Posttransplant diarrhea is a frequent complication of kidney transplantation. Chronically loose stool is often assumed by clinicians and patients to be an inevitable part of kidney transplant everyday life, accounting for both a lack of attention from clinicians and underreporting by patients (1). Posttransplant diarrhea is associated with reduced quality of life (1), hastened decline of graft function, and higher mortality (2).
Chronic norovirus infection has only recently emerged as one of the leading infectious causes of posttransplant diarrhea in kidney transplant recipients (3,4), highlighting how much remains unknown about the causative factors of posttransplant diarrhea. This finding also suggests that numerous cases of posttransplant diarrhea in the past have been incorrectly ascribed solely to the toxicity of immunosuppressive drugs, leading to diagnostic misconceptions and inappropriate treatments.
The lack of a clear definition of posttransplant diarrhea, a condition typically self-reported by patients, has led to significant confusion in the literature. To improve the consistency of these studies and the resulting clinical conclusions, investigators should use the World Health Organization–approved definition of diarrhea: three or more loose or liquids stools per day. Acute diarrhea lasts less than 14 days, whereas symptoms persisting for more than 14 days or 1 month is called persistent or chronic diarrhea, respectively.
This article aims to provide a comprehensive overview of the epidemiologic impact of diarrhea in kidney transplant recipients, the complications related to posttransplant diarrhea, and the possible causative factors.
EPIDEMIOLOGIC IMPACT OF POSTTRANSPLANT DIARRHEA
Based on Medicare claims in the United Network for Organ Sharing registry, the cumulative incidence of diarrhea is reported to be 11.5%, 17.5%, and 22.6% at 1, 2, and 3 years after renal transplantation, respectively. (2). This shows that the point incidence peaks within the first year and subsequently decreases over the following years (2). In clinical trials, the frequency of posttransplant diarrhea greatly varies by immunosuppressive regimen, ranging from 9% to 33% (5). However, in a survey of 4,232 Scandinavian renal transplant recipients, 53% of them reported diarrhea, whereas the incidence estimated by their physicians was only 6.9% (1). This finding emphasizes the extent to which posttransplant diarrhea is often underrecognized by practitioners. The burden of adverse gastrointestinal (GI) symptoms inversely correlates with indicators of life quality in kidney transplant recipients (6,7). Moreover, posttransplant diarrhea of unknown origin (noninfectious) was associated with a twofold increase in graft loss and risk of death in one large retrospective study (2). In this respect, norovirus-related posttransplant diarrhea has long been misdiagnosed, misleadingly labeled as noninfectious diarrhea, and might account for the high morbidity associated with posttransplant diarrhea of unknown origin. Indeed, norovirus-related diarrhea is associated with the greatest weight loss at admission as compared to other causes of diarrhea (3,4), frequently necessitates reduction of immunosuppression (4), and may lead to fatal outcome in bone marrow transplant recipients (8,9).
Diarrhea can impair renal graft function as a result of the ensuing dehydration and weight loss (4). In addition, decreased intestinal P-glycoprotein (or multi-drug resistance 1) enzymatic activity in the context of diarrhea leads to elevated tacrolimus trough levels (10) and subsequent renal toxicity. Steatorrhea and malabsorption may result from severe and chronic posttransplant diarrhea and induce enteric hyperoxaluria (4,11). Oxalate nephropathy is associated with inflammation and may have devastating effects on renal graft function (Fig. 1A and B) (4). Mycophenolate mofetil (MMF) dose adjustment or poor adherence to MMF treatment after GI complications is associated with a significantly increased risk of graft loss (12,13) and inflammation (4,14).
