OVERVIEW

Diarrhea After Kidney Transplantation: A New Look at

a Frequent Symptom
Florence Aulagnon,1,2 Anne Scemla,1,2 Susan DeWolf,3 Christophe Legendre,1,2,4,5,6 and Julien Zuber1,2,3,4,6,7
Diarrhea is a frequent but overlooked complication of kidney transplantation. Diarrhea is repeatedly neglected, often
considered by patients and clinicians an unavoidable side effect of immunosuppressive regimens. It is, however, associated with a significant impairment in life quality. Severe and chronic posttransplant diarrhea may lead to dehydration, malabsorption, rehospitalization, immunosuppression, noncompliance, and a greater risk of graft loss and
death. There is thus a need to optimize and standardize the management of posttransplant diarrhea with consistent
diagnostic and therapeutic strategies. A recent study has suggested that the increased sensitivity of molecular tools
might help in early pathogen identification and guidance of antimicrobial treatment. Most bacterial and protozoan
infections are readily curable with appropriate antimicrobial agents; cryptosporidiosis and C. difficile infections may
however be complicated by relapsing courses. In addition, identification of enteric viral genomes in stool has further
reduced posttransplant diarrhea of unknown origin. Chronic norovirus-related posttransplant diarrhea, arising from
the interplay of the virus and immunosuppressive drugs, has emerged as a new challenge in the field. Prospective and
controlled studies are necessary to evaluate the efficacy and safety of innovative anti-norovirus therapeutics, as well as
optimal immunosuppressive regimens, to enable viral clearance while preventing rejection and donor-specific antibody formation. This review seeks to provide a basis for the design of future clinical prospective studies.
Keywords: Diarrhea, Kidney transplantation, Norovirus, Immunosuppressive drugs.
(Transplantation 2014;98: 806Y816)

osttransplant 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

The authors declare no funding or conflicts of interest.

1
Service de Nephrologie et Transplantation Adulte, Hopital Necker, Assistance Publique-Hopitaux de Paris, Paris, France.
2
Universite Paris Descartes, Sorbonne Paris Cite, Paris, France.
3
Columbia University Medical Center, New York, NY.
4
RTRS Centaure, Nantes, France.
5
Labex Transplantex, Nantes, France.
6
Fondation Imagine, Paris, France.
7
Address correspondence to: Julien Zuber, M.D., Ph.D., Service de Nephrologie
et Transplantation Adulte, Hopital Necker, 149 rue de Se`vres 75015
Paris, France.
E-mail: julien.zuber@nck.aphp.fr; jgz2106@columbia.edu
F.A. and A.S. participated in the performance of the research and in writing
the article. S.D.W. C.L., and J.Z. participated in the performance of the
research and in editing the article.
Received 31 January 2014. Revision requested 5 March 2014.
Accepted 30 May 2014.
Copyright * 2014 by Lippincott Williams & Wilkins
ISSN: 0041-1337/14/9808-806
DOI: 10.1097/TP.0000000000000335

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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 OrganizationYapproved
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
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& Volume 98, Number 8, October 27, 2014

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* 2014 Lippincott Williams & Wilkins

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

Aulagnon et al.

807

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
Immunosuppressive Drugs
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

FIGURE 1. Clinical features in kidney transplant recipients with chronic diarrhea. (A, B) De novo posttransplant oxalate
nephropathy in a kidney transplant recipient, whose initial nephropathy was malformative uropathy, secondary to chronic
norovirus-associated diarrhea over 1 year in duration: numerous crystals of a monohydrate of calcium oxalate (arrows)
destroying the tubular structures within inflamed fibrosis (presence of inflammatory cells in scarred areas). Massons
trichrome stain 200 (left) and 400 (right). Photograph provided courtesy of Dr. Dominique Nochy. (C, D) Large bowel
PTLD in a kidney transplant recipient with chronic exudative diarrhea: (C) Large bowel ulcer revealing an early EBV+ PTLD;
(D) PET scan showing an isolated PTLD of the large intestine. PTLD, posttransplant lymphoproliferative disorder; EBV,
Epstein-Barr virus; PET, positron emission tomography.

