Home About us Current issue Back issues Submission Instructions Advertise Contact Login   

Search Article 
  
Advanced search 
 
Saudi Journal of Kidney Diseases and Transplantation
Users online: 106 Home Bookmark this page Print this page Email this page Small font sizeDefault font size Increase font size 
 


 
ORIGINAL ARTICLE Table of Contents   
Year : 2010  |  Volume : 21  |  Issue : 4  |  Page : 628-635
Prevalence of silent gastrointestinal complications in maintenance renal transplant population


1 Saskatchewan Transplant Program, St. Paul's Hospital, Saskatoon, Canada
2 Department of Community Health and Epidemiology, Division of Nephrology, Department of Medicine, University of Saskatchewan, Saskatoon, Canada
3 Transplantation and Immunology, Novartis Pharmaceuticals Canada Inc., Quebec, Canada

Click here for correspondence address and email

Date of Web Publication26-Jun-2010
 

   Abstract 

This study aims to determine the prevalence of silent GI complications within a stable renal transplant population and to investigate whether the conversion to enteric-coated myco­phenolate sodium (EC-MPS, Myfortic;) would improve symptom scores. This was a single­center, open-label, non-randomized, prospective study. Patients without any history of GI com­plaints were evaluated by means of the gastrointestinal symptom rating scale (GSRS), with subse­quent switch to EC-MPS in a group of patients. Silent complications were defined as patients who voiced no GI complaints at clinic visits despite a score of ≥ 2 on GSRS scale. A total of 236 stable patients participated in the trial. The prevalence of baseline scores ≥ 2 was relatively high with abdominal pain 29.66%, reflux 37.28%, indigestion 50%, constipation 58.47% and diarrhea 33.4%. Of 236 patients, 80 were converted to EC-MPS. There was statistically significant improvement on all scales in the subgroup of patients with GSRS score ≥ 2 (P< 0.05). In conclusion, the GSRS scale identified a high percentage of silent gastrointestinal complications in this renal transplant population. The converted patients with higher GSRS scores reported a sustained improvement.

How to cite this article:
Teplitsky S, Rosaasen N, Hossain MA, Dyck J, Fox TK, Shoker A. Prevalence of silent gastrointestinal complications in maintenance renal transplant population. Saudi J Kidney Dis Transpl 2010;21:628-35

How to cite this URL:
Teplitsky S, Rosaasen N, Hossain MA, Dyck J, Fox TK, Shoker A. Prevalence of silent gastrointestinal complications in maintenance renal transplant population. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2019 Jan 17];21:628-35. Available from: http://www.sjkdt.org/text.asp?2010/21/4/628/64617

   Introduction Top


The use of mycophenolate mofetil (MMF), in combination with cyclosporine and corticoste­roids, has proven to be one of the most suc­cessful transplantation treatments, improving patient and graft survival in renal transplant patients. [1],[2] However, current immunosuppres­sive regimens with MMF in renal transplan­tations have been frequently associated with gastrointestinal (GI) complications, [3] such as nausea, vomiting, diarrhea, etc., necessitating dose reduction, interruption, or termination of the treatment, and thus compromising treat­ment efficacy. GI side effects are well known to be associated with the other commonly used immunosuppressive medications, such as calci­neurin inhibitors, prednisone, and azathioprine (Imuran; ). Of importance, GI symptoms have been demonstrated to influence health-related quality of life in a range of diseases. [4,[5],[6] Based on recent data showing that one-year patient and renal graft survival exceeds 90% [7],[8] there is an increasing necessity to investigate both the prevalence of GI problems and alternative treat­ment(s) improving GI symptom burden.