CAUSES OF DIARRHEA
Mycophenolate Mofetil and Enteric-Coated Mycophenolate Sodium
Mycophenolate mofetil and enteric-coated mycophenolate sodium (EC-MPS) have long been implicated in posttransplant diarrhea. Diarrhea occurs in patients on MMF-based regimen with a frequency that broadly varies, depending on the definition, methods of inquiry, and drug doses. A frequency of diarrheic symptoms as high as 38.4% was reported in patients receiving 3 g per day of MMF at 3 years after transplantation (15,16). However, criteria for diarrhea, reported as adverse event, were not clearly specified (duration and nature of symptoms) in most of the large trials that assessed the efficacy and safety of MMF (15,16). In a GI-oriented questionnaire-based study, persistent (>14 days) diarrhea was reported by 19.3% of patients on MMF within the first year of treatment (17). A recent meta-analysis identified that the relative risk of diarrhea associated with the use of MMF is 1.57 (18). One proposed hypothesis is that GI epithelial cells may be partially dependent on the de novo pathway of purine synthesis for growth and proliferation. Mycophenolic acid (MPA) might thus inhibit the replication and repair of intestinal epithelium, leading to diarrhea. Controlled, randomized double-blind studies have shown a similar frequency of GI side effects with MMF and EC-MPS (19). A recent randomized and controlled open study, however, suggested that patients with MMF-related diarrhea that switch to EC-MPS may have a slightly, yet significant, greater chance of returning to a target MPA doses than those maintained on MMF (7).
Diarrhea in these patients not only results in watery bowel movements, but may also be associated with malabsorption, dehydration, and weight loss, (20). Several histologic patterns have been associated with MMF-MPA GI toxicity (21), including duodenal villous atrophy (22) and Crohn’s-like inflammatory lesions (20,23). These studies, however, did not include screening for norovirus infection, which might itself induce duodenal atrophy (24) or a Crohn’s-like disease in individuals with genetic susceptibility (25). Consistent with this hypothesis, Dalle et al. (23) reported that chronic diarrhea with a Crohn’s-like pattern on histology were frequently of infectious origin. These observations taken together have led many to question the extent of MMF-induced posttransplant diarrhea, raising concern that its actual incidence may be overestimated. There is indeed no clear correlation between MPA dose or MPA metabolite level and the occurrence of diarrhea (26). Additionally, MMF discontinuation leading to a reduction in diarrhea might result from decreased direct drug toxicity, but might also be attributable to a decrease in pathogen-associated diarrhea, especially norovirus-related (4).
Although less commonly implicated as a cause of posttransplant diarrhea, tacrolimus is associated with an increased risk of diarrhea in numerous studies, including randomized trials, when combined with MMF (2,5) as well as with azathioprine (27). In the Symphony study, the greatest risk of diarrhea was found in the low-dose tacrolimus group (5). Moreover, tacrolimus trough levels were significantly higher before the onset of symptoms in those who experienced diarrhea (28). These findings suggest that tacrolimus itself is toxic to the gut; the increased diarrhea associated with the combination of tacrolimus and MMF as compared to cyclosporine A and MMF may therefore not simply be caused by increased exposure to MPA (26). In addition, diarrhea further increases tacrolimus exposure, fueling a vicious cycle (10). It has been suggested that most of the tacrolimus-associated GI side effects have a mild course and rarely require drug discontinuation, though severe cases of diarrhea have also been reported (29). Of note, kidney transplant recipients experiencing tacrolimus-induced diarrhea may benefit from switching to a once daily tacrolimus regimen (30).
Mammalian Target of Rapammycin inhibitors
In the Symphony study, the posttransplant diarrhea rate was significantly higher with the combination of sirolimus-MMF compared to cyclosporine A-MMF (5). Efficacy and Safety of Everolimus With Enteric-Coated Mycophenolate Sodium in a Cyclosporine Microemulsion-free Regimen Compared to Standard Therapy in de novo Renal Transplant Patients and Efficacy on Renal Function of Early Conversion from Cyclosporine to Sirolimus 3 Months after Renal Transplantation studies have also emphasized a high incidence of posttransplant diarrhea under mammalian target of rapammycin inhibitors (mTORi) regimen, although the mechanism remains poorly understood.
