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Impact of Norovirus/Sapovirus-Related Diarrhea in Renal Transplant Recipients Hospitalized for Diarrhea

Roos-Weil, Damien1; Ambert-Balay, Katia2; Lanternier, Fanny1,3; Mamzer-Bruneel, Marie-France4; Nochy, Dominique5; Pothier, Pierre2; Avettand-Fenoel, Véronique3,6; Anglicheau, Dany3,4; Snanoudj, Renaud4; Bererhi, Lynda4; Thervet, Eric3,4; Lecuit, Marc1,3,7; Legendre, Christophe3,4; Lortholary, Olivier1,3; Zuber, Julien3,4,8

doi: 10.1097/TP.0b013e31821c9392
Clinical and Translational Research
Free

Background. Diarrhea of unspecified cause frequently occurs after renal transplantation and is usually ascribed to mycophenolic acid toxicity. Norovirus (NoV) and sapovirus (SaV) have been sporadically reported to cause chronic diarrhea in immunocompromised patients.

Methods. We undertook a retrospective study (2008–2009) to examine the clinical and epidemiologic significance of NoV and SaV infections in adult renal transplant recipients hospitalized for acute or chronic diarrhea.

Results. Ninety-six renal transplant recipients were hospitalized for diarrhea at our institution during a 16-month period, 87 of whom were included in the study, including 46 patients with chronic diarrhea. Among 41 patients with unexplained diarrhea, 20 patients were screened for NoV/SaV, 16 of whom were positive. Fifteen of them (94%) had chronic diarrhea. When compared with bacterial and parasitic infections, NoV/SaV infections were associated with a greater weight loss at the time of admission, a 8.7-fold longer duration of symptoms and a more frequent need for mycophenolic acid dosage reduction. Eighty-one percent of patients hospitalized for NoV/SaV-associated diarrhea experienced acute renal failure. Five and one patients subsequently had biopsy-diagnosed active graft rejection and oxalate nephropathy, respectively. Ten of the 14 patients who underwent a longitudinal study of NoV/SaV stool's clearance exhibited a prolonged viral shedding period with a median time of 289 days (107–581 days).

Conclusions. Our study indicates that NoV/SaV infection causes posttransplant chronic diarrhea potentially complicated by severe kidney graft impairment.

1Service des Maladies Infectieuses et Tropicales, Hôpital Necker-Enfants Malades, AP-HP, Centre d'infectiologie Necker Pasteur, Paris, France.

2Centre National de Référence des Virus Entériques, CHU de Dijon, Dijon, France.

3Université Paris Descartes, Paris, France.

4Service de Transplantation Rénale et Unité de Soins Intensifs, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.

5Service d'Anatomopathologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.

6Département de Virologie, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.

7Institut Pasteur, Groupe Microorganismes et barrières de l'hôte, Institut Pasteur, Paris, France.

The authors declare no conflict of interest.

8Address correspondence to: Julien Zuber, M.D., Ph.D., Service de transplantation rénale et soins intensifs, Université Paris Descartes, Hôpital Necker-Enfants Malades, 161 rue de Sèvres 75015 Paris, France.

E-mail: julien.zuber@nck.aphp.fr

D.R.-W. participated in performance of the research, data analysis, and writing of the manuscript; K.A.-B. and D.N. participated in performance of the research and writing of the manuscript; F.L. participated in patient recruitment and performance of the research; M.-F.M.-B., P.P., V.A.-F., D.A., R.S., and L.B. participated in performance of the research; E.T. and C.L. participated in performance of the research and editing the manuscript; M.L. participated in the performance of the research and editing the manuscript; O.L. participated in research design, performance of the research, and editing the manuscript; J.Z. participated in research design, patient recruitment, performance of the research, data analysis, and writing and editing the manuscript.

Received 19 November 2010. Revision requested 6 December 2010.

Accepted 26 March 2011.

