Short- and long-term effects of erythropoietin treatment on endothelial progenitor cell levels in patients with cardiorenal syndrome

Abstract

Objective: Patients with cardiorenal syndrome (CRS) have high cardiovascular morbidity. Endothelial progenitor cells (EPC) constitute an endogenous vascular repairsystem, protecting against atherosclerosis development. Erythropoietin (EPO) treatment may have beneficial effects by mobilizing EPC from the bonemarrow. Our objective is to determine EPC levels and effects of EPO therapy on EPC levels in CRS patients.

Design: Open-label randomized trial.

Setting: Part of the EPOCARES-trial, conducted in Utrecht (Netherlands).

Patients: Patients with CRS and anaemia and healthy controls were included. Interventions Patients were randomized to receive EPO therapy (50 IU/kg/wk) for 52 weeks or no EPO therapy.

Main outcome measures: CD34(+)KDR(+)-EPC, cultured EPC outgrowth and function at baseline, after 18 days and after 52 weeks.

Results: Patients showed lower CD34(+)KDR(+)-cell numbers compared to controls (6(12) vs. 19(19) cells/10(5) granulocytes; p = 0.010), despite increased levels of stromal cell-derived factor-1α; (3.1(0.8) vs 2.6(0.3) ng/ml; p = 0.001). EPC outgrowth and function were not different between patients and controls. EPC levels did not change after 18 days with or without EPO treatment. CD34(+)KDR(+)-cells significantly declined after 52 weeks in the non-treated group (p = 0.028). Long-term EPO therapy did not significantly affect this reduction in CD34(+)KDR(+)-EPC levels.

Conclusions: CRS patients showed reduced CD34(+)KDR(+)-EPC levels compared to controls, consistent with a reduced vascular regenerative potential and despite upregulated SDF-1α levels. Over a one-year follow-up period a marked 68% further reduction in EPC levels was observed in the patient group without EPO treatment. In spite of promising experimental studies, our longitudinal, randomized study did not show significant influence of either short- or long-term EPO therapy on reduced EPC levels in CRS patients.

Figure 1

Progenitor cell levels and function in patients with cardiorenal syndrome (CRS) compared to healthy controls. Comparison of circulating CD34⁺KDR⁺-cell levels (A), CD34⁺-cell levels (B), cultured endothelial progenitor cell (EPC) number (C) and function as determined by scratch wound analysis (D) between CRS patients (n=45) and healthy controls (n=20). NC, negative control.

Figure 2

Short-term effects of erythropoietin (EPO) treatment on circulating endothelial progenitor cell (EPC) in patients with cardiorenal syndrome (CRS). Comparison of circulating CD34+KDR+-cell levels (A), CD34+-cell levels (B), cultured EPC number (C) and function as determined by scratch wound analysis (D) between CRS patients treated with EPO for 18 days (n=30, open bars) and non-EPO treated patients (n=15, filled bars).

Figure 3

Long-term effects of erythropoietin (EPO) treatment on circulating endothelial progenitor cell (EPC) in patients with cardiorenal syndrome (CRS). Comparison of circulating CD34+KDR+-cell levels (A), CD34+-cell levels (B), cultured EPC number (C) and function as determined by scratch wound analysis (D) between CRS patients treated with EPO for 52 weeks (n=13, open bars) and non-EPO treated patients (n=13, filled bars).