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Volume: 14 Issue: 2 April 2016

FULL TEXT

ARTICLE
Prevalence and Characteristics of Duodenal Villous Atrophy in Renal Transplant Patients Presenting With Persistent Diarrhea in a Developing Country

Objectives: Persistent diarrhea is a common complication after solid-organ transplant, including kidney transplant. Data on duodenal villous atrophy as a cause of persistent diarrhea in renal transplant recipients are scarce.

Materials and Methods: We conducted a prospective analysis of 207 patients who received renal trans­plants from 2009 to 2012 with persistent diarrhea and who underwent upper gastrointestinal endoscopy and duodenal biopsies. Duodenal biopsies were examined for duodenal villous atrophy. Age, sex, transplant duration, and drugs were compared between patients with and without duodenal villous atrophy. After exclusion of known causes of duodenal villous atrophy, a 3-month course of antibiotics was given and outcomes were analyzed.

Results: Of 207 renal transplant recipients, 104 patients (49.8%) displayed duodenal villous atrophy. Of these, 92 (88.5%) were male patients. The mean age of patients with duodenal villous atrophy was 34.9 ± 10.3 years. The mean onset of persistent diarrhea in DVA-positive patients posttransplant was 2.16 ± 0.8 years. Celiac disease serology was positive in 18 (17.3) patients. Giardiasis was demonstrated in 11 patients (10.7%), whereas immunoproliferative small intestinal disease was shown in 7 patients (6.8%). The remaining 68 patients (65.38%) received antibiotics, with 50 recipients (74.6%) showing complete response, although 13 of these patients (26%) relapsed. Among the remaining 18 patients (26.47%), 9 (50%) had other causes and 9 (50%) had no cause found. Isoniazid prophylaxis showed statistically significant negative association with duodenal villous atrophy.

Conclusions: Duodenal villous atrophy is highly prevalent in renal transplant recipients irrespective of age, sex, and posttransplant duration. We found tropical sprue, giardiasis, immunoproliferative small intestinal disease, and celiac disease to be important causes of duodenal villous atrophy. Therefore, duodenal biopsy is recommended in renal transplant recipients with persistent diarrhea.


Key words : Renal transplant recipients, Giardiasis, Celiac disease

Introduction

Persistent diarrhea is a common complication after solid-organ transplant (SOT), accounting for 20% to 29.8% of admissions.1,2 Infectious diarrhea and drug-related diarrhea account for up to 60% of such cases.3

Persistent diarrhea alters a patient’s quality of life, causes fatigue and weight loss, increases the number of hospital admissions, increases serum creatinine levels, and causes alterations in immunosuppressive therapy dose levels.4 Diarrhea is also associated with an increased risk of graft failure and patient death after kidney transplant.2

Recently, Weclawiak and associates2 reported the prevalence of duodenal villous atrophy (DVA) to be 15.9% in SOT patients as a cause of persistent diarrhea. Studies in immunocompromised patients have shown celiac disease and tropical sprue as important causes of DVA, whereas, in SOT recipients, giardiasis (5.3% to 14%) and medications, most commonly mycophenolate mofetil (13% to 31%) and azathioprine (21%), have been implicated as frequent causes.4-7 Data regarding DVA as a cause of diarrhea in renal transplant recipients are scarce, particularly from developing countries. Specifically, there is only one study available on the prevalence of DVA in SOT recipients and none on renal transplant recipients exclusively. Therefore, in this study, our aim was to investigate the frequency of DVA and its possible causes in renal transplant patients so that patients could be screened for early diagnosis and appropriate treatment to improve both patient and graft survival.

Materials and Methods

Data collection procedure
In this prospective study, we collected data on all patients ≥ 18 years old who received renal transplants and presented with persistent diarrhea at Sindh Institute of Urology and Transplantation (Karachi, Pakistan) from 2009 to 2012. The study was approved by the Ethical Review Committee of our center. All of the protocols conformed to the ethical guidelines of the 1975 Helsinki Declaration. Written informed consent was obtained from all patients. Persistent diarrhea was defined as at least 3 loose stools in 24 hours lasting for at least 14 days. Patients were excluded from the study if the stool examination reported the presence of pus cells, red blood cells, or cysts or trophozoites of Entamoeba histolytica or Giardia lamblia. Upper gastrointestinal endoscopy was performed at our endoscopy center. Duodenal villous atrophy was diagnosed if histologic findings included 2 or more of the following: villous atrophy (total or partial), crypt hyperplasia, intraepithelial lymphocytosis (> 40 intraepithelial lymphocytes per 100 surface enterocytes), or chronic inflammatory cells in the lamina propria.2 Patients were divided into 2 groups: those with DVA on duodenal biopsy (DVA-positive group) and those with no DVA on duodenal biopsy (non-DVA group). Demographic characteristics and immunosuppressive drugs were compared in the 2 groups.

