Renal α-Klotho (α-KL) plays a fundamental role as a co-receptor for fibroblast 
growth factor 23 (FGF23), a phosphaturic hormone and regulator of 1,25(OH)2 
vitamin D3 (1,25VitD3). Disruption of FGF23-α-KL signaling is thought to be an 
early hallmark of chronic kidney disease (CKD) involving reduced renal α-KL 
expression and a reciprocal rise in serum FGF23. It remains unclear, however, 
whether the rise in FGF23 is related to the loss of renal α-KL. We evaluated 
α-KL expression in renal biopsy samples and measured levels of several 
parameters of mineral metabolism, as well as soluble α-KL (sKL), in serum and 
urinary samples from CKD patients (n = 236). We found that although renal α-KL 
levels were significantly reduced and serum FGF23 levels were significantly 
elevated in early and intermediate CKD, serum phosphate levels remained within 
the normal range. Multiple regression analysis showed that the increases in 
FGF23 were significantly associated with reduced renal function and elevated 
serum phosphate, but were not associated with loss of renal α-KL. Moreover, 
despite falling renal α-KL levels, the increase in FGF23 enhanced urinary 
fractional excretion of phosphate and reduced serum 1,25VitD3 levels in early 
and intermediate CKD, though not in advanced CKD. Serum sKL levels also fell 
significantly over the course of CKD, and renal α-KL was a significant 
independent determinant of sKL. These results demonstrate that FGF23 levels rise 
to compensate for renal failure-related phosphate retention in early and 
intermediate CKD. This enables FGF23-α-KL signaling and a neutral phosphate 
balance to be maintained despite the reduction in α-KL. In advanced CKD, 
however, renal α-KL declines further. This disrupts FGF23 signaling, and serum 
phosphate levels significantly increase, stimulating greater FGF23 secretion. 
Our results also suggest the serum sKL concentration may be a useful marker of 
renal α-KL expression levels.