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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 15  |  Issue : 4  |  Page : 320-324

Diarrhea in renal transplant recipients – Retrospective observational study from a center in South India


Institute of Nephrology, Madras Medical College, Chennai, Tamilnadu, India

Date of Submission29-Sep-2020
Date of Decision05-Jan-2021
Date of Acceptance14-Jan-2021
Date of Web Publication30-Dec-2021

Correspondence Address:
Dr. Jyothipriya Jyothindrakumar
Harimandiram, Kukiliya Lane, KLRA - 69, DPI Jn, Jagathy, Thiruvananthapuram - 695 014, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_123_20

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  Abstract 

Context: Diarrhea is one of the important causes of morbidity and graft dysfunction in renal transplant recipients. Aims: We aimed to study the risk factors and causes of diarrhea in renal transplant recipients and to assess the impact of diarrhea on graft function. Settings and Design: This was a retrospective observational study. Materials and Methods: A retrospective analysis of 912 renal allograft recipient records who underwent renal transplantation between January 2006 and June 2019 was performed. Patients with severe diarrhea requiring hospitalization were included. Investigations like stool microscopy including modified acid-fast stain and stool culture were performed. Statistical Analysis Used: Mean was calculated for normally distributed variables and median for not-normally distributed parameters. P < 0.05 was considered statistically significant. Univariate analysis was done to assess risk factors for diarrhea. Results: There were a total of 618 diarrheal episodes in 149 (16.3%) patients. Significant risk factors were deceased donor renal transplantation (58 [39%]) (P = 0.00024), the use of induction immunosuppression (44 [29.5%]) (P = 0.0002), and antirejection therapy (ART) (60 [40.3%]) (P = 0.0034). Infectious cause was identified in 85 (57%) patients, and cytomegalovirus was the predominant agent. Entamoeba histolytica (16 [10.7%]) was the predominant protozoal etiology. Temporary graft dysfunction during diarrheal episode occurred in 67 (45%) patients. Conclusions: Diarrhea occurred in 16.3% of renal transplant recipients. Deceased donor source, the use of induction immunosuppression, and ART were significant risk factors. Infectious cause was identified in 57% of diarrheal episodes. Following diarrhea, permanent graft dysfunction occurred in 10.7% of patients.

Keywords: Cytomegalovirus, diarrhea, graft dysfunction, postrenal transplantation


How to cite this article:
Jyothindrakumar J, Dhanasekaran R, Natarajan G, Thanigachalam DK, Rajendran P. Diarrhea in renal transplant recipients – Retrospective observational study from a center in South India. Indian J Transplant 2021;15:320-4

How to cite this URL:
Jyothindrakumar J, Dhanasekaran R, Natarajan G, Thanigachalam DK, Rajendran P. Diarrhea in renal transplant recipients – Retrospective observational study from a center in South India. Indian J Transplant [serial online] 2021 [cited 2022 Aug 10];15:320-4. Available from: https://www.ijtonline.in/text.asp?2021/15/4/320/334299




  Introduction Top


Diarrhea is a frequent complication of kidney transplantation with an incidence around 11% to 23%.[1] Diarrhea is one of the important causes of morbidity and graft dysfunction in renal transplant recipients.[2] Causes of diarrhea can be varied, from infectious to noninfectious etiologies.[3],[4] Since each diarrheal episode is an insult to renal allograft, prompt identification of etiology and early initiation of therapy is of paramount importance. This study aimed at assessment of etiologies and risk factors of diarrhea in renal transplant recipients and the impact of diarrhea on graft function.


  Materials and Methods Top


In this retrospective observational study, we reviewed the data of all renal allograft recipients who underwent renal transplantation between January 2006 and June 2019. Diarrhea was defined as three or more loose or liquid bowel movements per day. Inclusion criteria- Patients with severe diarrhea requiring hospitalization were included in this study. Exclusion criteria- Those unwilling to give informed consent were excluded. The demographic profiles, immunosuppression regimen, details of diarrheal illness, management, and outcomes of the patients were analyzed. All hospitalized patients with diarrhea had undergone investigations like stool microscopy including modified acid-fast stain, stool for parasitological examination, and stool culture. Tests for cytomegalovirus (CMV) infection and colonoscopy were performed when indicated.

Statistical analysis

Mean was calculated for normally distributed variables and median for not-normally distributed parameters. The categorical variables were compared using Fisher's exact test and Chi-square test. P < 0.05 was considered statistically significant. t-test was used to compare continuous variables that were normally distributed. Univariate analysis was done to assess risk factors for diarrhea.