Tests for tissue transglutaminase antibodies IgA and IgG and deamidated gliadin peptide antibodies were performed, when clinically indicated. Tablet ciprofloxacin 250 mg twice per day and tablet folic acid 5 mg once per day were given to patients for 3 months, if tests for tissue transglutaminase antibodies were negative and no other specific causes of DVA were found. Response to antibiotics was labeled as complete if both the cessation of diarrhea and weight improvement were documented at the end of therapy (Figure 1).

Statistical analyses
Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 15.0, IBM Corporation, Armonk, NY, USA). Results are presented as means ± SD for quantitative data or as numbers with percentages for qualitative data. Statistical differences in quantitative data were determined using t test or Mann-Whitney U test. The Fisher exact test or chi-square test was used for qualitative data. P < .05 was considered statistically significant.

Results

A total of 570 renal transplant recipients with persistent diarrhea were evaluated between January 2009 and December 2013. After exclusion on the basis of stool analysis results, 207 renal transplant recipients presenting with persistent diarrhea were included in this study. Of 207 patients, 182 (87.9%) were men. The mean age was 35.2 ± 10.55 years (range, 18-70 y). Comparisons of the demographic features and the clinical and laboratory charac­teristics between the DVA-positive and non-DVA groups are shown in Table 1.

Of the 207 study patients, 104 patients (49.8%) had positive histopathologic findings for DVA (Figure 2). The patients who were DVA positive were mostly men (n = 92; 88.5%), and the mean age was 34.9 ± 10.3 years (range, 18-66 y). In the DVA-positive group, 36 patients (36%) were between 30 and 40 years old, followed by 37 patients (35.6%) between 18 and 30 years old. The mean weight at the time of presentation was 49.6 ± 10.7 kg (range, 30-79 kg). The mean post­transplant onset of persistent diarrhea in DVA-positive patients was 2.14 ± 0.8 years (range, 1-4 y).

In the non-DVA group, the mean age was 35.11 ± 10.7 years (range, 18-70 y). There was no statistically significant difference in the mean age between the 2 groups (P = .81). Ninety patients were men (87.4%), and 13 were women (12.6%). There was also no statistically significant difference in sex distribution (P = .81). The mean posttransplant onset of persistent diarrhea in the non-DVA group was 1.92 ± 0.86 years (range, 1-4 y). There was also no significant difference in the posttransplant onset of diarrhea between the 2 groups (P = .78).

Table 2 lists the immunosuppressive regimens used in the 2 groups of renal transplant recipients. In the DVA-positive group, mycophenolate mofetil, azathioprine, tacrolimus, and cyclosporine were administered to 54 patients (51.9%), 50 patients (48.1%), 40 patients (38.5%), and 38 patients (36.5%); and in 47 patients (45.6%), 52 patients (50.5%), 38 patients (36.9%), and 39 patients (37.9%) in the non-DVA group. There was no statistically significant difference in the use of immunosuppressive agents between the 2 groups.

Isoniazid is used as a prophylactic agent for tuberculosis during the first year after transplant at our center. Isoniazid was used by 29 patients (28.2%) with no DVA and only 15 patients (14.4%) with DVA. Current isoniazid usage showed a statistically significant difference between the 2 groups (P = .016). Eleven patients (10.7%) in the DVA group and 18 patients (17.5%) in the non-DVA group presented with giardiasis (Figure 3), although stool samples did not show positivity for giardia. In the DVA group, duodenal biopsies from 7 patients (6.8%) showed features of immunoproliferative small intestine disease (IPSID) (Figure 3).

Tests for tissue transglutaminase IgA and IgG antibodies and deamidated gliadin peptide antibodies were positive in 15 patients (17.4%), 1 patient (2.0%), and 2 patients (4.1%). These patients were advised to follow a gluten-free diet.

The remaining 68 patients received ciprofloxacin and folic acid for 3 months. Among these, 50 renal transplant recipients (74.6%) showed complete response to therapy, whereas 18 recipients (25.4%) showed no response to therapy. In the patients who had no response, 2 had associated urinary tract infection, 2 tested positive for chicken pox, and 1 each received a diagnosis of pulmonary tuberculosis, graft abscess, lymphoma, Kaposi sarcoma, and candidemia. The cause of DVA could not be identified in the remaining 9 patients.

