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Circulating Klotho Associates With Cardiovascular Morbidity and Mortality During Hemodialysis
Christophe Marçais1, Delphine Maucort-Boulch2, Jocelyne Drai1
1University Lyon, UCBL, Service de Biochimie et Biologie Moléculaire, Centre Hospitalier Lyon Sud, CarMeN, CENS, F-69495 Pierre Bénite, France.
Insights
Maintaining adequate serum klotho levels (seKL) in hemodialysis patients is crucial for cardiovascular protection. Higher seKL is linked to reduced cardiovascular events and mortality over two years.
Area of Science:
- Gerontology
- Nephrology
- Cardiology
Background:
- The Klotho gene acts as an aging suppressor, with its deficiency linked to accelerated aging.
- Kidneys are the primary source of circulating klotho, and its levels decrease significantly in chronic kidney disease.
- Reduced renal klotho gene expression is observed in both animal models and human chronic kidney disease.
Purpose of the Study:
- To investigate the impact of low serum klotho (seKL) on cardiovascular morbidity and mortality in patients undergoing chronic dialysis.
- To assess whether preserved klotho function offers cardiovascular protection in hemodialysis patients.
Main Methods:
- Prospective cohort study (ARNOGENE) followed 238 hemodialysis patients for two years.
- Serum klotho levels (seKL) were measured and analyzed in relation to cardiovascular outcomes.
- Statistical adjustments were made for various clinical and biochemical parameters.
Main Results:
- Hemodialysis patients exhibited markedly reduced median seKL compared to controls.
- Patients with seKL above the first quartile (≥280 ng/L) showed significantly lower rates of combined cardiovascular events and death.
- This protective effect of higher seKL persisted after adjusting for multiple confounding factors.
Conclusions:
- Preserved serum klotho levels (seKL >280 ng/L) are associated with improved cardiovascular protection over two years in chronic hemodialysis patients.
- Klotho function may serve as a prognostic biomarker for cardiovascular disease in this population.
- Therapeutic strategies aimed at preserving or increasing klotho levels could be a target for cardiovascular disease management.
Background:
Klotho gene was identified as an aging suppressor. In animals, klotho overexpression extends life span, and defective klotho results in rapid aging and early death. The kidney is the main contributor to circulating klotho levels, and, during chronic kidney disease, renal klotho gene expression is drastically reduced in animals and humans as well.
Objective:
We aimed to determine the consequences of a serum klotho (seKL) defect on cardiovascular morbidity and mortality during chronic dialysis.
Design:
The ARNOGENE study was designed to prospectively follow a cohort of hemodialysis patients for 2 years without specific intervention. A total of 769 patients was recruited and followed from the end of 2008 until January 2011. A total of 238 patients was analyzed due to a technical sample conservation issue with other samples.
Results:
The median seKL was markedly reduced, 360.4 ng/L (interquartile range 176.5) as compared with nondialysis chronic kidney disease patients or healthy volunteers. Patients with a seKL above the first quartile (≥280 ng/L) had a significantly reduced occurrence of outcome combining cardiovascular events and cardiovascular death [odds ratio (OR) = 0.39; 0.19 to 0.78, P = 0.008] compared with patient with klotho <280 ng/L. This effect persisted (OR = 0.86; 0.76 to 0.99, P = 0.03) after adjustment on age, sex, diabetes, cardiac insufficiency, dialysis vintage, and serum hemoglobin, albumin, fibroblast growth factor-23, phosphate, and calcium.
Conclusions:
These results suggest that, during chronic hemodialysis, conservation of seKL >280 ng/L is associated with a better 2-year cardiovascular protection. Thus, a preserved klotho function supports cardiovascular protection and may represent a prognostic tool and therapeutic target for cardiovascular disease.