Severe Toxicity Associated with a Markedly Elevated Mycophenolic Acid Free Fraction in a Renal Transplant Recipient

Abstract

A 58-year-old man with end-stage renal failure secondary to polycystic kidney disease developed a profoundly elevated mycophenolic acid (MPA) free fraction and associated severe toxicity after cadaveric renal transplantation. Initial immunosuppressive therapy was 4 mg/kg body weight bid cyclosporin (Neoral^®; Novartis Pharmaceutical Co Ltd, Sydney, Australia) given orally with 1 g bid mycophenolate mofetil (MMF) (CellCept^®; Roche Products Pty Ltd, Sydney, Australia). In the first 5 days posttransplantation, the serum creatinine concentration fell, and the patient developed profound hypoalbuminemia (serum albumin <20 g/L) and hyperbilirubinemia (serum bilirubin >150 μmol/L) that resulted from progressing biliary obstruction. On day 5 posttransplantation, the 2-hour whole-blood cyclosporin concentration and total MPA area under the curve (AUC_0–6) were low (837 μg/L and 12.6 mg·h/L, respectively), while the total mycophenolic acid glucuronide (MPAG) AUC_0–6 was elevated (1317 mg·h/L). MMF was continued at the same dose, but tacrolimus substituted for cyclosporin. The patient subsequently experienced severe nausea, vomiting, hematemesis, and pancytopenia (nadir white cell count 1.6 × 10⁹/L, platelet count 32 × 10⁹/L, and hemoglobin 73 g/L) that were normalized after cessation of MMF. Retrospective measurement of the free MPA concentration on day 5 showed that free MPA AUC_0–6 was markedly elevated at 2.3 mg·h/L, as was the free fraction, at 18.3%. This case illustrates how altered protein binding can be associated with severe MMF toxicity caused by an increased free MPA concentration despite relatively low total MPA. These data support the monitoring of free MPA concentrations in those patients considered at risk for MMF-related toxicity.