Meta-Analysis
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Apr 27, 2022; 14(4): 827-845
Published online Apr 27, 2022. doi: 10.4254/wjh.v14.i4.827
Effects and safety of natriuretic peptides as treatment of cirrhotic ascites: A systematic review and meta-analysis
Rasmus Hvidbjerg Gantzel, Mikkel Breinholt Kjær, Peter Jepsen, Niels Kristian Aagaard, Hugh Watson, Lise Lotte Gluud, Henning Grønbæk
Rasmus Hvidbjerg Gantzel, Mikkel Breinholt Kjær, Peter Jepsen, Niels Kristian Aagaard, Hugh Watson, Henning Grønbæk, Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N 8200, Denmark
Lise Lotte Gluud, Gastroenterology Unit, Copenhagen University Hospital, Hvidovre 2650, Denmark
Lise Lotte Gluud, Department of Clinical Medicine, University of Copenhagen, Hvidovre 2650, Denmark
Author contributions: Gluud LL and Grønbæk H contributed equally to the work. All authors contributed to the design of the study. Gantzel RH and Kjær MB acquired the study data; Gantzel RH and Gluud LL performed the statistical analyses; all authors contributed to the interpretation of data; Gantzel RH drafted the manuscript; and all authors critically reviewed and approved the final manuscript.
Conflict-of-interest statement: Grønbæk H has received a research grant (No. ULA04-2019-1) from ADS AIPHIA Development Services AG (Switzerland) to investigate ularitide in patients with refractory ascites. Watson H owns stocks in Sanofi. Gantzel RH, Kjær MB, Jepsen P, and Aagaard NK have nothing to report. Financial support: Grønbæk H has received research funding from Intercept, Abbvie, NOVO Nordisk Foundation, Arla, and ADS AIPHIA Development Services AG. Grønbæk H is an advisory board member for Ipsen and speaker for Norgine. Gluud LL has received grants from Novo Nordisk, Alexion, and Gilead.
PRISMA 2009 Checklist statement: This review was performed in accordance with the PRISMA guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Henning Grønbæk, MD, PhD, Doctor, Professor, Research Associate, Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N 8200, Denmark. henngroe@rm.dk
Received: July 5, 2021
Peer-review started: July 5, 2021
First decision: November 11, 2021
Revised: November 22, 2021
Accepted: March 25, 2022
Article in press: March 25, 2022
Published online: April 27, 2022
Processing time: 291 Days and 0.2 Hours
ARTICLE HIGHLIGHTS
Research background

Ascites formation is the most frequent event of cirrhosis decompensation with no approved non-invasive treatment for patients with refractory ascites. However, natriuretic peptides may induce beneficial effects in patients with cirrhosis and ascites, by counterbalancing vasoconstriction and anti-natriuretic factors.

Research motivation

Only small studies with a broad pallet of designs, have investigated the renal and systemic effects and safety of natriuretic peptides in patients with cirrhosis and ascites. We were motivated to compile results regarding natriuretic peptides as treatment for ascites to advance pharmaceutical research concerning this disease.

Research objectives

We aimed to systematically review the effects and safety of natriuretic peptides in patients with cirrhosis and ascites. We collected results regarding changes in renal sodium and water excretion, plasma aldosterone concentration, and plasma renin activity, and to perform meta-analyses providing overall estimates of the effects of natriuretic peptide infusions. Safety assessments, in particular blood pressure decreases, were included and descriptively summarised.

Research methods

We adhered to the PRISMA guidelines and the Cochrane Handbook. A review protocol was preregistered at PROSPERO. The databases MEDLINE, Web of Science, Embase, Scopus, and Cochrane Library were searched and references reporting the renal and systemic effects of mono-therapy with atrial natriuretic peptide (ANP), B-type natriuretic peptide, urodilatin, or any synthetic equivalent in patients with cirrhosis and ascites were considered for inclusion. Treatment administration had to be intravenous, but trials were included regardless of dose, follow-up duration, and whether a continuous infusion or bolus injection was administered. The study screening and data extraction were performed independently by two reviewers. A random-effects model was applied for the meta-analysis. Reasons for heterogeneity were explored through subgroup and leave-one-out analyses.

Research results

Twenty-two studies were included and short-term ANP infusion was the only intensively studied treatment. Renal sodium and water excretion increased in response to continuous ANP infusion and was most pronounced when infusion rates > 30 ng/kg/min were applied. Furthermore, sodium excretion was higher in study subgroups with mild/moderate ascites compared with refractory ascites. The baseline plasma aldosterone concentration and renin activity were significantly lower in subgroups achieving a negative sodium balance compared with treatment non-responders, and may be relevant response predictors to include in future trials. Blood pressure decreases occurred less frequently with doses ≤ 30 ng/kg/min.

Research conclusions

Intravenous infusions of natriuretic peptides induce meaningful sodium and water excretion in patients with cirrhotic ascites. Continuous ANP infusions > 30 ng/kg/min induce the most pronounced renal effects, but with a higher risk of blood pressure decreases than doses ≤ 30 ng/kg/min.

Research perspectives

Future larger-scale clinical trials are justified to determine the therapeutic potential of natriuretic peptides in patients with cirrhotic ascites.