Oral ulcerations in a renal transplant recipient: a mycophenolate mofetil-induced complication?

Abstract

The major side effects of mycophenolate mofetil (MMF) are leukopenia, gastrointestinal (GI) disturbances, and a slight increase of viral infections (1). The GI symptoms may result in drug decrease or withdrawal in 63% and 15% of transplant recipients, respectively. We report the case of a 52-year-old patient who received a cadaver kidney transplant in September 1999. Maintenance immunosuppression consisted of cyclosporine (Neoral) 400 mg/day, prednisolone 10 mg/day, and MMF 2 g/day. In March 2000, the patient complained of mouth ulcerations with mild fever (37.7°C). The lesions were unsuccessfully treated by valacyclovir for 10 days. At admission to the hospital, the clinical examination showed diffuse mucosal ulcers in the mouth (Fig. 1) and around the anus, without fever or cutaneous lesions or enlargement of spleen or lymph nodes. White blood cells were 2,900/mm3 and platelets were 123,000/mm3. Transaminases were within normal range. Serum creatinine level was 142 μmol/L, and trough blood cyclosporine level was 120 ng/ml. Biological markers of cytomegalovirus, Epstein-Barr virus, or herpes simplex virus infection were negative. A biopsy specimen of the tongue lesions showed nonspecific inflammatory changes without viral inclusions or evidence for vasculitis. Polymerase chain reaction (PCR) for cytomegalovirus, herpes simplex virus, and Epstein-Barr virus in the histological material was negative. PCR for parvovirus B19 was positive in the lesion, although it was negative in the serum. Parvovirus B19 serology (ELISA) was positive for IgG and negative for IgM (as at the day of transplantation). So it was suspected that MMF was responsible for the oral lesions. MMF was totally stopped. Leukothrombopenia disappeared within 15 days; mucosal ulcerations totally regressed within 3 weeks. Figure 1: Diffuse mucosal lesions of the left side of the tongue.Mucosal ulcerations, fever, and leukothrombopenia in an immunocompromised host are generally due to hematologic disorders or viral infections. In our patient, a hematologic malignant disease was ruled out. Workup for viral infections was essentially negative. Actually PCR for parvovirus B19 was positive in the mucosal lesions but negative in the blood; IgM antibodies were also negative. In addition, the usual parvovirus B19 infection symptoms observed in renal transplant recipients (severe anemia or medullary aplasia, microangiopathic thrombocytopenia) were lacking (2). MMF frequently results in GI disturbances like nausea, vomiting, abdominal discomfort, and diarrhea. However, it may also be responsible for esophagitis, gastritis, duodenitis, ulcers (3), and villous atrophy with severe diarrhea (4). The exact mechanisms of this GI toxicity are unknown. In the majority of cases, absence of fever and rapid disappearance of symptoms after MMF withdrawal are in favor of a direct toxic impact of MMF on the GI mucosa rather than bacterial and/or viral proliferation induced by immunosuppression. In a French communication, severe buccal aphthosis was observed in a renal transplant patient receiving MMF and nicorandil: the symptoms persisted 4 weeks after nicorandil withdrawal, whereas they totally disappeared 3 weeks after MMF withdrawal (5). In our case, we think that MMF was involved in the oral ulcerations because we found no other etiologies and the lesions totally disappeared after MMF withdrawal. We suggest that MMF toxicity may, in some rare cases, manifest as severe oral ulcerations and that MMF withdrawal rapidly results in healing of these lesions. V. Garrigue1 S. Canet1 O. Dereure2 O. Panabieres3 D. Augias2 G. Chong1 G. Mourad1,4