"HEPATORENAL SYNDROME: ADVANCES IN TREATMENT AND PREVENTION"

Pere Ginès MD.

Liver Unit. Hospital Clínic. Institut d'Investigacions Biomèdiques August Pi-Sunyer (IDIBAPS).
University of Barcelona School of Medicine. Barcelona, Catalunya, Spain

gines@medicina.ub.es

Hepatorenal syndrome (HRS) is a very severe complication of patients with cirrhosis. The annual incidence in patients with ascites is approximately 8% ¹. It occurs in the latest phase of the disease and represents a major cause of death in these patients. Until recently HRS was considered an irreversible condition without effective therapy, except for the few cases that could be treated with liver transplantation. For this reason and because of its occurrence in patients with very advanced liver failure, a common clinical practice in patients with HRS was to stop all active treatments required by the patients and allow the disease progress until death. However, studies in recent years have demonstrated the efficacy of some therapeutic methods in patients with HRS. The aim of this chapter is to discuss the advances in the therapy of patients with HRS.

DEFINITION

Hepatorenal syndrome is a clinical condition that usually occurs in patients with advanced liver disease and portal hypertension that is characterized by a combination of disturbances in circulatory and kidney function ². The major abnormality in the systemic circulation is markedly reduced total systemic vascular resistance, which leads to a low arterial pressure. Kidney function is markedly impaired because of a severe reduction of renal blood flow. The reduction in renal blood flow is pathogenically related to the impairment in the systemic circulatory function. HRS occurs predominantly in the setting of cirrhosis, but it may also develop in other types of severe chronic liver diseases, such as alcoholic hepatitis, or in acute liver failure ^3-5. Because of its functional nature and lack of structural changes in the kidneys HRS is, theoretically, reversible if the mechanisms leading to the active renal vasoconstriction are corrected.

PATHOGENESIS

The theory that best fits with the observed alterations in the renal and circulatory function in HRS is the arterial vasodilation theory, which proposes that HRS is the result of the effect of vasoconstrictor systems acting on the renal circulation and activated as a homeostatic mechanisms to improve the extreme underfilling of the arterial circulation ^2,6-8. As a result of this increased activity of the vasoconstrictor systems, renal perfusion and glomerular filtration rate (GFR) are markedly reduced but tubular function is preserved. The activated vasoconstrictor systems are also responsible for the impaired sodium excretion (renin-angiotensin and sympathetic nervous systems) and free water excretion (arginine vasopressin) that also occur in patients with HRS ^2,7,8.

Most available data suggest that the arterial underfilling is due to a marked vasodilation of the splanchnic arterial circulation related to an increased splanchnic production of vasodilator substances, particularly nitric oxide ^9,10. In early phases of decompensated cirrhosis, renal perfusion would be maintained within normal levels because of an increased synthesis of renal vasodilator factors (mainly prostaglandins). In later phases of the disease, renal perfusion could not be maintained because of the extreme arterial underfilling causing maximal activation of vasoconstrictor systems and/or decreased formation of renal vasodilator factors, and HRS would develop.

CLINICAL AND LABORATORY FINDINGS

There are two well-differentiated clinical patterns of Hepatorenal syndrome in patients with cirrhosis. These two clinical patterns probably represent the two ends of the same pathogenic mechanism ²:

1. Type 1 HRS is characterized by rapid and progressive impairment of renal function. It represents the classical HRS, also known as "progressive functional renal failure" and the usual clinical picture is that of an acute renal failure. This type of HRS is arbitrarily defined as a 100% increase of the initial serum creatinine to a level greater than 2.5 mg/dl or a 50% reduction of the initial 24-hour creatinine clearance to a level lower than 20 ml/min in less than 2 weeks. In some patients, this type of HRS develops spontaneously without any identifiable precipitating factor, while in others it occurs in close chronological relationship with complications that may impair the effective arterial blood volume, such as spontaneous bacterial peritonitis ¹¹.

2. Type 2 HRS is characterized by a less severe and non-progressive reduction of glomerular filtration rate (at least in the short term). The main clinical consequence of this type of HRS is refractory ascites, due to a lack of response to diuretics.

Because of the absence of specific diagnostic tests, the diagnosis of HRS is currently made according to several diagnostic criteria which are based on the demonstration of a marked reduction in glomerular filtration rate (serum creatinine >1.5 mg/dl in the absence of diuretic therapy) and, most important, exclusion of other causes of renal failure that may occur in patients with cirrhosis ² (Table 1).

Table 1 Diagnostic criteria of hepatorenal syndrome.
Reproduced from Arroyo V et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology 1996; 23: 164.

