Klotho and Mortality in Chronic Kidney Disease: Actor, Risk Factor, or Predictor? (2024)

In this issue of the American Journal of Nephrology, Han et al. [1] provided strong evidence of the association between a low soluble α-Klotho concentration and increased all-cause mortality in a large cohort of 2,456 adult patients with chronic kidney disease (CKD) stages 1–5 from the National Health and Nutrition Examination Survey (NHANES).

CKD, characterized by a gradual and irreversible loss of kidney function, stands as a global health challenge that quietly weaves its way through populations worldwide. This condition affects >10% of the general population, amounting to >800 million individuals [2, 3]. The prevalence of CKD varies between regions and populations, with a higher incidence observed in low- and middle-income countries [2, 4]. Epidemiological studies reveal a complex interplay of factors contributing to the onset and progression of CKD, including age, genetics, lifestyle, and the increasing prevalence of conditions such as diabetes and hypertension [3].

Leading to a wide range of complications, including cardiovascular disease and end-stage renal disease, CKD has emerged as one of the leading causes of mortality. The 2013 GBD report showed that although relative mortality rates have declined for most communicable and noncommunicable diseases, CKD (all stages and including patients on dialysis) was one of the few conditions to show an increase since 1990. In 2017, CKD became the 12th leading cause of death and is projected to become the 5th leading cause of years of life lost worldwide by 2040 [5]. While this was not primarily evaluated by Han et al. [1], the outstanding cause of death in CKD patients is cardiovascular disease, accounting for 50% of all deaths in stage 4 and 5 CKD patients. In total, deaths due to CKD and cardiovascular disease deaths attributable to impaired kidney function accounted for 4.6% of global mortality in 2017 [4]. This increased mortality rate highlights the need for effective biomarkers to better identify and stratify patients at highest risk for CKD-associated mortality, who might maximally benefit from improved surveillance and early preventive therapies.

Klotho, initially identified for its antiaging properties, is now recognized for its crucial role in maintaining renal and systemic homeostasis. Discovered in 1997 by Dr. Makoto Kuro-o, Klotho was identified in a strain of mice that exhibited premature aging, multiple organ degeneration or failure, marked changes in mineral homeostasis, and shortened lifespan. Subsequent research has revealed its multiple functions, which extend beyond a mere marker of aging to a direct and indirect key regulator of diverse biological processes in multiple organs and tissues [6, 7]. Primarily expressed in the kidney and brain, Klotho exists in both membrane-bound and soluble forms. In the kidney, the membrane-bound Klotho functions as a co-receptor for fibroblast growth factor 23 (FGF23), regulating phosphate excretion and 1,25-dihydroxyvitamin D3 activation. The extracellular domain of transmembrane Klotho can be cleaved by proteases and released from the kidney into the circulation as soluble Klotho. Soluble Klotho acts as an endocrine or paracrine factor with pleiotropic effects on many organs, including the kidney, bone, brain, heart, or lung.

Preclinical data on Klotho have extensively demonstrated its protective role on the kidney. Klotho inhibits cell senescence, apoptosis, oxidative stress, and fibrosis and promotes autophagy, endothelial function, and mineral homeostasis. Soluble Klotho is decreased in animals and humans with CKD [6]. In addition, Klotho-deficient mice develop left ventricular hypertrophy, cardiac fibrosis, and extensive arterial calcification, all of which contribute to the elevated mortality observed in CKD populations. This clear implication of Klotho in the pathophysiology of kidney disease has stimulated interest in its translational value in clinical nephrology, but with limited definitive progress.

The use of Klotho as a potential diagnostic or prognostic biomarker of CKD and CKD-associated complications is not new. Several recent reviews have described conflicting results regarding the association between low serum Klotho concentrations and decline in renal function, cardiovascular events, and mortality in CKD patients [8]. The controversy stems from the fact that these associations have only been investigated in small observational studies, that Klotho is unstable during sample freeze/thaw cycles, and that commercially available assays for measuring circulating soluble Klotho lack standardization, performance, and overall reproducibility [8]. Interestingly, the study by Han et al. [1] may help us move beyond this status quo.

