Serum klotho is inversely associated with metabolic syndrome in chronic kidney disease: results from the KNOW-CKD study

Abstract

Background: Metabolic syndrome (MS) is prevalent in chronic kidney disease (CKD). Klotho, a protein linked to aging, is closely associated with CKD. Each component of MS and klotho has an association. However, little is known about the association between klotho and MS per se. We investigated the association between serum klotho levels and MS using baseline cross-sectional data obtained from a large Korean CKD cohort.

Methods: Of the 2238 subjects recruited in the KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD) between 2011 and 2016, 484 patients with missing data on serum klotho and extreme klotho values (values lower than the detectable range or > 6000 pg/mL) or with autosomal dominant polycystic kidney disease patients were excluded. The data of the remaining 1754 subjects were included in the present study. MS was defined using the revised National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP) III criteria. Serum klotho levels were measured using an enzyme-linked immunosorbent assay.

Results: Mean patient age was 54.9 ± 12.1 years and 1110 (63.3%) were male. The prevalence of MS among all study subjects was 63.7% (n = 1118). The median serum klotho level was 527 pg/mL (interquartile range [IQR]: 418-656 pg/mL). Serum klotho level was significantly lower in MS patients than patients without MS (Median [IQR]; 521 pg/mL [413, 651] vs. 541 pg/mL [427, 676], respectively; P = 0.012). After adjusting for age, sex, estimated glomerular filtration rate, and overt proteinuria, serum klotho was independently associated with MS (adjusted odds ratio [OR], 0.44; 95% confidence interval, 0.23-0.82; P = 0.010). Furthermore, the adjusted OR for MS was found to be significantly increased at serum klotho levels of < 518 pg/mL (receiver operating characteristic curve cut-off value).

Conclusions: Serum klotho was inversely associated with the presence of MS in patients with CKD.

Trial registration: This trial was registered on ClinicalTrials.gov on 26 June 2012 ( https://clinicaltrials.gov;NCT01630486 ).

Keywords: Chronic kidney disease; Klotho; Metabolic syndrome.

Fig. 1

Prevalence of the metabolic syndrome and components of metabolic syndrome in the study subjects. Sixty four percent of patients had MS. Of the components of MS, high blood pressure (95.8%) was the most common, followed by high fasting glucose (63.7%) and abdominal obesity (53.8%). MS, metabolic syndrome; HDL, high-density lipoprotein

Fig. 2

Prevalence of metabolic syndrome across CKD stages. The prevalence of MS was > 50% even for early stage CKD. The prevalence of MS was higher in advanced stages of CKD (P < 0.001). MS, metabolic syndrome

Fig. 3

Multivariable-adjusted odds ratios of metabolic syndrome according to levels of estimated glomerular filtration rate. An eGFR of 60 ml/min/1.73m², as a reference value of decreased renal function, was taken as the reference point (OR = 1.00). The adjusted OR of MS was significantly increased at eGFR levels of < 60 ml/min/1.73m². The model was adjusted for age, sex, eGFR, and overt proteinuria. The solid line represents the multivariable-adjusted ORs of MS according to levels of eGFR. The dashed lines indicate 95% confidence intervals. eGFR, estimated glomerular filtration rate; OR, odds ratio; MS, metabolic syndrome

Fig. 4

Serum klotho level according to metabolic syndrome and numbers of metabolic syndrome components. a Serum klotho was significantly lower in MS patients compared with patients without MS (median [interquartile range]; 521 pg/mL [413, 651] vs. 541 pg/mL [427, 676], respectively; P = 0.012). b Klotho levels tended to decrease as numbers of MS components increased (P = 0.038). MS, metabolic syndrome

Fig. 5

Serum klotho levels across CKD stages. Advanced CKD stages were associated with lower serum klotho levels (P < 0.001). CKD, chronic kidney disease

Fig. 6

Multivariable-adjusted odds ratio of metabolic syndrome according to levels of serum klotho. A serum klotho level of 518 pg/mL (ROC curve cut-off value) was taken as the reference point (OR = 1.00). The adjusted OR of MS was significantly increased at serum klotho levels of < 518 pg/mL. The model was adjusted for age, sex, eGFR, and overt proteinuria. The solid line represents the multivariable-adjusted ORs of MS according to levels of eGFR. The dashed lines indicate 95% confidence intervals. Overt proteinuria, 24-hour urine protein > 500 mg/day; ROC, receiver operating characteristic; eGFR, estimated glomerular filtration rate; OR, odds ratio; MS, metabolic syndrome