ArticleClinical journal of the American Society of Nephrology : CJASN2026
Associations of Blood Mitochondrial DNA Quality and Quantity with Risk of Kidney Function Decline.
Article in Clinical journal of the American Society of Nephrology : CJASN, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
key pointsIn older adults, a higher burden of mitochondrial DNA heteroplasmy was associated with a higher risk of kidney function decline. In older adults, higher mitochondrial DNA copy number was associated with a lower risk of kidney function decline.
backgroundBlood-based measures of mitochondrial DNA (mtDNA), including lower copy number and inherited mutations, have been associated with higher incidence of 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.
methodsWe 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% eGFR decline to <60 ml/min per 1.73 m 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 used to capture predicted deleterious consequences of mtDNA mutations. Modified Cox regression evaluated associations of each mtDNA exposure variable with the kidney outcomes.
resultsAmong participants in the random subcohort, the mean age was 74±3, 49% were female, and the mean baseline eGFR was 73±18 ml/min per 1.73 m 2 . In analyses adjusted for CKD risk factors, higher mMSS was associated with a higher risk of ≥40% eGFR decline to <60 ml/min per 1.73 m 2 (hazard ratio [HR] 1.23 [95% confidence interval [CI], 1.02 to 1.48] per SD higher; HR 2.60 [95% CI, 1.21 to 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 to 0.98] per SD higher; HR 0.55 [95% CI, 0.32 to 0.95] for highest versus lowest tertile) in adjusted analyses.
conclusionsIn 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.
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