Abstract
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.
Highlights
Introduction aKlotho (a-KL) is a single-pass transmembrane protein [1,2] expressed in multiple tissues, but present at high levels in the kidney
During the progression of chronic kidney disease (CKD), the decline in renal a-KL levels was followed by reductions in 1,25VitD3 and increases in serum fibroblast growth factor 23 (FGF23) and intact parathyroid hormone (PTH), which became significant in stage 3
Multiple regression analysis clearly showed that renal dysfunction is the most important factor contributing to the reduction in renal a-KL expression in CKD patients
Summary
Klotho (a-KL) is a single-pass transmembrane protein [1,2] expressed in multiple tissues, but present at high levels in the kidney. It was originally described as a senescence-related protein because mice lacking functional a-KL protein develop a syndrome resembling human aging [1]. Recent studies have shown that serum FGF23 levels gradually increase during the progression of chronic kidney disease (CKD), whereas renal a-KL expression declines [8,9,10]. The specific cause of the elevation in circulating FGF23 seen in CKD patients remains unclear, but one potential candidate is loss of renal a-KL expression, since the resultant a-KL deficiency could make the kidney resistant to the action of FGF23. There have been no studies characterizing the relation between serum FGF23 levels and renal a-KL levels in CKD patients
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