Exercise-based Rehabilitation in Cardio-renal-pulmonary Multimorbidity: Shared Pathophysiology, Functional Phenotypes, and Clinical Implications

Abstract

Heart failure (HF), chronic kidney disease (CKD), and chronic obstructive pulmonary disease (COPD) frequently coexist and collectively constitute a high-risk multimorbid state characterized by shared pathophysiology, compounded exercise intolerance, frailty, and worse clinical outcomes. These overlapping conditions interact through several mechanisms, including neurohormonal activation, systemic inflammation, oxidative stress, endothelial dysfunction, hemodynamic interactions, and skeletal muscle abnormalities. These mechanisms restrict functional capacity through both central and peripheral pathways. Exercise-based rehabilitation has emerged as an essential nonpharmacological intervention across cardiovascular, renal, and pulmonary medicine and is supported by robust evidence for improvements in exercise capacity and health-related quality of life in single-organ disease populations. However, patients with overlapping cardio-renal-pulmonary impairment remain underrepresented in rehabilitation trials, and evidence for the triple overlap of HF, CKD, and COPD remains particularly scarce. This narrative review synthesizes current evidence on the pathophysiology of cardio-renal-pulmonary multimorbidity and the mechanisms of exercise intolerance. Furthermore, it summarizes functional phenotypes, clinical assessments, and the effects of exercise-based rehabilitation across single-organ and overlapping disease states. Finally, practical implications for individualized exercise prescription, delivery models, and safety monitoring are discussed. We propose a phenotype-guided, function-centered framework for rehabilitation in this complex population and outline key research priorities to strengthen the evidence base for this high-risk, underserved population.