Diarrhea is a frequent complication after renal transplantation, with a 3-year posttransplant cumulative incidence of up to 22% (1,2). In addition to patient discomfort, postrenal transplant diarrhea is associated with acute renal failure (2), tacrolimus overexposure (3), and lower graft and patient survival (1). Although the majority of posttransplant diarrhea is because of unspecified causes (1, 4), it is often ascribed to mycophenolic acid (MPA) toxicity, resulting in an MPA dose reduction or discontinuation (2). However, the delayed and severe onset of diarrhea in most postrenal transplant patients is not consistent with MPA intolerance (1, 5). In addition, inappropriately changing an immunosuppressive regimen is not without risk with regard to the potential for acute rejection, and it should be done cautiously (6, 7). The Diarrhea Diagnosis Aid and Clinical Treatment (DIDACT) study, which prospectively assessed the frequency and causes of diarrhea after renal transplantation, found that approximately 50% of patients had their diarrhea resolved by interrupting nonimmunosuppressive drugs or by treating successfully bacterial or parasitic (B/P) infections before changing any immunosuppressive therapies (5). Among the patients with prolonged and unexplained diarrhea, only 65% of patients in whom MPA was tapered or discontinued experienced resolution of their diarrhea (5).

Enteric norovirus (NoV) and sapovirus (SaV) are two separate genera in the enteric virus family Caliciviridae (8–10). NoV is the overall leading cause of acute gastroenteritis, being the first and second leading causes in adults and children, respectively, and accounts for more than 90% of gastroenteritis outbreaks (8–10). In immunocompetent individuals, symptoms usually last for a few days, whereas viral shedding may last up to 3 weeks (9). The clinical spectrum of NoV infections in immunocompromised patients is less defined, but sporadic observations (11–14) and two recent small cohort studies (15, 16) have suggested that NoV infection may induce chronic and fluctuating diarrhea in both solid organ and bone marrow transplant recipients. However, conclusive data on the role of NoV infections in postrenal transplant diarrhea of unspecified cause are critically lacking. Therefore, we conducted a retrospective study to evaluate the clinical and epidemiologic spectra of NoV and SaV infections in a recent cohort of adult renal transplant recipients hospitalized at our institution for diarrhea during a 16-month period.

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RESULTS

Cohort Description

Ninety-six renal transplant recipients were hospitalized between July 2008 and November 2009 for diarrhea. Full clinical data and complete follow-up data were available for 87 patients, who had a combined 123 hospital stays, encompassing 750 hospitalization days. Among the 87 eligible patients, 10 (group I) and 6 (group II) had prompt resolution of their diarrhea spontaneously after admission and after withdrawal of nonimmunosuppressive drugs, respectively (Fig. 1). Thirty other patients were treated successfully with antibiotics (Fig. 1). In 20 patients (group IV), a B/P pathogen was identified in fecal samples, including Clostridium difficile (n=9), Cryptosporidium spp. (n=3), Microsporidium spp. (n=2), and Campylobacter jejuni (n=3). The other 10 patients (group III) were given empiric antibiotics shortly after admission because of fever (n=8), hemodynamic instability (n=1), or recent travel to a tropical area (n=1). The 41 remaining patients experienced diarrhea of an unspecified cause. Twenty of them were screened for caliciviruses, 16 of whom were positive (group V), whereas 21 others were not investigated (group VI; Fig. 1). Six other patients were systematically screened for caliciviruses at hospital admission (n=1, 1, 2, and 2 in the groups I, II, III, and IV, respectively). All were negative.

FIGURE 1.

FIGURE 1.

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Characteristics of NoV/SaV-Infected Patients

In an attempt to better define the epidemiologic characteristics and clinical features of NoV/SaV infection in renal transplant recipients, we compared NoV/SaV-infected patients with those with B/P enteric infections (Table 1). The two groups did not differ with regards to epidemiologic characteristics, past history of acute rejection, or immunosuppressive regimen. The transplant-to-diarrhea onset interval was 68±61 and 37±37 months in the B/P and NoV infection groups, respectively. The onset of diarrhea occurred within the first 12 months posttransplant in only seven patients, including three with C. difficile infection and four with NoV infection. Regarding their clinical presentation, the two groups were comparable with the exception of a greater weight loss at the time of first hospital presentation (8.6%±4.3% vs. 3.2%±4.1% of body weight, P=0.001) and a trend toward lower C reactive protein level (6.6±2.0 vs. 41.0±115 mg/L, P=0.07) in the NoV/SaV group. Consistently, dehydration and prerenal acute renal failure were frequently observed in both groups, affecting up to 81% of patients with NoV/SaV infection at the time of admission.

