 10–14 days
fidaxomicin 20mg two times per day for 10 days
First relapse: same for first episode
Second relapse: vancomycin taper with pulse
third relapse: consider fecal microbiota transplantation, prolonged oral vancomycin
CMV-
Diagnosis : endoscopic evidence of GIT involvement- Owl eye intranuclear inclusions and IHC staining for pp65.
Treatment :
Cytomegalovirus Oral valganciclovir
IV ganciclovir (if any concern for decreased absorption)
Optimal duration is dependent on patient’s clinical and virological response :
1- at least 2 weeks .
2- Become a symptoms .
3- The viral load should not be detectable – negative PCR .
Because of risk of recurrence, CMV prophylaxis for 30-90 days after treatment of tissue invasive disease is recommended.
Noravirus – It is the key factor in the induction of post transplant diarrhea.
Diagnosis: PCR ( stool, food and vomitus) .
Treatment:
1- supportive care with fluid and electrolyte replacement.
2- immunosuppressive reduction.
Prevention : hand hygiene and environmental sanitization.
Rotavirus-
Diagnosed : immune assay.
Treatment : mainly supportive.
Prevention : live attenuated, contraindicated in post-transplant period.
Adenovirus-
diagnosed ; culture, antigen detection, PCR and histopathology.
Management :
1- supportive
2- reduction of immunosuppression
CONCLUSION
Physicians should be familiar with common causes that result in posttransplant diarrhea. A directed approach to diagnosis and treatment will not only help to resolve diarrhea, but also prevent potentially life-threatening consequences such as loss of the graft. Prior to implicating an immunosuppressant medication as the culprit, a meticulous evaluation for other possible causes of diarrhea should always
be conducted. Infectious agents and the concomitant use of other diarrhea genic medications such as
proton-pump inhibitors, antibiotics and diuretics must first be excluded. Prospective studies are
needed to better assess in kidney transplant patients the true prevalence, risk factors and complications
of diarrhea by norovirus, rotavirus and AdV. Such studies will help guide the care of these patients and provide appropriate prevention and prompt diagnosis.
Development of effective vaccines and antiviral therapies for these common viruses will likely improve patient and graft survival.
This a narrative review level of evidence : 5
Causes and management of postrenal transplant diarrhoea: an underappreciated cause of transplant-associated morbidity
Summarise.
Introduction.
Epidemiologic Impact.
Causes.
Diagnosis and therapeutic strategies.
Level of evidence; 5
Please summarise this article?
Introduction
Post-transplant diarrhea is common affecting nearly one fourth of transplant recipients.
Chronic diarrhea after transplantation is common and associated with increased morbidity, hospitalization, allograft loss and poor quality of life.
Steatorrhea and malabsorption can lead to secondary enteric hyperoxaluria with subsequent oxalate nephropathy (intense inflammation of allograft). Diarrhea is defined as > 3 loose stool/day. Persistent (>2 weeks) and chronic (> 1month)
The Quality of life, graft survival and mortality are all negatively impacted by chronic diarrhea post-transplant. Transplant physician must assess the diarrhea in Transplant recipients, try to determine its source and differentiate between infectious and non-infectious causes of diarrhea.
Epidemiology.
The cumulative incidence of diarrhea is 11.5, 17.5, and 22.6% at 1-, 2-, and 3-years post-Kidney transplant, respectively (UNOS registry). Yet, 53% of participants in a large survey of Kidney transplant recipients reported having diarrhea, despite their doctors’ estimates of the prevalence being only 6.9%. This finding shows how frequently post-TX diarrhea goes undiagnosed by healthcare professionals. Most of the diarrheal events are self-limited & lack a known cause. The most frequent causes were CMV GI infection, norovirus infection, & Clostridium difficile infection.
Causes of post-transplant diarrhea.
Data from the DIDACT study; Diarrhea resolved in 50% of patients either by cessation of diarrhea associated non-IS drugs or by the treatment of concurrent infections (mostly Campylobacter or CMV). In the remainders, changes in IS therapy (mostly MMF) led to remission in 2/3 of cases. CMV was the most prevalent infection\ etiology of post-TX diarrhea was found in 50% of cases. Medication use is the 2nd most common reason.
Causes Of Infectious Diarrhea Post-Kidney transplant.
The most common identifiable causes include clostridium difficile infection, norovirus infection, CMV infection and drug induced.
Bacteria such as clostridium deficile is the most common cause of nosocomial diarrhea and accounts for most infectious diarrhea in the 1st months post-Transplant,
Clostridium deficile infection occurs in 3.5–4.5%, most common nosocomial infection in 1st month posttransplant, more common in age > 55 years, use of ATG, re-TX, liver transplant and with use of broad-spectrum antibiotics as quinolones, it is associated with 2.3-8.5% risk of mortality. It can lead to diarrhea, intestinal obstruction, abscesses, or toxic megacolon.
CMV is the most important risk factor for CMV disease is D+/R– GI involvement (40% of patients). Other risk factors are D+/R–status, lymphodepleting antibodies & more potent IS regimens. Viruses such as CMV, adenovirus, norovirus, rotavirus, and sapovirus.
Norovirus:
Has 2 phases: acute phase; presented with nausea, vomiting, significant diarrhea (10–20 watery stools per day), abdominal pain and sometimes fever. Then followed by a chronic phase; (cycles of relatively normal stools followed by periods of poorly formed stools). Lately, chronic norovirus infection has become one of the most common infectious causes (17–26% of cases). This suggests that many infectious causes of diarrhea may have previously been misdiagnosed as being caused by IS medications, resulting in inappropriate diagnostic & treatment approaches.
Rotavirus infections:
occur in 1.5% of SOT recipients.
Adenovirus:
is common in early posttransplant course (isolated in 6.5–22.5% of cases).
Viremia in the 1st few months post-TX (6.5–22.5%), & GI symptoms occur in 10%.
Microsporidia
Cryptosporidium (Cryptosporidium parvum & Cryptosporidium hominis).
Diagnostic work up should include;
Review all medications and stop unnecessary ones.
A- Routine investigations;
Renal function tests and electrolytes
Complete blood count, c reactive protein
Stool analysis
B- Searching for the cause;
CNI level, CMV PCR, Stool culture and CD toxin in stool, and parasitic infection (Cryptosporidium, Entamoeba histolytica, Giardia lamblia, Campylobacter, Shigella, Salmonella, Vibrio, Yersinia enterocolitica, adenovirus and sapovirus), enzyme immunoassay for giardia and cryptosporidium and breath test for bacterial overgrowth.
Clostridium diff. infection:
Cell-based cytotoxicity assay is the gold standard test
Real-time PCR tests or fecal enzyme immunoassays (simpler, less expensive, & faster) are commonly used.
Tissue-invasive CMV disease:
CMV viremia is suggestive of the diagnosis.
Laboratory tests include biopsy, CMV IgM & or elevation in IgG, conventional culture, Shell Vial assay, CMV pp65 Ag, PCR, & Real-time PCR.
Norovirus:
Diagnosed by PCR run on stool, vomitus, foods & environmental specimens.
Rotavirus:
Immune-based assays rapidly detect rotavirus antigens in stool.
Adenovirus:
Diagnosed by viral culture, direct antigen detection, histopathology & PCR.
Cryptosporidiosis:
Oocysts in the stool
Modified acid-fast stains.
IF assays & ELISA (100% sensitivity & specificity)
Imaging, Colonoscopy and Biopsy:
may be needed if there is suspicious of malignancy, IBD or CMV colitis with negative PCR (15% of cases will have CMV PCR negative
If these tests are negative & the diarrhea persists, empiric anti-diarrheal medications, probiotics &/or lactose-free diet tried.
Non-infectious causes of diarrhea
Immunosuppression drugs (MMF mainly, CNI and mTORi). Others as (laxatives, anti-diabetics, PPI, anti-arrhythmic drugs).
Mechanism of MMF induced diarrhea: It inhibits de-novo pathway of purine synthesis essential for growth, Proliferation, and generation of enterocytes.
Treatment of MMF induced or associated diarrhea requires either:
Shift from MMF to EC-MPS that may be beneficial, or Short-term conversion to AZA (while long term graft outcome is lower with AZA than MMF in addition to higher risk of skin cancer).
MMF has the highest prevalence (RR 1.57), & numerous IS medications frequently used in TX may cause diarrhea. Dose reduction is generally followed by a decline or cessation of diarrhea. It is unclear how MMF causes diarrhea.
It’s debatable whether switching from MMF to EC-MPS helps lessen symptoms of diarrhea. According to a recent RCT, patients who switch from MMF to EC-MPS may have a marginally but significantly higher likelihood of returning to the target MPA levels than those who stay on MMF.
Switch from MPA to AZA is usually avoided because of risk of reduced graft survival with AZA versus MMF.
Mechanism of TAC induced diarrhea:
It occurs in 30-60 % of cases, it may stimulate intestinal motilin receptors, but it is usually mild, self-limited, and not require drug discontinuation. Shift to extended release (advagraf) may be beneficial.
mTORi induced diarrhea:
It occurs in 14-40 % of cases, it is related to jejunal villous atrophy, it is usually self-limited.
ATG induced diarrhea:
Use of ATG can activate T cells to release TNF which then interferes with Na ion absorption and disrupts the intestinal mucosal barrier.
Both ATG & OKT3 can cause diarrhea in 1/3 of patients; this diarrhea is self-limiting (lasts 3–4 d).
Others including, GVHD (graft versus host disease), IBD, malabsorption, and microscopic colitis).
Malignancy such as cancer colon, PTLD
Management.
In most cases, the cause is not identified, and diarrhea is self-limited. Supportive therapy including intravenous fluids for treatment of dehydration. Symptomatic therapy including loperamide to decrease bowel motions which is indicated in persistent (> 2 weeks) or chronic diarrhea (> 1 month)
Modulation and monitoring of immunosuppression.
Reduction of immunosuppression in the form of reducing the dose of MMF by 50% after estimation of the rejection risk and keeping low target trough for CNI (5-8 ng/ml)
Shifting from MMF to enteric coated mycophenolate (debatable)
Shifting from MMF to azathioprine (not preferred due to reduced graft survival, increased risk of rejection and increased risk of skin cancer associated with azathioprine use)
Switching from tacrolimus to extended released formulation or to cyclosporine.
Switching from sirolimus to CNI since around 14-41 % of cases taking sirolimus experienced diarrhia. Close follow up of CN level as there may be an increase in tacrolimus level with diarrhea due to disruption of P-glycoprotein efflux pump in the damaged enterocytes.
Treatment of the cause;
Treatment of major infectious causes
Clostridium difficile
First episode: Metronidazole 500mg TDS for 14 days
Severe disease: Vancomycin PO QID for 14 days or Fidaxomicin 20mg BID for 10 days.
First relapse: same for 1st episode
Second relapse: Vancomycin taper with pulse
Third relapse: Consider fecal microbiota TX (FMT), prolonged oral vancomycin.
CMV:
Oral valganciclovir, IV ganciclovir (if decreased absorption)
Norovirus: Rehydration, Antimotility drugs, Reduction in IS drugs.
Adenovirus:
Supportive care and IS reduction.
Microsporidia-related diarrhea:
Fumagillin may lead to sustained clearance with minimal IS reduction.
Drug-induced thrombocytopenia limits its use.
Cryptosporidium:
No specific therapy
No difference between therapy with nitazoxanide or paromomycin and placebo.
Conclusions;
First; Other possible causes should be evaluated.
Very carefully assess other potential causes of diarrhea before accusing an IS drug of being the culprit.
it is necessary to rule out infectious agents and the other diarrhea-causing drugs such PPIs, antibiotics, and diuretics.
Prospective studies are required to determine the true prevalence more accurately, complications, and risk factors of diarrhea caused by norovirus, rotavirus and Adv in KTX recipients.
Improved patient and transplant survival is predicted to result from the development of potent vaccinations and antiviral treatments for these widespread viruses.
What is the level of evidence provided by this article?
Narrative review ==> Level V
SUMMARY
Causes and management of postrenal transplant diarrhea: an underappreciated cause of transplant-associated morbidity
Introduction
The main causes of diarrhea after transplantation are infections, immunosuppressive drugs, antibiotics and other drugs. The cumulative incidence of diarrhea has been reported to be 11.5, 17.5 and 22.6% at 1, 2 and 3 years after renal transplantation, respectively. In one large retrospective study, posttransplant diarrhea of unknown origin (noninfectious) was associated with a two-fold increase in graft loss and risk of death.
This review elaborates the current literature on both infectious and noninfectious diarrhea in renal transplant recipients and provides a diagnostic algorithm for the evaluation of posttransplant diarrhea.
CAUSES OF DIARRHEA
DIDACT study indicate that an infectious cause of posttransplant diarrhea is present in approximately 50% of cases with CMV being the most common pathogen.
Bacteria: Clostridium difficile, Campylobacter spp, Salmonella spp, Bacterial overgrowth, Aeromonas spp, Escherichia coli
Viruses: CMV, Norovirus, Sapobavirus, Rotavirus, Adenovirus
Parasitic: Giardia, Cryptosporidium, Isosopora Cyclospora, Microsporidium, Entameoba
Immunosurpressive medications: MMF, Tacrolimus, Cyclosporine, Sirolimus
Nonimmunosuppressive medications: Antibacterial, Antiarrhythmic, Antidiabetic, Laxatives, Proton pump inhibitors, Protease inhibitors
Others : GVHD, PTLD, IBD, Colon cancer, Malabsorption, Microscopic colitis, Malakoplakia
DIAGNOSIS AND THERAPEUTIC STRATEGY
C. difficile
The gold standard for C. difficile detection is the cell-based cytotoxicity assay.
Initial treatment of SOT includes fidaxomicin, metronidazole or vancomycin, with vancomycin preferred for cases of more severe infection
Fidaxomicin, ramoplanin and tigecycline are newer antibiotics that are effective for the treatment of severe or recurrent disease
A newer area of interest is the use of fecal microbiota transplantation (FMT) in the management of refractory CDI.
CMV
Cmv pcr, serology, for invasive disease- endoscopy and biopsy- CMV is confirmed on histopathology with characteristically swollen cells containing ‘owl’s eye’ intranuclear inclusions, or by immunohistochemical staining for pp65.- treatment includes -oral vangancyclovir/iv gancyclovir
Multiplex pcr-based screening for enteric pathogen
EGD Colonoscopy, capsule endoscopy- biopsy- to rule out IBD, PTLD
Breath test- to see bacterial overgrowth.- treatment with antimicrobial
Microsporidia : Fumagilin has been a major breakthrough in the treatment and may lead to sustained clearance of E. bieneusi, with minimal reduction in immunosuppression
Cryptosporidiosis -diagnosed by visualization of oocysts in the stool, modified acid-fast stains, Immunofluorescent assays and ELISA (sensitivity and specificity approaching 100%). In meta-analysis, there was no observed difference between therapy with nitazoxanide or paromomycin and placebo for immunosuppressed patients with cryptosporidiosis.
Norovirus diagnosis by PCR (stool, vomitus, foods and environmental specimens) treatment -reduction of immunospuression
Rotavirus -diagnosis- immune-based assays to detect rotavirus antigens in stool samples. Other diagnostic methods such as cell culture, real time-PCR and electron microscopy remain as reference methods because of their high specificity and sensitivity. Currently, no antirotaviral therapy, treatment of rotavirus infection is mainly supportive. In the United States, two live oral vaccines against rotavirus currently are licensed for use: RotaTeq (RV5) and Rotarix (RV1) . Because both vaccines are live attenuated vaccines, transplant candidates should receive the vaccines before transplantation; their use posttransplant is contraindicated
Adenovirus can be diagnosed by viral culture, direct antigen detection, histopathology and PCR .Generally, diarrhea caused by AdV can be managed with supportive care and a reduced immunosuppressive regimen.
For noninfectious diarrhea
Withdrawal of non-immunosuppressive causing diarrhea then
The first change in immunosuppression consists of MMF dose reduction or switching to EC-MPS, followed ultimately by MMF-EC-MPS withdrawal if symptoms persist.
Conclusion
A directed approach to diagnosis and treatment will not only help to resolve diarrhea, but also prevent potentially life threatening consequences, such as loss of graft.
Level of evidence for narrative review is 5
Causes and management of post-renal transplant diarrhea:
Introduction;
-Chronic diarrhea after kidney transplantation is a common complaint.
-The main causes of diarrhea after transplantation are infections, immunosuppressive drugs, antibiotics and other drugs.
-The cumulative incidence of diarrhea has been reported to be 11.5 % (at 1 year) & 17.5 % (at 2 years) and 22.6% (at 3 years) after renal transplantation.
Causes of Diarrhea;
Immunosuppressive Drugs:
-Drug-induced diarrhea is a major problem as many of the immunosuppressive agents commonly used in transplantation may cause diarrhea, with the highest incidence associated with MMF, and enteric-coated mycophenolate sodium (EC-MPS).
-The mechanism of MMF-induced diarrhea remains unknown.
-One possible mechanism is that gastrointestinal epithelial cells may be partially dependent on the de-novo pathway of purine synthesis for growth and proliferation, and are therefore vulnerable to Mycophenolic acid (MPA) inhibition leading to diarrhea.
-The use of tacrolimus may be associated with diarrhea in 29–64% of patients depending upon the dose and duration of drug usage.
-The mechanism by which calcineurin inhibitors cause diarrhea remains unclear, it may affect in stimulation of the intestinal motilin receptors.
-A decrease in the incidence of gastrointestinal symptoms, including diarrhea, after conversion to a daily, extended release formulation of tacrolimus was reported in a recent study in renal transplant recipients.
-Sirolimus causes self-limiting diarrhea in 14– 42% of treated patients.
-The mechanism by which sirolimus causes diarrhea is poorly understood, although drug-induced jejunal villous atrophy and the promotility macrolide class of drugs have been proposed as possible explanations.
-In up to one-third of patients, antithymocyte globulin (ATG) and anti–T cell antibody (OKT3) therapies are both associated with diarrhea, which predictably lasts for 3–4 days and resolves spontaneously.
-Activating T cells to release tumor necrosis factor which then interferes with sodium ion absorption and also disrupts the intestinal mucosal barrier is one mechanism by which these antibodies may cause diarrhea.
Infections:
-After the first few months post-transplant, opportunist pathogens become more evident as a cause of infection, C. difficile, CMV and norovirus are important causes of diarrhea in this population.
