Questionnaire-based evaluation of gastrointestinal disorders in de novo renal-transplant patients receiving either mycophenolate mofetil or enteric-coated mycophenolate sodium
Nassim Kamar1,
Loubna Oufroukhi1,
Patrick Faure2,
David Ribes1,
Olivier Cointault1,
Laurence Lavayssiere1,
Marie Béatrice Nogier1,
Laure Esposito1,
Dominique Durand1 and
Lionel Rostaing1
1 Department of Nephrology, Dialysis and Multiorgan Transplantation, CHU Rangueil, Toulouse and 2 Department of Gastroenterology, CHU Rangueil, Toulouse, France
Correspondence and offprint requests to: Nassim Kamar, Department of Nephrology, Dialysis and Transplantation, CHU Rangueil, 1 avenue Jean Poulhès, TSA 50032, 31059 Toulouse Cedex 9, France. Email: nassim.kamar{at}free.fr
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Abstract
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Background. Gastrointestinal (GI) disorders are one of the main adverse events in patients treated by mycophenolic acid (MPA). The aim of our prospective questionnaire-based study was to assess GI side-effects in de novo renal-transplant patients receiving either mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS).
Methods. Between January 2002 and April 2003, all patients receiving MPA with a functioning allograft at 1 month post-transplantation were enrolled in this study (n = 130). Ninety-three of them received MMF (group I), and 37 patients received EC-MPS (group II). Each month, every patient completed a questionnaire regarding GI disorders.
Results. During the first year post-transplantation, GI disorders occurred in 31 patients from the MMF group (33.3%) and 12 patients from the EC-MPS group (32.4%) (not significant). The incidence of upper GI disorders was also similar in both groups. Diarrhoea was observed in 18 patients (19.3%) from group I, and in five patients from group II (13.5%) (not significant). Its frequency and severity were similar in both groups. Weight loss was observed in three patients receiving MMF. Diarrhoea resolved spontaneously in 10 patients from group I and in all patients from group II. For the other eight patients in group I, the diarrhoea required MMF discontinuation in three patients and dose reduction in five patients.
Conclusions. In conclusion, in this questionnaire-based evaluation, the incidence of GI disorders was similar in patients receiving either MMF or EC-MPS during the first year post-transplantation.
Keywords: diarrhoea; dose modification; enteric-coated mycophenolic sodium; gastrointestinal disorders; mycophenolate mofetil
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Introduction
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Mycophenolate mofetil (MMF) is the cornerstone drug of maintenance immunosuppression regimens after kidney transplantation because of its beneficial effect in preventing both acute rejection and chronic allograft nephropathy [13]. However, all immunosuppressive drugs currently used after organ transplantation have several side effects, as does MMF. With MMF, the two most frequently observed adverse events are leucopaenia and gastrointestinal (GI) disorders, especially diarrhoea. In some patients, diarrhoea is well tolerated, whereas it can be more severe for others, leading to weight loss and malabsorption syndrome. Nevertheless, in both cases, it may alter the quality of life of the patients, and increase the post-transplant treatment costs [4].
Recently, enteric-coated mycophenolate sodium (EC-MPS) (myfortic®; Novartis Pharma, Basel, Switzerland), a new formulation of mycophenolic acid, has been developed to reduce GI disorders [5]. For both de novo renal-transplant patients [6] and renal-maintenance patients [7], EC-MPS has been found to be as efficient and as safe as MMF. GI adverse events were similar in patients receiving MMF or EC-MPS. The aim of our study was to assess, prospectively, the incidence of GI disorders in de novo renal-transplant patients receiving either MMF or EC-MPS by using a specific questionnaire. We also assessed GI-related MMF or EC-MPS dose modifications, i.e. discontinuations, interruptions and reductions.