Declaration of patient consent

The patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that the names and initials would not be published, and all standard protocols will be followed to conceal their identity.

Ethics statement

The Indian Council of Medical Research/Good Clinical Practice guidelines were followed as per the Institutional Ethics Committee (EC number: EC Reg. No.ECR/270Inst./TN/2013/RR-16). This study was carried out as per the Declaration of Helsinki.


  Results Top


During the study period, 149 (16.3%) of 912 renal transplant recipients developed diarrhea that necessitated hospitalization.

There were a total of 618 diarrheal episodes. Among 149 patients with posttransplant diarrhea, 119 (79%) were males. Fifty-eight (39%) patients were deceased donor renal transplant (DDRT) recipients and 91 (61%) were live renal transplant recipients.

The demographic profile and clinical characteristics of the patients with diarrhea are shown in [Table 1].
Table 1: Demographic profile and clinical characteristics

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Sixty-four (42.9%) patients had diarrhea within 1 year of transplantation and 85 (57.1%) had diarrhea after 1 year. Among the 64 patients who had diarrhea in the 1st year of transplantation, 7 patients had diarrhea <1 month of transplantation, 26 had diarrhea in 1–6 months of posttransplant period, and 31 had in 6–12 months of posttransplant period.

Eighty-three (55.7%) patients were on tacrolimus-mycophenolate mofetil (MMF) regimen, 29 (19.5%) on cyclosporine (CSA)-MMF, 15 (11%) on CSA-azathioprine, 12 (8%) on MMF alone, and 6 (4%) on azathioprine alone regimen. All patients had received steroid. There were a total of 124 (83.2%) patients who were on MMF regimen. After hospitalization, the dose of MMF was reduced in 94 (63.1%) patients, MMF was switched over to azathioprine in 20 (13.6%), and MMF was temporarily stopped in 36 (24.2%) patients.

Statistically significant risk factors of diarrhea in our study were deceased donor renal transplantation (DDRT) (58 [39%]) (P = 0.00024), the use of induction immunosuppression (44 [29.5%]) (P = 0.0002), and antirejection therapy (ART) (60 [40.3%]) (P = 0.0034). The use of MMF (124 [83%]) and diabetes mellitus (37 [24.8%]) were not statistically significant risk factors. Risk factor analysis is given in [Table 2].
Table 2: Risk factors of postrenal transplantation diarrhea

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The most common cause of diarrhea was infection, seen in 85 (57%) patients, the causes being CMV in 42 (28.2%) patients, protozoal in 36 (24.2%) patients, and bacterial in 7 (4.7%) patients. Even after extensive workup, in 64 (42%) patients, the cause of diarrhea could not be identified. The important causes of diarrhea in our study are given in [Table 3].
Table 3: Causes of diarrhea

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Stool analysis results of bacterial and protozoal etiology are shown in [Table 4].
Table 4: Stool analysis of bacterial and protozoal etiology

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The time of occurrence of infectious diarrhea after transplantation is given in [Figure 1] and [Figure 2].
Figure 1: Timeline of infectious diarrhea

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Figure 2: Causes of infection in 1 year posttransplant

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Colonoscopy was done in 19 (12.8%) patients in whom 3 patients had CMV colitis. Appropriate treatment was given according to the etiology of diarrhea. The outcomes of acute diarrhea are given in [Table 5].
Table 5: Outcomes of acute diarrhea

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  Discussion Top


Gastrointestinal (GI) complications after renal transplantation have shown to be associated independently with poor graft outcomes.[5] Among GI complications, diarrhea is very common.[3] Posttransplant diarrhea is associated with reduced quality of life,[6] hastened decline of graft function, and higher mortality.[7] Diarrhea can impair renal graft function as a result of the ensuing dehydration and hypovolemia.[8] In addition, decreased intestinal P-glycoprotein (or multidrug resistance 1) enzymatic activity in the context of diarrhea leads to elevated tacrolimus trough levels[9] and subsequent calcineurin inhibitor toxicity. MMF dose adjustment or poor adherence to MMF treatment after GI complications is associated with a significantly increased risk of graft loss.[10],[11]

In our study, majority (85 [57.1%]) of the diarrheal episodes occurred after 1 year of transplantation. Of the diarrheal episodes which occurred in the 1st year of transplantation, maximum cases (31 patients) were reported in the 6–12-month period, followed by 1–6-month period (26 patients).

