The effect of interactions between proteinuria, activity of fibroblast growth factor 23 and serum phosphate on renal progression in patients with chronic kidney disease: a result from the KoreaN cohort study for Outcome in patients With Chronic Kidney Disease study

Background. Recent experimental study reported that proteinuria increases serum phosphate by decreasing biologic activity of fibroblast growth factor 23 (FGF-23). We examined this relationship in a large chronic kidney disease (CKD) cohort and evaluated the combined effect of proteinuria, FGF-23 activity and serum phosphate on CKD progression. Methods. The activity of FGF-23, measured by the fractional excretion of phosphate (FEP)/FGF-23 ratio, was compared according to the degree of proteinuria in 1909 patients with CKD. Primary outcome was CKD progression defined as >= 50% decline of estimated glomerular filtration rate, doubling of serum creatinine and start of dialysis. Results. There was a negative relationship between 24-h urine protein (24-h UP) and FEP/FGF-23 ratio (gamma -0.07; P=0.005). In addition, after matching variables associated with serum phosphate, patients with more proteinuria had higher serum phosphate (P<0.001) and FGF-23 (P=0.012), and lower FEP/FGF-23 ratio (P=0.007) compared with those with less proteinuria. In the matched cohort, low FEP/FGF-23 ratio was an independent risk factor for CKD progression (hazard ratio 0.87 per 1 log increase; 95% confidence interval 0.79-0.95; P=0.002), and there was significant interaction between 24-h UP and FEP/FGF-23 ratio (P=0.039). Furthermore, 24-h UP and serum phosphate also had a significant interaction on CKD progression (P<0.001). Conclusions. Proteinuria is associated with decreased biologic activity of FGF-23 and increased serum phosphate. Furthermore, diminished activity of FGF23 is an independent risk factor for renal progression in proteinuric CKD patients.