Lack of Hepcidin Ameliorates Anemia and Improves Growth in an Adenine-induced Mouse Model of Chronic Kidney Disease


Oleh Akchurin, Angara Sureshbabu, Steve B Doty, Yuan-Shan Zhu, Edwin Patino, Susanna Cunningham-Rundles, Mary E Choi, Adele L. Boskey, Stefano Rivella


Growth delay is common in children with chronic kidney disease (CKD), often associated with poor quality of life. The role of anemia in uremic growth delay is poorly understood. Here we describe an induction of uremic growth retardation by 0.2% adenine diet in wild type (WT) and hepcidin gene (Hamp) knock-out (KO) mice, compared with their respective littermates fed a regular diet. Experiments were started at weaning (3 weeks). After 8 weeks, blood was collected and mice were euthanized. Adenine-fed WT mice developed CKD (BUN 82.8±11.6 mg/dL, creatinine 0.57±0.07 mg/dL) and were 2.1 cm shorter compared to WT controls. WT adenine-fed mice were anemic, had low serum iron, elevated Hamp, elevated IL6 and TNF-alpha. WT adenine fed mice had advanced mineral bone disease (serum phosphorus 16.9±3.1 mg/dL, FGF23 204.0±115.0 ng/mL) with loss of cortical and trabecular bone volume seen on micro-CT. Hamp disruption rescued the anemia phenotype resulting in improved growth rate in mice with CKD, thus providing direct experimental evidence of the relationship between Hamp pathway and growth impairment in CKD. Hamp disruption ameliorated CKD-induced growth hormone - insulin-like growth factor 1 axis derangements and growth plate alterations. Disruption of Hamp did not mitigate the development of uremia, inflammation, mineral and bone disease in this model. Taken together, these results indicate that adenine diet can be successfully used to study growth in mice with CKD. Hepcidin appears to be related to pathways of growth retardation in CKD suggesting that investigation of hepcidin lowering therapies in juvenile CKD is warranted.