After the diagnosis of diarrhea, we tried finding out the nonimmunosuppressive drugs that can result in diarrhea. In our study, 83.2% of patients were on MMF regimen. Alteration in MMF regimen was made in those patients who did not show any infectious etiology, who failed to respond to empiric antibiotics, and in whom a nonimmunosuppressive drug causing diarrhea could not be found out. Although MMF is being considered as one of the prominent causes of posttransplant diarrhea, in our study, it was not a statistically significant risk factor.

The proportion of patients affected with diarrhea in our study was 16.3%, whereas it was 8.9% in another Indian study by Bhadauria et al.[12] and it was 22% and 12.6% in the studies done by Bunnapradist et al.[7] and Altıparmak et al.,[13] respectively. Statistically significant risk factors in our study were deceased donor source, the use of induction immunosuppression agent, and ART during recent past. Infections (85 [57%] patients) were the most common cause of diarrhea, and among them, CMV (42 [28.2%]) was the predominant cause. CMV prophylaxis was given for 3 months posttransplant for all deceased donor recipients, post-ART, and after treatment of documented CMV disease as secondary prophylaxis. However, none of the patients had CMV diarrhea while they were on CMV prophylaxis. In spite of the advances in antiviral therapies, CMV is still an important cause of morbidity and mortality in renal transplant recipients.[14] In the study done by Bhadauria et al.,[12] similar to our study, the most common etiology of diarrhea was infection, but the predominant causative organism was Cryptosporidium. Altıparmak et al.[13] in their study had identified Shigella and Giardia, as the most common causes of infectious diarrhea. Etiology of diarrhea remained unidentified in 42% of patients in our study, whereas in the studies conducted by Bunnapradist et al.[7] and Altıparmak et al.,[13] it was 18% and 19.5%, respectively. Following CMV diarrhea, the next most common infectious cause in our study was protozoal diarrhea (36 [24.1%]). Entamoeba histolytica (16 [10.7%]) and Giardia (8 [5.4%]) were the most common among them.  Escherichia More Details coli (3 [2%]) and Klebsiella (2 [1.3%]) were the predominant organisms causing bacterial diarrhea. CMV was the predominant cause of infectious diarrhea both during the 1st year of transplantation and after that period. However, in the 1st month of transplantation, rather than CMV, it was the protozoa that was the main culprit of infectious diarrhea. Protozoal organisms were identified by stool microscopic examination with the relevant specific stains (including modified acid-fast staining for Cryptosporidium and modified trichrome staining for Microsporidia) and bacterial agents by the analysis of stool culture. CMV infection was confirmed by CMV polymerase chain reaction, and colonoscopy was done when indicated. The presence of CMV colitis was documented in three patients.

Reduction of immunosuppression needs to be exercised judiciously as inappropriate reduction can result in an increased risk of acute rejection[11] and de novo donor-specific antibody formation.[15] The prospective Diarrhea Diagnosis Aid and Clinical Treatment study formulated a stepwise approach that aimed to eliminate nonimmunosuppressive drugs as the causative agents and to treat infectious causes before adjusting the immunosuppressive regimen.[16] In this landmark study, infectious causes accounted for 64% of the cases.

The most frequent complication due to diarrhea in our study was temporary graft dysfunction (67 [45%] patients). However, 16 (10.7%) patients had persistent graft dysfunction, and graft biopsy was done in those patients when indicated. In our study, three patients died due to the late presentation with severe metabolic acidosis.

Although we had done Clostridium difficile toxin A and toxin B workup in few cases of unresolved diarrhea, we never encountered C. difficile infection. Furthermore, none of the patients in our study had diarrhea due to posttransplant lymphoproliferative disease as well as colon cancer.

The strength of our study is that we had a large cohort of transplant recipients with diarrhea with a longer follow-up period and we also studied the impact of diarrhea on graft function.

Limitations to the study

There are few limitations to this study. It was a retrospective study, and the definition of diarrhea was a subjective one. We included only patients who required hospitalization in our study. Investigation modalities such as capsule endoscopy and small-bowel biopsy and molecular stool panel were not performed in cases where etiology of diarrhea was undetermined. We also could not perform endoscopic examination of duodenal contents for giardiasis and also tests for excluding bacterial overgrowth.