A pathogen is readily identified in 20% to 30% of cases of posttransplant diarrhea when assessed with standard assays and in up to 70% with molecular techniques (3). The burden of infectious causes increases with time posttransplant, whereas drug toxicity dominates early posttransplant period (31). When compared with immunocompetent individuals, solid organ transplant (SOT) patients are in general more susceptible to opportunistic pathogens (32) (Table 1).
Intestinal dysbiosis, referring to the alteration of the gut microbiota, is associated with a growing number of pathogenic conditions, including rheumatoid and intestinal immune-mediated diseases, dysmetabolic syndrome, obesity, cardiovascular complications, psychologic disorders, and certain malignancies (33,34). In addition to these systemic effects, which go far beyond the scope of this review, an imbalance in commensal flora increases the risk of pathogenic microbes, the most concerning of which at present is Clostridium difficile (35). Although antibiotic use is the leading cause of major intestinal dysbiosis, other conditions associated with changes in gut microbiota include certain dietary elements and, specific to transplantation, lymphodepletive induction (36) and rejection episodes (37). Increased understanding about the role of dysbiosis in many human diseases has fueled attempts to restore normal gut flora by means of fecal microbiota transplantation, most commonly in relapsing and severe C. difficile infections (34).
Clostridium difficile is the most common cause of nosocomial diarrhea and accounts for most infectious diarrhea within the first months after transplantation (4,32). The increasing incidence and greater severity of C. difficile–associated diseases have been widely observed in inpatients, including in SOT populations, over the past several years (38–40). This trend reflects a higher virulence of C. difficile strains and greater host susceptibility (40). The most important risk factor for C. difficile–associated diseases in kidney transplant recipients is recent antibiotic use (41). A markedly elevated white blood cell count (above 25,000/μL) and the pattern of pancolitis on CT scan suggests a complicated form, whose incidence usually ranges from 2.5% to 5% (41), but was reported as high as 12.4% in 165 SOT patients infected with a highly virulent strain NAP1/BI/027 (39). The greatest challenge for toxigenic Clostridium infections remains the prevention and treatment of relapsing and refractory forms. Two recent case reports demonstrated the efficacy and safety of fecal microbiota transplantation in SOT recipients with refractory C. difficile infection (42).
Although Campylobacter species infections (including C. jejuni) are commonly self-limited in immunocompetent hosts, severe colitis, or enteritis can occur in immunocompromised patients (43). Therefore, although specific antibiotic therapy is not necessary in immunocompetent patients, it is mandatory in transplant patients. The incidence of Campylobacter species–related diarrhea in kidney transplant recipients may vary widely depending on the screening technique, from 4% to 10% with standard cultures and assays (32,44) to 28% with polymerase chain reaction (PCR) (3).
Escherichia coli, including enteropathogenic (EPEC) and enterotoxigenic E. coli, is one of the main causes of travel-acquired diarrhea. Diagnosis, based on molecular techniques, is not routinely performed; thus, the impact of E. coli on diarrhea in transplantation is difficult to estimate. By multiplex PCR, EPEC was the primary pathogen detected from samples; however, it was detected at a frequency quite similar in samples from asymptomatic patients, raising the question of its pathogenicity (3).
Other enteric pathogens, including Salmonella species, Shigella species, and Yersinia species are identified in 2% to 3% of patients with diarrhea. Diarrhea because of Listeria monocytogenes has become extremely rare since the use of trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis.
Small intestinal bacterial overgrowth is defined by the presence of an excessive number of coliform bacteria in the upper part of the small bowel, which may result in fat malabsorption and bile acid diarrhea, depending on the type of microbial flora.
The incidence of cytomegalovirus (CMV) diseases involving the GI tract has dramatically decreased with the use of universal prophylaxis. Cytomegalovirus tissue invasion is confirmed in biopsies by means of CMV-specific immunostaining. The sensitivity of plasma quantitative PCR for detecting CMV GI tract disease is reportedly poor (45). However, a recent study demonstrated a great sensitivity of plasma quantitative PCR in kidney and liver transplant recipients with CMV-related GI tract disease, especially in the D+/R− subset (100%) (46). Intravenous ganciclovir remains the gold standard treatment of tissue-invasive CMV disease, though oral valganciclovir has been demonstrated to be effective on CMV gastroenteritis and colitis (26.6% of the patients enrolled in the Study of Valcyte [Valga, ciclovir po] Compared to Ganciclovir iv in Patients With CMV Disease who are Solid Organ Transplant Recipients) (47). Immunosuppression reduction may be useful to prevent relapses.
