Hepatorenal syndrome: The last pieces of the puzzle or not yet?
Authors: Isabel Graupera, Pere Ginès
Journal: Hepatology (2015)

Potential conflict of interest: Dr. Ginès consults for Ferring, Noorik, and Ikaria. He received grants from Sequana Medical and Grifols. Part of the work discussed in this article has been funded by the FIS (PI12/00330) integrated in the Plan Nacional I+D+I and cofunded by ISCIII‐Subdirección General de Evaluación and European Regional Development Fund (ERDF). I.G. is the recipient of a research grant 'Rio Hortega' from the Instituto de Salud Carlos III, Madrid, Spain. See Article on Page 567. Liver cirrhosis constitutes a major cause of death worldwide. In 2013, cirrhosis was the thirteenth cause of death globally and the sixth cause of years of life lost in developed countries.1 In Europe and the United States, and possibly in many other areas of the world, the economic health burden caused by the disease is huge because it is one of the main causes of hospital admission in adults, numerous of them in intensive care for severe complications, and is associated with a large number of hospital readmissions and visits to outpatient clinics. Despite this importance as a global health issue, the mainland marks in the management of complications of cirrhosis have been possible as a result of investigator‐initiated research and not of pharmaceutical companies. Since the late 1960s, several drugs and therapeutic procedures have been introduced for management of the different complications of cirrhosis and represent the current standard of care for these conditions (Table 1). All of them, except for vasoconstrictors in the management of variceal bleeding (VB) and rifaximin for the prevention of hepatic encephalopathy (HE), are the result of independent research initiated by investigators. Table 1 - Landmarks in the Management of Complications of Cirrhosis Condition Drug/Procedure Year Treatment/prevention of ascites Spironolactone 1961 Treatment of HE Lactulose 1966 Prevention of variceal rebleeding Propranolol 1981 Treatment of VB Terlipressin/somatostatin 1982 Treatment of infections Cephalosporins 1985 Treatment of portal hypertension TIPS 1987 Prevention of SBP Norfloxacin 1990 Treatment of HRS Terlipressin 1996 Prevention of HRS in SBP Albumin 1999 Prevention of HE Rifaximin 2010 Abbreviation: TIPS, transjugular intrahepatic portosystemic shunt. Hepatorenal syndrome (HRS) constitutes a unique example of how improvement in pathophysiological knowledge may lead to discovery of effective treatments with the use of limited resources. Sheila Sherlock, Murray Epstein, and a number of other investigators in the 1950s‐1970s reported that HRS was a unique form of renal failure that occurred in patients with advanced cirrhosis and was the result of a remarkable vasoconstriction of the renal arterial circulation.2 Moreover, they added two more pieces to the puzzle: Renal vasoconstriction occurred in the absence of contraction of plasma volume and was unresponsive to volume expansion or treatment with renal vasodilator substances. These concepts, together with findings in patients as well as experimental models of cirrhosis of the existence of hyperdynamic circulation, with high cardiac output, decreased systemic vascular resistance, and increased activity of vasoconstrictor systems, led to the proposal of the arterial vasodilation hypothesis, which was fundamental to the understanding of the relationship between kidney function and systemic circulation in cirrhosis.4 Studies in keeping with this concept that were essential for the subsequent development of a specific treatment of HRS were performed by Robert Schrier and his colleagues in Denver using the head‐out water immersion model. These studies assessed the hypothesis of whether the combination of central volume expansion, caused by head‐out water immersion, together with vasoconstriction with noradrenaline, would improve circulatory and kidney function in cirrhosis with ascites. Interestingly, head‐out water immersion plus noradrenaline normalized not only the activity of vasoconstrictor systems, but also renal sodium and water excretion.5 These findings paved the way for research studies investigating the effects of vasoconstrictors plus albumin in the management of HRS. The first studies assessing the potential efficacy of vasopressin analogs in patients with cirrhosis and kidney impairment were performed by Lenz et al.6 These investigators provided the proof of concept that a short‐term (4‐hour) administration of ornipressin was able to increase arterial pressure, suppress activity of vasoconstrictor systems, and improve renal function in patients with renal impairment. Subsequent studies in Clichy and Barcelona demonstrated that administration of a combination of terlipressin and albumin for a long period (7 to 14 days) reversed HRS in a significant number of patients.7 Subsequently, randomized, controlled studies confirmed terlipressin as the first effective drug in the management of HRS in patients with cirrhosis.9 The majority of studies on terlipressin were performed with the drug being used off label, because terlipressin was only approved for the management of acute VB. The consequence of the investigator‐initiated studies on telipressin in HRS led to the approval of terlipressin for the indication of HRS in many countries. In the current issue of Hepatology, Cavallin