Kidney Problems in Cirrhosis Dig Dis 2015;33:548–554 DOI: 10.1159/000375346
The Treatment of Hepatorenal Syndrome Marta Cavallin a Silvano Fasolato a, b Simona Marenco c Salvatore Piano a Marta Tonon a, b Paolo Angeli a, b a
U.O. Clinica Medica V and b Unit of Hepatic Emergencies and Liver Transplantation, Department of Medicine, DIMED, University of Padua, Padua, and c Department of Internal Medicine, Gastroenterology Unit, University of Genoa, Genoa, Italy
Abstract Hepatorenal syndrome (HRS) is a severe complication that often occurs in patients with cirrhosis and ascites. HRS is a functional renal failure that develops mainly as a consequence of a severe cardiovascular dysfunction which is characterized by an extreme splanchnic arterial vasodilation and a reduction of cardiac output. HRS may develop in two clinical types: as an acute and rapidly progressive renal failure (AKI-HRS) or as chronic and not progressive renal failure (CKD-HRS). Several small studies and some randomized control studies have been published on the use of terlipressin plus albumin in the treatment of HRS, mainly on AKI-HRS. Terlipressin plus albumin was shown to improve renal function in almost 35–45% of patients with AKI-HRS, as well as to improve short-term survival in these patients. Terlipressin was most commonly used by intravenous boluses moving from an initial dose of 0.5–1 mg every 4 h to 3 mg every 4 h in the case of a nonresponse. In other studies, terlipressin was also given by continuous intravenous infusion. Thus, the best way to administer terlipressin in the treatment of HRS has not yet been defined. α-Adrenergic drugs, such as intravenous norepinephrine or oral midodrine plus subcutaneous octreotide, administered with albumin have also been
© 2015 S. Karger AG, Basel 0257–2753/15/0334–0548$39.50/0 E-Mail [email protected] www.karger.com/ddi
used in the treatment of AKI-HRS, with promising results. However, we need further studies in order to define whether they can represent a real therapeutic alternative. In conclusion, available data are sufficient to state that the use of terlipressin plus albumin has really changed the management of HRS. Nevertheless, some crucial unsolved issues still exist, in particular: (a) how to predict nonresponse to treatment, (b) how to manage nonresponse to treatment and (c) how to consider the response in those patients who are candidates for liver transplant in the priority allocation process. © 2015 S. Karger AG, Basel
Introduction
A marked renal arterial vasoconstriction and the consequent reduction of renal arterial perfusion are thought to be the main pathophysiological bases of hepatorenal syndrome (HRS). It develops in patients with advanced cirrhosis as a consequence of an extreme overactivation of the endogenous systemic vasoconstrictor systems, namely the renin-angiotensin system, the sympathetic nervous system and the nonosmotic release of vasopressin due to a severe reduction of effective circulating volume. This reduction is believed to be due to both an extreme splanchnic arterial vasodilation and an impairment of cardiac output [1–4]. Splanchnic arterial vasodilation is thought to be mainly the consequence of an increased release of Prof. Paolo Angeli Unit of Hepatic Emergencies and Liver Transplantation Department of Medicine, University of Padua Via Giustiniani 2, IT–35128 Padua (Italy) E-Mail pangeli @ unipd.it
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Key Words Albumin · Acute kidney injury · Cirrhosis · Terlipressin · α-Adrenergic drug
Use of Terlipressin in the Treatment of HRS
To date, four randomized controlled clinical trials comparing terlipressin and albumin in the treatment of HRS, mainly of AKI-HRS, with albumin alone have been published [8–11]. In addition, terlipressin plus albumin has been used in several uncontrolled clinical studies. Taking these studies as a whole, terlipressin has been used in more than 300 patients [12–23]. In most of these patients, terlipressin was administered as an intravenous bolus starting from an initial dose of 0.5 mg every 4–6 h [12– 20, 23]. Only in a few studies was the drug administered as a continuous intravenous infusion starting from an initial dose of 2 mg/day [21, 22]. In patients without a clinical response, defined as a reduction of serum creatinine (sCr) 50% in patients with AKIHRS. The response was further defined as complete or partial according to the final sCr: 1.5 mg/dl, respectively. The rate of response commonly ranges between 40 and 50% when terlipressin was given alone [14, 15]; however, the rate of reversal of HRS, which is the achievment of normal serum creatinine levels, is lower in patients receiving terlipressin than in patients reThe Treatment of HRS
ceiving both terlipressin and albumin [18, 19]. It is important also to emphasize that response rates above 65% were observed with terlipressin and albumin in patients with AKI-HRS associated with sepsis [21, 23]. No controlled clinical study showed a significant effect of terlipressin plus albumin on survival when this association was compared to albumin alone or to placebo. Nevertheless, a subsequent systematic review and metaanalysis of all the randomized controlled clinical trials showed that this treatment may slightly increase survival in patients with type 1 HRS [24, 25]. During the treatment with terlipressin plus albumin, the normalization or decrease in sCr can take several days. Therefore, the treatment is usually continued for up to 10–15 days. It has been stated that after the withdrawal HRS can recur in up to 20% of cases and that recurrence can be efficiently retreated with terlipressin and albumin [26]. As a result, in patients with continuous recurrence of type 1 HRS, which has been recently defined as a relapse of type 1 HRS more than once within 72 h after the discontinuation of treatment with terlipressin and albumin [27], this therapeutic strategy can result in a longterm administration of terlipressin and albumin, continuing for months rather than weeks [27, 28]. The most common side effect of terlipressin is diarrhea, which in most cases is self-limiting and thus does not require the discontinuation of the drug unless it is associated with severe abdominal pain. The most severe adverse effects of terlipressin are cardiovascular or ischemic complications (chest pain, abdominal pain or arrhythmia), which have been reported in an average of 12% of patients treated. This is the reason why severe cardiovascular ischemic conditions should be considered contraindications to the use of terlipressin in patients with cirrhosis, and a close clinical and ECG monitoring should be performed during the treatment.
