Pleiotropic renal actions of erythropoietin.

CONTEXT: Erythropoietin (EPO), which is used clinically as recombinant human EPO (rHuEPO) for anaemia associated with end-stage renal failure and cancer chemotherapy, also has pleiotropic properties. Although EPO and its receptor are primary mediators of the normal physiological response to hypoxia, rHuEPO can provide impressive protection against acute ischaemic injury in several organs and tissues. The longer-acting hyperglycosylated derivative of EPO, darbepoetin-alpha, is also used for anaemia and has pleiotropic properties. However, the ability of EPO or its analogues to act directly to reduce the severity of renal injury associated with chronic renal failure is not known. STARTING POINT: Ferdinand Bahlmann and colleagues (Circulation 2004; 110: 1006-12) investigated whether low-dose subcutaneous darbepoetin-alpha could protect against renal dysfunction and injury in rats with induced chronic renal failure. Given once weekly, the drug improved renal function and reduced histological evidence of renal injury. Treated rats also had greater weight gain than controls, with no change in systemic blood pressure. The drug did not increase packed-cell volume and it improved survival. WHERE NEXT?: Although the pleiotropic actions of rHuEPO can ameliorate ischaemic and nephrotoxic acute renal failure, Bahlmann's work is the first evidence that darbepoetin-alpha reduces the renal dysfunction and injury of chronic renal failure. Thus rHuEPO and its analogues might have a use in patients with different types of renal failure. These pleiotropic actions, seen at lower doses, must be separated from the haemopoietic properties that occur at clinical doses and which, at the highest doses, might lead to unwanted effects. Novel analogues of EPO are devoid of haemopoietic activity but still possess protective properties. Their ability to reduce renal injury and dysfunction awaits investigation.