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The role of klotho in chronic kidney disease.

ABSTRACT: Chronic kidney disease (CKD) is an inherently systemic disease that refers to a long-term loss of kidney function. The progression of CKD has repercussions for other organs, leading to many kinds of extrarenal complications. Intensive studies are now being undertaken to reveal the risk factors and pathophysiological mechanism of this disease. During the past 20 years, increasing evidence from clinical and basic studies has indicated that klotho, which was initially known as an anti-aging gene and is mainly expressed in the kidney, is significantly correlated with the development and progression of CKD and its complications. Here, we discuss in detail the role and pathophysiological implications of klotho in ion disorders, the inflammation response, vascular calcification, mineral bone disorders, and renal fibrosis in CKD. Based on the pathogenic mechanism of klotho deficiency and klotho decline in urine early in CKD stage 2 and even earlier in CKD stage 1, it is not difficult to understand that soluble klotho can serve as an early and sensitive marker of CKD. Moreover, the prevention of klotho decline by several mechanisms can attenuate renal injuries, retard CKD progression, ameliorate extrarenal complications, and improve renal function. In this review, we focus on the functions and pathophysiological implications of klotho in CKD and its extrarenal complications as well as its potential applications as a diagnostic and/or prognostic biomarker for CKD and as a novel treatment strategy to improve and decrease the burden of comorbidity in CKD.

SUBMITTER: Zou D

PROVIDER: S-EPMC6198535 | biostudies-other | 2018 Oct

REPOSITORIES: biostudies-other

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The role of klotho in chronic kidney disease.

Zou Di D Wu Wen W He Yan Y Ma Sichao S Gao Ji J

BMC nephrology 20181022 1

Chronic kidney disease (CKD) is an inherently systemic disease that refers to a long-term loss of kidney function. The progression of CKD has repercussions for other organs, leading to many kinds of extrarenal complications. Intensive studies are now being undertaken to reveal the risk factors and pathophysiological mechanism of this disease. During the past 20 years, increasing evidence from clinical and basic studies has indicated that klotho, which was initially known as an anti-aging gene an ...[more]

PMID: 30348110

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Project description:BackgroundThe anti-aging protein Klotho plays a protective role in kidney disease, but its potential as a biomarker for chronic kidney disease (CKD) is controversial. Additionally, the main pathways through which Klotho exerts its effects on CKD remain unclear. Therefore, we used bioinformatics and clinical data analysis to determine its role in CKD.ResultsWe analyzed the transcriptomic and clinical data from the Nephroseq v5 database and found that the Klotho gene was mainly expressed in the tubulointerstitium, and its expression was significantly positively correlated with estimated glomerular filtration rate (eGFR) and negatively correlated with blood urea nitrogen (BUN) in CKD. We further found that Klotho gene expression was mainly negatively associated with inflammatory response and positively associated with lipid metabolism in CKD tubulointerstitium by analyzing two large sample-size CKD tubulointerstitial transcriptome datasets. By analyzing 10-year clinical data from the National Health and Nutrition Examination Survey (NHANES) 2007-2016, we also found that Klotho negatively correlated with inflammatory biomarkers and triglyceride and positively correlated with eGFR in the CKD population. Mediation analysis showed that Klotho could improve renal function in the general population by modulating the inflammatory response and lipid metabolism, while in the CKD population, it primarily manifested by mediating the inflammatory response. Restricted cubic spline (RCS) analysis showed that the optimal concentration range for Klotho to exert its biological function was around 1000 pg/ml. Kaplan-Meier curves showed that lower cumulative hazards of all-cause mortality in participants with higher levels of Klotho. We also demonstrated that Klotho could reduce cellular inflammatory response and improve cellular lipid metabolism by establishing an in vitro model similar to CKD.ConclusionsOur results suggest that Klotho exerts protection in CKD, which may be mainly related to the regulation of inflammatory response and lipid metabolism, and it can serve as a potential biomarker for CKD.

Project description:Chronic kidney disease (CKD) has been associated with a higher risk of cardiovascular disease (CVD). CKD patients present a decrease in the levels of the protein Klotho that accompanies the decrease in kidney function. This protein has been related to protective effects against CVD. However, it is unclear whether circulating Klotho, and its expression in peripheral blood cells (PBCs) are also associated with subclinical atherosclerosis in CKD. The present study aimed to study the relationship between Klotho and subclinical atherosclerosis in a population of patients with moderate to severe CKD. We determined the serum levels and gene expression in PBCs levels of Klotho and three inflammatory cytokines in 103 patients with CKD and investigated their relationship with two surrogate markers of subclinical atherosclerotis: ankle-brachial index (ABI) and carotid intima-media thickness (CIMT). Patients with subclinical atherosclerosis presented lower serum and PBCs expression levels of Klotho. Both variables were associated with the presence of subclinical atherosclerosis, being directly related with ABI and inversely with CIMT (P < 0.0001 for both). Multiple regression analysis demonstrated that both variables were significant determinants for ABI (adjusted R2 = 0.511, P < 0.0001) and CIMT (adjusted R2 = 0.445, P < 0.0001), independently of traditional and emergent cardiovascular risk factors. Moreover, both constituted protective factors against subclinical atherosclerosis [OR: 0.993 (P = 0.002) and 0.231 (P = 0.025), respectively]. Receiver operating characteristic analysis pointed to the utility of serum Klotho (area under the curve [AUC]: 0.817, 95% CI: 0.736-0.898, P < 0.001) and its gene expression in PBCs (AUC: 0.742, 95% CI: 0.647-0.836, P < 0.001) to distinguish subclinical atherosclerosis. The reductions in serum and PBCs expression levels of Klotho in CKD patients are independently associated with the presence of for subclinical atherosclerosis. Further research exploring whether therapeutic approaches to maintain or elevate Klotho could reduce the impact of CVD in CKD patients is warranted.

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The role of klotho in chronic kidney disease.

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The role of klotho in chronic kidney disease.

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