The inflection point: α-Klotho levels and the risk of all-cause mortality

Abstract

Purpose: The controversial nature of the association between α-Klotho and mortality risk in the general population warrants further investigation. This study aims to examine the correlation between circulating α-Klotho levels and the risk of all-cause mortality.

Methods: A sample size of 13,748 individuals from the NAHNES 2005-2016 cycles was included in this study. The effect of different α-Klotho levels (divided into quartiles) on survival was assessed using Kaplan-Meier (KM) curves. Cox proportional hazards models were used to analyze the linear relationship between log α-Klotho and the risk of all-cause mortality. Restricted cubic spline Cox proportional hazards regression model was used to analyze the non-linear relationship between log α-Klotho and risk of all-cause mortality. Threshold effect analysis was performed to determine the most favorable inflection point for log α-Klotho. Stratification and sensitivity analyses were performed to assess the robustness of the results.

Results: A total of 1,569 deaths were reported during the median follow-up period of 5.33 years (2.83-7.83 years). Among the log α-Klotho quartile groups, quartile 1 had the highest mortality rate compared to quartiles 2, 3, and 4. Multifactorial Cox regression analysis revealed a weak association between log α-Klotho and a 44% reduction in the risk of all-cause mortality (p=0.0473). We also found a U-shaped non-linear association between log α-Klotho and risk of all-cause mortality, with an optimal inflection point identified at 2.89 pg/mL. The stability of the U-shaped association between log α-Klotho and mortality risk was observed in various stratification and sensitivity analyses.

Conclusion: This study identified a U-shaped association between circulating α-Klotho levels and risk of all-cause mortality, with a notable inflection point at 2.89 pg/mL. Further investigation is warranted to fully elucidate the potential mechanisms underlying the association between α-Klotho and risk of all-cause mortality in the broader population.

Keywords: NHANES; U-shaped relationship; all-cause mortality; inflection point; α-Klotho.

Figure 1

KM curves to analyze outcomes of included study subjects. (A) Analysis based on α-Klotho quartiles; (B-D) Analysis based on duration of follow-up (<5, 5-10 and >10 years).

Figure 2

U-shaped non-linear relationship between log α-Klotho and mortality. RR: relative risk. (A) No variables were adjusted. (B) Adjusted for age, sex, ethnic, poverty income ratio, education. (C) Adjusted for Model 1+fasting blood glucose, hemoglobin A1c, serum uric acid, triglyceride, total cholesterol, high-density lipoprotein, low-density lipoprotein, urinary albumin-to-creatinine ratio, estimated glomerular filtration rate, body mass index, smoking, drinking, hypertension, diabetes, cardiovascular disease, chronic kidney disease. (D) Adjusted for Model 2+poverty income ratio dummy variable, fasting blood glucose dummy variable, hemoglobin A1c dummy variable, triglyceride dummy variable, high-density lipoprotein dummy variable, low-density lipoprotein dummy variable, urinary albumin-to-creatinine ratio dummy variable, estimated glomerular filtration rate dummy variable, body mass index dummy variable, hypertension dummy variable, diabetes mellitus dummy variable, cardiovascular disease dummy variable, chronic kidney disease dummy variable, smoking dummy variable, drinking dummy variable.

Figure 3

Non-linear relationship between log α-Klotho and mortality at different follow-up durations. RR: relative risk. (A) Association of log α-Klotho with mortality in less than 5 years, (B) Association of log α-Klotho with mortality over 5-10 years, (C) Association of log α-Klotho with mortality in >10 years. Adjusted for age, sex, ethnic, poverty income ratio, education, fasting blood glucose, hemoglobin A1c, serum uric acid, triglyceride, total cholesterol, high-density lipoprotein, low-density lipoprotein, urinary albumin-to-creatinine ratio, estimated glomerular filtration rate, body mass index, smoking, drinking, hypertension, diabetes, cardiovascular disease, chronic kidney disease, poverty income ratio dummy variable, fasting blood glucose dummy variable, hemoglobin A1c dummy variable, triglyceride dummy variable, high-density lipoprotein dummy variable, low-density lipoprotein dummy variable, urinary albumin-to-creatinine ratio dummy variable, estimated glomerular filtration rate dummy variable, body mass index dummy variable, hypertension dummy variable, diabetes mellitus dummy variable, cardiovascular disease dummy variable, chronic kidney disease dummy variable, smoking dummy variable, drinking dummy variable.