Diuretic resistance in cardiorenal syndrome: mechanisms, monitoring and phenotype-tailored management

Congestion drives most hospitalizations for acute and chronic heart failure (HF), reflecting the pivotal role of sodium and water retention in disease progression. Loop diuretics remain the first-line decongestive therapy, yet up to one-third of patients exhibit an inadequate natriuretic response—defined as diuretic resistance (DR)—which is strongly associated with prolonged hospitalization, readmissions and adverse outcomes. DR is a multifactorial phenomenon arising from pharmacokinetic limitations, tubular adaptations, neurohormonal activation, and hemodynamic disturbances. Impaired renal perfusion, elevated venous pressures, and chloride depletion are key contributors that mutually reinforce one another and blunt diuretic efficacy. Early recognition through urinary sodium measurement and urine output monitoring is essential to guide therapy before resistance becomes entrenched. Beyond optimizing loop diuretic delivery, management strategies should include sequential nephron blockade, correction of electrolyte and acid–base imbalances and avoidance of excessive sodium restriction. Certain patient phenotypes—right heart failure (RHF), advanced chronic kidney disease (CKD), obesity-related HF with preserved ejection fraction (HFpEF), and frail or elderly patients—pose additional challenges due to overlapping mechanisms of resistance and increased treatment vulnerability. Each requires a tailored approach that balances decongestion with preservation of renal function and systemic perfusion. In refractory cases, extracorporeal fluid removal or peritoneal dialysis may be necessary, while newer pharmacologic agents—such as sodium–glucose cotransporter 2 inhibitors (SGLT2i), mineralocorticoid receptor antagonists (MRAs), and glucagon-like peptide-1 receptor agonists GLP-1 RAs)—offer complementary benefits. This review synthesizes mechanistic insights, bedside monitoring tools and phenotype-specific strategies for the management of DR in cardiorenal syndrome (CRS).