International Journal of Molecular Sciences Review Management of Cirrhotic Ascites under the Add-on Administration of Tolvaptan Takuya Adachi, Yasuto Takeuchi, Akinobu Takaki *, Atsushi Oyama, Nozomu Wada, Hideki Onishi, Hidenori Shiraha and Hiroyuki Okada Department of Gastroenterology and Hepatology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan; [email protected] (T.A.); [email protected] (Y.T.); [email protected] (A.O.); [email protected] (N.W.); [email protected] (H.O.); [email protected] (H.S.); [email protected] (H.O.) * Correspondence: [email protected]; Tel.: +81-86-235-7219 Abstract: Tolvaptan is a recently available diuretic that blocks arginine vasopressin receptor 2 in the renal collecting duct. Its diuretic mechanism involves selective water reabsorption by affecting the water reabsorption receptor aquaporin 2. Given that liver cirrhosis patients exhibit hyponatremia due to their pseudo-aldosteronism and usage of natriuretic agents, a sodium maintaining agent, such as tolvaptan, is physiologically preferable. However, large scale studies indicating the patients for whom this would be effective and describing management under its use have been insufficient. The appropriate management of cirrhosis patients treated with tolvaptan should be investigated. In the present review, we collected articles investigating the effectiveness of tolvaptan and factors associated with survival and summarized their management reports. Earlier administration of tolvaptan before increasing the doses of natriuretic agents is recommended because this may preserve effective arterial Citation: Adachi, T.; Takeuchi, Y.; blood volume. Takaki, A.; Oyama, A.; Wada, N.; Onishi, H.; Shiraha, H.; Okada, H. Keywords: tolvaptan; liver cirrhosis; ascites Management of Cirrhotic Ascites under the Add-on Administration of Tolvaptan. Int. J. Mol. Sci. 2021, 22, 5582. https://doi.org/10.3390/ 1. Introduction ijms22115582 Liver cirrhosis and related complications are still regarded as unresolved issues. Although the prevalence of hepatitis C has decreased with the development of anti-hepatitis Academic Editor: Hirayuki Enomoto C virus (HCV) direct anti-viral agents (DAAs), the incidence of alcohol-related and non- alcoholic steatohepatitis (NASH)-related cirrhosis is increasing [1]. Received: 30 April 2021 The management of ascites and edema is one of the main themes in the treatment of cir- Accepted: 22 May 2021 rhosis. Diuretics are the first and main agents to control water retention [2]. Spironolactone Published: 25 May 2021 is the first diuretic used for the management of cirrhotic ascites, followed by furosemide. However, both agents block sodium reabsorption; thus, hyponatremia and a reduction of Publisher’s Note: MDPI stays neutral effective arterial blood volume (EABV) commonly occur as side effects [3]. The arginine with regard to jurisdictional claims in vasopressin (AVP) receptor is another target for hydration [4,5]. Terlipressin, an AVP published maps and institutional affil- iations. analog with a high affinity for vasopressin-1 (V1) receptors, has been shown to be effective via dilated splanchnic vascular vasoconstriction [4]. Another agent that acts on AVP is tolvaptan, which is a highly selective AVP V2 receptor antagonist [5]. The effectiveness of terlipressin has long been shown, while studies on tolvaptan have been insufficient [2]. We would like to focus on the clinical impact of tolvaptan and the management of Copyright: © 2021 by the authors. patients under tolvaptan administration by reviewing recently published articles. Licensee MDPI, Basel, Switzerland. This article is an open access article 2. Methods distributed under the terms and conditions of the Creative Commons We summarized the mechanisms underlying the development of ascites in cirrhosis, Attribution (CC BY) license (https:// and the management of ascites with diuretics other than tolvaptan, according to textbooks creativecommons.org/licenses/by/ and cirrhosis management guidelines [2,3,6–9]. We found articles investigating the effect of 4.0/). tolvaptan in cirrhotic ascites via Pubmed, using these search terms: ‘cirrhosis x tolvaptan’, Int. J. Mol. Sci. 2021, 22, 5582. https://doi.org/10.3390/ijms22115582 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 13 2. Methods We summarized the mechanisms underlying the development of ascites in cirrhosis, and the management of ascites with diuretics other than tolvaptan, according to textbooks Int. J. Mol. Sci. 2021, 22, 5582 and cirrhosis management guidelines [2,3,6–9]. We found articles investigating the effect2 of 14 of tolvaptan in cirrhotic ascites via Pubmed, using these search terms: ‘cirrhosis x tolvaptan’, ‘cirrhosis ascites tolvaptan’, and ‘cirrhosis x hyponatremia x tolvaptan’. In Sec- tion 4.2.2, we summarized the articles we found and our findings concerning the mecha- ‘cirrhosis ascites tolvaptan’, and ‘cirrhosis x hyponatremia x tolvaptan’. In Section 4.2.2, we nisms of action, and discussed how to manage cirrhotic ascites under add-on administra- summarized the articles we found and our findings concerning the mechanisms of action, tion of tolvaptan. and discussed how to manage cirrhotic ascites under add-on administration of tolvaptan. 