American Journal of Transplantation 2006; 6: 1466–1472 Blackwell Munksgaard

 C 2006 The Authors C 2006 The American Society of Journal compilation  Transplantation and the American Society of Transplant Surgeons

doi: 10.1111/j.1600-6143.2006.01320.x

Severe Diarrhea in Renal Transplant Patients: Results of the DIDACT Study B. Maesa, ∗ , K. Hadayab , B. de Moorc , P. Cambierd , P. Peeterse , J. de Meesterf , J. Donckg , J. Sennesaelh and J-P. Squiffleti a Heilig Hartziekenhuis Roeselare-Menen, Roeselare, Belgium b University Hospital Erasme, Brussels, Belgium c Virga Jesse Ziekenhuis, Hasselt, Belgium d CHR La Citadelle, Liege, ` Belgium e University Hospital, Ghent, Belgium f Onze-Lieve-Vrouw Ziekenhuis, Aalst; Belgium g Sint-Lucas Ziekenhuis, Ghent, Belgium h University Hospital VUB, Brussels, Belgium i Universite´ Catholique de Louvain, Brussels, Belgium ∗ Corresponding author: Bart Maes, [email protected]

Diarrhea is common in transplant recipients. While the majority of cases are mild and transient, some are severe and prolonged, which can threaten graft survival through dehydration. While it is known that some immunosuppressive agents can elicit diarrhea, there does not appear to be any consensus on the role that other nonimmunosuppressive causes can play in transplant patients. The aim of the present open, nonrandomized, multicenter study was to identify nonimmunosuppressive factors involved in severe diarrhea in renal transplant patients. Patients (n = 108) with severe diarrhea (≥3 stools/day for ≥7 days) were enrolled from 16 Belgian transplant centers. Patients were diagnosed according to an agreed flowchart that consisted of identification of possible infections, followed by changes in empirical and immunosuppressive treatment. Approximately 50% of patients experienced resolution of severe diarrhea following treatment for infections, dietary problems or diarrheacausing concomitant medications. In conclusion, a large proportion of the severe diarrhea observed in renal transplant recipients is not associated with immunosuppressive therapy and can be treated through anti-infectives, changes to concomitant medication and other empirical treatments. Correct diagnosis of the cause of severe diarrhea in such patients should help to protect graft survival in transplant recipients. Key words: Adverse effects, immunosuppression, infection, kidney transplantation, renal transplant, severe diarrhea Received 23 June 2005, revised 1 February 2006 and accepted for publication 10 February 2006

1466

Introduction Both new and conventional immunosuppressive drugs are able to provide excellent patient and organ survival rates following kidney transplantation. Thus, in addition to short- and long-term efficacy, treatment choice is becoming more dependent upon other factors such as the adverse events. Gastrointestinal (GI) adverse events (infections [bacterial, viral, fungal], abdominal pain, nausea/vomiting, dyspepsia and diarrhea) (1,2) are common in transplant recipients, with one of the most frequent being diarrhea. Diarrhea is unpleasant and inconvenient for the patient, but severe diarrhea can lead to weight loss and dehydration (3), increased serum creatinine (4) and fluctuating immunosuppressive drug levels (5–7). However, the reporting of diarrhea within clinical trials can be problematic. First, diarrhea is mostly reported by patients or physicians without the use of strict and uniform definitions, i.e. number of stools per day, duration of diarrhea. Second, the different study designs employed by, and the multiple combination therapies used within, various clinical trials make the identification of the cause of diarrhea quite difficult. Finally, while the diarrhea experienced by transplant patients is generally ascribed to their immunosuppressive therapy, there can be several other causes including abdominal surgery, concurrent diseases (diabetes mellitus, uremia) (8), infections (4,9,10) and concomitant medications (1). As changes to immunosuppressive therapy can be the result of perceived drug-related adverse effects, and as such changes are associated with an increased risk of acute rejection (11,12), it seems imperative that the cause of GI complications in patients receiving immunosuppressant therapy should be fully investigated. Furthermore, the relationship of GI complications to all relevant nonimmunosuppressive treatments should be tested before any changes to immunosuppressive therapy are made. The aim of the current study was to prospectively collect data on the diagnosis of severe diarrhea in renal transplant patients, defined in a standardized manner, with the aim of determining nonimmunosuppressive causative factors and minimizing changes to patients’ immunosuppressive therapy.