Major criteria

1 Low glomerular filtration rate, as indicated by serum creatinine greater than 1.5 mg/dl or 24-hour creatinine clearance lower than 40 ml/min

2 Absence of shock, ongoing bacterial infection, fluid losses and current treatment with nephrotoxic drugs

3 No sustained improvement in renal function (decrease in serum creatinine to 1.5 mg/dl or less or increase in creatinine clearance to 40 ml/min or more) following diuretic withdrawal and expansion of plasma volume with 1.5 l of a plasma expander

4 Proteinuria lower than 500 mg/day and no ultrasonographic evidence of obstructive uropathy or parenchymal renal disease

Additional criteria

1 Urine volume lower than 500 ml/day

2 Urine sodium lower than 10 mmol/l

3 Urine osmolality greater than plasma osmolality

4 Urine red blood cells less than 50 per high power field

5 Serum sodium concentration lower than 130 mmol/l

All major criteria must be present for the diagnosis of hepatorenal syndrome. Additional criteria are not necessary for the diagnosis, but provide supportive evidence.

PROGNOSIS

HRS is the complication with the worst prognosis of cirrhosis and its development is associated with a very low survival expectancy ^1,2,12,13. Spontaneous recovery is very uncommon. The major determinant of survival is the type of HRS. Patients with type 1 HRS have a hospital survival rate of less than 10% and an expected median survival time of only 2 weeks ^1,14. In contrast, patients with type 2 HRS show a much longer median survival time, which is of approximately 6 months. The second major determinant of survival in HRS is the severity of liver disease, as assessed by the Child-Pugh classification ^15,16.

MANAGEMENT

For many years, no effective therapy existed for patients with HRS, except for liver transplantation. Recently, several effective new methods have been introduced which are discussed below.

Vasoconstrictors

A number of non-randomized studies published in the late 1990's and early 2000's have shown that the administration of vasoconstrictor drugs to patients with cirrhosis and HRS causes a marked improvement of renal function in a large proportion of patients ^17,27. The rationale for the use of vasoconstrictors in patients with HRS is to improve effective arterial blood volume by causing a vasoconstriction of the extremely dilated arterial splanchnic vascular bed. The improvement in the arterial circulatory function leads to a suppression in the activity of vasoconstrictor systems and a subsequent increase in renal perfusion and glomerular filtration rate ²⁸.

Two types of drugs have been reported to be effective in HRS: vasopressin analogues (ornipressin and terlipressin) and alpha-adrenergic agonists (noradrenaline and midodrine), which act on V1 vasopressin receptors and a-1 adrenergic receptors, respectively, present in vascular smooth muscle cells. In most studies, both drugs have been given in combination with iv albumin to further improve the arterial underfilling. A summary of the results obtained in published studies is shown in table 2. Currently, terlipressin, is the vasoconstrictor drug used more frequently in HRS ^{15,16,19,23-26}. Ornipressin is also effective but its use is not recommended because of the development of severe ischemic complications in up to one third of patients ^17,21.

Table 2 Summary of published studies on the use of vasoconstrictors in Hepatorenal syndrome

	n	Treatment	Days of treatment	Complete response (n)	Mean survival (days)	Liver transplant (n)
Guevara et al	8 8	OP + AB	3 15	0 4(50%)	0 ND 41	0 0
Gulber et al	7	OP + DP + AB	14 (5-27)	4(57%)	54	1
Uriz et al	9	TP + AB	9 (5-15)	7(78%)	47	3
Mulkay et al.	12	TP + AB	26 (8-68)	11(92%)	42	3
Ortega et al	13 8	TP + AB TP	8	10(77%) 2(25%)	50 14	5
Moreau et al	99	TP	9	57	21	30
Angeli et al.	85	MD + AB + OC DP + AB	5 8	5(62%) 1(20%)	140 8	2 1
Duvoux et al	12	NA + AB + FS	12	10(83%)	10	3
TP = terlipressin; OP = ornipressin; NA = noradrenaline; DP = dopamine; AB = albumin; FS = furosemide; MD = midodrine; OC = octreotide

Because there are no randomized studies investigating the efficacy and safety of terlipressin in patients with HRS, the existing information should be taken with caution. The currently available information can be summarized as follows:

1. The administration of terlipressin (0.5-2 mg/4-6h iv) is associated with a complete renal response, as defined by a reduction of serum creatinine from pretreatment values to a level below 1.5 mg/dl, in 50-75% of patients treated ^{15,16,23,25,26}. Because of the lack of dose-finding studies, the dose and frequency of terlipressin with the best efficacy/safety ratio is unknown.

2. In most studies, treatment with terlipressin has been maintained until serum creatinine decreased below 1.5 mg/dl (responder patients) or for a maximum of 15 days. It is unknown whether the continued administration of the drug after the end-point of 1.5 mg/dl of serum creatinine has been reached may cause a further beneficial effect on renal function.