Use of Other Pharmacological Approaches: α-Adrenergic Drugs
The rationale for the use of α-adrenergic drugs such as norepinephrine alone or oral midodrine combined with subcutaneous octreotide, together with intravenous albumin, in the treatment of AKI-HRS deserves some comment. First, unlike terlipressin, there has so far been no clinical study in which the effect of either norepinephrine or midodrine has been evaluated in patients with cirrhosis. In an experimental model of cirrhosis, it can be observed that norepinephrine was capable of increasing the Dig Dis 2015;33:548–554 DOI: 10.1159/000375346
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endogenous vasodilators due to portal hypertension and/ or hepatic failure, while the inadequate cardiac output can be the extreme manifestation of a systolic dysfunction which is part of the so-called cirrhotic cardiomyopathy [5]. Based on pharmacodynamic studies on the effects of terlipressin on the splanchnic circulation in patients with cirrhosis [6], this drug was introduced in the treatment of HRS at the end of 1990s in order to reduce portal hypertension by counteracting the splanchnic arterial vasodilation. Albumin was combined with terlipressin to further improve the effective circulating volume and, as a consequence, arterial renal perfusion. This rationale for the use of terlipressin plus albumin was later proved in patients with cirrhosis and ascites without renal failure [7]. This review will mainly focus on the use of terlipressin and other vasoconstrictors plus albumin in the treatment of acute kidney injury (AKI)-HRS.
Table 1. Drug effects in cirrhosis
Drug
Effect on Effect on portal Effect on MAP splanchnic arterial pressure vasodilation
Effect on renal Effect on urinary blood flow sodium excretion
Terlipressin Noradrenalin Midodrine Octreotide
+++ +++ NA ++
+++ No +/No No
+++ No NA +/++
+++ +++ +/++ +
++ + +/No No
NA = Not appropriate; + = mild effect; ++ = moderate effect; +++ = high effect; No = no effect. Data specifically obtained in patients with HRS are in italics.
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circulation in cirrhosis (table 1), but also on the experimental evidence that the responsiveness to vasoconstrictors of the mesenteric artery may be normalized by the inhibition either of glucagon or nitric oxide [36, 37]. The choice of inhibiting glucagon release is based on clinical and experimental data showing that the inhibition of prostacyclin or nitric oxide synthesis may induce renal failure per se in patients or animals with cirrhosis, because these compounds counteract the action of vasoconstrictors on renal perfusion [38, 39]. No controlled clinical study has so far been performed with midodrine plus octreotide administered together with albumin. In the largest uncontrolled studies this therapeutic option was shown to be effective in almost 40% of patients with AKI-HRS [40, 41]. In all studies except one [42], treatment was administered according to the originally proposed schedule [35]. Thus, octreotide was administered via the subcutaneous route with a starting dose of 100 mg 3 times a day, which was titrated up to 200 mg thrice daily as necessary. Midodrine was started at an oral dose of 7.5 mg 3 times a day and titrated up to a maximum dose of 15 mg 3 times a day as tolerated based on the systolic blood pressure. Albumin was given in differing concentrations at a dose ranging from 20 to 100 g/ day. Similarly to what has been said about noradrenalin, in total midodrine plus octreotide and albumin have so far been used in less than 120 patients with AKI-HRS [40–42]. Thus, we need further studies to clarify its role in the treatment of HRS. Octreotide alone has no impact on improving renal function [42, 43].