Norovirus or “Norwalk-like virus” is a single positive strand RNA virus belonging to the Caliciviridae family. Norovirus has emerged as the leading cause of acute gastroenteritis in immunocompetent individuals and chronic diarrhea in immunocompromised patients (24,48). Norovirus accounts for 17% to 26% of severe posttransplant diarrhea in kidney transplant recipients (3,4,49) (Table 2). Chronic diarrhea and long-term viral shedding after initial symptomatic resolution are hallmark features of norovirus infection in SOT patients (4,48). Although asymptomatic viral shedding may call into question the causal role of norovirus in post-renal transplant diarrhea, norovirus is more frequently found in the stools of patients with diarrhea than those with no history of diarrhea (3). The histology pattern with light microscopy in patients with active norovirus infection is often nonspecific, including mild inflammation and intestinal villi blunting (24,50); virus detection by means of PCR in stool or biopsy may therefore be useful for diagnosis (51). In the setting of sustained and extensive norovirus infection, fat malabsorption and enteric hyperoxaluria may occur (Fig. 1A and B) (4). Recently a vaccine, composed of virus-like particles, has been developed and successfully used to prevent norovirus infection (52). Prospective studies are warranted to assess the efficacy of pretransplant norovirus vaccination to prevent posttransplant norovirus-chronic infection. Attempts to cure chronic norovirus infection with ribaririne (53), nitazoxanide (54), or oral immunoglobulins (55) are sporadic, still inconclusive, and merit further investigations with prospective and controlled studies (48). At present, reduction of immunosuppression is the most effective strategy to manage norovirus infection (4). A switch to mTORi-based regimen may be a promising approach (56), perhaps because of an indirect antiviral effect. We initially reported that the resolution of diarrhea most frequently required MMF-EC-MPS dose adaptation (4). This finding was recently confirmed in 59 consecutive patients with norovirus-related diarrhea (Aulagnon F, manuscript in preparation). Importantly, however, we observed that MMF could be reintroduced and eventually well tolerated in the patients who had cleared the viral infection (4). Altogether this suggests 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.
Posttransplant adenovirus infection is more common in children, particularly under the age of 5 years, than in adults, as a consequence of both an immunologically naïve status and greater exposure to the virus (57). In adults, adenovirus viremia is commonly observed in the early posttransplant course (6.5%–22.5%), most frequently in the absence of symptoms, but may be associated with gastrointestinal symptoms in 10% of the cases (58). Adenovirus genome detection by stool PCR is broadly accepted as the most accurate diagnostic assay. Persistence of symptoms may require a reduction in immunosuppression, with cidofovir used in the most severe and life-threatening forms.
Rotavirus: Rotavirus is the leading cause of gastroenteritis in children. In adults with solid organ transplantation, it is a well recognized yet rare cause of diarrhea. Self-limited diarrhea is the main presentation in SOT and immunocompetent individuals (59).
Fungal and Parasitic Infections
Microsporidia are opportunistic intracellular spore-forming protozoa that cause disease in immunocompromised hosts. Enterocytozoon bieneusi is by far the most frequent strain found in kidney transplant recipients (60,61). Severe watery diarrhea is the main clinical manifestation, but disseminated and life-threatening forms have been reported. The diagnosis is made by the identification of spores in stool (modified trichrome staining) or by a PCR-based assay, which is the test with greater sensitivity. The recent availability of fumagilin has been a major breakthrough in the treatment of microsporidia-related diarrhea, treatment with which may lead to sustained clearance of E. bieneusi, with minimal reduction in immunosuppression. The use of fumagilin may, however, be limited because of drug-induced thrombocytopenia (60,61).
