William J He1, Changwei Li2, Zhijie Huang2, Siyi Geng2, Varun S Rao2, Tanika N Kelly2, L Lee Hamm2,3, Morgan E Grams4,5,6, Dan E Arking7, Lawrence J Appel4,5,8, Casey M Rebholz. 1. Boston University School of Medicine, Boston, Massachusetts. 2. Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana. 3. Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana. 4. Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland. 5. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. 6. Division of Nephrology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland. 7. Department of Genetic Medicine, McKusick-Nathans Institute, Johns Hopkins University, Baltimore, Maryland. 8. Division of General Internal Medicine, Department of Medicine, Johns Hopkins University, Baltimore, Maryland.
Abstract
BACKGROUND AND OBJECTIVES: Mitochondrial 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, & MEASUREMENTS: Chronic 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. RESULTS: Among 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). CONCLUSIONS: These findings suggest lower mitochondrial DNA copy number is associated with higher risk of CKD progression, independent of established risk factors among patients with CKD.
BACKGROUND AND OBJECTIVES: Mitochondrial 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, & MEASUREMENTS: Chronic 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. RESULTS: Among 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). CONCLUSIONS: These findings suggest lower mitochondrial DNA copy number is associated with higher risk of CKD progression, independent of established risk factors among patients with CKD.
Authors: Foram N Ashar; Yiyi Zhang; Ryan J Longchamps; John Lane; Anna Moes; Megan L Grove; Josyf C Mychaleckyj; Kent D Taylor; Josef Coresh; Jerome I Rotter; Eric Boerwinkle; Nathan Pankratz; Eliseo Guallar; Dan E Arking Journal: JAMA Cardiol Date: 2017-11-01 Impact factor: 14.676
Authors: Carl A Anderson; Fredrik H Pettersson; Geraldine M Clarke; Lon R Cardon; Andrew P Morris; Krina T Zondervan Journal: Nat Protoc Date: 2010-08-26 Impact factor: 13.491
Authors: Afshin Parsa; Peter A Kanetsky; Rui Xiao; Jayanta Gupta; Nandita Mitra; Sophie Limou; Dawei Xie; Huichun Xu; Amanda Hyre Anderson; Akinlolu Ojo; John W Kusek; Claudia M Lora; L Lee Hamm; Jiang He; Niina Sandholm; Janina Jeff; Dominic E Raj; Carsten A Böger; Erwin Bottinger; Shabnam Salimi; Rulan S Parekh; Sharon G Adler; Carl D Langefeld; Donald W Bowden; Per-Henrik Groop; Carol Forsblom; Barry I Freedman; Michael Lipkowitz; Caroline S Fox; Cheryl A Winkler; Harold I Feldman Journal: J Am Soc Nephrol Date: 2016-10-11 Impact factor: 10.121
Authors: Adrienne Tin; Morgan E Grams; Foram N Ashar; John A Lane; Avi Z Rosenberg; Megan L Grove; Eric Boerwinkle; Elizabeth Selvin; Josef Coresh; Nathan Pankratz; Dan E Arking Journal: J Am Soc Nephrol Date: 2016-01-21 Impact factor: 10.121
Authors: Wei Yang; Dawei Xie; Amanda H Anderson; Marshall M Joffe; Tom Greene; Valerie Teal; Chi-yuan Hsu; Jeffrey C Fink; Jiang He; James P Lash; Akinlolu Ojo; Mahboob Rahman; Lisa Nessel; John W Kusek; Harold I Feldman Journal: Am J Kidney Dis Date: 2013-10-30 Impact factor: 8.860
Authors: A Koller; F Fazzini; C Lamina; B Rantner; B Kollerits; M Stadler; P Klein-Weigel; G Fraedrich; F Kronenberg Journal: J Intern Med Date: 2020-02-09 Impact factor: 8.989