title: Mitochondrial dysfunction and oxidative stress in patients with chronic kidney disease.
abstract: Mitochondria abnormalities in skeletal muscle may contribute to frailty and sarcopenia, commonly present in patients with chronic kidney disease (CKD). Dysfunctional mitochondria are also a major source of oxidative stress and may contribute to cardiovascular disease in CKD We tested the hypothesis that mitochondrial structure and function worsens with the severity of CKD Mitochondrial volume density, mitochondrial DNA (mtDNA) copy number, BNIP3, and PGC1α protein expression were evaluated in skeletal muscle biopsies obtained from 27 subjects (17 controls and 10 with CKD stage 5 on hemodialysis). We also measured mtDNA copy number in peripheral blood mononuclear cells (PBMCs), plasma isofurans, and plasma F2-isoprostanes in 208 subjects divided into three groups: non-CKD (eGFR>60 mL/min), CKD stage 3-4 (eGFR 60-15 mL/min), and CKD stage 5 (on hemodialysis). Muscle biopsies from patients with CKD stage 5 revealed lower mitochondrial volume density, lower mtDNA copy number, and higher BNIP3 content than controls. mtDNA copy number in PBMCs was decreased with increasing severity of CKD: non-CKD (6.48, 95% CI 4.49-8.46), CKD stage 3-4 (3.30, 95% CI 0.85-5.75, P = 0.048 vs. non-CKD), and CKD stage 5 (1.93, 95% CI 0.27-3.59, P = 0.001 vs. non-CKD). Isofurans were higher in patients with CKD stage 5 (median 59.21 pg/mL, IQR 41.76-95.36) compared to patients with non-CKD (median 49.95 pg/mL, IQR 27.88-83.46, P = 0.001), whereas F2-isoprostanes did not differ among groups. Severity of CKD is associated with mitochondrial dysfunction and markers of oxidative stress. Mitochondrial abnormalities, which are common in skeletal muscle from patients with CKD stage 5, may explain the muscle dysfunction associated with frailty and sarcopenia in CKD Further studies are required to evaluate mitochondrial function in vivo in patients with different CKD stages.
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee jorge.gamboa@vanderbilt.edu.
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Gamboa
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Frederic T
authors.initials: FT
authors.lastname: Billings
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Bojanowski
authors.affiliation: Department of Physiology, East Carolina University, Greenville, North Carolina.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Gilliam
authors.affiliation: Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Chang
authors.initials: C
authors.lastname: Yu
authors.affiliation: Kidney Research Institute, University of Washington, Seattle, Washington.
authors.forename: Baback
authors.initials: B
authors.lastname: Roshanravan
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: L Jackson
authors.initials: LJ
authors.lastname: Roberts
authors.affiliation: Kidney Research Institute, University of Washington, Seattle, Washington.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Himmelfarb
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: T Alp
authors.initials: TA
authors.lastname: Ikizler
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Brown
mesh_terms: D000328:Adult; D000818:Animals; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology*; D051436:Renal Insufficiency, Chronic / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology
keywords: BNIP3; PGC1α; chronic kidney disease; mitochondria; mitochondrial DNA copy number; oxidative stress; skeletal muscle