An enteric-coated formulation of mycophe­nolate sodium (EC-MPS, Myfortic; , Novartis) was designed in an attempt to help alleviate the upper GI symptoms related to mycophe­nolic acid (MPA) by virtue of its release into the small intestine. Registration trials of EC­MPS were able to demonstrate that EC-MPS is equally efficacious as MMF in de novo renal transplant patients and that stable maintenance renal transplant patients can be converted from MMF to EC-MPS without compromising the renal allograft. [9],[10] One of these studies showed that despite a similar incidence of GI symp­toms in MMF and EC-MPS treated groups, there was a trend towards fewer dose reduc­tions/dose discontinuations due to GI adverse events (AE) in the EC-MPS group. [9] Further investigations utilized the Gastrointestinal Symp­tom Rating Scale (GSRS) to examine the GI burden and the impact of GI AEs on health­related quality of life in renal transplant pa­tients treated with MPA in two different for­mulations i.e., MMF and EC-MPS. The PROGIS trial was a multi-center, open-label prospective study in MMF-treated renal transplant patients, in which patients experiencing GI complaints were converted to equimolar EC-MPS, while patients without GI complaints remained on MMF. [11] Patients were evaluated by means of several questionnaires: GSRS, Gastrointestinal Quality of Life Index, Psychological Well­Being Index, and the Overall Treatment Effect scale for Health-Related Quality of Life. The study demonstrated that patients converted from MMF to EC-MPS had a significantly re­duced GI symptom burden and improvement in GI-specific and general well being. Of im­portance, the value of the GSRS as an instru­ment capable to differentiate renal transplant patients with and without GI problems by symp­tom severity, was demonstrated in a cross sec­tional, international, non-randomized study. [12]The GSRS is an easily applied interview-based rating scale, which was supported and vali­dated to be sensitive in revealing and scoring GI symptoms considering such characteristics as intensity, frequency, duration of attacks and impact on daily living. [12],[13],[14],[15]

Currently, there is little information available about the prevalence of GI complications in presumably stable renal transplant outpatients, including those who do not actively complain of GI symptoms during routine follow-up, but who might benefit from conversion to EC­MPS. Renal transplant patients who do not report GI complaints during routine follow-up are silent gastrointestinal complications and, in order to unveil their GI complaints, we used the GSRS as an outcome tool. It was considered that the GSRS would identify the prevalence of silent gastrointestinal complications more effectively than a routine interview in our trans­plant program. We also investigated the hypo­thesis that conversion to EC-MPS would im­prove the GSRS scoring. Moreover, we endea­vored to determine whether the beneficial effect of EC-MPS on GI symptoms was sustained over time.


   Materials and Methods Top


Study design and conduct

The information obtained from this single­center, open-label, non-randomized, prospec­tive study was entered into the database of the Saskatchewan Transplant Program. Stable kid­ney transplant patients were surveyed by trained interviewers using the GSRS. The information on GI health before and after the conversion to EC-MPS was collected. We define silent GI complications to be those patients who do not actively complain of GI symptoms during rou­tine follow-up despite a score of ≥ 2 on the GSRS scale. We chose the cut off score of two because it is well known that normal indivi­duals have a GSRS score of < 2.0. [16]

Ethics

The study was conducted in compliance with the declaration of Helsinki of 1975 as revised in 1983, and Good clinical practice guidelines, and in accordance with local institutional re­view board requirements.

Patient population and evaluation schedule

Adult stable kidney transplant outpatients above 16 years of age were eligible to enter the study. Patients were excluded if they had pre­vious actively disclosed GI complaints or asked for medical help for GI problems, experienced an episode of acute rejection within two weeks prior to the study, were undergoing an acute medical intervention or hospitalization, or were participating in another investigational product study.

The presence of GI symptoms and their se­verity were evaluated as scored by the GSRS. Irrespective of the results of the GSRS score, patients were told that MMF and EC-MPS were equally effect in their immunosuppres­sive efficacy, but that their side effect profile, particularly with respect to effects on the GI tract, may be different, and finally that it was uncertain if either drug was superior.

[Figure 1] illustrates the study design. At base­line, all patients were asked to answer the GSRS questionnaire prior to their interaction with the physician. Patients converted to EC­MPS became the Converted Cohort (Cohort C), while patients with no change to baseline im­munosuppression became the Non Converted Cohort (Cohort NC). Transplant physicians were blinded to the scores. Equimolar EC-MPS do­sage, corresponding to the MMF dose was prescribed. Specifically, 500 mg, 1000 mg, 1500 mg, 2000 mg, and 3000 mg of MMF were switched to 360 mg, 720 mg, 1080 mg, 1440 mg and 2160 mg of EC-MPS, respectively. All of the patients from both cohorts were asked to answer the GSRS at baseline. In addition, the patients of Cohort C answered the question­naire at the subsequent study visits 2 (2.88 ± 1.24 months) and 3 (8.07 ± 2.79 months). In the Cohort C, a further analysis focused on the subgroup of patients with baseline GSRS scores ≥ 2. Cohort NC was further analyzed based on two subgroups: patients receiving MMF, and patients on non-MMF regimen. To evaluate our second objective, the GI-related impact of the conversion to EC-MPS therapy, the popu­lation consisted of the patients of Cohort C, who adhered to the study design and had no major protocol violations.

