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The Epidemiological Landscape of Clostridium Difficile Infections in the Post-Renal

Transplant Population: An Analysis of Incidence, Risk Factors, and Prognostic


Determinants and Outcomes

Aryeh Joshua Price and George JiaQi Li


Faculty of Arts and Science, University of Toronto
November 10, 2014
Introduction
Kidney transplantation is the most aggressive treatment option for end-stage renal
disease. It offers many advantages such as improved quality of life and lower rates of
mortality when compared with other renal replacement therapies1. However, despite the
advantages, the postoperative maintenance required to keep the graft functioning renders

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transplant

recipients

population

vulnerable

to

morbidities

such

as

infection.

Immunosuppression and antibiotic usage, both of which are common in the kidney transplant
population, are established risk factors for one possible infectious agent, Clostridium
difficile2,3. Within the current literature, there is immense variability in the incidence and
outcomes of C. difficile infections in kidney transplant recipients. The methods used to
diagnose C. difficile vary, with the majority of studies using diagnostic methods that are
considered suboptimal, especially within the context of epidemiological studies. The
epidemiology of C. difficile infections in kidney transplant recipients has not been well
characterized in the current literature, even though this population appears to be at high risk.
You need to clearly state the study objectives of your literature review. This will help
you later in the methodology section.

I. Clostridium difficile
C. difficile is a gram-positive bacterium that colonizes the human gastrointestinal
tract3. Symptoms of the infection only occur if patients are colonized with toxicogenic strains
of C. difficile. The colonization of the bacteria is often nosocomial, and carriers of the bacteria
may never become symptomatic3. C. difficile is transmitted via the fecal-oral route, and is able
to form spores that are capable of resisting harsher conditions than the bacterium itself 3 this
makes it particularly amenable to transmission in a hospital setting. Under normal
circumstances, any C. difficile proliferation is limited by competition with other
microorganisms comprising the gut microbiota3. However, pharmaceuticals such as broadspectrum antibiotics often disrupt this balance, facilitating the colonization and expansion of
C. difficile colonies, which may have resistance to these drugs 4. At this point, if the C. difficile
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strain is toxicogenic, it will produce sufficient amounts of C. difficile toxins A and/or B (tcdA
and tcdB) to cause the manifestation of symptoms 3. Traditionally, this leads to frequent
diarrhea and potentially colitis5. However, in severe cases, toxic megacolon and even death
may occur5.
C. difficile infection (CDI) rates are on the rise, with a paper published by Cohen et al.
in 2010 reporting that CDI was the chief cause of infectious diarrhea in hospital admissions?
s4. A study by Reveles et al. showed an increase in the incidence of CDI from 4.5
discharges/1000 discharges in 2001 to 8.2 discharges/1000 discharges in 2010 6. CDI creates
large economic burdens on hospitals, with an estimated total incurred cost in the United States
to be over 3 billion dollars per year in 20127.
II. Clostridium difficile Infections Post-Kidney Transplant
Kidney transplantation involves the surgical movement of a kidney from a donor into
a recipient to supplement or replace the function of the recipients diseased or dysfunctional
native kidneys. Due to natural variations in tissues and immune systems between individuals,
immunosuppressive regimens are often required during and postafter- transplant to prevent
rejection of the donor organ. Kidney transplant recipients are therefore particularly
susceptible to infection due to their compromised immunological status on top of other
chronic health concerns that may be present. Broad-spectrum antibiotics are also often given
to kidney transplant recipients pre- and post-transplant prophylactically to minimize the
chances of infections due to the operation 8. As kidney transplantation is considered the most
aggressive treatment for ESRD, kidney recipients often have increased exposure to the
hospital environment due to the need for other renal replacement therapies prior to
transplantation. Patients requiring dialysis often travel to the hospital many times a week,