Of the 50 patients who had an initial response to antibiotics, 13 patients (27.9 %) presented with repeat symptoms of diarrhea and weight loss. Among these, 4 patients responded to a repeat course of antibiotics, whereas 6 patients had accompanying infection, including herpes zoster (n = 1), pulmonary tuberculosis (n = 2), cellulitis (n = 1), cytomegalovirus gastritis (n = 1), and urinary tract infection (n = 1). One patient was diagnosed with lymphoma on computed tomographic scan and lymph node biopsy, and 2 patients had chronic rejection.

Discussion

Microbial infections, abdominal pain, and diarrhea are common gastrointestinal-related adverse events seen in SOT recipients, among which diarrhea is the most frequent.1-4 Posttransplant diarrhea not only leads to weight loss, dehydration, deranged serum creatinine, and inconsistent immunosuppressive drug levels, it also enhances the risk of graft loss and patient death.1,5-8

In our analyses of baseline characteristics, sex distribution in our study group was different from a previous study in which female sex and diabetes emerged as independent risk factors for diarrhea.1 Overall, most of our patients were men (n = 182; 87.9%). The variability in gender distribution can be due to the sociocultural reasons, in which male patients receive priority for renal transplant more frequently than females.

Regarding onset of diarrhea in renal transplant recipients, a previous study suggested that more than 50% of patients have an onset of 2 years or more after transplant, which is consistent with this study where mean duration of onset was 2.16 ± 0.8 years (range, 1-4 y).4

Giardia infections can be diagnosed on wet stool preparations and modified trichrome-stained perma­nent smears. Because of the occasional presence of cysts and trophozoites in stool, the sensitivity of Giardia lamblia detection in stools is only about 50%, despite examination of multiple stool specimens.9 In this study, patients with positive stool samples were excluded. Giardia infestation also can be identified on duodenal aspirate and duodenal mucosal biopsy examination. Duodenal biopsy has been reported to be more accurate than stool specimen examinations.10 In this study, giardiasis was diagnosed on duodenal biopsy in 30 patients (14.7%) of 207 with negative stool samples. The difference in the prevalence from the previous studies could be due to the differences in the methods of identification (ie, stool examination in previous studies versus only duodenal biopsy in our study).6,11 Several nonspecific histologic changes have been identified with giardiasis infestation in the normal population, including increases in intraepithelial lymphocytes, changes in villous architecture, presence of lymphoid follicles, and eosinophilic infiltration in the lamina propria. Villous flattening was identified in 33 patients (41.2%) in a study of 80 patients with giardiasis,12 whereas atrophic villous architecture was observed in 61.2% of patients in another study.13 In our study, giardiasis with villous atrophy was seen in 11 of 104 renal transplant recipients (10.7 %) in the DVA-positive group. The disparity in results may be due to the differences in the study population (ie, normal population vs renal transplant recipients).

Only 1 case report has reported celiac disease as a cause of weight loss in renal transplant recipients14; however, our study is the first to report celiac disease as a cause (celiac disease has been shown in 18 patients). These patients responded to gluten-free diet (data not shown). Although tests for tissue transglutaminase antibody and deamidated gliadin peptide antibody were not conducted before trans­plant, all of the study patients were asymptomatic. The factors that may have triggered the onset of celiac disease were not investigated in the present report.

Immunoproliferative small intestinal disease is an infectious pathogen-associated lymphoma. It is diagnosed on the basis of characteristic histologic findings such as extensive infiltration of small intestinal lamina propria with plasma cells and/or lymphocytes.15 Campylobacter jejuni has been demonstrated in some studies as a possible factor.16 To the best of our knowledge, no study has been conducted on transplant patients to estimate the prevalence of IPSID. In this study, we identified 7 patients (6.8 %) with IPSID.

