Erythropoietin protects against ischaemic acute renal injury

Erythropoietin (EPO) has recently been shown to exert important cytoprotective and anti-apoptotic effects in experimental brain injury and cisplatin-induced nephrotoxicity. The aim of the present study was to determine whether EPO administration is also renoprotectivein both in vitro and in vivo models ofischaemic acute renal failure Methods. Primary cultures of human proximal tubule cells (PTCs) were exposed to either vehicle or EPO (6.25–400 IU/ml) in the presence of hypoxia (1% O2), normoxia (21% O2) or hypoxia followed by normoxia for up to 24 h. The end-points evaluated included cell apoptosis (morphology and in situ end labelling [ISEL], viability [lactate dehydrogenase (LDH release)], cell proliferation [proliferating cell nuclear antigen (PCNA)] and DNA synthesis (thymidine incorporation). The effects of EPO pre-treatment (5000 U/kg) on renal morphology and function were also studied in rat models of unilateral and bilateral ischaemia–reperfusion (IR) injury. Results. In the in vitro model, hypoxia (1% O2) induced a significant degree of PTC apoptosis, which was substantially reduced by co-incubation with EPO at 24 h (vehicle 2.5±0.5% vs 25 IU/ml EPO 1.8±0.4% vs 200 IU/ml EPO 0.9±0.2%, n = 9, P

Novel renoprotective actions of erythropoietin: New uses for an old hormone

Erythropoietin (EPO) has been used widely for the treatment of anaemia associated with chronic kidney disease and cancer chemotherapy for nearly 20 years. More recently, EPO has been found to interact with its receptor (EPO-R) expressed in a large variety of non-haematopoietic tissues to induce a range of cytoprotective cellular responses, including mitogenesis, angiogenesis, inhibition of apoptosis and promotion of vascular repair through mobilization of endothelial progenitor cells from the bone marrow. Administration of EPO or its analogue, darbepoetin, promotes impressive renoprotection in experimental ischaemic and toxic acute renal failure, as evidenced by suppressed tubular epithelial apoptosis, enhanced tubular epithelial proliferation and hastened functional recovery. This effect is still apparent when administration is delayed up to 6 h after the onset of injury and can be dissociated from its haematological effects. Based on these highly encouraging results, at least one large randomized controlled trial of EPO therapy in ischaemic acute renal failure is currently underway. Preliminary experimental and clinical evidence also indicates that EPO may be renoprotective in chronic kidney disease. The purpose of the present article is to review the renoprotective benefits of different protocols of EPO therapy in the settings of acute and chronic kidney failure and the potential mechanisms underpinning these renoprotective actions. Gaining further insight into the pleiotropic actions of EPO will hopefully eventuate in much-needed, novel therapeutic strategies for patients with kidney disease.

Delayed administration of darbepoetin or erythropoietin protects against ischemic acute renal injury and failure

Administration of human recombinant erythropoietin ( EPO) at time of acute ischemic renal injury ( IRI) inhibits apoptosis, enhances tubular epithelial regeneration, and promotes renal functional recovery. The present study aimed to determine whether darbepoetin-alfa ( DPO) exhibits comparable renoprotection to that afforded by EPO, whether pro or antiapoptotic Bcl-2 proteins are involved, and whether delayed administration of EPO or DPO 6 h following IRI ameliorates renal dysfunction. The model of IRI involved bilateral renal artery occlusion for 45 min in rats ( N = 4 per group), followed by reperfusion for 1-7 days. Controls were sham-operated. Rats were treated at time of ischemia or sham operation ( T0), or post-treated ( 6 h after the onset of reperfusion, T6) with EPO ( 5000 IU/kg), DPO ( 25 mu g/kg), or appropriate vehicle by intraperitoneal injection. Renal function, structure, and immunohistochemistry for Bcl-2, Bcl-XL, and Bax were analyzed. DPO or EPO at T0 significantly abrogated renal dysfunction in IRI animals ( serum creatinine for IRI 0.17 +/- 0.05mmol/l vs DPO-IRI 0.08 +/- 0.03mmol/l vs EPO-IRI 0.04 +/- 0.01mmol/l, P = 0.01). Delayed administration of DPO or EPO ( T6) also significantly abrogated subsequent renal dysfunction ( serum creatinine for IRI 0.17 +/- 0.05mmol/l vs DPO-IRI 0.06 +/- 0.01mmol/l vs EPO-IRI 0.03 +/- 0.03mmol/l, P = 0.01). There was also significantly decreased tissue injury ( apoptosis, P < 0.05), decreased proapoptotic Bax, and increased regenerative capacity, especially in the outer stripe of the outer medulla, with DPO or EPO at T0 or T6. These results reaffirm the potential clinical application of DPO and EPO as novel renoprotective agents for patients at risk of ischemic acute renal failure or after having sustained an ischemic renal insult.