TABLE 1

TABLE 1

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Caliciviruses Identification and Characterization

NoV and SaV were identified in 15 and 1 renal transplant recipients, respectively (Table 2). The median interval between onset of symptoms and diagnosis was 56 days (range 9–981 days). All but two acquired their infection in the community, and we did not find evidence to support nosocomial or community outbreak. Two patients (cases 1 and 3) developed nosocomial diarrhea after sharing the same hospital room with a patient experiencing NoV-related diarrhea (case 11). Genome sequencing of the viral strains isolated in these three patients revealed a high level of nucleotide identity (99.7%), suggestive of patient-to-patient nosocomial transmission.

TABLE 2

TABLE 2

Genogroup II largely predominated, accounting for 93% (14/15) of all NoV strains. Genotypes were determined for all but three NoV strains. GII-4 was the most commonly identified genotype, accounting for 67% (8/12) of the viruses whose genome was sequenced (Table 2). NoV GII-4 encompassed several variants, including 2006a (n=1), 2006b (n=6), and Cairo (n=1). Two patients presented a concomitant cytomegalovirus (CMV) reactivation in blood but did not fulfill the criteria for CMV-associated digestive disease, because the CMV genome was not detected, and no cytopathic effect was observed in colon biopsies. Other enteric viruses were excluded by a complete screening in 13 of them.

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Management and Evolution of NoV-Induced Diarrhea

Among the 87 eligible patients, 46 have experienced chronic diarrhea, lasting more than 4 weeks, including 0, 2, 3, 8, 15, and 18 in groups I, II, III, IV (B/P), V (NoV/SaV), and VI, respectively (Fig. 1). The mean duration of NoV-associated diarrhea was 8.7 months, much longer than for patients with B/P infections in whom symptoms lasted approximately 1 month (Table 1, P<0.0001). Among NoV-infected patients, 94% (15/16) experienced chronic diarrhea, and six patients relapsed after a symptom-free interval ranging from 2 to 13 months (Fig. 2). Four patients complained of mild digestive discomfort after the resolution of diarrhea (Fig. 2). Prolonged diarrhea led to colonoscopy in four patients (25%), but macroscopic and microscopic examinations were nonspecific. Four patients received unsuccessful empiric antimicrobial therapy, but all patients with B/P infections responded to antimicrobial therapy (Table 1). In an attempt to reduce the immunosuppressive burden, MPA was the drug preferentially reduced because of its potential side effect of digestive toxicity (Figs. 1 and 2). At admission, tacrolimus trough levels were increased to 13.8±5.4 and 15.1±4.7 ng/mL in the B/P and NoV/SaV groups, respectively. Tacrolimus overexposure was believed to be related to diarrhea-induced changes in tacrolimus pharmacokinetic interactions (3), and it led to an immediate reduction of daily dosage by 0.34%±0.21% and 0.27%±0.19% in the B/P and NoV/SaV groups, respectively. These changes allowed all patients to recover to a stable and optimized tacrolimus trough level, ranging from 6 to 10 ng/mL.

FIGURE 2.

FIGURE 2.

Resolution of diarrhea more frequently required MPA reduction and even withdrawal in the NoV/SaV group (Table 1; Fig. 1). MPA dose was changed in 35% vs. 100% of patients (P=0.0002), and MPA was withdrawn in 0% vs. 56.3% of patients (P=0.0001) in the B/P and NoV/SaV groups, respectively (Table 1; Fig. 1). In the NoV/SaV group, three and six patients were switched from MPA to azathioprine immediately and for persisting diarrhea, respectively, despite a mean MPA reduction of 51.3%±13.4% for 236±161 days. Similar to cases of MPA reduction, case 2 was switched from tacrolimus to sirolimus secondary to evidence of calcineurin inhibitor-related arteriolar nephrotoxicity.

