Chronic kidney disease exacerbates ischemic leg myopathy in patients with peripheral artery disease
Authors: Kim Kyoungrae , Thome Trace , Salyers Zachary , Yang Qingping , Stone Lauren , Vugman Nicholas , Anderson Erik , Fazzone Brian , Schmidt Emilie , O’Malley Kerri , Berceli Scott , Scali Salvatore , Ryan Terence 
Published: May 2023

Introduction: Patients with peripheral artery disease (PAD) present with one or more comorbid risk factors that accelerate disease evolution and worsen clinical outcomes. Notably, PAD patients with chronic kidney disease (CKD) have greater risk for major adverse limb events and mortality; The objective of this study was to determine the impact of CKD on skeletal muscle strength and mitochondrial health in patients with and without PAD. Methods: We performed a cross-sectional analysis of skeletal muscle strength and mitochondrial health in four groups of patients (79 males and 21 females, 65.6±10.0 years old): PAD only (Toe brachial index, TBI<0.5 and eGFR>60 mL/min), CKD only (TBI>0.75 and eGFR:15-45 mL/min), PAD with CKD (TBI<0.5 and eGFR:15-45 mL/min), and adult controls without PAD and CKD (TBI>0.75 and eGFR>60 mL/min). Maximal isometric plantar flexor strength was measured using a force dynamometer. Gastrocnemius muscle biopsies were obtained for comprehensive mitochondrial diagnostics. Results: Plantar flexor muscle strength was lowest in PAD patients with CKD, which had a significant difference from adult controls (PAD+CKD: 161.1±53.3 N vs. Control: 272.9±70.0 N, P<0.01), a trending difference ( P=0.08) from PAD patients without CKD (238.8±81.0 N), and no difference ( P=0.20) from CKD patients (231.7±79.5 N). Analysis of mitochondrial oxidative phosphorylation (OXPHOS) revealed that both CKD and PAD with CKD groups had significant reduction (30~40%) in mitochondrial bioenergetic function ( JO2) at various levels of energy demand mimicking from resting skeletal muscle to maximal contraction compared with adult controls and PAD without CKD group (P<0.05). Similarly, OXPHOS conductance was significantly reduced in the PAD with CKD group compared with both adult controls and PAD patients without CKD (PAD+CKD: 1.4±0.5 vs. Control: 2.5±1.0 and PAD: 2.6±0.8, P<0.01). Surprisingly, patients with CKD only had lower OXPHOS conductance (1.7±0.6) compared to adult controls ( P=0.05) and patients with PAD only ( P=0.02). Interestingly, PAD patients without CKD had no difference in mitochondrial function compared with adult controls ( P=0.98). Conclusion: Taken together, the results suggest that CKD plays a critical role in exacerbating skeletal myopathy determined by muscle weakness and mitochondrial dysfunction in patients with PAD. Evidence from this study suggests that mitochondrial dysfunction may be a primary site of convergence of these two diseases. Funding source: National Institutes of Health grant R01HL149704 and American Heart Association grant POST903198. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.