Reduced Renal α-Klotho Expression in CKD Patients and Its Effect on Renal Phosphate Handling and Vitamin D Metabolism

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.

Vitamin D Attenuates Endothelial Dysfunction in Uremic Rats and Maintains Human Endothelial Stability

“…Indeed, α‐Klotho deficiency in mice leads to a limited vasodilatory response and increased permeability in the endothelial cells among other vascular complications also observed in CKD patients 22, 23, 24, 41. As reported previously in other uremic in vivo models20, 21 and CKD patients,42, 43 we confirmed that impaired kidney function induced downregulation of mRNA and α‐Klotho protein levels in kidney tissue accompanied by lower serum concentrations. However, it was unexpected that neither vitamin D deficiency nor paricalcitol supplementation affected α‐Klotho in the kidney tissue or its concentration in serum.…”

Renal Production, Uptake, and Handling of Circulating αKlotho

“…aKlotho is found in urine and serum of rodents and humans 2,20,42,56 ; and the kidney has the highest abundance of aKlotho compared with other organs. Clinical and experimental animal studies showed low renal tubular aKlotho expression in both acute kidney injury and CKD 10,40,42,43,[56][57][58][59][60][61][62] and low circulating aKlotho levels in kidney diseases of a variety of etiologies in animals 42,43,56,62 and humans. 32,44,61,63 These data suggest that the kidney contributes to circulating aKlotho.…”

Decreased Conversion of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3 Following Cholecalciferol Therapy in Patients with CKD

“…This finding is particularly interesting given the proposed action of FGF23 to stimulate renal 24-hydroxylase activity, which contradicts our findings. On the basis of published data suggesting renal a-Klotho, an obligate FGF23 coreceptor, is markedly reduced in CKD (38), it is plausible that the inability of FGF23 to stimulate 24-hydroxylase activity in this setting results from resistance to FGF23. Because FGF23 concentrations are higher in more advanced stages of CKD, it is possible that the inverse relationship between FGF23 and 24,25(OH) 2 D 3 changes simply represents declining 24-hydroxylase function with nephron loss.…”