Endocrinol Metab.  2024 Jun;39(3):407-415. 10.3803/EnM.2024.1978.

Roles of Parathyroid Hormone and Fibroblast Growth Factor 23 in Advanced Chronic Kidney Disease

• Nakagawa Y
• Komaba H

• KMID: 2556632
• DOI: http://doi.org/10.3803/EnM.2024.1978

Abstract

Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) each play a central role in the pathogenesis of chronic kidney disease (CKD)-mineral and bone disorder. Levels of both hormones increase progressively in advanced CKD and can lead to damage in multiple organs. Secondary hyperparathyroidism (SHPT), characterized by parathyroid hyperplasia with increased PTH secretion, is associated with fractures and mortality. Emerging evidence suggests that these associations may be partially explained by PTH-induced browning of adipose tissue and increased energy expenditure. Observational studies suggest a survival benefit of PTHlowering therapy, and a recent study comparing parathyroidectomy and calcimimetics further suggests the importance of intensive PTH control. The mechanisms underlying the regulation of FGF23 secretion by osteocytes in response to phosphate load have been unclear, but recent experimental studies have identified glycerol-3-phosphate, a byproduct of glycolysis released by the kidney, as a key regulator of FGF23 production. Elevated FGF23 levels have been shown to be associated with mortality, and experimental data suggest off-target adverse effects of FGF23. However, the causal role of FGF23 in adverse outcomes in CKD patients remains to be established. Further studies are needed to determine whether intensive SHPT control improves clinical outcomes and whether treatment targeting FGF23 can improve patient outcomes.

Keyword

Chronic kidney disease-mineral and bone disorder; Fibroblast growth factor-23; Glycerol-3-phosphate; Parathyroid hormone; Hyperparathyroidism, secondary

Figure

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  Fig. 1. Roles of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) in the pathogenesis of chronic kidney disease-mineral and bone disorder. In patients with impaired kidney function, FGF23 production by osteocytes increases. Recent experimental data have shown that glycerol-3-phosphate (G-3-P), a byproduct of glycolysis in proximal tubular cells, stimulates FGF23 production in bone. Increased FGF23 reduces 1,25-dihydroxyvitamin D (1,25D), which stimulates PTH secretion, leading to secondary hyperparathyroidism. Elevated PTH not only causes high-turnover bone disease, but also induces wasting and muscle atrophy through browning of adipose tissue, which contributes to increased mortality. Elevated FGF23 is implicated in the development of left ventricular hypertrophy, which may also lead to increased mortality. Npt2a, sodium-dependent phosphate transport protein 2A.

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