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Evidence of Prolonged Viral Shedding

Fourteen patients were subsequently investigated for NoV/SaV with a median time interval of 289 days (range 107–902 days) between the first and last NoV/SaV molecular screening (Fig. 2). Importantly, the last viral investigation was performed after diarrhea remission in 10 asymptomatic or paucisymptomatic (mild digestive discomfort) patients (Fig. 2). Four patients (three NoV and one SaV) cleared the virus at 157, 196, 440, and 902 days after the first positive test, whereas 10 remained positive after a median time of 289 days (range 107–581 days) (Fig. 2). NoV viral load was quantitatively assessed in the first and last fecal samples from seven NoV-infected patients, whose diarrhea has resolved. Surprisingly, aside from two patients who cleared the virus, viral load was higher in the last sample in all but one patient, showing a lack of correlation between symptomatic improvement and viral shedding (data not shown).

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Graft Outcome in NoV/SaV-Infected Patients

The time from the onset of diarrhea to the last follow-up examination was 18.5±7.0 months. After the episode of NoV/SaV infection, four and six patients underwent at least one protocol and medically indicated graft biopsy, respectively. Graft biopsies disclosed evidence of antibody- and cellular-mediated rejection in four and one patients, respectively. Biopsies performed in three other patients displayed acute tubular necrosis and calcineurin inhibitor-related nephrotoxicity.

Case 16 underwent a graft biopsy 21 months after the onset of diarrhea. The biopsy showed hallmark lesions of acute oxalate nephropathy associating massive inflammatory infiltrates within extensive interstitial fibrosis in the vicinity of intraepithelial birefringent crystals occluding the lumen of proximal tubules. These findings were in striking contrast to the absence of lesions observed in the previous protocol biopsy, performed at 1-year posttransplant. At last follow-up, ultrasound examination showed graft nephrocalcinosis. Given the patient's chronic diarrhea, the hypothesis of an enteric form of hyperoxaluria was investigated. Numerous crystals of a monohydrate of calcium oxalate (CaOx) were observed in the urine, and the urine oxalate:creatinine ratio was increased to 0.140 mg/g (normal values <0.030 mg/g). Other causes of enteric hyperoxaluria were excluded. In three other cases (cases 3, 5, and 7), renal biopsies showed sparse birefringent crystals, which were free in the lumen of the tubules. Neither fibrosis nor interstitial inflammation was associated with these intraluminal crystals.

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DISCUSSION

Posttransplant diarrhea, infectious or not, has been associated with the most powerful maintenance immunosuppressive regimen: a combination of tacrolimus and MPA (1). It has been proposed that the use of tacrolimus rather than cyclosporine may induce MPA overexposure and digestive tract toxicity because of pharmacokinetic interactions (17). This “toxic paradigm” is intimately linked to the widespread belief in the transplant community that MPA-related toxicity presents early as posttransplant diarrhea (2). However, in our study as in others, severe diarrhea typically had a late and fulminant onset, occurring long after the introduction of immunosuppressive drugs (1, 5). In this specific context, the chronologic sequence of diarrhea does not support MPA toxicity, thus putting into question the rationale for its reduction or withdrawal given the greater risk of acute rejection (5–7).

Alternatively, but not mutually exclusive with the MPA toxicity hypothesis, tacrolimus and MPA might induce overimmunosuppression and thereby favor an increased susceptibility to unrecognized enteric infectious agents. This hypothesis is further supported by the higher frequency of diarrhea in liver transplant recipients treated with combined tacrolimus and azathioprine when compared with patients receiving cyclosporine and azathioprine (18). In this respect, our study suggests that chronic NoV/SaV infections may account for a significant proportion of chronic and intermittent late-onset posttransplant diarrhea, severe enough to require hospitalization. Therefore, our results should be extrapolated with caution to outpatients with self-limited diarrhea. Consistent with a recent study, our study supports the clinical usefulness of NoV/SaV screening in the setting of chronic and severe diarrhea in renal transplant recipients (16). It is worth noting that colonoscopy in the patients with NoV/SaV-associated diarrhea seemed to be useless for diagnosis, as evidenced in 25% of our patients and in 78% of patients in another series (16). Therefore, we recommend that NoV/SaV screening should be performed before colonoscopy and initiation of empiric antibiotic therapy when investigating for posttransplant chronic and severe diarrhea (Fig. 3). After retrospectively clustering our inpatients according to a diagnostic flow chart (Fig. 1), similar to the one used in the DIDACT study (5), we found a high rate (16/20) of positive NoV/SaV screenings in selected transplant recipients with prolonged diarrhea and negative common etiologic workups. NoV/SaV-infected patients represented 16.7% of the whole study population, a frequency in keeping with a recent report (16), and accounted for 30.6% of the subpopulation with chronic diarrhea (15/49). However, given that 21 patients fulfilling these criteria were not investigated for NoV/SaV, it is reasonable to assume that our study may have underestimated the frequency of NoV/SaV infections.