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greatly increasing their chances of contracting a nosocomial infection such as CDI.
Immunosuppression, administration of broad-spectrum antibiotics and increased hospital
exposure are all established risk factors of CDI2,3,9 this makes kidney transplant recipients a
population that seems to be particularly at risk for CDI.
III. Literature Search Methodology
A literature search on Clostridium difficile infections in kidney transplant recipients
was conducted using Ovid MEDLINE with results from 1946 to September week 2 2014.
Keywords used included kidney transplantation, clostridium, clostridium difficile and
clostridium infections. The initial search resulted in a total of 38 articles. Two articles were
duplicates, and review of titles and abstracts resulted in a final total of 17 relevant articles.
Articles on other bacteria in the Clostridium genus were excluded. A large amount of these
articles consisted of case studies, and multi-organ transplants were kept due to the lack of
literature. Out of these articles, 11 were case reports and 6 were retrospective chart reviews.
IV. Incidence and Detection
The reported incidence of CDI in kidney transplant recipients is not well documented,
and varies greatly in the current literature. The incidence rates reported range from lower than
1% to as high as 8%. A single center retrospective study published by Neofytos et al. in 2013
reported a mean incidence rate of 6.1% in a total of 603 kidney transplant recipients, where
the CDI diagnosis was included if it occurred from 7 days pre-transplant to 6 months posttransplant8. Another study published by Altiparmak et al. in 2002 reported that out of 308
kidney transplant recipients, only 2 were diagnosed with CDI (0.6%) 5. This large variation in
incidence may be attributable to the methods used by each study to diagnose for CDI.

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A variety of diagnostic techniques are available for the detection of CDI, ranging from
tests for the toxins produced by C. difficile to testing for bacterial DNA sequences directly.
The three most commonly used techniques are enzyme immunoassays (EIA), real-time
polymerase chain reaction (PCR) and bacterial stool culture for C. difficile10. Out of these, the
EIA technique, which detects for tcdA and tcdB, is most commonly used10. PCR and stool
culture both directly detect the presence of the C. difficile bacteria itself10. The EIA technique
is used to diagnose CDI in the majority of current literature, as it is the fastest and most cost
effective method10, making it a clinically useful tool. However, EIA is considered the least
sensitive method, with reported sensitivity rates being between 32% and 73% 10. As such, EIA
results are not recommended for usage in epidemiological studies according to guidelines set
out by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious
Diseases Society of America (IDSA)4. All studies reported in the current literature used the
EIA toxin test to diagnose for CDI, with the exception of one study that switched to PCR
midway through8. A study published by Monteiro et al. in 2014 found that there was a high
level of discrepancy between all three methods of detection for CDI, but that PCR was the
most sensitive test, and recommended a combination of PCR and EIA to diagnose CDI
clinically10. The guidelines set by the SHEA and IDSA, which were last updated in 2010,
suggested that stool culture tests should be used in epidemiological studies. However, the
potential of PCR was acknowledged, and it was suggested that more studies be conducted
before it be put into routine usage. Therefore, usage of the more sensitive PCR and stool
culture techniques should be considered in further epidemiological studies.
Nicely written!
V. Risk Factors

