title: Identification of diuretic non-responders with poor long-term clinical outcomes: a 1-year follow-up of 176 non-azotaemic cirrhotic patients with moderate ascites.
abstract: In cirrhosis, the development of ascites and the response to diuretics are determined by the RAAS (renin-angiotensin-aldosterone system) and renal sodium handling system. We hypothesized that SNPs (single nucleotide polymorphisms) affecting candidate genes in the RAAS and renal sodium handling pathway may influence initial diuretic responsiveness and affect clinical outcome in non-azotaemic cirrhotic patients with moderate ascites. We prospectively recruited 176 patients and 245 controls and determined their genetic polymorphisms for 24 SNPs of ten genes involved in the RAAS and renal sodium handling pathway. In cirrhotic patients with moderate ascites, multivariate analysis showed that diuretic unresponsiveness was predicted by a high basal plasma aldosterone level, by a high aldosterone/renin ratio and by specific risk genotypes of ACE (gene encoding angiotensin-converting enzyme), CYP11B2 (gene encoding aldosterone synthase) and ADDA (gene encoding α-adducin). This association between genetic polymorphisms and diuretic unresponsiveness was confirmed by an independent validation cohort. Notably, additive effects in relation to diuretic unresponsiveness were observed in cases where there was the simultaneous presence of the three risk genotypes. Among patients carrying any of the risk genotypes, more episodes of paracentesis and ascites-related readmission after 3 months of treatment, as well as a reduced 1-year survival rate, were observed. In addition to traditional predictors, our present study provides additional genetic and neurohormonal predictors that will help to identify diuretic non-responders among cirrhotic patients with moderate ascites. Among those carrying unfavourable risk genotypes, additional therapies, including paracentesis and albumin infusion, should be started as early as possible.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, and Institute of Public Health, National Yang-Ming University, Taipei 11217, Taiwan. yyyang@vghtpe.gov.trw
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Yang
authors.forename: Han-Chieh
authors.initials: HC
authors.lastname: Lin
authors.forename: Ming-Wei
authors.initials: MW
authors.lastname: Lin
authors.forename: Chi-Jen
authors.initials: CJ
authors.lastname: Chu
authors.forename: Fa-Yauh
authors.initials: FY
authors.lastname: Lee
authors.forename: Ming-Chih
authors.initials: MC
authors.lastname: Hou
authors.forename: Shou-Dong
authors.initials: SD
authors.lastname: Lee
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Lee
authors.forename: Tze-Tze
authors.initials: TT
authors.lastname: Liu
authors.forename: Tjin-Shing
authors.initials: TS
authors.lastname: Jap
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000450:Aldosterone / Q000097:blood; D001201:Ascites / Q000188:drug therapy*; D015415:Biomarkers / Q000097:blood; D004232:Diuretics / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D004812:Epidemiologic Methods; D056726:Genetic Association Studies; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000235:genetics / Q000502:physiology; D012964:Sodium / Q000378:metabolism; D017211:Treatment Failure; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015415:Biomarkers; D004232:Diuretics; D000450:Aldosterone; D012964:Sodium; D012083:Renin