Estimated Proximal Tubule Fluid Phosphate Concentration as an Early Marker of Phosphate Metabolism Abnormalities and a Predictor of Kidney-Related Outcomes in Patients with CKD

Background: Although elevated estimated proximal tubule fluid phosphate concentration (ePTFp) has been linked to tubular damage in mouse models and human cross-sectional studies, prospective observational studies assessing the relationship between ePTFp and kidney-related outcomes in patients with chronic kidney disease (CKD) are lacking. This study evaluated the association between ePTFp and kidney-related outcomes, and the modifying effect of phosphate regulatory biomarkers in CKD patients. Methods: Patients were recruited at Nara Medical University between 2020 and 2022 and prospectively followed until the end of March 2024. The association between baseline ePTFp (urine phosphate/creatinine concentration × serum creatinine level × 3.33) and the risk of a 40% decline in estimated glomerular filtration rate (eGFR) or progression to kidney failure requiring replacement therapy (KFRT) was examined using a Cox proportional hazards model. Results: Among the 796 patients (median age, 71 years; 63.9% males; median eGFR, 38.5 mL/min/1.73 m2; and median ePTFp, 2.1 mg/dL), 199 reached the composite endpoint of a 40% decline in eGFR or initiation of KFRT during a median follow-up of 26.9 months. Restricted cubic spline analysis demonstrated that ePTFp exhibited an inflection point and subsequently increased beyond the upper limits of the serum levels of fibroblast growth factor 23 (25 pg/mL), intact parathyroid hormone (45.3 pg/mL), and phosphate (3.5 mg/dL). In contrast, ePTFp showed a consistent upward trend with decreasing levels of 1,25-dihydroxyvitamin D3. No significant association was observed between ePTFp and daily urinary phosphate excretion. Log-transformed ePTFp was independently and incrementally associated with an increased risk of kidney-related outcome (hazard ratio [95% confidence interval]: 1.66 [1.06–2.61]). Additionally, no interaction effect was observed in the subgroup analysis stratified by CKD-mineral and bone disorder markers. Conclusion: Compared with conventional markers, ePTFp is an early indicator of phosphate metabolism abnormalities and may serve as a reliable prognostic biomarker for adverse kidney outcomes in CKD patients. Funding: Private Foundation Support, Government Support – Non-U.S.