High Soluble Klotho Levels Linked to Lower CKD Prevalence in Adults With Diabetes, Hypertension

The findings suggest hypertension as a modifier in the relationship between sKlotho and CKD prevalence.

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New findings shed light on the relationship between serum soluble Klotho (sKlotho) and chronic kidney disease (CKD) in diabetes, the topic of a long-standing, controversial discussion.¹ Among individuals with diabetes and hypertension, those with higher levels of sKlotho, a protein known to protect kidney function, showed a significantly lower prevalence of CKD.

Previous studies have linked Klotho and hypertension; however, current treatments primarily focus on reducing blood pressure instead of addressing the underlying causes, as the mechanisms behind hypertension are not fully understood.²

This study aimed to explore the highly debated role of sKlotho in diabetic kidney disease and as it relates to hypertension.¹ “Our results confirmed a negative association between sKlotho levels and CKD prevalence in adults with [diabetes], which was observed only in participants with hypertension,” the authors wrote.

The study analyzed data from 3302 adults aged 40 and older with diabetes who participated in the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2016. Using multivariate logistic regression models stratified by hypertension status, they found that the prevalence of CKD was lower among individuals with both diabetes and hypertension who had high sKlotho levels (≥ 806 pg/mL), compared with those with low levels (< 806 pg/mL). The adjusted OR for CKD in this group was 0.54 (95% CI, 0.41-0.72; P < .001).

Critically, no such association between sKlotho and CKD was observed in those with diabetes but without hypertension. The researchers also found a statistically significant interaction between hypertension and sKlotho on both additive and multiplicative scales (0.65; 95% CI, 0.42-0.99), indicating a synergistic effect, where the combined presence of low sKlotho and hypertension posed a greater risk for CKD than either factor alone.

Among participants with diabetes and without hypertension, researchers observed a trend: individuals with very high sKlotho levels (> 1400 pg/mL) appeared to have a higher prevalence of CKD. Further analysis suggested that these individuals also had higher blood glucose and kidney function markers, potentially reflecting more intensive use of anti-diabetic medications, some of which are known to upregulate Klotho expression. However, the implications of this observation remain unclear and warrant further investigation.

The cross-sectional design limits the ability to draw causal inferences, and the researchers acknowledged that reverse causality and unmeasured confounding may be present. Furthermore, sKlotho levels and kidney function were measured at a single time point, which limits assessment of temporal relationships. The study population also only included US adults, which may restrict the generalizability of the findings to other regions or ethnic groups.

While the casualties of these associations demand further investigation, the authors concluded that the findings suggest hypertension as a modifier in the relationship between sKlotho and CKD prevalence, potentially explaining past inconsistencies in the literature.

References

1. Hong T, Lian Z, Zhang C, Zhang W, Ye Z. Hypertension modifies the association between serum Klotho and chronic kidney disease in US adults with diabetes: a cross-sectional study of the NHANES 2007-2016. Ren Fail. 2025;47(1):2498089. doi:10.1080/0886022X.2025.2498089

2. Kanbay M, Demiray A, Afsar B, et al. Role of Klotho in the development of essential hypertension. Hypertension. 2021;77(3):740-750. doi:10.1161/hypertensionaha.120.16635