BackgroundIn contrast with various pre-clinical studies, recent clinical trials suggest that high dose erythropoietin (EPO) treatment following kidney transplantation does not improve short-term outcome and that it even increases the risk of thrombotic events. ARA290 is a non-erythropoietic EPO derivative and does not increase the risk of cardiovascular events, but potentially has cytoprotective capacities in prevention of renal ischemia/reperfusion injury.MethodsEight female Dutch Landrace pigs were exposed to unilateral renal ischemia for 45 minutes with simultaneous cannulation of the ureter of the ischemic kidney. ARA290 or saline was administered by an intravenous injection at 0, 2, 4 and 6 hours post-reperfusion. The animals were sacrificed seven days post-reperfusion.ResultsARA290 increased glomerular filtration rate during the observation period of seven days. Furthermore, ARA290 tended to reduce MCP-1 and IL-6 expression 15 minutes post-reperfusion. Seven days post-reperfusion ARA290 reduced interstitial fibrosis.ConclusionsThe improvement in renal function following renal ischemia/reperfusion and reduced structural damage observed in this study by ARA290 warrants further investigation towards clinical application.

SummaryThe protective, nonerythropoietic effects of erythropoietin (EPO) have become evident in preclinical models in renal ischaemia/reperfusion injury and kidney transplantation. However, four recently published clinical trials using high-dose EPO treatment following renal transplantation did not reveal any protective effect for short-term renal function and even reported an increased risk of thrombosis. This review focusses on the current status of protective pathways mediated by EPO, the safety concerns using high EPO dosage and discusses the discrepancies between pre-clinical and clinical studies. The protective effects are mediated by binding of EPO to a heteromeric receptor complex consisting of two b-common receptors and two EPO receptors. An important role for the activation of endothelial nitric oxide synthase is proposed. EPO-mediated cytoprotection still has enormous potential. However, only nonerythropoietic EPO derivatives may induce protection without increasing the risk of cardiovascular events. In preclinical models, nonerythropoietic EPO derivatives, such as carbamoylated EPO and ARA290, have been tested. These EPO derivatives improve renal function and do not affect erythropoiesis. Therefore, nonerythropoietic EPO derivatives may be able to render EPO-mediated cytoprotection useful and beneficial for clinical transplantation. Transplantation of deceased donor kidneysDelayed graft function (DGF) and primary nonfunction (PNF) are serious complications of renal transplantation. Overall, DGF is associated with a 41% increased risk of graft loss and a 38% increased risk of rejection [1]. In Europe, deceased donor kidneys represent 73% of all transplanted kidneys in 2011 [2]. Thus, improvement of shortand long-term function of transplanted deceased donor kidneys is an important focus in transplantation research.Renal ischaemia/reperfusion (I/R) injury is a significant cause of reduced short-term function after transplantation. Deceased organ donation can be divided into two types of donation: organs donated after brain death (DBD, deceased brain dead) and after cardiac death (DCD, deceased cardiac dead). Short-term function of kidneys is significantly more compromised in DCD than in DBD-derived kidneys. The incidence of both DGF and PNF is 72% and 23% after DCD compared to 18% and 4% after DBD, respectively. The increased incidence of PNF results in reduced longterm graft survival of DCD kidneys [3].Despite many important achievements in transplantation, such as improved surgical techniques, better treatment of complications and a profound reduction in kidney rejection, overall graft survival has only marginally increased [4,5]. This phenomenon is probably in part because of the current Achilles' heel in transplantation: the use of large numbers of older and high-risk donor organs that have suffered from substantial I/R injury. As we suspect that future donor resources will not return to the ideal

BackgroundARA290 is a non-erythropoietic EPO derivative which only binds to the cytoprotective receptor complex (EPOR2-βcR2) consisting of two EPO-receptors (EPOR) and two β common receptors (βcR). ARA290 is renoprotective in renal ischemia/reperfusion (I/R). In a renal I/R model we focussed on timing of post-reperfusional administration of ARA290. Furthermore, we investigated the anti-inflammatory properties of ARA290.MethodsTwenty-six male Lewis/HanHsd rats were exposed to unilateral ischemia for 30 minutes, with subsequent removal of the contralateral kidney. Post-reperfusion, ARA290 was administered early (one hour), late (four hours) or repetitive (one and four hours). Saline was used as vehicle treatment. Rats were sacrificed after three days.ResultsEarly ARA290 treatment improved renal function. Late- or repetitive treatment tended to improve clinical markers. Furthermore, early ARA290 treatment reduced renal inflammation and acute kidney injury at three days post-reperfusion. Late- or repetitive treatment did not affect inflammation or acute kidney injury.ConclusionsARA290 attenuated renal ischemia/reperfusion injury. This study showed the anti-inflammatory effect of ARA290 and suggests early administration in the post-reperfusional phase is most effective. ARA290 is a candidate drug for protection against ischemic injury following renal transplantation.