Phenotype-Driven Approach Reframes Cardiorenal–Metabolic (CKM) Syndrome for Integrated Therapeutic Strategies

The Cardiorenal–Metabolic (CKM) syndrome represents a complex, bidirectional interplay between metabolic dysfunction, chronic kidney disease (CKD), and cardiovascular disease (CVD). Traditionally, these conditions have been managed as separate entities, leading to fragmented care and suboptimal outcomes. Current standard-of-care often addresses symptoms or individual risk factors rather than the underlying systemic maladaptive interactions, such as neurohormonal activation, endothelial injury, oxidative stress, and chronic low-grade inflammation. This review highlights the critical need to shift clinical focus towards earlier prevention and coordinated, integrated care that recognizes CKM as a continuum, not merely a coexistence of comorbidities.

This paper presents a narrative review designed to provide a phenotype-oriented synthesis of the Cardiorenal–Metabolic (CKM) syndrome. The authors aimed to integrate the evolving understanding of CKM, moving beyond a glucose-centric view to a more holistic, organ-protective prevention strategy. The methodology involved a comprehensive literature review to conceptualize CKM as a continuum and to explore the therapeutic implications of established models through an interpretive clinical lens, termed 'Cardiometabolic 2.0'. This approach emphasizes identifying distinct clinical profiles within CKM to guide tailored interventions.

The review synthesizes the understanding of Cardiorenal–Metabolic (CKM) syndrome as a dynamic continuum, emphasizing that cardiovascular risk arises from maladaptive interactions among metabolic, renal, and vascular systems, rather than just additive comorbidities. It highlights the central pathophysiological hallmarks, including progressive microvascular dysfunction, increased arterial stiffness, and impaired renal autoregulation, which collectively promote both cardiac remodeling and renal injury. The authors propose a shift towards a 'Cardiometabolic 2.0' framework, advocating for an integrated, phenotype-informed, organ-protective prevention strategy. This framework moves beyond traditional glucose-centered management to consider the diverse clinical profiles of CKM patients. The review underscores that identifying specific CKM phenotypes is crucial for tailoring therapeutic interventions, thereby addressing the complex interplay of obesity, metabolic risk factors, CKD, and CVD. This approach aims to mitigate the bidirectional amplification between cardiac and renal dysfunction, which is strongly associated with increased risks of heart failure, kidney disease progression, and cardiovascular mortality.

The core finding is the conceptualization of CKM as a condition driven by multiple pathways leading to systemic alterations, necessitating a phenotype-driven therapeutic strategy for improved patient outcomes.