Copyright 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

2%Y7% of all posttransplant

diarrhea

20%Y30% of diarrhea
in inpatients

Salmonella species (32)

Enteropathogenic:
Escherichia coli (3)

Copyright 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Parasites
Microsporidia:
Enterocytozoon
bieneusi (60,61)

3.6% of all posttransplant

diarrhea (PCR screening)
Chronic diarrhea
Fumagillin-induced
thrombocytopenia

96 mo

96 mo

96 mo

96 mo

96 mo

Reduction of
immunosuppression

Dehydration, weight loss

Bacteremia
Rectal abscess
Meningoencephalitis
Cerebral abscesses
Relapse

Biliary tract infection

Bacteremia

Guillain-Barre syndrome
Bacteremia/disseminated
infection
Relapse
Steatorrhea
Malnutrition
Bacteremia

Death

Graft loss

Toxic megacolon or
perforation: 2.8%Y15%
Relapse: 8%Y33%

Complications

Fumagillin: 20 mg TID
for 14 days

Based on the antibiogram:

3rd generation cephalosporin,
carbapenem, fluoroquinolones,
TMP/SMX
Surgery for focal suppuration
Based on the antibiogram:
betalactamin or cephalosporin,
fluoroquinolones
Amoxicillin for 14Y21 days
Taminoglycosides for 7 days
Or TMP/SMX

Fluoroquinolones or
amoxicillinVclavulanic acid

Metronidazole oral: 500 mg 3 TID

for 10Y14 days
Vancomycin oral: 125 mg 4/day
for 10Y14 days
1st relapse: same treatment
or Fidaxomicine : 200 mg
BID, for 10 days
2nd relapse: tapered or pulsed
Vancomycin regimen
Azithromycin or quinolones

Currently recommended
treatment

Transplantation

12%? Limited data

Bacterial
overgrowth (44)

96 mo

0 to 6 mo mostly

Interval between
transplantation and infection

www.transplantjournal.com

Listeria monocytogenes

5%Y28% of all
posttransplant diarrhea

Campylobacter
jejuni (3)

Incidence: from 3.5% to 16%

of hospitalized kidney
transplant recipients

Frequency

Infectious causes of post-renal transplant diarrhea

Bacteria
Clostridium difficile
(38,68)

TABLE 1.

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Copyright 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

1Y6 mo

96 mo

Pneumonia

Hemorrhagic cystitis
Allograft dysfunction/
rejection

Dehydration
Malnutrition
Dysfunction of
intestinal barrier
Agranulocytosis
Dehydration

Graft failure

Chronicity and chronic

viral shedding

Other tissue-invasive disease

(hepatitis, encephalitis,
nephritis, pneumonia)
Death

Dehydration

Lymph nodes
Dysfunction of
intestinal barrier
Malnutrition

Biliary or splenic
involvement

Death

Biliary involvement
Persistant periodic
episodes

Reduction of immunosuppression
Cidofovir for severe infections?
Ribavirin?
IV immunoglobulins?

m-TORi(56)
Symptomatic treatment

Possible salvage therapies:

Leflunomide, artesunate,
CMX001, maribavir
Reduction of immunosuppression
Reduction of immunosuppression
No virus-specific
treatment available
Therapeutics whose
efficacy remains
to be evaluated:
Ribavirin (53)
Nitazoxanide (54)
Oral immunoglobulins (55)

In case of resistance: Foscavir

or cidofovir

Antiviral treatment:
IV ganciclovir or
oral valganciclovir

Albendazole or nitazoxanide

Reduction of immunosuppression
Nitazoxanide
TAzithromycin
Paromomycin?
Long-term therapy,
at least 2Y4 weeks
TMP/SMX
Pyrimethamine
Sulfadiazine
Metronidazole 500 mg TID

BID, two times per day; D+/Rj, donor positive, recipient negative; mTORi, m-TOR inhibitors; TID, three times per day; TMP/SMX, trimethoprim/sulfamethoxazole (cotrimoxazole); IV, intravenous.

Adenovirus (57)

1%Y15% of all
posttransplant diarrhea
0.7% of patients

Rotavirus (3)

912 mo

D+/Rj CMV serologic status

3%Y10% of biopsy proven

gastrointestinal disorders
in D+/Rj patients.

