Context:α-Klotho has emerged as a powerful regulator of the aging process. To date, the expression profile of α-Klotho in human tissues is unknown, and its existence in some human tissue types is subject to much controversy.Objective:This is the first study to characterize systemwide tissue expression of transmembrane α-Klotho in humans. We have employed next-generation targeted proteomic analysis using parallel reaction monitoring in parallel with conventional antibody-based methods to determine the expression and spatial distribution of human α-Klotho expression in health.Results:The distribution of α-Klotho in human tissues from various organ systems, including arterial, epithelial, endocrine, reproductive, and neuronal tissues, was first identified by immunohistochemistry. Kidney tissues showed strong α-Klotho expression, whereas liver did not reveal a detectable signal. These results were next confirmed by Western blotting of both whole tissues and primary cells. To validate our antibody-based results, α-Klotho-expressing tissues were subjected to parallel reaction monitoring mass spectrometry (data deposited at ProteomeXchange, PXD002775) identifying peptides specific for the full-length, transmembrane α-Klotho isoform.Conclusions:The data presented confirm α-Klotho expression in the kidney tubule and in the artery and provide evidence of α-Klotho expression across organ systems and cell types that has not previously been described in humans.

Exercise intolerance is an important comorbidity in patients with CKD. Anaerobic threshold (AT) determines the upper limits of aerobic exercise and is a measure of cardiovascular reserve. This study investigated the prognostic capacity of AT on survival in patients with advanced CKD and the effect of kidney transplantation on survival in those with reduced cardiovascular reserve. Using cardiopulmonary exercise testing, cardiovascular reserve was evaluated in 240 patients who were waitlisted for kidney transplantation between 2008 and 2010, and patients were followed for #5 years. Survival time was the primary endpoint. Cumulative survival for the entire cohort was 72.6% (24 deaths), with cardiovascular events being the most common cause of death (54.2%). According to Kaplan-Meier estimates, patients with AT ,40% of predicted peak VO 2 had a significantly reduced 5-year cumulative overall survival rate compared with those with AT $40% (P,0.001). Regarding the cohort with AT ,40%, patients who underwent kidney transplantation (6 deaths) had significantly better survival compared with nontransplanted patients (17 deaths) (hazard ratio, 4.48; 95% confidence interval, 1.78 to 11.38; P=0.002). Survival did not differ significantly among patients with AT $40%, with one death in the nontransplanted group and no deaths in the transplanted group. In summary, this is the first prospective study to demonstrate a significant association of AT, as the objective index of cardiovascular reserve, with survival in patients with advanced CKD. High-risk patients with reduced cardiovascular reserve had a better survival rate after receiving a kidney transplant.

The sharp rise in the prevalence of chronic kidney disease (CKD) that parallels an increase in the prevalence of obesity in the recent years is a cause for great concern. CKD increases the rate of cardiovascular disease (CVD), development of end-stage renal disease, and leads to premature death. Although no direct causality link between obesity and CKD can yet be established, this appears highly likely. CKD should be regarded as a major complication of overweight and obesity, regardless of whether the association was independent or through the influence of diabetes, hypertension, CVD, metabolic syndrome and high fructose intake. We review the literature on the complex but positive association between obesity and CKD, the pathological effect of excess adiposity in kidney injury and the potential role of weight reduction therapy in reducing the burden of CKD.

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