{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T16:06:36Z","timestamp":1788969996837,"version":"build-2803163510"},"reference-count":103,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Pers. Med.","JPM"],"abstract":"<jats:p>Heart failure affects more than 64 million people worldwide, and admissions for acute decompensation account for a substantial proportion of cardiovascular healthcare expenditure. Achieving complete decongestion remains the principal objective of inpatient management, yet many patients are discharged with persistent volume overload, a consistent predictor of early rehospitalization and mortality. Loop diuretics have remained the cornerstone of decongestive therapy for more than six decades; however, their effectiveness is frequently limited by diuretic resistance, leaving many patients incompletely decongested despite dose escalation. Diuretic resistance reflects adaptive sodium retention distributed across multiple nephron segments, a process that extends well beyond the loop itself. Distal-tubular-remodeling-enhanced proximal sodium reabsorption, neurohormonal activation, post-diuretic sodium retention, and impaired tubular drug delivery collectively blunt natriuretic responsiveness, explaining why progressive loop\u2013dose escalation often yields diminishing returns. Sequential nephron blockade provides a physiology-based strategy that matches the adjunct agent to the predominant mechanism of sodium retention. We integrate contemporary randomized evidence with renal tubular physiology to propose a mechanism-based approach: acetazolamide for patients with hypochloremic metabolic alkalosis and enhanced proximal sodium reabsorption, thiazide-type diuretics when distal cotransporter escape predominates, vasopressin antagonists for dilutional hyponatremia complicating congestion, and sodium\u2013glucose cotransporter 2 inhibitors as foundational therapy that combines modest acute natriuresis with durable cardiorenal protection. Early assessment of natriuretic response using spot urine sodium further enables individualized treatment escalation. Together, these concepts move sequential nephron blockade beyond empirical combination diuretic therapy toward a mechanism-based strategy for overcoming diuretic resistance. We propose a personalized, phenotype-driven framework in which early urinary sodium response, kidney function, serum chloride, acid\u2013base status, serum sodium, background SGLT2 inhibitor therapy, and venous congestion imaging guide the selection, escalation, and de-escalation of adjunctive therapy, with the goal of more complete and safer decongestion in acute decompensated heart failure. Matching adjunct choice to a patient\u2019s individual biochemical phenotype, rather than applying diuretics in a fixed sequence, exemplifies precision medicine applied to acute decongestive therapy.<\/jats:p>","DOI":"10.3390\/jpm16090466","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T15:01:56Z","timestamp":1788966116000},"page":"466","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Personalized Sequential Nephron Blockade for Diuretic Resistance in Acute Decompensated Heart Failure: A Narrative Review for the Cardiorenal Clinician"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4823-9910","authenticated-orcid":false,"given":"Guido","family":"Gembillo","sequence":"first","affiliation":[{"name":"Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Concetto","family":"Sessa","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Dialysis, Maggiore Nino Baglieri Hospital, 97015 Modica, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1678-3778","authenticated-orcid":false,"given":"Luca","family":"Zanoli","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Visconti","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Dialysis, Ospedali Riuniti Villa Sofia Cervello, University of Palermo, 90146 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Federica","family":"Ricca","sequence":"additional","affiliation":[{"name":"Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9112-5540","authenticated-orcid":false,"given":"Lorenzo","family":"Lo Cicero","sequence":"additional","affiliation":[{"name":"Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy"},{"name":"PhD Program in Molecular and Clinical Medicine, University of Palermo, 90100 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7276-3256","authenticated-orcid":false,"given":"Andrea","family":"Corsonello","sequence":"additional","affiliation":[{"name":"Unit of Geriatric Medicine, Italian National Research Center on Aging (IRCCS INRCA), 87100 Cosenza, Italy"},{"name":"Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Petrina","sequence":"additional","affiliation":[{"name":"Cardiology Unit, Giovanni Paolo II Hospital, 97100 Ragusa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7862-5751","authenticated-orcid":false,"given":"Antonino","family":"Nicosia","sequence":"additional","affiliation":[{"name":"Cardiology Unit, Giovanni Paolo II Hospital, 97100 Ragusa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0171-3358","authenticated-orcid":false,"given":"Luca","family":"Soraci","sequence":"additional","affiliation":[{"name":"Unit of Geriatric Medicine, Italian National Research Center on Aging (IRCCS INRCA), 87100 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Fede","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Maggiore Nino Baglieri Hospital, 97015 Modica, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guglielmo","family":"Piccione","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Maggiore Nino Baglieri Hospital, 97015 Modica, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiano","family":"Lumera","sequence":"additional","affiliation":[{"name":"Coronary Care Unit (CCU), Department of Cardiology, Riccardo Guzzardi Hospital, 97019 Vittoria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Morale","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Dialysis, Maggiore Nino Baglieri Hospital, 97015 Modica, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4279-6559","authenticated-orcid":false,"given":"Domenico","family":"Santoro","sequence":"additional","affiliation":[{"name":"Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3272","DOI":"10.1093\/cvr\/cvac013","article-title":"Global Burden of Heart Failure: A Comprehensive and Updated Review of Epidemiology","volume":"118","author":"Savarese","year":"2023","journal-title":"Cardiovasc. 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