FIGURE 3.

FIGURE 3.

By comparison with B/P infections, NoV/SaV infections were remarkable for a dramatic weight loss at presentation and a much longer duration of symptoms. It is worth noting that 15 of 16 NoV/SaV-infected patients had chronic diarrhea (19). Consequently, NoV/SaV infections may be associated with increased morbidity and even mortality in immunocompromised patients (15). In our study, more than 80% of NoV/SaV-infected patients experienced at least one episode of acute renal failure. Most of them recovered baseline graft function after rehydration and resolution of diarrhea. However, three patients had a significant degradation of graft function, as defined by at least a 50% increase in the creatinine level. In addition, five patients subsequently underwent a biopsy and showed features of rejection, which might have been triggered or enhanced by the tapering of immunosuppression. To our knowledge, we report the first case of oxalic nephropathy secondary to chronic NoV-associated diarrhea. NoV-induced acute gastroenteritis has been associated with mild steatorrhea and partial villous atrophy (9, 20), and it is likely that extensive and chronic involvement of the small intestine in immunocompromised patients may enhance NoV-induced malabsorption and steatorrhea, a prerequisite condition for enteric hyperoxaluria (21, 22).

Another striking observation from this study is the constant need to reduce MPA—and in 56% of patients interrupt MPA—to achieve remission of NoV-associated diarrhea. This observation demonstrates the difficulty in discriminating between the respective roles of the drug and the virus concerning the persistence of diarrhea. In addition, this underscores the idea that switching from MPA to azathioprine not only removes a drug toxic to the intestine but also significantly reduces the immunosuppressive burden. Hypogammaglobulinemia frequently occurs after renal transplantation in patients treated with MPA (23, 24). Importantly, switching from MPA to azathioprine frequently results in normalization of immunoglobulin levels (24). A longitudinal study in 14 of our patients demonstrated prolonged viral shedding in 10 of them, consistent with previous reports in immunocompromised individuals (16, 25).

However, the prolonged viral shedding, still persisting after the resolution of diarrhea, may question the pathogenicity of the virus in immunocompromised patients. Importantly, the absence of NoV detection in controls, having not experienced any posttransplant diarrhea, would have reinforced the causality between viral shedding and diarrhea. Unfortunately, our retrospective study was not designed to address this issue, highlighting the need for further studies. Nevertheless, several arguments support the role of NoV infection in these late-onset diarrhea cases: (1) the patients were symptom-free until the brutal and delayed onset of diarrhea after transplantation, although they had been given higher MPA doses before than after the onset of NoV-associated diarrhea. (2) The diarrhea evolved most frequently in two phases, an early phase with 10 to 20 watery stools per day and subsequently a chronic phase with a lower number of poorly formed stools. The chronologic sequence is therefore highly suggestive of an infection with the acute phase evolving into the chronic phase. (3) None of the six patients who were systematically screened for NoV/SaV at hospital admission and were retrospectively clustered in subgroups I through IV had a positive screening. (4) Although difficult to assess retrospectively from clinical records, most NoV carriers still complained of digestive discomfort after the resolution of diarrhea. Whether these mild symptoms resulted from a persistent truncated infection or from postinfectious irritable bowel syndrome is still an unresolved issue (26). (5) The two patients whose MPA dose was increased after the resolution of diarrhea, while still shedding NoV, experienced a relapse of the diarrhea, in contrast with the two patients who had cleared the virus. Altogether these findings suggest that the possibility of diarrhea relapse after immunosuppressive treatment, reinforcement hangs over asymptomatic or paucisymptomatic carriers of NoV, like a sword of Damocles.

