CASE REPORT  Mycophenolate mofetil

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Unusually late-onset mycophenolate mofetil–related colitis Bryan F. Curtin, Vikrant P. Rachakonda, and Erik C. von Rosenvinge

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ycophenolate mofetil is an immunosuppressant that is widely used to prevent human allograft rejection in bone marrow and solid organ transplantations.1 Noninfectious diarrhea is common in organ transplant recipients treated with mycophenolate mofetil; other gastrointestinal symptoms in such patients include dyspepsia, nausea, and vomiting. While episodes may occur with variable duration of exposure, to our knowledge there are no reported cases of newonset, biopsy-proven mycophenolate mofetil toxicity of the colon after more than 10 years of continuous therapy. Here we present the case of a cardiac transplant recipient who developed mycophenolate mofetil–related toxicity of the colon after 13 years of continuous therapy. Case report A 33-year-old man who 13 years previously underwent orthotopic cardiac transplantation for congenital dilated cardiomyopathy was transferred to our hospital. He had a three-month history of diarrhea and weight loss, with more recent onset of acute kidney injury. His initial immunosuppression regimen had

Purpose. Serious gastrointestinal complications arising 13 years after the initiation of posttransplant immunosuppressant therapy with mycophenolate mofetil are reported. Summary. Over a three-month period, a male heart transplant recipient who had taken oral mycophenolate mofetil (2 g daily) for 13 years as part of an immunosuppressant maintenance regimen developed diarrhea and weight loss leading to renal failure and metabolic acidosis. There was no evidence of opportunistic infection, and immunostaining for cytomegalovirus yielded negative results. Colonoscopy revealed areas of congested, erythematous, and nodular mucosa. Histological examination of mucosal biopsy specimens revealed pathological abnormalities typical of those seen in cases of mycophenolate mofetil– associated colitis. On discontinuation of mycophenolate mofetil use, the patient’s diarrhea resolved and his renal function

consisted of prednisone, tacrolimus, and mycophenolate mofetil 2 g per day orally. The patient had been switched from tacrolimus to sirolimus 7 years prior due to tacrolimusassociated nephrotoxicity. On examination, the man was afebrile and normotensive. His abdomen was soft and nondistended,

Bryan F. Curtin, M.D., is Resident in Internal Medicine, Department of Internal Medicine; and Vikrant P. Rachakonda, M.D., Ph.D., is Fellow in Gastroenterology/Hepatology, Department of Internal Medicine, University of Maryland Medical Center, Baltimore. Erik C. von Rosenvinge, M.D., is Assistant Professor of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School

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improved. Colitis, diarrhea, and other gastrointestinal complications are commonly reported in patients receiving mycophenolate mofetil, an immunosuppressant widely used to prevent rejection of solid organ or bone marrow transplants; however, the onset of such symptoms after more than a decade of continuous use of the drug has not been previously reported. This case suggests that mycophenolate mofetil toxicity should be considered in the evaluation of late-onset posttransplant diarrhea regardless of the duration of therapy. Conclusion. A 33-year-old man maintained on mycophenolate mofetil for 13 years after heart transplantation developed diarrhea, weight loss, and acute kidney injury over a three-month period. Colonoscopy and biopsy revealed pathological changes consistent with mycophenolate mofetil toxicity, and the patient’s symptoms resolved after the drug was discontinued. Am J Health-Syst Pharm. 2014; 71:1858-61

with normal bowel sounds. There were no tenderness to palpation, no masses, and no organomegaly. Notable laboratory test results included a creatinine concentration of 8.45 mg/dL, a bicarbonate concentration of 14 mg/dL, and a lactate concentration of 1.8 mmol/L. The patient had normal transaminase, amylase,

of Medicine and Department of Veterans Affairs Maryland Health Care System, Baltimore. Address correspondence to Dr. Curtin ([email protected]). The authors have declared no potential conflicts of interest. DOI 10.2146/ajhp140085