Information on demographic characteristics (i.e. age and gender), and concomitant medica­tions was also collected. The safety evaluation included the incidence of admission to hospital as a result of the treatment conversion, as well as parameters of kidney function, such as se­rum creatinine (Cr) and estimated Glomerular Filtration Rate (eGFR) measured at the study visits (i.e., baseline visit, visit 2 and visit 3). All data were transferred to an electronic data­base for analysis. The safety population inclu­ded all the enrolled patients. Baseline scores between the two groups were compared.

Patient-reported outcomes

The GSRS scale consists of five sub-classes (abdominal pain, reflux, indigestion, constipa­tion, and diarrhea). Sub-scale scores range from 1 to 7, with > 2 indicating the presence of GI symptoms [16] and higher scores representing higher symptom burden. The GSRS question­naire was used to detect GI complaints that pa­tients may be reluctant to disclose upon ques­tioning.


   Statistical Methods Top


The change in patient-reported GSRS scores from baseline to visits two and three were compared. We used paired t-test analysis which is known to be suitable for analysis for a large sample such as ours. [17] The paired t-test was used to examine differences over time within each cohort for continuous variables. The associations between the outcome variable and the risk factors were considered in a multi­variable analysis done by logistical regression. Five outcome variables (abdominal pain, re­flux, indigestion, constipation and diarrhea) and five risk factors (age, sex, kidney function measured by serum creatinine, concomitant treatment with PPI, diabetes) were considered for each one of the outcome variables. All statistical tests used were two-sided with a 0.05 level of significance. All patient-reported outcome results were reported as mean ± SD.


   Results Top


Patient disposition and treatment assignment

The study included 236 patients. The majo­rity of patients were male (59%) with a mean age of 49 ± 13 years. The mean age of the groups C and NC was 48.52 ± 14.8 and 49.67 ± 13.13 years, respectively. The mean time after transplant was 86.57 ± 99.45 months amongst the entire group. Of these, 90% of patients were taking corticosteroids and 89% a calcineurin inhibitor. The percentage of pa­tients receiving a PPI medication at baseline was 29% of the entire study population, with the distribution of the PPI treatment in Cohorts C and NC at 36% and 26% respectively.

[Figure 1] illustrates the disposition of the pa­tients in the study. At baseline, 74.5% of the total population was taking MMF. Of 236 patients, 80 were converted to EC-MPS (Cohort C). A total of 156 patients were maintained on their baseline treatment (Cohort NC); 96 of these patients continued their MMF treatment, while 60 patients were on an immunosuppressive regimen other than MMF.

The mean daily dose of equimolar EC-MPS corresponding to the MMF dose for the con­verted group was similar (P> .05) before and after conversion.

Three (3.8%) patients from cohort C withdrew from the study. Eighteen (22.5%) patients con­verted back to MMF: three patients between the baseline and visit two, and the rest between visits two and three. Patients requested con­version from EC-MPS to MMF for the fol­lowing reasons: seven (8.8%) perceived wor­sening of GI symptoms, five (6.3%) patients due to "feeling unwell", three (3.8%) patients due to issues with the medication packaging, and three provided no reason. The patients who switched back to MMF were also eva­luated at the subsequent visits, and their GSRS scores did not appear to significantly change.

Patient reported outcome results

In the total population, the baseline mean GSRS scores exceeded the level of two for the sub-scales of indigestion and constipation. Over­all, the analyses performed on the Cohorts C and NC showed similar scores at baseline.

In the overall population, the baseline pre­valence of GSRS scores equal to or above two appeared to be relatively high [Table 1], and these scores in Cohort C were higher than the NC group in general. In the NC group, GI symp­toms were equal among the MMF and non­MMF group except diarrhea [Table 2].

