黒尾 誠

Fibroblast growth factor-23 (FGF23) is a bone-derived hormone that promotes urinary phosphate excretion in response to phosphate loading. While essential for phosphate homeostasis, elevated FGF23 increases phosphate concentration in the renal tubular fluid, promoting calcium-phosphate crystal formation and tubular injury. Here we show that bone resorption mobilizes phosphate into the circulation and mimics the pathophysiology of dietary phosphate loading. Enhanced bone resorption, induced by soluble receptor activator of NF-κB ligand (sRANKL) administration or microgravity exposure on the International Space Station, increased circulating FGF23 levels and caused renal tubular injury in mice. Pre-treatment with bisphosphonate, an inducer of osteoclast apoptosis, prevented sRANKL-induced increases in FGF23 and tubular damage. These findings suggest that bone mineral loss may contribute to renal tubular injury in clinical settings, including immobilization, osteoporosis, and chronic kidney disease-mineral bone disorder.

Abstract The circulating fibroblast growth factor 23 (FGF23) is a potential therapeutic target for cardiorenal syndrome. However, current evidence on the determinants, particularly the modifiable factors of circulating FGF23 levels that increase independently of the kidney function, remains limited. In this study, we aimed to investigate the association between physical performance measures and circulating FGF23 levels in middle-aged and older adults with normal kidney function. This cross-sectional study assessed circulating FGF23 levels and physical performance parameters, including the handgrip strength, knee extension strength, maximal gait speed, the 30-second chair stand test (30s-CST), sit-and-reach test, and aerobic exercise capacity in 158 participants. Multiple regression analyses were performed to evaluate the independent associations between circulating FGF23 levels and physical performance measures after adjusting for potential confounders including age, sex, the presence of lifestyle-related disease, serum phosphate and phosphate-regulating hormone, estimated glomerular filtration rate, and urinary albumin-to-creatinine ratio. Higher circulating FGF23 levels were associated with lower handgrip strength, knee extension strength, maximal gait speed, 30s-CST score, and aerobic exercise capacity. These associations remained significant after adjusting for confounders, except for the association with handgrip strength and aerobic exercise capacity, which was attenuated when renal function variables were included. However, when all physical performance parameters were included in a model, knee extension strength and aerobic exercise capacity were identified as independent determinants of circulating FGF23 levels. Physical performance, particularly knee extension strength, and to a lesser extent aerobic exercise capacity, was independently or partially associated with circulating FGF23 levels in individuals with normal kidney function. Maintaining physical performance may help regulate circulating FGF23 levels, highlighting a potential role in preventing its elevation.

Age-related loss of lower extremity muscle strength is pronounced in individuals with chronic kidney disease (CKD). In contrast, an increase in intrarenal flow pulsatility results in initial age-related changes in renal hemodynamics, leading to the development of CKD. To date, it remains unclear whether lower extremity muscle strength determines elevated renal flow pulsatility. This study aimed to determine the association of lower extremity muscle strength and function with intrarenal hemodynamics in individuals with and without CKD. One hundred seventy-six individuals without CKD (aged 63 ± 9 years) and 101 individuals with CKD (aged 66 ± 8 years) were included in this study. Using Doppler ultrasound, the renal resistive index (RI) was measured as a parameter of renal hemodynamics. Knee extensor muscle strength (KES), gait speed (GS), and the 30 s chair stand test (30s-CST) were used to measure lower extremity muscle strength and function. Multivariate analyses showed that GS and 30s-CST scores were independent determinants of renal RI, whereas the KES score was not associated with renal RI in individuals with and without CKD. In the two-way analysis of covariance, renal RI was the highest in individuals with CKD who had lower KES, GS, and 30s-CST scores. Reduced lower extremity muscle strength and function are independent determinants of elevated renal flow pulsatility in individuals with and without CKD.