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Klotho variants and chronic hemodialysis mortality.

ABSTRACT: Patients with end-stage renal disease (ESRD) suffer exceptionally high mortality rates in their first year of chronic hemodialysis. Both vitamin D and fibroblast growth factor (FGF)-23 levels correlate with survival in these patients. Klotho is a protein in the vitamin D/FGF-23 signaling pathway that has been linked with accelerated aging and early mortality in animal models. We therefore hypothesized that genetic variation in the Klotho gene might be associated with survival in subjects with ESRD. We tested the association between 12 single nucleotide polymorphisms (SNPs) in the Klotho gene and mortality in a cohort of ESRD patients during their first year on hemodialysis (n = 1307 white and Asian). We found a significant association between the CC genotype of one tag SNP, rs577912, and increased risk for 1-yr mortality (RR, 1.76; 95% CI, 1.19-2.59; p = 0.003). This effect was even more marked among patients who were not treated with activated vitamin D supplementation (HR, 2.51; 95% CI, 1.18-5.34; p = 0.005). In lymphoblastoid cell lines derived from HapMap subjects, the CC genotype was associated with a 16-21% lower Klotho expression compared with the AA/AC genotype. Our data suggest that a specific Klotho variant (rs577912) is linked to survival in ESRD patients initiating chronic hemodialysis and that therapy with activated vitamin D may modify this risk.

SUBMITTER: Friedman DJ

PROVIDER: S-EPMC2765930 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Klotho variants and chronic hemodialysis mortality.

Friedman David J DJ Afkarian Maryam M Tamez Hector H Bhan Ishir I Isakova Tamara T Wolf Myles M Ankers Elizabeth E Ye Jun J Tonelli Marcello M Zoccali Carmine C Kuro-o Makoto M Moe Orson O Karumanchi S Ananth SA Thadhani Ravi R

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20091101 11

Patients with end-stage renal disease (ESRD) suffer exceptionally high mortality rates in their first year of chronic hemodialysis. Both vitamin D and fibroblast growth factor (FGF)-23 levels correlate with survival in these patients. Klotho is a protein in the vitamin D/FGF-23 signaling pathway that has been linked with accelerated aging and early mortality in animal models. We therefore hypothesized that genetic variation in the Klotho gene might be associated with survival in subjects with ES ...[more]

PMID: 19419323

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Project description:Rationale & objectivePatients with chronic kidney failure have markedly elevated fibroblast growth factor 23 (FGF-23) levels and decreased soluble Klotho levels. However, no studies have examined the effects of hemodialysis initiation on the levels of these hormones and other parameters of mineral metabolism.Study designProspective single-arm study.Setting & participants20 individuals with incident kidney failure initiating hemodialysis.ExposureInitiation of hemodialysis. Dose adjustments of phosphate binders and vitamin D receptor activators and use of calcimimetics, erythropoiesis-stimulating agents, and intravenous iron were prohibited.OutcomesChanges in serum levels of FGF-23, soluble Klotho, and other biochemical parameters of mineral metabolism, measured before and after each hemodialysis session, for a total of 4 sessions over 5 days.Analytical approachRepeated-measures analysis of variance.ResultsAt baseline, participants had 18-fold higher median FGF-23 levels and 1.6-fold lower mean soluble Klotho levels compared with age- and sex-matched healthy individuals. Initiation of hemodialysis led to progressive reductions in serum phosphorus, intact parathyroid hormone, and FGF-23 levels, with dialysis-related fluctuations. No reductions were observed in levels of α1-microglobulin, which has molecular weight comparable to FGF-23. The magnitude of the FGF-23 level reductions was strongly associated with concomitant changes in serum phosphorus levels but not with the changes in intact parathyroid hormone levels. Soluble Klotho levels did not change after the initiation of hemodialysis.LimitationsSingle-arm design, small sample size, short follow-up period.ConclusionsInitiation of hemodialysis in patients with chronic kidney failure led to progressive reductions in FGF-23 levels in association with reductions in serum phosphorus levels. These results suggest that phosphorus is a strong inducer of FGF-23 production and that regulation of FGF-23 production is a rapid process.

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Klotho variants and chronic hemodialysis mortality.

Publications

Klotho variants and chronic hemodialysis mortality.

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