[Role of iron deficiency in erythropoietin sensitivity in dialysis patients with elevated C-reactive protein]

Chronic inflammation is a well-known cause of hyporesponsiveness of the bone marrow to erythropoietin (Epo). Factors which contribute to Epo resistance in the presence of inflammation include inhibition of erythroid precursor proliferation and functional iron deficiency induced by inflammatory cytokines. The specific role of iron deficiency in this clinical context, however, has not yet been clarified.

Our dialysis population consisted of 200 patients, from which 163 (91 males, mean age 67 +/- 12 years) who had been in dialysis for at least 4 (mean 62.4 +/- 71) months were selected for further study. Two groups were defined on the basis of C-reactive protein (CRP) concentrations: Group A (normal CRP < 5 mg/L; 78 patients) and Group B (elevated CRP > 15 mg/L; 43 patients). The remaining 42 patients with CRP in the range of 5 to 15 mg/L were excluded from the study.

Erythropoietin dose and the parameter EpoDose/hemoglobin (Hb) were both greater in Group B (dose: 150 +/- 65 vs. 106 +/- 56 U/kg, p<0.001; EpoDose/Hb: 14.0 +/- 6 vs. 9.8 +/- 6, p<0.001. The two groups were stratified on the basis of transferrin saturation (tSAT) greater or less than 20%: A1 (tSAT > 20%, n = 52), A2 (tSAT < 20%, n = 26), B1 (tSAT > 20%, n = 19) and B2 (tSAT < 20%, n = 24). Erythropoietin dose and EpoDose/Hb were lower in A1 compared to A2 (dose: 96 +/- 52 vs. 124 +/- 6 U/kg, p<0.05; EpoDose/Hb: 8.4 +/- 5 vs. 12.4 +/- 7, p < 0.05), whereas in the B subgroups the variables were equally elevated (dose: 151 +/- 71 vs 142 +/- 59 U/kg, ns; EpoDose/Hb: 14.4 +/- 7 vs. 13.6 +/- 6, ns). Patients in subgroups A2 and B2 were treated with intravenous Fe gluconate 31 mg after each dialysis session for 6 months. Erythropoietin dose and EpoDose/Hb were significantly reduced only in subgroup A2 with normal CRP (dose: from 126 +/- 55 to 95 +/- 52 U/kg, p < 0.05; EpoDose/Hb: from 12.4 +/- 7 to 8.4 +/- 5, p < 0.05), whereas no improvement was observed in subgroup B2 with elevated CRP (dose: from 142 +/- 59 to 151 +/- 65 U/kg, ns; EpoDose/Hb: from 13.6 +/- 6 to 14.4 +/- 7, ns).

Our data demonstrate that dialysis patients with CRP greater than 15 mg/L require an erythropoietin dose approximately 40% higher than patients with normal CRP, both in the presence and absence of iron deficiency. Iron therapy in patients with normal CRP and tSAT < 20% significantly improved the response to erythropoietin, but was completely ineffective in patients with increased CRP. These results suggest that functional iron deficiency plays a marginal role in resistance to erythropoietin observed in patients with elevated CRP concentrations.