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Association of the G-protein and α2-adrenergic receptor gene and plasma norepinephrine level with clonidine improvement of the effects of diuretics in patients with cirrhosis with refractory ascites: a randomised clinical trial
  1. Y Y Yang1,2,
  2. H C Lin3,
  3. W P Lee4,
  4. C J Chu3,
  5. M W Lin2,
  6. F Y Lee5,
  7. M C Hou3,
  8. J S Jap5,
  9. S D Lee3
  1. 1Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
  2. 2Division of Preventive Medicine, Institute of Public Health, National Yang-Ming University, Taipei, Taiwan
  3. 3Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
  4. 4Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan
  5. 5Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
  1. Correspondence to Dr. YY Yang, Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road; Division of Preventive Medicine, Institute of Public Health, National Yang-Ming University, Section 2, Li-Nong Street, Taipei 11217, Taiwan; yangyy{at}vghtpe.gov.tw
  2. Dr. MW Lin, Division of Preventive Medicine, Institute of Public Health, National Yang-Ming University, Section 2, Li-Nong Street, Taipei 11221, Taiwan; mwlin{at}ym.edu.tw

Abstract

Objective Clonidine is an α2-adrenoceptor agonist which, by coupling with G-protein, has been proposed as an alternative treatment for refractory ascites of patients with cirrhosis for several years. Genetic polymorphisms of β-adrenoceptor and angiotensin II type 1 receptor blockers have been reported to affect drug response in patients with cirrhosis. This study evaluated the clonidine–diuretic response rate, favourable predictors and genetic components of the clonidine–diuretic response in patients with cirrhosis with refractory ascites.

Methods 270 patients with cirrhosis with refractory ascites were randomised equally into two treatment groups to receive diuretics alone or the clonidine–diuretics association. The primary end point was clonidine–diuretic response rate. Secondary end points were mean daily dose of diuretics, times of paracentesis, ascites-related readmission and 1-year survival rate.

Results Good clonidine responders had better natriuresis and diuresis as well as a significant decrease in abdominal circumference, plasma renin, aldosterone and norepinephrine levels. The overall clonidine–diuretics response rate was 55–60%. In patients with cirrhosis, the prevalence of ARDA2C WD/DD and GNB3 CT/TT genotypes was 71% and 77%, respectively. Among the responders, 71% of patients with cirrhosis had the ARDA2C WD/DD genotype and 67% has the GNB3 CT/TT genotype. Besides higher baseline norepinephrine levels, the presence of both ARDA2C WD/DD and GNB3 CT/TT genotypes showed a positive predictive value of 82% and a negative predictive value of 79% for good clonidine response.

Conclusions These results suggest that neurohormonal and genetic testing may be used as predictive factors for the additive effects of clonidine on the diuresis and natriuresis effects of diuretics in patients with cirrhosis with refractory ascites.

  • Cirrhosis
  • clonidine
  • refractory ascites
  • genetic polymorphism

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Footnotes

  • Y-YY and L-HC share the first authorship of this paper. Y-YY (major) and L-MW are co-corresponding authors on this paper.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Ethics committee of Taipei Veterans General Hospital.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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