Pathophysiology of Wound Development and Chronicity in Renal Disease: A Narrative Review

Abstract

Renal disease, including chronic kidney disease (CKD) and end-stage renal disease (ESRD), has a profound impact on wound healing. Multiple studies have demonstrated that renal disease leads to an increased risk of diabetic foot ulcers, the formation of unique wounds like calciphylaxis, slower wound healing and a higher risk of amputation. This review details the interrelated mechanisms by which renal disease impacts wound healing. Motor and sensory neuropathies contribute to wound formation via foot deformities and decreased sensation. Neuropathies also decrease neuropeptide release, impairing angiogenesis and inflammatory regulation. Accumulation of uremic toxins in renal disease leads to vessel wall calcification, impairing blood supply and predisposing patients to calciphylaxis. Vitamin and mineral deficiencies lead to impaired clotting, development of a chronic inflammatory state and decreased collagen production. Renal disease and its comorbidities are also associated with immune dysregulation, increasing the risk of wound infections and promoting the persistence of pro-inflammatory macrophages. While hypoxia-inducible factor-1α (HIF-1α) promotes angiogenesis under hypoxic conditions in normal wound healing, oxidative stress and chronic hypoxia in renal disease generate an environment that compromises the activity of HIF-1α. Inadequate erythropoietin response to hypoxia also leads to anaemia, further impairing oxygen delivery to wound sites. Clinically, these factors result in increased 10-year mortality for patients with DFU and CKD compared to those with DFU alone, both with and without amputation. We must utilise our understanding of the pathophysiology of impaired wound healing in renal disease to target preventative measures, optimise treatment and improve overall outcomes.

Keywords: amputation; arterial calcification; hypoxia; renal disease; uremia; wound healing.