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The risk factors for CDI in the general population are well documented, however in
the context of kidney transplantations there are very few studies published, with risk factors
varying greatly. The study conducted by Neofytos et al. analyzed risk factors, comparing
kidney transplant recipients with CDI to kidney transplant recipients that did not develop
CDI. They found that major predictors of CDI were vancomycin-resistant enterococci
colonization (P=0.03), high-risk transplants (P=0.006) and the usage of high-risk antibiotics
(P=0.001)8. In this study, high-risk transplants were defined as being blood group and human
leukocyte antigen (HLA) incompatible, while high-risk antibiotics included broad-spectrum
antibiotics such as clindamycin, fluoroquinolones, carbapenems, antipseudomonal penicillins,
and third- and fourth-generation cephalosporins8. A study by Keven et al. also found that
88.6% of their kidney transplant patients with CDI has a history of antibiotic usage in the
month prior to their diagnosis11. However, no matched control group was presented in this
study. The usage of anti-thymocyte globulin for induction immunosuppression was also a
significant risk factor (P=0.02)8. Immunosuppressive agents such as tacrolimus and
mycophenolate mofetil have also been implicated as possible risk factors 12,13, however no
studies were available to support this. On the contrary, a study conducted by Apaydin et al.
found that antibiotic therapy and immunosuppression were not significant risk factors for the
presence of tcdA (P>0.05)14. However, these opposing results may again be due to the
methods of diagnosis used in each study. All currently identified strains of toxicogenic C.
difficile are known to produce tcdB, whereas not all toxicogenic strains produce tcdA 3. As the
study by Apaydin et al. used EIA to exclusively test for tcdA, there may have been falsenegatives not only due to the sub-optimal sensitivity of EIA, but also from patients colonized
with strains of C. difficile that only produce tcdB and not tcdA.

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One possible risk factor that is not documented in the literature is the asymptomatic
colonization of the patients pre-transplant. The diagnosis of and testing for CDI usually
occurs only after diarrhea is observed in patients therefore there is no screening for
asymptomatic C. difficile pre-transplant, as it is not considered clinically useful 4. As all cohort
studies found were retrospective clinical chart reviews, data on asymptomatic colonization
was not able to be collected for epidemiological purposes. However, current literature
suggests that asymptomatic colonization with C. difficile may be a significant risk factor for
the development of CDI8. As kidney transplant recipients are likely to have spent long periods
of time in the hospital pre-transplant (either for other renal replacement therapies or in
preparation for the transplant), they have a higher chance of becoming asymptomatic carriers
of C. difficile. Therefore, further epidemiological studies should screen for asymptomatic
carriers of C. difficile pre-transplant and identify any possible related risk factors.
The majority of the conducted literature search consisted of case reports, a large
amount of which reported the incidence of CDI along with a co-morbidity. Co-morbidities
included hemolytic uremic syndrome15, cytomegalovirus16,17 and toxoplasmosis18. This
suggests that these morbidities may be risk factors for CDI, or that CDI may be a risk factor
for these morbidities.
VI. Management
The management of CDI in the general population has been well characterized in the
literature. As set out by the SHEA and IDSA, the standard of care involves withdrawal of the
causative antibiotic regimens and subsequent replacement with targeted antibiotics such as
metronidazole and vancomycin4. This approach appeared to be effective within the context of
kidney transplant recipients as well. Patients in studies by Neofytos et al. and Keven et al.

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were all treated with combinations of metronidazole and vancomycin 8,11. In the first study, all
patients were still alive 6 months after their CDI diagnosis, and only 10.8% had a recurrent
CDI infection8. The second study reported that one patient passed away from recurrent CDI
due to inanition, while two other kidney transplant recipients developed fulminant colitis,
requiring colectomy for toxic megacolon. One patient survived, while the other passed away
post-colectomy. It is generally recommended that CDI should be detected early and treated
aggressively to prevent development of complications 4,11. Keven et al.s study also suggested
that metronidazole should be administered prophylactically post-transplant in order to reduce
the incidence of CDI. Indeed, after implementing prophylaxis with metronidazole in their
transplant population, preliminary evidence showed a significant reduction in the incidence of
CDI (1.1% versus 5.5%, P=0.009)11. It was noted that further studies should be conducted in
this area.
Increasingly, fecal microbiota transplantation (FMT) is being used as an alternative
therapy for CDI9. The procedure involves the transfer of stool from a healthy donor to the
affected patient gut19. FMT can provide a source of healthy gut flora that can repopulate the
affected patients bowels and restore non-pathogenic levels of C. difficile. Preliminary
evidence from van Nood et al. suggests that using FMT as a therapy for recurrent CDI has
enhanced efficacy over the use of vancomycin alone (P<0.001)20. Out of the 43 patients
enrolled in the study, 94% were cured through fecal transplantation, while 31% taking only
vancomycin and 23% with combined vancomycin and bowel lavage were cured 11. However,
this procedure is a relatively recent innovation, and its effects on kidney transplant recipients
with CDI have not been studied.
VII. Prognostic Determinants and Outcomes

