Dr. Bray Links

Wednesday, February 3, 2016

Mitochondria: a new therapeutic target in chronic kidney disease

During CKD, the progressive deterioration of renal function [1] induces several biological and clinical dysfunctions including alteration in cellular energetic metabolism, change in nitrogen input/output, protein malnutrition, resistance to insulin and considerable enhancement of synthesis of inflammation/oxidative stress mediators [2–6].

Several authors have reported that in CKD, even in the early stage, there is an abundant production of reactive oxygen species (ROS) [7] mainly due to an hyperactivation of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [8–10], elevated synthesis of oxidative stress markers [e.g., F2-isoprostanes, malondialdehyde (MDA), advanced oxidation protein products (AOPP)] and release of uremic toxins. The level of all these factors is inversely correlated with the glomerular filtration rate (GFR) [5, 11–13].

The early stages of CKD require nutritional and pharmacological interventions to minimize uremic symptoms and maintain volume homeostasis (conservative therapy), while in the final stage of renal failure these alterations may induce the development of severe and life-threatening clinical complications and renal replacement therapies (RRT: hemodialysis and peritoneal dialysis) are necessary.

Although necessary to ensure patients’ survival, hemodialysis (HD) and peritoneal dialysis (PD) exacerbate oxidative stress [14, 15] by exposing blood to the contact with low biocompatible dialytic devices or fluids. In HD, the contact of peripheral blood mononuclear cells (PBMCs) with plastificants and filters [16] and the microbial contamination together with the release of pyrogens in dialysate induce ROS synthesis as part of the immune response [17–22]. Moreover, similarly to CKD, HD patients show an increased free radical-catalyzed peroxidation of arachidonoyl lipids with elevated production of lipid peroxidation products [MDA, 4-hydroxynonenal (HNE) and F2-isoprostanes] [23, 24]. Other markers of oxidative stress shown to be elevated in HD include lipid hydroperoxides, oxidized-LDL and AOPP [11, 25–30].

At the same time, plasma levels of both non-enzymatic (e.g., vitamin C, vitamin E) [31] and enzymatic antioxidants [e.g., superoxide dismutase (SOD) and catalase, glutathione peroxidase (GPx) and paraoxonase (PON1)] are reduced in CKD and HD patients [32–35].

The above mentioned imbalance between oxidants and antioxidants in patients with advanced renal impairment can accelerate renal injury progression and may contribute to the high rate of clinical complications in both CKD patients in conservative and dialysis treatment. Major complications include cardiovascular disease, atherosclerosis, amyloidosis and DNA-Damage-Associated Malignancy [36].


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