Anemia affects over half of the 10 million Americans with pre-dialysis chronic kidney disease (CKD) and is associated with a variety of adverse effects including mortality and decreased quality of life. Anemia which does not respond to treatment with erythropoiesis stimulating agents (ESA) is common in clinical practice. Much evidence points to adverse health effects associated with escalation of ESA therapy in CKD patients with treatment resistant anemia. However, little progress has been made toward identifying other mechanisms which contribute to anemia in CKD in order to identify safe and effective adjunctive treatments. Hepcidin, an anti-microbial peptide produced by the liver, whose production is stimulated by inflammation, interferes with the utilization of iron stores for erythropoiesis. The specific contribution of hepcidin to the development of anemia in children with CKD has not been explored in a prospective manner. In addition, emerging evidence suggests that 25-hydroxy vitamin D (25D) deficiency is a novel risk factor for anemia in CKD, which may be due to 25D-dependent immunomodulation. Interruption of the inflammatory stimuli which increase hepcidin production could make the management of CKD-associated anemia with iron supplementation and ESAs more effective. The long-term goal of the proposed research is to define the contribution of hepcidin mediated mechanisms to the anemia of early CKD, and to understand whether hepcidin production may be modified by a therapeutic intervention.
The Specific Aims of this project are to (1) define how elevated serum levels of hepcidin are associated with hemoglobin and ESA hypo-responsiveness within the established NIH funded Chronic Kidney Disease in Children (CKiD) prospective cohort study, and (2) to evaluate the effects of ergocalciferol (vitamin D2) supplementation on serum levels of hepcidin, hemoglobin, and ESA dose in a prospective interventional trial in children with pre-dialysis CKD. Our central hypothesis is that in mild to moderate CKD, elevated serum hepcidin is associated with anemia (as defined by low hemoglobin). Furthermore, we hypothesize that in the setting of CKD, supplementation with ergocalciferol will be associated with a decrease in serum hepcidin and increase in hemoglobin. Our hypotheses have been formulated on the basis of an extensive review of the literature on vitamin D, hepcidin and anemia, and our own preliminary data produced by measuring serum hepcidin values in 124 children enrolled in CKiD, in whom higher hepdidin levels are associated with anemia, and preliminary study of normal children showing low 25D levels associated with anemia. The rationale for the combination of observational and interventional approaches proposed is to accelerate our understanding of the biologic mechanisms contributing to the anemia of CKD and simultaneously to develop new and innovative interventions to treat this common co-morbidity in childhood CKD.

Public Health Relevance

Anemia affects more than half of the over 10 million Americans with chronic kidney disease (CKD), and is associated with poor health outcomes including heart disease and death. Anemia in CKD is often resistant to current treatments, suggesting that there may be other causes of anemia in CKD that have yet to be identified. Definition of the relative contributions of specific pathways to anemia in CKD will identify future treatments for this anemia, with the long term goal of improving quality of life, and decreasing both overall illness and the cost of anemia treatment in the CKD population.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Mentored Patient-Oriented Research Career Development Award (K23)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Rankin, Tracy L
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Johns Hopkins University
Schools of Medicine
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Atkinson, Meredith A; Warady, Bradley A (2018) Anemia in chronic kidney disease. Pediatr Nephrol 33:227-238
Atkinson, Meredith A; Leonard, Mary B; Herskovitz, Rita et al. (2018) Changes in Hepcidin and Hemoglobin After Anti-TNF-alpha Therapy in Children and Adolescents With Crohn Disease. J Pediatr Gastroenterol Nutr 66:90-94
Atkinson, Meredith A; Juraschek, Stephen P; Bertenthal, Michael S et al. (2017) Pilot study of the effect of cholecalciferol supplementation on hepcidin in children with chronic kidney disease: Results of the D-fense Trial. Pediatr Nephrol 32:859-868
Atkinson, Meredith A; Kim, Ji Young; Roy, Cindy N et al. (2015) Hepcidin and risk of anemia in CKD: a cross-sectional and longitudinal analysis in the CKiD cohort. Pediatr Nephrol 30:635-43
Lestz, Rachel M; Fivush, Barbara A; Atkinson, Meredith A (2014) Association of higher erythropoiesis stimulating agent dose and mortality in children on dialysis. Pediatr Nephrol 29:2021-8
Atkinson, Meredith A; Melamed, Michal L; Kumar, Juhi et al. (2014) Vitamin D, race, and risk for anemia in children. J Pediatr 164:153-158.e1
Atkinson, Meredith A; Pierce, Christopher B; Fadrowski, Jeffrey J et al. (2012) Association between common iron store markers and hemoglobin in children with chronic kidney disease. Pediatr Nephrol 27:2275-83
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Atkinson, Meredith A; Furth, Susan L (2011) Anemia in children with chronic kidney disease. Nat Rev Nephrol 7:635-41