title: Carbamylated Erythropoietin Outperforms Erythropoietin in the Treatment of AKI-on-CKD and Other AKI Models.
abstract: Erythropoietin (EPO) may be a beneficial tissue-protective cytokine. However, high doses of EPO are associate with adverse effects, including thrombosis, tumor growth, and hypertension. Carbamylated erythropoietin (CEPO) lacks both erythropoietic and vasoconstrictive actions. In this study, we compared the renoprotective, hemodynamic, and hematologic activities and survival effects of identical EPO and CEPO doses in rat models of clinically relevant AKI presentations, including ischemia-reperfusion-induced AKI superimposed on CKD (5000 U/kg EPO or CEPO; three subcutaneous injections) and ischemia-reperfusion-induced AKI in old versus young animals and male versus female animals (1000 U/kg EPO or CEPO; three subcutaneous injections). Compared with EPO therapy, CEPO therapy induced greater improvements in renal function and body weight in AKI on CKD animals, with smaller increases in hematocrit levels and similarly improved survival. Compared with EPO therapy in the other AKI groups, CEPO therapy induced greater improvements in protection and recovery of renal function and survival, with smaller increases in systolic BP and hematocrit levels. Overall, old or male animals had more severe loss in kidney function and higher mortality rates than young or female animals, respectively. Notably, mRNA and protein expression analyses confirmed the renal expression of the heterodimeric EPO receptor/CD131 complex, which is required for the tissue-protective effects of CEPO signaling. In conclusion, CEPO improves renal function, body and kidney weight, and survival in AKI models without raising hematocrit levels and BP as substantially as EPO. Thus, CEPO therapy may be superior to EPO in improving outcomes in common forms of clinical AKI.
authors.affiliation: Department of Medicine, Massachusetts General Hospital Medicine Group, Boston, Massachusetts.
authors.forename: Florian E
authors.initials: FE
authors.lastname: Tögel
authors.affiliation: Department of Medicine, Division of Nephrology and.|Department of Medicine, Section of Nephrology, Veterans Affairs Medical Center Salt Lake City, Salt Lake City, Utah.
authors.forename: Jon D
authors.initials: JD
authors.lastname: Ahlstrom
authors.affiliation: Department of Medicine, Division of Nephrology and.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Medicine, Division of Nephrology and.
authors.forename: Zhuma
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Medicine, Division of Nephrology and.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Division of Nephrology and christof.westenfelder@hsc.utah.edu.|Department of Medicine, Section of Nephrology, Veterans Affairs Medical Center Salt Lake City, Salt Lake City, Utah.|Department of Physiology, University of Utah, Salt Lake City, Utah; and.
authors.forename: Christof
authors.initials: C
authors.lastname: Westenfelder
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy*; D000367:Age Factors; D000818:Animals; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D005260:Female; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy*; D012737:Sex Factors
chemical_list: C488171:carbamylated erythropoietin; D004921:Erythropoietin
keywords: acute renal failure; chronic kidney disease; erythropoietin