No abstract

In ESRD patients on long-term HD, single nucleotide polymorphisms in the promoter region of the proinflammatory cytokines IL-6 and TNF-alpha, and the regulatory monokine IL-10, show a strong association with indices of comorbidity and function, and biological and nutritional markers.

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The role of mitochondrial injury in the pathogenesis of complications of uremia is incompletely defined, although diminished bioenergetic capacity and the accumulation of mitochondrial DNA (mtDNA) mutations have been reported. This study was undertaken to evaluate the prevalence of mtDNA injury in 180 patients who had ESRD and were enrolled into the baseline phase of the HEMO study and to relate these markers to all-cause mortality. The mitochondrial injury markers studied in peripheral blood mononuclear cells were the mtDNA copy number per cell, measured by quantitative PCR, and the presence of the mtDNA 4977 mutation. After frequency-matching healthy control subjects for age, mtDNA copy number was lower among older dialysis patients compared with older healthy subjects (P ϭ 0.01). A one-log increase in mtDNA copy number was independently associated with a decreased hazard for mortality (adjusted hazard ratio 0.64; 95% confidence interval 0.46 to 0.89). The mtDNA 4977 deletion was present in 48 (31%) patients and was independently associated with a decreased hazard for mortality (adjusted hazard ratio 0.33; 95% confidence interval 0.19 to 0.56). In summary, the mtDNA 4977 seems to predict survival in ESRD, but a reduced mitochondrial copy number seems to predict a poor outcome. Although further exploration of these associations is needed, evaluation of mitochondrial DNA copy number and somatic mtDNA mutations may provide simple genomic biomarkers to predict clinical outcomes among patients with ESRD. The uremic syndrome is characterized by abnormalities in energy metabolism, manifest as changes in basal metabolic rate, relative catabolism, negative nitrogen balance, protein energy malnutrition, insulin resistance, and dyslipidemia. 1 Mitochondria are integral to these metabolic processes, which they probably influence through cytokine-and adipokine-mediated mechanisms. 2 Early studies with 31-phosphorus nuclear magnetic resonance demonstrated that mitochondrial oxidative capacity was diminished in muscle of patients established on dialysis. 3 More recent studies showed a high prevalence of somatic mitochondrial DNA (mtDNA) mutations, specifically the "common deletion" (a 4977-bp deletion between nucleotide positions 8470 and 13,447 [mtDNA 4977 ]) in skeletal muscle of patients with ESRD. 4 Human mtDNA is particularly prone to oxidant injury because mitochondria generate reactive oxygen species during ATP production. 5 mtDNA injury may be qualitativedeletion or point mutations-or quantitative-abnormalities of mtDNA copy number per cell, mtDNA being polyploid. 6 mtDNA mutations are classically studied in skeletal muscle tissue, but recent observations suggested that the use of periph-