Lower circulating soluble Klotho level is associated with increased risk of all-cause mortality in chronic kidney disease patients: a systematic review and meta-analysis

Purpose This study aimed to investigate the association between circulating soluble Klotho level and risk of all-cause mortality in chronic kidney disease (CKD) patients using systematic review and meta-analysis technique. Methods Potentially eligible studies were identified from Medline and EMBASE databases from inception to March 2020 using a search strategy that consisted of terms for "Klotho" and "Mortality". Eligible study must be a cohort study that consists of one cohort of CKD patients with higher circulating soluble Klotho level and another cohort of CKD patients with lower circulating soluble Klotho level. The study must also report relative risk (RR), incidence rate ratio, hazard risk ratio or standardized incidence ratio with 95% confidence intervals (95% CIs) comparing all-cause mortality between CKD patients with lower circulating soluble Klotho level versus CKD patients with higher circulating soluble Klotho level. If the study divides patients (per circulating soluble Klotho level) into more than two groups, a comparison between the highest and the lowest group would be extracted. Point estimates with standard errors were retrieved from each study and were combined together using the generic inverse variance method. Results A total of 2964 articles were retrieved. After two rounds of an independent review by two investigators, six prospective cohort studies met the eligibility criteria and were included into the meta-analysis. CKD patients with lower circulating soluble Klotho level had a significantly increased risk of all-cause mortality with the pooled risk ratio of 1.88 (95% CI 1.29-2.74;I(2)0%). The funnel plot was fairly symmetric and did not reveal any suggestive evidence of publication bias. Conclusion The current study found a significant association between lower circulating soluble Klotho level and increased risk of all-cause mortality in CKD patients. However, this meta-analysis carries some limitations, including relatively small sample size, lack of adjustment for potential confounders and between-study heterogeneity in baseline characteristics of the patients and cut-off values used to categorize patients into higher and lower circulating serum Klotho level group.