Unsolved Issues in the Treatment of HRS
The introduction of the use of vasoconstrictors and albumin represents a milestone in the management of AKI-HRS [49]. However, the treatment is effective in 35– Cavallin/Fasolato/Marenco/Piano/Tonon/ Angeli
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superior mesenteric artery resistance but not reducing portal pressure. In addition, in cirrhotic rats, norepinephrine was not capable of improving renal perfusion [29]. In spite of these potential disadvantages, when norepinephrine was compared to terlipressin in the treatment of AKI-HRS in three small controlled clinical studies, similar results were found in terms of both the rate of response and 30-day survival [30–32]. It should be emphasized that most of the patients included in one of these studies had CKD-HRS [32]. Furthermore, none of these controlled clinical studies had an adequate sample size to offer assessment of the equivalence between terlipressin and norepinephrine with certainty. However, norepinephrine may potentially have a favorable effect on cardiac output by restoring the proper functioning of the adrenergic receptor pathway in the cardiac tissue through the simultaneous administration of albumin, thanks to its property of volemia expansion [33]. In all the controlled and uncontrolled studies, noradrenalin was used by continuous intravenous infusion at the initial dose of 0.5 mg/h. In the case of a nonresponse, the dose was progressively increased up to a maximum of 3 mg/h [30–32, 34]. In all the studies, noradrenalin was always used together with albumin with doses ranging from 20 to 70 g/day [30–32, 34]. The new aspects of the action of albumin on cardiac tissue in cirrhosis and their possible effect favoring the action of norepinephrine in the treatment of HRS are exciting. Nevertheless, norepinephrine has been used in less than 70 patients with AKI-HRS to date [31–34]. Therefore, according to the conclusion of a recent study [35] about the treatment of HRS type 1, further studies are needed to clarify its role in the treatment of AKI-HRS. The rationale for the use of oral midodrine and subcutaneous or intravenous octreotide is slightly more complex and deserves to be clarified [35]. It is based not only on the simple sum of the effects of the two drugs on the splanchnic
study by the EASL-Clif Consortium [66]. More precisely, it has been observed that a CLIF-SOFA score of >11 has a 92% sensitivity and 100% specificity in predicting no response to terlipressin therapy [23]. This observation opens a further discussion on potential specific features of the pathophysiology of AKI-HRS in patients with ACLF. Moreover, it introduces a limit in the prognostic value of the KDIGO (Kidney Disease: Improving Global Outcome) criteria (which, like AKIN, evaluate serum creatinine and urine output to diagnose AKI, but furthermore to assess its severity) in patients with ACLF. The prognostic evaluation in patients with cirrhosis who are hospitalized for an acute decompensation should take into account the failures of organs other than the kidney. More specifically, the CLIF-SOFA score has a better prognostic value compared to the AKIN (Acute Kidney Injury Network) criteria in these patients which are commonly used worldwide to identify AKI [67, 68]. The management of nonresponse to vasoconstrictors plus albumin in patients with AKI-HRS is the subject of intense discussion at present. Combinations of different drugs have been suggested but never tested. A second strategy – a combination of drugs and nonpharmacological support – has not only been suggested, but also tested. The combination between midodrine plus octreotide and albumin and TIPS (transjugular intrahepatic portosystemic shunt), even if exciting from a clinical point of view, is of limited value since TIPS is contraindicated in a high percentage of patients with AKI-HRS [48]. The combination of terlipressin and albumin and an extracorporeal liver support system using fractionated plasma separation and adsorption improves survival in patients with AKI-HRS [68]. However, this observation is the result of the analysis of only a subgroup of patients. Thus, while we are waiting for further studies specifically designed for patients with AKI-HRS who do not respond to vasoconstrictors plus albumin, renal replacement therapy (RRT) is often applied in clinical practice, particularly in patients who are candidates for liver transplantation (LT), even though the risk, the best approach and the outcome of RRT have never been evaluated specifically in these patients. In the perspective of LT, two final points should be briefly discussed, since they are not completely solved or established. These are: (i) when to assign patients with AKI-HRS to a simultaneous liver kidney transplantation and (ii) how to evaluate the response to vasoconstrictors and albumin in prioritizing organ allocation for patients on the waiting list for LT. With regard to the first point, it has been observed that the degree of tubular damage in