Cryptosporidia (C. parvum and C. hominis) are intracellular protozoan known to cause outbreaks of self-limited diarrhea in immunocompetent hosts exposed to contaminated water sources. In transplanted patients, cryptosporidiosis may lead to profuse and persistent diarrhea (62) sometimes leading to malabsorption, profound dehydration, and life-threatening complications. Biliary cryptosporidiosis has been associated with a greater risk of relapse, sclerosing cholangitis, subsequent liver allograft failure (63), and pancreatitis. The diagnosis of Cryptosporidium infection is made primarily by the presence of oocysts in a modified stool acid-fast staining. Immunofluorescent assays and enzyme-linked immunosorbent assay can significantly increase diagnostic sensitivity to as high as 100%. There is no optimal therapy for Cryptosporidium, and the clinical course is frequently relapsing in nature. Immunosuppression reduction may be required and long-term therapy, including nitazoxanide, azithromycin, spiramycin, or paromomycin, has been shown to be effective (62,64).
In contrast to Cryptosporidium and microsporidia, intestinal amebiasis, balantidiasis, and giardiasis are nonopportunistic protozoan infections, occasionally involved in diarrhea after transplantation, with a similar course as in immunocompetent individuals. Isospora (Cystoisospora) belli is a rare cause of posttransplant diarrhea, easily prevented by TMP-SMX prophylaxis.
Concurrent diseases (diabetes, uremia), posttransplant lymphoproliferative disorders (Fig. 1C and D), nonimmunosuppressive medications (44), including antibiotics, antihypertensive drugs, colchicine, allopurinol, proton pump inhibitors, statins, iron supplements, oral antidiabetic medications, recurrent or de novo posttransplant inflammatory bowel disease, and graft-versus-host disease (in combined liver and kidney allograft recipients) may cause posttransplant diarrhea.
DIAGNOSTIC FLOW CHART AND STEPWISE THERAPEUTIC STRATEGY
Inappropriate reduction of immunosuppression can result in an increased risk of acute rejection (14) and de novo donor-specific antibody formation (65). There is therefore a general consensus that posttransplant diarrhea should be fully investigated before changing the immunosuppressive regimen. The prospective Diarrhea Diagnosis Aid and Clinical Treatment study evaluated a stepwise prospective diagnostic and therapeutic flow chart that aimed to eliminate nonimmunosuppressive drug toxicity causative factors and treat infectious causes before adjusting the immunosuppressive regimen (44). The most striking finding of this landmark study was that in approximately 50% of the patients, diarrhea resolved without any change in immunosuppressive therapy. Infectious causes accounted for 64% of the cases, of whom more than half were diagnosed with bacterial overgrowth. However, it is worth noting that only one third of the 39 patients diagnosed with bacterial overgrowth responded to antibiotics. This finding emphasizes both the difficulty diagnosing bacterial overgrowth, inherent to the limitations of the breath test, and the lack of standardization of its treatment. Empiric antibiotic therapy without diagnostic testing has thus been proposed for the treatment of suspected bacterial overgrowth. This strategy is not without caveats (drug side effects, antibiotic resistance). In our experience, empiric antibiotics were suitable and efficient to treat patients presenting with febrile diarrhea, though stool culture taken before onset of antibiotics ultimately failed to identify a pathogen (4). However, unwarranted use of antibiotics may profoundly alter natural gut flora, whose antipathogen and anti-inflammatory roles are increasingly recognized (33,34). Therefore, to guide the use of antibiotics in patients with afebrile posttransplant diarrhea, we propose extensive screening for enteric pathogens before any empirical treatment (3,4). A recent study used a combination of seven commercially available multiplex PCR assays to screen extensively for enteric bacteria, parasites, and viruses (Fig. 2) in stool from kidney transplant recipients with diarrhea (3). Multiplex PCR assays demonstrated a much greater sensitivity compared to conventional cultures and assays to detect posttransplant diarrhea-associated pathogens (72% vs. 26%), particularly Campylobacter, norovirus, and coinfection (3). However, the use of such highly sensitive tool is not without caveats because it may lead to the detection of nonpathogenic microorganisms, such as EPEC, often present at low concentrations as part of the natural flora (3). In addition, these tools are not yet readily available at many institutions, and the turnaround time associated with collecting a large enough number of samples to run effectively multiplex PCR raise some hurdles to translating this molecular approach into routine clinical practice. Cost-effectiveness studies are needed.
