Abstract
Introuction: Uraemia leads to changes in cardiac structure, metabolic remodeling and anaemia, key factors in the development of heart failure in patients with chronic kidney disease. Previous studies have identified abnormalities in mitochondrial function, potentially impairing energy provision and enhancing oxidative stress. This study characterised oxidant status and changes in mitochondrial function in uraemia and the impact of correcting anaemia via intravenous iron therapy. Methods: Experimental uraemia was induced in male Sprague-Dawley rats via a subtotal nephrectomy and parenteral iron administration given 6 weeks post-surgery. Oxidative stress from tissue samples was evaluated by measuring pro-oxidant activities and anti-oxidant capacities in both sham and uraemic animals with and without iron supplementation. Thiobarbituric acid-reactive substances (TBARS), aconitase activity and cardiolipin were measured. Mitochondrial function was assessed using the Seahorse XFp analyser on isolated mitochondria excised from cardiac tissue. Results: Oxidative stress in this uraemic model was increased in cardiac tissue (increased GSSG/GSH ratio, TBARS and increased activities of pro-oxidant enzymes). There was no impact on skeletal tissue. Parenteral iron ameliorated oxidative stress by enhancing the anti-oxidant defense system in cardiac tissue and skeletal tissue. Examination of respiratory reserve in cardiac mitochondria demonstrated that parenteral iron restored mitochondrial function. This experimental model of uraemia demonstrated a specific oxidative stress on the heart muscle without significant changes in skeletal oxidant status. Iron therapy improved anti-oxidant defence system, consequently reducing oxidative stress in the heart and skeletal tissue. There was an improvement in cardiac mitochondrial function. Conclusions: This experimental evidence indicates that iron therapy could reduce vulnerability to oxidative stress and potentially improve both cardiac and skeletal functional capacity from improvements in mitochondrial function.
Highlights
Chronic kidney disease associated anaemia is characterised as normocytic and normochromic and arises from erythropoietin deficiency, chronic inflammation and iron deficiency amongst other causes [12]
The uraemic heart exhibited a net increase in prooxidative activity as evidenced by increased cardiac oxidised glutathione (GSSG) relative to the reduced form (GSH) (69% increase in GSSG/GSH ratio, Fig. 2A,B; p < 0.01), enhanced lipid peroxidation indicated by a 38% rise in thiobarbituric acid-reactive substances (TBARS) levels (Fig. 2C; p < 0.01) and a significantly (79%) upregulated
Cardiac glutathione peroxidase (GPx) and glutathione reductase (GR) activities were significantly increased by 30% (Fig. 3A; p < 0.01) and 88% (Fig. 3B; p < 0.01) respectively without changes in superoxide dismutase (SOD) (Fig. 3C) and catalase (Fig. 3D)
Summary
Chronic kidney disease associated anaemia is characterised as normocytic and normochromic and arises from erythropoietin deficiency, chronic inflammation and iron deficiency amongst other causes [12]. CONFIRM-HF verified these results in a larger randomised controlled trial [19] Taken together these studies suggest that IV iron may have beneficial effects on the heart which may impact on reduced cardiovascular events, improved functional capacity and reduced symptoms if present. The aim of this study was to further examine the cardiac oxidative response to IV iron administration and test the hypothesis that supplementation with intravenous iron “normalises” mitochondrial function, improves cardiolipin content and mitochondrial bioenergetics (increases the mitochondrial efficiency of respiration) and reduces the vulnerability of the uraemic heart and uraemic skeletal muscle to oxidative stress and may improve oxidant capacity (via restoration of systemic antioxidant activity). These changes may lead to clinical improvements in cardiac and skeletal function
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