Soluble klotho and mortality: The Ludwigshafen Risk and Cardiovascular Health Study

Brandenburg, Vincent; Kleber, Marcus E.; Vervloet, Marc G.; Larsson, Tobias E.; Tomaschitz, Andreas; Pilz, Stefan; Stojaković, Tatjana; Delgado, Graciela; Grammer, Tanja B.; Marx, Nikolaus; März, Winfried; Scharnagl, Hubert

doi:10.1016/j.atherosclerosis.2015.08.017

Cited by 38 publications

(31 citation statements)

References 31 publications

(30 reference statements)

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“…Conflicting results have been published on the protective effect of soluble Klotho on cardiovascular events in the general population [ 44 , 45 ]. Notably, while the prevalence of Klotho deficiency in our CKD-T population was low (12%) in comparison to the prevalence of FGF23 levels of ≥95th percentile (42%), both low Klotho levels and high FGF23 levels were determinants for worse cardiac diastolic function.…”

Section: Discussionmentioning

confidence: 99%

The FGF23–Klotho axis and cardiac tissue Doppler imaging in pediatric chronic kidney disease—a prospective cohort study

et al. 2017

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BackgroundChronic kidney disease-associated mineral bone disorder (CKD-MBD) is common in pediatric kidney disease patients and a risk factor for future cardiovascular disease (CVD). Fibroblast growth factor-23 (FGF23) and Klotho are novel key players in CKD-MBD, and has been suggested to be involved in the development of CVD.MethodsThis prospective cohort study included 74 pediatric patients; 31 with CKD (age range 0.8–18.8 years, glomerular filtration rate (GFR) range 9–68 mL/min/1.73 m2) and 43 transplanted patients (CKD-T; age range 3.3–17.7 years, GFR range 10–99 mL/min/1.73 m2) examined annually for 3 years. We assessed longitudinal patterns and predictors of FGF23 and soluble Klotho, as well as associations to cardiac remodeling and function using echocardiographic pulse wave Doppler (PWD) and color-coded tissue Doppler imaging (cc-TDI).ResultsThe prevalence of high FGF23 levels (≥95th percentile) was 60% in CKD and 42% in CKD-T patients, despite a low prevalence of hyperphosphatemia and normal Klotho levels. Low GFR at baseline was a predictor for high mean log FGF23 during follow-up in CKD and CKD-T patients (β = −0.2, p < 0.001). A high log FGF23 z-score longitudinally was borderline significantly associated with elevated left ventricular mass index (LVMI) in CKD patients (β = 1.8, p = 0.06). In addition, high log FGF23 (β = −0.43, p = 0.01) and low log Klotho (β = 0.44, p = 0.006) over time were associated with a worse left ventricular diastolic function (cc-TDI e′/a′) in CKD-T patients.ConclusionsIn pediatric CKD and CKD-T patients, the FGF23 level increase and Klotho level decrease with progressing renal failure, despite well-controlled phosphate levels. Following adjustments, both high FGF23 and low Klotho levels were strongly associated with a worse left ventricular diastolic function longitudinally. The potential role of FGF23 and Klotho in cardiac morbidity in pediatric CKD requires further investigation.Electronic supplementary materialThe online version of this article (doi:10.1007/s00467-017-3766-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The FGF23–Klotho axis and cardiac tissue Doppler imaging in pediatric chronic kidney disease—a prospective cohort study

et al. 2017

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“…In the heart, expression of Klotho is limited to the sinoatrial node 20 . Although a protective role of soluble Klotho in the development of LVH has been reported in animal models 21 , clinical studies failed to confirm an association between soluble Klotho and cardiovascular mortality in patients with normal renal function 22 . Elevated serum FGF23 levels were found to be strongly associated with LVH in patients with reduced kidney function 4 , 5 .…”

Section: Introductionmentioning

confidence: 99%

Genetic Ablation of Fgf23 or Klotho Does not Modulate Experimental Heart Hypertrophy Induced by Pressure Overload

Slavić

Ford

Modert

et al. 2017

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Left ventricular hypertrophy (LVH) ultimately leads to heart failure in conditions of increased cardiac pre- or afterload. The bone-derived phosphaturic and sodium-conserving hormone fibroblast growth factor-23 (FGF23) and its co-receptor Klotho have been implicated in the development of uremic LVH. Using transverse aortic constriction (TAC) in gene-targeted mouse models, we examine the role of Fgf23 and Klotho in cardiac hypertrophy and dysfunction induced by pressure overload. TAC profoundly increases serum intact Fgf23 due to increased cardiac and bony Fgf23 transcription and downregulation of Fgf23 cleavage. Aldosterone receptor blocker spironolactone normalizes serum intact Fgf23 levels after TAC by reducing bony Fgf23 transcription. Notably, genetic Fgf23 or Klotho deficiency does not influence TAC-induced hypertrophic remodelling, LV functional impairment, or LV fibrosis. Despite the profound, aldosterone-mediated increase in circulating intact Fgf23 after TAC, our data do not support an essential role of Fgf23 or Klotho in the pathophysiology of pressure overload-induced cardiac hypertrophy.

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“…In hemodialysis patients, low klotho levels were associated with CV events, independently from other CKD-MBD factors [115]. Analysis of the LURIC (Ludwigshafen Risk and Cardiovascular Health) study did not show any additional predictive power of CV and mortality risk in patients with normal kidney function [116]. On the contrary, in patients with CKD, as presented by the KNOW-CKD study, serum klotho was shown to be an independent biomarker of a left ventricular mass index, but not of arterial stiffness [117].…”

Section: Role Of Klothomentioning

confidence: 95%

Should We Consider the Cardiovascular System While Evaluating CKD-MBD?

Rroji

Figurek

Spasovski³

2020

Toxins

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Cardiovascular (CV) disease is highly prevalent in the population with chronic kidney disease (CKD), where the risk of CV death in early stages far exceeds the risk of progression to dialysis. The presence of chronic kidney disease-mineral and bone disorder (CKD-MBD) has shown a strong correlation with CV events and mortality. As a non-atheromatous process, it could be partially explained why standard CV disease-modifying drugs do not provide such an impact on CV mortality in CKD as observed in the general population. We summarize the potential association of CV comorbidities with the older (parathyroid hormone, phosphate) and newer (FGF23, Klotho, sclerostin) CKD-MBD biomarkers.

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Soluble klotho and mortality: The Ludwigshafen Risk and Cardiovascular Health Study

Cited by 38 publications

References 31 publications

The FGF23–Klotho axis and cardiac tissue Doppler imaging in pediatric chronic kidney disease—a prospective cohort study

The FGF23–Klotho axis and cardiac tissue Doppler imaging in pediatric chronic kidney disease—a prospective cohort study

Genetic Ablation of Fgf23 or Klotho Does not Modulate Experimental Heart Hypertrophy Induced by Pressure Overload

Should We Consider the Cardiovascular System While Evaluating CKD-MBD?

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