Association of Mitochondrial DNA Copy Number with Risk of Progression of Kidney Disease

Abstract

Background and objectivesMitochondrial DNA copy number is a biomarker of mitochondrial function, which has been hypothesized to contribute to pathogenesis of CKD through podocyte injury, tubular epithelial cell damage, and endothelial dysfunction. The prospective association of mitochondrial DNA copy number with CKD progression has not been previously evaluated.Design, setting, participants, & measurementsChronic Renal Insufficiency Cohort study participants had serum levels of mitochondrial DNA copy number calculated from probe intensities of mitochondrial single nucleotide polymorphisms genotyped on the Illumina HumanOmni 1-Quad Array. CKD progression was defined as kidney failure or halving of eGFR from baseline. Cox proportional hazards models were used to calculate hazard ratios for mitochondrial DNA copy number and risk of CKD progression.ResultsAmong 2943 participants, mean age was 58 years, 45% were women, and 48% self-identified as Black. There were 1077 patients who experienced CKD progression over a median follow-up of 6.5 years. The incidence rate of CKD progression was highest for those in the lowest tertile of mitochondrial DNA copy number (tertile 1, 58.1; tertile 2, 50.8; tertile 3, 46.3 per 1000 person-years). Risk for CKD progression was higher for participants with lower levels of mitochondrial DNA copy number after adjustment for established risk factors (for tertile 1 versus 3, hazard ratio, 1.28 [95% confidence interval, 1.10 to 1.50]; for tertile 2 versus 3, hazard ratio, 0.99 [95% confidence interval, 0.85 to 1.16]; trend P=0.002). Similar results were seen among those with albuminuria (for tertile 1 versus 3, hazard ratio, 1.24; 95% confidence interval, 1.05 to 1.47), but there were no statistically significant associations among individuals without albuminuria (for tertile 1 versus 3, hazard ratio, 1.04; 95% confidence interval, 0.70 to 1.53; interaction P<0.001).ConclusionsThese findings suggest lower mitochondrial DNA copy number is associated with higher risk of CKD progression, independent of established risk factors among patients with CKD.

Mitochondrial DNA and Kidney Function

“…Diverse approaches to maintain mitochondrial function include the regulation of ROS metabolism, antagonism of mitochondrial oxidants, promotion of mitochondrial biogenesis and ATP synthesis, inhibition of mitochondrial fragmentation, and inhibition of the mitochondrial permeability transition pore. Studies like the one published by He et al (4) encourage us to pursue such approaches and lend further support to the hypothesis that maintaining mitochondria homeostasis may prevent kidney pathogenesis and disease progression.…”

“…Moreover, in GCKD, a low mitochondrial DNA copy number was a predictor of all-cause mortality (6). In contrast, He et al (4) found no difference in the prevalence of cardiovascular disease or diabetes mellitus in the three tertiles of mitochondrial DNA copy number in the CRIC study, nor did they find an association of mitochondrial DNA copy number with mortality.…”

“…The quality of these estimates very much depends on the SNP microarray used. The MitoPipeline algorithm applied by He et al (4) was reported to have a correlation coefficient of about r =0.50 with measurements done by quantitative PCR (7), such as applied in GCKD, which is not a perfect correlation. However, a major advantage of using SNP array data is that the raw probe signal intensities are available from widely used microarray data so that data on mitochondrial DNA copy number are obtained as a by-product.…”

“…In this issue of CJASN , He et al (4) report studies on the association of mitochondrial DNA copy number with the risk for progression of kidney disease and mortality in 2943 individuals with CKD enrolled into the Chronic Renal Insufficiency Cohort (CRIC) study. They observed that patients in the lowest tertile compared with the highest tertile of mitochondrial DNA copy number had a 28% higher risk for CKD progression.…”

Roles of Mitochondrial DNA Damage in Kidney Diseases: A New Biomarker

“…A later study in chronic renal insufficiency cohort reported that the lower mtDNA copy number was correlated with a higher risk of CKD progression, independent of established risk factors in CKD patients [ 62 ]. mtDNA release in platelets driven by a receptor for immune complex FcγRIIA is the key source of mitochondrial antigens in systemic lupus erythematosus [ 7 ].…”