Abstract
The CKD-associated decline in soluble α-Klotho levels is considered detrimental. Some in vitro and in vivo animal studies have shown that anti-oxidant therapy can upregulate the expression of α-Klotho in the kidney. We examined the effect of anti-oxidant therapy on α-Klotho concentrations in a clinical cohort with mild tot moderate chronic kidney disease (CKD). We performed a post-hoc analysis of a prospective randomized trial involving 62 patients with mild to moderate CKD (the ATIC study), all using an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) for 12 months. On top of that, the intervention group received anti-oxidative therapy consisting of the combination of pravastatin (40 mg/d) and vitamin E (α-tocopherol acetate, 300 mg/d) while the placebo was not treated with anti-oxidants. α-Klotho concentrations were measured at baseline and after 12 months of anti-oxidant therapy. Data were analysed using T-tests and Generalized Estimating Equations, adjusting for potential confounders such as vitamin D, parathyroid hormone, fibroblast-growth-factor 23 (FGF23) and eGFR. The cohort existed of 62 patients with an eGFR (MDRD) of 35 ± 14 ml/min/1.72m2, 34 were male and mean age was 53.0 ± 12.5 years old. Anti-oxidative therapy did successfully reduce oxLDL and LDL concentrations (P <0.001). α-Klotho concentrations did not change in patients receiving either anti-oxidative therapy (476.9 ± 124.3 to 492.7 ± 126.3 pg/mL, P = 0.23) nor in those receiving placebo 483.2 ± 142.5 to 489.6 ± 120.3 pg/mL, P = 0.62). Changes in α-Klotho concentrations were not different between both groups (p = 0.62). No evidence was found that anti-oxidative therapy affected α-Klotho concentrations in patients with mild-moderate CKD.
Highlights
Prevention and better treatment of cardiovascular (CV) disease in CKD is one of the main challenges in current nephrology
The α-Klotho gene was discovered in 1997 as an anti-aging gene [4]. α-Klotho is predominantly produced in the kidneys [5]. α-Klotho expression is downregulated by CKD-associated uremic toxins and oxidative stress and enhanced activity of the renin-angiotensin-aldosterone system (RAAS) [6,7,8]
In this study 93 subjects with mild-moderate CKD, on background treatment of inhibition of the renin-angiotensin system (RAS) by either angiotensin receptor blockers (ARB) or angiotensin converting enzyme (ACE)-inhibition were randomised to either a anti-oxidant regime comprising of pravastatin (40 mg/d) starting at baseline followed by the addition of vitamin E at month 6, or placebo for 12 months
Summary
Prevention and better treatment of cardiovascular (CV) disease in CKD is one of the main challenges in current nephrology. A rapidly increasing body of evidence supports involvement of the fibroblast growth factor 23 (FGF23)-klotho-vitamin D axis in the pathogenesis of cardiovascular disease in CKD patients [2]. Therapeutic reduction of oxidative stress in patients with CKD, for instance with HMG-CoA reductase inhibitors, could improve CV outcome [3]. Whether antioxidant therapy induces favorable changes in the FGF23-Klotho-vitamin D axis and thereby improvements in CV outcome is unknown. Α-Klotho expression is downregulated by CKD-associated uremic toxins and oxidative stress and enhanced activity of the renin-angiotensin-aldosterone system (RAAS) [6,7,8]. A vicious circle could ensue, because vitamin D deficiency increases renin and subsequently angiotensin II, which is known to suppress α-Klotho and leads to subsequent high FGF23 concentrations, which in turn suppress vitamin D activation[9]. Lower αKlotho concentrations are associated with progressive CKD[10], higher prevalence of cardiovascular disease[11], arterial stiffness [12], vascular calcification[13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