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65% of patients and we still need to solve three major problems. First, how to explain nonresponse to the treatment, second, how to predict a nonresponse and, finally, how to manage it. AKI-HRS has been defined as a functional renal failure, thus, by definition, without any evidence of renal parenchymal damage [50, 51]. Nevertheless, the current criteria for the diagnosis of HRS are not capable of excluding renal parenchymal damage. Indeed, when new diagnostic tools were used (i.e. renal biopsy or new biomarkers), evidence of renal parenchymal damage was found in patients with AKI-HRS [52, 53]. Another specific potential limit for the effectiveness of terlipressin plus albumin is the negative effect of terlipressin on the cardiac output in patients with cirrhosis. Terlipressin per se does not change stroke volume [54], and can reduce cardiac output by increasing peripheral resistances [55] in patients with cirrhosis. Thus, the only positive effect on cardiac output in patients with AKI-HRS who receive terlipressin plus albumin is accounted for by albumin and is related to the expansion in blood volume and the consequent increase in cardiac preload, as previously discussed [33]. Moving to factors which can predict the nonresponse to treatment with vasoconstrictors plus albumin in patients with AKI-HRS, we need to focus only on terlipressin and albumin because no data referring to the α-adrenergic drugs exist to date. High baseline values of both sCr and serum total bilirubin as well as a small increase in mean arterial pressure (MAP) with treatment [56–58] have been identified as predictors of nonresponse in patients with AKI-HRS. Focusing on baseline sCr, it has been observed that the probability of response decreases from 50 to 30% and then to 10% for sCr values of less than 3 mg/dl, 3–5 mg/dl and more than 5 mg/dl, respectively [56]. These findings emphasize the need to diagnose and treat AKI-HRS as early as possible. Accordingly, the current diagnostic criteria of AKI-HRS in patients with cirrhosis have been revised and this should lead to improved treatment in these patients [59–65]. A small increase in MAP, defined as being 6 weeks before LT should be considered as an indication to combined simultaneous liver kidney transplantation [66]. With regard to the second point, a new policy of priority allocation in the waiting list should be applied to responders to terlipressin and albumin. Indeed, these patients suffer from a serious injustice. As a matter of fact, their 3-month mortality rate is higher than that predicted by their baseline-calculated MELD score [67]. By lowering sCr with response to terlipressin and increasing the serum sodium concentration, the treatment can significantly lower the MELD as well as the MELD Na score [47] by up to 8–9 points in our experience, thereby delaying for several weeks or months the time of LT. Taking into account that the survival rate in responders at 3 months is almost 50% [18], a new and specific policy of priority organ allocation is needed for these patients. In particular, the paradoxical effect of treatment on the time of LT
in responders to terlipressin and albumin with or without a single recurrence of HRS can be avoided by continuing to consider their baseline pre-HRS MELD score rather than the MELD during or after the end of vasoconstrictor treatment. In responders who experience a continuous recurrence of AKI-HRS, the paradoxical effect is even more important and should be studied, considering the pharmacological treatment of HRS as RRT in the calculation of the MELD [68].
Conclusions
The introduction of vasoconstrictors and albumin in the treatment of AKI-HRS represents a landmark in the treatment of this complication in patients with advanced cirrhosis. Nevertheless, it is important to recognize that much work remains to be done in order to solve the many contentious points before the solution to these issues can be established.
Disclosure Statement The authors received no financial support for the research and/ or authorship of this article.
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55 Belcher JM, Garcia-Tsao G, Sanyal AJ, Bhogal H, Lim JK, Ansari N, Coca SG, Parikh CR, TRIBE-AKI Consortium: Association of AKI with mortality and complications in hospitalized patients with cirrhosis. Hepatology 2013; 57:753–762. 56 Piano S, Rosi S, Maresio G, Fasolato S, Cavallin M, Romano A, Morando F, Gola E, Frigo AC, Gatta A, Angeli P: Evaluation of the Acute Kidney Injury Network criteria in hospitalized patients with cirrhosis and ascites. J Hepatol 2013;59:482–489. 57 Fagundes C, Barreto R, Guevara M, Garcia E, Solà E, Rodríguez E, Graupera I, Ariza X, Pereira G, Alfaro I, Cárdenas A, Fernández J, Poch E, Ginès P: A modified acute kidney injury classification for diagnosis and risk stratification of impairment of kidney function in cirrhosis. J Hepatol 2013;59:474–481. 58 Tsien CD, Rabie R, Wong F: Acute kidney injury in decompensated cirrhosis. Gut 2013; 62:131–137. 59 De Carvalho JR, Villela-Nogueira CA, Luiz RR, Guzzo PL, da Silva Rosa JM, Rocha E, Moraes Coelho HS, de Mello Perez R: Acute kidney injury network criteria as a predictor of hospital mortality in cirrhotic patients with ascites. J Clin Gastroenterol 2012;46:e21–e26. 60 Wong F, O’Leary JG, Reddy KR, Patton H, Kamath PS, Fallon MB, Garcia-Tsao G, Subramanian RM, Malik R, Maliakkal B, Thacker LR, Bajaj JS, North American Consortium for Study of End-Stage Liver Disease: New consensus definition of acute kidney injury accurately predicts 30-day mortality in patients with cirrhosis and infection. Gastroenterology 2013;145:1280–1288. 61 Moreau R, Jalan R, Gines P, Pavesi M, Angeli P, Cordoba J, Durand F, Gustot T, Saliba F, Domenicali M, Gerbes A, Wendon J, Alessandria C, Laleman W, Zeuzem S, Trebicka J, Bernardi M, Arroyo V, CANONIC Study Investigators of the EASL-CLIF Consortium: Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013;144:1426–1437.