-Chronic norovirus infection has only recently emerged as one of the leading infectious causes (approximately 17–26% of severe post-transplant diarrhea) of post-transplant diarrhea in kidney transplant recipients.
-In these patients, the course of norovirus infection tends to be more complicated, with up to 94% having chronic diarrhea and 81% having episodes of diarrhea-induced acute renal failure.
-CMV is one of the most common infectious complications affecting SOT patients and is associated with significant morbidity and occasional mortality, the most common target organ is the gastrointestinal tract, causing CMV gastrointestinal disease.
-In one study, rotavirus infection was diagnosed in 1.5% of SOT recipients, with most cases occurring in pediatric patients (63%) and in those who received a liver transplant.
-In adults, adenovirus (AdV) viremia is commonly observed in the early post-transplant course (6.5-22.5%), and may be associated with gastrointestinal symptoms in 10% of the cases.
-C. difficile is the most common cause of nosocomial diarrhea and accounts for most infectious diarrhea within the first months after transplantation.
-The incidence of C. difficile infection (CDI) in transplanted patients has been reported to be approximately 3.5–4.5% in adult renal transplantation patients.
-Risk factors that are specific to the SOT population include age above 55 years, use of ATG, retransplantation and the type of organ transplanted, with the highest rate among liver recipients.
-The single most important risk factor for the development of CDI is recent antibiotic use.
-Among antibacterials, the fluoroquinolones are associated with the highest risk.
-CDI has a significant effect on mortality of SOT recipients, with mortality rates between 2.3 and 8.5%, and is an independent risk for death.
-Among parasities, the protozoan or metazoan are most common.
-Gastrointestinal infection due to microsporidia has been recorded in patients with SOT who experienced diarrhea and weight loss.
-Enterocytozoon bieneusi is by far the most frequent strain found in kidney transplant recipients.
-Cryptosporidia (Cryptosporidia parvum and Cryptosporidia hominis) are intracellular protozoans known to lead to severe acute diarrhea, chronic diarrheal illness and extraintestinal infection in transplanted patients.
Diagnosis and Therapeutic Strategy;
C. difficile:
-The gold standard for C. difficile detection is the cell-based cytotoxicity assay.
-However, most laboratories use the easier, less expensive and more rapid fecal enzyme immunoassays or real-time PCR test.
-These tests have high sensitivity and specificity (90%) for the detection of CDI.
-Transplanted patients can be asymptomatic carriers of C. difficile, but most often they develop diarrhea, intestinal obstruction, abscesses or toxic megacolon.
-Initial treatment of SOT includes fidaxomicin, metronidazole or vancomycin, with vancomycin preferred for cases of more severe infection.
-Only about 70% of patients will respond to treatment with metronidazole; persistent and more severe cases will require oral vancomycin.
-The greatest challenge for toxigenic Clostridium infections remains the prevention and treatment of relapsing and refractory forms.
-In transplant recipients, it has been estimated that up to 20% of cases will have at least one relapse.
-Fidaxomicin, ramoplanin and tigecycline are newer antibiotics that are effective for the treatment of severe or recurrent disease.
-A newer area of interest is the use of fecal microbiota transplantation (FMT) in the management of refractory CDI.
-The recent availability of fumagilin has been a major breakthrough in the treatment of microsporidia-related diarrhea, treatment that may lead to sustained clearance of E. bieneusi, with minimal reduction in immunosuppression.
CMV disease:
-The diagnosis of tissue-invasive CMV disease is suggested by the presence of CMV viremia. Many patients with CMV colitis will have evidence of CMV replication in the blood via PCR, although approximately 15% will not.
-In general, patients with CMV colitis can be managed with intravenous ganciclovir (GCV) or oral valganciclovir (valGCV).
-Intravenous GCV is often used if there is concern for inadequate absorption of oral valGCV (e.g. in patients with vomiting and diarrhea) or early in the treatment of proven CMV colitis.
-Optimal duration of antiviral therapy depends on the patient’s clinical and virologic responses, not on a fixed period.
-Before antiviral therapy is stopped, the following three criteria should be met: the treatment was given for at least 2 weeks, clinical symptoms have resolved and viral load is no longer detectable, if initially detected.
-Because recurrent CMV disease has been reported in 15–35% of SOT recipients with tissue-invasive CMV disease, many experts recommend the use of valGCV for secondary prophylaxis for 30–90 days after successful treatment.
Norovirus:
-Diagnosis of norovirus by PCR can be run on stool, vomitus, foods and environmental specimens.
-Supportive care is the first line of treatment with an emphasis on replenishment of fluids and electrolytes.
-At present, the most effective strategy to manage norovirus infection is the reduction of immunosuppression.
-It is important to know that norovirus is the key factor in the induction of posttransplant diarrhea, whereas MMF plays a critical role in the chronicity of the symptoms by preventing both the clearance of the virus and the repair of intestinal epithelium.
-At present, no vaccines are available for norovirus, although several candidate vaccines are under investigation.
-Because of the lack of specific treatment or vaccination, prevention plays an especially important role in norovirus infection control, especially hand hygiene and environmental sanitization.
Rotavirus:
-In diagnosis of rotavirus, immune-based assays are most routinely used to rapidly detect rotavirus antigens in stool samples.
-Other diagnostic methods such as cell culture, real time-PCR and electron microscopy remain as reference methods because of their high specificity and sensitivity.
-Currently, no anti-rotaviral therapies are available, and the treatment of rotavirus infection in SOT patients is mainly supportive.
-Contact precautions are recommended to prevent viral transmission.
-Contaminated surfaces should be disinfected by 95% ethanol or other alcohol-containing disinfectant, because general disinfectants (e.g. bleach) are ineffective.
-In the United States, two live oral vaccines against rotavirus currently are licensed for use: RotaTeq (RV5) and Rotarix (RV1).
-Because both vaccines are live attenuated vaccines, transplant candidates should receive the vaccines before transplantation; their use posttransplant is contraindicated.
Adenovirus:
-AdV can be diagnosed by viral culture, direct antigen detection, histopathology and PCR.
-Although culture has traditionally been considered the gold standard for diagnosing AdV, it may take up to 28 days to develop cytopathic effects, and serotypes associated with diarrhea do not grow well in cell culture.
-Limited data are available on the optimal treatment of AdV infections.
-Generally, diarrhea caused by AdV can be managed with supportive care and a reduced immunosuppressive regimen.
-Diligent infectious control measures, including contact and droplet precautions, can help prevent infections in the SOT population.
Conclusion;
-A directed approach to diagnosis and treatment will not only help to resolve diarrhea, but also prevent potentially life-threatening consequences such as loss of the graft.
-Meticulous evaluation for possible causes of diarrhea Prior to implicating an immunosuppressant medication as the culprit.
-Infectious agents and the concomitant use of other diarrhea genic medications such as proton-pump inhibitors, antibiotics and diuretics must first be excluded .
-Prospective studies are needed to better assess in kidney transplant patients the true prevalence, risk factors and complications of diarrhea by norovirus, rotavirus and AdV.
-Development of effective vaccines and antiviral therapies for these common viruses will likely improve patient and graft survival.
What is the level of evidence provided by this article?
-This is Narrative review (LOE V)
Introduction
Chronic diarrhea after kidney transplantation is associated with fatigue, increased hospitalization, and has a negative impact on the patient’s quality of life, graft survival and mortality.
It may also lead to steatorrhea and malabsorption. Oxalate nephropathy is associated with inflammation which can have detrimental effects on graft survival. Some of the risk factors that kidney transplant recipients have include immune suppression and exposure to broad spectrum antimicrobial therapy.
The main causes of diarrhea after transplantation are
This article reviewed current literature regarding infectious and non-infectious diarrhea and renal transplant recipients to provide a diagnostic algorithm for the evaluation post transplant diarrhea.
Epidemiologic impact
53% of 4232 Scandinavian renal transplant recipients reported diarrhea, but the incidence estimated by their physicians was only 6.9%. This showed that the physicians greatly under-reported diarrhea.
One study noted that chronic diarrhea results in poor quality of life, graft loss and risk of death.
A study in the US noted that the majority of the diarrheal episodes had no identifiable cause and were self-limited. The most common identifiable causes included Clostridium difficile infection (13.1% patients), norovirus infection (3.9% patients) and cytomegalovirus (CMV) gastrointestinal infection (3.5% patients).
Causes of diarrhea
Noninfectious diarrhea is common among renal transplant recipients. It leads to increased risk of graft loss and mortality.
The highest incidence is associated with MMF. The mechanism of MMF-induced diarrhea remains unknown. The enterocytes are dependent on the de novo pathways of purine synthesis for growth and these are inhibited the MMF. Histologically, 2 different morphologic patterns of mycophenolate-induced diarrhea can be identified:
The use of tacrolimus may be associated with diarrhea in 29–64% of patients depending upon the dose and duration of drug usage. It is thought that a macrolide structure may result in stimulation of the intestinal motilin receptors.
Sirolimus causes self-limiting diarrhea in 14-42% of treated patients due to drug-induced jejunal villous atrophy.
Infectious diarrhea is more common. The pathogens commonly involved are CMV and C. difficile. After the first month of transplantation, when the patients are more immune suppressed, opportunist pathogens become more evident. Chronic Noro virus infection has emerged as one of the leading infectious causes of posttransplant diarrhea in kidney transplant recipients.
CMV is associated with significant morbidity and sometimes mortality. Risk factors for CMV disease include seronegative recipients of seropositive organs (D þ /R–) and, to a lesser extent, seropositive recipients (D–/R þ ), lymphodepleting antibodies and more potent immunosuppressive regimens. Adenovirus viremia is observed in early post transplant phase.
C. difficile is a common cause of nosocomial diarrhea. Risk factors include age above 55 years, use of ATG, retransplantation and the type of organ transplanted. Gastrointestinal infection due to microsporidia has been recorded in patients with SOT who experienced diarrhea and weight loss. Cryptosporidia have been implicated to cause severe acute diarrhea, chronic diarrheal illness and extraintestinal infection in transplanted patients.
Diagnosis and therapeutic strategy
It is important to evaluate and diagnose the cause of the diarrhea in a transplant recipient, especially between infectious and noninfectious causes.
The gold standard for C. difficile detection is the cell-based cytotoxicity assay, but a PCR is cheaper and more accessible to most labs. Both tests, have high sensitivity and specificity. Transplant recipient may develop diarrhea, intestinal obstruction, abscesses or toxic megacolon due to C. difficile. Only about 70% of patients respond to treatment with metronidazole. Persistent and more severe cases require oral vancomycin. Fecal microbiota transplantation (FMT) is a new option for refractory C. difficile infection (CDI), but further studies are required as current data is limited. Fumagilin treatment may also lead to sustained clearance of E. bieneusi. But it may cause drug induced thrombocytopenia.
Tissue invasive CMV infection is diagnosed by the presence of CMV viremia. CMV can be confirmed with PCR and histopathology. Histopathology shows, characteristically swollen cells containing ‘owl’s eye’ intranuclear inclusions. In general, patients with CMV colitis can be managed with intravenous ganciclovir (GCV) or oral valganciclovir (valGCV). The optimal duration of the therapy depends on the patient’s response.
Norovirus can be diagnosed by PCR on samples of stool, vomitus, food and environmental specimen. Currently, the most effective strategy to manage norovirus infection is the reduction of immunosuppression. It may lead to MMF discontinuation, which has been associated with an increased risk of rejection.
Rotavirus can be detected by PCR of stool samples, and treatment is mainly supportive. Prevention is key, and contaminated surfaces should be disinfected. Transplant candidates should receive the vaccines before transplantation. The vaccines are live attenuated vaccine, and hence cannot be used post transplant. For some patients an endoscopy or colonoscopy with biopsy may be required after transplantation.
This may be due to:
Treatment of diarrhea, with hydration and focused use of antimicrobials or changes in immune suppression is important in its management.
Conclusion
The transplant team should be familiar with the common causes that result in post transplant diarrhea. A more direct approach to diagnosis and treatment will help prevent potentially life-threatening consequences. Further studies are required to better assist the true prevalence, risk factors, causative agent and complications of specific pathogens in kidney transplant recipients. Further studies will assist in the development of appropriate management and effective prevention mechanisms, which will consequently improve patient and graft survival.
Level of evidence:
This is a narrative review: LOE V
Causes and management of transplant diarrhoea: an cause of transplant-associated morbidity
Please summarise this article?
Introduction
Post-transplant diarrhea is common affecting nearly one fourth of transplant recipients at three years after transplantation.
Chronic diarrhea after transplantation is common and associated with increased morbidity, hospitalization, allograft loss and poor quality of life.
Steatorrhea and malabsorption can lead to secondary enteric hyperoxaluria with subsequent oxalate nephropathy (intense inflammation of allograft).
Diarrhea is defined as > 3 loose stool/day.
Persistent (>2 weeks) and chronic (> 1month)
The Quality of life, graft survival and mortality are all negatively impacted by chronic diarrhea post-transplant.
Transplant physician must assess the diarrhea in Kidney Transplant recipients, try to determine its source and differentiate between infectious and non-infectious causes of diarrhea.
Epidemiology.
The cumulative incidence of diarrhea is 11.5, 17.5, and 22.6% at 1-, 2-, and 3-years post-Kidney transplant, respectively (UNOS registry).
Yet, 53% of participants in a large survey of Kidney transplant recipients reported having diarrhea, despite their doctors’ estimates of the prevalence being only 6.9%. This finding shows how frequently post-TX diarrhea goes undiagnosed by healthcare professionals.
Most of the diarrheal events are self-limited & lack a known cause. The most frequent causes were CMV GI infection, norovirus infection, & Clostridium difficile infection.
Causes of post-transplant diarrhea;
Data from the DIDACT study;
Diarrhea resolved in 50% of patients either by cessation of diarrhea associated non-IS drugs or by the treatment of concurrent infections (mostly Campylobacter or CMV).
In the remainders, changes in IS therapy (mostly MMF) led to remission in 2/3 of cases.
CMV was the most prevalent infection\ etiology of post-TX diarrhea was found in 50% of cases. Medication use is the 2nd most common reason.
Causes Of Infectious Diarrhea Post-Kidney transplant;
The most common identifiable causes include clostridium difficile infection, norovirus infection, CMV infection and drug induced.
Viral: CMV most common, Norovirus, Rotavirus, Adenovirus, Sapobavirus
Bacterial: Clostridium difficile, Campylobacter, Salmonella, E coli, Bacterial overgrowth.
Parasitic: Cryptosporidium, Giardia, Isosopora Cyclospora, Microsporidium and Entamoeba.
CMV is the most important risk factor for CMV disease is D+/R– GI involvement (40% of patients). Other risk factors are D+/R–status, lymphodepleting antibodies & more potent IS regimens.
Bacteria such as clostridium deficile is the most common cause of nosocomial diarrhea and accounts for most infectious diarrhea in the 1st months post-Transplant,
Clostridium deficile infection occurs in 3.5–4.5%, most common nosocomial infection in 1st month posttransplant, more common in age > 55 years, use of ATG, re-TX, liver transplant and with use of broad-spectrum antibiotics as quinolones, it is associated with 2.3-8.5% risk of mortality. It can lead to diarrhea, intestinal obstruction, abscesses, or toxic megacolon.
Viruses such as CMV, adenovirus, norovirus, rotavirus, and sapovirus
Parasites such as giardiasis, entamoeba histolotica, cryptosporidium
salmonella, shigella, E coli, and bacterial overgrowth
Norovirus:
Has 2 phases: acute phase; presented with nausea, vomiting, significant diarrhea (10–20 watery stools per day), abdominal pain and sometimes fever.
Then followed by a chronic phase; (cycles of relatively normal stools followed by periods of poorly formed stools).
Lately, chronic norovirus infection has become one of the most common infectious causes (17–26% of cases). This suggests that many infectious causes of diarrhea may have previously been misdiagnosed as being caused by IS medications, resulting in inappropriate diagnostic & treatment approaches.
Rotavirus infections:
occur in 1.5% of SOT recipients.
Adenovirus:
is common in early posttransplant course (isolated in 6.5–22.5% of cases).
Viremia in the 1st few months post-TX (6.5–22.5%), & GI symptoms occur in 10%.
Microsporidia
Cryptosporidium (Cryptosporidium parvum & Cryptosporidium hominis).
Diagnostic work up should include;
Review all medications and stop unnecessary ones.
A- Routine investigations;
Renal function tests and electrolytes
Complete blood count, c reactive protein
Stool analysis
B- Searching for the cause;
CNI level, CMV PCR, Stool culture and CD toxin in stool, and parasitic infection (Cryptosporidium, Entamoeba histolytica, Giardia lamblia, Campylobacter, Shigella, Salmonella, Vibrio, Yersinia enterocolitica, adenovirus and sapovirus), enzyme immunoassay for giardia and cryptosporidium and breath test for bacterial overgrowth.
Clostridium diff. infection:
Cell-based cytotoxicity assay is the gold standard test
Real-time PCR tests or fecal enzyme immunoassays (simpler, less expensive, & faster) are commonly used.
Tissue-invasive CMV disease:
CMV viremia is suggestive of the diagnosis.
Laboratory tests include biopsy, CMV IgM & or elevation in IgG, conventional culture, Shell Vial assay, CMV pp65 Ag, PCR, & Real-time PCR.
Norovirus:
Diagnosed by PCR run on stool, vomitus, foods & environmental specimens.
Rotavirus:
Immune-based assays rapidly detect rotavirus antigens in stool.
Adenovirus:
Diagnosed by viral culture, direct antigen detection, histopathology & PCR.
Cryptosporidiosis:
Oocysts in the stool
Modified acid-fast stains.
IF assays & ELISA (100% sensitivity & specificity)
Imaging, Colonoscopy and Biopsy:
may be needed if there is suspicious of malignancy, IBD or CMV colitis with negative PCR (15% of cases will have CMV PCR negative
If these tests are negative & the diarrhea persists, empiric anti-diarrheal medications, probiotics &/or lactose-free diet tried.
Non-infectious causes of diarrhea
Drug induced:
Immunosuppression drugs (MMF mainly, CNI and MTORi).
Others as (laxatives, anti-diabetics, PPI, anti-arrhythmic drugs).
Mechanism of MMF induced diarrhea:
It inhibits de-novo pathway of purine synthesis essential for growth, Proliferation, and generation of enterocytes.