  Conclusions Top


Diarrhea occurred in 16.3% of renal transplant recipients in our study. Deceased donor source, the use of induction immunosuppression, and ART were significant risk factors. Infectious cause was identified in 57% of diarrheal episodes. CMV (28.2%) was a significant cause for diarrhea. Following diarrhea, permanent graft dysfunction occurred in 10.7% of patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Rubin RH. Gastrointestinal infectious disease complications following transplantation and their differentiation from immunosuppressant-induced gastrointestinal toxicities. Clin Transplant 2001;15 Suppl 4:11-22.  Back to cited text no. 1
    
2.
Pescovitz MD, Navarro MT. Immunosuppressive therapy and post-transplantation diarrhea. Clin Transplant 2001;15 Suppl 4:23-8.  Back to cited text no. 2
    
3.
Ponticelli C, Passerini P. Gastrointestinal complications in renal transplant recipients. Transpl Int 2005;18:643-50.  Back to cited text no. 3
    
4.
Helderman JH, Goral S. Gastrointestinal complications of transplant immunosuppression. J Am Soc Nephrol 2002;13:277-87.  Back to cited text no. 4
    
5.
Hardinger KL, Brennan DC, Lowell J, Schnitzler MA. Long-term outcome of gastrointestinal complications in renal transplant patients treated with mycophenolate mofetil. Transpl Int 2004;17:609-16.  Back to cited text no. 5
    
6.
Ekberg H, Kyllönen L, Madsen S, Grave G, Solbu D, Holdaas H. Clinicians underestimate gastrointestinal symptoms and overestimate quality of life in renal transplant recipients: A multinational survey of nephrologists. Transplantation 2007;84:1052-4.  Back to cited text no. 6
    
7.
Bunnapradist S, Neri L, Wong W, Lentine KL, Burroughs TE, Pinsky BW, et al. Incidence and risk factors for diarrhea following kidney transplantation and association with graft loss and mortality. Am J Kidney Dis 2008;51:478-86.  Back to cited text no. 7
    
8.
Roos-Weil D, Ambert-Balay K, Lanternier F, Mamzer-Bruneel MF, Nochy D, Pothier P, et al. Impact of norovirus/sapovirus-related diarrhea in renal transplant recipients hospitalized for diarrhea. Transplantation 2011;92:61-9.  Back to cited text no. 8
    
9.
Lemahieu W, Maes B, Verbeke K, Rutgeerts P, Geboes K, Vanrenterghem Y. Cytochrome P450 3A4 and P-glycoprotein activity and assimilation of tacrolimus in transplant patients with persistent diarrhea. Am J Transplant 2005;5:1383-91.  Back to cited text no. 9
    
10.
Takemoto SK, Pinsky BW, Schnitzler MA, Lentine KL, Willoughby LM, Burroughs TE, et al. A retrospective analysis of immunosuppression compliance, dose reduction and discontinuation in kidney transplant recipients. Am J Transplant 2007;7:2704-11.  Back to cited text no. 10
    
11.
Knoll GA, MacDonald I, Khan A, van Walraven C. Mycophenolate mofetil dose reduction and the risk of acute rejection after renal transplantation. J Am Soc Nephrol 2003;14:2381-6.  Back to cited text no. 11
    
12.
Bhadauria D, Goel A, Kaul A, Sharma RK, Gupta A, Ruhela V, et al. Cryptosporidium infection after renal transplantation in an endemic area. Transpl Infect Dis 2015;17:48-55.  Back to cited text no. 12
    
13.
Altiparmak MR, Trablus S, Pamuk ON, Apaydin S, Sariyar M, Oztürk R, et al. Diarrhoea following renal transplantation. Clin Transplant 2002;16:212-6.  Back to cited text no. 13
    
14.
Goral S, Ynares C, Dummer S, Helderman JH. Acyclovir prophylaxis for cytomegalovirus disease in high-risk renal transplant recipients: Is it effective? Kidney Int Suppl 1996;57:S62-5.  Back to cited text no. 14
    
15.
Liefeldt L, Brakemeier S, Glander P, Waiser J, Lachmann N, Schönemann C, et al. Donor-specific HLA antibodies in a cohort comparing everolimus with cyclosporine after kidney transplantation. Am J Transplant 2012;12:1192-8.  Back to cited text no. 15
    
16.
Maes B, Hadaya K, de Moor B, Cambier P, Peeters P, de Meester J, et al. Severe diarrhea in renal transplant patients: Results of the DIDACT study. Am J Transplant 2006;6:1466-72.  Back to cited text no. 16
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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