MIZORIBINE AS AN ALTERNATIVE TO AZATHIOPRINE IN PEDIATRIC RENAL TRANSPLANTATION

A boy with Senior-Loken syndrome and congenital liver fibrosis progressed toward renal insufficiency. During the course of the disease, liver tests showed a mild anicteric cholestasis (alanine aminotransferase, 73 IU/L;γ-glutamyl transpeptidase, 85 IU/L; total bilirubin, 3 μmol/L; 5′-nucleotidase, 12 IU/L; prothrombin, 100%; fibrinogen, 3.1 g/L), and a liver biopsy showed portal fibrosis with ductal proliferation. He received a cadaver kidney when he was 6 years old, and triple-drug immunosuppression was given using azathioprine (Aza; 2 mg/kg/day), prednisone (Pred; 60 mg/m2/day), and antithymocyte globulin for 10 days; cyclosporine (CsA) was started on day 5. The postoperative period was uneventful and his serum creatinine level dropped from 523 μmol/L (day 1) to 60 μmol/L (day 11). On day 6, he presented with hepatic cytolysis (alanine aminotransferase,×10; γ-glutamyl transpeptidase, 74 UI/L) leading to Aza withdrawal that was followed by a rapid normalization of liver enzymes. Under a double treatment with CsA and Pred, he experienced repeated episodes of acute steroid-sensitive rejection (days 9, 45, 270, and 300), with a slow progression toward graft deterioration (serum creatinine, 180 μmol/L on day 340). Two further attempts with low-dose Aza led to liver cytolysis, which disappeared when Aza was withdrawn. Mizoribine (Mzb; Innovex GmbH, Freiburg, Germany) was therefore introduced on day 347 at a dose of 1 mg/kg/day; this dose was progressively increased to 2 mg/kg/day according to plasma trough level, concomitantly with liver tests and blood cell count. Under a combination of Pred, CsA, and Mzb, the child no longer had episodes of acute rejection, and his renal function remained stable (serum creatinine, 186μmol/L after 1 year under Mzb). The liver tests remained normal and the tolerance was excellent. The use of Aza might be limited by its adverse effects, mainly marrow and liver toxicity (1). Mzb, an imidazole nucleoside-derived agent, inhibits lymphocyte proliferation by selective nucleic acid synthesis blockade, which results in both humoral and cellular immunity inhibition(2). It has been shown to be less toxic than Aza, but the immunosuppressive effect of each drug is hard to compare(1). Most studies on Mzb come from Japan, and the recommended dose is 1-2 mg/kg/day. Because of a predominant renal metabolism, overimmunosuppression and adverse effects should be avoided by adapting the dose to the glomerular filtration rate and by monitoring Mzb plasma trough level (3, 4). The pharmacokinetic profile was investigated in adult kidney transplant patients using a one-compartment open model with a first-order absorption process (5): the peak serum level appeared 2.4 hr after oral administration of 50-100 mg, and the plasma clearance depended mainly on renal function (3, 5). Sagawa et al. studied the safety of Mzb in five renal allograft recipients, two of whom had impaired hepatic function: liver and renal function tests remained unchanged (6). Other studies comparing Aza and Mzb showed that both graft survival and side effects were comparable (1, 6, 7). Mzb is unable to reverse overt an acute rejection episode or rapidly progressive chronic rejection when applied as a rescue (2). However, it can be an effective maintenance treatment in patients with stable graft function, even with slowly progressive chronic dysfunction, such as in our patient. On the other hand, preexisting liver damage does not seem to be influenced by Mzb. Mizoribine can therefore be considered in pediatric kidney transplant recipients with a liver dysfunction that potentially is a contraindication to the use of azathioprine. Grace Faraj1 Pierre Cochat1,2 Françoise Serre-Beauvais3 Paul Vialtel4 Carole Chevallier1 Béatrice Cuzin5 Raymonde Bouvier6 Alain Lachaux7 Unité de Néphrologie Pédiatrique; Service d'Urologie et Chirurgie de la Transplantation; Laboratoire Central d'Anatomie Pathologie; Service d'Hépato-gastro-entérologie et Nutrition Pédiatriques; Hôpital Edouard Herriot, Lyon; Université Claude Bernard, Lyon; Laboratoire de Pharmacologie; Service de Néphrologie; Centre Hospitalier Régional Universitaire, Grenoble; France