IBD-like toxicity (predominant crypt distortion).
GVHD associated toxicity (predominant apoptosis).
Treatment of MMF induced or associated diarrhea requires either:
Shift from MMF to EC-MPS that may be beneficial, or Short-term conversion to AZA (while long term graft outcome is lower with AZA than MMF in addition to higher risk of skin cancer).
MMF has the highest prevalence (RR 1.57), & numerous IS medications frequently used in TX may cause diarrhea.
Dose reduction is generally followed by a decline or cessation of diarrhea.
It is unclear how MMF causes diarrhea. Two distinct histological patterns are seen: (i) IBD-like MPA-associated toxicity with predominant crypt distortion, & (ii) GVHD like type with predominant apoptosis.
It’s debatable whether switching from MMF to EC-MPS helps lessen symptoms of diarrhea. According to a recent RCT, patients who switch from MMF to EC-MPS may have a marginally but significantly higher likelihood of returning to the target MPA levels than those who stay on MMF.
Switch from MPA to AZA is usually avoided because of risk of reduced graft survival with AZA versus MMF.
Mechanism of TAC induced diarrhea:
It occurs in 30-60 % of cases, it may stimulate intestinal motilin receptors, but it is usually mild, self-limited, and not require drug discontinuation.
Shift to extended release (advagraf) may be beneficial.
MTORi induced diarrhea:
It occurs in 14-40 % of cases, it is related to jejunal villous atrophy, it is usually self-limited.
ATG induced diarrhea:
Use of ATG can activate T cells to release TNF which then interferes with Na ion absorption and disrupts the intestinal mucosal barrier.
Both ATG & OKT3 can cause diarrhea in 1/3 of patients; this diarrhea is self-limiting (lasts 3–4 d).
Others including, GVHD (graft versus host disease), IBD, malabsorption, and microscopic colitis).
Malignancy such as cancer colon, PTLD
Management;
In most cases, the cause is not identified, and diarrhea is self-limited.
Supportive therapy including intravenous fluids for treatment of dehydration.
Symptomatic therapy including loperamide to decrease bowel motions which is indicated in persistent (> 2 weeks) or chronic diarrhea (> 1 month)
Modulation and monitoring of immunosuppression;
Reduction of immunosuppression in the form of reducing the dose of MMF by 50% after estimation of the rejection risk and keeping low target trough for CNI (5-8 ng/ml)
Shifting from MMF to enteric coated mycophenolate (debatable)
Shifting from MMF to azathioprine (not preferred due to reduced graft survival, increased risk of rejection and increased risk of skin cancer associated with azathioprine use)
Switching from tacrolimus to extended released formulation or to cyclosporine.
Switching from sirolimus to CNI since around 14-41 % of cases taking sirolimus experienced diarrhia.
Close follow up of CN level as there may be an increase in tacrolimus level with diarrhea due to disruption of P-glycoprotein efflux pump in the damaged enterocytes.
Treatment of the cause;
For clostridium deficille infection: treatment lines include metronidazole 500 mg 3 times daily for 10–14 days, vancomycin 125 mg oral four times per day for 10–14 days, fidaxomicin 20 mg two times per day for 10 days, fecal microbiota transplantation, prolonged oral vancomycin.
Antibiotics for bacterial diarrhea and bacterial overgrowth
Anti-parasitic for parasites
Ganciclovir for CMV colitis for the first 2 weeks and shift to valganciclovir provided that the patient can tolerate oral, till 2 successive PCR samples are negative, then start secondary prophylaxis using valganciclovir for 1-3 month.
Specific treatment in case of cancer colon or PTLD
Treatment of major infectious causes
Clostridium difficile
First episode: Metronidazole 500mg TDS for 14 days
Severe disease: Vancomycin PO QID for 14 days or Fidaxomicin 20mg BID for 10 days.
First relapse: same for 1st episode
Second relapse: Vancomycin taper with pulse
Third relapse: Consider fecal microbiota TX (FMT), prolonged oral vancomycin.
CMV:
Oral valganciclovir, IV ganciclovir (if decreased absorption)
Norovirus: Rehydration, Antimotility drugs, Reduction in IS drugs.
Adenovirus:
Supportive care and IS reduction.
Microsporidia-related diarrhea:
Fumagillin may lead to sustained clearance with minimal IS reduction.
Drug-induced thrombocytopenia limits its use.
Cryptosporidium:
No specific therapy
No difference between therapy with nitazoxanide or paromomycin and placebo.
Conclusions;
First; Other possible causes should be evaluated.
Very carefully assess other potential causes of diarrhea before accusing an IS drug of being the culprit.
it is necessary to rule out infectious agents and the other diarrhea-causing drugs such PPIs, antibiotics, and diuretics.
Prospective studies are required to determine the true prevalence more accurately, complications, and risk factors of diarrhea caused by norovirus, rotavirus and Adv in KTX recipients.
Improved patient and transplant survival is predicted to result from the development of potent vaccinations and antiviral treatments for these widespread viruses.
What is the level of evidence provided by this article?
Narrative review ==> Level V
INTRODUCTION:
Chronic diarrhea after kidney transplantation is a common complaint, associated with fatigue, increased hospitalizations and negative impacts on recipient quality of life.
EPIDEMIOLOGIC IMPACT:
Posttransplant diarrhea is often underrecognized by practitioners, and is associated with a two-fold increase in graft loss and risk of death. Common causes include Clostridium difficile, norovirus, and cytomegalovirus. 32% of those diagnosed with diarrhea had reductions or changes in their immune suppression.
CAUSES OF DIARRHEA: GENERAL:
The DIDACT study found that an infectious cause of posttransplant diarrhea is present in approximately 50% of cases, with CMV being the most common pathogen.
CAUSE OF DIARRHEA:
IMMUNOSUPPRESSIVE DRUGS:
Drug-induced diarrhea is a major problem in transplantation, with the highest incidence associated with Mycophenolic acid (MPA) inhibition. MMF reduced graft loss by 27%, increased skin cancer risk, and caused diarrhea in 29-64% of patients.
CAUSE OF DIARRHEA: INFECTIONS
Diarrhea is commonly caused by CMV and C. difficile in solid organ transplant (SOT) recipients, but it is important to remember that the individual is also being exposed to common community-associated pathogens (e.g. norovirus and enteropathogenic bacteria). Chronic norovirus infection is the leading infectious cause of posttransplant diarrhea in kidney transplant recipients, with up to 94% having chronic diarrhea and 81% having episodes of diarrhea-induced acute renal failure.
CMV is one of the most common infectious complications affecting SOT patients and is associated with significant morbidity and occasional mortality. CMV is the most common target organ for SOT patients, with 7.2% developing CMV disease.
DIAGNOSIS AND THERAPEUTIC STRATEGY:
The gold standard for C. difficile detection is the cell-based cytotoxicity assay, but most laboratories use fecal enzyme immunoassays or real-time PCR tests. Fecal microbiota transplantation (FMT) is promising, but its high adverse effect rate warrants further study.
The most accurate means to diagnose CMV-associated colitis is endoscopic evidence of gastrointestinal involvement and immunohistochemical staining for pp65.Antiviral therapy can be managed with intravenous GCV or oral valganciclovir. Before antiviral therapy is stopped, three criteria must be met: treatment was given for at least 2 weeks, clinical symptoms have resolved and viral load is no longer detectable.
Diagnosis of norovirus by PCR can be run on stool, vomitus, foods and environmental specimens .The most effective strategy to manage norovirus infection is the reduction of immunosuppression, and prevention is important.
Perform esophagogastroduodenoscopy and colonoscopy with biopsies to investigate persistent diarrhea after kidney transplantation due to intestinal ulcerations, CMV colitis, duodenal villous atrophy, and post-transplantation de-novo inflammatory bowel disease. Treatment is of utmost importance.
CONCLUSION:
Physicians should be familiar with common causes of posttransplant diarrhea and take a directed approach to diagnosis and treatment to prevent potentially life-threatening consequences. Prospective studies are needed to better assess the prevalence, risk factors and complications of diarrhea by norovirus, rotavirus and AdV.
level 5
This narrative review, published in 2017, provides an overview of an important clinical topic: diarrhoea occurring in solid-organ transplant (SOT) recipients. The authors highlight that incidence of diarrhoea in SOT recipients may be grossly underestimated: for example a Scandinavian study identified a huge discrepancy in reported incidence rates of post-transplant diarrhoea between clinicians and patients: 6.9% versus 53% respectively. Post-transplant diarrhoea can be a significant cause of morbidity as well as having potential impact on graft and patient survival.
Issues related to diarrhoea in renal transplant recipients:
Impact on patient:
· Increased hospitalisation
· Reduced patient quality of life
Impact on graft function/survival:
· Acute kidney injury associated with gastrointestinal losses
· Steatorrhoea/malabsorption hyperoxaluria with associated risk of oxalate nephropathy and reduced graft function
· Potential need to reduce immunosuppression with risk of rejection
· Poor absorption of crucial immunosuppression medications
· Overall reduced allograft and patient survival
The key diagnostic dilemma regarding post-transplant diarrhoea in SOT recipients is determining whether it is an infectious aetiology or a side-effect of medication: the treatment approaches for both are very different and erroneous treatment could lead to further harm.
Infectious causes of post-transplant diarrhoea:
An infectious aetiology is thought to be responsible for approximately 50% of cases of post-transplant diarrhoea.
Common infectious causes:
1. Cytomegalovirus (CMV) = commonest cause, highest risk patients are D+/R-
2. clostridium difficile (commonest hospital-acquired cause) – recent broad-spectrum antibiotic use often plays a role
3. bacterial overgrowth
4. norovirus – beware of chronic norovirus infection in SOT recipients who have a biphasic illness with the first phase being similar to that seen in non-immunosuppressed patients but the more chronic phase being different and sometimes mis-diagnosed
Other infectious causes:
5. rotavirus- limited data, further studies would aid knowledge in this area
6. adenovirus (AdV) – seen in early post-transplant period, 10% cases have GI symptoms
7. other bacterial causes: campylobacter, salmonella, aeromonous, E. coli
8. parasitic causes: giardia, cryptosporidium, isopopora Cyclospora, Microsporidium, Entameoba
Non-infectious causes of post-transplant diarrhoea
Commonly this is medication-related with the most common cause being:
· mycophenolate (MMF)
Other (less common) medication causes include:
· tacrolimus, ciclosporin
· sirolimus
· broad-spectrum antibiotics
· proton pump inhibitors
· laxatives
More rarely, a non-medication cause may be responsible such as:
· post-transplant lymphoproliferative disorder
· malabsorption
· inflammatory bowel disease
The authors summarise what is currently understood about MMF-induced diarrhoea. The exact mechanism remains unclear but there are 2 histological types: inflammatory bowel disease-like MPA toxicity which shows predominantly crypts being affected and graft-versus host-like MPA associated toxicity which demonstrates mainly cell apoptosis. The evidence that a switch to enteric coated mycophenolate sodium can alleviate post-transplant diarrhoea is mixed. However, a switch to azathioprine is generally not recommended as it is associated with poorer graft outcomes.
The authors have provided their own flow diagram for the management of post-transplant diarrhoea. They emphasise that the importance lies in correctly identifying the aetiology of the diarrhoea. Each patient’s experience is likely to be very different and this makes constructing a universal diagnosis/treatment algorithm very difficult. However, perhaps the most important take-home message from the paper is to clearly ask the patient about any symptoms of diarrhoea at each review in order to avoid the large discrepancy in patient-reported versus physician-reported incidence of post-transplant diarrhoea.
Level of evidence
This narrative review provides a succinct summary of post-transplant diarrhoea causes, diagnosis and management and is a useful introductory guide. However, the review methods are not discussed and there could be bias in the papers the authors have focussed upon. As such it provides level 5 evidence.
I like your well-structured summary, level of evidence, analysis and take home messages typed as conclusion.
I like your step-wise approach.
Please change to azathioprine or to a smaller dose sirolimus as an adjunct if that patient can not be give azathioprine to avoid interaction with allopurinol.
SUMMARY:
INTRODUCTION
· Chronic diarrhea after kidney transplantation is a common complaint, but it can have negative impacts on the recipient’s quality of life, graft survival, and mortality. · Predisposing characteristics include immunosuppression and exposure to polypharmacy. · The main causes of posttransplant diarrhea are infections, immunosuppressive drugs, antibiotics, and other drugs.
· A diagnostic algorithm is needed to evaluate posttransplant diarrhea.
EPIDEMIOLOGIC IMPACT
· The DIDACT study found that an infectious cause of posttransplant diarrhea is present in approximately 50% of cases, with CMV being the most common pathogen.
· Changes in immunosuppressive therapy (most commonly MMF) led to remission of diarrhea in about two-thirds of cases.
· A survey of 4232 Scandinavian renal transplant recipients found that 53% reported diarrhea, whereas the incidence estimated by their physicians was only 6.9%.
· A recent study from a single transplant center in the United States reviewed the diagnostic yield of tests for diarrhea among hospitalized transplant recipients over a period of 18 months.
CAUSES OF DIARRHEA: GENERAL
· The DIDACT study identified an infectious cause of posttransplant diarrhea in approximately 50% of cases, with CMV being the most common pathogen.
· Changes in immunosuppressive therapy led to remission in two-thirds of cases.
CAUSE OF DIARRHEA: IMMUNOSUPPRESSIVE DRUGS
· Noninfectious diarrhea is a major problem among renal transplant recipients, with the highest incidence associated with MMF.
· A recent meta-analysis identified the relative risk of diarrhea associated with the use of MMF at 1.57.
· The mechanism of MMF-induced diarrhea remains unknown, but two morphologic patterns can be distinguished: crypt distortion and graft-versus host-like MPA-associated toxicity.
· Switching from MPA to EC-MPS may help reduce diarrhea symptoms, but is usually avoided due to reduced graft survival.
· The U.S. Renal Transplant Scientific Registry showed that MMF reduced the relative risk of graft loss by 27%, and death-censored graft survival was significantly better among MMF-treated versus AZA-treated patients.
CAUSE OF DIARRHEA: INFECTIONS
· Diarrhea in SOT recipients is often caused by opportunistic pathogens, including CMV and C. difficile. Chronic norovirus infection is one of the leading causes of posttransplant diarrhea, with up to 94% having chronic diarrhea and 81% having episodes of diarrhea-induced acute renal failure.
· Risk factors for CMV disease include seronegative recipients, lymphodepletion antibodies, and more potent immunosuppressive regimens.
· The most important risk factors for the development of CMV disease in SOT patients are seropositive donor/seronegative recipients’ gastrointestinal involvement, rotavirus infection, adenovirus viremia, C. difficile infection, recent antibiotic use, protozoan or metazoan infection, and extraintestinal infection.
DIAGNOSIS AND THERAPEUTIC STRATEGY
· Diagnosis of diarrhea in transplant recipients is important, and fecal enzyme immunoassays and real-time PCR tests are used to detect C. difficile.
· Treatment includes fidaxomicin, metronidazole, or vancomycin, and newer antibiotics such as fidaxomicin, ramoplanin and tigecycline.
· Fecal microbiota transplantation (FMT) is promising, but limited due to drug-induced thrombocytopenia. Cryptosporidiosis is diagnosed by visualization of oocysts in the stool, with immunofluorescent assays and ELISA having a sensitivity and specificity approaching 100%.
· CMV-associated colitis is diagnosed by endoscopic evidence of gastrointestinal involvement and can be managed with intravenous ganciclovir or oral valganciclovir.
· The most effective strategy to manage norovirus infection is to reduce immunosuppression, as norovirus is the key factor in posttransplant diarrhea.
· Prevention plays an important role in norovirus infection control, including hand hygiene and environmental sanitization.
· Contact precautions are recommended to prevent viral transmission, and two live oral vaccines against rotavirus are licensed for use.
· AdV can be diagnosed by viral culture, direct antigen detection, histopathology, and PCR.
· Treatment should include supportive care and a reduced immunosuppressive regimen.
· Treatment of persistent posttransplant diarrhea with hydration and focused use of antimicrobials or changes in immunosuppression is essential.
CONCLUSION
· Physicians should be aware of common causes of posttransplant diarrhea and use a directed approach to diagnosis and treatment.
· Prospective studies are needed to better assess the true prevalence, risk factors, and complications of diarrhea by norovirus, rotavirus, and AdV.
· Development of effective vaccines and antiviral therapies for these common viruses will improve patient and graft survival.
===============================
level of evidence
Level 5
I like your well-structured rather extensive summary, level of evidence, analysis and take home messages typed as conclusion.
I note that you have written as I quote ‘two live oral vaccines against rotavirus are licensed for use.’
Is it safe to give live vaccines to a transplant recipient?
Thanks, Dear Professor for the concern,
In the United States, two live oral vaccines against rotavirus currently are licensed to use, but as they are live attenuated vaccines, transplant candidates should receive the vaccines before transplantation; their use post-transplant is contraindicated.
Yes, Dr Sawiwan
Please summarise this article.This narrative review addresses the post-transplant diarrhea epidemiology, causes, and algorithm for the diagnosis
Introduction
Post-transplant chronic diarrhea is a common problem and considered an ignored condition that can affect a patient’s quality of life, increase the rate of hospitalization, generally unwell, increase morbidity, and impact graft survival, the main risk factors that can be shared among SOT includes the immunosuppression and polypharmacy including immunosuppression medications broad-spectrum antibiotics, and infections. it’s important to identify the underlying causes of chronic diarrhea and differentiate between infectious and non-infectious causes, improve the diagnostic tools this review study address the current evidence in regard f of infectious and noninfectious causes of chronic diarrhea after transplantation and share diagnostic algorithm with emphases of the need for more studies to address the real incidence of post-transplant chronic diarrhea, risk factors, and the impact of certain viral infections like norovirus, adenovirus, and rotavirus.
Causes of diarrhea
Infectious
bacterial infection
Clostridium(CDI), Campylobacter spp. Salmonella spp. Bacterial overgrowth Aeromonous spp. Escherichia coli
C. difficile is the most common cause of nosocomial diarrhea and accounts for most infectious diarrhea within the first months after transplantation
The incidence of C. difficile infection (CDI) is between 3.5–4.5%, specific risk factors for CDI include age > 55, recent AB use includes ciprofloxacin group, use of ATG induction, retransplantation, and more after liver transplantation. CDI is associated with increased mortality rates between 2.3 and 8.5% and is an independent risk for death.
