黒尾 誠

Abstract Background and Hypothesis Elevated phosphate concentration in proximal tubular fluid promotes calcium phosphate microcrystallopathy, thereby accelerating the progression of chronic kidney disease (CKD). However, the clinical significance of proximal tubular phosphate exposure in humans remains uncertain. We aimed to determine whether estimated proximal tubular fluid phosphate concentration (ePTFp) is independently associated with age-related kidney function decline in adults with and without CKD. Methods We conducted a 5-year prospective cohort study involving 308 adults with and without CKD. ePTFp—a novel, noninvasive index—and serum fibroblast growth factor 23 (FGF23) concentrations were derived from blood and urine measurements. Kidney function decline, expressed as estimated glomerular filtration rate (eGFR) slope, was modeled using linear mixed-effects analysis. Associations of ePTFp and serum FGF23 with eGFR slope were examined using multivariable regression analysis, adjusting for potential covariates at baseline, including age, sex, several comorbidities, current smoking status, eGFR, and urinary glomerular and tubular injury markers. Results Over 5 years, eGFR declined in participants with and without CKD, with a steeper decline in those with CKD. Higher baseline ePTFp and serum FGF23 were inversely correlated with eGFR slope. In multiple adjusted models, elevated ePTFp remained independently associated with faster eGFR decline, whereas the serum FGF23 association was attenuated after covariate adjustment. Conclusions Elevated ePTFp was independently linked to accelerated kidney function decline, underscoring the clinical relevance of calcium phosphate microcrystallopathy. ePTFp may represent a practical biomarker with implications for prevention and treatment strategies targeting the aging kidney with proximal tubular phosphate exposure.

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.