N-acetylcysteine Treatment Attenuates Hemodialysis Access-related Limb Pathophysiology in Mice with Chronic Kidney Disease

The objective of this study was to determine if treatment with N-acetylcysteine (NAC) could reduce access-related limb dysfunction in mice. We conducted a preclinical randomized trial examining the efficacy of NAC as a treatment modality to reduce limb pathophysiology following arteriovenous fistula (AVF) creation in mice with chronic kidney disease. Male and female C57BL6J mice were fed an adenine supplemented diet to induce chronic kidney disease prior to surgical creation of an AVF in the iliac vascular bundle. Assessments of central and hindlimb vascular hemodynamics, hindlimb neuromotor function and morphology, as well as muscle mitochondrial function were performed. AVF creation significantly increased peak aortic and infrarenal vena cava blood flow velocities, but NAC treatment had no significant impact either (P=0.9866 and P=0.3109, respectively) indicating that fistula maturation was not impacted by NAC treatment. Hindlimb muscle and paw perfusion recovery, as well as muscle capillary density in the AVF limb were unaffected by NAC treatment. However, NAC treatment significantly increased the mass of the tibialis anterior (P=0.0120) and soleus (P=0.0452) muscles post-AVF. There was a significant main effect of NAC treatment on hindlimb grip strength at post-operative day (POD) 12 (P=0.0003), driven by significantly higher grip strength in both male (P=0.0273) and female (P=0.0031) mice treated with NAC. There was also a significant main effect of NAC treatment on walking speed at POD12 (P=0.0447), and post-hoc testing revealed improvement in male mice (P=0.0091) treated with NAC. The area of post-synaptic acetylcholine receptors (P=0.0263) and motor endplates (P=0.0240) were also increased by NAC treatment. Interestingly, hindlimb skeletal muscle mitochondrial oxidative phosphorylation was trending higher in female mice treated with NAC but was not statistically significant (P=0.0973). Muscle glutathione levels and redox status were not significantly impacted by NAC treatment in either sex. In summary, NAC treatment was found to attenuate some aspects of neuromotor pathology in mice with chronic kidney disease following AVF creation.