Hepatorenal Syndrome: Paradigm Shifts in Pathophysiology, the Transplantation Paradox, and Future Precision Management.

Hepatorenal syndrome (HRS) is a severe kidney-dysfunction phenotype in patients with advanced cirrhosis and ascites. This review examines the historical and clinical evolution from type 1/type 2 HRS to explicit HRS-AKI, HRS-AKD, and HRS-CKD definitions. Contemporary criteria use dynamic serum creatinine and urine-output changes, assess response after adequate volume resuscitation when indicated, and recognize that structural kidney injury may coexist. The pathophysiological framework integrates portal hypertension, splanchnic vasodilation, systemic inflammation, bacterial translocation, and cardiac dysfunction. Terlipressin plus individualized albumin improves HRS reversal, but biochemical response does not consistently confer an overall survival benefit. Creatinine reduction may lower MELD-based priority; however, available studies do not demonstrate a uniform reduction in access to liver transplantation. Cystatin C and neutrophil gelatinase-associated lipocalin provide adjunctive phenotypic and prognostic information but lack validated treatment thresholds. Liver transplantation remains definitive treatment for eligible patients. Simultaneous liver-kidney transplantation requires criteria-based assessment, whereas kidney-after-liver transplantation provides a safety-net option for persistent severe kidney dysfunction after liver transplantation alone. CLIF-C ACLF and emerging models such as ReMELD-Na may complement risk assessment but do not independently replace governing allocation systems. Precision management requires serial reassessment, early transplant-center coordination, and multidisciplinary integration of hemodynamics, kidney-injury phenotype, treatment safety, and recovery potential.