Interestingly, a recent study provided evidence of continuous viral evolution in long-term immunocompromised NoV carriers (16). A higher viral load at later time points, despite the resolution of diarrhea, may reflect the difficulty of normalizing the dilution and quality of isolated RNA from acellular biologic fluids and a large fluctuation in NoV shedding from the same patient on the same day (25). Therefore, in an attempt to evaluate the efficacy of treatment, we propose to interpret such a quantitative assessment with caution.

To conclude, our study indicates that NoV infections is a frequent and considerably underestimated cause of posttransplant chronic diarrhea in renal transplant recipients hospitalized for diarrhea. In addition to acute renal failure, NoV infection and its management may be complicated by severe and irreversible renal graft impairment. We acknowledge that the retrospective design of this study, the nonsystematic screening for NoV in transplant recipients with diarrhea, and the biased selection of inpatients who likely had the most severe cases of diarrhea are limitations to the assessment of the true prevalence, risk factors, and complications of chronic NoV infections. Prospective studies are thus warranted to address these important concerns, to validate a diagnostic algorithm that includes an early investigation for NoV infection (Fig. 3), and to assess the correlation between immunosuppressive regimens, resolution of diarrhea, and viral clearance.

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MATERIALS AND METHODS

Study Population

This single-center retrospective study performed in an active cohort of 1700 renal transplant recipients included all consecutive patients hospitalized for diarrhea at our institution between July 2008 and November 2009. Patients were identified through electronic medical record-based information that coded medical activity and patient diagnoses.

The diagnosis of diarrhea was defined by passing loose, watery stools three or more times a day. Chronic diarrhea was defined as diarrhea lasting more than 1 month (19). Resolution of diarrhea was defined as stool consistency near normal (soft or formed) according to patient perception and reaching a stool frequency of less than three per day without the use of antidiarrhetic medication. Mild digestive discomfort was defined as mild symptoms such as abdominal pain, bloating, flatulence and soft stools, which did not fulfill criteria for diarrhea. Acute renal failure was defined as an increase of serum creatinine at least 50% above baseline. Acute rejection episodes were diagnosed by biopsy and graded according to the Banff '97 classification revised in 2007 (27).

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Microbiologic Investigations

At the onset of symptoms, all patients had microbiologic stool examinations, including cultures and assays for pathogenic bacteria and standard detection of protozoans. Serum CMV polymerase chain reaction (PCR) was performed in all patients admitted with fever and exhibiting leukopenia and thrombocytopenia and hepatic cytolysis. In addition, intestinal biopsies were examined for CMV-related cytopathic effects. CMV in situ DNA hybridization was performed in all suspected cases. Finally, a total of 26 patients were screened for enteric viruses by reverse transcription PCR. All but three were investigated at the French National Reference Center for enteric viruses, which included complete enteric virus screening for adenovirus, rotavirus (A and C), astrovirus, SaV, NoV, enterovirus, parechovirus, aichi virus, torovirus, and coronavirus. Three others were screened only for NoV, rotavirus, adenovirus, and enterovirus in the Department of Virology at Necker Hospital.

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NoV Genotypes

NoV genotypes were determined for the 12 isolates identified at the National Reference Center through partial viral genome sequencing of an RNA polymerase gene fragment and a capsid gene fragment as described previously (28).

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Quantitative Assessment of Fecal Viral Load

The real-time PCR was performed on an ABI Prism 7500 Fast detector (Applied Biosystems, France) using the TaqMan One-Step PCR Master Mix reagent (Applied Biosystems) and previously published primers and probes for GI (29) and GII (30). The number of NoV RNA copies was estimated by comparing the sample CT value with standard curves.

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Statistical Analyses

Results are expressed as mean±standard deviation for continuous variables. Comparisons were based on Fischer's exact test for categorical data and the Mann Whitney U test for continuous data. All statistical analyses were performed using GraphPad Prism Software (GraphPad Software Inc, La Jolla, CA).

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ACKNOWLEDGMENT

The Renal Transplant Unit at Necker Hospital belongs to the “Fondation Centaure,” which supports a French research network in transplantation.

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Keywords:

Renal transplantation; Chronic diarrhea; Norovirus; Calicivirus

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