Chairman's Workshop Report: R-HuEPO hyporesponsiveness--who and why?

Abstract

The most common cause of limited response to recombinant human erythropoietin (r-HuEPO) is unrecognized, mild-to-moderate iron deficiency, either at the start of treatment or secondary to enhanced iron utilization by newly formed erythrocytes. Iron stores in patients with chronic renal failure (CRF) are often depleted through gastrointestinal bleeding, blood loss during haemodialysis, and blood sampling. Mobilization of iron stores may be inadequate, especially during rapid haemoglobin regeneration. Aluminium overload may also interfere with gastrointestinal and cellular iron uptake. Overt or unrecognized infection or inflammation is another common cause of hyporesponsiveness, and is a consequence of increased blood concentrations of cytokines such as tumour necrosis factor (TNF), interleukin-1 (IL-1), and interferon-gamma (IFN-gamma), which suppress erythrocyte stem-cell proliferation. Less common causes include severe secondary hyperparathyroidism and myeloma (during chemotherapy). Response to r-HuEPO can be best predicted by baseline fibrinogen (a marker of subclinical inflammation); baseline transferrin receptor (sTfR) concentrations (a marker of functional iron deficiency); and sTfR increment after 2 weeks (a marker of early change in erythropoietic activity).

Recombinant human erythropoietin therapy after allogeneic hematopoietic cell transplantation with a nonmyeloablative conditioning regimen: Low donor chimerism predicts for poor response

“…Previous reports have also indicated that a major ABO mismatch does not prevent appropriate response to rHuEPO [41]. Because of the major inflammatory response they elicit, infections often result in a delay or loss of response to rHuEPO therapy in other settings [14,17,42], but not in our NMSCT patients. The use of an unrelated donor increases the risk of infection as well as of acute GVHD, a complication associated with further inhibition of endogenous EPO production [16,17,43] and a cytokine storm potentially inhibiting marrow erythropoiesis [44], but this did not prevent response to rHuEPO in our patients.…”

Polymorphisms in two genes, IL-1B and ACE, are associated with erythropoietin resistance in Korean patients on maintenance hemodialysis

“…Chronic inflammation can modify the process of erythropoiesis, probably via various inflammatory cytokines (Danielson, 1995;Cooper et al, 2003). Pro-inflammatory cytokines, which are under some degree of genetic control, may be associated with EPO resistance.…”

Slow Intravenous Iron Administration Does Not Aggravate Oxidative Stress and Inflammatory Biomarkers during Hemodialysis: A Comparative Study between Iron Sucrose and Iron Dextran

“…However, a considerable amount of patients do not respond well to rhEPO therapy and the most common cause of this is inadequate supply of iron needed for erythropoiesis [6]. Intravenous (i.v.)…”