 EPO-Induced Pure Red-Cell Aplasia
British nephrologist offers management options
Pure red-cell aplasia (PRCA) associated with the administration of erythropoiesis-stimulating agents (ESAS) is a relatively rare but serious complication among patients being treated for chronic kidney disease.
Although some side effects have been seen in the use of ESAS since their introduction in the late 1980s it was not until the last two years that PRCA cases have risen dramatically.
"Two years ago, there was nothing known about pure red-cell aplasia," said noted British nephrologist Iain V. Macdougall. Cases "really blew up in 2002," when 154 cases were reported by the New England Journal of Medicine, said the consultant nephrologist at the Renal Unit of King's College Hospital in London. Speaking in a symposium hosted by Roche Philippines during the 2004 annual convention of the Philippine Society of Nephrology, Macdougall said that the rise coincided with the introduction of a modified formulation of Eprex, a recombinant human erythropoietin (r-HuEPO), outside the United States in early 1998. He said at least 174 cases have been attributed to Eprex with 62 more under investigation.
RARE BUT CURABLE
PRCA is a severe, nonregenerative form of anemia with selective erythroid aplasia of the bone marrow. It is, according to Macdougall, a rare disease but frequently curable. It causes a very low reticulocyte count (<10,000/ml). But the white-cell and platelet counts are normal. The bone marrow has normal cellularity but the erythroblasts are very sparse.
In investigating a suspected case of PRCA, the first thing to be considered is the patient's severe resistance to EPO. If there is no severe resistance to EPO, "then you have to think that it is not pure red-cell aplasia, and look for other causes of poor response to EPO," he pointed out. These might be iron deficiency, infection, or inflammation during dialysis.
But once resistance is established, three other conditions have to be met to diagnose at PRCA: hemoglobin count is around 5 to 6 g/dl requiring transfusion, reticulocyte count is between 0 and 10 x 109/l, and the white-blood-cell and platelet counts are normal. Once all these three are established, the diagnosis of PRCA could then be confirmed by examining the bone marrow and measuring the EPO antibodies.
Macdougall cited a number of reasons why recombinant human erythropoietin has become immunogenic. The replacement of the stabilizing agent human serum albumin (HSA) by polysorbate 80 in the 1998 formulation of Eprex, increased use of subcutaneous administration, and problems in handling and storage (break in cold storage chain) appear to have played a key role in the rise in PRCA cases associated with Eprex.
Eprex is the only EPO that uses polysorbate 80 as stabilizer. For instance, epoetin beta (Recormon) uses polysorbate 20, glycine, a complex of five other amino acids, calcium chloride, and urea for stabilizers. As for subcutaneous administration, he said it was a problem only with Eprex and not with other EPO brands.
MANAGEMENT OF EPO-INDUCED PRCA
"Stop EPO therapy if you get a case." This, Macdougall pointed out, is the first step in the management of PRCA. He also suggested performing when possible a kidney transplant for patients on dialysis. The patient may also be given corticosteroids and cyclophosphamide or cyclosporin.
Can EPO treatment be resumed after the disappearance of antibodies? Macdougall cited one case at King's College Hospital. The patient was treated with Eprex, the hemoglobin went up, but very rapidly dropped to 5g/dl along with reticulocyte count, requiring regular blood transfusions. The patient was treated with anti-CD20 monoclonal antibody, followed by cyclosporin. "Then we thought we could rechallenge the patient, so we decided to give the patient Recormon 2000 IU subcutaneously three times a week," he related.
The reticulocyte count started to come up but the patient still had low hemoglobin.The EPO was increased to 4000 IU three times a week. The reticulocyte count increased and the hemoglobin went up to 13.2 (see Figure).
Based on this case, Macdougall believed that "it is possible to rechallenge PRCA patients with EPO under immunosuppressive cover." While acknowledging that one case is not enough to have conclusive results, he noted that a large series is not possible in a rare disease like PRCA. "On the basis of this experience we are [now] rechallenging some of the other cases in the UK," he added. More research is needed, he stressed, acknowledging that caution is required in rechallenging PRCA patients as "this is still in its early days."
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