Cardiorenal syndrome: A systematic review of pathophysiology, classification, biomarkers, echocardiographic strain, therapeutic strategies and prognostic implications

Background: Cardiorenal Syndrome (CRS) represents a complex bidirectional interaction between cardiac and renal dysfunction and is associated with substantial morbidity and mortality. Conventional parameters, including left ventricular ejection fraction (LVEF) and serum creatinine, are limited in detecting early subclinical dysfunction. Emerging evidence highlights the role of echocardiographic strain imaging, particularly global longitudinal strain (GLS), in identifying early myocardial impairment and improving risk stratification in CRS.

Objectives: To systematically evaluate the pathophysiology, classification, biomarkers, echocardiographic strain, therapeutic strategies, and prognostic implications of CRS across its subtypes.

Methods: A systematic search of PubMed, Embase, Scopus, and the Cochrane Library was conducted for studies published between 2005 and 2025. Randomized controlled trials, cohort studies, and observational studies involving adult patients with CRS (Types 1–5) were included. Data extraction and quality assessment were performed independently by two reviewers in accordance with PRISMA guidelines. Outcomes of interest included all-cause mortality, renal function decline, heart failure hospitalization, and the diagnostic and prognostic performance of biomarkers and strain parameters.

Results: A total of 72 studies encompassing 131,845 patients were included. CRS Type 1 and Type 2 accounted for the majority of cases (>70%) and were associated with the highest adverse event rates. The prevalence of CRS in acute heart failure ranged from 25% to 40%, with 1-year mortality exceeding 30%. Pathophysiological mechanisms extended beyond reduced cardiac output and included venous congestion, neurohormonal activation, systemic inflammation, and endothelial dysfunction.

Biomarkers such as neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C demonstrated superior early detection of renal injury compared with conventional measures, while natriuretic peptides retained strong prognostic utility.

Importantly, echocardiographic strain imaging emerged as a sensitive marker of subclinical myocardial dysfunction. GLS impairment was consistently observed even in patients with preserved LVEF and was independently associated with worsening renal function and adverse outcomes. Across studies, reduced GLS (less negative values) was associated with increased mortality and hospitalization risk (hazard ratios 1.4–2.2).

Therapeutically, renin–angiotensin–aldosterone system inhibitors and sodium–glucose cotransporter-2 inhibitors (SGLT2 inhibitors) reduced composite cardiorenal endpoints by approximately 20–30%, while device-based therapies such as ultrafiltration were beneficial in selected refractory cases.

Conclusions: CRS is a multifaceted syndrome driven by complex hemodynamic and non-hemodynamic mechanisms and is associated with consistently poor outcomes. Integration of echocardiographic strain imaging with biomarker-based approaches enhances early detection and prognostic stratification beyond conventional measures. Emerging therapies, particularly SGLT2 inhibitors, provide significant cardiorenal protection. Future research should focus on standardized diagnostic frameworks and personalized, imaging-guided management strategies.