In the Cohort C, two subsequent visits (V2 and V3) were documented; V2 at 2.88 ± 1.24 months, and V3 at 8.07 ± 2.79 months res­pectively. In the Cohort C, there was no sta­tistically significant difference in the GSRS scores before and after conversion. However, in the subgroup analysis of the converted pa­tients with higher baseline GSRS scores (≥ 2), there was a significant improvement in scores for each of five symptoms (P< 0.05) [Table 3]. As such, the benefit of the conversion to EC­MPS proved to be sustained over time, as shown on [Figure 2].

Five outcome variables were analyzed sepa­rately using multivariable logistic regression: abdominal pain, reflux, indigestion, constipation, and diarrhea. [Table 4] shows multivariable ana­lysis of factors that were thought to contribute to GSRS scores in the total population and sub­groups. Overall in our patients, among the fac­tors studied, only the use of a PPI was asso­ciated with lower scores, in particular for ab­dominal pain (P= 0.001) and indigestion (P= 0.000), after adjusting for other variables. There was also a trend towards reduced dia­rrhea scores in patients receiving PPIs. Multi­variate analysis in group C did not reveal any particular factor associated with symptoms except PPI use had trend towards improvement in diarrhea symptoms. Patients who were ta­king PPI's had lower baseline scores of abdo­minal pain (P= 0.004) and this positive effect continued at visit two (P= 0.47), but it did not last any further. [Table 5] shows the comparison of baseline scores between converted and non­converted groups. Abdominal pain, reflux and indigestion were statistically higher in the converted group suggesting that the silent suf­ferers were more willing to discuss their con­dition further and to take steps to improve them.

Safety

Tabulation of laboratory analyses did not reveal any significant changes. No episodes of acute rejection were reported in patients con­verted to equimolar doses of EC-MPS, and there were no graft losses or deaths during the study. One patient in Cohort C was excluded from the study when he developed lymphoma. There were no admissions to the hospital due to the conversion to EC-MPS, and no cases of severe leucopenia.


   Discussion Top


This was the first prospectively designed study to investigate the prevalence of silent GI com­plications in the renal transplant population using the GSRS questionnaire and may benefit from conversion to EC-MPS. The GSRS scale was a useful tool and identified a high per­centage of silent gastrointestinal complications in this population. In the total analysis, the pre­valence of baseline scores equal to or above two were present in more than 30 % overall. By design, the study was not randomized, and no parallel treatments comparison was per­formed. Nevertheless, there was an advantage to this study in that there was no bias caused by differences between the cohorts, since the outcome analysis was focused on comparing results within the cohort converted to the EC­MPS therapy.

Data produced by multivariate analysis de­monstrated that, among potentially contributing factors, there was a significant positive impact of the use of PPIs on the GSRS scores, in par­ticular abdominal pain and indigestion scores. In the sub-analysis of the converted group, the use of a PPI had only a short-term positive impact on abdominal pain scores.

The conversion to EC-MPS therapy did not result in lowering the mean GSRS scores. How­ever, sub analysis of the converted patients with higher GSRS scores reported an improve­ment in GI symptoms, which was shown to be statistically significant and sustained over time. Finally, there were no unexpected safety issues as a result of the con-version to the EC-MPS therapy. There are limitations to this study. First, physicians were not blinded to the medi­cations they were however blinded to the scores. Therefore there may be a bias in the conclusion. We hoped, however, that the use of a scoring system would help avoid some of the potential biases due to the unblinded design. Another limitation is that we did not repeat the GSRS questionnaire to evaluate the non con­verted cohorts over the same duration of the study. This was due to the previous studies reporting the clinical applicability of GSRS score system in transplant patients and there­fore we did not repeat the questionnaire in the unconverted group.


   Conclusion Top


In conclusion, this single center study con­firmed a high prevalence of GI complications in renal transplant patients on the current immu­nosuppressive regimen. No difference in over­all GI symptoms were noted after conversion from MMF to EC-MPS, however, in patients with a high GSRS score improvement in symp­toms were noted.


   Acknowledgement Top


The study was supported with an unrestricted grant from Novartis, Canada.

