Soluble α‑Klotho Levels, Glycemic Control And Renal Function in US Adults With Type 2 Diabetes Ⅱ
Nov 21, 2023
Discussion
This is to our knowledge the frst study evaluating determinants of s-Klotho concentrations in a large, unselected sample of patients with T2D from the general population. Our main findings are that s-Klotho levels are significantly higher in patients with preserved kidney function and worse glycemic control. Both relationships were robust in both men and women and after adjustment for potential confounders.
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Several smaller studies investigated the relationship between s-Klotho levels and eGFR, demonstrating lower circulating levels being associated with worsening kidney function, particularly in patients on hemodialysis. Our study expands on these results by focusing on the largest population to date of patients with T2D with and without CKD and by demonstrating that reduced eGFR, and not albuminuria is a signifcant determinant. This was evident by the lack of difference in s-Klotho concentrations between patients with albuminuric and non-albuminuric CKD phenotypes. While both phenotypes are associated with increased mortality rates in patients with T2D [19], we may speculate that s-Klotho concentrations might not capture glomerular disease leading to albumin excretion, but rather be a marker of the number of functional nephrons and therefore be more strictly related to eGFR. Additional studies are needed to evaluate whether low s-Klotho may be considered also a risk factor, and not only a marker, of renal impairment, as recently suggested by a longitudinal study performed on older adults [6].
The second association, related to higher s-Klotho levels being present in patients with worse glycemic control, independently of kidney function, is a novel finding. The association was robust in both men and women, across groups of eGFR and after adjustment for age, sex, race ethnicity and CVD. Since Klotho is reported as an anti-aging gene and T2D has been considered by some as a condition of accelerated senescence, one would expect lower levels in patients with worse diabetes control. This unexpected finding might be related to the effects of glycosuria increasing metabolic demands in the proximal and distal kidney tubules, which in turn might lead to increased Klotho expression and/or cleavage resulting in higher serum concentrations. It should be noted that a previous study showed that exposure to high glucose levels did not alter Klotho expression in human-isolated tubular epithelial cells [12]. It is nonetheless possible that a different response might be elicited in the intact nephron, based on potential paracrine and endocrine regulators.
The lack of association between s-Klotho and CVD is in line with a previous study by Zhang et al. in patients with T2D [20]. The authors did not identify signifcant relationships between micro- and macro-vascular diabetes complications and s-Klotho concentrations, with the exception of diabetic nephropathy.
Our study has several strengths. It is the largest study to date performed in an unselected sample of US adults with T2D, including both sexes and patients of different ethnic backgrounds. The high number of patients included yielded high statistical power to perform subgroup and sensitivity analyses and evaluate the impact of several predictors in multivariable models. Being based on NHANES data, our results have a high degree of external validity as the purpose of the survey is to be representative of the overall US population. Finally, the acquisition of clinical, laboratory, and anthropometric data was standardized and homogenous.
The present study also has some limitations that need to be acknowledged. First, its cross-sectional design does not allow causal inference to be demonstrated. On this aspect, future longitudinal investigations might shed light on the potential ability of s-Klotho to predict clinically relevant outcomes in patients with T2D. In fact, given that s-klotho levels have been shown to be associated with several variables, it is difficult to confer a clear biological meaning to our observation.
Second, concern has been raised as to the accuracy of the ELISA kit commercially available for s-Klotho measurement [21, 22]. Although the assay used in the present study might be less specific compared with highly labor-intensive immunoprecipitant immune blot assay methods [23], our results confirm previous findings on the association between s-Klotho and CKD. Moreover, it could be hypothesized that inaccuracy in the assay might lead to bias results toward the null, rather than producing a positive finding. Third, the assessment of kidney function was performed by the CKD EPI equation and not by more accurate techniques such as creatinine clearance or the gold standard inulin clearance; nevertheless, equations based on serum creatinine are well-suited for large epidemiological studies. Fourth, as data for the current study were obtained before 2015, the proportion of patients treated with drugs now representing the worldwide frst choice in treating T2D (i.e., glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter 2 inhibitors) is very limited. Given that these agents might impact s-klotho levels, results obtained in the current study might not be applied to patients treated with these novel agents.
Conclusions
In conclusion, in this large population-based cross-sectional study including 2989 patients with T2D, serum levels of s-Klotho are positively associated with eGFR and HbA1c levels. On the other hand, no signifcant role was identified for obesity and CVD. Additional studies elucidating the mechanisms explaining the effect of worse glycemic control on s-Klotho concentration and exploring its predictive ability of clinically meaningful events are needed.
References
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