Severe Diarrhea Diagnosis in Transplantation

Methods The DIarrhea Diagnosis Aid and Clinical Treatment (DIDACT) study was an open, nonrandomized, multicenter study designed to prospectively collect diagnostic data from renal transplant patients with severe diarrhea, using a uniform definition of diarrhea. The study ran from July 1, 2002, to July 1, 2004.

Patients All Belgian transplant centers (n = 16; seven transplant centers, nine nephrology units) were contacted to include patients in the study. Patients could be enrolled into the study if they had severe diarrhea (≥3 stools/day for ≥7 consecutive days) irrespective of the time from transplant and the immunosuppressive protocol. Patients were excluded from the study if they had acute abdominal symptoms that required intervention within 48 h of enrollment. All patients provided written informed consent and the study was conducted in full compliance with the principles of the Declaration of Helsinki and all subsequent amendments and the Good Clinical Practice Guidelines. The study protocol was approved by the Ethical Committee of the University of Leuven.

Study protocol Baseline and demographic data, and all medications including dose were noted at the study entry. All patients receiving tacrolimus, sirolimus or cyclosporine also had trough levels recorded. A stepwise diagnostic flowchart was developed and applied following consensus among the study investigators and was directed from examining the effects of infections to the effects of immunosuppressive drugs (Figure 1). Step 1: The first step was to determine the impact of nonimmunosuppressive diarrhea-inducing drugs. At the first visit, all medications being taken by the patient were recorded and checked against a list of drugs known to cause diarrhea (including but not limited to anti-arrhythmics, antibiotics, anti-hypertensives, diuretics, anti-diabetic medication, laxatives, proton-pump inhibitors, protease inhibitors). If any drug was judged likely to be contributing to the diarrhea and considered safe to be withdrawn, the drug was stopped, or replaced, at the discretion of the investigator. Step 2: At the same visit, a microbiological stool examination was performed. The stool examination included cultures for pathogenic bacteria (including but not limited to Shigella spp., Salmonella spp., Vibrio spp., Aeromonas spp., Escherichia coli, Campylobacter spp.), stains and cultures for acid-fast bacteria (Mycobacterium complex), examinations for ova and parasites (including but not limited to Isospora belli, Cryptosporidia, Microsporidia, Pneumocystis carinii, Balantidium coli) and assays for fungi (including but not limited to Candida spp., Cryptococcus spp., Aspergillus spp.). An assay for Clostridium difficile toxin was also performed. Step 3: Screens for viruses (adenovirus, enterovirus, rotavirus and cytomegalovirus [CMV]) were also performed. If a positive CMV case was identified or suspected, then a biopsy specimen was taken from the upper and/or lower GI tract for histology and immunoperoxidase staining. A reevaluation of the incidence of diarrhea was performed within 1 week. Step 4: If no diagnosis or remission from diarrhea was obtained following Step 3, the patient was subjected to more invasive procedures (Figure 1). Bacterial overgrowth was excluded by the 14 C-glycocholic acid or D-xylose breath tests, if available. If the test was positive, or if the bacterial overgrowth was suspected upon a clinical basis, then the patient was given relevant antibiotic therapy at the discretion of the investigator. Patients were

American Journal of Transplantation 2006; 6: 1466–1472

Figure 1: Diagnostic flowchart.

1467

Maes et al. followed up 1–2 weeks later to determine whether such treatment had been successful. Step 5: If patients’ diarrhea had still not resolved, the investigator was then allowed to adapt the immunosuppressive regimen at their discretion. Again, patients were reevaluated after 1–2 weeks to determine the effect of the change. Step 6: Patients with persistent diarrhea were then investigated via a colonoscopy with mucosal biopsies being taken for histological examination. All endoscopic biopsies were fixed in Carnoy’s fixation fluid, paraffinembedded and stained with hematoxylin and eosin. Additional mucicarmine and periodic acid Schiff staining for routine light microscopic assessment were also performed, including stains for parasites, spirochetes, fungi, acidfast bacilli and CMV. Macroscopic lesions were characterized by nature (erosion, ulceration, neoplastic, mucosal fragility, bleeding) and extent (diffuse, localized [rectum, right colon, left colon, colon transversum, terminal ileum]). Each biopsy specimen was scored for the presence or absence of (sub)mucosal inflammatory infiltrates; architectural changes of the villi and crypts; cytologic abnormalities of the epithelial cells; infectious inclusions; other abnormalities. If lesions were found, appropriate therapy was initiated and the patient was reevaluated within 1–2 weeks. Step 7: If patients’ diarrhea had still not resolved, empirical treatment with anti-diarrheal drugs, supplemental bacteria (e.g. Lactobacillus casei Shirota) or diets (including lactose-free diets) was allowed. Patients were again reevaluated within 1–2 weeks after this step.

