P2.03: Recombinant Human Erythropoietin Alters Subcutaneous Resistance Artery Endothelial Function Through A Mechanism Involving Oxidative Stress and Endothelin-1 in Patients with Stage 4 Chronic Kidney Disease

Abstract

Objective

Recent studies have raised concern about the safety of recombinant human erythropoietin (RhuEPO) because of evidence of an increase in the risk of cardiovascular disease in chronic kidney disease (CKD) patients. In the present study we investigated the effect of RhuEPO on the function of resistance arteries isolated from CKD patients.

Design and method

19 patients (mean age 63 ± 14 years) with stage 4 CKD (mean eGFR 20 ± 5 mL/min/1.73m²), none treated with RhuEPO, were included. Resistance arteries from gluteal subcutaneous tissue were assessed on a pressurized myograph. Endothelium-dependent and independent relaxations were tested with acetylcholine and sodium nitroprusside respectively, with RhuEPO (0, 1, 10 and 20 UI/mL). Tempol (10⁻³ M), a superoxide dismutase mimetic, was used to inhibit oxidative stress. ABT-627 (10⁻⁷M) was used as a selective endothelin subtype A receptor antagonist.

Results

At 20 UI/mL, RhuEPO had no effect on norepinephrine-induced vasoconstriction (n = 10) nor on sodium nitroprusside-induced relaxation (n = 10). RhuEPO altered endothelium-dependent relaxation in a dose-dependent manner (maximal relaxation with RhuEPO at 0, 1, 10, 20 UI/ mL, 77.7 ± 3.5 %, 68.5 ± 4.7%, 53.2 ± 3.8 %, 45.7 ± 4.6 %, P<0.001, n = 7–14). Tempol and ABT-627 partially reversed the altered endothelial function in presence of RhuEPO 20 UI/mL (P<0.01, P<0.01, respectively). Conclusion: RhuEPO alters endothelial function of subcutaneous resistance arteries in predialysis CKD patients via a mechanism in part involving oxidative stress and signaling through endothelin subtype A receptors, which could contribute to the deleterious effect of RhuEPO described in large interventional trials.