Associations of Blood Mitochondrial DNA Quality and Quantity with Risk of Kidney Function Decline

Background: Blood-based measures of mitochondrial DNA (mtDNA), including lower copy number and inherited mutations, have been associated with higher incidence of chronic kidney disease (CKD). However, the effect of mtDNA heteroplasmy, the age-associated accumulation of somatic mutations, is not well elucidated. We evaluated associations of mtDNA heteroplasmy and copy number (mtDNA-CN) with risk of kidney function decline. Methods: We conducted a case-cohort study among community-living participants of the Health, Aging, and Body Composition study. A random subcohort of 502 participants was selected at baseline. One hundred and fifty-seven cases with a ≥40% estimated glomerular filtration rate (eGFR) decline to less than 60 ml/min/1.73m 2 over 10 years of follow-up were identified, including 30 cases from the subcohort. Additional analyses evaluated ≥30% eGFR decline, present in 207 participants, including 80 within the subcohort. MtDNA heteroplasmy and mtDNA-CN were quantified from peripheral blood buffy coat specimens at baseline. A modified mitochondrial local constraint score sum (mMSS) was utilized to capture predicted deleterious consequences of mtDNA mutations. Modified Cox regression evaluated associations of each mtDNA exposure variable with the kidney outcomes. Results: Among participants in the random subcohort, the mean age was 74±3, 49% were female, and the mean baseline eGFR was 73±18 mL/min/1.73m 2 . In analyses adjusted for CKD risk factors, higher mMSS was associated with a higher risk of ≥40% eGFR decline to less than 60 ml/min/1.73m 2 (hazard ratio (HR) 1.23 [95% confidence interval (CI): 1.02, 1.48] per standard deviation (SD) higher; HR 2.60 [95% CI: 1.21, 5.56] for mMSS >0.5 versus 0). Higher mtDNA-CN was associated with a lower risk of ≥30% eGFR decline (HR 0.79 [95% CI: 0.63, 0.98] per SD higher; HR 0.55 [95% CI: 0.32, 0.95] for highest versus lowest tertile) in adjusted analyses. Conclusions: In older community-dwelling adults, higher mtDNA heteroplasmy was associated with a higher risk of kidney function decline, while higher mtDNA-CN was associated with a lower risk of kidney function decline. These findings expand the measures of mitochondrial health that may provide insight into kidney disease progression and warrant exploration in higher-risk populations.