Viral infection, most common, CMV colitis, norovirus, rotavirus, adenovirus
Chronic norovirus infection has only recently emerged as one of the leading infectious causes
(Approximately 17–26% of severe posttransplant diarrhea) with the biphasic course ( acute and chronic form of diarrhea )
CMV colitis very common cause of diarrhea with tissue-invasive colitis
Parasitic infections
Giardia
Cryptosporidium
Isosopora Cyclospora
Microsporidium
Entameoba
microsporidia have been recorded in patients with SOT who experienced diarrhea and weight loss.
Noninfectious
Drug-induced
MMF (most common, mechanism not clear)
Tacrolimus, cyclosporine, sirolimus
Nonimmunosuppressive medications like broad-spectrum antibiotics and most common include ciprofloxacin with risk of clostridium defficilea, others like antiarrhythmics drugs, PPI , protease inhibitors, laxative
Other causes of chronic diarrhea after transplantations include PTLD, GVHD, denovo IBS, malignancies, microscopic colitis
A diagnostic approach for chronic diarrhea after transplantation
Stool culture and parasitology, viral screen panel includes, CMV PCR, adenovirus PCR, Rotavirus, norovirus, and other gastroenteritis viral screen by Rapid antigen test (RAT) in the stool, immunoassay, cell Viral cultures, CDI toxin A, B antigens cell-based cytotoxicity assay. fecal enzyme immunoassays or real-time PCR tests with 90% sensitivity.
Cryptosporidiosis is mostly diagnosed by visualization of oocysts in the stool. Immunofluorescent assays and ELISA tests have 100% sensitivity and specificity and are better than modified ACID-FAST staining
In the case of tissue-invasive CMV disease, the best in addition to the presence of CMV viremia is to confirm by tissue biopsy by looking for typical owl eye viral inclusion bodies
Around 15% of patients with CMV colitis will have negative CMV PCR with low specificity only 77%, while tissue biopsy is found 100% specific for the diagnoses of CMV disease
Treatment
Depending on the underlying pathology, and by principles all patients with diarrhea should have their medications reviewed for potential causes of diarrhea, and unnecessary agents should be stopped and followed by specific testing for different causes of diarrhea, stepwise approach before reduction of immunosuppression
1. CDI treatment depends on the severity and the frequency of infection, mild to moderate CDI need isolation and in addition to supportive medical care need medical therapy with oral AB, like metronidazole for 10-12 days fidaxomicin, metronidazole, or vancomycin, with vancomycin preferred for cases of more severe infection
about 70% of patients will respond to treatment with metronidazole; persistent and
more severe cases will require oral vancomycin. in combination with oral vancomycin main challenges with the management of CDI, is the risk of relapse and failure for medical treatment ( refractory CDI ) leading to Complicated severe CDI with toxic megacolon, which might need surgical intervention including hemicolectomy ileostomy and broad-spectrum AB
Fidaxomicin, ramoplanin, and tigecycline are newer antibiotics that are effective for the treatment of severe or recurrent disease also new monoclonal AB and microbiota fecal transplantation are still in clinical research
2. rotaviral infection is mainly supportive therapy
Prevention by contact precaution and use 95% alcohol disinfection to the surfaces, two vaccination available for rotavirus infection RotaTeq (RV5) and Rotarix (RV1), both live attenuated and should be given before the transplantation
3.CMV colitis can be managed with intravenous ganciclovir (GCV) or oral valganciclovir (valGCV) duration of antiviral therapy depends on
the patient’s clinical and virologic responses should be at least for 2-3 weeks provided that patient symptoms are resolved and repeated CMV PCR is no more detected at least for two consecutive cmv pcr tests.
What is the level of evidence provided by this article? narrative review level 5
I like your well-structured rather extensive summary, level of evidence, analysis and take home messages typed as conclusion.
I like your step-wise diagnostic approach.
Posttransplant diarrhea
Posttransplant diarrhea is one of the commonest complications that negatively impact the graft and patient survival in organ transplant recipients (OTRs), it is usually underestimated by physician that is why its incidence is incorrect but in general, its incidence is cumulative; increased in the third year more than second year which is more than first year posttransplant.
Graft loss and death are two fold increased if compared with OTRs without diarrhea especially non infectious diarrhea.
Several risk factors are present in all OTRs like hospitalization, susceptibility to infection by various organisms, immunosuppressive medications like mycophenolate mofetil (MMF), other drugs like antibiotics.
Definition of chronic diarrhea post solid organ transplant:
It is three or more times of motion of unformed stool per day for at least one month, and is associated with weight loss.
Causes of diarrhea:
Posttransplant diarrhea may be infectious or noninfectious, the commonest cause of infectious is cytomegalovirus (CMV) which is responsible for fifty percent of the cases, and the commonest cause of noninfectious diarrhea which is drug related is immunosuppressive medication which is MMF.
1- Infectious causes of diarrhea:
a- Bacterial causes like clostridium difficile and bacterial overgrowth which are the commonest bacterial causes, other bacteria can cause diarrhea like campylobacter spp., salmonella spp., and Escherichia coli (E-coli).
b- Viral causes like CMV which is the commonest viral infection, other viruses like Noroviruses, Rotavirus, and Adenovirus.
c- Parasitic causes like Giardia, Entamoeba, Cryptosporidium and Microsporidium.
2- Non-infectious causes: mostly done after six months of transplantation.
a- Immunosuppressive medications like MMF which is the commonest, others like cyclosporin, sirolimus and tacrolimus.
b- Non-immunosuppressive medications like antibiotics, laxatives, proton pump inhibitors, antidiabetics, protease inhibitors.
3- Other causes:
a- Malabsorption
b- Cancer colon
c- Inflammatory bowel disease (IBD)
d- Rare causes like posttransplant lymphoproliferative disease (PTLD), graft versus host disease (GVHD).
Non-infectious diarrhea:
1- The commonest cause of non-infectious diarrhea is MMF which represents twelve to thirty percent of the cases, its mechanism is unknown, but may be related to partial dependance of gastrointestinal epithelial cells on de novo purine synthesis for growth and proliferation so become vulnerable to mycophenolic acid (MPA) inhibition, duodenal villous atrophy (DVA), crypt distortion (IBD like disease), apoptosis (GVHD like disease), direct intestinal cell injury, imbalance between tolerance and immunity, defect in regeneration of intestinal cells, infection may be associated.
DVA is present in the most of cases of MPA associated diarrhea, and it improved after its dose reduction and resolves completely after its cessation.
GIT symptoms associated with MMF is dyspepsia, epigastric pain and diarrhea which are associated with poor quality of life.
Its management:
a- It responds to dose reduction.
b- Shift to enteric coated mycophenolate sodium EC-MPS, which is associated with improvement in gastrointestinal symptoms.
c- Shift to azathioprine, this may have negative impact on graft survival on long term and it increased risk of skin cancer especially squamous cell carcinoma, hence, has negative impact on patient survival on long term, but can save the situation on short term follow up.
d- It is usually associated with poor graft outcome, because of full MPA exposure is associated with less biopsy proven acute rejection.
e- When facing considerable GIT symptoms, therapeutic dose monitoring of MPA should be implemented to control dose reduction.
2- Calcineurin inhibitors (CNI) like cyclosporin and tacrolimus result in mild diarrhea, its mechanism is related to stimulation of intestinal motilin receptors, no need for dose reduction or change medication, but gastrointestinal symptoms are increased when shifting from cyclosporin to tacrolimus in the presence of MPA, as it increases the level of MPA.
3- Sirolimus can induce mild self limited diarrhea, of unknown mechanism, and may be related to jejunal villous atrophy and stimulation of motilin receptors like CNI.
Double Hit theory
Means mixed infective organism with MPA toxicity, like cryptosporidium especially within tacrolimus.
Norovirus: has biphasic illness in immunocompromised patients, acute phase which includes fever, nausea, vomiting, abdominal pain, watery diarrhea ten to twenty times per day , and can induce acute kidney injury, then chronic phase which involves episodes of diarrhea alternating with normal stool.
Clostridium difficile infection (CDI): it is the commonest hospital acquired infection causing diarrhea especially in the first month post renal transplant, has several risk factors like age more than fifty five years, heavy immunosuppression by antithymocyte globulin (ATG), retransplantation, type of transplanted organ; highest risk among liver transplant recipients, also recent antibiotic use with special attention to fluoroquinolones which remains the single most common risk factor, may present asymptomatic, diarrhea, intestinal obstruction, or toxic megacolon.
CMV infection which is the commonest viral infection and is related to the degree of immunosuppression, the seropositive donor to seronegative recipient remains the single commonest risk factor, the target organ of CMV is GIT.
Management (diagnosis and treatment):
1- CDI
a- diagnosed by real time PCR or fecal enzyme immunoassay which is easy, less expensive, and has high sensitivity and specificity.
b- Treated by metronidazole 500 mg three times daily for two weeks, but in severe cases oral vancomycin should be given for two weeks.
c- Tigecycline, and ramoplanin restored to severe or recurrent cases.
d- Human monoclonal antibodies against C. difficile toxin A and B is introduced recently.
e- Fecal microbiota transplantation (FMT) ; installation of processed feces donor into the colon or duodenum of the recipient.
2- Cryptosporidium diagnosed by immunofluorescence assay, ELISA which has 100% sensitivity and specificity, and has no specific treatment.
3- CMV gastrointestinal disease associated
a- can be diagnosed by endoscopic biopsy for histopathological diagnosis which revealed swollen cells with intranuclear viral inclusions giving owl eye appearance or can diagnosed by immunohistochemistry staining for PP65, both are gold standard methods to diagnose CMV colitis , this regardless CMV PCR.
b- Can be treated by intravenous ganciclovir or oral valganciclovir if there is no risk of malabsorption due to vomiting and diarrhea (may be early in disease), this for at least two weeks and can be extended according to the clinical situation, and should not be stopped except after the following: at least two weeks duration of treatment, no clinical symptoms present, no detectable viremia if initially present.
Oral valganciclovir should be given as secondary prophylaxis for 1-3 months.
4- Norovirus diagnosed by PCR of stool or vomits, and treated by rehydration, antimotility drugs, and supportive treatment.
It is the important cause of posttransplant diarrhea, and its chronicity leads to holding of MPA which expose to rejection.
No specific treatment or vaccine , so, implementation of hand hygiene instructions and environmental sanitation are the key for prevention.
5- Rota virus diagnosed by PCR, no specific treatment and can be prevented by live attenuated rota vaccine which should be given pretransplant only and is contraindicated posttransplant.
6- Adenovirus diagnosed by viral culture and PCR, has no specific treatment.
Conclusions and take home message:
1- Posttransplant diarrhea should taken into consideration and not to be neglected.
2- Medical team should be aware by all causes of diarrhea and its management.
3- Drug induced diarrhea rather than MPA should be kept in the mind.
level of evidence 1
Level 1 evidence!
Can you please explain that, dear Dr Riham.
1.Please summarise this article.
Introduction
The recipient’s quality of life, graft survival, & mortality are all negatively impacted by chronic diarrhea pos-KTX.
Clinicians must assess diarrhea in KTX recipients, try to determine its source, & distinguish between infectious & noninfectious causes of diarrhea.
Epidemiology
The cumulative incidence of diarrhea is 11.5, 17.5, & 22.6% at 1, 2, & 3 years post-KTX, respectively (UNOS registry).
Yet, 53% of participants in a large survey of KTX recipients reported having diarrhea, despite their doctors’ estimates of the prevalence being only 6.9%. This finding shows how frequently post-TX diarrhea goes undiagnosed by healthcare professionals.
Most of the diarrheal events are self-limited & lack a known cause. The most frequent causes were CMV GI infection, norovirus infection, & Clostridium difficile infection.
Causes of post-transplant diarrhea
Data from the DIDACT study
Diarrhea resolved in 50% of patients either by cessation of diarrhea-associated non-IS drugs or by the treatment of concurrent infections (mostly Campylobacter or CMV).
In the remainders, changes in IS therapy (mostly MMF) led to remission in 2/3 of cases.
CMV was the most prevalent infection, & an infectious etiology of post-TX diarrhea was found in 50% of cases. Medication use is the 2nd most common reason.
Noninfectious causes of diarrhea
MMF has the highest prevalence (RR 1.57), & numerous IS medications frequently used in TX may cause diarrhea.
Dose reduction is generally followed by a decline or cessation of diarrhea.
It is unclear how MMF causes diarrhea. Two distinct histological patterns are seen: (i) IBD-like MPA-associated toxicity with predominant crypt distortion, & (ii) GVHD like type with predominant apoptosis.
It’s debatable whether switching from MMF to EC-MPS helps lessen symptoms of diarrhea. According to a recent RCT, patients who switch from MMF to EC-MPS may have a marginally but significantly higher likelihood of returning to the target MPA levels than those who stay on MMF.
Switch from MPA to AZA is usually avoided because of risk of reduced graft survival with AZA versus MMF.
Depending on the dosage & length of treatment, 29–64% of patients on tacrolimus may experience diarrhea.
SIR causes self-limiting diarrhea in 14–42% of patients.
Both ATG & OKT3 can cause diarrhea in 1/3 of patients; this diarrhea is self-limiting (lasts 3–4 d).
Infectious causes of post-KTX diarrhea
CMV & C. difficile (CDI):
The most important risk factor for CMV disease is D+/R– GI involvement (40% of patients). Other risk factors are D+/R–status, lymphodepleting antibodies & more potent IS regimens.
CDI is the most common cause of nosocomial diarrhea & accounts for most infectious diarrhea in the 1st months post-TX. The incidence of CDI is 3.5–4.5% in adult KTX patients. Risk factors include age > 55 years, use of ATG, re-TX & the type of organ TX (highest in liver TX). Recent antibiotic use, particularly fluoroquinolone, is the single biggest risk factor. Mortality rate from CDI is 2.3 to 8.5%.
Norovirus:
Lately, chronic norovirus infection has become one of the most common infectious causes (17–26% of cases). This suggests that many infectious causes of diarrhea may have previously been misdiagnosed as being caused by IS medications, resulting in inappropriate diagnostic & treatment approaches.
Rotavirus infections:
occur in 1.5% of SOT recipients.
AdV:
Viremia in the 1st few months post-TX (6.5–22.5%), & GI symptoms occur in 10%.
Microsporidia
Cryptosporidia (Cryptosporidia parvum & Cryptosporidia hominis).
Diagnosis
CDI:
Cell-based cytotoxicity assay is the gold standard test
Real-time PCR tests or fecal enzyme immunoassays (simpler, less expensive, & faster) are commonly used.
Tissue-invasive CMV disease:
CMV viremia is suggestive of the diagnosis.
Laboratory tests include biopsy, CMV IgM & or elevation in IgG, conventional culture, Shell Vial assay, CMV pp65 Ag, PCR, & Real-time PCR.
Norovirus:
Diagnosed by PCR run on stool, vomitus, foods & environmental specimens.
Rotavirus:
Immune-based assays rapidly detect rotavirus antigens in stool.
AdV:
Diagnosed by viral culture, direct antigen detection, histopathology & PCR.
Cryptosporidiosis:
Oocysts in the stool
Modified acid-fast stains.
IF assays & ELISA (100% sensitivity & specificity)
Diagnostic approach from DIDACT study
1. Review all medications & stop unnecessary ones.
2. Specific testing for different causes of the diarrhea, including bacterial culture, assessment for ova & parasites, PCR for CMV & C. difficile & stool lactoferrin.
3. Breath test for bacterial overgrowth
4. Reduction in immune suppression
5. Colonoscopy.
6. If these tests are negative & the diarrhea persists, empiric anti-diarrheal medications, probiotics &/or lactose-free diet tried.
Treatment of major infectious causes
Clostridium difficile
First episode:
Metronidazole 500mg TDS/10–14 days
Severe disease:
Vancomycin PO QID/10–14 days
Fidaxomicin 20mg BID/10 days
First relapse: same for 1stepisode
Second relapse:
Vancomycin taper with pulse
Third relapse:
Consider fecal microbiota TX (FMT), prolonged oral vancomycin.
CMV:
Oral valganciclovir
IV ganciclovir (if decreased absorption)
Norovirus:
Rehydration
Antimotility drugs
Reduction in IS drugs.
AdV:
Supportive care & IS reduction.
Microsporidia-related diarrhea:
Fumagilin may lead to sustained clearance with minimal IS reduction.
Drug-induced thrombocytopenia limits its use.
Cryptosporidium:
No specific therapy
No difference between therapy with nitazoxanide or paromomycin & placebo.
Conclusions
=========================
2.What is the level of evidence provided by this article?
Level V
I like your well-structured rather extensive summary, level of evidence, analysis and take home messages typed as conclusion.
I like your step-wise approach.
Causes and management of postrenal transplant diarrhea: an underappreciated cause of transplant-associated morbidity
Please summaries this article.
Causes of post-transplant diarrhea
A- Infectious diarrhea
B-Non-infectious diarrhea
· Drug induced: MMF, CNI, sirolimus, antibiotics, proton pump inhibitors
· Malignancy such as cancer colon, PTLD
How to approach:
The main important issue is to differentiate between infectious causes from noninfectious causes
v detailed history should be taken about onset, course and durations of diarrhea and if there is any symptoms of infection like fever, upper GIT manifestations and any other family member developed same picture.
v Examination: looking for any signs of infection or malignancy
v Investigations include:
· Basic investigations include: UE1, electrolytes including magnesium, Complete blood count, c reactive protein, Stool analysis and culture, CL.deficiel toxin, CMV PCR, tacrolimus level
· stool multiplex PCR for viral if available which include screening for three viruses, nine bacteria and three parasites.
· colonoscopy, and biopsy may be needed because CMV colitis with negative PCR occurs in 15% of cases.
Management
1. Supportive therapy including intravenous fluids for treatment of dehydration
2. Immunosuppression
a. Shifting from MMF to enteric coated mycophenolate maybe of benefit.
b. To keep tacrolimus level on the lower side
3. Treatment of the cause
What is the level of evidence provided by this article?
I like your well-structured rather extensive summary, level of evidence, analysis and take home messages typed as conclusion.
I like your step-wise approach.
Caution: Not many patient benefit from conversion conversion of MMF to myfortic. Please change to azathioprine or to a smaller dose sirolimus as an adjunct if that patient can not be give azathioprine to avoid interaction with allopurinol.
