Red-Cell Aplasia Due to Antibodies against Human Recombinant Erythropoietin (rHuEPO) in a Peritoneal Dialysis Patient Treated with rHuEPO

Editor: Decreased synthesis of erythropoietin (EPO) is the main cause of anemia in chronic renal failure (CRF) (1,2). Erythropoietin, with 165 amino acids and a molecular weight of 30 400 Da, is produced mainly in renal fibroblasts. Hypoxemia is the key factor promoting synthesis of EPO. The human recombinant EPO (rHuEPO) gene was cloned in 1985 and its use in the treatment of anemia due to CRF was approved in 1987. Depending on slight differences in glycosylation, there are two different molecules, aand p-rHuEPO, with identical activity (3). The route of administration of rHuEPO is usually subcutaneous (SC), which allows a better bioavailability and fewer side effects (4). rHuEPO was considered not to be immunogenic and, until 1998, only 3 patients with red-cell aplasia (RCA) due to serum antibodies against rHuEPO had been described. Since then,. 21 new cases have been registered. The pathogenesis for the formation of these antibodies is not clear, but they are probably related to hormone use. After discontinuing rHuEPO, the antibody titers decrease. Immunosuppressive treatment has been proposed. We report here an 81-year-old male with CRF secondary to nephroangiosclerosis, also suffering mild hypertension, coronary artery disease, and peripheral vascular disease, started on peritoneal dialysis in October 2000. His HBV, HCV, and HIV serologies were negative. Until March 2001, he maintained hemoglobin values of 12 g/dL and hematocrit of 36% without rHuEPO. His iron metabolism was normal; serum aluminum and intact parathyroid hormone levels were 5 ug/dl, and 55 pg/mL respectively, with no other remarkable abnormalities. In April 2001, Hb and Hct values decreased to 10.3 g/dL and 29% respectively, and treatment with a-rHuEPO was started using 4000 U/week SC. Initial response to the therapy was good (Hb 11.6 g/dL, Hct 34lflin July 2001). In August 2001 he developed severe anemia (Hb 7.2 g/dL, Hct 22%) without any apparent blood loss. A transfusion of 1200 g concentrated red cells was given and the rHuEPO dose was increased to 6000 VI week SC. One month later, an identical picture was seen, now requiring 2400 g of concentrated red cells. The rHuEPO dose was increased further to 8000 and then 12000 U/week SC. Various tests to determine the cause of his anemia showed folic acid and vitamin B12 serum levels were normal, and hemolysis parameters, heterophile antibodies (Microgen Bioproducts, Innogenetics, Barcelona, Spain), fecal occult blood test, barium enema, chest x ray, and thoracoabdominal scan were all negative. Viral serologies were obtained, but before they were available a bone marrow study was carried out: it showed pure RCA. An analysis of peripheral blood showed lympho-monocytoid forms, suggesting a viral infection. Based on these data and while still waiting for the microbiological test results, the whole picture was thought to be secondary to a parvovirus infection and treatment with steroids was begun. In October 2001, the steroids were stopped due to poor tolerance. No improvement in the anemia was apparent and a 900-g concentrated red cell transfusion was indicated. In November 2001 the anemia worsened due to active hemorrhoidal bleeding. The microbiological test results were received: anti-CMV IgG and IgM negative, anti-VCA IgG/lgM positive/negative, and antiparvovirus B19 IgG/lgM positive/negative. Based on the negative serology, a RCA secondary to anti-rHuEPO antibodies was suspected. A blood sample was taken to determine antibodies against rHuEPO, rHuEPO administration was stopped, and anabolic steroids were prescribed. Transfusions with a total of 3600 g concentrated red cells were given. At this time, the patient asked that treatment be discontinued and he died at home a few days later. AntirHuEPO antibodies (radioimmunoprecipitation) were positive: 1.5% with 1/50 dilution, 3.8% with 1/20 dilution (normal value < 0.9% for any dilution). The advent of aand p-rHuEPO caused a marked change in the treatment of uremic anemia, with an almost total resolution of the so-called "uremic syndrome," the symptoms of which were related mainly to anemia. At the same time and secondary to this, blood transfusions became much less frequent (5). At present, darbepoetin (NESP) allows for less frequent administration (6).