3. 3.The The Mechanisms Mechanisms of of Ascites Ascites in in Cirrhosis Cirrhosis + TheThe pathogenesis pathogenesis of of Na Na and+ and water water retention retention in incirrhosis cirrhosis is isrelated related not not to to an an intrinsic intrinsic abnormalityabnormality of of the the kidneys, kidneys, but but rather toto extra-renalextra-renal mechanisms, mechanisms, as as kidneys kidneys from from patients pa- tientswith with end-stage end-stage liver liver disease disease could could work work appropriately appropriately if they if are they transplanted are transplanted to patients to patientswith normal with normal liver function.liver function. Various Various factors factors are involvedare involved in thein the appearance appearance of of ascites as- citesin cirrhosisin cirrhosis (Figure (Figure1). 1). Portal Portal hypertension hypertension is is initiated initiated byby increased hepatic hepatic resistance resistance toto portal portal blood blood flow, flow, caused caused by by the the distortion distortion of of the the vascular vascular architecture architecture [10]. [10]. Hepatic Hepatic sinusoidalsinusoidal cellular cellular alterations alterations induce induce constric constrictiontion of of the the sinusoids. sinusoids. Perisinusoidal Perisinusoidal chronic chronic inflammatoryinflammatory cell cell infiltration infiltration and and hepatic hepatic stel stellatelate cell cell (HSC) (HSC) activation activation induce induce sinusoidal sinusoidal constrictionconstriction via via cytokines cytokines and and cell-cell cell-cell direct direct contact. contact. Furthermore, Furthermore, vasodilation vasodilation and vas- and oconstrictionvasoconstriction balance balance are very are complex very complex in cirrhosis in cirrhosis patients. patients. The splanchnic The splanchnic vascular vascular bed is beddilated is dilated and hyporesponsive and hyporesponsive to vasoconstrictors, to vasoconstrictors, while whileseveral several vasoactive vasoactive molecules molecules are unbalanced.are unbalanced. The overflow The overflow and andunderfilling underfilling hypothesis hypothesis is a is hypothesized a hypothesized mechanism mechanism of of ascitesascites formation formation in incirrhotic cirrhotic patients patients [11]. [11 ]. Figure 1. A schematic diagram of the mechanisms of ascites development in cirrhosis. RAAS, Figurerenin-angiotensin 1. A schematic aldosterone diagram of system; the mechanisms SNS, sympathetic of ascites nerve development system. in cirrhosis. RAAS, renin-angiotensin aldosterone system; SNS, sympathetic nerve system. In the overflow hypothesis, increased hepatic vascular resistance and sinusoidal pres- sureIn induce the overflow non-volume-dependent hypothesis, increased renal Nahepa+ retention.tic vascular Hepatic resistance venous and and sinusoidal sinusoidal pressureconstriction induce resulting non-volume-dependent from liver fibrosis renal increase Na+ retention. hepatic afferentHepatic nervevenous activity. and sinusoi- This is dalfollowed constriction by the resulting adenosine-mediated from liver fibrosis hepatorenal increase reflex. hepatic Given afferent that an nerve adenosine activity. A1 This recep- is torfollowed antagonist by the inhibited adenosine-mediated Na+ retention inhepato a cirrhoticrenal ratreflex. model, Given the that fibrosis an adenosine related-reflex A1 is believed to be an important initiator of ascites [12]. This non-volume dependent renal Na+ retention can result in total plasma volume expansion and an increase in portosplanchnic bed pressure to overflow ascites. Increased volume of ascites might induce compression of the renal vein, resulting in congestive renal failure [13]. In the underfilling hypothesis, increased hepatic vascular resistance and hypoalbu- minemia induce transudation of fluid clinically shown to be ascites, resulting in hypo- volemia. Given that plasma volume expansion requires effective oncotic pressure, the Int. J. Mol. Sci. 2021, 22, 5582 3 of 14 overflow pathology is usually evident in the early cirrhotic stage in those who maintain serum albumin levels. As cirrhosis progresses, the underfilling pathology would become evident. Factors that