Beyond Blood Pressure: Salt Sensitivity as a Cardiorenal Phenotype—A Narrative Review

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  Figure 1. Conceptual framework for the assessment of salt sensitivity. Salt sensitivity is traditionally evaluated by observing BP responses to controlled dietary sodium manipulation, typically involving sequential low-salt and high-salt intake over several days to one week, with standardized BP measurements. Assessment relies on dynamic BP evaluation using office measurements, ABPM, or HBPM, in combination with reassessment of volume status and routine biomarkers of sodium balance and renal function, including serum electrolytes, creatinine/eGFR, albuminuria, and urinary sodium excretion. Adjunctive and investigational approaches are shown separately to emphasize their supportive and mechanistic role. These include diuretic challenge testing, genetic susceptibility markers (e.g., RAAS-related polymorphisms), and experimental sodium-handling biomarkers such as urinary angiotensinogen and urinary exosomal sodium transporter markers (e.g., ENaC, NCC). These methods are primarily applied in research or selected clinical settings and are not currently standardized for routine clinical diagnosis of salt sensitivity. Given the absence of a universally accepted clinical gold standard, the…

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  Figure 2. Integrated pathophysiological mechanisms underlying SSBP. The figure illustrates the converging renal, neurohormonal, vascular, immune–inflammatory, and genetic mechanisms contributing to the development of SSBP. Impaired renal sodium excretion leads to intravascular volume expansion and activation of the RAAS, promoting sodium retention and potassium excretion through pathways involving WNK4–SPAK/OSR1 signaling and Rac1-mediated MR activation. Ιncreased sympathetic nervous system activity, norepinephrine spillover, endothelial dysfunction, and vascular remodeling augment peripheral vascular resistance. Sodium overload also triggers immune and inflammatory responses, including activation of dendritic cells and macrophages, oxidative stress, IsoLG formation, and gut dysbiosis, further amplifying local and systemic inflammation. Genetic and epigenetic susceptibility modulates these processes, predisposing individuals to impaired sodium handling and exaggerated BP responses. Collectively, these interacting pathways establish a self-reinforcing cardiorenal–hypertensive phenotype characteristic of SSBP. Abbreviations: BP, blood pressure; IsoLG, isolevuglandins; MR, mineralocorticoid…

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  Figure 3. Clinical framework for the recognition and phenotype-guided management of SSBP. This schematic illustrates a stepwise, clinically oriented approach to SSBP, progressing from population-level screening and clinical suspicion to targeted investigations and individualized therapeutic decision-making. Risk factors prompting screening include older age, CKD, obesity, HFpEF, insulin resistance, African ancestry and family history. Clinical features raising suspicion include non-dipping or highly variable blood pressure patterns, salt-dependent edema, albuminuria, weight gain, and reduced exercise capacity. Diagnostic evaluation relies on dynamic blood pressure monitoring (ABPM/HBPM), laboratory assessment of renal function and electrolytes, and evaluation of natriuretic response. Management emphasizes individualized sodium balance and phenotype-guided therapy, including diuretics, RAAS blockade, mineralocorticoid receptor antagonists, SGLT2i, and incretin-based therapies when indicated. This framework reflects commonly applied clinical principles rather than a formal diagnostic algorithm. Abbreviations: ABPM, ambulatory blood pressure monitoring; BP, blood pressure; CKD, chronic kidney…

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  Figure 4. Framework of dynamic BP metrics and laboratory assessment in SSBP. The bidirectional correlation between dynamic hemodynamic evaluation and biochemical monitoring in the identification and management of SSBP. Dynamic BP indices, including ABPM and HBPM parameters, BP variability, and emerging wearable technologies measurements in combination with key laboratory markers relevant to SSBP pathophysiology, encompassing serum electrolytes (Na+, K+, Cl−), creatinine/eGFR, albuminuria/ACR, metabolic indicators, and markers of diuretic response target to early identification of hemodynamic and biochemical abnormalities (microvascular dysfunction, plasma volume expansion, renal sodium retention, and tissue RAAS/MR activation) that progressively result in major clinical consequences; target-organ damage, cardiovascular events, CKD progression, and the HFpEF phenotype. This integrative model provides a more complete risk profile, and facilitates precision diagnosis and individualized management in SSBP. Abbreviations: ABPM, ambulatory blood pressure monitoring; ACR, albumin-to-creatinine ratio; BP, blood pressure; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate;…

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  Figure 5. Pathophysiology, clinical manifestations and main therapeutic management of SSBP. Abbreviations: ACE, angiotensin-converting enzyme; ACR, albumin-to-creatinine ratio; ARBs, angiotensin receptor blockers; eGFR, estimated glomerular filtration rate; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1 receptor agonist; HFpEF, heart failure with preserved ejection fraction; LVH, left ventricular hypertrophy; MRAs, mineralocorticoid receptor antagonists; RAAS, renin–angiotensin–aldosterone system; SGLT2, sodium–glucose cotransporter 2; SNS, sympathetic nervous system; SSBP, salt-sensitive blood pressure.