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Subjects and methods
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Between January 2002 and April 2003, 159 patients received a kidney graft at our institution. All patients who were taking either MMF- or EC-MPS-based therapies, and had a functioning renal allograft at 1 month post-transplantation, were enrolled in this study (n = 130). We excluded (i) patients treated with a combination of tacrolimus and sirolimus (n = 19), (ii) those with a non-functioning graft at 1 month post-transplantation (n = 8; six in the MMF group and two in the EC-MPS group), and (iii) those not receiving MMF or EC-MPS at 1 month (n = 2). There were 77 men and 53 women, ranging in age from 18 to 69 years (median, 45.5). Ninety-three patients received MMF (Cellcept®; Hoffmann-LaRoche, Basel, Switzerland), and 37 were treated with EC-MPS (myfortic®). All patients treated with EC-MPS who were included in a clinical trial funded by Novartis Pharma received an induction therapy by basiliximab, followed by triple sequential immunosuppression, which included cyclosporine A (Neoral®; Novartis, Basel, Switzerland), EC-MPS and steroids. The immunosuppression regimen of patients from the MMF group was heterogeneous because all our patients were included in clinical trials. Most of these were funded by Fujisawa, Wyeth-Lederle and Fresenius. Seventy-nine patients, i.e. 85%, had undergone induction therapy with either polyclonal antibodies (n = 54, 68%) or anti-CD25 monoclonal antibodies (n = 25, 32%). Calcineurin inhibitor agents were given to 82 patients: 46 patients received cyclosporine A (49%) (Neoral®) and 36 received tacrolimus (39%) (Prograf®; Fujisawa, München, Germany). The remaining 11 patients were treated with sirolimus (12%). None of them received a combination of a calcineurin inhibitor and sirolimus. Almost all of the patients (93.5%) received steroids during the first year. EC-MPS was given at a dose of 720 mg b.i.d. MMF doses were, respectively, 500 mg b.i.d. in association with tacrolimus, 750 mg b.i.d. with sirolimus, and 1 g b.i.d. with cyclosporine A. The targets of cyclosporine A at the 2 h level were 10001300 ng/ml during the first 3 months, 8001000 ng/ml between months 3 and 6 and, thereafter, between 700 and 800 ng/ml. The targets of tacrolimus trough levels were 1015 ng/ml from transplantation to month 3, and from 8 to 12 ng/ml thereafter. Finally, sirolimus trough levels were targeted between 8 and 12 ng/ml. Cyclosporine A doses in the MMF and EC-MPS groups were, respectively, 5.23±0.2 vs 5.44±0.2 mg/kg/day at 1 month (P = ns), 3.92±0.19 vs 4.01±0.17 mg/kg/day at 3 months (P = ns), 3.27±0.18 vs 3.51±0.17 mg/kg/day at 6 months (P = ns) and 3.1±0.16 vs 3.23±0.15 mg/kg/day at 12 months (P = ns). Tacrolimus doses were 0.14±0.01 mg/kg/day at 1 month, 0.12±0.01 mg/kg/day at 3 months, 0.1±0.01 mg/kg/day at 6 months and 0.09±0.008 mg/kg/day at 12 months. Sirolimus doses were 0.08±0.008 mg/kg/day at 1 month, 0.08±0.02 mg/kg/day at 3 months, 0.06±0.01 mg/kg/day at 6 months and 0.06±0.01 mg/kg/day at 12 months. During the first 6 months post-transplantation, all patients received sulfamethoxazole-trimetoprime therapy for Pneumocystis carinii prophylaxis. With respect to cytomegalovirus prophylaxis, only those in the D+/R group received IV ganciclovir therapy, i.e. 500 mg/day for the first 2 post-transplant weeks, followed by valaciclovir therapy, i.e. 3000 mg/day for the next 90 days.
Study design
Each patient completed a questionnaire (see below), regarding GI disorders, at monthly intervals during the first year after transplantation. All patients agreed to complete the questionnaire. It was completed in the presence of the transplant physician at each routine visit, i.e. monthly from the first to the sixth month, and then at the nine and twelve months after transplantation. For the four remaining months, i.e. the seventh, eighth, tenth and eleventh months post-transplantation, one of us (L. Oufroukhi) phoned the patients for responses to the questionnaire. In patients who experienced diarrhoea, complementary examinations were performed, including clinical examination, assessment of haematological and biochemistry parameters, as well as cytomegalovirus viremia, standard stool culture and parasitological examination, and search for Clostridium difficile (stool culture and toxin). In cases where there was weight loss and/or biological malabsorption symptoms and/or a diarrhoea frequency of more than three stools per day for more than 2 months, an esophago-gastroduodenoscopy with duodenal biopsies, with or without colonoscopy, was performed. When diarrhoea occurred less than three times per day for 2 months, transplant physicians waited until the next visit, i.e. 1 month later, and then reduced the MMF dose if diarrhoea was still persisting. In cases where diarrhoea persisted for a further month, then the MMF dose was interrupted or discontinued (Figure 1).