62 Angeli P, Rodríguez E, Piano S, Ariza X, Morando F, Solà E, Romano A, Garcia E, Pavesi M, Risso A, Gerbes A, Willars C, Bernardi M, Arroyo V, Ginès P, for the CANONIC Study Investigators of the EASL-CLIF Consortium: Acute kidney injury and acute-on-chronic liver failure classifications in prognosis assessment of patients with acute decompensation of cirrhosis. Gut 2015, Epub ahead of print. 63 Bentley W: Towards evidence-based emergency medicine: Best BETs from the Manchester Royal Infirmary. BET 3: RIFLE criteria versus Acute Kidney Injury Network (AKIN) criteria for prognosis of acute renal failure. Emerg Med J 2011; 28(10):900–901. 64 Kribben A, Gerken G, Haag S, et al: Effects of fractionated plasma separation and adsorption on survival in patients with acute-onchronic liver failure. Gastroenterology 2012; 142:782–789. 65 Nadim MK, Genyk YS, Tokin C, Fieber J, Ananthapanyasut W, Ye W, Selby R: Impact of etiology of acute kidney injury on outcomes following liver transplantation: acute tubular necrosis versus hepatorenal syndrome. Liver Transpl 2012;18:539–548. 66 Eason JD, Gonwa TA, Davies CL, Sung RS, Gerber D, Bloom RD: Proceedings of consensus conference on simultaneous liver kidney transplantation (SLK). Am J Transplant 2008; 8:2243–2251. 67 Alessandria C, Ozdogan O, Guevara M, Restuccia T, Jiménez W, Arroyo V, Rodés J, Ginès P: MELD score and clinical type predict prognosis in hepatorenal syndrome: relevance to liver transplantation. Hepatology 2005; 41: 1282–1289. 68 Angeli P, Gines P: Hepatorenal syndrome, MELD score and liver transplantation: an evolving issue with relevant implications for clinical practice. J Hepatol 2012; 57: 1135– 1140.
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48 Fagundes C, Pépin MN, Guevara M, Barreto R, Casals G, Solà E, Pereira G, Rodríguez E, Garcia E, Prado V, Poch E, Jiménez W, Fernández J, Arroyo V, Ginès P: Urinary neutrophil gelatinase-associated lipocalin as biomarker in the differential diagnosis of impairment of kidney function in cirrhosis. J Hepatol 2012;57:267–273. 49 Solanki P, Kiszka-Kanowitz M, Henriksen JH, Hansen EF, Møller S, Bendtsen F: Effect of terlipressin on blood volume distribution in patients with cirrhosis. Scand J Gastroenterol 2004;39:486–492. 50 Krag A, Bendtsen F, Mortensen C, Henriksen JH, Møller S: Effects of a single terlipressin administration on cardiac function and perfusion in cirrhosis. Eur J Gastroenterol Hepatol 2010;22:1085–1092. 51 Boyer TD, Sanyal AJ, Garcia-Tsao G, Blei A, Carl D, Bexon AS, Teuber P, Terlipressin Study Group: Predictors of response to terlipressin plus albumin in hepatorenal syndrome (HRS) type 1: relationship of serum creatinine to hemodynamics. J Hepatol 2011; 55:315–321. 52 Nazar A, Pereira GH, Guevara M, MartínLlahi M, Pepin MN, Marinelli M, Solá E, Baccaro ME, Terra C, Arroyo V, Ginès P: Predictors of response to therapy with terlipressin and albumin in patients with cirrhosis and type 1 HRS. Hepatology 2010;51:219–226. 53 Velez JCQ, Nietert PJ: Therapeutic response to vasoconstrictors in hepatorenal syndrome parallels increase in mean arterial pressure: a polled analysis of clinical trials. Am J Kidney Dis 2011;58:928–938. 54 Wong F, Nadim MK, Kellum JA, Salerno F, Bellomo R, Gerbes A, Angeli P, Moreau R, Davenport A, Jalan R, Ronco C, Genyk Y, Arroyo V: Working Party proposal for a revised classification system of renal dysfunction in patients with cirrhosis. Gut 2011;60:702–709.
The Treatment of Hepatorenal Syndrome Marta Cavallin a Silvano Fasolato a, b Simona Marenco c Salvatore Piano a Marta Tonon a, b Paolo Angeli a, b a
U.O. Clinica Medica V and b Unit of Hepatic Emergencies and Liver Transplantation, Department of Medicine, DIMED, University of Padua, Padua, and c Department of Internal Medicine, Gastroenterology Unit, University of Genoa, Genoa, Italy
Abstract Hepatorenal syndrome (HRS) is a severe complication that often occurs in patients with cirrhosis and ascites. HRS is a functional renal failure that develops mainly as a consequence of a severe cardiovascular dysfunction which is characterized by an extreme splanchnic arterial vasodilation and a reduction of cardiac output. HRS may develop in two clinical types: as an acute and rapidly progressive renal failure (AKI-HRS) or as chronic and not progressive renal failure (CKD-HRS). Several small studies and some randomized control studies have been published on the use of terlipressin plus albumin in the treatment of HRS, mainly on AKI-HRS. Terlipressin plus albumin was shown to improve renal function in almost 35–45% of patients with AKI-HRS, as well as to improve short-term survival in these patients. Terlipressin was most commonly used by intravenous boluses moving from an initial dose of 0.5–1 mg every 4 h to 3 mg every 4 h in the case of a nonresponse. In other studies, terlipressin was also given by continuous intravenous infusion. Thus, the best way to administer terlipressin in the treatment of HRS has not yet been defined. α-Adrenergic drugs, such as intravenous norepinephrine or oral midodrine plus subcutaneous octreotide, administered with albumin have also been
© 2015 S. Karger AG, Basel 0257–2753/15/0334–0548$39.50/0 E-Mail [email protected] www.karger.com/ddi
used in the treatment of AKI-HRS, with promising results. However, we need further studies in order to define whether they can represent a real therapeutic alternative. In conclusion, available data are sufficient to state that the use of terlipressin plus albumin has really changed the management of HRS. Nevertheless, some crucial unsolved issues still exist, in particular: (a) how to predict nonresponse to treatment, (b) how to manage nonresponse to treatment and (c) how to consider the response in those patients who are candidates for liver transplant in the priority allocation process. © 2015 S. Karger AG, Basel