3. In responder patients, the improvement in urine volume tends to occur immediately after the first doses of terlipressin (within 12-24 hours), while that of glomerular filtration rate usually occurs slowly over several days. In some, but not all cases, treatment also causes an increase in sodium excretion and improvement or normalization of serum sodium concentration.

4. In most studies, iv albumin has been given at variable doses for the duration of therapy with terlipressin. The suggestion has been made that iv albumin improves the beneficial effects of terlipressin on renal function ¹⁶. However, this remains to be proven conclusively in a prospective, randomized, comparative study.

5. Recurrence of HRS after treatment withdrawal is uncommon (approximately 15% of patients). The explanation for this low recurrence rate is unknown. Treatment of recurrence is usually effective.

6. The incidence of ischemic side effects which require the discontinuation of terlipressin ranges between 5-10% of patients. However, it has to be taken into account that most, if not all, studies excluded high-risk patients with ischemic heart or artery diseases.

7. The possible beneficial effect of terlipressin on survival of patients with HRS has not been proved yet due to the lack of comparative studies including a control group of non-treated patients. However, the observation of several studies that responder patients had a longer transplant-free survival compared to non-responders together with the well-known fact that spontaneous improvement of HRS is extremely uncommon suggests that terlipressin treatment may actually improve survival of patients with HRS.

8. The above information on effects of vasoconstrictor drugs refers mainly to type 1 HRS, as the majority of patients included in the publishes studies suffered from this type of HRS. Although some reports suggest that vasoconstrictors also improve renal function in patients with type 2 HRS ¹⁶, their efficacy in this setting remains to be confirmed.

Alpha-adrenergic agonists (noradrenaline, midodrine) represent an attractive alternative to terlipressin because of its very low cost, wide availability, and apparently similar efficacy compared with that of terlipressin ^22,27. However, the information on the efficacy and side effects of alpha-adrenergic agonists in patients with type 1 HRS is still very limited.

Transjugular intrahepatic portosystemic shunts

Since portal hypertension is the triggering event leading to circulatory dysfunction in cirrhosis, the decrease of portal pressure is a rational approach for the treatment of HRS. There are several case reports showing reversal of HRS following surgical portacaval shunts ^29,30. However, the applicability of major surgical procedures in patients with HRS is small, because of the extremely high mortality of these procedures in high-risk patients.

The development of transjugular intrahepatic portosystemic shunts (TIPS) has reintroduced the idea of treating HRS by porto caval shunts. TIPS consists of the insertion of an intrahepatic stent between the portal and the hepatic veins using a transjugular approach and its main effect is to achieve a reduction in portal pressure by a nonsurgical method ³¹.

Only four non-controlled trials have been published describing the effect of TIPS on patients with type 1 HRS. Considering altogether, renal function improved in some _patients one to four weeks after TIPS placement. This improvement correlated with a decreased activity of the vasoconstrictor systems, mainly the renin-angiotensin system, and, to a lesser extent, the sympathetic nervous system ^32,33.

De novo hepatic encephalopathy or worsening of previous hepatic encephalopathy occurred in one-third of patients, but it could be controlled with lactulose in more than half. Median survival after TIPS in patients with type 1 HRS ranged between two and four months ^32,33. As with vasoconstrictor drugs, it is likely, but not proved, that the improved renal function results in increased survival ³³. It should be pointed out that the information currently available on the use of TIPS in type 1 HRS has been obtained in a very selected population of patients and may not be applicable to the whole population of patients with type 1 HRS. In fact, TIPS is considered contraindicated in patients with severe liver failure (high serum bilirubin levels and/or Child-Pugh score greater than 12) or severe hepatic encephalopathy because of the risk of inducing irreversible liver failure or chronic disabling hepatic encephalopathy ^31,34.

No studies have been reported comparing TIPS and vasoconstrictors in type 1 HRS. Currently, vasoconstrictors appear to be the treatment of choice in type 1 HRS because of an apparent similar efficacy, wider availability, greater applicability, and lower costs compared with TIPS.

There have been no specific studies assessing the efficacy of TIPS in patients with Type 2 HRS. However, a sub analysis of patients with refractory ascites and type 2 HRS included in one randomised study showed that TIPS reduced ascites recurrence rate and the risk of progression from type 2 to type 1 HRS but did not improve survival as compared with a control group of patients treated with repeated large-volume paracentesis with iv albumin

Liver transplantation

Liver transplantation is the treatment of choice for patients with cirrhosis and HRS who are candidates to the procedure because it allows the cure of both the liver disease and the associated renal failure, which is reversible after transplantation ^36-40. Immediately after transplantation a further impairment in GFR may be observed and some patients may require hemodialysis. Because cyclosporine or tacrolimus may contribute to this impairment in renal function, it has been suggested that the administration of these drugs should be delayed until a recovery of renal function is observed, usually 48 to 72 hours after transplantation.

