PURE RED CELL APLASIA INDUCED BY FK506

Abstract

FK506, a new potent immunosuppressant, is widely used in organ transplantation (1, 2). Previous studies on the use of FK506 in renal transplantation have shown this compound to be as efficacious as cyclosporine (CsA*)-based immunosuppression (3). The adverse effects of FK506 are also similar to those of CsA, and include nephrotoxicity (4). However, adverse effects of FK506 on the hematopoietic system have not been described in detail. We recently observed a case of reversible pure red cell aplasia (PRCA) in a renal transplant recipient who was receiving FK506 therapy. A 34-year-old Japanese man had chronic glomerulonephritis that led to renal failure requiring hemodialysis. After receiving a renal transplant from his father in October 1993, he was administered CsA and prednisolone (PSL) for immunosuppression. Oral CsA was initiated at a dose of 12 mg/kg daily, which was tapered to maintain whole blood trough drug levels between 100 and 250 ng/ml. His early postoperative course was uneventful. However, 3 weeks after the transplantation, he exhibited leukopenia and anemia. The leukopenia was thought to have been caused by CsA, although it is a rare adverse effect of this agent. The anemia was thought to reflect persistence of preoperative anemia due to uremia and was considered to be caused in part by CsA. The dose of CsA was reduced and mizoribine was added to the regimen. Granulocyte colony-stimulating factor and recombinant erythropoietin were also administered. However, such treatment failed to correct the leukopenia and anemia. CsA and mizoribine were discontinued 32 days after transplantation and FK506 was substituted, at a dose of 0.15 mg/kg twice daily, with the dose adjusted to maintain the trough levels of drug in whole blood between 5 and 15 ng/ml. Although the leukopenia improved rapidly, the anemia, which was normocytic and normochromic, became more severe and progressive. Hemoglobin concentration was 4.8 g/dl and reticulocytes were absent. Laboratory examinations showed no evidence of hemorrhagic or hemolytic disease. The serum level of erythropoietin was elevated. Examination of bone marrow aspirates revealed normocellularity with an increase in the number of erythroblasts showing megaloblastic changes 43 days after transplantation. At 52 days there was mild hypocellularity, and at 64 days there was extreme hypocellularity with a complete absence of erythroblasts. Normal megakaryocytes and myeloid precursors were present in the bone marrow. We diagnosed the patient as having PRCA and initiated methylprednisolone pulse therapy, 1 g intravenously, daily for 3 days. The oral dose of PSL was increased to 50 mg daily for 3 days, then tapered every 3 days to a daily dose of 15 mg. Simultaneously, we administered recombinant erythropoietin at a dose of 12,000 U 3 times a week. In addition, 14 U of packed red cells were transfused. The anemia persisted despite such intensive treatment. We decided to change the immunosuppressive medication from FK506 to CsA 98 days after transplantation because we suspected that the PRCA was induced by FK506. CsA was restarted at a dose of 6 mg/kg daily, i.e., one half the initial dose. Two weeks after discontinuing FK506 and changing to CsA, the reticulocyte count increased to 6.1% (Fig. 1). The hemoglobin concentration increased to 7.4 g/dl 3 weeks later, and to 11.8 g/dl 5 weeks later. The white blood cell count and the platelet count each remained normal. Repeated bone marrow aspiration showed recovery of the erythropoiesis. The patient was discharged with good function of the transplanted kidney 138 days after transplantation. With continued CsA and PSL administration, his condition remained hematologically normal. In vitro studies showed that FK506 at a concentration of 10 ng/ml did not suppress the burst-forming unit-erythroid activity of the patient's bone marrow. Selective anemia progressed with continued FK506 therapy in our renal transplant recipient. The withdrawal of FK506 and the substitution of CsA was accompanied by resolution of the anemia and by bone marrow recovery. These observations suggest that reversible PRCA may be associated with FK506 therapy. FK506 and CsA have a similar mechanism of immunosuppressive molecular action. FK506 and CsA function as prodrugs, and their immunosuppressive effects result from the formation of active complexes between the drug and immunophilins-FK506 binding protein (FKBP) and cyclophilin (CyP), respectively-which are peptidyl-prolyl cis-trans isomerases (5). This similarity may be why FK506 and CsA share some of the same adverse effects, such as nephrotoxicity and neurotoxicity (4). However, FK506 and CsA differ significantly from each other with regard to the incidence of other adverse effects, such as hirsutism and hypertension (4). The difference in adverse effect profiles between FK506 and CsA may be due to differences in the number of copies of FKBP and CyP genes (6), although differences in the functional diversity of FKBP and CyP molecules are unknown at present. Our case indicates that reversible PRCA may be associated with FK506 therapy. In contrast, CsA has recently been used in treating PRCA (7). The mechanism by which selective anemia progresses to PRCA with continued FK506 administration is unclear. In vitro FK506 does not appear to have a direct suppressive effect on the burst-forming unit-erythroid activity of bone marrow. FK506 may induce PRCA whereas CsA does not because of differences in the effects of FKBP and CyP on the hematopoietic system.Figure 1: Hemoglobin concentration and reticulocyte count in relation to the immunosuppressive drug dosages taken by the patient. Transfusions consisted of 2 U of packed red cells on each occasion.