Journal of Hepatology
Volume 40, Issue 1 , Pages 159-161, January 2004

The growing evidence that renal function should be improved in patients with cirrhosis and hepatorenal syndrome before liver transplantation

Laboratoire d'Hémodynamique Splanchnique et de Biologie Vasculaire, INSERM U-481, and Service d'Hépatologie, Hôpital Beaujon, F-92118 Clichy, France

See Article, pages 140–146

Article Outline

 

Hepatorenal syndrome (HRS) is a prerenal failure (i.e. functional renal failure) that complicates end-stage cirrhosis [1]. There are two types of HRS: type 1 (the acute form of the syndrome) and type 2 (the chronic form) [1]. Since patients with HRS have a very poor short-term prognosis [2], they are given priority for liver transplantation in some centers [3], [4], [5]. However, patients with type 1 HRS may die very quickly, i.e. before receiving liver transplantation [2], [6]. Renal failure per se is an independent predictive factor of death in patients awaiting liver transplantation [6]. Moreover, patients with HRS who are transplanted have a higher in-hospital mortality rate than those without HRS [7], [8], [9], [10], [11], [12]. In a large series of patients who received liver transplant, a pretransplantation gomerular filtration rate below 29 ml/min per 1.73 m2 of body-surface area (a common finding in patients with HRS) was a risk factor for the development of post-tranplantation chronic renal failure mainly due to calcineurin-inhibitor therapy [13]. Together, these findings suggest that in patients with HRS, improvement of renal function may increase survival until liver transplantation and may improve the outcome post-transplantation.

In many centers, patients with HRS are treated with renal replacement therapy, including hemofiltration, hemodialysis, or albumin dialysis [14], [15]. However, the impact of these techniques on pretransplantation survival is unclear [16]. Moreover, the use of renal replacement therapy before liver transplantation has been shown to be a predictive factor of the development of post-transplantation chronic renal failure (see below) [13]. Thus, more information on the effects of renal replacement therapy are needed.

It has been suggested that splanchnic vasoconstrictors could be used to treat renal failure in patients with HRS [16]. Drug candidates include agonists of V1a-vasopressin receptors (i.e. the vasopressin analogues terlipressin and ornipressin) [6], [17], [18], [19], [20], and agonists of α1-adrenoceptors (i.e. midodrine, noradrenaline) [21], [22]. These vasoconstrictors have been used in combination with 20% human albumin [6], [17], [18], [19], [20], [21], [22]. The rationale for using vasoconstrictor therapy in patients with HRS is strong. Indeed, these patients have marked splanchnic vasodilation resulting in decreased systemic vascular resistance [23]. This systemic vasodilation triggers a cascade of events leading to renal (preglomerular) vasoconstriction [16]. In addition, systemic vasodilation causes arterial hypotension (below 80 mmHg) and thus decreased renal perfusion pressure [24]. Preglomerular vasoconstriction and decreased renal perfusion pressure play a crucial role in the marked decrease in the glomerular filtration rate [16]. Thus, it is not suprising that splanchnic vasoconstrictors whose target is the central mechanism of prerenal failure in patients with HRS (i.e. splanchnic vasodilation) induced sustained improvement of renal function in 60–80% of patients with HRS [6], [18], [19], [20], [21], [22], [24]. Moreover, except ornipressin which may induce serious ischemic side-effects [17], the other molecules are safe; which is important since patients with HRS are in poor condition [25]. Finally, there is evidence that terlipressin may improve the probability of survival and increase the chance of reaching liver tranplantation in patients with HRS [6], [18]. Therefore, vasoconstrictor therapy (mainly with terlipressin) can be used as a bridge while waiting for liver tranplantation. It should be emphasized that these findings were obtained mainly in patients with type 1 HRS and that little is known on the effects of vasoconstrictors in patients with type 2 HRS awaiting liver transplantation.