Week 10, Causes and management of postrenal transplant diarrhea:
Summary
· Chromic diarrhea after transplantation is common and associated with increased morbidity, hospitalization, allograft loss and poor quality of life.
· Steatorrhea and malabsorption can lead to secondary enteric hyperoxaluria with subsequent oxalate nephropathy (intense inflammation of allograft).
· Diarrhea is defined as > 3 loose stool/day.
· Persistent (>2 weeks) and chronic (> 1month).
· Causes: either infectious or none infectious, as exposure to polypharmacy as immunosuppressive drugs, antibiotics and other drugs.
· Infectious causes as: (most common are CMV and Clostridium difficile)
o Viral: CMV (most common), Norovirus, Rotavirus, Adenovirus, Sapobavirus
o Bacterial: Clostridium difficile, Campylobacter, Salmonella, E coli, Bacterial overgrowth.
o Parasitic: Cryptosporidium, Giardia, Isosopora Cyclospora, Microsporidium and Entameoba.
· None infectious causes:
o Drug induced:
§ IS drugs (MMF mainly, CNI and MTORi).
§ Others as (laxatives, anti-diabetics, PPI, anti arrhthmic drugs).
o Other disorders: GVHD, IBD, PTLD, cancer colon, malabsorption and microscopic colitis).
· Identification of the cause is crucial, as reduction of IS in case of suspected drug induced diarrhea can lead to AR and graft loss and in addition the delay in identification of microbial cause of infectious diarrhea can lead to poor patient and graft outcome.
· Mechanism of MMF induced diarrhea:
o It inhibits de-novo pathway of purine synthesis essential for growth, Proliferation and generation of enterocytes.
o IBD-like toxicity (predominant crypt distortion).
o GVHD associated toxicity (predominant apoptosis).
o Ttt of MMF induced or associated diarrhea requires either: Shift from MMF to EC-MPS that may be beneficial, or short-term conversion to AZA (while long term graft outcome is lower with AZA than MMF in addition to higher risk of skin cancer).
· Mechanism of TAC induced diarrhea:
o It occurs in 30-60 % of cases, it may stimulate intestinal motilin receptors, but it is usually mild, self-limited and not require drug discontinuation.
o Shift to extended release (advagraf) may be beneficial.
· MTORi induced diarrhea:
o It occurs in 14-40 % of cases, it is related to jejunal villous atrophy, it is usually self-limited.
· ATG induced diarrhea:
o Use of ATG can activate T cells to release TNF which then interferes with Na ion absorption and disrupts the intestinal mucosal barrier.
· Infectious diarrhea:
o Norovirus: has 2 phaseshttps://s.w.org/images/core/emoji/14.0.0/svg/2639.svg acute phase; presented with nausea, vomiting, significant diarrhea (10–20 watery stools per day), abdominal pain and sometimes fever. Then followed by a chronic phase (cycles of relatively normal stools followed by periods of poorly formed stools).
o CMV infection: occurs in 7 % of KTRs, most common site involved is GIT (occurs in 1/3 patents, risk factors (strong IS as ATG induction, D+/R-).
o Rotavirus, limited data, but more common in children and in liver transplantation.
o Adenovirus: is common in early posttransplant course (isolated in 6.5–22.5% of cases).
o C. difficile infection occurs in 3.5–4.5%, most common nosocomial infection in 1st month posttransplant, more common in liver transplant and with use of broad-spectrum antibiotics as quinolones, it is associated with 2.3-8.5% risk of mortality. It can lead to diarrhea, intestinal obstruction, abscesses or toxic megacolon.
· Protozoa: microsporidia (severe diarrhea and weight loss) and Cryptosporidia (severe acute diarrhea, chronic diarrheal illness + extraintestinal infection.
· Diagnosis:
o The first-line microbiologic stool investigations is standard stool cultures for pathogenic bacteria, examinations for parasites and fungi, C. difficile toxin assay and quick tests for rotavirus, adenovirus and norovirus.
o In case of fever, CMV D+/R-, cytopenia, liver enzymes studies, and plasma CMV Q-PCR is indicated.
o CMV tissue invasive disease (+VE PCR (viremia, but -ve in 15 % of cases) + PCR can be performed on whole blood, plasma and leukocytes. Definitive diagnosis of CMV depends on endoscopy and biopsy (characteristic owl eye appearance, swollen cells with intranuclear inclusions, or by immunohistochemical staining for pp65.
o Norovirus: diagnosed by PCR can be run on stool or vomitus.
o Rotavirus: ELISA, cell culture, real time-PCR and electron microscopy.
o Adenovirus: viral culture, direct antigen detection, histopathology and PCR, clinical manifestations and biopsy help to differentiate infection from carrier stae.
o Clostridium is diagnosed by fecal enzyme immunoassays or real-time PCR test (easier than standard cell-based cytotoxicity assay).
o Cryptosporidium is diagnosed by oocyst visualization in the stool and Immunofluorescent assays as ELISA.
o Breath test is used for diagnosis of bacterial overgrowth
· Treatment= treatment of the cause.
o Clostridium difficile is treated by 10-14 days of metronidazole or oral vancomycin for severe cases. Fidaxomicin, ramoplanin and tigecycline are newer antibiotics that can be use in severe or recurrent disease. In addition, human monoclonal antibodies against C. difficile toxins A and B and fecal microbiota transplantation (FMT) in refractory cases (however FMT is debatable and may lead to adverse effect in transplant population).
o Protozoa: No specific treatment against cryptosporidium and neither nitazoxanide or paromomycin had beneficial effect over placebo while fumagilin is very effective in treatment of microsporidia.
o CMV colitis: IV ganciclovir (GCV) or oral valganciclovir (valGCV). IV is used in patients with vomiting and diarrhea). Optimal duration is based on patient’s clinical and virologic responses, stop treatment at least 2 weeks after clinical resolution of symptoms and negative PCR. Recurrent CMV disease is reported in 15–35% of SOT recipients with tissue-invasive CMV disease, so oral valganciclovir may be recommended for 30–90 days after successful treatment.
o Norovirus (ttt is mainly supportive with fluids and anti-motility+ reduction of IS). No available vaccine and many suggested treatment lines as oral or IV immunoglobulin, breast milk, ribavirin and nitazoxanide seem ineffective. So, hand hygiene is the most important strategy to prevent infection.
o Rotavirus (ttt is supportive), prevention (hygiene+ 2 licensed oral vaccine (RotaTeq and Rotarix), but they are live attenuated (used only pretransplant, and contraindicated after transplant)).
o Adenovirus (ttt is mainly supportive with fluids and anti-motility+ reduction of IS).
· If all diagnostic tests are negative and the diarrhea persists, empiric antidiarrheal medications, probiotics and/or lactose-free diet should be tried.
· Esophagogastroduodenoscopy and colonoscopy with biopsies to investigate persistent diarrhea in KTR is still debatable. However, it may be of value in the following situations, intestinal ulcers in PTLD, CMV colitis with concurrent -ve plasma CMV PCR, severe duodenal villous atrophy that indicates change MMF and post transplantation de-novo IBD that is 10 times more common than the general population.
· Prior to implicating IS medication as the culprit, a meticulous evaluation for other possible causes of diarrhea should be conducted. Infectious agents and the concomitant use of other diarrhea genic medications such as PPI, antibiotics and diuretics must first be excluded.
· Level of evidence: narrative review (level 5)
Summary
Introduction
Chronic diarrhoea is a common complaint in the post-transplant period that is overlooked by both the clinician and recipient.
Though overlooked, chronic and severe diarrhoea may lead to steatorrhea and malabsorption.
Enteric hyoeroxaluria may occur leading to oxalate nephropathy.
Thus chronic diarrhoea affects the recipient’s quality of life, graft survival and mortality.
Poly-pharmacy and an immunosuppressed state and the most significant risk factors.
Causes of diarrhoea
There is limited data on the causes of diarrhoea in kidney transplant recipients.
The DIDACT study the most common cause of diarrhoea was infections- CMV and drug related.
Immunosuppressive drugs
Most immunosuppressive medications cause diarrhoea with the highest incidence with MMF.
Diarrhoea caused by MMF disappears with dose reductions.
MMF and EC-MPS both have been implicated to cause diarrhoea; and whether switching MMF to EC-MPS helps alleviate symptoms is a matter of debate.
Two histological morphological types have been identified: Inflammatory bowel disease like MPA associated toxicity where there is disruption of crypt and graft versus host like MPA associated toxicity-there is predominant apoptosis.
Tacrolimus may also cause diarrhoea though it depends with the dose and the duration, however unlike MMF induced diarrhoea, it has a mild course and doesn’t require dose reduction.
Sirolimus has also been implicated to cause diarrhoea though it is self-limiting lasting for approximately 2 weeks.
Lymphocyte depleting agents-ATG and OKT3 also cause diarrhoea which resolves spontaneously in 3-4 days.
Infections
C.difficile, noravirus and CMV are the most common causes.
Noravirus- biphasic illness in the immunocompromised. Acute phase characterised by fever, vomiting, nausea, abdominal pain and diarrhoea. Chronic phase where there are cyclical phases of well formed stools alternating with periods of poorly formed stools.
CMV- Risk factors include CMV seropositivity status pre-transplantation D+/R-, use of lymphocyte depleting agents and more potent immunosuppressive regimens.
C.difficile- accounts for most cases of infectious diarrhoea in the firsts months post-transplant. Most significant risk factor is recent antibiotic use with fluoroquinolones associated with the highest risk.
Diagnosis and therapeutic strategy
It is imperative to differentiate infectious and non-infectious causes to avoid unnecessary dose reductions.
C.difficile – gold standard for diagnosis is cell based cytotoxicity assay, fecal enzyme based immunoassay and real time PCR can be used. Treatment is with either metronidazole or vancomycin or fidaxomicin.
There is limited data on the use of FMT in the transplant population.
CMV- definitive diagnosis relies on endoscopic evidence of GIT involvement- Owl eye intranuclear inclusions and IHC staining for pp65. Treatment is with IV ganciclovir or oral valganciclovir.
Optimal duration is dependent on patient’s clinical and virological response.
Before discontinuation of treatment the following criteria must be meant:
Because of risk of recurrence, CMV prophylaxis for 30-90 days after treatment of tissue invasive disease is recommended.
Noravirus – It is the key factor in the induction of post transplant diarrhoea, while MMF plays a critical role in the chronicity of the virus by impairing the clearance of the virus and repair of the intestinal epithelium.
PCR on stool, food and vomitus can be done for diagnosis.
First line in management is supportive with fluid and electrolyte replacement.
Second is immunosuppressive reduction.
Currently there are no vaccines available, prevention is thus by proper hand hygiene and environmental sanitisation.
Rotavirus- diagnosed via immune based assay.
Management is mainly supportive.
Currently there are 2 vaccines available which are live attenuated, hence should be given prior to transplantation and contraindicated in the post-transplant period.
Adenovirus- can be diagnosed via culture, antigen detection, PCR and histopathology. Detection in patient’s sample should be correlated with clinical and histopathology to distinguish asymptomatic infection.
Management is supportive and reduction of immunosuppression.
DIDACT study.
Large prospective study that was done to identify the cause of diarrhoea post renal transplantation.
Most common cause was CMV and campylobacter jejunii.
50% diarrhoea resolved without change of immunosuppressive therapy.
A third of patients diagnosed with bacterial overgrowth responded to antibiotics.
Stepwise approach
First step of evaluation of diarrhoea is drug evaluation and stopping any medication that are not immunosuppressive that could be associated with the diarrhoea.
Next is evaluation of the diarrhoea with culture, PCR, evaluate for parasites, C.Difficile, adenovirus, rotavirus and noravirus.
If negative empirical antidiarrhoeal treatment, lactulose free diet and probiotics should be tried.
If diarrhoea persists then reduction of immunosuppression should be considered.
MMF should be switched to EC-MPS, if diarrhoea still persists then both should be withdrawn.
Endoscopy and colonoscopy with biopsy should be considered to investigate persistent diarrhoea.
Conclusion
Prior to implicating immunosuppressive agents a meticulous evaluation of other possible causes should be evaluated.
Other non-immunosuppressive medications and infections should be ruled out.
Further studies are required to evaluate the true prevalence, risk factors, and complications of diarrhoea caused by noravirus,rotavirus and adenovirus.
Level of evidence: V
I like your well-structured rather extensive summary, level of evidence, analysis and take home messages typed as conclusion.
I like your step-wise approach.
Caution: Pleas change to azathioprine or to a smaller dose sirolimus as an adjunct if that patient can not be give azathioprine to avoid interaction with allopurinol.
Causes and management of post-renal transplant diarrhea: an underappreciated cause
of transplant-associated morbidity.
INTRODUCTION.
One of most common complications in post kidney transplant recipients is chronic diarrhea which is mainly due to common sharing risk factors such as immunocompromised status which lead to infectious diarrhea as a common cause of diarrhea , drugs induced diarrhea due to immunosuppressive medications and others, as there are variety of causes so single standard approach is difficult and not clear so far.
EPIDEMIOLOGIC IMPACT
The cumulative incidence of diarrhea has been reported to be 11.5, 17.5 and 22.6% at 1, 2 and 3 years after renal transplantation, respectively, chronic diarrhea is some studies shown that it was associated with a two-fold increase in graft loss and risk of death. Other study shown that the most common identifiable causes included Clostridium difficile
infection, norovirus infection, and cytomegalovirus (CMV) gastrointestinal infection.
About 32% of individuals taking Mycophenolate mofetil (MMF) or mycophenolic acid and diagnosed with diarrhea had reductions or changes in their immune suppression.
CAUSES OF DIARRHEA: GENERAL.
DIDACT study shown that an infectious cause of post-transplant diarrhea is present in approximately 50% of cases with CMV being the most common pathogen and the next most frequent cause is related to medication use.
CAUSE OF DIARRHEA: IMMUNOSUPPRESSIVE DRUGS.
Unfortunately many of the immunosuppressive agents commonly used in transplantation may cause diarrhea, with the highest incidence associated with MMF and still the main cause not well known but the theory mainly due to purine inhibition effect of KIT epithelial cells, tacrolimus also lead to diarrhea in 29–64% of patients depending upon the dose and duration of drug usage and shifting to extended release formulation of tacrolimus shown some improvement.
CAUSE OF DIARRHEA: INFECTIONS.
Chronic norovirus infection has only recently emerged as one of the leading infectious causes (approximately 17–26% of severe post-transplant diarrhea), usually is biphasic which consist of the initial acute phase (10–20 watery stools per day), abdominal pain and sometimes fever then followed by a chronic phase, when patients can experience cycles of relatively normal stools followed by periods of more poorly formed stools.
CMV also one of the most common cause of diarrhea post kidney transplant and the most significant risk factor for the development of CMV disease is seropositive donor/seronegative recipients gastrointestinal involvement that occurs in up to 40% of patients.
The incidence of C. difficile infection (CDI) in transplanted patients has been reported to be approximately 3.5–4.5% in adult renal transplantation patients.
DIAGNOSIS AND THERAPEUTIC STRATEGY.
1-The gold standard for C. difficile detection is the cell-based cytotoxicity assay. However, most laboratories use the easier, less expensive and more rapid fecal enzyme immunoassays or real-time PCR test. These tests have high sensitivity and specificity (90%) for the detection of CDI and initial treatment of SOT includes fidaxomicin, metronidazole or vancomycin, with vancomycin, now there is a good effect for use of human monoclonal antibodies against C. difficile toxins A and B and new trend for fecal microbiota transplantation (FMT).
2-Cryptosporidiosis is generally diagnosed by visualization of oocysts in the stool, there is no specific TTT but studies shown that no difference between nitazoxanide or paromomycin and placebo for immunosuppressed
patients with cryptosporidiosis.
3-CMV colitis will have evidence of CMV replication in the blood via PCR, although approximately 15% will not, so the gold standard for diagnosis histopathology by endoscopy and patients
with CMV colitis can be managed with intravenous ganciclovir (GCV) or oral Val ganciclovir .
4-xTAG Gastrointestinal Pathogen Panel (Luminex Corp., Austin, Texas, USA), which allows for simultaneous detection of three viruses (norovirus G-I/G-II, rotavirus A and AdV 40/41), nine bacteria and three parasites, mainly treatment is supportive for norovirus with oral or intravenous immunoglobulin, breast milk, ribavirin and nitazoxanide.
5-We can use vaccine against rotavirus but before transplantation as there are live attenuated vaccine.
Finally, the approach will be consisting of bacterial culture, assessment for ova and parasites, PCR for CMV
and C. difficile and stool lactoferrin. The next steps were breath test for bacterial overgrowth, reduction in immune suppression and colonoscopy.
CONCLUSION.
Diarrhea post kidney transplant has deleterious effect on graft and recipient survival and we need to be more systematic and approached when dealing with this issue and not starting our approach by blaming the immunosuppression and should be familiar with other infections causes and still need more studies to assess the prevalence of the causes and looking for new vaccination and anti-viral therapy.
Level of evidence: V (a narrative review article).
I like your well-structured rather extensive summary, level of evidence, analysis and take home messages typed as conclusion.
Introduction
Chronic diarrhea after kidney transplantation is a common complaint, often assumed by clinicians and patients to be an inevitable part of kidney transplantation.
This is neglected despite its association with fatigue, increased hospitalizations and negative impacts on recipient quality of life.
Renal transplant recipients share certain predisposing characteristics for the development of posttransplant diarrhea, among the more significant of which include a generalized immunosuppressed state and exposure to polypharmacy, most notably broad-spectrum antimicrobial therapy.
The main causes of diarrhea after transplantation are infections, immunosuppressive drugs, antibiotics and other drugs.
We review the current literature regarding both infectious and noninfectious diarrhea in renal transplant recipients and provide a diagnostic algorithm for the evaluation of posttransplant diarrhea
Epidemiology
The cumulative incidence of diarrhea has been reported to be 11.5, 17.5 and 22.6% at 1, 2 and a Renal Division, Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
In a survey of 4232 Scandinavian renal transplant recipients, 53% of participants reported diarrhea, whereas the incidence estimated by their physicians was only 6.9% [1&.
The burden of adverse gastrointestinal symptoms inversely correlates with indicators of life quality in kidney transplant recipients.