CASE REPORT  Mycophenolate mofetil

and lipase concentrations. The white blood cell count was 11,700/mL, and the hematocrit value was 27.6%. The serum mycophenolic acid (MPA) concentration was 1.0 mg/mL (therapeutic range, 2.0–4.0 mg/mL), and the serum MPA glucuronide level was 111 mg/mL (therapeutic range, 25–100 mg/mL). Urinalysis showed mild proteinuria (a dipstick test value of 1+ [30 mg/dL]) but was otherwise normal. Infection studies were negative, including blood, urine, and stool cultures; stool studies for ova and parasites, as well as Clostridium difficile, Cryptosporidium, Cyclospora, Giardia, and Isospora species; and a serum polymerase chain reaction assay for cytomegalovirus. Fluid and bicarbonate losses due to severe diarrhea were believed to be the etiology for renal failure and metabolic acidosis, respectively. The results of upper endoscopy with random duodenal biopsies were normal. Colonoscopy revealed patchy areas of mildly congested, erythematous, and nodular mucosa. The terminal ileum was intubated and appeared normal. Right-sided and left-sided colon biopsies showed crypt cell apoptotic bodies, crypt distortion, and mixed neutrophilic and eosinophilic infiltration of the lamina propria, all of which are typical of mycophenolate mofetil–related colitis (Figure 1). There was no evidence of opportunistic infection, and immunostaining for cytomegalovirus was negative. Upon discontinuation of mycophenolate mofetil, the patient’s diarrhea resolved and his renal function improved. Although alternative agents were considered, tacrolimus was restarted because of its superior efficacy in preventing heart transplant rejection. Fortunately, the patient’s creatinine concentration returned to the baseline level (1.6 mg/dL).

et al.,2 a score of 2 was calculated, indicating a possible ADR related to mycophenolate mofetil use in our patient. Diarrhea is the most common gastrointestinal adverse effect of mycophenolate mofetil therapy; the rate of occurrence is difficult to as-

certain from clinical studies for multiple reasons, including reporting bias, variable definitions of diarrhea, and difficulties in establishing etiologies for diarrhea.3 Nonetheless, reported rates of mycophenolate mofetil–related diarrhea in liver transplant recipients

Figure 1. Hematoxylin and eosin staining (original magnification, 200×) of left-sided (A) and right-sided (B) colon biopsy specimens demonstrates crypt cell apoptosis (arrows), mixed neutrophilic and eosinophilic infiltration of the lamina propria, and crypt distortion.

Discussion Using the adverse drug reaction (ADR) probability scale of Naranjo Am J Health-Syst Pharm—Vol 71 Nov 1, 2014

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range from 14% to 51%; in renal transplant recipients, from 12.7% to 38.4%. 4,5 In several studies, a higher rate of diarrhea was reported with mycophenolate mofetil at a daily dose of 3 g, suggesting a dosedependent effect.4,5 However, this dose-dependent effect was not shown in subsequent trials.6,7 Mycophenolate mofetil in combination with tacrolimus, sirolimus, and (to a lesser extent) cyclosporine has been shown to increase the risk of diarrhea.8 MPA reversibly inhibits inosine 5′-monophosphate dehydrogenase, the rate-limiting enzyme for guanosine triphosphate formation in purine synthesis, and through this mechanism selectively inhibits lymphocyte proliferation.9 The primary method of metabolism of MPA in humans is glucuronidation, which creates an intermediary molecular form that can be secreted into the bile and reabsorbed, promoting a cycle of enterohepatic circulation.10 Repeated cycling of MPA increases intestinal exposure and is thought to play a major role in the gastrointestinal toxicity of MPA. Mycophenolate mofetil, the prodrug of MPA, is used commonly in conjunction with tacrolimus, sirolimus, or cyclosporine to prevent solid organ allograft rejection. One reason mycophenolate mofetil has such a variable toxicity profile in clinical practice pertains to the difficulty of monitoring MPA levels. MPA has incredibly complex pharmacokinetics, and several factors have been shown to influence gastrointestinal MPA exposure, including liver and kidney functions, albumin levels, and the effects of concomitantly administered immunosuppressive agents. There is currently no universally accepted MPA monitoring protocol because of the intricacies of MPA pharmacokinetics and the required calculations, as well as a lack of measuring tests.11,12 Two relatively recent trials did not produce definitive results showing 1860