17%Y26% of all
posttransplant diarrhea

3Y6 mo (after
prophylaxis
discontinuation)

96 mo

96 mo

91 mo

5%Y20% of all posttransplant

diarrhea
Esophagitis, colitis
30%Y50% of patients with
CMV disease

1.9%Y21% of all
posttransplant diarrhea

G0.1%

India: 20%
Turkey: 21%
France: 1.9%

Norovirus (3,4,49)

Viruses
CMV (32,47,69,70)

Giardia Lamblia (3)

Isospora belli

Cryptosporidium (3,32,64)

* 2014 Lippincott Williams & Wilkins

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(15,16). In a GI-oriented questionnaire-based study, persistent (914 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
Crohns-like inflammatory lesions (20,23). These studies,
however, did not include screening for norovirus infection,
which might itself induce duodenal atrophy (24) or a
Crohns-like disease in individuals with genetic susceptibility (25). Consistent with this hypothesis, Dalle et al. (23)
reported that chronic diarrhea with a Crohns-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 pathogenassociated diarrhea, especially norovirus-related (4).

Tacrolimus
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 tacrolimusassociated 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).

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Mammalian Target of Rapammycin inhibitors

In the Symphony study, the posttransplant diarrhea rate
was significantly higher with the combination of sirolimusMMF 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.
Infectious
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).
Bacteria
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. difficileYassociated
diseases have been widely observed in inpatients, including in
SOT populations, over the past several years (38Y40). This
trend reflects a higher virulence of C. difficile strains and
greater host susceptibility (40). The most important risk factor for C. difficileYassociated diseases in kidney transplant
recipients is recent antibiotic use (41). A markedly elevated
white blood cell count (above 25,000/KL) 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

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* 2014 Lippincott Williams & Wilkins

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 speciesYrelated 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.
Viruses
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+/Rj 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

Aulagnon et al.

811

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 naBve
status and greater exposure to the virus (57). In adults, adenovirus viremia is commonly observed in the early
posttransplant course (6.5%Y22.5%), 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. Selflimited diarrhea is the main presentation in SOT and immunocompetent individuals (59).
Fungal and Parasitic Infections
Microsporidia are opportunistic intracellular sporeforming 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

Copyright 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

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Transplantation

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

TABLE 2.

& Volume 98, Number 8, October 27, 2014

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),

Clinical reports of norovirus infection in kidney transplant recipients

Reference

Study design

Roos Weil et al. (4)

Retrospective single
center study
87 KTR hospitalized for
diarrhea over a
16-mo period

Nov frequency
Nov: 16/87=18,4% of
patients hospitalized
for diarrhea

Diagnosis by stool Q-PCR

Schorne et al. (49)

Westhoff et al. (50)

Prospective consecutive
single center study

Nov: 13/78= 16.7% of

patients with severe or
prolonged diarrhea

78 KTR with severe diarrhea

over a 24-mo period
Diagnosis by stool Q-PCR
Case report
2 KTR

Chehade et al. (71)

Coste et al. (3)

Case report
1 pediatric KTR
Diagnosis by stool Q-PCR
Prospective single
center study
49 KTR with severe
diarrhea over a
14-mo period
Diagnosis by stool
multiplex PCR

15/16 (94%) of chronic

diarrhea
6/16 (37.5%) experienced
a relapse after a
symptom-free interval
ranging from 2 to
13 mo
When compared with
bacterial and parasitic
diarrhea:
Greater weight loss
at admission
(8.5T3.3 vs 3.2T4.1)
More frequent change
in MPA daily dose
(100% vs. 35%)
More frequent MPA
withdrawal
(56.3% vs 0%)
Longer symptoms duration
(262T281 days vs.
28.7T22.2 days)
Severe dehydration
and allograft
dysfunction (5/13)
Chronic diarrhea
(24Y898 days)
Acute renal allograft failure
Relapsing diarrhea for more
than 3 mo
Broadened and shortened
duodenal villi with
chronic inflammation in
the lamina propria and
within the intraepithelial
compartment
Agranulocytosis

Diagnosis by stool Q-PCR

Nov: 14/54=26% of
patients hospitalized
for severe diarrhea,
including 9 patients
with coinfection

Duration of
viral shedding

Key features

Median viral shedding:

289 days (107Y508)
in 10 patients

Chronic Nov viral

shedding in 69%
Median viral shedding:
230 [97Y898] days
Nov viral shedding for
3 and 7.5 mo

Nov infected patients

showed greater weight
loss compared to other
infectious or non
infectious causes
of diarrhea

KTR, kidney transplant recipients; MPA, mycophenolic acid; Nov, norovirus; Q-PCR, quantitative polymerase chain reaction.