A recent study from a single transplant center in the United States reviewed the diagnostic yield of tests for diarrhea among hospitalized transplant recipients over a period of 18 months.
The majority of the diarrheal episodes had no identifiable cause and were self-limited.
About 32% of individuals taking mycophenolate mofetil or mycofenolic acid and diagnosed with diarrhea had reductions or changes in their immune suppression
General causes of diarrhea
There are relatively little data regarding the cause of posttransplant diarrhea.
A large, prospective study – the Diarrhea Diagnosis Aid and Clinical Treatment (DIDACT) study – was conducted to identify the cause of posttransplant diarrhea in renal transplant recipients .
. There was a resolution of diarrhea in approximately 50% of patients either by discontinuation of diarrhea-associated nonimmunosuppressive drugs or by the treatment of concurrent infections.
In the remainder of patients, changes in immunosuppressive therapy led to remission of diarrhea in about twothirds of cases.
Considered together, the data from the DIDACT study indicate that an infectious cause of posttransplant diarrhea is present in approximately 50% of cases with CMV being the most common pathogen.
The most frequent cause is related to medication use.
Causes of diarrhea ; immunosuppressive drugs
Noninfectious diarrhea is not uncommon among renal transplant recipients and has been reported to increase the risk of graft loss and mortality.
Drug-induced diarrhea is a major problem as many of the immunosuppressive agents commonly used in transplantation may cause diarrhea, with the highest incidence associated with MMF.
Chronic diarrhea after kidney transplantation has negative impacts on the recipient’s quality of life, graft survival and mortality.
It is important that clinicians evaluate and attempt to diagnose the cause of diarrhea and make a distinction between noninfectious and infectious causes of diarrhea in kidney transplant recipients.
Prospective studies are needed to better assess the true prevalence, risk factors and complications of diarrhea by norovirus, rotavirus and AdV in kidney transplant patients
Dialysis and transplantation
Dose reduction is followed by the decrease or the disappearance of diarrhea ,MMF and enteric-coated mycophenolate sodium (EC-MPS) have long been implicated in posttransplant diarrhea.
A recent meta-analysis identified that the relative risk of diarrhea associated with the use of MMF is 1.57.
One possible mechanism is that gastrointestinal epithelial cells may be partially dependent on the de-novo pathway of purine synthesis for growth and proliferation, and are vulnerable to mycophenolic acid inhibition leading to diarrhea.
Whether switch of immunosuppression from MMF to EC-MPS helps reduce diarrhea symptoms is a matter of debate.
A recent randomized and controlled open study suggested that patients with MMF -related diarrhea who switch to EC-MPS may have a slightly, yet significant, greater chance of returning to a target MPA doses than those maintained on MMF.
Renal transplant scientific registyry showed that
The use of tacrolimus may be associated with diarrhea in 29–64% of patients depending upon the dose and duration of drug usage.
The mechanism by which calcineurin inhibitors cause diarrhea remains unclear, it is hypothesized that a macrolide structure may result in stimulation of the intestinal motilin receptors.
Most of the tacrolimus-associated gastrointestinal side-effects have a mild course and rarely require drug discontinuation.
A recent study in renal transplant recipients has reported a decrease in the incidence of gastrointestinal symptoms, including diarrhea, after conversion to a daily, extended release formulation of tacrolimus.
One mechanism by which these antibodies may cause diarrhea is by activating T cells to release tumor necrosis factor which interferes with sodium ion absorption and disrupts the intestinal mucosal barrier.
Causes of diarrhea ; infection
Diarrhea is commonly infectious ,and the microbes usually responsible are CMV andC.defficile , but the literature describes a wide range of organisms in solid organ transplant (SOT) recipients .
Chronic norovirus infection has only recently emerged as one of the leading infectious This finding suggests that numerous cases of posttransplant diarrhea in the past may have been incorrectly solely ascribed to toxicity of immunosuppressive drugs, leading to diagnostic misconceptions and inappropriate treatments.
In these patients, the course of norovirus infection tends to be more complicated, with up to.
This acute phase is frequently followed by a chronic phase, when patients can experience cycles of relatively normal stools followed by periods of more poorly formed stools.
Causes and management of postrenal transplant diarrhea shin and chandraker
CMV is one of the most common infectious complications affecting SOT patients and is associated with significant morbidity and occasional mortality.
The most significant risk factors for the development of CMV disease is seropositive donor/seronegative recipients gastrointestinal involvement that occurs in up to 40% of patients.
Rotavirus infection was diagnosed in 1.5% of SOT recipients, with most cases occurring in pediatric patients (63%) and in those who received a liver transplant.
A wide range of clinical syndromes associated with AdV in SOT recipients has been described, with the most clinically severe infections involving the transplanted organ or disseminated disease.
Risk factors that are specific to the SOT population include age above 55 years, use of ATG, retransplantation and the type of organ transplanted, with the highest rate among liver recipients.
Cryptosporidia (Cryptosporidia parvum and Cryptosporidia hominis) are intracellular protozoans known to lead to severe acute diarrhea, chronic diarrheal illness and extraintestinal infection in transplanted patients.
Diagnostic and therapeutic
It is important to evaluate and attempt to diagnose the cause of diarrhea in a transplant recipient.
It is imperative that the clinician makes a distinction between noninfectious and infectious causes of diarrhea
Another important factor to consider in the SOT recipient is the consequence of unnecessary reduction in immune-suppressive medications to try and manage diarrhea.
Most laboratories use the easier, less expensive and more rapid fecal enzyme immunoassays or real-time PCR test
These tests have high sensitivity and specificity (90%) for the detection of CDI.
A newer area of interest is the use of fecal microbiota transplantation (FMT) in the management of refractory CDI.
Patients with CMV colitis can be managed with intravenous ganciclovir (GCV) or oral valganciclovir.
. Because recurrent CMV disease has been reported in 15–35% of SOT recipients with tissue-invasive CMV disease, many experts recommend the use of valGCV for secondary prophylaxis for 30–90 days after successful treatment.
Consider reduction in immuniosuppressive drugs
A commercially available assay is the U.S Food and Drug Administration-approved xTAG Gastrointestinal Pathogen Panel (Luminex Corp., Austin, Texas, USA), which allows for simultaneous detection of three viruses, nine bacteria and three parasites
This assay has not yet been systematically tested in the immunocompromised population.
Immune-based assays are most routinely used to rapidly detect rotavirus antigens in stool samples.
Other diagnostic methods such as cell culture, real time-PCR and electron microscopy remain as reference methods because of their high specificity and sensitivity.
The optimization and adjustment of the immunosuppression in patients with persistent posttransplant diarrhea is an unresolved issue that warrants prospective studies.
The first change in immunosuppression consists of MMF dose reduction or switching to EC-MPS, followed by MMF-EC-MPS withdrawal,if symptoms persist
Findings
MMFreduced the relative risk of graft loss by 27%.
The most significant risk factors for the development of CMV disease is seropositive donor/seronegative recipients gastrointestinal involvement that occurs in up to 40% of patients.
It has been estimated that up to 20% of cases will have at least one relapse.
Conclusion
Physicians should be familiar with common cause that result in posttransplant diarrhea.
A directed approach to diagnosis and treatment will help to resolve diarrhea, and prevent potentially life-threatening consequences such as loss of the graft.
Prior to implicating an immunosuppressant medication as the culprit, a meticulous evaluation for other possible causes of diarrhea should always be conducted.
Prospective studies are needed to better assess in kidney transplant patients the true prevalence, risk factors and complications of diarrhea by norovirus, rotavirus and AdV.
Such studies will help guide the care of these patients and provide appropriate prevention and prompt diagnosis.
Development of effective vaccines and antiviral therapies for these common viruses will likely improve patient and graft survival
Level of evidence is 5
I like your well-structured rather extensive summary, level of evidence, analysis and take home messages typed as conclusion.
Please summarise this article.
Causes of post-transplant diarrhia
A- Infectious diarrhea
B- Drug induced
C- Malignancy such as cancer colon, PTLD
D- Others including graft versus host disease, IBD (denovo IBD occurs 10 times more frequent than in general population), malabsorption
Diagnostic work up should include
A- Routine investigations
B- Searching for the cause
–
Management
1- Supportive therapy including intravenous fluids for treatment of dehydration
2- Symptomatic therapy including lopramide to decrease bowel motions which is indicated in persistant (> 2 weeks) or chronic diarrhea (> 1 month)
3- Modulation and monitoring of immunosuppression
–
4- Treatment of the cause
What is the level of evidence provided by this article?
I like your well-structured rather extensive summary, level of evidence, analysis and take home messages typed as conclusion.Typing whole sentence in bold amounts to shouting.
Summary
INTRODUCTION:
Clinicians and patients expect chronic diarrhea following kidney donation. Despite its link with fatigue, more hospitalizations, worse quality of life for recipients, lower graft survival, and higher death, this is ignored. Chronic posttransplant diarrhea may cause enteric hyperoxaluria and steatorrhea. Inflammatory oxalate nephropathy may damage renal transplant function.
Epidemic impact:
Based on Medicare claims in the United Network for Organ Sharing registry, diarrhea was 11.5%, 17.5%, and 22.6% at 1, 2, and 3 years following kidney donation.
DIARRHOEA CAUSES:
nonimmunosuppressive medications linked to diarrhea (antibiotics, laxatives, anti-diabetics, PPIs, and protease inhibitors).
managing many illnesses at once (Campylobacter or CMV).
MMF, cyclosporine, sirolimus, anti-T cell antibody (ATG), and tacrolimus are examples of immunosuppressive drugs.
Infection caused by bacteria
Clostridium difficile (the reported incidence of C. difficile infection (CDI) in transplanted patients is 3.5% to 4.5% among adults who have had renal transplantation.
Bacteria: Campylobacter spp, Salmonella spp. Cyclosporine Bacterial overgrowths Sirolimus Aeromonas spp. Escherichia coli
Viruses Nonimmunosuppressive medications CMV, Norovirus, Sapobavirus, Rotavirus, and Adenovirus
Parasitic Other Giardia, Cryptosporidium, Isosopora Cyclospora, Microsporidium, Entamoeba.
DIAGNOSIS AND THERAPEUTIC STRATEGY:
Cell-based cytotoxicity assays identify C. difficile best. Most labs utilize fecal enzyme immunoassays or real-time PCR, which are simpler, cheaper, and faster.
These CDI tests are 90% sensitive and specific.
Transplanted individuals may carry C. difficile asymptomatically, but most develop diarrhea, intestinal blockage, abscesses, or toxic megacolon. SOT is first treated with fidaxomicin, metronidazole, or vancomycin, with vancomycin recommended for severe infections.
Viremia suggests a tissue-invasive CMV illness. PCR shows CMV replication in blood in most CMV colitis patients, while 15% do not. Serology may help diagnose new-onset infections but not current illnesses in adults.
The PCR test for the diagnosis of norovirus can be run on a stool, vomitus, food, and environmental specimens.
Immunosuppression is the best norovirus treatment. MMF prevents viral clearance and intestinal epithelial healing, which prolongs posttransplant diarrhea. Norovirus causes it.
Immune-based assays are most often employed to quickly identify rotavirus antigens in stool samples.
Epidemiologic research has linked diarrhea to numerous infections. The prospective Diarrhea Diagnosis Aid and Clinical Treatment research used a stepwise diagnostic and treatment flow chart to remove nonimmunosuppressive medication toxicity and address infectious causes before modifying the immunosuppressive regimen.
Esophagogastroduodenoscopy and colonoscopy with biopsies may explore chronic diarrhea following kidney transplantation. First, large bowel posttransplant lymphoproliferative disease may induce intestinal ulcerations, exudative enteropathy, and persistent diarrhea.
Second, CMV colitis with negative plasma PCR is described. Finally, significant duodenal villous atrophy may induce doctors to modify the immunosuppressive regimen faster, whether drug-related or infectious. Lastly, post-transplantation de-novo inflammatory bowel illness is up to 10 times more common. Diarrhea must be treated with fluids, antimicrobials, and immune suppression.
Prospective studies are needed to optimize immunosuppression in posttransplant diarrhea patients.
What is the level of evidence provided by this article?level 5, narrative review
I like your well-structured rather extensive summary, level of evidence, analysis and take home messages typed as conclusion.Typing whole sentence in bold amounts to shouting.
Summary
Introduction
This article a narrative review that focusses on the discussion of both infectious and non-infectious diarrhea post kidney transplant and the evaluation or diagnosis of the same. The study is based on current available literature and outlines the consideration that a targeted approach to post transplant diarrhea is crucial to achieve effective treatment of diarrhea in the patient, protect the allograft, and prevent fatal complications that could be potentially irreversible.
Discussion
Chronic diarrhea, although a relatively common complaint among transplant recipients, is often overlooked by the transplant team as inevitable. However this condition can have serious consequences on the welfare of the graft and the patient. It causes fatigue in the patient, and possible increased period of hospitalization and negative impact on quality of life for the recipient.
Complications that can occur from untreated chronic diarrhea include steatorrhea and malabsorption, leading to enteric hyperoxaluria. Oxalate nephropathy can occur in association with inflammation and negatively impact kidney function of the graft.
In order to treat post transplant diarrhea, it is imperative to first identify the cause of the diarrhea episode in the patient, and to group it under one of two categories, namely, infectious cause and non-infectious cause.This will help the transplant team to treat the diarrhea quickly and effectively.
Infectious causes of diarrhea include the following :
Non-infectious causes of post transplant diarrhea include the following
Diagnosis of the cause is dependent on the cause. However, identification needs to be done as rapidly as possible to avoid damage or loss of allograft.
Infectious causes such as Clostridium difficile can be diagnosed by doing cell based cytotoxicity assay, which is the gold standard for detection of this infection. Real time PCR can also be done for diagnosis. Initial treatment in this case will include fidaxomicin, metronidazole or vancomycin. Vancomycin is used for severe or resistant cases. It is administered orally to the patient. Most cases will, however, respond adequately to metronidazole. Recurrent disease can be treated with fidaxomicin or other newer antibiotics such as ramoplanin and tigecycline.
A newer treatment for refractory CDI includes fecal microbiota transplantation (FMT). Donor feces is processed into the colon of the recipient. The results are still being studied, and appear promising, but are associated with high adverse effects.
CMV is diagnosed through PCR, and endocopic evidence of GI involvement. Histopathology reveals owl’s eye intranuclear inclusions. Treatment includes IV ganciclovir or oral valganciclovir.
Conclusion
Chronic diarrhea is common in the post transplant period following kidney transplant, but it cannot be taken lightly due to the potential for serious complications affecting both the allograft and the recipient’s quality of life. Treatment is based on accurate diagnosis of whether the diarrhea is due to an infectious or non-infectious cause. Different causes have been listed under both these categories in this article, and relevant diagnostic methods as well as treatment strategies have been discussed.
Further studies are needed to speeden the process of identification of cause, as well as prevent the occurrence of post transplant diarrhea in these patients. Effective vaccines and antivirals need to be developed to this regard in order to safely improve both graft as well as patient survival.
Level of evidence
This article is a narrative review with level of evidence 5.
I like your well-structured rather extensive summary, level of evidence, analysis and take home messages typed as conclusion.
Introduction:
Epidemiology:
The cumulative incidence of diarrhea post-transplant is 11.5, 17.5 and 22.6% at 1, 2 and 3 years, respectively.
Posttransplant diarrhea of unknown origin increases graft loss and risk of death by two folds.
Infectious causes of diarrhea post-transplant:
The DIDACT study found that an infectious cause of posttransplant diarrhea is present in approximately 50% of cases, with CMV being the most common pathogen.
CMV and C. difficile, as well as opportunist pathogens, are the main causes of diarrhea in SOT recipients. On these causes, management should concentrate.
Chronic norovirus infection is a leading cause of post-transplant diarrhea in kidney transplant recipients, with up to 94% having chronic diarrhea and 81% having episodes of diarrhea-induced acute renal failure.
CMV is common, mostly affect the gastrointestinal tract. Risk factors include seronegative recipients of seropositive organs, lymphodepleting antibodies, and more potent immunosuppressive regimens.
Rotavirus infection is mostly occurring in pediatric and liver transplants.
Adenovirus viremia is more common in adults early post-trasnplant (6.5–22.5%), involving the transplanted organ or disseminated disease.
The most frequent cause of nosocomial diarrhea in transplant recipients is C. difficile infection (CDI), with recent antibiotic use posing the greatest risk. Mortality rates range from 2.3 to 8.5%, indicating a significant impact.
Microsporidia and Cryptosporidia are the most common parasities in kidney transplant recipients, leading to severe diarrhea, chronic diarrheal illness, and extraintestinal infection.
Immunosuppressive related diarrhea:
Higher incidence with MMF associated diarrhea, with two morphologic patterns: predominant crypt distortion and predominant apoptosis. It resolves by reducing the dose or changing the drug.
Tacrolimus may cause diarrhea in 29-64% of patients, but most side-effects are mild and rarely require drug discontinuation.
Sirolimus causes self-limiting diarrhea due to jejunal villous atrophy and structural homology with promotility macrolide.
ATG and OKT3 therapies can cause diarrhea by activating T cells to release tumor necrosis factor, disrupting sodium ion absorption and mucosal barrier.
Diagnosis and therapeutic strategy:
– The cell-based cytotoxicity assay is the gold standard for C. difficile detection, but most laboratories opt for the simpler, faster, and less expensive fecal enzyme immunoassays or real-time PCR tests. Fidaxomicin, metronidazole, or vancomycin are some first-line treatment. FMT (fecal microbiota transplant), donor feces are injected into the recipient’s colon or duodenum, has a high success rate, but it also has a high rate of negative effects.
– IS reduction and Fumagilin is the treatment of microsporidia (diagnosed by IF assay (100% sensitive and specific), but its use is limited due to drug-induced thrombocytopenia.
– The diagnosis of tissue-invasive CMV disease is suggested by the presence of CMV viremia in the blood. PCR is the most accurate means to diagnose CMV-associated colitis, but it has disadvantages such as lower sensitivity, long incubation period, insufficient virus quantity and the high rate of false negativity. Endoscopic evidence of gastrointestinal involvement is used to confirm CMV, and IV antiviral therapy (GCV or oral valganciclovir). Before stopping antiviral, three criteria must be met: the treatment was given for at least 2 weeks, clinical symptoms have resolved and viral load is no longer detectable.
