Tacrolimus and Pure Red-Cell Aplasia

To the Editor: Acquired pure red-cell aplasia can arise spontaneously or can be associated with viral infection or be drug related (1Krantz SB Pure red-cell aplasia..N Eng J Med. 1974; 291: 345-350Crossref PubMed Scopus (119) Google Scholar,2Kurtzman G Frickhofen N Kimball J Jenkins DW Nienhuis AW Young NS Pure red-cell aplasia of 10-years duration due to persistent parvovirus B19 infection and its cure with immunoglobulin therapy..N Eng J Med. 1989; 321: 519-523Crossref PubMed Scopus (380) Google Scholar). Most recently, pure red-cell aplasia-associated anti-body production with the use of epoetin has drawn the attention of physicians worldwide (3Casadevall N Nataf J Viron B et al.Pure red-cell aplasia and antiery- thropoeitin antibodies in patients treated with recombinant erythropoietin..N Eng J Med. 2002; 346: 469-475Crossref PubMed Scopus (1113) Google Scholar). Transplant-associated pure red-cell aplasia has been reported with the use of mycophenolate mofetil, cyclosporine and tacrolimus(4Geetha D Zachary JB Baldado HM Kronz JD Kraus ES Pure red cell aplasia caused by Parvovirus B19 infection in solid organ transplant recipients: A case report and review of literature..Clin Transplant. 2000; 14: 586-591Crossref PubMed Scopus (102) Google Scholar). We describe a kidney transplant recipient with pure red-cell aplasia presumptively associated with tacrolimus. In August 2002, a 20-year-old female, with end-stage renal disease due to SLE, received a 1-1-1 HLA A,B,Dr mismatched kidney from her 20-year-old brother. The transplantation was uneventful. At the time of transplantation there was no active SLE and the patient had been on hemodialysis for 2 months. Before transplantation an adequate hemoglobin level was achieved using β-erythropoeitin subcutaneously. Post-transplantation immunosuppressive drugs consisted of tacrolimus, my- cophenolate mofetil and prednisone, other medicaments used were omeprazole 40 mg and co-trimoxazole 480 mg. From day 30 after transplantation a slow decrease in hemoglobin to 3.8 mmol/L (6.12 g/dL) at day 60 was observed, despite tapering and eventually discontinuing MMF. Blood transfusion was necessary. All other medica-ments except for prednisone and tacrolimus were stopped. Hereafter the hemoglobin again dropped to 3.8 mmol/L in 2 months, with an absent reticulocyte response with adequate folate and ferritine levels. A bone marrow biopsy revealed pure red-cell aplasia. No giant pronormoblasts with prominent cytoplasmic inclusions were present. Additional laboratory results showed no activity of SLE, repeated negative erythropoeitin-antibody tests, no signs of a thymoma on CT-scan and repeated negative serology and PCR for B-19 virus (5Aberham C Pendl C Gross P Zerlauth G Gessner M A quantitative, internally controlled real-time PCR Assay for the detection of parvovirus B19 DNA..J Virol Methods. 2001; 92: 183-191Crossref PubMed Scopus (92) Google Scholar). This PCR used for the quantitative detection of B19 DNA is based on real-time PCR using ABI Prism SDS7700 (TaqMan), which allows precise quantitation of viral loads over seven orders of magnitude. Each individual sa ple includes an exogenous internal control (internal quality marker) to prevent false negative results. This marker is a linearized plasmid containing the identical sequence of the B19 target sequence but with an altered probe hybridization site. Both B19 and the internal quality marker will be amplified and co-detected because of different labeled probes. Tacrolimus was switched to cyclosporine because of a presumptive diagnosis of tacolimus induced pure red-cell aplasia. After another 2 months a complete recovery of the red-cell line was observed, with hemoglobin levels returning to normal values. No re-challenge with tacrolimus was given because of the severity of the side effect. A positive effect of cyclosporine in reversing the pure red-cell aplasia can not be excluded (6Misra S Moore TB Ament ME Busuttil RW McDiarmid SV Red cell aplasia in children on tacrolimus after liver transplantation..Transplantation. 1998; 65: 575-577Crossref PubMed Scopus (39) Google Scholar,7Suzuki S Osaka Y Nakai I et al.Pure red cell aplasia induced by FK506..Transplantation. 1996; 61: 831-832Crossref PubMed Scopus (29) Google Scholar). However, in contrast to these reports we discontinued cyclosporine and have converted the patient to mycophenolate mofetil without recurrent pure red-cell aplasia. This favors an important role for tacrolimus. Recently, a similar case report was published by Nosari et al. who described a liver transplant recipient who developed pancytopenia (bone marrow hypoplasia), with anemia starting as soon as 13 days after transplantation under prednisone, azathioprine and tacrolimus therapy. Azathioprine was stopped without a positive effect on hematological parameters. Only after switching tacrolimus for cyclosporine 6 months later the patient recovered 12 months after transpalntation (8Nosari A Marbello L De Carlis LG et al.Bone marrow hypoplasia complicating tacrolimus (FK 506) therapy..Int J Hematol. 2004; 79: 130-132Crossref PubMed Scopus (21) Google Scholar). Although this side effect is extremely rare, transplant physicians should be aware of this completely reversible cause of anemia.