Introduction
A marked renal arterial vasoconstriction and the consequent reduction of renal arterial perfusion are thought to be the main pathophysiological bases of hepatorenal syndrome (HRS). It develops in patients with advanced cirrhosis as a consequence of an extreme overactivation of the endogenous systemic vasoconstrictor systems, namely the renin-angiotensin system, the sympathetic nervous system and the nonosmotic release of vasopressin due to a severe reduction of effective circulating volume. This reduction is believed to be due to both an extreme splanchnic arterial vasodilation and an impairment of cardiac output [1–4]. Splanchnic arterial vasodilation is thought to be mainly the consequence of an increased release of Prof. Paolo Angeli Unit of Hepatic Emergencies and Liver Transplantation Department of Medicine, University of Padua Via Giustiniani 2, IT–35128 Padua (Italy) E-Mail pangeli @ unipd.it
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Key Words Albumin · Acute kidney injury · Cirrhosis · Terlipressin · α-Adrenergic drug
Use of Terlipressin in the Treatment of HRS
To date, four randomized controlled clinical trials comparing terlipressin and albumin in the treatment of HRS, mainly of AKI-HRS, with albumin alone have been published [8–11]. In addition, terlipressin plus albumin has been used in several uncontrolled clinical studies. Taking these studies as a whole, terlipressin has been used in more than 300 patients [12–23]. In most of these patients, terlipressin was administered as an intravenous bolus starting from an initial dose of 0.5 mg every 4–6 h [12– 20, 23]. Only in a few studies was the drug administered as a continuous intravenous infusion starting from an initial dose of 2 mg/day [21, 22]. In patients without a clinical response, defined as a reduction of serum creatinine (sCr) 50% in patients with AKIHRS. The response was further defined as complete or partial according to the final sCr: 1.5 mg/dl, respectively. The rate of response commonly ranges between 40 and 50% when terlipressin was given alone [14, 15]; however, the rate of reversal of HRS, which is the achievment of normal serum creatinine levels, is lower in patients receiving terlipressin than in patients reThe Treatment of HRS
ceiving both terlipressin and albumin [18, 19]. It is important also to emphasize that response rates above 65% were observed with terlipressin and albumin in patients with AKI-HRS associated with sepsis [21, 23]. No controlled clinical study showed a significant effect of terlipressin plus albumin on survival when this association was compared to albumin alone or to placebo. Nevertheless, a subsequent systematic review and metaanalysis of all the randomized controlled clinical trials showed that this treatment may slightly increase survival in patients with type 1 HRS [24, 25]. During the treatment with terlipressin plus albumin, the normalization or decrease in sCr can take several days. Therefore, the treatment is usually continued for up to 10–15 days. It has been stated that after the withdrawal HRS can recur in up to 20% of cases and that recurrence can be efficiently retreated with terlipressin and albumin [26]. As a result, in patients with continuous recurrence of type 1 HRS, which has been recently defined as a relapse of type 1 HRS more than once within 72 h after the discontinuation of treatment with terlipressin and albumin [27], this therapeutic strategy can result in a longterm administration of terlipressin and albumin, continuing for months rather than weeks [27, 28]. The most common side effect of terlipressin is diarrhea, which in most cases is self-limiting and thus does not require the discontinuation of the drug unless it is associated with severe abdominal pain. The most severe adverse effects of terlipressin are cardiovascular or ischemic complications (chest pain, abdominal pain or arrhythmia), which have been reported in an average of 12% of patients treated. This is the reason why severe cardiovascular ischemic conditions should be considered contraindications to the use of terlipressin in patients with cirrhosis, and a close clinical and ECG monitoring should be performed during the treatment.
Use of Other Pharmacological Approaches: α-Adrenergic Drugs
The rationale for the use of α-adrenergic drugs such as norepinephrine alone or oral midodrine combined with subcutaneous octreotide, together with intravenous albumin, in the treatment of AKI-HRS deserves some comment. First, unlike terlipressin, there has so far been no clinical study in which the effect of either norepinephrine or midodrine has been evaluated in patients with cirrhosis. In an experimental model of cirrhosis, it can be observed that norepinephrine was capable of increasing the Dig Dis 2015;33:548–554 DOI: 10.1159/000375346
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endogenous vasodilators due to portal hypertension and/ or hepatic failure, while the inadequate cardiac output can be the extreme manifestation of a systolic dysfunction which is part of the so-called cirrhotic cardiomyopathy [5]. Based on pharmacodynamic studies on the effects of terlipressin on the splanchnic circulation in patients with cirrhosis [6], this drug was introduced in the treatment of HRS at the end of 1990s in order to reduce portal hypertension by counteracting the splanchnic arterial vasodilation. Albumin was combined with terlipressin to further improve the effective circulating volume and, as a consequence, arterial renal perfusion. This rationale for the use of terlipressin plus albumin was later proved in patients with cirrhosis and ascites without renal failure [7]. This review will mainly focus on the use of terlipressin and other vasoconstrictors plus albumin in the treatment of acute kidney injury (AKI)-HRS.
