Hyperphosphatemia increases inflammation to exacerbate anemia and skeletal muscle wasting independently of FGF23-FGFR4 signaling

Abstract

Elevations in plasma phosphate concentrations (hyperphosphatemia) occur in chronic kidney disease (CKD), in certain genetic disorders, and following the intake of a phosphate-rich diet. Whether hyperphosphatemia and/or associated changes in metabolic regulators, including elevations of fibroblast growth factor 23 (FGF23) directly contribute to specific complications of CKD is uncertain. Here we report that similar to patients with CKD, mice with adenine-induced CKD develop inflammation, anemia and skeletal muscle wasting. These complications are also observed in mice fed high phosphate diet even without CKD. Ablation of pathologic FGF23-FGFR4 signaling did not protect mice on an increased phosphate diet or mice with adenine-induced CKD from these sequelae. However, low phosphate diet ameliorated anemia and skeletal muscle wasting in a genetic mouse model of CKD. Our mechanistic in vitro studies indicate that phosphate elevations induce inflammatory signaling and increase hepcidin expression in hepatocytes, a potential causative link between hyperphosphatemia, anemia and skeletal muscle dysfunction. Our study suggests that high phosphate intake, as caused by the consumption of processed food, may have harmful effects irrespective of pre-existing kidney injury, supporting not only the clinical utility of treating hyperphosphatemia in CKD patients but also arguing for limiting phosphate intake in healthy individuals.

Competing Interest Statement

This study was supported by NIH grants F31-DK-117550 (BC), T90-DE-022736 (KH), F31-DK-115074 (CY), K24-DK-116180 (OG), R01-DK-087727 (JLB), U01-DK-119950 (IBS), R01-DK-126680 (TG), R01-HD-096863 (EN), K08-DK-111980 (MH), R01-HL-128714 and R01-HL-145528 (CF); and by grants from the Deutsche Forschungsgemeinschaft (DK) and the National Science Foundation (IC). Furthermore, CF was supported by the UAB-UCSD O'Brien Core Center for Acute Kidney Injury Research, the AMC21 program of the Department of Medicine at UAB and the Tolwani Innovation Award from the Division of Nephrology at UAB; JLB was supported by the Patricia and Scott Eston Massachusetts General Hospital Research Scholar Award. CF has served as a consultant for Bayer and Calico Labs, and he is the founder and currently the CSO of a startup biotech company (Alpha Young LLC); OG has received honoraria and grant support from Akebia and Amgen, grant support from GSK, honoraria from Ardelyx, Reata, and AstraZeneca, and serves on the Data Monitoring Committee for QED; JLB has ownership interest in Ferrumax Pharmaceuticals and has been a consultant for Incyte Corporation, and Alnylam Pharmaceuticals.