– Norovirus infection treated by reduction of immunosuppression, supportive care is the first line of treatment with correction of fluids and electrolytes, and oral or intravenous immunoglobulin, breast milk, ribavirin and nitazoxanide have been tried in limited numbers of patients. No vaccines are available for norovirus, Prevention is important, especially hand hygiene and environmental sanitization.
– Real time PCR and stool electronmicroscopy used to detect rotavirus in stool samples, and no antirotaviral therapies are available. Contact precautions are recommended to prevent viral transmission, and two live oral vaccines against rotavirus are licensed for use: RotaTeq (RV5) and Rotarix (RV1).
– Adenovirus can be treated with supportive care and a reduced immunosuppressive regimen, and it can be diagnosed using viral culture, direct antigen detection, histopathology, and PCR. Infections can be avoided in the SOT population with the use of diligent control measures.
Before modifying the immunosuppressive regimen, a stepwise prospectived diagnostic and therapeutic flow chart that aimed to eliminate non-immunosuppressive drug toxicity causative factors and treat infectious causes was used.
Bacterial culture, examination for parasites and ova, PCR for CMV and C. difficile, and stool lactoferrin were all part of the testing. Probiotics, a lactose-free diet, and/or empiric antidiarrheal medications should be tried if the tests are negative.
Conclusion:
The study identify the differential diagnosis of post-transpalnt diarrhea, a stepwise prospective diagnostic and therapeutic flow chart can eliminate non-immunosuppressive drug causative factors and treat infectious causes.
Further studies needed to assess prevalence, risk factors and complication of norovirus, rotavirus and AdV, and development of effective vaccines and antiviral therapies to improve patient and graft survival.
What is the level of evidence provided by this article?
Level of evidence V- review article.
I like your well-structured rather extensive summary, level of evidence, analysis and take home messages typed as conclusion.Typing whole sentence in bold or typing in capitals amounts to shouting.
Summary of the article
Causes and management of postrenal transplant diarrhoea: an underappreciated cause of transplant-associated morbidity
1. The main causes of diarrhea after transplantation are infections, immunosuppressive drugs, antibiotics and other drugs.
2. The cumulative incidence of diarrhea has been reported to be 11.5, 17.5 and 22.6% at 1, 2 and 3 years after renal transplantation.
3. The most common identifiable causes included Clostridium difficile infection(13.1%), norovirus infection(3.9%) and cytomegalovirus (CMV) gastrointestinal infection.
CAUSES OF DIARRHEA:
1. GENERAL
a) diarrhea-associated nonimmunosuppressive drugs(antibiotics, laxatives, anti-diabetic, PPI and protease inhibitor).
b) treatment of concurrent infections (Campylobacter or CMV).
2. IMMUNOSUPPRESSIVE DRUGS: MMF, Tacrolimus(29-64%), Cyclosporine, Sirolimus(14-42%), ATG and anti-T cell antibody (OKT3).
3. INFECTIONS
a) Bacterial infection:
· Clostridium difficile: (the incidence of C. difficile infection (CDI) in transplanted patients has been reported to be approximately 3.5 – 4.5% in adult renal transplantation patients.
· Campylobacter spp, Salmonella spp, Bacterial overgrowth, Aeromonous spp and Escherichia coli.
b) Parasitic: Giardia, Cryptosporidium, Isosopora Cyclospora, Microsporidium and Entameoba.
c) Viruses:
· CMV (40%).
· Norovirus(17-26% of severe posttransplant diarrhea).
· Sapobavirus & Rotavirus.
· Adenoviruses (AdV) viremia is commonly observed in the early posttransplant course (6.5 – 22.5%), and may be associated with gastrointestinal symptoms in 10% of the cases.
4. Other causes: GVHD, PTLD, IBD, Colon cancer, Malabsorption, Microscopic colitis and Malakoplakia.
DIAGNOSIS AND THERAPEUTIC STRATEGY
1. C. difficile:
a) The gold standard for C. difficile detection is the cell-based cytotoxicity assay.
b) fecal enzyme immunoassays or real-time PCR test are mostly used by many laboratories.
c) In general, initial treatment of SOT includes fidaxomicin, metronidazole or vancomycin, with vancomycin preferred for cases of more severe infection.
· First episode: metronidazole 500mg three times per day for 10–14 days.
· Severe disease: vancomycin oral four times per day for 10–14 days fidaxomicin 20 mg two times per day for 10 days.
· First relapse: same for first episode.
· Second relapse: vancomycin taper with pulse.
· third relapse: consider fecal microbiota transplantation, prolonged oral vancomycin.
2. CMV:
· diagnosed by the presence of CMV viremia, CMV pp65 Antigen and CMV PCR.
· For treatment: Oral valganciclovir or IV ganciclovir (if any concern for decreased absorption).
3. Cryptosporidiosis is generally diagnosed by visualization of oocysts in the stool.
4. Rotavirus:
· In diagnosis of rotavirus, immune-based assays are most routinely used to rapidly detect rotavirus antigens in stool samples.
· Cell culture, real time-PCR and electron microscopy remain as reference methods because of their high specificity and sensitivity.
· The treatment of rotavirus infection in SOT patients is mainly supportive.
· Contact precautions are recommended for prevention beside pre-transplant life attenuated vaccine of rotavirus(RotaTeq (RV5) and Rotarix (RV1)).
5. Adenovirus(AdV):
· can be diagnosed by viral culture, direct antigen detection, histopathology and PCR.
· AdV can be managed with supportive care and a reduced immunosup- pressive regimen.
6. Norovirus:
· Diagnosis of norovirus by PCR can be run on stool, vomitus, foods and environmental specimens.
· For treatment, the followings to be considered: Rehydration, Antimotility drugs and reduction in immunosuppressive drugs.
· Chronic norovirus-related diarrhea remains a major concern often leading to MMF discontinuation, which has been associated with an increased risk of rejection.
7. Persistent chronic diarrhoea: OGD with colonoscopy and biopsies +/- capsular endoscopy.
· To look for intestinal ulcerations because of large bowel post-transplant lymphoproliferative disorder, that may be accompanied by exudative enteropathy and chronic diarrhea.
· CMV colitis with concurrent negative CMV plasma PCR has been reported.
· The presence of severe duodenal villous atrophy may prompt clinicians to change more rapidly the immunosuppressive regimen, regardless of the cause (drug-related or infectious).
· Post-transplantation de-novo inflammatory bowel disease occurs up to 10 times more frequently than in the general population.
8. Breath test(14c-glycocholic acid or D-xylose) to diagnose bacterial over-growth. Anti-microbial agents are the treatment of choice.
9. Diarrhoea due to malabsorption gives a suspicion of PTLD, IBD when there is grossly bloody diarrhoea and/or a FH of IBD.
The level of evidence provided by this article:
This is a narrative review article with level of evidence grade 5.
I like your well-structured rather extensive summary, level of evidence, analysis and take home messages typed as conclusion.
II. Causes and management of postrenal transplant diarrhoea: an underappreciated cause of transplant-associated morbidity
Please summarise this article.
INTRODUCTION
EPIDEMIOLOGIC IMPACT
CAUSES OF DIARRHEA:
====================================================================
CAUSE OF DIARRHEA: INFECTIONS
===================================================================
DIAGNOSIS AND THERAPEUTIC
STRATEGY
====================================================================
CONCLUSION
====================================================================
What is the level of evidence provided by this article?
The level of evidence is 5
====================================================================
I like your well-structured rather extensive summary, level of evidence, analysis and take home messages typed as conclusion.Typing whole sentence in bold or typing in capitals amounts to shouting.
Thank you alot Prof.Sharma
Epidemiology:
Causes of diarrhea:
Immunosuppression drugs:
Infections:
Chronic norovirus:
CMV:
Rotavirus:
Adenovirus:
C. difficile:
Parasites:
Diagnosis & treatment:
Diagnosis & treatment of C difficile:
Cryptosporidiosis diagnosis & treatment:
CMV diagnosis & treatment:
Norovirus diagnosis & treatment:
Rotavirus diagnosis & management:
Adenovirus diagnosis & treatment:
The prospective Diarrhea Diagnosis Aid & Clinical Treatment study show:
Level of evidence is 5
I like your well-structured rather extensive summary, level of evidence, analysis and take home messages typed as conclusion.
Please summarise this article.
INTRODUCTION
o Chronic diarrhea after kidney transplantation is a common complaint, may be associated with fatigue, increased hospitalizations and negative impacts on recipient quality of life, graft survival and higher mortality
o Steatorrhea and malabsorption may result from severe and chronic posttransplant diarrhea and induce enteric hyperoxaluria and Oxalate nephropathy
o The main causes of diarrhea after transplantation are infections, immuno-suppressive drugs, antibiotics and other drugs
Aim of the study: review both infectious and noninfectious diarrhea in renal transplant recipients and provide a diagnostic algorithm for the evaluation of posttransplant diarrhea
EPIDEMIOLOGIC IMPACT
The cumulative incidence of diarrhea is 11.5, 17.5 and 22.6% at 1, 2 and 3 years after renal transplantation, respectively
Post transplant diarrhea is often under-recognized by practitioners
CAUSES OF DIARRHEA
The data from the Diarrhea Diagnosis Aid and Clinical Treatment (DIDACT) study indicate that an infectious cause of posttransplant diarrhea is present inapproximately 50% of cases with (CMV is the most common pathogen). The next most frequent cause is related to medication use
Causes of posttransplant diarrhea:
Infection
1. Bacteria: clostridium difficilea , campylobacter spp. , salmonella spp, bacterial overgrowtha , aeromonous spp, scherichia coli
2. Viruses: CMV, norovirus , sapobavirus , rotavirus , adenovirus
3. Parasitic: Giardia , Cryptosporidium , Isosopora Cyclospora , Microsporidium, Entameoba
Noninfection:
1. Immunosurpressive medications: MMF, tacrolimus, cyclosporine, sirolimus
2. Nonimmunosuppressive medications: antibacterial, antiarrhythmic, antidiabetic laxatives, proton pump inhibitors, protease inhibitors
Other
GVHD, PTLD, IBD, colon cancer, malabsorption, microscopiccolitis, malakoplakia
Immunosuppressive drugs
o The highest incidence associated with MMF (the relative risk is 1.57)
o Dose reduction is usually followed by the decrease or the disappearance of diarrhea
o Switch of immunosuppression from MMF to EC-MPS is a matter of debate
o Tacrolimus may be associated with diarrhea in 29–64% of patients depending upon the dose and duration of drug usage (mild course and rarely require drug discontinuation)
o Sirolimus causes self-limiting diarrhea in 14–42% of patients
o In up to one-third of patients, ATG and OKT3 therapies are both associated with diarrhea, which lasts for 3–4 days and resolves spontaneously
Infections
o Diarrhea is commonly infectious usually CMV and C. difficile
o Chronic norovirus infection causes 17–26% of severe posttransplant diarrhea in kidney transplant recipients (biphasic illness-acute and chronic phase)
o CMV: The most common target organ is the GIT
o Rotavirus: can cause severe course in both pediatric and adult SOT patients
o Adenovirus: may be associated with gastrointestinal symptoms in 10% of the cases
o C. difficile: the most common cause of nosocomial diarrhea and accounts for most infectious diarrhea within the first months after transplantation. The incidence is 3.5–4.5%. The single most important risk
factor for the development of CDI is recent antibiotic use. The mortality rate is 2.3-8.5%
DIAGNOSIS AND THERAPEUTIC STRATEGY
o Make a distinction between noninfectious and infectious causes of diarrhea and avoid unnecessary
reduction in immune-suppressive medications
Clostridium difficile:
First episode: metronidazole 500 mg three times per day for 10–14 days
Severe disease: vancomycin oral four times per day for 10–14 days or fidaxomicin 20 mg two times per day for 10 days
First relapse: same for first episode
Second relapse: vancomycin taper with pulse
Third relapse or more: consider fecal microbiota transplantation, prolonged oral vancomycin
o Cryptosporidiosis: diagnosed by visualization of oocysts in the stool mmunofluorescent assays and ELISA have a sensitivity and specificity approaching 100%, which is significantly better than the traditional modified acid-fast stains
o Noroviru: diagnosis by PCR can be run on stool, vomitus, foods and environmental specimens. Management is rehydration, antimotility drugs and reduction in immunosuppressive drug
o Rotavirus: immune-based assays to rapidly detect rotavirus antigens in stool samples. Other diagnostic
methods are cell culture, real time-PCR and electron microscopy. Treatment is mainly supportive
o Adenovirus: can be diagnosed by viral culture, direct antigen detection, histopathology and PCR
CONCLUSION
o Physicians should be familiar with common causes that result in posttransplant diarrhea
o A directed approach to diagnosis and treatment will help to resolve diarrhea and prevent potentially life- threatening consequences, such as loss of the graft
o Prospective studies are needed to better assess prevalence, risk factors and complications of diarrhea by norovirus, rotavirus and adenovirus in kidney transplant patients.
What is the level of evidence provided by this article?Level V
I like your well-structured rather extensive summary, level of evidence, analysis and take home messages typed as conclusion.
SUMMARY
Introduction
Chronic diarrhea after a kidney transplant is quite common though usually neglected particularly by the physician despite patient complaints and the possibility of having a negative impact on the quality of life of the patient. The level of immunosuppression and the inevitable polypharmacy after kidney transplant are the two common similarities among the patients that can be linked to a contributory factor to the aetiology of the disease. Among the many causes of chronic diarrhea after kidney transplantation, this article reviewed the infectious and noninfectious causes, and also try to provide a diagnostic pathway for them
Epidemiologic impact
Causes of Diarrhea
a) Immunosuppressive drugs: this is a common non-infectious cause that has been known with morbidity and mortality among transplant patients as these drugs are a must to be taken to sustain the graft. The commonly implicated drugs are:
b) Infectious cause :
Diagnostic and Therapeutic Strategy
The two most important factors during diagnosis are to be able to distinguish between infection and non – infectious causes of diarrhea and also to pay close attention to graft function when reducing the immunosuppressive drugs. The following investigation can be requested based on the frequency and epidemiology
If the above investigation comes back negative, then proceed to do
Treatment
Infectious causes
Conclusion
Post-kidney transplant diarrhea is a common presentation, and it is very important for physician to be equipped with good knowledge in identifying common causes and how to make a definitive diagnosis. Further landscape studies is required to be able to provide specific therapy to common causes of chronic diarrhea following transplantation.
Level of evidence is 5
I like your well-structured rather extensive summary, level of evidence, analysis and take home messages typed as conclusion.
Introduction;
– Diarrhea is a common complaint in KTR, it lead to significant morbidity and negatively affect quality of life, graft and patient survival.
– Predisposing factors in KTR includes; the overall immunosuppressed state and exposure to polypharmacy.
Epidemiology:
– The cumulative incidence;11.5, 17.5 and 22.6% at 1, 2 and 3 years post-Tx.
– The problem is under-recognized by practitioners.
– It increase the risk of graft loss and death by two-folds.
– The majority had no identifiable cause and were self-limited.
Causes of post-transplant diarrhea:
Infectious diarrhea:
Bacterial: C. difficile, Campylobacter spp, Salmonella spp, Bacterial overgrowth, E.coli
Viruses: CMV, Norovirus, Rotavirus, Adenovirus
Parasitic; Giardia , Cryptosporidium, Microsporidium , Entameoba
Non-infectious diarrhea:
medications: MMF, Tacrolimus, Cyclosporine and Sirolimus
Other medications; Antibacterial, Antiarrhythmic, Antidiabetic, Laxatives, PPI, Protease inhibitors
Other: GVHD, PTLDb IBD Colon cancer Malabsorption Microscopic colitis, Malakoplakia
*Data from the Diarrhea Diagnosis Aid and Clinical Treatment (DIDACT) study indicate that:
– Infectious cause is present in 50% of cases with CMV being the most common pathogen.
– The next most frequent cause is related to medication use with the highest incidence associated with MMF.
Diarrhea 2ry to Immunosuppressive drugs:
– Multiple IS drugs can cause post-transplant diarrhea, MMF being the most frequent.
– The relative risk of diarrhea associated with the use of MMF is 1.57.
– MMF-inhibit purine synthesis, which is needed for growth and proliferation of epithelial cells.
– Histologically many patterns; if mainly crypt distortion, called IBD-like MPA-associated toxicity and if predominant apoptosis, also called GVHD-like MPA-associated toxicity
– Dose reduction lead to decrease or the disappearance of diarrhea.
– Switching from MMF to EC-MPS helps reduce diarrhea symptoms is a matter of debate.
– Switch from MPA to azathioprine is usually avoided because of reported reduced graft survival with AZA.
– Tacrolimus use may lead to diarrhea in 29–64%, by stimulating intestinal motilin receptors, usually mild course and rarely require drug discontinuation.
– Sirolimus causes self-limiting diarrhea in 14–42% of treated patients, by causing jejunal villous atrophy
– ATG and OKT3 are both associated with self-limited diarrhea, by interfere with sodium absorption and disrupts the intestinal barrier
Infectious diarrhea:
-Usually CMV and C. difficile are responsible.
–In the first month post-Tx opportunistic pathogen is uncommon, it become more common after few months postTx.
-Norovirus infection; recently emerged as one of the leading infectious causes (in 17–26% of severe cases).
– 94% chronic diarrhea and 81% with episodes of diarrhea-induced AKI.
–CMV gastrointestinal disease is common among SOT 7.2% developed CMV disease, of which approximately
one-third had gastrointestinal involvement
-Risk factors include (D+/R–) in 40 % and, (D–/R+), lymphodepleting antibodies and intensity of IS.
– Rotavirus infection, data are limited. diagnosed in 1.5% of SOT, sever course reported in pediatric and liver transplant recipient.
–Adenovirus (AdV) may be associated with gastrointestinal symptoms in 10% of the cases, wide range of clinical syndrome reported in SOT.
-C. difficile
-It is the most common cause of nosocomial diarrhea and accounts for most infectious diarrhea within the first months after transplantation, reported in 3.5–4.5% in KTR, mortality in SOT is reported 2.3 – 8.5%
– The single most important risk factor for the development of CDI is recent antibiotic use, with fluoroquinolones.
– Cryptosporidia lead to severe acute & chronic diarrhea and extra-intestinal infection.
-Microsporidia in SOT lead to diarrhea and weight loss.
– Enterocytozoon bieneusi is by far the most frequent strain found in KTR.