Screening for small intestinal bacterial overgrowth may be useful in those in whom sensitive assays fail to identify a sole or mixed infection. In the Diarrhea Diagnosis Aid and Clinical Treatment study, a colonoscopy was performed in 41 patients who had persistent diarrhea despite changes in the immunosuppressive regimen. However, endoscopic studies identified no lesions in 22 patients and only found nonspecific macroscopic and microscopic lesions in the majority of other patients (44). This result was consistent with other reports, demonstrating that colonoscopy rarely leads to a specific diagnosis (66). These studies call into question the role and timing of endoscopy in the work-up of diarrhea; however, there remain several arguments definitively in support of the need to perform esophagogastroduodenoscopy and colonoscopy with biopsies to investigate persistent diarrhea after kidney transplantation. First, intestinal ulcerations because of large bowel posttransplant lymphoproliferative disorder may be accompanied by exudative enteropathy and chronic diarrhea (Fig. 1C and D). Second, CMV colitis with concurrent negative CMV plasma PCR have been reported (45). Third, 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) (22). Lastly, posttransplantation de novo inflammatory bowel disease occurs up to 10 times more frequently than in the general population (67). The optimal timing of endoscopic investigations therefore critically depends on the clinical setting. If there is any component of the history or laboratory evaluation suggestive of these diagnoses, endoscopy of the upper and lower GI tracts should be undertaken without delay (Fig. 2). If these studies fail to find any cause, capsule endoscopy combined with double-balloon enteroscopy may be necessary to explore further the small bowel. In the absence of these warning signs, endoscopy may be performed only if the symptoms persist despite adequate antibiotic therapy and alterations of the immunosuppressive regimen.
The optimization and adjustment of the immunosuppression in patients with persistent posttransplant diarrhea is an unresolved issue that warrants prospective studies. 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 (4,12) if symptoms persist. We propose that patients who cannot tolerate at least 50% of the recommended MMF-EC-MPS dose should be changed to azathioprine to avoid inadequate immunosuppression (Fig. 2). Tacrolimus or sirolimus dose reduction and subsequent switching to cyclosporine may be attempted if drug toxicity is suspected. For management of posttransplant diarrhea secondary to chronic norovirus infection, prospective studies are necessary to evaluate whether calcineurin inhibitor discontinuation (3) and a switch to mTORi (56) most efficiently and effectively leads to the resolution of diarrhea.
Diarrhea is a frequent and often debilitating complication of kidney transplantation. A large registry analysis has identified the negative impact of posttransplant diarrhea on graft and patient survival. The origin of posttransplant diarrhea is most often related to infectious and immunosuppressive drug-related causes. Early identification of an enteric pathogen, ultimately with molecular techniques if standard assays and cultures remain negative, is instrumental to initiate appropriate anti-microbial therapy. Chronic norovirus-related diarrhea remains a major concern often leading to MMF discontinuation, which has been associated with an increased risk of rejection. This emphasizes the critical need for prospective studies guided by modern molecular diagnostics to evaluate innovative anti-norovirus therapeutics and optimal management of immunosuppression.
The authors thank Pr. Dany Anglicheau (Department of Renal Transplantation, Necker, Paris), Dr. Véronique Avettand-Fenoel (Department of Virology, Necker Hospital, Paris) and Dr. Fanny Lanternier, Pr. Marc Lecuit and Pr. Olivier Lortholary (Department of Infectious and Tropical Diseases, Necker Hospital, Paris) for helpful discussions.
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