Data capture and analysis All data were electronically captured using Palm organizers connected to the physician’s computer, allowing automatic and anonymous processing of the electronic case record form by an independent third party. Continuous variables are summarized as means ± standard deviation. Univariate baseline comparisons between groups were performed using the Wilcoxon rank sum test.

Results A total of 108 patients from 16 centers were enrolled in the study. Demographic and baseline characteristics of the study population are summarized in Table 1. The majority of patients were over 40 years of age and had a median follow-up of more than 2 years. Patients had a median of 5 stools per day for a period of 20 days. The severity of diarrhea experienced by patients was confirmed by their weight loss and the increase in serum creatinine levels observed (see Table 1). Step 1: Effect of stopping nonimmunosuppressive drugs At enrollment, 72 of 108 (67%) patients were taking drugs that have been associated with diarrhea, and in 14 patients these drugs were stopped (antihypertensives [n = 5], proton pump inhibitors [n = 2], H 2 antagonists [n = 2], hypoglycemics [n = 1], antibiotics [n = 3], allopurinol [n = 2], octreotide [n = 1] and ticlodipine [n = 1]). This resulted in the remission of diarrhea in 7 patients (6% of total; Figure 2). 1468

Table 1: Demographics and patient characteristics Characteristic Sex, n (%) Male Female Age, years 60 Median follow-up after transplantation, months 24 Median duration of severe diarrhea, days 30 Median number of stools per day 3–5 6–9 ≥10 Patients with nightly stools, n (%) Frequency Fever (38.5 ± 0.5◦ C) at onset of diarrhea, n (%) Serum creatinine (mg/dL) 3 months prior to study start At enrollment Patients with increase, n (%) Weight (kg) 3 months prior to enrollment At enrollment Patients with decrease, n (%)

Value 61 (56) 47 (44) 48.6 ± 13.2 30 (28) 53 (49) 25 (23) 27 (1–285) 30 (28) 21 (19) 57 (53) 20 (7–100) 42 (39) 30 (28) 36 (33) 5 (3–15) 49 (45) 45 (42) 14 (13) 35 (32) 2.6 ± 1.3 12 (11) 1.95 ± 0.79 2.40 ± 1.30 67 (62) 66.2 ± 13.9 63.4 ± 14.0 89 (82)

Continuous data presented as mean ± SD or median (range), all other data presented as n (%).

Steps 2–4: Effect of treating infections Microbiological examination of stools gave a positive diagnosis in 22 patients. The majority of infections were bacterial (n = 17 including Campylobacter jejuni [n = 11], Salmonella spp. [n = 2], Clostridium difficile [n = 2], other [n = 2]) with other infections being parasitic (n = 2), protozoan (n = 2) or viral (n = 1) in nature. Treatment of infection resulted in remission in 17 of 22 patients (16% overall). Eight patients were diagnosed with CMV infection and treatment with intravenous (IV) ganciclovir (10–24 days) resulted in remission in 5 patients. Bacterial overgrowth was suspected in a total of 39 patients and treatment with antibiotics (fluoroquinolones or tetracyclines for 10– 14 days) resulted in the remission of diarrhea in 13 patients (Figure 2). Treatment of infections led to diarrhea remission in 35 patients (33% overall). In total, cessation of diarrhea-causing nonimmunosuppressive drugs, and treatment of infections led to the remission of diarrhea in 42 of 108 patients (39% overall). Step 5: Effect of changes to immunosuppressive therapy Changes to the dose of one or more immunosuppressive drugs (at the discretion of the investigator) were performed American Journal of Transplantation 2006; 6: 1466–1472

Severe Diarrhea Diagnosis in Transplantation

Figure 2: Flowchart showing patients cured at each diagnostic stage. CMV = cytomegalovirus; IS = immunosuppressive.

in 65 of 108 patients (60%) with changes to a total of 70 drugs being performed in a series of steps. Changes in the doses of mycophenolate mofetil (MMF), tacrolimus, steroids, azathioprine, cyclosporine and sirolimus, as well as the number of patients who subsequently experienced remission of their diarrhea, are summarized in Table 2. Most patients (96 of 108 [89%]) received MMF, followed by steroids (82 of 108 [76%]), tacrolimus (70 of 108 American Journal of Transplantation 2006; 6: 1466–1472