a benefit in therapeutic drug monitoring of MPA.13,14 Studies have not consistently shown that higher MPA levels correlate with higher risks of diarrhea, colitis, and other gastrointestinal toxicities of mycophenolate mofetil. 6,15 Improved monitoring and further understanding of the relationship between MPA levels and toxicity may help reduce the rates of these complications. Our patient had chronic kidney disease at baseline (as evidenced by creatinine concentrations of 1.4–1.6 mg/dL), and theoretically this may have led to an increased risk of mycophenolate mofetil–related colitis. Distinctive histologic features of mycophenolate mofetil–related colitis have been described; a pattern of injury resembling graft-versus-host disease and characterized by crypt cell apoptosis, enterocyte atypia, and glandular architectural distortion was noted in a study by Papadimitriou et al.16 Findings similar to those seen in Crohn’s colitis, including inflammatory infiltration of the lamina propria and dilated crypts lined by flattened epithelium, have also been reported in association with mycophenolate mofetil use. Dalle et al.17 described the pathological characteristics of mycophenolate mofetil–associated colitis in great detail. They reported similarities to Crohn’s disease, such as focal inflamed and dilated crypts with discontinuous architectural changes and increased mucin secretion without apoptosis. The temporal relationship between the initiation of mycophenolate mofetil use and the development of diarrhea is not well studied. In multiple six-month trials of mycophenolate therapy, diarrhea was reported as the most common adverse effect of treatment.18-20 In a retrospective analysis of persistent posttransplant diarrhea, noninfectious diarrhea occurred at significantly longer posttransplant intervals than infectious cases.21 A smaller study of mycophenolate mofetil–related

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diarrhea included patients who had received transplants up to 22 years previously, but the duration of therapy was not reported.22 To our knowledge, this is the first report of new-onset, biopsy-proven mycophenolate mofetil–related colitis after 13 years of continuous therapy. This case suggests that mycophenolate mofetil toxicity should be considered in the evaluation of late-onset posttransplant diarrhea. Conclusion A 33-year-old man maintained on mycophenolate mofetil for 13 years after heart transplantation developed diarrhea, weight loss, and acute kidney injury over a three-month period. Colonoscopy and biopsy revealed pathological changes consistent with mycophenolate mofetil toxicity, and the patient’s symptoms resolved after the drug was discontinued. References 1. Langman LJ, Legatt DF, Halloran PF, Yatscoff RW. Pharmacodynamic assessment of mycophenolic acid-induced immunosuppression in renal transplant recipients. Transplantation. 1996; 62:666-72. 2. Naranjo CA, Busto U, Sellers EM et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981; 30:239-45. 3. Ginsburg PM, Thuluvath PJ. Diarrhea in liver transplant recipients: etiology and management. Liver Transpl. 2005; 11:88190. 4. European Mycophenolate Mofetil Cooperative Study Group. Placebo-controlled study of mycophenolate mofetil combined with cyclosporine and corticosteroids for prevention of acute rejection. Lancet. 1995; 345:1321-5. 5. Mathew TH. A blinded, long-term, randomized multicenter study of mycophenolate mofetil in cadaveric renal transplantation: results at three years. Transplantation. 1998; 65:1450-4. 6. Heller T, van Gelder T, Budde K et al. Plasma concentrations of mycophenolic acid acyl glucuronide are not associated with diarrhea in renal transplant recipients. Am J Transplant. 2007; 7:1822-31. 7. Borrows R, Chusney G, James A et al. Determinants of mycophenolic acid levels after renal transplantation. Ther Drug Monit. 2005; 27:442-50. 8. Waillard JB, Rerolle JP, Picard N et al. Risk of diarrhoea in a long-term cohort of renal transplant patients given mycophenolate mofetil: the significant role of

