Erythropoietin administration protects against functional impairment and cell death after ischaemic renal injury in pigs

Abstract

Objective: To determine whether the administration of erythropoietin at the time of ischaemic renal injury (IRI) inhibits apoptosis, enhances tubular epithelial regeneration and promotes renal functional recovery, as it does in rodent models, in a higher mammalian model.

Materials and methods: The model of IRI involved unilateral nephrectomy in pigs, followed a week later by renal artery occlusion for 1 h, followed by reperfusion for 5 days. Pigs were randomized to receive erythropoietin 5000 units/kg intravenously at the time of ischaemia, followed by 1000 units/kg subcutaneously daily, or no treatment (six pigs each). Renal function and structure were analysed; blood and urine were collected daily to determine serum creatinine level, blood urea nitrogen, and creatinine clearance. Animals were killed after 5 days to obtain the injured kidneys. The kidneys were examined histologically for evidence of cellular mitosis, apoptosis and necrosis.

Results: Erythropoietin significantly abrogated renal dysfunction after IRI compared with controls at 12 h after injury; the mean (sem) creatinine clearance (as a percentage of baseline) for IRI was 68.2 (6)% vs erythropoietin-IRI 94.9 (8.9)% (P = 0.027), although by 36 h this was no longer significant, with values of 73.8 (12.7)% vs 95.9 (12)%, respectively (P = 0.23). Erythropoietin also significantly reduced the amount of cell death on histological analysis after 5 days of reperfusion, with a median (range) for IRI of 5.5 (1-45) vs erythropoietin-IRI of 1.5 (0-4) (P = 0.043).

Conclusion: This study confirms the potential clinical applications of erythropoietin as a novel therapeutic agent in patients at risk of IRI.