Although immunosuppressive agents increase the susceptibility of transplant recipients to infectious diarrhea, drug-related mucosal injury is another possibility.17 Around 16% to 64% of immuno­suppressive therapy-related incidences of diarrhea have been previously reported through clinical trials, which were dependent on the duration of study and regimen used.1 Recent findings in renal transplant recipients suggested that unexplained causes of severe diarrhea account for less than 20% of cases after exclusion of and treatment of infectious causes and decreases in dose immunosuppressive agents.4

All immunosuppressive therapies have been reported to be associated with diarrhea, including mycophenolate mofetil,18 sirolimus,3 tacrolimus and corticosteroids, cyclosporine and corticosteroids, and azathioprine. A recent study on DVA in SOT patients concluded that a main cause of DVA (24.6%) can be secondary to mycophenolate mofetil therapy.2 In our study, mycophenolate mofetil was administered to 54 patients (51.9%), azathioprine to 50 patients (48.1%), tacrolimus to 40 patients (38%), and cyclosporine to 38 patients (36.5%) who developed DVA after transplant. The difference in immuno­suppressive regimens can be due to the versatility of organs transplanted. Our study only focused on renal transplant recipients. Although most of our patients with DVA received mycophenolate mofetil and azathioprine followed by tacrolimus and cyclosporine, there was no statistically significant difference found versus the non-DVA group.

According to a 2007 report, in Southeast Asia, Pakistan has the highest incidence of tuberculosis in the general population (250/100 000).19 After renal transplant, recipients are at increased risk of developing tuberculosis,20 with incidences from 12.4% to 15.2% reported in different studies.21, 22 The efficacy of isoniazid in tuberculosis prevention is well documented in transplant patients. As per our institution’s policy and recommendations, renal transplant patients receive isoniazid for 1 year from date of transplant.23 Isoniazid has shown a statistically significant protective role on DVA development (P = .016), as most patients on INH therapy (n = 29; 28.2%) in our study did not develop DVA. The mechanism of its protection may be due to its bactericidal action, suggesting an infectious origin of villous atrophy.

Tropical sprue is characterized by malabsorption of nutrients due to its involvement of the small intestine. It is proposed that the duodenal morphological changes occur because of toxins and fermentation products, elaborated by persistent overgrowth of coliform bacteria. However, chronic small bowel overgrowth or blind loop syndrome does not produce the same features despite bacterial overgrowth. After exclusion of giardiasis and IPSID on biopsy, 68 patients were given ciprofloxacin and folic acid for 3 months as per protocol.22 Among these, 50 patients (74.6%) achieved complete response, with improvement in both weight and diarrhea. Relapse was observed in 13 patients (27.9%).

It has been reported that reinfection or relapse of tropical sprue occurs in 20% of patients living in tropical areas,23 which is consistent with our study, where relapse occurred in 27.9% of patients. However, labeling the reappearance of symptoms as relapse can be debated, as only 5 patients needed a repeat course of antibiotics, whereas the remaining patients had associated infection or malignancy.

One recent study demonstrated a frequency of 15.9% of DVA in SOT patients who underwent esophagogastroduodenoscopy and duodenal biopsy for chronic diarrhea.2 In our study, we found the frequency of DVA to be 49.5% in the renal transplant population, which is markedly higher than the previous study. The difference in results can be attributed to a number of factors. First, the previous study2 was conducted in SOT recipients, whereas our study was conducted exclusively in renal transplant recipients. Second, the recipients included in our study reside in an area endemic for tropical sprue24 and celiac disease.25 This can be a possible factor for higher prevalence of DVA. Third, our study found for the first time IPSID and celiac disease in renal transplant recipients as a possible cause of chronic diarrhea, which has not been reported previously. In addition, the previous study only reported 2 cases of giardiasis, whereas our study reported 30 patients with giardiasis, of which only 11 patients (10.7%) had villous stunting.

Our study has some limitations: it is a single-center study, the immunosuppressive regimen used was not uniform, and follow-up was brief. However, we did find some interesting observations in our study, such as no association with immuno­sup­pressive regimens or change of immuno­suppression. Most patients with DVA from no specific cause in our study responded to an antibiotic regimen. An association with celiac disease, giardiasis, IPSID, and infections like urinary tract infection, cytomegalovirus gastritis, and tuberculosis was established. We found a protective role of current INH use from the development of DVA.

Conclusions

In conclusion, DVA is highly prevalent cause of persistent diarrhea in renal transplant recipients irrespective of age, gender, and duration of transplant. In our patients, tropical sprue, giardiasis, celiac disease, and IPSID were important causes of DVA. Therefore, duodenal biopsy should be recommended in renal transplant recipients with unexplained persistent diarrhea. The protective role of INH on DVA needs to be further addressed in a prospectively designed study.


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Volume : 14
Issue : 2
Pages : 146 - 152
DOI : 10.6002/ect.2015.0183


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From the 1Department of Hepatogastroenterology; the 2Department of Nephrology; and the 3Department of Pathology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
Corresponding author: Farina M. Hanif, Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi-74200, Pakistan
Phone: +009 221 9921 5752
Fax: +009 221 3272 6165
E-mail: farinahanif@hotmail.com