[65%]) and cyclosporine (26 of 108 [24%]). MMF was associated with the largest number of dose reductions or stoppages (n = 34), followed by tacrolimus (n = 12), steroids (n = 10) and cyclosporine (n = 3). All patients who stopped or reduced cyclosporine had remission of diarrhea. Remission rates for other drugs were 65% for MMF, 42% for tacrolimus and 60% for steroids. Treatment was discontinued in 11%, 6% and 4% of patients receiving MMF, tacrolimus and steroids, respectively. In 11 patients, following cessation of individual immunosuppressive 1469

Maes et al. Table 2: Dose reductions/discontinuations during study

Drug

Patients receiving drug

Patients with dose reduced/stopped (% of total)

Dose reduced (% of total)

Dose stopped (% of total)

Remission of diarrhea (% of dose reduced/stopped)

Mycophenolate mofetil Tacrolimus Steroids Cyclosporine

96 70 82 26

34 (35) 12 (17) 10 (12) 3 (12)

23 (24) 7 (10) 5 (6) 3 (12)

11 (11) 5 (7) 5 (6) 0 (0)

22 (65) 5 (42) 6 (60) 3 (100)

Table 3: Dose and trough levels (mean ± SD) of immunosuppressive drugs at enrollment and at the end of the study Enrollment

End of study

Drug

n

Dose (mg/day)

Trough level (lg/L)

n

Dose (mg/day)

Trough level (lg/L)

Mycophenolate mofetil Tacrolimus Steroids Azathioprine Cyclosporine Sirolimus

96 70 82 4 26 5

1580 ± 460 5.39 ± 2.79 6.33 ± 3.83 88 ± 25 157 ± 49 5.40 ± 2.41

N/D 14 ± 7 N/D N/D 137 ± 75 11 ± 5

85 66 79 9 26 8

1330 ± 550 5.15 ± 2.83 6.19 ± 3.67 75 ± 28 158 ± 53 4.43 ± 2.51

N/D 12 ± 6 N/D N/D 127 ± 66 10 ± 5

N/D = not determined.

therapies, other therapies were initiated to provide adequate antirejection coverage. These included tacrolimus (n = 1), steroids (n = 2), azathioprine (n = 5) and sirolimus (n = 3). The average dose and trough plasma levels of immunosuppressive therapy measured at enrollment and at the end of the study can be seen in Table 3. While the trough levels of tacrolimus at the end of the study may appear supratherapeutic for a population of transplant patients 2 years posttransplant, these levels were not different between patients who responded to therapy and those who did not (11 ± 6 lg/mL vs. 13 ± 5 lg/mL). Step 6: Colonoscopy In 41 patients who still had diarrhea following alteration of immunosuppressive therapy, a colonoscopy with multiple mucosal biopsies was performed. No lesions were detected in 22 patients. In the remaining 19 patients, 6 patients had macroscopic lesions, which were documented by nature (erosive [n = 3], ulcerative [n = 3]) and extent (diffuse [n = 2], localized [rectum, n = 2; left colon, n = 1; right colon, n = 1]); 2 patients had villous atrophy. In these 19 patients, immunosuppressive therapy was further changed (MMF [n = 11], tacrolimus [n = 8], steroids [n = 6] and cyclosporine [CsA; n = 1]), resulting in remission in 13 patients (12% overall). Step 7: Empirical treatment The remaining 28 patients, who either had no lesions or did not respond to a change in their immunosuppressive therapy, were then treated with antidiarrheal drugs, supple1470

mental bacteria, changes in diet, or a combination of these approaches. These treatments resulted in the resolution of diarrhea in 11 patients (10% overall; Figure 2). Diagnosis or remission could not be obtained in 17 patients (16% overall). Of these 17 remaining patients, 5 had a positive stool culture, 3 were positive for CMV and 4 had endoscopic lesions. No diagnosis could be given in the other 5 patients.