Questionnaire
At the first visit, i.e. at the first month post-transplantation, patients completed the following items in the presence of the transplant physician: ethnic origin, journeys in tropical countries within the year before renal transplantation, gastrointestinal surgery, history of gastrointestinal disease. At each visit, the patient also completed the following items: presence of diarrhoea, defined as the occurrence of liquid stools for at least 2 weeks, regardless of the number of stools per day, during the month before the visit; the number of liquid stools per day (
1/day;
2/day); the number of days per week during which liquid stools occurred (<1/week; 13 days/week; >3 days/week); the characteristics of liquid stools (watery, with blood, or pus, or mucus); the timing of liquid stools in comparison with immunosuppressive drug and meal intakes; the presence of nausea, and/or vomiting, and/or dyspepsia, and/or upper abdominal pain and/or gastric distension.
Statistical analysis
Reported values represent either the means±SE or the medians (ranges). Proportions were compared by the
2 or Fisher's exact tests. Quantitative variables were compared with the non-parametric MannWhitney test and Student's t-test. A P-value below 0.05 was considered to be statistically significant.
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Results
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Patients' characteristics
Patients' characteristics, except for cold ischaemia time, were similar in both groups and are summarized in Table 1. The number of patients who had received a transplantation from a living donor tended to be greater in the EC-MPS group (P = 0.08). Even if cold ischaemia time was significantly lower in patients receiving EC-MPS compared to those treated with MMF (P = 0.03), it was similar in the two groups when patients who had received a kidney from a living donor were excluded and was, respectively, 22±0.8 h in the MMF group vs 19.8±1.4 h in the EC-MPS group (not significant). All patients were Caucasians. None of them had travelled in a tropical country in the year before transplantation. A similar proportion of patients in each group had a history of gastrointestinal disease and/or gastrointestinal surgery: 16 patients (17.2%) in the MMF group vs 6 patients (16.2%) in the EC-MPS group (not significant).
Gastrointestinal disorders
Thirty-one patients from the MMF group (33.3%) and 12 patients from the EC-MPS group (32.4%) complained of GI disorders during the first year post-transplantation (not significant). The incidence of upper GI disorders, defined as the occurrence of symptoms affecting the GI tract from the oesophagus trough to the duodenum, was also similar in both groups at, respectively, 11 patients (11.8%) in the MMF group and 7 patients (18.9%) in the EC-MPS group (not significant). The incidences of upper abdominal pain, stomach distension, nausea and vomiting were also similar in both groups (Table 1). Diarrhoea was observed in 18 out of 93 patients (19.3%) from the MMF group, and in 5 out of 37 patients from the EC-MPS group (13.5%) (not significant). Among the patients who experienced diarrhoea, five patients from the MMF group and only one patient from the EC-MPS expressed the HLA DQ2 antigen (not significant). All patients from the EC-MPS group were treated with cyclosporine A whereas in the MMF group, eight patients were treated with cyclosporine A, seven patients received tacrolimus, and three patients were treated with sirolimus. At 1, 3, 6 and 12 months post-transplantation, cyclosporine A concentrations at 2 h after intake, as well as tacrolimus and sirolimus trough levels, were similar in patients who either did or did not experience diarrhoea (data not shown).
Diarrhoea characteristics
The time between transplantation and the first diarrhoea episode was similar in both groups at, respectively, 2.5±0.7 months in the MMF group and 1.66±0.3 months in the EC-MPS group (not significant). All diarrhoea episodes were afebrile. When diarrhoea occurred, its frequency and its severity were similar in both groups (Table 2). Patients in both groups complained of diarrhoea regardless of the time of immunosuppressive drug and/or meal intakes. During diarrhoea episodes, stools were watery, without presence of blood, pus or mucus in all patients. Among the patients who developed diarrhoea, six patients from the MMF group and only one patient from the EC-MPS group had a previous history of gastrointestinal disorder or GI surgery (not significant).
Weight loss was observed in only three patients receiving MMF. Their weight losses were 6 kg in 6 months, 5 kg in 4 months and 5 kg in 3 months. None of the patients enrolled in this study developed a malabsorption syndrome.