Copyright 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

ND

ND

* 2014 Lippincott Williams & Wilkins

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 TMPSMX prophylaxis.

Aulagnon et al.

813

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

Miscellaneous
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

FIGURE 2. Diagnostic flow-chart and therapeutic strategy for post-renal transplant diarrhea. (#) The first line microbiologic stool investigations consist of standard stool
cultures for pathogenic bacteria, examinations for parasites
and fungi, C. difficile toxin assay, and quick tests for Rotavirus, Adenovirus, and norovirus. (j) If the first-line investigations fail to isolate an enteric pathogen, a broad and
sensitive screening with multiplex PCR assays may be
useful to identify the following agents: Campylobacter species, enteropathogenic and enterotoxigenic E. coli, Shigella
species, Salmonella species, Yersinia, Clostridium difficile,
Cryptosporidium, Enterocytozoon bieneusi, Enteric viruses
(rotavirus, adenovirus, norovirus, and enterovirus). (X): In
case of fever, CMV D+/Rj serologic status, cytopenia, liver
enzymes studies, and plasma CMV Q-PCR should be
performed. Aza, azathioprine; CMV, cytomegalovirus; CNI,
calcineurin inhibitors; D+/Rj, donor positive; EC-MPS,
enteric-coated mycophenolate sodium; GCV, ganciclovir; IBD,
inflammatory bowel disease; mTORi, m-TOR inhibitors; MMF,
mycophenolate mofetil; MPA, mycophenolic acid; OGD, oesogastroduodenoscopy; PCR, polymerase chain reaction; SIBO,
small intestine bacterial overgrowth; ValGCV, valganciclovir.

Copyright 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

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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. Costeffectiveness 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.

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& Volume 98, Number 8, October 27, 2014

CONCLUSION

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.
ACKNOWLEDGMENTS
The authors thank Pr. Dany Anglicheau (Department of
Renal Transplantation, Necker, Paris), Dr. Veronique AvettandFenoel (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.
REFERENCES
1.

2.
3.
4.
5.
6.
7.

8.
9.
10.
11.
12.

13.

Ekberg H, Kyllonen L, Madsen S, et al. Clinicians underestimate

gastrointestinal symptoms and overestimate quality of life in renal
transplant recipients: a multinational survey of nephrologists. Transplantation 2007; 84: 1052.
Bunnapradist S, Neri L, Wong W, et al. Incidence and risk factors for
diarrhea following kidney transplantation and association with graft
loss and mortality. Am J Kidney Dis 2008; 51: 478.
Coste JF, Vuiblet V, Moustapha B, et al. Microbiological diagnosis of
severe diarrhea in kidney transplant recipients by use of multiplex
PCR assays. J Clin Microbiol 2013; 51: 1841.
Roos-Weil D, Ambert-Balay K, Lanternier F, et al. Impact of
norovirus/sapovirus-related diarrhea in renal transplant recipients
hospitalized for diarrhea. Transplantation 2011; 92: 61.
Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007; 357: 2562.
Ekberg H, Kyllonen L, Madsen S, et al. Increased prevalence of gastrointestinal symptoms associated with impaired quality of life in
renal transplant recipients. Transplantation 2007; 83: 282.
Ortega F, Sanchez-Fructuoso A, Cruzado JM, et al. Gastrointestinal
quality of life improvement of renal transplant recipients converted
from mycophenolate mofetil to enteric-coated mycophenolate sodium
drugs or agents: mycophenolate mofetil and enteric-coated mycophenolate sodium. Transplantation 2011; 92: 426.
Roddie C, Paul JP, Benjamin R, et al. Allogeneic hematopoietic stem
cell transplantation and norovirus gastroenteritis: a previously
unrecognized cause of morbidity. Clin Infect Dis 2009; 49: 1061.
Schwartz S, Vergoulidou M, Schreier E, et al. norovirus gastroenteritis
causes severe and lethal complications after chemotherapy and hematopoietic stem cell transplantation.Blood 2011; 117: 5850.
Lemahieu W, Maes B, Verbeke K, et al. Cytochrome P450 3A4 and Pglycoprotein activity and assimilation of tacrolimus in transplant
patients with persistent diarrhea. Am J Transplant 2005; 5: 1383.
Rankin AC, Walsh SB, Summers SA, et al. Acute oxalate nephropathy
causing late renal transplant dysfunction due to enteric hyperoxaluria.
Am J Transplant 2008; 8: 1755.
Bunnapradist S, Lentine KL, Burroughs TE, et al. Mycophenolate
mofetil dose reductions and discontinuations after gastrointestinal
complications are associated with renal transplant graft failure.
Transplantation 2006; 82: 102.
Takemoto SK, Pinsky BW, Schnitzler MA, et al. A retrospective analysis
of immunosuppression compliance, dose reduction and discontinuation in kidney transplant recipients Am J Transplant 2007; 7: 2704.