After this initial impairment in renal function, GFR starts to improve and reaches an average of 30-40 ml/min by 1-2 months postoperatively. This moderate renal failure persists during follow-up, is more marked than that observed in transplantation patients without HRS, and is probably due to a greater nephrotoxicity of cyclosporine or tracrolimus in patients with renal impairment prior to transplantation. The hemodynamic and neurohormonal abnormalities associated with HRS disappear within the first month after the operation and the patients regain a normal ability to excrete sodium and free water ⁴¹.

Patients with HRS who undergo transplantation have more complications, spend more days in the intensive care unit, and have a higher in-hospital mortality rate than transplantated patients without HRS ^36-40. The long-term survival of patients with HRS who undergo liver transplantation however is good, with a three-year probability of survival of 60% ^36-40. This survival rate is slightly reduced compared with that of transplantation in patients without HRS (which ranges between 70% and 80%).

The main problem regarding the use of liver transplantation for type 1 HRS is that a significant proportion of patients die before transplantation is made because of the short survival expectancy and prolonged waiting times in most transplant centers. Assigning these patients a high priority for transplantation from a cadaveric donor can solve this issue. Currently, this is done on the basis of the MELD score (Model for End-stage Liver Disease) a new disease severity index, which is obtained by a formula including serum bilirubin, serum creatinine, and INR ^42,44.

Patients with HRS have high MELD scores even in the presence of relatively preserved liver function. This system was implemented in United States in early 2002 and the initial results of its use have been reported recently ⁴⁵. The policies for allocation of livers from cadaveric donors are not uniform in other countries and in some settings patients with HRS are not prioritized for transplantation. Whichever the system used for organ allocation, HRS should probably be treated before transplantation is made in an attempt to improve renal function. This may help reduce the (moderately) higher morbidity and mortality reported in patients transplanted with HRS compared with those of patients transplanted without HRS ^46-48. A recent study has shown that patients with HRS treated with vasoconstrictors (i.e vasopressin analogues) before transplantation have an outcome after transplantation which is not different from that of patients transplanted without HRS ⁴⁹.

Other therapeutic methods

Renal replacement therapy (i.e. hemodialysis) is frequently used in the management of patients with type 1 HRS, especially in those who are candidates to liver transplantation, in an attempt to maintain patients alive until liver transplantation is performed or an unlikely spontaneous improvement in renal function occurs ^50,51. Unfortunately, the potential beneficial effect of renal replacement therapy has not been unequivocally demonstrated.

It is the clinical experience that most patients do not tolerate hemodialysis and develop important side effects, including severe arterial hypotension, bleeding, and infections that may contribute to death during treatment. Moreover, findings that indicate the need for renal replacement therapy (severe fluid overload, _acidosis or hyperkalemia) are uncommon, at least in early stages of type 1 HRS. Therefore, the initial therapy for these patients should probably include measures aimed at improving circulatory function (i.e vasocons trictors) and not hemodialysis.

Recently, extracorporeal albumin dyalisis, a system that uses an albumin-containing dialysate that is recirculated and perfused trough a charcoal and anion-exchanger columns, has been shown to improve systemic hemodynamics and reduce the plasma levels of renin in patients with type-1 HRS ^52,53. In a small series of patients a benefical effect with improved survival was reported. However, further studies are needed to confirm these findings. The efficacy of drugs with renal vasodilator activity, such as dopamine or prostaglandins, has not been proved and is therefore not recommended ⁵⁰. Finally, N-acetyl-cysteine has shown some efficacy in a small series of patients but these results need confirmation in larger series of patients ⁵⁴.

PREVENTION

Two randomized controlled studies in large series of patients have shown that HRS can be prevented in specific clinical settings. In the first study ⁵⁵, the administration of albumin (1.5 g/kg i.v. at infection diagnosis and 1 g/kg i.v. 48 hr later) together with cefotaxime in patients with cirrhosis and spontaneous bacterial peritonitis markedly reduced the incidence of impairment in circulatory function and the occurrence of type-1 HRS as compared to a control group of patients receiving cefotaxime alone (10% incidence of HRS in patients receiving albumin versus 33% in the control group). Moreover, the hospital mortality rate (10% versus 29%) and the 3-month mortality rate (22% versus 41%) were lower in patients receiving albumin. In a second study ⁵⁶, the administration of pentoxyfilline (400 mg t.i.d.) to patients with severe acute alcoholic hepatitis reduced the occurrence of HRS (8% in the pentoxyfilline group versus 35% in the placebo group) and hospital mortality (24% versus 46%, respectively). Since bacterial infections and acute alcoholic hepatitis are two important precipitating factors of type-1 HRS, these prophylactic measures may decrease the incidence of this complication. Although the beneficial effects obtained in these two clinical trials would ideally require confirmation in other studies, they represent the first big step forward towards an effective prevention of HRS in patients with end-stage liver disease.

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