Reduction of Oxidative Stress in Chronic Kidney Disease Does Not Increase Circulating α-Klotho Concentrations

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.

Fish Oil Supplementation Reduces Inflammation but Does Not Restore Renal Function and Klotho Expression in an Adenine-Induced CKD Model

“…Given the persistence of loss of renal function in our model, irrespective of the fish oil administration, Klotho deficiency is expected, since the kidneys produce/release α-Klotho into the circulation and help clearing it [ 27 ]. Moreover, in the CKD setting, over production of reactive oxygen species [ 39 ], elevation of uremic toxins [ 40 ], high serum phosphate/excess FGF23 [ 41 ], and low serum 1,25-dihydroxy vitamin D3 (1,25 Vit D3) are expected to further suppress Klotho production [ 37 , 42 , 43 ]. Unfortunately, parameters of mineral metabolism such as phosphate, FGF23, and 1,25 Vit D3 have not been measured in the present study.…”

“…Other factors which could account for by renal Klotho deficiency in some circumstances depend on its epigenetic modulation. Methylation of the Klotho gene promoter, which has been shown to reduce its activity up to 40%, may inhibit Klotho gene expression in CKD [ 39 , 44 , 45 ] and TGF-β is known to induce global changes in DNA methylation [ 46 ]. Accordingly, demethylation of Klotho gene promoter remarkably reversed renal Klotho deficiency and reduced renal fibrosis [ 25 ].…”

Are Antioxidants Useful in Preventing the Progression of Chronic Kidney Disease?

“…Conclusions are also limited by the absence of oxidative stress markers in most studies, which makes it difficult to associate renal protection with oxidative stress. Of the 18 articles included, only one evaluated plasma malondialdehyde [ 33 ] and two others also measured plasma-oxidized low-density lipoprotein [ 16 , 24 ]. Their results are heterogeneous: (i) slight renal protection associated with a decrease in oxidative stress [ 33 ], (ii) no renal protection along with no modification of oxidative stress markers [ 24 ], and (iii) no improvement in kidney function despite a net reduction in oxidative stress [ 16 ].…”

“…Of the 18 articles included, only one evaluated plasma malondialdehyde [ 33 ] and two others also measured plasma-oxidized low-density lipoprotein [ 16 , 24 ]. Their results are heterogeneous: (i) slight renal protection associated with a decrease in oxidative stress [ 33 ], (ii) no renal protection along with no modification of oxidative stress markers [ 24 ], and (iii) no improvement in kidney function despite a net reduction in oxidative stress [ 16 ]. In addition, the sample size was insufficient to reach robust conclusions in all cases.…”

Oxidative stress and free radicals in liver and kidney diseases; an updated short-review

“…There are many compounds for therapy of CKD patients including L-Carnitine, vitamin E, vitamin C, coenzyme Q10, α-lipoic acid, selenium, green tea, resveratrol, curcumin and omega-3 polyunsaturated fatty acids, which can administer alone or as a combination (26). However, these positive effects have not been confirmed everywhere (27). In addition to kidney, the liver is also prone to oxidative stress-related damages.…”