Proteinuria and
hyperphosphatemia are risk factors for cardiovascular disease in patients with
chronic kidney disease (CKD). Although the interaction between
proteinuria and the serum
phosphate level is well established, the mechanistic link between the two, particularly the extent to which this interaction is mediated by
phosphate-regulating factors, remains poorly understood. In this study, we examined the association between
proteinuria and the serum
phosphate level, as well as potential mediators, including circulating
fibroblast growth factor (FGF23)/klotho, the 24-h urinary
phosphate excretion rate to glomerular filtration rate ratio (EP/GFR), and the 24-h tubular
phosphate reabsorption rate to GFR ratio (TRP/GFR). The analyses were performed with data from 1793 patients in whom 24-h urine
protein and
phosphate, serum
phosphate, FGF23, and klotho levels were measured simultaneously, obtained from the KoreaN cohort study for Outcome in patients With
Chronic Kidney Disease (KNOW-CKD). Multivariable linear regression and mediation analyses were performed. Total, direct, and indirect effects were also estimated. Patients with high serum
phosphate levels were found to be more likely to exhibit greater
proteinuria, higher FGF23 levels, and lower klotho levels. The 24-h EP/GFR increased and the 24-h TRP/GFR decreased with increasing
proteinuria and CKD progression. Simple mediation analyses showed that 15.4% and 67.9% of the relationship between
proteinuria and the serum
phosphate level were mediated by the FGF23/klotho ratio and 24-h EP/GFR, respectively. Together, these two factors accounted for 73.1% of the relationship between
serum markers. These findings suggest that
proteinuria increases the 24-h EP/GFR via the FGF23/klotho axis as a compensatory mechanism for the increased
phosphate burden well before the reduction in renal function is first seen.