CASE REPORT  Mycophenolate mofetil

the UGT1A8*2 variant allele. Br J Clin Pharmacol. 2009; 69:675-83. 9. Ransom JT. Mechanism of action of mycophenolate mofetil. Ther Drug Monit. 1995; 17:681-4. 10. Kobayashi M, Saitoh H, Kobayashi M et al. Cyclosporin A, but not tacrolimus, inhibits the biliary excretion of mycophenolic acid glucuronide possibly mediated by multidrug resistance-associated protein 2 in rats. J Pharmacol Exp Ther. 2004; 309:1029-35. 11. Von Gelder T, Le Meur Y, Shaw LM et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit. 2006; 28:145-54. 12. Capone D, Tarantino G, Kadilli I et al. Evaluation of mycophenolic acid systemic exposure by limited sampling strategy in kidney transplant recipients receiving enteric-coated mycophenolate sodium (EC-MPS) and cyclosporine. Nephrol Dial Transplant. 2011; 26:3019-25. 13. Le Meur Y, Büchler M, Thierry A et al. Individualized mycophenolate mofetil dosing based on drug exposure significantly

improves patient outcomes after renal transplantation. Am J Transplant. 2007; 7:2496-503. 14. Van Gelder T, Silva HT, de Fijter JW et al. Comparing mycophenolate mofetil regimens for de novo renal transplant recipients: the fixed-dose concentrationcontrolled trial. Transplantation. 2008; 86:1043-51. 15. Daudén E, Sánchez-Peinado C, RuizGenao D et al. Plasma trough levels of mycophenolic acid do not correlate with efficacy and safety of mycophenolate mofetil in psoriasis. Br J Dermatol. 2004; 150:132-5. 16. Papadimitriou JC, Cangro CB, Lustberg A et al. Histologic features of mycophenolate mofetil-related colitis: a graft-versushost disease-like pattern. Int J Surg Pathol. 2003; 11:295-302. 17. Dalle IJ, Maes BD, Geboes KP et al. Crohn’s-like changes in the colon due to mycophenolate? Colorectal Dis. 2005; 7:27-34. 18. Vanrenterghen Y, Lebranchu Y, Hene R et al. Double-blind comparison of two cor-

ticosteroid regimens plus mycophenolate mofetil and cyclosporine for prevention of acute allograft rejection. Transplantation. 2000; 70:1352-9. 19. Dudley C, Pohanka E, Riad H et al. Mycophenolate mofetil substitution for cyclosporine A in renal transplant recipients with chronic progressive allograft dysfunction: the “creeping creatinine” study. Transplantation. 2005; 9:446-75. 20. Davies NM, Grinyo J, Heading R et al. Gastrointestinal side effects of mycophenolic acid in renal transplant recipients: a reappraisal. Nephrol Dial Transplant. 2007; 22:2440-8. 21. Bamias G, Boletis J, Argyropoulos T et al. Early ileocolonoscopy with biopsy for the evaluation of persistent posttransplantation diarrhea. World J Gastroenterol. 2010; 16:3834-40. 22. Maes BD, Dalle IJ, Geboes KP et al. Erosive enterocolitis in mycophenolate mofetil-treated renal-transplant recipients with persistent afebrile diarrhea. Transplantation. 2003; 75:665-72.

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Unusually late-onset mycophenolate mofetil-related colitis.

Serious gastrointestinal complications arising 13 years after the initiation of posttransplant immunosuppressant therapy with mycophenolate mofetil ar...
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