et al., from the group in Padova, report the results of a randomized study comparing terlipressin and albumin versus midodrine, octreotide, and albumin in the treatment of HRS.10 One of the pieces missing in the puzzle of HRS treatment was whether the combination of midodrine/octreotide/albumin is equally effective to terlipressin and albumin in the management of HRS. The possibility of using midodrine, an orally active alpha‐adrenergic agonist, is attractive because of its simplicity in the administration and lower cost, compared with telipressin. The potential efficacy of midodrine combined with octreotide and albumin in the treatment of HRS derives from small proof‐of‐concept studies, but there have been no randomized, controlled studies comparing midodrine/octreotide/albumin versus terlipressin and albumin head to head.11 Moreover, there are no randomized, controlled trials in HRS comparing midodrine/octreotide/albumin versus other treatments, placebo, or albumin alone. In the study of Cavallin et al., a complete response to treatment was observed in 55.5% of patients receiving terlipressin, compared to only 4.8% of those receiving midodrine/octreotide/albumin. There were no differences in the characteristics of patients in both groups or in the duration of treatment. Moreover, 5 of 6 nonresponders to triple therapy were switched to terlipressin and 5 of them had response, further supporting the greater efficacy of terlipressin and albumin versus midodrine/octreotide/albumin. The better efficacy of terlipressin and albumin was likely related to a higher increase in arterial pressure observed during administration of the drug. Therefore, it appears as though terlipressin and albumin is better than midodrine/octreotide/albumin because it causes a greater improvement of circulatory function in patients with HRS. The study also confirmed findings from previous trials indicating that reversal of HRS is associated with improved survival. To our knowledge, the study by Cavallin et al.10 is the first investigation in which the combination of midodrine/octreotide/albumin has been evaluated in the context of a randomized, comparative clinical trial. The results of this study are important because this treatment is currently recommended in clinical guidelines as an alternative to terlipressin and albumin in the management of type 1 HRS in countries where terlipressin is not available. The rate of complete response observed in patients receiving triple therapy in the current study was low (4.8%), lower than that reported in the control arm of randomized studies in type 1 HRS (8.7%‐19%), suggesting that this treatment may not be superior to albumin alone.9 On the basis of these results, we consider that the use of triple therapy as first‐line treatment for type 1 HRS in countries where terlipressin is not available should be reconsidered. In this regard, it is important to point out that noradrenaline plus albumin has been reported to have a similar efficacy to that of terlipressin and albumin in randomized, comparative studies. Nevertheless, it would be important to compare the efficacy and safety of the combination of midodrine/octreotide/albumin with that of noradrenaline and albumin in prospective, randomized studies. Severe cardiovascular events (CVEs) are a significant clinical issue in the pharmacological management of type 1 HRS. In this regard, in the study by Cavallin et al.,10 1 patient in the terlipressin arm died because of a stroke. In randomized, controlled trials, the frequency of severe CVEs, including arterial hypertension, cardiac arrhythmias, myocardial infarction, and intestinal or peripheral ischemia, in patients treated with vasoconstrictors was of 14%, compared to 0% in control arms.12 Therefore, a careful selection of patients, excluding those with underlying cardiovascular conditions, together with a strict clinical surveillance of patients receiving terlipressin, is recommended to minimize the frequency and severity of side effects. The possibility that terlipressin given as continous infusion instead of bolus may reduce the frequency of adverse events has been suggested, but remains to be proved. Finally, it is also important to emphasize that terlipressin therapy should not be generalized to all patients with cirrhosis and acute kidney injury regardless of its cause, but limited exclusively to patients with type 1 HRS, in whom the efficacy of this treatment has been proved. The injudicious use of terlipressin in patients with cirrhosis and increased serum creatinine levels should be avoided to prevent severe undesirable side effects in patients without indication for this treatment. In conclusion, once more an investigator‐initiated research has provided an answer to an important clinical question in the field of HRS. Is the puzzle complete? Not yet. There are some important pieces still missing, such as how to improve kidney function in nonresponders to terlipressin and albumin, how kidney biomarkers can help in the differential diagnosis of HRS and guiding response to therapy, or how HRS can be prevented in patients with infections other than spontaneous bacterial peritonitis (SBP), to cite just the most important. Puzzles in medicine are never complete, but with the effort of investigators in this field, we are seeing more pieces than empty spaces. HRS is no longer the feared untreatable complication of cirrhosis that once was.