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The prognostic determinants of CDI in kidney transplant patients have yet to be fully
elucidated. However, within the broader context of solid organ transplantation, a 2014
retrospective chart review study looking at 170 patients reported possible prognostic
determinants. Recurrent CDI (OR 0.21, P=0.0128), treatment with vancomycin (OR 0.27,
P=0.011), vasopressor support (OR 0.23, P=0.0161) and treatment before 2004 (OR 0.44,
P=0.0446) were all predictors of clinical cures not being achieved after 2 weeks 21. The finding
that suggests vancomycin may be related to longer treatment times is problematic, as
vancomycin is one of the drugs recommended as a therapy for CDI 4. However, it was
acknowledged that since the study was not a randomized trial, vancomycin might have been
given preferentially to patients who were originally diagnosed with more severe cases of CDI.
Another study reported that old age (OR 1.1, P=0.029), high leukocyte count (OR 2.2,
P<0.0001), increased serum creatinine (OR 1.6, P<0.0001), gastric acid suppression (OR 1.8,
P=0.0002) and narcotic usage (OR 2.1, P<0.0001) were all prognostic determinants for
severe-complicated CDI22. The study looked at a total of 1446 inpatients, and severecomplicated CDI was defined as requiring admission to the intensive care unit, requiring
colectomy or death within 30 days of diagnosis 22. Further studies to determine the prognostic
determinants of CDI in the kidney transplant population should be conducted in order to
optimize care for affected patients. Increased serum creatinine as a prognostic determinant of
CDI is a potential area of increased interest, as it is commonly used as a measure of renal
health.
The effects of CDI on graft function have also not been well studied. There were no
reported cases of graft failure or rejection due to CDI in the current literature. This appears to
suggest, at least in the short-term, that CDI has little impact on the outcome of the kidney

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transplant. However, no studies have been published on the long-term effects of CDI on graft
outcomes. In recent studies, death due to CDI in kidney transplant recipients has also been
extremely low, with a less than 1% mortality rate5,8. Again within the broader context of solid
organ transplantation, a study by Hsu et al. found that in their cohort of 170 patients, 13
patients (8%) died during hospitalization and 49 patients (29%) died within 1 year of their
CDI diagnosis21. However, none of these deaths were directly attributed to CDI21.
Conclusion
Although kidney transplant recipients appear to be at high-risk for Clostridium
difficile infections, its epidemiology in this population has not been well characterized in
current literature. All studies reporting the incidences of CDI in kidney transplant recipients
consistently use methods of CDI diagnosis that are known to not be sensitive enough for
accurate epidemiological data. Risk factors, prognostic determinants and outcomes in the
context of kidney transplantation have also not been well described. All studies found were
single center retrospective cohort studies and case reports, with inherent limitations in patient
population and availability of data. An ideal retrospective study would include a large cohort
along with comprehensive and accurate clinical data on patients. One such database that may
allow for this is the Comprehensive Renal Transplant Research and Information System
(CoReTRIS), which allows for the curation of transplant related clinical features 23. This
system has the potential to eliminate many of the inconsistencies and confounding variables in
published datasets and provides a large cohort for clinical investigation. Future studies should
make use of this resource to better characterize the epidemiology of Clostridium difficile
infection after transplantation. Further studies should also aim to use accurate and sensitive
diagnostic methods such as PCR or stool culture, and better identify possible epidemiological

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factors with relation to kidney transplant outcomes. This would facilitate better management
of the infection, resulting in possible decreased costs and better patient outcomes.

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