Copyright 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Aulagnon et al.

* 2014 Lippincott Williams & Wilkins

14.
15.

16.
17.

18.

19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.

Knoll GA, MacDonald I, Khan A, et al. Mycophenolate mofetil dose

reduction and the risk of acute rejection after renal transplantation.
J Am Soc Nephrol 2003; 14: 2381.
Mathew TH. A blinded, long-term, randomized multicenter study of
mycophenolate mofetil in cadaveric renal transplantation: results at
three years. Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. Transplantation 1998; 65: 1450.
Remuzzi G, Lesti M, Gotti E, et al. Mycophenolate mofetil versus
azathioprine for prevention of acute rejection in renal transplantation
(MYSS): a randomised trial. Lancet 2004; 364: 503.
Kamar N, Oufroukhi L, Faure P, et al. Questionnaire-based evaluation
of gastrointestinal disorders in de novo renal-transplant patients receiving either mycophenolate mofetil or enteric-coated mycophenolate
sodium Nephrol Dial Transplant 2005; 20: 2231.
Knight SR, Russell NK, Barcena L, et al. Mycophenolate mofetil
decreases acute rejection and may improve graft survival in renal
transplant recipients when compared with azathioprine: a systematic
review. Transplantation 2009; 87: 785.
Budde K, Curtis J, Knoll G, et al. Enteric-coated mycophenolate sodium can be safely administered in maintenance renal transplant
patients: results of a 1-year study Am J Transplant 2004; 4: 237.
Maes BD, Dalle I, Geboes K, et al. Erosive enterocolitis in mycophenolate
mofetil-treated renal-transplant recipients with persistent afebrile diarrhea. Transplantation 2003; 75: 665.
Selbst MK, Ahrens WA, Robert ME, et al. Spectrum of histologic
changes in colonic biopsies in patients treated with mycophenolate
mofetil. Mod Pathol 2009; 22: 737.
Weclawiak H, Ould-Mohamed A, Bournet B, et al. Duodenal villous
atrophy: a cause of chronic diarrhea after solid-organ transplantation.
Am J Transplant.
Dalle IJ, Maes BD, Geboes KP, et al. Crohns-like changes in the colon
due to mycophenolate? Colorectal Dis 2005; 7: 27.
Glass RI, Parashar UD, Estes MK. Norovirus gastroenteritis. N Engl J
Med 2009; 361: 1776.
Cadwell K, Patel KK, Maloney NS, et al. Virus-plus-susceptibility gene
interaction determines Crohns disease gene Atg16L1 phenotypes in
intestine. Cell 2010; 141: 1135.
Heller T, van Gelder T, Budde K, et al. Plasma concentrations of
mycophenolic acid acyl glucuronide are not associated with diarrhea
in renal transplant recipients Am J Transplant 2007; 7: 1822.
Group TUSMFLS. A comparison of tacrolimus (FK 506) and cyclosporine for immunosuppression in liver transplantation. The U.S.
Multicenter FK506 Liver Study Group. N Engl J Med 1994; 331: 1110.
Ekberg H, Bernasconi C, Noldeke J, et al. Cyclosporine, tacrolimus and
sirolimus retain their distinct toxicity profiles despite low doses in the
Symphony study. Nephrol Dial Transplant 2010; 25: 2004.
Helderman JH, Goral S. Gastrointestinal complications of transplant
immunosuppression. J Am Soc Nephrol 2002; 13: 277.
Veroux M, Grosso G, Ekser B, et al. Impact of conversion to a once
daily tacrolimus-based regimen in kidney transplant recipients with
gastrointestinal complications. Transplantation 2012; 93: 895.
Bamias G, Boletis J, Argyropoulos T, et al. Early ileocolonoscopy with
biopsy for the evaluation of persistent post-transplantation diarrhea.
World J Gastroenterol 2010; 16: 3834.
Arslan H, Inci EK, Azap OK, et al. Etiologic agents of diarrhea in solid
organ recipients. Transpl Infect Dis 2007; 9: 270.
Cho I, Blaser MJ. The human microbiome: at the interface of health
and disease. Nat Rev Genet 2012; 13: 260.
Smits LP, Bouter KE, de Vos WM, et al. Therapeutic potential of fecal
microbiota transplantation. Gastroenterology 2013; 145: 946.
Chang JY, Antonopoulos DA, Kalra A, et al. Decreased diversity of the
fecal Microbiome in recurrent Clostridium difficile-associated diarrhea. J Infect Dis 2008; 197: 435.
Li QR, Wang CY, Tang C, et al. Reciprocal interaction between intestinal microbiota and mucosal lymphocyte in cynomolgus monkeys
after alemtuzumab treatment. Am J Transplant 2013; 13: 899.
Oh PL, Martinez I, Sun Y, et al. Characterization of the ileal microbiota
in rejecting and nonrejecting recipients of small bowel transplants.
Am J Transplant 2012; 12: 753.
Dubberke ER, Burdette SD. Clostridium difficile infections in solid
organ transplantation. Am J Transplant 2013; 4: 42.
Boutros M, Al-Shaibi M, Chan G, et al. Clostridium difficile colitis:
increasing incidence, risk factors, and outcomes in solid organ
transplant recipients. Transplantation 2012; 93: 1051.

