Erythropoietin treatment for anemia and human non-erythroid responses

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

Erythropoietin is required erythropoiesis and ex vivo primary human hematopoietic progenitor cell cultures that differentiate along the erythroid lineage with erythropoietin treatment and in vivo mouse models of erythropoietin stimulated erythropoiesis were used as to assess to assess erythroid molecular of processes and potential bone marrow environmental factors that affect red blood cell production and erythropoietin response. Using mice as a model system to assess non-erythroid response to increased erythropoietin stimulated erythropoiesis, In animal studies we observed that mice treated with erythropoietin and transgenic mice overexpressing human erythropoietin exhibited significant reduction in trabecular bone accompanying increased erythropoietin stimulated erythropoiesis. This non-erythroid bone response was independent of erythropoietin stimulated erythropoiesis, was not observed in mice with erythropoietin receptor restricted to erythroid tissue, and required erythropoietin receptor in non-erythroid cells such as osteoblasts. For three decades, erythropoietin has been used for treatment of anemia in chronic kidney disease and end stage renal disease. We determined the potential impact of human erythropoietin treatment on bone health using the United States Renal Data System (USRDS) datasets containing data on erythropoietin usage in hemodialysis patients. Erythropoietin treatment in chronic kidney disease and end stage renal disease has reduced the need for blood transfusions and improved quality of life. Recombinant human erythropoietin treatment for chronic kidney disease received FDA approval in 1989. While incidence of hip fractures decreased in the United States generally after 1990, it increased among hemodialysis patients coincident with introduction of erythropoietin treatment for chronic kidney disease and subsequent erythropoietin dose escalation. Analysis of the USRDS datasets (1997-2013) showed hip fracture rates for 747,832 patients increased from 12.0 per 1000 patient years in 1997 to 18.9 in 2004, then decreased to 13.1 by 2013. Average erythropoietin dose increased from 11,900 units/week in 1997 to 18,300 in 2004, then decreased to 8,800 by 2013. Multivariable Cox regression analysis revealed that during this time, for erythropoietin doses ranging from 50-149, 150-299, and > 300 units/kg/week, the adjusted hazard ratios for hip fractures increased from 1.08 to 1.22 and 1.41 respectively. These findings were replicated in a separate multivariable analysis of 128,941 patients from the Consolidated Renal Operations in a Web-enabled Network (CROWNWeb) datasets for 2013. These findings implicate erythropoietin treatment as a previously unrecognized dose-related risk factor for hip fractures in hemodialysis patients and suggest minimizing erythropoietin dose to ameliorate anemia rather than using high doses to correct anemia in renal failure patients. For culture studies of erythropoietin stimulated erythropoiesis, human CD34+ hematopoietic cells from peripheral blood were used to assess gene expression and protein processing during erythropoietin stimulated erythropoiesis. While increasing erythropoietin receptor expression increased erythropoiesis, decreasing oxygen tension and modifying nitric oxide synthase activity adversely affected erythropoiesis. Future studies will examine erythropoietin-nitric oxide synthase interaction in erythroid differentiating primary human hematopoietic cell cultures and in in vivo in mouse models with modified erythropoietin signaling and/or modified nitric oxide synthase activity.