Discussion The present study is the first to prospectively examine transplant recipients for severe diarrhea using predefined criteria for diagnosis. The study has shown that severe diarrhea can occur many months post-transplantation, and that approximately 50% of patients may experience resolution of their diarrhea without the need for changes in their immunosuppressive therapy. As there are no formal guidelines for the prevention/treatment of diarrhea in renal transplant patients, the main aim of this exploratory study was to highlight the nonimmunosuppressive factors that are involved in the development of severe diarrhea in renal transplant patients. By necessity, we had to employ a stepwise progression of changes. However, this was not ideal as it meant that patients who had multiple causes of diarrhea were not treated effectively, as evidenced by the number of patients with diarrhea at the end of the study who were successfully treated with empirical methods. Furthermore, it should be American Journal of Transplantation 2006; 6: 1466–1472

Severe Diarrhea Diagnosis in Transplantation

noted that, in practice, the proposed investigations should be employed on a case-by-case basis depending on the presenting symptoms of the patient. In addition, while the nonmandatory nature of immunosuppressive changes within the study was a potential source of confounding, the present study was not designed to determine the effect of such changes on the incidence of diarrhea. Such an objective would require the design of specific clinical trials to answer this question, possibly including standardized dose reductions. Diarrhea is often reported as an adverse event in trials of immunosuppressive agents in transplant recipients (13–17). However, defined criteria for diarrhea have not generally been used in these studies. In some cases, the level to which diarrhea is investigated may only extend to the investigator or patient stating whether the patient has diarrhea or not. In contrast, the current study is the first to prospectively investigate severe diarrhea (>3 stools/day for >1 week) in transplant patients using defined diagnostic criteria. The presence of severe diarrhea in these patients was confirmed by the patients’ observed weight loss and increased serum creatinine. It is presumed that patients with nonsevere diarrhea (1 year of transplant, a similar proportion of patients in each group experienced diarrhea that was linked to an infection (37% vs. 30%). It could also be argued that patients who experience late-onset diarrhea are selected out for having tolerated their immunosuppression in the early post-transplant period, and thus may bias the results. However, if Steps 5 and 6 are considered together, changes in immunosuppressive therapy resulted in resolution of diarrhea in 8 of 30 patients (27%) transplanted within 1 year and 20 of 78 patients (26%) transplanted >1 year after onset of diarrhea. This suggests that the present data are not biased. The time to onset of diarrhea in renal transplant patients needs to be examined in trials specifically designed to study this end point. American Journal of Transplantation 2006; 6: 1466–1472

An important point to note from the current study is that diarrhea was resolved in approximately 50% of patients by the cessation of diarrhea-causing nonimmunosuppressive drugs or the treatment of concurrent infections. This avoided the need for modification of the patient’s immunosuppressive therapy that have been associated with acute and chronic rejection of the graft (5,11). Thus, in transplant patients with severe diarrhea, such investigations should be mandatory, even if the patient does not present with overt symptoms of drug toxicity or GI infections. In the remaining 50% of patients, changes in immunosuppressive therapy (with or without a colonoscopy) resulted in the remission of diarrhea in approximately two thirds of cases, and it is possible that further changes to the remaining third of patients’ immunosuppressive therapy would have resulted in additional resolution of diarrhea. Dose changes were initiated most frequently in patients receiving MMF, which was used in the majority of patients. It should be noted that in only 22 of 34 (65%) patients in whom the dose of MMF was reduced, and 7 of 11 (64%) patients who stopped MMF completely, diarrhea also resolved. Thus, other factors may have played a role in the generation of diarrhea in these patients. Indeed, the nonmandatory nature of the treatments performed within the study means that some infections or lesions were not noted before changes in immunosuppressive therapy were initiated. Indeed, of the 17 patients who still had diarrhea at the end of the study, 8 were found to have infections, which had not responded to specific antimicrobial therapy. The treatment response rates in the current study were generally quite low (∼50%) and reflect the difficulty in identifying the cause of diarrhea in immunosuppressed patients; infections may be missed in blood or stool samples provided, or the risk factor identified may not actually be causative for the diarrhea. Furthermore, the nonmandatory nature of treatments during the study may also have played a role in these low response rates. There is a perception in the transplant community that MMF should be the first drug to be reduced/discontinued should diarrhea occur. However, the present data suggest that other causes were involved in the generation of diarrhea in patients receiving MMF. This agrees with the results of large Phase III studies where the incidence of diarrhea observed with MMF varied greatly (13–31%) and was similar to that with azathioprine (21%) or placebo (13%) (14,18,19). Thus, the strategy to permanently reduce (or even stop) MMF in all patients with unexplained diarrhea should be questioned, especially given the possible risk to the patient with respect to acute graft rejection and survival. Indeed, a recent publication has suggested that patients exposed to CsA and MMF might be less susceptible to diarrhea than patients exposed to tacrolimus and MMF, through the differential effects of CsA and tacrolimus on P-glycoprotein activity and enterohepatic recirculation (20). However, the contribution of individual immunosuppressive drugs to the diarrhea experienced by transplant patients has not been thoroughly studied. Prospective, 1471