Diagnosis, therapy and outcome
Only one patient from the MMF group provided a standard stool culture that revealed the presence of Pseudomonas aeruginosa, which was successfully treated with antibiotics. None of the patients had diarrhoea that was related to cytomegalovirus infection. No ova or parasites were detected in faecal specimens. Culture and toxins for Clostridium difficile were negative in all patients.
An upper oesophagogastroduodenoscopy with duodenal biopsies was performed in four patients: the three who had lost weight, and an additional patient who complained of severe diarrhoea, i.e. more than three times per day for more than 2 months. It was found to be normal in two patients, revealed gastric mucosal atrophy and erosions in one patient, and showed an oesophagitis with a duodenal ulcer in the fourth patient. None of the patients developed duodenal villous atrophy. In two of the four patients with severe gastrointestinal manifestations, a colonoscopy was performed and was found to be normal. The two other patients declined the colonoscopy.
Diarrhoea disappeared spontaneously after nearly 1 month in all patients receiving EC-MPS (n = 5) and in 10 of the 18 renal-transplant patients treated with MMF (not significant). In the remaining eight patients receiving MMF, a MMF dose reduction was required for five patients and MMF was discontinued for three patients. These three patients initially underwent a dose reduction of 50% before MMF discontinuation at either 120, 150 or 290 days post-transplantation. These three patients regained weight after MMF was stopped. Hence, overall, eight patients required dose reduction. The median rate of MMF reduction was of 50% (3375%). The median time between renal transplantation and MMF dose reduction was, 90 days (61230 days). After diarrhoea had resolved, only two out of the five patients who had MMF dose reduction were once again given a full dose of MMF.
Overall, 46 out of 93 (49.46%) of the patients underwent dose modification in the MMF group as compared to only 8 out of 37 (21.62%) in the EC-MPS group (P = 0.005). The main reason was haematological disorders, affecting 26 out of 46 (56%) in the MMF group and 2 out of 8 (25%) in the EC-MPS group (P = 0.08), respectively.
Patient survival and graft function
At 1 year, patient and graft survivals were 100% in both groups. None of the patients presented with an acute rejection after MMF dose modification. At 1 year post-transplantation, serum creatinine level and creatinine clearance, calculated according to the Cockcroft and Gault formula, were similar in MMF and EC-MPS groups at, respectively, 119 (67288) µmol/l and 61.3 (21.2163) ml/min in the MMF group vs 123 (69224) µmol/l and 62.1 (36.8117.7) ml/min in the EC-MPS group (not significant). At 1 year post-transplantation, serum creatinine level and creatinine clearance were also similar in patients who experienced diarrhoea episodes compared with those who had not. Their creatinine data were, respectively, 124 (88256) µmol/l and 62.9 (21.286.3) ml/min in patients who suffered from diarrhoea, and 119 (67288) µmol/l and 61.9 (22.3163.5) ml/min in patients without diarrhoea (not significant). During the first year post-transplantation, positive cytomegalovirus viremia by PCR was detected in 35 patients from the MMF group (37.6%) and in 17 patients from the EC-MPS group (45.9%) (not significant).
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Discussion
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To the best of our knowledge, this study is the first one to assess, by using a specific questionnaire, the incidence of GI side-effects in renal-transplant patients treated with two different MPA formulations. Almost all immunosuppressive drugs are associated with some form of GI disorders. This might be related either to their immunosuppressive properties, which lead to an increased rate of infections including those of the GI tract, or to the immunosuppressive drugs themselves [8]. MMF is the drug most frequently responsible for GI disorders [9]. The incidence of diarrhoea ranged from 12.7 to 37.3% in renal-transplant patients receiving 2 or 3 g per day of MMF [9]. MMF-associated diarrhoea might be benign, but might also be severe leading to malabsorption syndrome, which might be related to duodenal villous atrophy [10] or erosive enterocolitis [11]. Jejunal villous atrophy has also been found in rats receiving EC-MPS with cyclosporine A, and in those receiving MMF with or without cyclosporine A [12]. In humans, it has been suggested that MMF might induce duodenal villous atrophy, e.g. a coeliac-like disease, especially in patients with predisposing genetic factors, e.g. HLA DQ2 [10]. In the present study, none of the patients developed a duodenal villous atrophy. HLA DQ2 phenotype was similarly observed in patients complaining or not from diarrhoea. In a cohort of 26 renal-transplant patients suffering from severe diarrhoea and malabsorption syndrome, Maes et al. [11] found erosive enterocolitis in all patients but one. In almost 60% of the patients, an infectious origin has been demonstrated. In the remaining patients, the authors suggested the presence of a Crohn's disease-like colitis [11]. Only one of the patients enrolled in this study had a positive stool culture. None of them has erosive enterocolitis.