 
   References Top

1.Cherikh WS, Kauffman HM, Maghirang J, et al. Efficacy comparison of discharge immuno­suppressive regimens in cadaveric kidney transplantation. What is the best combination? Am J Transplant 2002;2(S3):468.  Back to cited text no. 1      
2.Ojo AO, Meier-Krieshe HU, Hanson JA, et al. Mycophenolate mofetil reduces late renal allograft loss independent of acute rejection. Transplantation 2000;69:2405-9.  Back to cited text no. 2      
3.Behrend M. Adverse gastrointestinal effects of mycophenolate mofetil. Drug Safety 2001;24: 645.  Back to cited text no. 3  [PUBMED]  [FULLTEXT]  
4.Quigley EM, Hungin AP. Review article: qua­lity-of-life issues in gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2005; 22:41.  Back to cited text no. 4  [PUBMED]    
5.Revicki DA, Zodet MW, Joshua-Gotlib S, et al. Health-related quality of life improves with treatment-related GERD symptom resolution after adjusting for baseline severity. Health Qual Life Outcomes 2003;1:73.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]  
6.Prasad M, Rentz AM, Revicki DA. The impact of treatment for gastro-oesophageal reflux di­sease on health-related quality of life: a literature review. Pharmacoeconomics 2003; 21:769.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]  
7.Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B. Lack of improvement in renal allo­graft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant 2004;4:378.  Back to cited text no. 7  [PUBMED]    
8.Hariharan S, Johnson CP, Bresnahan BA, et al. Improved graft survival after renal transplan­tation in the United States, 1988 to 1996. N Engl J Med 2000;342:605.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]  
9.Salvadori M, Holzer H, de Mattos A, et al. Enteric-coated mycophenolate sodium is the­rapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 2004; 4: 231.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]  
10.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 2003; 4:237-43.  Back to cited text no. 10      
11.Chan L, Mulgaonkar Sh, Walker R, et al. Patient-reported gastrointestinal symptom burden and health-related quality of life following conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium. Trans­plantation 2006;81(9):1290-7.  Back to cited text no. 11      
12.Kleinman L, Faull R, Walker R, et al. Gastro­intestinal-specific patient-reported outcome instruments differentiate between renal trans­plant patients with or without GI complica­tions. Transplant Proc 2005;37:846-9.  Back to cited text no. 12  [PUBMED]  [FULLTEXT]  
13.Svedlund J, Sjodin I, Dotevall G. GSRS - A clinical rating scale for gastrointestinal symp­toms in patients with irritable bowel syndrome and peptic ulcer disease. Digest Dis Sci 1988; 33(2):129-34.  Back to cited text no. 13      
14.Svedlund J, Sjodin I, Ottosson JO, Dotevall G. Controlled study of psychotherapy in irritable bowel syndrome. Lancet 1983;2:589-92.  Back to cited text no. 14      
15.Sjodin I, Svedlund J, Ottosson JO, Dotevall G. Controlled study of psychotherapy in chronic peptic ulcer disease. Psychosomatics 1986;27: 187-200.  Back to cited text no. 15      
16.Revicki DA et al. Reliability and validity of the Gastrointestinal Symptom Rating Scale in patients with gastroesophageal reflux disease. Qual Life Res 1998;7(1);75-83.  Back to cited text no. 16      
17.Hill T, Lewicki P. Statistics Methods and Applications. StatSoft, Tulsa. 2007.  Back to cited text no. 17      

Top
Correspondence Address:
Ahmed Shoker
Director of Transplant Program, Department of Medicine, Division of Nephrology, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8
Canada
Login to access the Email id


PMID: 20587864

Rights and Permissions


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

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



 

Top
 
 
    Similar in PUBMED
    Search Pubmed for
    Search in Google Scholar for
    Email Alert *
    Add to My List *
* Registration required (free)  
 


 
    Abstract
    Introduction
    Materials and Me...
    Statistical Methods
    Results
    Discussion
    Conclusion
    Acknowledgement
    References
    Article Figures
    Article Tables
 

 Article Access Statistics
    Viewed2633    
    Printed96    
    Emailed0    
    PDF Downloaded495    
    Comments [Add]    

Recommend this journal