Knowledge on the hepatorenal syndrome (HRS) has substantially improved in recent years. These advances relate to all aspects of the syndrome, including a widely accepted definition, a consensus-based diagnostic criteria that help differentiate HRS from other causes of renal failure also present in patients with cirrhosis, an improved understanding of the pathogenic mechanisms, successful methods of prevention in specific settings, and, more importantly, the introduction of effective therapies, mainly vasoconstrictor drugs.1–3
The administration of vasoconstrictor drugs to patients with cirrhosis and renal dysfunction was first reported in the 1950s.4, 5 However, due to limited success, the treatment was abandoned for many decades. The main reason for the reappraisal of vasoconstrictors in the management of HRS was the growing pathophysiological evidence that renal vasoconstriction responsible for renal failure in HRS was the final consequence of a marked vasodilation of the splanchnic circulation.6–8 This vasodilation impairs the effective arterial blood volume and gives rise to a remarkable activation of vasoconstrictor systems aimed at maintaining effective arterial blood volume and arterial pressure by means of vasoconstriction of several arterial beds, particularly the kidneys. Phase 2 studies in patients with HRS have demonstrated that the administration of vasoconstrictors (mainly vasopressin analogues, particularly terlipressin, but also α-adrenergic agonists, such as noradrenaline or midodrine) improves renal function in approximately two-thirds of patients with HRS, with relatively low incidence of severe side effects (less than 10% of patients).9–17 Moreover, and most importantly, it appears that patients in whom renal function improves after therapy have a longer survival compared to nonresponders.14, 15 Although exciting, these results should be interpreted with caution due to the small number of patients included in most studies and the lack of large randomized prospective controlled investigations. This type of study is absolutely necessary to put the usefulness of vasoconstrictors for HRS into clinical perspective.
In the current issue of HEPATOLOGY, Wong et al. have explored the use of sequential treatments in patients with HRS—i.e., vasoconstrictor therapy followed by transjugular intrahepatic portosystemic shunt (TIPS).18 TIPS has previously been shown to have beneficial effects on renal function in HRS.19 In this prospective study, 14 patients with cirrhosis and type 1 HRS were treated with a combination of midodrine, octreotide, and albumin, followed by insertion of TIPS in selected patients with a relatively preserved liver function (INR lower than 2, bilirubin lower than 5 mg/dL, and Child-Turcotte-Pugh score lower than 12). The main finding of this study was the improvement of renal function achieved by the pharmacological therapy being further enhanced by TIPS. In fact, after the sequential treatment, there was an almost complete normalization of renal function and a remarkable improvement of circulatory function with normalization of effective arterial blood volume. Although the low number of evaluated patients and lack of randomization limit to some extent the relevance of the study, the information provided is of interest from both a pathogenic and a clinical perspective.
One of the intriguing issues surrounding the treatment of HRS with vasoconstrictors is the observation that, despite the improvement, renal function does not reach normal levels in the majority of patients, with persistence of mild-to-moderate renal failure after therapy, as indicated by low renal plasma flow and glomerular filtration rate values.9–12, 16, 17 This observation has been confirmed in the study of Wong et al.18 The reason for this lack of normalization of renal function is unknown but could be the result of the existence of a component of renal failure unresponsive to changes in circulatory function, or that the effective arterial blood volume, although improved, is not normalized with pharmacological therapy. The results of Wong et al.18 support this latter option.
The mechanism by which TIPS adds to the beneficial effect of pharmacological therapy on circulatory function is not known and remains speculative. It could be the result of the reduction in portal pressure caused by TIPS's exerting direct beneficial effects on renal function due to a suppression of a putative hepatorenal reflex.20 Unfortunately, portal pressure was not measured in this study. Nevertheless, the observation by Wong et al.18 that after TIPS there was a progressive normalization of effective arterial blood volume suggests that the beneficial effect of TIPS is related to an improvement in systemic circulatory function. This observation presents an attractive hypothesis, whereby the normalization of effective arterial blood volume is the result of TIPS's improving cardiac performance, which is impaired in patients with advanced cirrhosis.21–24
There is increasing evidence that the existence of cirrhosis is associated with an impaired cardiac function, generally known as cirrhotic cardiomyopathy.21–24 This condition may affect both systolic and diastolic function of the left ventricle and may be secondary to a number of factors, including impaired cardiac contractility and relaxation and decreased cardiac preload. The relative contribution of each of these factors to the impaired cardiac performance is not known. Although cirrhotic cardiomyopathy is generally clinically silent and patients do not develop clinical signs of overt cardiac failure, such as dyspnea or pulmonary edema, there is evidence that the impaired cardiac function may contribute to the abnormalities of circulatory function and development of HRS in specific settings, such as spontaneous bacterial peritonitis.25, 26 Therefore, it is possible that the impaired effective blood volume that leads to renal vasoconstriction in HRS is not only due to splanchnic arterial vasodilation causing an abnormal distribution of blood volume but also to an impaired cardiac function due to cirrhotic cardiomyopathy (Fig. 1). Although cardiac output is high in absolute values in most patients with advanced cirrhosis, it may be low relative to the markedly dilated splanchnic arterial bed.
Considering this background, recent studies indicate that the insertion of TIPS in patients with cirrhosis increases cardiac preload and improves diastolic function without causing significant impairment in systolic function.27, 28 These effects appear to be particularly important in patients with reduced effective arterial blood volume.28 The results of Wong et al.18 are consistent with these findings. In fact, the insertion of TIPS was associated with a marked and significant increase in the already high baseline cardiac output together with a remarkable increase in the low central blood volume and central cardiovascular volume (the latter being responsible for the regulation of vasoconstrictor systems activity) without causing signs of cardiac failure. The significant reduction observed in systemic vascular resistance appears to be a compensatory mechanism to accommodate the increased cardiac preload due to the shunting of blood from the splanchnic circulation to the general circulation. Although not proved, an increase in cardiac preload may, at least in part, contribute to the beneficial effect of albumin administration in the prevention of HRS in patients with spontaneous bacterial peritonitis and the better efficacy of terlipressin in patients with HRS when given in combination with albumin, as compared with terlipressin alone.15, 29, 30
Finally, from a clinical perspective, the results of Wong et al.18 confirm findings from previous studies indicating an association between the improvement of renal function in patients with HRS and an improved survival.14, 15 In fact, 7 out of the 10 patients who responded to pharmacological therapy survived for at least 6 months (3 of them after liver transplantation), while all 4 nonresponders died within a period of 2 months. The potential beneficial effect of TIPS in improving survival after pharmacological therapy could not be demonstrated due to the low sample size and nonrandomized design of the study and would require prospective assessment.
Research on management of HRS has entered an exciting period. There are a large number of issues that still remain to be prospectively evaluated, including the effect of different therapies on survival, comparison of different pharmacological approaches, comparison of pharmacological versus nonpharmacological therapies, and identification of predictors of response to therapy. Nevertheless, the study by Wong et al. represents another piece of the puzzle in the management of patients with HRS.