Recently, enteric-coated mycophenolate sodium has been developed in order to reduce GI disorders. With respect to GI disorders, two large trials, one in de novo renal-transplant patients [6] and another in maintenance renal-transplant patients [7] failed to show a significant difference between the two forms of MMF. In this prospective study, we focused our investigations specifically on gastrointestinal disorders, especially diarrhoea, the most disturbing adverse event. Overall, GI tolerability was similar in both groups of patients. The overall incidence of GI adverse events observed within the first year in this study (33.3% in the MMF group vs 33.4% in the EC-MPS group) was lower than those reported by Budde et al. [7] (61.3% in the MMF group vs 60.4% in the EC-MPS group), and Salvadori et al. [6] (80% in the MMF group vs 80.8% in the EC-MPS group). The incidence of upper GI adverse events was similar in the present study (11.8% in the MMF group vs 18.9% in the EC-MPS group) to those found by Budde et al. [7] at 3, 6 and 12 months post-transplantation, and ranged from 13.5 to 16.6% in the MMF group and from 13.2 to 15.7% in the EC-MPS group. In contrast, upper GI adverse events were more frequently reported in the Salvadori et al. [6] study, i.e. 54.3% in the MMF group vs 53.5% in the EC-MPS group. In maintenance renal-transplant patients [7], the incidence of diarrhoea observed at 12 months in the MMF group (6.7%) was lower than the rates previously reported in the registration trials, and was not statistically different from that observed in the EC-MPS treated patients (3.8%) [7]. In our study, the incidence of diarrhoea was also similar in MMF- and EC-MPS-treated patients at, respectively, 19.35% vs 13.5% (not significant). When diarrhoea occurred, the time since transplantation as well as its severity and frequency were similar in both groups. Hence, our prospective study confirms previous findings regarding similar GI tolerability in renal-transplant patients receiving either MMF or EC-MPS. MPA is mainly eliminated by glucuronadition in the liver [13], but also in the kidney and in the small bowel [14]. Even if the mechanisms of MMF related-diarrhoea remain unknown, the enterohepatic circulation of MPA glucuronide seems to be, at least in part, responsible for this diarrhoea [15]. In addition, the use of intravenous MMF failed to avoid GI disorders, suggesting a systemic effect of MPA and not simply a local effect [16]. Hence, it is not surprising to find no difference between MMF and EC-MPS as far as GI tolerance is concerned.
MMF dose adjustments were found to increase the risk of acute rejection [17,18], and to reduce renal graft survival [4,18]. In previous reports, GI-related dose modifications ranged from 6.1 to 22.2% in MMF-treated patients [4,6,7,17,18], and from 8.2 to 15% in patients treated with EC-MPS [6,7]. In the present study, GI-related MMF dose discontinuations and/or reductions occurred in only eight patients (8.6%) from the MMF group, and none in the EC-MPS group. These differences might be related to the fact that our study was prospective and dedicated to GI side-effects in renal-transplant patients. Because of the approach we used in GI symptomatic patients, we were rarely forced to modify MMF doses. Thus, in 15 out of the 23 patients experiencing diarrhoea, it disappeared spontaneously without any dose modification.
There are many limitations to this non-randomized study. The number of patients enrolled in this study is small and is lower in the EC-MPS group. We also used a non-validated questionnaire. However, this questionnaire is descriptive. Finally, the immunosuppressive treatment was heterogeneous in both groups. In the MMF group, some patients also received tacrolimus or sirolimus, two drugs also known to induce diarrhoea [19,20], whereas all patients from the EC-MPS group were given cyclosporine A. Nevertheless, the incidence of diarrhoea was similar in both groups. A larger trial with homogenous immunosuppressive therapy is required to confirm these data.
In conclusion, the incidence of GI disorders during the first year post-transplantation was similar in patients receiving either MMF- or EC-MPS-containing regimens.
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Acknowledgments
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We thank Roche France for its financial support in collecting the data.
Conflict of interest statement. None declared.
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Received for publication: 23. 3.05
Accepted in revised form: 15. 6.05