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Kidney Int. 2019 Aug;96(2):480-488. doi: 10.1016/j.kint.2019.04.021. Epub 2019 May 10.

Mitochondrial DNA copy number is associated with mortality and infections in a large cohort of patients with chronic kidney disease.

Author information

1
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
2
Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany; Renal Division, Department of Medicine IV, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany.
3
Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.
4
Institute for Biomedicine, EURAC Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy.
5
Department of Nephrology and Hypertension, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
6
Division of Nephrology, Department of Internal Medicine I, Division of Nephrology and Comprehensive Heart Failure Centre, University Hospital Würzburg, Würzburg, Germany.
7
Department of Nephrology and Hypertension, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Erlangen, Germany; Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.
8
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria. Electronic address: Florian.Kronenberg@i-med.ac.at.

Abstract

Damage of mitochondrial DNA (mtDNA) with reduction in copy number has been proposed as a biomarker for mitochondrial dysfunction and oxidative stress. Chronic kidney disease (CKD) is associated with increased mortality and risk of cardiovascular disease, but the underlying mechanisms remain incompletely understood. Here we investigated the prognostic role of mtDNA copy number for cause-specific mortality in 4812 patients from the German Chronic Kidney Disease study, an ongoing prospective observational national cohort study of patients with CKD stage G3 and A1-3 or G1-2 with overt proteinuria (A3) at enrollment. MtDNA was quantified in whole blood using a plasmid-normalized PCR-based assay. At baseline, 1235 patients had prevalent cardiovascular disease. These patients had a significantly lower mtDNA copy number than patients without cardiovascular disease (fully-adjusted model: odds ratio 1.03, 95% confidence interval [CI] 1.01-1.05 per 10 mtDNA copies decrease). After four years of follow-up, we observed a significant inverse association between mtDNA copy number and all-cause mortality, adjusted for kidney function and cardiovascular disease risk factors (hazard ratio 1.37, 95% CI 1.09-1.73 for quartile 1 compared to quartiles 2-4). When grouped by causes of death, estimates pointed in the same direction for all causes but in a fully-adjusted model decreased copy numbers were significantly lower only in infection-related death (hazard ratio 1.82, 95% CI 1.08-3.08). A similar association was observed for hospitalizations due to infections in 644 patients (hazard ratio 1.19, 95% CI 1.00-1.42 in the fully-adjusted model). Thus, our data support a role of mitochondrial dysfunction in increased cardiovascular disease and mortality risks as well as susceptibility to infections in patients with CKD.

KEYWORDS:

chronic kidney disease; infections; mitochondrial DNA copy number; mortality

PMID:
31248648
DOI:
10.1016/j.kint.2019.04.021

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