Maes et al.

randomized trials in patients with well-defined noninfectious diarrhea, who switch from one immunosuppressive agent to another, are probably the best way to answer these questions. Presently, the only randomized trials that have directly compared the GI adverse events between different drugs, MMF and enteric-coated mycophenolate sodium, have failed to show any significant differences between the two treatments (21–23). In conclusion, this study shows that the etiology of severe diarrhea following transplantation is complex. As diarrhea is generally less life threatening than the loss of a graft, it is suggested that the management of diarrhea should be restrained until it becomes severe and prolonged. At this point, an etiology should be sought so that appropriate treatment can be given. Furthermore, treatments, such as the stopping of diarrhea-causing drugs, administration of anti-infectives and changes in diet and lifestyle should be considered before any changes in immunosuppression, which should occur slowly and under careful monitoring, are performed. Additional prospective, randomized trials are required to determine the extent and most appropriate treatment for diarrhea in transplant patients.

Acknowledgments This study was supported by a grant from F. Hoffmann-La Roche Ltd, Belgium.

References 1. Pescovitz MD, Navarro MT. Immunosuppressive therapy and post-transplantation diarrhea. Clin Transplant 2001; 15 (Suppl 4): 23–28. 2. Helderman JH, Goral S. Gastrointestinal complications of transplant immunosuppression. J Am Soc Nephrol 2002; 13: 277–287. 3. Shankar VK, Zilvetti M, Handa A, Bowler IC, Gray DW. Chronic diarrhea and weight loss due to vibrio parahaemolyticus infection in a renal transplant recipient. Transplantation 2004; 78: 487. 4. Altiparmak MR, Trablus S, Pamuk ON et al. Diarrhoea following renal transplantation. Clin Transplant 2002; 16: 212–216. 5. Maes BD, Lemahieu W, Kuypers D et al. Differential effect of diarrhea on FK506 versus cyclosporine A trough levels and resultant prevention of allograft rejection in renal transplant recipients. Am J Transplant 2002; 2: 989–992. 6. Asano T, Nishimoto K, Hayakawa M. Increased tacrolimus trough levels in association with severe diarrhea, a case report. Transplant Proc 2004; 36: 2096–2097. 7. Sato K, Amada N, Sato T et al. Severe elevations of FK506 blood concentration due to diarrhea in renal transplant recipients. Clin Transplant 2004; 18: 585–590. 8. Valdovinos MA, Camilleri M, Zimmerman BR. Chronic diarrhea in diabetes mellitus: Mechanisms and an approach to diagnosis and treatment. Mayo Clin Proc 1993; 68: 691–702. 9. Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med 1998; 338: 1741–1751.

1472

10. Rubin RH. Gastrointestinal infectious disease complications following transplantation and their differentiation from immunosuppressant-induced gastrointestinal toxicities. Clin Transplant 2001; 15 (Suppl 4): 11–22. 11. Pelletier RP, Akin B, Henry ML et al. The impact of mycophenolate mofetil dosing patterns on clinical outcome after renal transplantation. Clin Transplant 2003; 17: 200–205. 12. 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– 2386. 13. Sollinger HW. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation 1995; 60: 225–232. 14. The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. The tricontinental mycophenolate mofetil renal transplantation study group. Transplantation 1996; 61: 1029– 1037. 15. Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group. Transplantation 1997; 63: 977–983. 16. Groth CG, Backman L, Morales JM et al. Sirolimus (rapamycin)based therapy in human renal transplantation: Similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation 1999; 67: 1036– 1042. 17. Kahan BD. Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: A randomised multicentre study. The Rapamune US Study Group. Lancet 2000; 356: 194–202. 18. The European Mycophenolate Mofetil Cooperative Study Group. Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. European mycophenolate mofetil cooperative study group. Lancet 1995; 345: 1321–1325. 19. Wiesner R, Rabkin J, Klintmalm G et al. A randomized double-blind comparative study of mycophenolate mofetil and azathioprine in combination with cyclosporine and corticosteroids in primary liver transplant recipients. Liver Transpl 2001; 7: 442–450. 20. 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: 1383–1391. 21. Granger DK, ERL B 301 Renal Transplant Study Group; ERL B 302 Renal Transplant Study Group. Enteric-coated mycophenolate sodium: Results of two pivotal global multicenter trials. Transplant Proc 2001; 33: 3241–3244. 22. 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 2004; 4: 237–243. 23. 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: 231–236.

American Journal of Transplantation 2006; 6: 1466–1472