40.
41.

42.

43.
44.
45.

46.

47.

48.
49.

50.

51.
52.
53.
54.

55.

56.

57.
58.

59.

60.

61.

62.
63.

64.

65.

66.

815

Peltekian KM. Clostridium difficile on the transplantation radar.

Transplantation 2012; 93: 974.
Len O, Rodriguez-Pardo D, Gavalda J, et al. Outcome of Clostridium
difficile-associated disease in solid organ transplant recipients: a prospective and multicentre cohort study. Transpl Int 2012; 25: 1275.
Friedman-Moraco RJ, Mehta AK, Lyon GM, et al. Fecal Microbiota
Transplantation for Refractory Clostridium difficile Colitis in Solid
Organ Transplant Recipients. Am J Transplant. 2014.
Imai N, Uchida D, Hanada M, et al. A case of Campylobacter enteritis
in a renal transplant recipient. Transplantation 2013; 95: e78.
Maes B, Hadaya K, de Moor B, et al. Severe diarrhea in renal transplant
patients: results of the DIDACT study. Am J Transplant 2006; 6: 1466.
Grim SA, Pereira E, Guzman G, et al. CMV PCR as a diagnostic tool
for CMV gastrointestinal disease after solid organ transplantation.
Transplantation 2010; 90: 799.
Durand CM, Marr KA, Arnold CA, et al. Detection of cytomegalovirus
DNA in plasma as an adjunct diagnostic for gastrointestinal tract disease in
kidney and liver transplant recipients. Clin Infect Dis 2013; 57: 1550.
Asberg A, Jardine AG, Bignamini AA, et al. Effects of the intensity of
immunosuppressive therapy on outcome of treatment for CMV disease in organ transplant recipients. Am J Transplant 2010; 10: 1881.
Bok K, Green KY. Norovirus gastroenteritis in immunocompromised
patients. N Engl J Med 2012; 367: 2126.
Schorn R, Hohne M, Meerbach A, et al. Chronic norovirus infection
after kidney transplantation: molecular evidence for immune-driven
viral evolution. Clin Infect Dis 2010; 51: 307.
Westhoff TH, Vergoulidou M, Loddenkemper C, et al. Chronic
norovirus infection in renal transplant recipients. Nephrol Dial Transplant 2009; 24: 1051.
Kaufman SS, Chatterjee NK, Fuschino ME, et al. Calicivirus enteritis
in an intestinal transplant recipient. Am J Transplant 2003; 3: 764.
Atmar RL, Bernstein DI, Harro CD, et al. norovirus vaccine against experimental human Norwalk Virus illness. N Engl J Med 2011; 365: 2178.
Chang KO, George DW. Interferons and ribavirin effectively inhibit Norwalk virus replication in replicon-bearing cells. J Virol 2007; 81: 12111.
Rossignol JF, El-Gohary YM. Nitazoxanide in the treatment of viral
gastroenteritis: a randomized double-blind placebo-controlled clinical
trial. Aliment Pharmacol Ther 2006; 24: 1423.
Florescu DF, Hill LA, McCartan MA, et al. Two cases of Norwalk virus
enteritis following small bowel transplantation treated with oral human serum immunoglobulin. Pediatr Transplant 2008; 12: 372.
