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.