Diagnosis and therapeutic strategy:
– It is important to differentiate between noninfectious and infectious causes of diarrhea.
– Reduction of immunosuppression to manage diarrhea should be never taken lightly as it carries risk of graft loss.
C. difficile
– The gold standard cell-based cytotoxicity assay or fecal enzyme assay or real-time PCR.
– Patients can be asymptomatic carriers, and may develop diarrhea, intestinal obstruction, abscesses or toxic megacolon.
– Initial treatment of SOT includes fidaxomicin, metronidazole or vancomycin ( for persistent severe infection)
– The prevention treatment of relapsing and refractory forms is challenging.
– Encouraging results from using human monoclonal antibodies against C. difficile toxins A and B.
– Fidaxomicin, ramoplanin and tigecycline are effective for the treatment of severe or recurrent disease.
– A newer area of interest is the use of fecal microbiota transplantation (FMT) in the management of refractory CDI.
Cryptosporidiosis
– Diagnosed by visualization of oocysts in the stool.
– Immunofluorescent assays and ELISA higher sensitivity and specificity.
– Treatment; nitazoxanide or paromomycin
Tissue-invasive CMV
-CMV viremia is suggestive, however, it is negative in 15%
Endoscopy / biopsy for histopathology for definitive diagnosis ‘gold standard’; IHC staining for pp65 and pathognomic cells owl’s eye’ intranuclear inclusions.
-Treated with IV ganciclovir or oral valganciclovir (valGCV) followed by valGCV prophylaxis for 30–90 days to decrease the risk of recurrence.
Norovirus
Diagnosis PCR on stool, vomitus, foods and environmental specimens. Treated supportively, immunosuppression reduction as MMF plays role in its chronicity. The use of IVIG, ribavirin and nitazoxanide (selected cases). No available vaccine.
Prevention by strict infection control measures (hand hygiene and environmental sanitization).
Rotavirus
Diagnosis by stool immune-based assays, culture, real time-PCR. No available anti-viral therapies and the treatment of is mainly supportive and infection control measures to reduce transmission. Live attenuated vaccination is available and should be give pre-transplantation
Adenovirus:
diagnosis by viral culture, direct antigen detection, histopathology and PCR. Management by supportive care and a reduced immunosuppressive and strict infectious control measures to prevent transmission.
The DIDACT Study:
– Evaluated a stepwise prospective diagnostic and therapeutic flow chart
– Aimed to diagnose and treat infectious causes and exclude other causes before adjusting the IS.
– They found Campylobacter jejuni enteritis and CMV colitis being the most common in 28%
– Diarrhea resolved without any change in IS in 50%.
– 1/3 had bacterial overgrowth responded to antibiotics.
-For all patient to review medications for potential causes of diarrhea, and to stopped unnecessary one.
– Specific testing; bacterial culture, ova and parasites, PCR for CMV and C. difficile and stool lactoferrin.
-Test for bacterial overgrowth; breath test.
– Reduction of IS.
– if all test are negative consider empiric antidiarrheal, probiotics, and lactose- free diet should be tried.
– Colonoscopy: PTLD; exudative enteropathy, CMV colitis with negative viral load, duodenal villous atrophy; drug toxicity, de-novo IBD.
-Treatment: with hydration and specific antimicrobials or modification in IS by reduce MMF dose/ or switching to
EC-MPS, if no improvement complete withdrawal.
Conclusion:
-Physicians should be aware about post-transplant diarrhea.
– Meticulous evaluation and stepwise approach for diagnose and treatment will help to resolve diarrhea, and prevent potentially life-threatening consequences as graft loss.
Level of evidence: 5 narrative review.
I like your well-structured rather extensive summary, level of evidence, analysis and take home messages typed as conclusion.
Summary of the Article
Introduction
Causes of diarrhea after transplantation
1.Immunosuppressants
a) Predominant crypt distribution, other names ;
b) IBD-like MPA-associated toxicity and predominant apoptosis.
c) graft-versus host-like MPA- associated toxicity.
2.Infection associated diarrhea
a) Older recipients.
b) Use of ATG.
c) Retransplantation and higher incidence among liver Tx.
d) Recent antibiotic use (higher with fluoroquinolones).
Diagnosis
a) A stepwise protective approach for identification of pathogens and therapeutic flow chart.
b) Aimed to eliminate causative factors, infectious and non-infectious cause of diarrhea in SOT recipients.
c) 30 of 108 recipietns diagnose with infectious diarrhea (Compylobacter jejuni enteritis, and CMV colitis the most common pathogens).
d) 50% of patients diarrhea resolved without IS reduction.
e) Only 39 patients diagnose with bacterial overgrowth were respond to antibiotics.
f) All patient should have medication review for possible medication related diarrhea and stop unnecessary medications.
g) Specific tests; cultures, PCRs and ova and parasite assessment.
h) IS reduction.
i) +/- colonoscopy (intestinal ulceration due to PTLD, CMV colitis, villoud atrophy, and de novo IBD)
j) If all -ve and diarhae persist, empric antidiarrheal medications, probiotics and/or lactose free diet, should be tried.
k) Hydration, IS reduction, specific antimicrobials therapy.
Conclusion
Level of evidence
Level ((V)) review article
I like your well-structured summary, level of evidence, analysis and take home messages typed as conclusion.
Introduction
It is supposed that chronic diarrhea post transplantation is inevitable along with it’s drawbacks on recipient’s quality of life ,graft survival and mortality..
It can lead to steatorrhea ,malabsorption ,enteric hyperoxaluria and oxalate nephropathy
Immunosuppression, broad spectrum antimicrobial treatment ,other treatment and infectious causes can predispose to post transplant diarrhea.
The current review assess Infectious and non infectious diarrhea post renal transplantation.
Epidemiology
The cumulative incidence of diarrhea increase with time post transplantation meanwhile it is underestimated.
The diarrheal episodes were self-limited, the most common cause was Clostridium difficile infection norovirus infection and cytomegalovirus (CMV) gastrointestinal infection .
Immune suppression were reduced in some cases with diarrhea on MMF or Mycofenolic acid.
Causes of diarrhea
A prospective study –the Diarrhea Diagnosis Aid and Clinical Treatment (DIDACT) study was carried out to detect the causes ,demonstrating that 50% of cases were due to CMV being the most common etiology.
Infectious causes of diarrhea include
· bacterial as campylobacter,C.difficle ,Ecoli and bacterial overgrowth.
Non infectious causes of diarrhea
· viral as CMV ,Norovirus ,Rotavirus ,adenovirus
· parasitic as Giardia and entameba
Non infectious causes
Immunosuppressives as MMF ,Tac ,Cyclosporine ,Sirolimus
Non immunosuppressives as antibacterial ,antidiabetic ,antiarrhythmic
Others as GVHD ,PTLD ,IBD ,Cancer colon ,malabsorption.
Diarrhea subsided in half the cases due to stopping of diarrhea-associated nonimmune suppressive drugs or due to treatment of concurrent infection.
Cause of diarrhea immunosuppressive drugs
Many immunosuppressives can cause diarrhea particularly MMF ,which lead to increased risk of graft loss and mortality but the mechanism is unknown a supposed mechanism was that gastrointestinal epithelial cells depend partially on the de-novo pathway of purine synthesis for growth and proliferation, rendering it vulnerable to Mycophenolic acid causing diarrhea.
Dose reduction can treat diarrhea ;regarding switching from MMF to enteric coated mycophenolate sodium to decrease diarrhea is controversial.
Shifting from MPA to azathioprine is not recommended due to high graft loss risk.
A study revealed that Azathioprine significantly increase skin cancer risk .
Inflammatory bowel disease like MPA-associated toxicity and graft-versus host-like MPA -associated toxicity are 2 histological types.
Tacrolimus dose and drug duration can affect diarrhea risk.
The mechanism of CNI induced diarrhea is unknown but supposed to be due to the macrolide structure that can stimulate intestinal motilin receptors.
Tac induced diarrhea is mild and usually doesnot require stopping of the drug
Dailt extended release formula of Tac can reduce diarrhea.
Sirolimus can cause self limiting diarrhea in some cases,the mechanism is unknown but could be due to induced jejunal atrophy.
In some cases , ATG and anti–T cell antibody (OKT3) can lead to self limited diarrhea ,through activating T cells to produce TNF that prevent sodium ion absorption and disrupts the intestinal mucosal barrier.
Infectious cause of diarrhea
Infection is a common cause of diarrhea as CMV and C difficle in SOT .
After the first few months, opportunistic infection can be the leading cause of diarrhea due to the complete immunosuppression state .
Also community-associated organisms as norovirus are implicated
Chronic norovirus is one of the recently detected causes of post transplant diarrhea in SOT raising the possibility of previous misdiagnosis.
It can be complicated by chronic diarrhea or acute attacks of diarrhea induced AKI.
Chronic norovirus diarrhea has 2 phases the first acute phase presents with extensive diarrhea and chronic phase of normal formed stool.
CMV gastroenteritis is one of the most common causes of diarrhea in SOT.
Risk factors are D+/R- and after that comes D-/R+, lymphodepleting antibodies and more potent immunosuppressives .
For Rota virus induced diarrhea there isnot much data ,in fact it was detected in adult and pediatric SOT espeically pediatrics with liver transplant
Adenovirus diarrhea can occur early post transplant in 10% of SOT cases. There are severe infection forms involving the transplanted organ or disseminated disease was described.
C. difficile is the most common cause of nosocomial diarrhea and common to occur within the first months post transplantation.
Risk factor include recent antibiotic use particularly fluoroquinolones ,age >55 years, ATG use, re transplantation and type of organ transplanted, as much prevalent among liver recipients
CDI is accompanied by high mortality rate .
The metazoan infection is most common parasite.
SOT with diarrhea and weight loss due to microsporidia infection
Enterocytozoon bieneusi is common in kidney transplant recipients .
Cryptosporidia (Cryptosporidia parvum and Cryptosporidia homini) can lead acute ,chronic infection with extraintestinal spread.
Diagnosis and treatment
Distinguishing between infectious and non infectious causes is essential to avoid unnecessary reduction of immunosuppression and graft loss
For C. difficle diagnosis
,cell-based cytotoxicity assay is the standard , but fecal enzyme immunoassays or real-time PCR test are more practical.
C. difficile is usually asymptomatic in transplant recipient but when activated can lead to diarrhea, intestinal obstruction, abscesses or toxic megacolon.
C.difficle treatment in SOT includes fidaxomicin, metronidazole or vancomycin for severe infection
prevention and treatment of relapsing and refractory forms of C. difficle is difficult .
Fidaxomicin, ramoplanin and tigecycline are effective for the treatment of severe or recurrent disease.
Human monoclonal antibodies against C. difficile toxins A and toxin B.
Fecal microbiota transplantation (FMT) for treatment of refractory CDI
Microsporidia-related diarrhea
can be treated by fumagilin with favourable outcomes but associated thrombocytopenia limited it’s use.
Cryptosporidiosis
diagnosed by oocysts detection in stool, Immunofluorescent assays and ELISA having high sensitivity and specificity .
Tissue-invasive CMV disease is
diagnosed by CMV viremia detection in most cases.
CMV colitis diagnosis by
· serology is usefull for diagnosis of new disease onset
· conventional culture has lower sensitivity ,long incubation period and the high rate of false negativity.
· Shell Vial Assay is a rapid test but has a low sensitivityrate.
· CMV pp65 Antigen Test can be used for blood and cerebrospinal fluid.
· PCR method can be done with whole blood, plasma and leukocytes.
· the definitive diagnosis is by endoscopic evidence of gastrointestinal involvement.
· Pathological specimen revealing owl’s eye’ intranuclear inclusions, or b.y immunohistochemical staining for pp65 which is the standard test for diagnosis but viral inclusions are rarely detected
Treatment with intravenous ganciclovir or oral valganciclovir ,treatment can be stopped if given for at least 2 weeks, clinical symptoms subsided and viral load is undetectable .
For tissue-invasive CMV disease,it is recommended to use valGCV for secondary prophylaxis for 30–90 days after successful treatment
Norovirus
Diagnosed by PCR in stool, vomitus, foods and environmental specimens.
FDA approved xTAG Gastrointestinal Pathogen Panel for simultaneous detection of 3 viruses (norovirus G-I/G-II, rotavirus A and AdV 40/41), 9 bacteria and 3parasites but not tested in immunocompromised cases.
Treatment include supportive therapy ,immunosuppression reduction.
Chronic norovirus-related diarrhea mandates MMF discontinuation
Prevention through hand hygiene and sanitation is the main method as no vaccines are available .
Rotavirus
Diagnosed by immune-based assays for rapid detection in stool.
Other tests are cell culture, real time-PCR and electron microscopy with high specificity and sensitivity .
Treatment is supportive as no antirotaviral therapies are available.
Prevention through contact precautions , in USA there are 2 live attenuated vaccines that can be given before transplant.
Adenovirus
diagnosed by viral culture which is the gold standard but takes a long time , direct
antigen detection utility in immunocompromised is unknown, histopathology and PCR.
Treated with supportive care and a reduced immunosuppressive regimen.
Prevention by contact and droplet infection.
A study on SOT cases with CMV colitis and campylobacter jejuni enteritis showed that 50% of the patients, diarrhea resolved without immunosuppressive therapy change and only third of the cases had bacterial overgrowth that responded to antibiotics.
An algorithm was introduced to evaluate the case before manipulating immunosuppressives including bacterial culture, ova and parasites testing, PCR for CMVand C. difficile and stool lactoferrin. Then excluding bacterial overgrowth by breath test , afterwards reduction
in immune suppression and colonoscopy. If results are negative and the diarrhea persists, empiric
antidiarrheal medications, probiotics and/or lactose-free diet can be given .
Esophagogastroduodenoscopy and colonoscopy with biopsies to investigate persistent diarrhea after kidney transplantation to exclude IBD ,CMV coloitis , large bowel posttransplant lymphoproliferative disorder.
Treatment of diarrhea, with proper hydration and antimicrobials or reduction of immune suppression, is the main therapy.
Conclusion
A directed algorithm to diagnose and treat post transplant diarrhea will help cure it diarrhea, also will prevent potentially drastic outcomes as graft loss .
-level of evidence is V as a review article
I like your well-structured detailed summary, level of evidence, analysis and take home messages typed as conclusion.
Article-2
Q1.
Introduction
· Kidney transplantation is a risk factors for posttransplant diarrhea due to the immune suppression, infections and drugs such as immune suppressive medications, antibiotics, and other drugs as well
Epidemiology
· According to UNOS, the cumulative incidence was confirmed to be 11.5, 17.5 and 22.6% at 1, 2-, and 3-years following kidney transplantation
Causes of diarrhea
· The DIDACT study (the Diarrhea Diagnosis Aid and Clinical Treatment study) revealed that, infection (mainly CMV) is responsible for 50% of causes of posttransplant diarrhea. This is followed by immune suppressive drugs (mainly MMF) in two-third of the remaining cases
Drug-induced diarrhea/ immune suppression
· MMF (high incidence), tacrolimus, cyclosporin, & sirolimus
Major infectious causes of posttransplant diarrhea
A. Bacteria
* Clostridium difficile
· Most common nosocomial infection
· Incidence is between 3.4 to 4.5%
· Risk factors are; Age >55, ATG induction, re-transplantation, liver transplantation, and recent antibiotic exposure particularly fluoroquinolones (single important risk factor)
· High mortality between up to 8.5%
· Clinical presentation; May be asymptomatic carrier, diarrhea, intestinal obstruction, abscesses or toxic mega colon
· Diagnosis; cell-based cytotoxic assay (gold standard), fecal immune assays, or real time PCR
· Treatment; First episode metronidazole, severe disease vancomycin or fidaxomicin, first relapse treated the same as first episodes.
· Second relapse consider vancomycin taper with pulse
· >= 3 relapse consider fecal microbiota transplantation, or prolonged oral vancomycin
· Surgery may be considered for surgical issues such as a toxic mega colon, abscesses or obstruction
B. Viruses
* CMV
· CMV colitis or tissue-invasive CMV is diagnosis can be suggested by PCR in up to 85% of case (may be negative in 15%). How ever, the gold standard is histopathology with the presence of viral inclusion bodies ‘owl eye appearance’ or immune histochemical staining of the tissue for CMV pp 65 antigens. The challenge is that, the inclusion bodies are very rare and you cannot easily see them.
· Treatment is by oral valganciclovir or IV ganciclovir in cases of malabsorption
· The treatment should not be stopped unless, the patient is treated for at least two weeks, the symptoms has resolved, and the viral load is undetectable in at least one occasion
· CMV relapse is common in 15 to 35% of patients and therefore, the treatment should be followed by a prolonged course of oral valganciclovir up to 3 months
* Norovirus
· Member of enteric virus and diagnosed mainly by PCR of any specimen including stool, vomitus, and food
· Interactions between Norovirus and MMF; Norovirus initiate the diarrhea in renal recipient and MFF play a key role in chronicity by preventing viral clearance as well as the repair of the intestinal epithelium
· Chronic norovirus diarrhea is major concern because it is a common cause of MMF discontinuation and increased risk of rejection
· Treatment; Supportive, rehydration, anti-motility agents, and reduction of immune suppression
· Prevention; No vaccine, hand washing for 20 s with optional use of hand sanitizers but not substitute
Other differential diagnosis of posttransplant diarrhea:
A. Infection
· Bacterial; Campylobacer ssp, salmonella ssp, bacterial overgrowth, aeromomous spp, E. coli
· Viruses; Rotavirus, adenovirus, sapovirus
· Parasites; Giardia, cryptosporidium, isosopora Cyclospora, Microsporidium, Entameoba
B. Non-infection
· Non-immune suppressive drugs e.g antibiotics, PPI, antidiabetic
· Others e.g., GVHD, PTLD, IBD, colon cancer
Conclusion
· Posttransplant diarrhea may be associated with poor quality of life and may increase risk of allograft dysfunction. The transplant clinician must evaluate and attempt to diagnose the cause of diarrhea and differentiate between infectious and non-infectious causes of posttransplant diarrhea. Future prospective studies to guide better understanding of this issue is highly needed.
Q2.
· Narrative review, level 5
Anti-motility to be given only after ruling out infective causes. I like your well-structured detailed summary, level of evidence, analysis and take home messages typed as conclusion.
Thnxs, sure prof