Effects of Continuous Erythropoietin Receptor Activator in Sepsis-Induced Acute Kidney Injury and Multi-Organ Dysfunction

Background: Despite advances in supportive care, sepsis-related mortality remains high, especially in patients with acute kidney injury (AKI). Erythropoietin can protect organs against ischemia and sepsis. This effect has been linked to activation of intracellular survival pathways, although the mechanism remains unclear. Continuous erythropoietin receptor activator (CERA) is an erythropoietin with a unique pharmacologic profile and long half-life. We hypothesized that pretreatment with CERA would be renoprotective in the cecal ligation and puncture (CLP) model of sepsis-induced AKI. Methods: Rats were randomized into three groups: control; CLP; and CLP+CERA (5 mu g/kg body weight, i.p. administered 24 h before CLP). At 24 hours after CLP, we measured creatinine clearance, biochemical variables, and hemodynamic parameters. In kidney tissue, we performed immunoblotting-to quantify expression of the Na-K-2Cl cotransporter (NKCC2), aquaporin 2 (AQP2), Toll-like receptor 4 (TLR4), erythropoietin receptor (EpoR), and nuclear factor kappa B (NF-kappa B)-and immunohistochemical staining for CD68 (macrophage infiltration). Plasma interleukin (IL)-2, IL-1 beta, IL-6, IL-10, interferon gamma, and tumor necrosis factor alpha were measured by multiplex detection. Results: Pretreatment with CERA preserved creatinine clearance and tubular function, as well as the expression of NKCC2 and AQP2. In addition, CERA maintained plasma lactate at normal levels, as well as preserving plasma levels of transaminases and lactate dehydrogenase. Renal expression of TLR4 and NF-kappa B was lower in CLP+CERA rats than in CLP rats (p<0.05 and p<0.01, respectively), as were CD68-positive cell counts (p<0.01), whereas renal EpoR expression was higher (p<0.05). Plasma levels of all measured cytokines were lower in CLP+CERA rats than in CLP rats. Conclusion: CERA protects against sepsis-induced AKI. This protective effect is, in part, attributable to suppression of the inflammatory response.

Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP, Sao Paulo Research Foundation)

Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP, Sao Paulo Research Foundation)

Laboratorios de Investigacao Medica (LIMs, Medical Investigation Laboratories) of the Faculdade de Medicina da Universidade de Sao Paulo (FMUSP, University of Sao Paulo School of Medicine)

Laboratorios de Investigacao Medica (LIMs, Medical Investigation Laboratories) of the Faculdade de Medicina da Universidade de Sao Paulo (FMUSP, University of Sao Paulo School of Medicine)

Hospital das Clinicas

Hospital das Clinicas

Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES, Office for the Advancement of Higher Education)

Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES, Office for the Advancement of Higher Education)

Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, National Council for Scientific and Technological Development)

Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, National Council for Scientific and Technological Development)