Association of Mitochondrial DNA Copy Number With Risk of Progression of Kidney Disease in the Chronic Renal Insufficiency Cohort (CRIC) Study

Introduction: Mitochondrial DNA copy number (mtDNA-CN) is a biomarker of mitochondrial function that has been associated with chronic kidney disease (CKD) and all-cause mortality in several community-based studies. However, there has been little research on mtDNA-CN and progression of CKD. Hypothesis: We hypothesized that higher mtDNA-CN will be associated with lower risk for CKD progression in a cohort of CKD patients. Methods: A total of 2,943 Chronic Renal Insufficiency Cohort (CRIC) study participants had mtDNA-CN calculated from probe intensities of mitochondrial single nucleotide polymorphisms (SNP) genotyped on the Illumina HumanOmni 1-Quad Array. To correct for batch effects, DNA quality, DNA quantity, and latent confounding factors, mtDNA-CN was regressed on 15 principal components generated from autosomal SNP probe intensity signals. mtDNA-CN residuals were then standardized to a mean of 0 and standard deviation of 1 and used in this analysis. CKD progression was defined as incident end-stage renal disease (ESRD) or halving of eGFR from baseline. Cox proportional hazards models were used to calculate hazard ratios for mtDNA-CN and risk of CKD progression. Results and Conclusions: Compared to patients in the lowest mtDNA-CN tertile, those in the middle tertile [HR=0.78, 95% CI: (0.68, 0.91)] and highest tertile [HR=0.78, 95% CI: (0.67, 0.91)] had a statistically significantly lower risk for CKD progression after adjustment for established risk factors (Table). Similar results were seen in race- and sex-stratified analyses (Table). These findings suggest that mtDNA-CN may have potential clinical utility in improving CKD risk classification. Furthermore, mitochondrial dysfunction has been hypothesized to contribute to renal disease through podocyte injury, tubular epithelial cell damage, and endothelial dysfunction. Future research on the mechanisms underlying mtDNA-CN and CKD progression may lead to novel strategies for CKD management.