In this issue of the Journal, Restuccia et al. from Barcelona have helped complete the puzzle by adding an important piece that was lacking thus far; i.e. information on post-transplantation outcome in patients who received vasoconstrictor therapy for HRS before transplantation [26]. In this case-control study, the outcome of nine patients with HRS (three with type 1 and six with type 2) treated with vasopressin analogues before transplantation was compared with that of a contemporary group of 27 patients without pretransplantation HRS matched for age, severity of cirrhosis, and type of immunosuppression. At transplantation, cases and controls had similar characteristics, except for serum creatinine and blood urea nitrogen values which were higher in the former. Three years after transplantation, the probability of survival did not significantly differ between the two groups (100 vs. 83%, in cases and controls, respectively). No significant differences were found between the two groups for post-operative acute renal failure which occurred in 22 and 30% of patients, respectively. This renal failure occurred early (most often during the initial hospitalization for transplantation) and was reversible after treatment of the cause and/or reduction of dosage of calcineurin inhibitors. The two groups were also similar for other post-transplantation complications, i.e. severe bacterial infections (22 vs. 33%), acute rejection (33 vs. 41%), transfusion requirements (six units vs. eight units). Together, these results show that patients with HRS treated with vasopressin analogues before liver transplantation have a post-transplantation outcome similar to that of patients who did not have HRS before they received liver transplant. The study of Restuccia et al. supports the treatment of HRS before liver transplantation.

Since Restuccia et al. mainly studied patients with type 2 HRS, their findings suggest that vasoconstrictor therapy may be useful in these patients. However, the number of patients studied was small [26]. Thus, new studies should be performed to confirm the beneficial effects of vasoconstrictor therapy in patients with type 2 HRS before and after liver transplantation. This is important because type 2 HRS is a fairly common complication of cirrhosis. In addition, the effects of vasoconstrictor therapy before transplantation on post-transplantation outcome should be evaluated in a large series of patients with type 1 HRS.

As noted above, calcineurin-inhibitor therapy is a main cause of chronic renal dysfunction after the transplantation of nonrenal organs, including the liver [13]. Calcineurin inhibitors cause chronic renal failure by inducing tubular atrophy, interstitial fibrosis, and focal hyalinosis of small arteries and arterioles [27]. During the 5 years following liver transplantation, 18% of patients develop chronic renal failure (defined as a glomerular filtration rate of 29 ml/min per 1.73 m2 of body-surface area or less), with one-third who require maintenance dialysis or kidney transplantation [13]. In patients who receive a liver transplant, the occurrence of chronic renal failure is probably an important prognostic factor. Indeed, the occurrence of chronic renal failure in patients who have received a nonrenal transplant has been shown to significantly increase the risk of death [13]. The independent predictive factors of the occurrence of chronic renal failure after liver transplantation are: older age, female sex, low pretransplantation glomerular filtration rate value (see above), renal replacement therapy before transplantation, pretransplantation hepatitis C infection, diabetes mellitus before transplantation, acute renal failure during initial hospitalization for transplantation, treatment with cyclosporine compared to treatment with tacrolimus [13].

In the study by Restuccia et al. the two groups had several risk factors for post-transplantation chronic renal failure: female sex (56 and 50%, in cases and controls, respectively), pretransplantation hepatitis C virus (44 and 48%, respectively), post-operative acute renal failure (see above), cyclosporine therapy (78% in both groups) [26]. Despite the presence of these risk factors, none of the patients developed post-transplantation kidney dysfunction [26]. The reasons for this are unclear. It should be noted that during the post-transplantation period, Restuccia et al. measured serum creatinine but not the glomerular filtration rate, which is more accurate for assessing renal function. Therefore, they may have missed subtle renal impairment after liver transplantation. Thus, new studies should be performed. In particular, it would be important to evaluate the post-transplantation glomerular filtration rate in patients with type 1 or 2 HRS who received vasoconstrictor therapy before liver transplantation.

Patients with refractory ascites are candidates for liver transplantation [1]. These patients often have a decrease in renal plasma flow and a slight decrease in glomerular filtration rate between 40 and 70 ml/min (without overt type 2 HRS) [28]. Moderate decreases in the pretransplantation glomerular filtration rate have been shown to be associated with an increased risk of post-transplantation chronic renal failure induced by calcineurin-inhibitor therapy [13]. Thus, in patients with refractory ascites and moderate decreases in renal perfusion, improvement of renal hemodynamics before transplantation may help prevent kidney dysfunction after liver transplantation. Interestingly, the acute administration of terlipressin alone or combined with atrial natriuretic peptide has been shown to increase renal perfusion in patients with refractory ascites [29]. Studies are needed on this topic.

Therefore, in patients with end-stage cirrhosis waiting for liver transplantation, improvement of renal function with vasoconstrictor therapy may improve the post-transplantation outcome.

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PII: S0168-8278(03)00569-5

doi:10.1016/j.jhep.2003.10.024

Journal of Hepatology
Volume 40, Issue 1 , Pages 159-161, January 2004

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