Erythropoietin-mediated protection in kidney transplantation: nonerythropoietic EPO derivatives improve function without increasing risk of cardiovascular events

Abstract

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

Defining the optimal duration for normothermic regional perfusion in the kidney donor: A porcine preclinical study

“…,31 and by the gradual expansion of peritoneal effusion.HIF-1α is an important pathway of IRI [32][33][34]. EPO upregulation is important for hypoxia adaptation,35 improving renal function and structure in rats 36. EPO upregulation is important for hypoxia adaptation,35 improving renal function and structure in rats 36.…”

Induction of erythropoietin gene expression in epithelial cells by chemicals identified in GATA inhibitor screenings

“…GATA4 and GATA5 regulate BCL2L1 gene expression against cardiotoxic agents and hypoxic stimuli, respectively (Aries, Paradis, Lefebvre, Schwartz, & Nemer, 2004;Wu, Wang, Lin, Liu, & Chen, 2016). In addition to these broad observations of the relationship between cellular responses to stressors and GATA factors, EPO exerts critical cytoprotective functions, and this notion is supported by various observations (Joyeux-Faure, 2007;Maiese, Li, & Chong, 2005;Mammis, McIntosh, & Maniker, 2009;van Rijt, van Goor, Ploeg, & Leuvenink, 2014;Sharples & Yaqoob, 2006). Therefore, we suggested that GATA factors may act to tune and optimize the local levels of EPO production through binding to the GATA-binding motif Genes to Cells KANEKO Et Al. in the promoter-proximal region.…”

Use of Aspirin in normalization of recombinant human erythropoietin-mediated hyper-reactivity of platelets in rats

“…Cardiovascular risk associated with EPO treatment may be reduced by using other EPO derivatives. [2728] We observed that in vitro stimulation of rat whole blood with high concentration of rHuEPO did not alter any agonist-induced aggregation. Therefore it seems feasible that rHuEPOdoes not exert direct effects on circulating platelets, but rather modulates platelet during synthesis and maturation in the bone marrow.…”