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Reduced renal ?-Klotho expression in CKD patients and its effect on renal phosphate handling and vitamin D metabolism.

ABSTRACT: Renal ?-Klotho (?-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-?-KL signaling is thought to be an early hallmark of chronic kidney disease (CKD) involving reduced renal ?-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 ?-KL. We evaluated ?-KL expression in renal biopsy samples and measured levels of several parameters of mineral metabolism, as well as soluble ?-KL (sKL), in serum and urinary samples from CKD patients (n?=?236). We found that although renal ?-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 ?-KL. Moreover, despite falling renal ?-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 ?-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-?-KL signaling and a neutral phosphate balance to be maintained despite the reduction in ?-KL. In advanced CKD, however, renal ?-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 ?-KL expression levels.

SUBMITTER: Sakan H

PROVIDER: S-EPMC3900516 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Reduced renal α-Klotho expression in CKD patients and its effect on renal phosphate handling and vitamin D metabolism.

Sakan Hirokazu H Nakatani Kimihiko K Asai Osamu O Imura Akihiro A Tanaka Tomohiro T Yoshimoto Shuhei S Iwamoto Noriyuki N Kurumatani Norio N Iwano Masayuki M Nabeshima Yo-Ichi Y Konishi Noboru N Saito Yoshihiko Y

PloS one 20140123 1

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 sam ...[more]

PMID: 24466013

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Project description:Excess fibroblast growth factor 23 (FGF23), excess PTH, and an increase in extracellular calcium cause hypophosphatemia by lowering the maximum renal phosphate reabsorption threshold (TmP/GFR). We recently reported two cases of X-linked hypophosphatemia (XLH) with severe tertiary hyperparathyroidism who had normalization of TmP/GFR upon being rendered hypoparathyroid following total parathyroidectomy, despite marked excess in both C-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23). We explored the effects of FGF23, PTH, and calcium on TmP/GFR in a cross-sectional study (n = 74) across a spectrum of clinical cases with abnormalities in TmP/GFR, PTH, and FGF23. This comprised three groups: FGF23-dependent hypophosphatemia (n = 27), hypoparathyroidism (HOPT; n = 17), and chronic kidney disease (n = 30). Measurements included TmP/GFR, cFGF23, PTH, ionized calcium, vitamin D metabolites, and bone turnover markers. The combined effect of cFGF23, PTH, and ionized calcium on TmP/GFR was modeled using hierarchical multiple regression and was probed by moderation analysis with PROCESS. Modeling analysis showed independent effects on TmP/GFR by cFGF23, PTH, and ionized calcium in conjunction with a weak but significant effect of the interaction term for PTH and FGF23; probing showed that the effect was most prominent during PTH deficiency. Teriparatide 20 μg daily was self-administered for 28 days by one case of X-linked hypophosphatemia with hypoparathyroidism (XLH-HOPT) to assess the response of TmP/GFR, cFGF23, iFGF23, nephrogenous cyclic adenosine monophosphate (NcAMP), vitamin D metabolites, and bone turnover markers. After 28 days, TmP/GFR was lowered from 1.10 mmol/L to 0.48 mmol/L; this was accompanied by increases in NcAMP, ionized calcium, and bone turnover markers. In conclusion, the effect of FGF23 excess on TmP/GFR is altered by PTH such that the effect is ameliorated by hypoparathyroidism and the effect is augmented by hyperparathyroidism. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Project description:Background: Recent literature suggests that α-Klotho, a widely recognized anti-aging protein, is involved in longevity as well as in many diseases, including Alzheimer's disease, and depression. Although the Klotho gene encodes α-Klotho, a single transmembrane protein with intracellular and extracellular domains, the relationship between Klotho gene polymorphism and circulating α-Klotho levels in patients with major depressive disorder (MDD) is not clear. Methods: A total of 144 MDD patients and 112 age-matched healthy controls were included in this study. The Klotho genetic polymorphisms (rs9536314, rs9527025, and rs9315202) and plasma α-Klotho levels were measured by PCR and ELISA, respectively. The severity of depressive symptoms was estimated using the Hamilton Depression Scale (HAMD). Results: We found a significantly lower level of plasma α-Klotho in the MDD patients than in controls. Among them, only elderly MDD patients (first episode) showed significantly lower α-Klotho levels than the age-matched controls, while elderly recurrent and young MDD patients showed no difference in plasma α-Klotho levels from age-matched controls. The young MDD group showed a significantly earlier onset age, higher plasma α-Klotho levels, and lower HAMD scores than those in the elderly MDD group. While the plasma α-Klotho levels were higher in rs9315202 T alleles carrier regardless age or sex, the rs9315202 T allele was negatively correlated with disease severity only in the elderly MDD patients. Conclusion: The results of our study showed that only elderly MDD patients showed a decrease in plasma α-Klotho levels along with an increase in disease severity as well as an association with the number of rs9315202 T alleles, and not young MDD patients compared to age-matched controls. Our data suggest that circulating α-Klotho levels combined with Klotho genetic polymorphisms are important in elderly MDD patients, particularly carriers of the Klotho gene rs9315202 T allele.

Dataset Information

Reduced renal ?-Klotho expression in CKD patients and its effect on renal phosphate handling and vitamin D metabolism.

Publications

Reduced renal α-Klotho expression in CKD patients and its effect on renal phosphate handling and vitamin D metabolism.

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