Table 1. Drug effects in cirrhosis
Drug
Effect on Effect on portal Effect on MAP splanchnic arterial pressure vasodilation
Effect on renal Effect on urinary blood flow sodium excretion
Terlipressin Noradrenalin Midodrine Octreotide
+++ +++ NA ++
+++ No +/No No
+++ No NA +/++
+++ +++ +/++ +
++ + +/No No
NA = Not appropriate; + = mild effect; ++ = moderate effect; +++ = high effect; No = no effect. Data specifically obtained in patients with HRS are in italics.
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circulation in cirrhosis (table 1), but also on the experimental evidence that the responsiveness to vasoconstrictors of the mesenteric artery may be normalized by the inhibition either of glucagon or nitric oxide [36, 37]. The choice of inhibiting glucagon release is based on clinical and experimental data showing that the inhibition of prostacyclin or nitric oxide synthesis may induce renal failure per se in patients or animals with cirrhosis, because these compounds counteract the action of vasoconstrictors on renal perfusion [38, 39]. No controlled clinical study has so far been performed with midodrine plus octreotide administered together with albumin. In the largest uncontrolled studies this therapeutic option was shown to be effective in almost 40% of patients with AKI-HRS [40, 41]. In all studies except one [42], treatment was administered according to the originally proposed schedule [35]. Thus, octreotide was administered via the subcutaneous route with a starting dose of 100 mg 3 times a day, which was titrated up to 200 mg thrice daily as necessary. Midodrine was started at an oral dose of 7.5 mg 3 times a day and titrated up to a maximum dose of 15 mg 3 times a day as tolerated based on the systolic blood pressure. Albumin was given in differing concentrations at a dose ranging from 20 to 100 g/ day. Similarly to what has been said about noradrenalin, in total midodrine plus octreotide and albumin have so far been used in less than 120 patients with AKI-HRS [40–42]. Thus, we need further studies to clarify its role in the treatment of HRS. Octreotide alone has no impact on improving renal function [42, 43].
Unsolved Issues in the Treatment of HRS
The introduction of the use of vasoconstrictors and albumin represents a milestone in the management of AKI-HRS [49]. However, the treatment is effective in 35– Cavallin/Fasolato/Marenco/Piano/Tonon/ Angeli
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superior mesenteric artery resistance but not reducing portal pressure. In addition, in cirrhotic rats, norepinephrine was not capable of improving renal perfusion [29]. In spite of these potential disadvantages, when norepinephrine was compared to terlipressin in the treatment of AKI-HRS in three small controlled clinical studies, similar results were found in terms of both the rate of response and 30-day survival [30–32]. It should be emphasized that most of the patients included in one of these studies had CKD-HRS [32]. Furthermore, none of these controlled clinical studies had an adequate sample size to offer assessment of the equivalence between terlipressin and norepinephrine with certainty. However, norepinephrine may potentially have a favorable effect on cardiac output by restoring the proper functioning of the adrenergic receptor pathway in the cardiac tissue through the simultaneous administration of albumin, thanks to its property of volemia expansion [33]. In all the controlled and uncontrolled studies, noradrenalin was used by continuous intravenous infusion at the initial dose of 0.5 mg/h. In the case of a nonresponse, the dose was progressively increased up to a maximum of 3 mg/h [30–32, 34]. In all the studies, noradrenalin was always used together with albumin with doses ranging from 20 to 70 g/day [30–32, 34]. The new aspects of the action of albumin on cardiac tissue in cirrhosis and their possible effect favoring the action of norepinephrine in the treatment of HRS are exciting. Nevertheless, norepinephrine has been used in less than 70 patients with AKI-HRS to date [31–34]. Therefore, according to the conclusion of a recent study [35] about the treatment of HRS type 1, further studies are needed to clarify its role in the treatment of AKI-HRS. The rationale for the use of oral midodrine and subcutaneous or intravenous octreotide is slightly more complex and deserves to be clarified [35]. It is based not only on the simple sum of the effects of the two drugs on the splanchnic
study by the EASL-Clif Consortium [66]. More precisely, it has been observed that a CLIF-SOFA score of >11 has a 92% sensitivity and 100% specificity in predicting no response to terlipressin therapy [23]. This observation opens a further discussion on potential specific features of the pathophysiology of AKI-HRS in patients with ACLF. Moreover, it introduces a limit in the prognostic value of the KDIGO (Kidney Disease: Improving Global Outcome) criteria (which, like AKIN, evaluate serum creatinine and urine output to diagnose AKI, but furthermore to assess its severity) in patients with ACLF. The prognostic evaluation in patients with cirrhosis who are hospitalized for an acute decompensation should take into account the failures of organs other than the kidney. More specifically, the CLIF-SOFA score has a better prognostic value compared to the AKIN (Acute Kidney Injury Network) criteria in these patients which are commonly used worldwide to identify AKI [67, 68]. The management of nonresponse to vasoconstrictors plus albumin in patients with AKI-HRS is the subject of intense discussion at present. Combinations of different drugs have been suggested but never tested. A second strategy – a combination of drugs and nonpharmacological support – has not only been suggested, but also tested. The combination between midodrine plus octreotide and albumin and TIPS (transjugular intrahepatic portosystemic shunt), even if exciting from a clinical point of view, is of limited value since TIPS is contraindicated in a high percentage of patients with AKI-HRS [48]. The combination of terlipressin and albumin and an extracorporeal liver support system using fractionated plasma separation and adsorption improves survival in patients with AKI-HRS [68]. However, this observation is the result of the analysis of only a subgroup of patients. Thus, while we are waiting for further studies specifically designed for patients with AKI-HRS who do not respond to vasoconstrictors plus albumin, renal replacement therapy (RRT) is often applied in clinical practice, particularly in patients who are candidates for liver transplantation (LT), even though the risk, the best approach and the outcome of RRT have never been evaluated specifically in these patients. In the perspective of LT, two final points should be briefly discussed, since they are not completely solved or established. These are: (i) when to assign patients with AKI-HRS to a simultaneous liver kidney transplantation and (ii) how to evaluate the response to vasoconstrictors and albumin in prioritizing organ allocation for patients on the waiting list for LT. With regard to the first point, it has been observed that the degree of tubular damage in
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65% of patients and we still need to solve three major problems. First, how to explain nonresponse to the treatment, second, how to predict a nonresponse and, finally, how to manage it. AKI-HRS has been defined as a functional renal failure, thus, by definition, without any evidence of renal parenchymal damage [50, 51]. Nevertheless, the current criteria for the diagnosis of HRS are not capable of excluding renal parenchymal damage. Indeed, when new diagnostic tools were used (i.e. renal biopsy or new biomarkers), evidence of renal parenchymal damage was found in patients with AKI-HRS [52, 53]. Another specific potential limit for the effectiveness of terlipressin plus albumin is the negative effect of terlipressin on the cardiac output in patients with cirrhosis. Terlipressin per se does not change stroke volume [54], and can reduce cardiac output by increasing peripheral resistances [55] in patients with cirrhosis. Thus, the only positive effect on cardiac output in patients with AKI-HRS who receive terlipressin plus albumin is accounted for by albumin and is related to the expansion in blood volume and the consequent increase in cardiac preload, as previously discussed [33]. Moving to factors which can predict the nonresponse to treatment with vasoconstrictors plus albumin in patients with AKI-HRS, we need to focus only on terlipressin and albumin because no data referring to the α-adrenergic drugs exist to date. High baseline values of both sCr and serum total bilirubin as well as a small increase in mean arterial pressure (MAP) with treatment [56–58] have been identified as predictors of nonresponse in patients with AKI-HRS. Focusing on baseline sCr, it has been observed that the probability of response decreases from 50 to 30% and then to 10% for sCr values of less than 3 mg/dl, 3–5 mg/dl and more than 5 mg/dl, respectively [56]. These findings emphasize the need to diagnose and treat AKI-HRS as early as possible. Accordingly, the current diagnostic criteria of AKI-HRS in patients with cirrhosis have been revised and this should lead to improved treatment in these patients [59–65]. A small increase in MAP, defined as being 6 weeks before LT should be considered as an indication to combined simultaneous liver kidney transplantation [66]. With regard to the second point, a new policy of priority allocation in the waiting list should be applied to responders to terlipressin and albumin. Indeed, these patients suffer from a serious injustice. As a matter of fact, their 3-month mortality rate is higher than that predicted by their baseline-calculated MELD score [67]. By lowering sCr with response to terlipressin and increasing the serum sodium concentration, the treatment can significantly lower the MELD as well as the MELD Na score [47] by up to 8–9 points in our experience, thereby delaying for several weeks or months the time of LT. Taking into account that the survival rate in responders at 3 months is almost 50% [18], a new and specific policy of priority organ allocation is needed for these patients. In particular, the paradoxical effect of treatment on the time of LT
in responders to terlipressin and albumin with or without a single recurrence of HRS can be avoided by continuing to consider their baseline pre-HRS MELD score rather than the MELD during or after the end of vasoconstrictor treatment. In responders who experience a continuous recurrence of AKI-HRS, the paradoxical effect is even more important and should be studied, considering the pharmacological treatment of HRS as RRT in the calculation of the MELD [68].
Conclusions
The introduction of vasoconstrictors and albumin in the treatment of AKI-HRS represents a landmark in the treatment of this complication in patients with advanced cirrhosis. Nevertheless, it is important to recognize that much work remains to be done in order to solve the many contentious points before the solution to these issues can be established.
Disclosure Statement The authors received no financial support for the research and/ or authorship of this article.
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