From a nationally representative population of 50,588 adults surveyed by NHANES in the USA between 2007 and 2016, Han et al. [1] selected 12,006 individuals with complete demographic and clinical data, as well as no exclusion criteria (e.g., pregnancy or malignancy). Of these, 2,456 (20%) had CKD, as defined by reduced estimated glomerular filtration rate (eGFR) (<60 mL/min/1.73 m²) or urinary albumin-to-creatinine ratio ≥30 mg/g. Patients with CKD were predominantly women (51.5%), had a median age of 62 years, and the majority had early-stage CKD (50% of CKD stage 1 and 2). Mortality was 22% over a median follow-up period of 7 years, ranging from 11% in patients with CKD stage 1–40% in patients with CKD stage 4 and 5. The concentration of soluble Klotho was measured in pristine serum samples from the CKD patients using a commercially available enzyme-linked immunosorbent assay. Although potential technical limitations remain, the enzyme-linked immunosorbent assay kit used in the NHANES study was extensively validated to ensure the most accurate results possible, including, but not limited to, assessment of assay linearity, intra- and inter-assay accuracies, and determination of healthy reference ranges. Patients with lower serum Klotho concentrations were older, more often hypertensive, and had a lower eGFR. Despite some inconsistencies in the literature, this latter result is in accordance with most clinical studies describing a correlation between low soluble Klotho levels and decline in renal function [6, 8]. Klotho is known to improve bone mineral disorder in CKD by regulating phosphaturia and thus blood phosphate accumulation and by inhibiting PTH and active 1,25-dihydroxyvitamin D3 production [6]. In this study [1], serum Klotho was not associated with blood phosphate. Information on PTH and 1,25-dihydroxyvitamin D3 concentrations was missing in the NHANES data.

The relationship between Klotho levels and death has also been debated [7, 8]. In this study, Han et al. [1] clearly demonstrated that in CKD patients with Klotho concentrations <760 pg/mL, higher serum Klotho was associated with a reduced risk of death, with an overall hazard ratio of 0.86 (per Klotho increase of 100 pg/mL; 95% confidence interval: 0.78, 0.94). Interestingly, this association persisted after adjustment for a number of clinical and demographic covariates but was lost in CKD patients with Klotho levels >760 pg/mL. The relationship between Klotho and mortality in CKD patients is therefore not linear but L-shaped, with an inflective point at 760 pg/mL. This was nicely interpreted by the authors who concluded “So it’s not just about having lots of Klotho; it’s about having the right amount” [1].

Despite these compelling results, some caveats may be worth debating. First, elevated FGF23 has been shown to be an independent risk factor for mortality in dialysis and non-dialysis patients [7]. Therefore, as discussed by the authors, the lack of information on FGF23 levels in the NHANES data prevented adjustment for an important potential confounding factor. Second, serum Klotho levels are known to be associated with CKD progression as defined by eGFR decline or renal replacement therapy [8]. Furthermore, while patients with CKD stage 3 and 4 have a two- to threefold increased risk of cardiovascular mortality, this risk further increases up to 20-fold in patients on dialysis [3]. However, the Han et al. [1] study did not specify whether patients on dialysis at baseline were included or whether initiation of dialysis or kidney transplantation before death was considered a concurrent event, all of which could confound the observed association between Klotho and mortality over a long follow-up period. Finally, although the results presented by Han et al. [1] clearly demonstrated the association between Klotho and mortality in patients with CKD, the authors did not investigate its predictive value as a biomarker. Further studies are warranted to move beyond the role of Klotho as a risk factor to its value as a predictor. Indeed, as highlighted by the authors, there is an urgent need to identify biomarkers of poor prognosis in CKD to improve the clinical management of these patients.

In conclusion, the convincing results of Han et al. [1] need to be validated in additional prospective cohorts in pre-dialysis and dialysis patients with further adjustment for important confounders such as FGF23. The question remains whether serum Klotho can be defined as a biomarker for CKD-associated mortality. Nevertheless, this study may be an exciting step toward improving current clinical management to identify patients with CKD at high risk for future adverse outcomes.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

No funding was received.

Author Contributions

A.P.-G., L.F., J.-P.S., and J.K. conceived and wrote the article.

Funding Statement

No funding was received.

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