Engelen MA, Gunia S, Stypmann J. Elimination of norovirus in a chronic
carrier under immunosuppression after heart transplantationVeffect of
everolimus. Transpl Int 2011; 24: e102.
Florescu MC, Miles CD, Florescu DF. What do we know about adenovirus in renal transplantation? Nephrol Dial Transplant 2013; 28: 2003.
Humar A, Kumar D, Mazzulli T, et al. A surveillance study of adenovirus infection in adult solid organ transplant recipients. Am J
Transplant 2005; 5: 2555.
Stelzmueller I, Wiesmayr S, Swenson BR, et al. Rotavirus enteritis in
solid organ transplant recipients: an underestimated problem?. Transpl
Infect Dis 2007; 9: 281.
Champion L, Durrbach A, Lang P, et al. Fumagillin for treatment
of intestinal microsporidiosis in renal transplant recipients. Am J
Transplant 2010; 10: 1925.
Lanternier F, Boutboul D, Menotti J, et al. Microsporidiosis in solid
organ transplant recipients: two Enterocytozoon bieneusi cases and
review. Transpl Infect Dis 2009; 11: 83.
Bandin F, Kwon T, Linas MD, et al. Cryptosporidiosis in paediatric
renal transplantation. Pediatr Nephrol 2009; 24: 2245.
Campos M, Jouzdani E, Sempoux C, et al. Sclerosing cholangitis associated to cryptosporidiosis in liver-transplanted children. Eur J
Pediatr 2000; 159: 113.
Minz M, Udgiri NK, Heer MK, et al. Cryptosporidiasis in live related
renal transplant recipients: a single center experience. Transplantation
2004; 77: 1916.
Liefeldt L, Brakemeier S, Glander P, et al. Donor-specific HLA antibodies in a cohort comparing everolimus with cyclosporine after
kidney transplantation. Am J Transplant 2012; 12: 1192.
Rice JP, Spier BJ, Cornett DD, et al. Utility of colonoscopy in the
evaluation of diarrhea in solid organ transplant recipients. Transplantation 2009; 88: 374.

Copyright 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

816
67.
68.

www.transplantjournal.com

Nepal S, Navaneethan U, Bennett AE, Shen B. De novo inflammatory

bowel disease and its mimics after organ transplantation. Inflamm
Bowel Dis 2013; 19: 1518.
Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the
society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol
2010; 31: 431.

Transplantation

69.
70.
71.

& Volume 98, Number 8, October 27, 2014

Kotton CN. CMV: prevention, diagnosis and therapy. Am J Transplant

2013; 13: 24; quiz
Paya C, Humar A, Dominguez E, et al. Efficacy and safety of
valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus
disease in solid organ transplant recipients. Am J Transplant 2004; 4: 611.
Chehade H, Girardin E, Delich V, et al. Acute norovirus-induced
agranulocytosis in a pediatric kidney transplant recipient. Transpl
Infect Dis 2012; 14: E27.

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