Association between Soluble Klotho and Change in Kidney Function: The Health Aging and Body Composition Study

Abstract

CKD appears to be a condition of soluble klotho deficiency. Despite known associations between low soluble klotho levels and conditions that promote kidney damage, such as oxidative stress and fibrosis, little information exists regarding the longitudinal association between soluble klotho levels and change in kidney function. We assayed serum soluble -klotho in 2496 participants within the Health Aging and Body Composition study, a cohort of older adults. The associations between soluble klotho levels and decline in kidney function (relative decline: eGFR decline ≥30%; absolute decline: eGFR decline>3 ml/min per year) and incident CKD (incident eGFR <60 ml/min per 1.73 m and >1 ml/min per year decline) were evaluated. We adjusted models for demographics, baseline eGFR, urine albumin-to-creatinine ratio, comorbidity, and measures of mineral metabolism. Among participants, the mean (SD) age was 75 (3) years, 52% were women, and 38% were black. Median (25th, 75th percentiles) klotho level was 630 (477, 817) pg/ml. In fully adjusted models, each two-fold higher level of klotho associated with lower odds of decline in kidney function (odds ratio, 0.78 [95% confidence interval, 0.66 to 0.93] for 30% decline in eGFR, and 0.85 [95% confidence interval, 0.73 to 0.98] for >3 ml/min per year decline in eGFR), but not of incident CKD (incident rate ratio, 0.90 [95% confidence interval, 0.78 to 1.04]). Overall, a higher soluble klotho level independently associated with a lower risk of decline in kidney function. Future studies should attempt to replicate these results in other cohorts and evaluate the underlying mechanism.

Tubular Cell Senescence in the Donated Kidney Predicts Allograft Function, but Not Donor Remnant Kidney Function, in Living Donor Kidney Transplantation

“…Although a direct association between the plasma level of soluble αKlotho and tubular expression of αKlotho protein was not clearly determined, higher expression of soluble αKlotho is associated with less pathological evidence of aging, such as kidney fibrosis and systemic markers of oxidative stress [34, 35], which indicated the kidney protective effect of αKlotho [36]. In clinical reports, decreases in plasma levels of soluble αKlotho were independently associated with arterial stiffness [37], early chronic kidney disease [38], and a higher risk of decline in kidney function [39] in a non-chronic kidney disease population. These reports indicate that the plasma level of soluble αKlotho is a good biomarker for tubular cell senescence, even in living kidney donors who have sufficient kidney function.…”

Diabetic Nephropathy from RAAS to Autophagy: The Era for New Players

“…It is likely that Klotho may exert a multitude of actions to mitigate the activation of intrarenal RAS as well as systemic aldosterone production. Overall, strong evidence demonstrates the suppression of renal Klotho expression in diabetic renal disease, and more vigorous functional studies are needed to define the renoprotective action of this antiaging protein as well as its relationship with intrarenal RAS [30][31][32][33][34][35].…”

Protective factors as biomarkers and targets for prevention and treatment of diabetic nephropathy: From current human evidence to future possibilities

“…It has been shown that Klotho deficiency turns the kidney prone to damage from oxidative stress, ischemia and inflammation, whereas its supplementation (in acute as well as chronic settings) attenuates fibrosis-related kidney diseases 30,31 . Circulating Klotho is decreased in mouse models of diabetes and in patients in early stages of CKD, even in the absence of GFR loss, and it could be further related to a higher risk of eGFR decline 32,33 . In the most recent meta-analysis that considered eight prospective studies (although just two studies were carried out on diabetes 34,35 , it was found that decreased Klotho levels were associated with increased adverse kidney outcomes, which indicated that Klotho could be a prognostic biomarker for patients with CKD 36 .…”