Overlapping Diabetes- and CKD-Driven Vascular Phenotypes of Peripheral Artery Disease: A Limb-First Framework for Chronic Limb-Threatening Ischemia

Abstract

Peripheral artery disease (PAD) and chronic limb-threatening ischemia (CLTI) impose an increasing global burden. Although procedural success exceeds 90%, 1-year amputation rates remain >20%, highlighting a disconnect between technical success and clinical benefit. PAD is commonly treated as a uniform atherosclerotic condition; however, distinct biological phenotypes drive heterogeneous outcomes and require individualized management. Diabetes mellitus and chronic kidney disease (CKD), present in >70% of patients with CLTI, promote divergent pathological mechanisms. Diabetes is characterized by intimal inflammation, endothelial dysfunction, and microangiopathy, whereas CKD is dominated by medial calcification due to disordered mineral metabolism, limiting the reliability of the ankle-brachial index. Diabetes–CKD coexistence, observed in 35–50% of cases, produces combined occlusive and rigid vascular features and carries a disproportionately high risk of poor wound healing, major amputation, and early mortality—a burden that current lesion-centric approaches consistently fail to adequately address. This review integrates mechanistic insights, diagnostic considerations, and clinical evidence supporting phenotype-based management. We propose a practical framework that aligns phenotype recognition with targeted strategies: endovascular intervention with metabolic optimization for diabetes-predominant PAD, calcium-modifying approaches or bypass surgery for CKD-predominant PAD, and early prognostic counseling with palliative integration for combined phenotypes. This limb-first paradigm reframes revascularization as a biologically informed intervention and provides evidence-based pathways to improve outcomes in contemporary CLTI care.