JVS - Vascular Science (Jan 2022)
Influences of renal insufficiency and ischemia on mitochondrial bioenergetics and limb dysfunction in a novel murine iliac arteriovenous fistula model
Abstract
Objective: Hand disability after hemodialysis access surgery has been common yet has remained poorly understood. Arteriovenous fistula (AVF) hemodynamic perturbations have not reliably correlated with the observed measures of hand function. Chronic kidney disease (CKD) is known to precipitate myopathy; however, the interactive influences of renal insufficiency and ischemia on limb outcomes have remained unknown. We hypothesized that CKD would contribute to access-related hand dysfunction via altered mitochondrial bioenergetics. Using a novel murine AVF model, we sought to characterize the skeletal muscle outcomes in mice with and without renal insufficiency. Methods: Male, 8-week-old C57BL/6J mice were fed either an adenine-supplemented diet to induce renal insufficiency (CKD) or a casein-based control chow (CON). After 2 weeks of dietary intervention, the mice were randomly assigned to undergo iliac AVF surgery (n = 12/group) or a sham operation (n = 5/group). Measurements of aortoiliac hemodynamics, hindlimb perfusion, and hindlimb motor function were collected for 2 weeks. The mice were sacrificed on postoperative day 14 to assess skeletal muscle histopathologic features and mitochondrial function. To assess the late outcome trends, 20 additional mice had undergone CKD induction and sham (n = 5) or AVF (n = 15) surgery and followed up for 6 weeks postoperatively before sacrifice. Results: The adenine-fed mice had had a significantly reduced glomerular filtration rate and elevated blood urea nitrogen, confirming the presence of CKD. The sham mice had a 100% survival rate and AVF cohorts an 82.1% survival rate with an 84.4% AVF patency rate. The aorta and inferior vena cava velocity measurements and the vessel diameter had increased after AVF creation (P < .0001 vs sham). The AVF groups had had a 78.4% deficit in paw perfusion compared with the contralateral limb after surgery (P < .0001 vs sham). Mitochondrial function was influenced by the presence of CKD. The respiratory capacity of the CKD-sham mice (8443 ± 1509 pmol/s/mg at maximal energy demand) was impaired compared with that of the CON-sham mice (12,870 ± 1203 pmol/s/mg; P = .0001). However, this difference was muted after AVF creation (CKD-AVF, 4478 ± 3685 pmol/s/mg; CON-AVF, 5407 ± 3582 pmol/s/mg; P = .198). The AVF cohorts had had impairments in grip strength (vs sham; P < .0001) and gait (vs sham; P = .012). However, the presence of CKD did not significantly alter the measurements of gross muscle function. The paw perfusion deficits had persisted 6 weeks postoperatively for the AVF mice (P < .0001 vs sham); however, the myopathy had resolved (grip strength, P = .092 vs sham; mitochondrial respiration, P = .108 vs sham). Conclusions: CKD and AVF-induced distal limb ischemia both impaired skeletal muscle mitochondrial function. Renal insufficiency was associated with a baseline myopathy that was exacerbated by the acute ischemic injury resulting from AVF creation. However, ischemia was the primary driver of the observed phenotype of gross motor impairment. This model reliably reproduced the local and systemic influences that contribute to access-related hand dysfunction and provides a platform for further mechanistic and therapeutic investigation. : Clinical Relevance: Access-related hand dysfunction (ARHD) has remained a common hemodialysis access surgery complication. Because of the poor mechanistic insight, the currently available therapies have been limited to surgical remediation of the hemodynamic changes in the limb for only the most severe clinical manifestations. Furthermore, expectant management or access revision will not be ideal options, especially for patients with mild to moderate ARHD, owing to the perioperative risk and implications for long-term access durability. Therefore, skeletal muscle mitochondrial-based therapy represents an intriguing treatment strategy. However, the characteristics of mitochondrial function after arteriovenous fistula placement are unknown. In the present study, we have characterized the ischemic and uremic influences on skeletal muscle physiology to identify the pathogenic drivers of ARHD.
