Data showed that 24-h creatinine clearance takes longer to obtain, is more complicated to measure and does not improve diagnostic accuracy. Therefore, the current recommendation is to use serum creatinine. Secondly, in the 1996’s diagnostic criteria, HRS diagnosis was made after a non-specified period of diuretic withdrawal and volume expansion with saline. New data clearly favour plasma expansion with albumin rather than with saline. Additionally, new diagnostic criteria refer specifically that the attempt of volume expansion should last no more than 48h to begin treatment of HRS. Also, the 1996’s criteria specifically referred that was necessary to exclude gastrointestinal or renal losses of fluid whereas in the new diagnostic criteria the clinician focuses on whether volume expansion improves creatinine. Thirdly, in the 1996’s diagnostic criteria, an acute infection actually excluded HRS. Nowadays we know that only sepsis must be excluded, as the most common trigger for the development of type 1 HRS is actually bacterial infection, particularly spontaneous bacterial peritonitis (SBP). This way, treatment can (should) be started without waiting for complete recovery from the infection. Finally, in the 1996’s diagnostic criteria, existed additional criteria (low urinary volume, serum and urinary sodium – U Na < 10mEq/day – and high urine to plasma osmolality ratio).

The hepatorenal syndrome is a diagnosis of exclusion, and other diseases need to be considered^5,18,13,15, namely:

– Severe sepsis

CLINICAL PRESENTATION

Type 1 HRS24:

Type 2 HRS2:

Type 3 HRS:

ADDITIONAL DIAGNOSTIC WORKUP

Liver disease may be associated with near normal values for both the BUN (due to decreased urea production) and the serum creatinine (due to muscle wasting) despite a relatively large reduction in GFR^27,28. The presence of kidney disease in this setting can be documented by a reduction in creatinine clearance, but significant overestimation of GFR can still occur^28,29-31. Because of the problems with changes in creatinine production and secretion, other endogenous compounds have been evaluated in an effort to provide a more accurate estimation of GFR, including cystatin C and urinary biomarkers such as neutrophil gelatinase-associated lipocalin (NGAL).

Cystatin C: It has been proposed that cystatin C-based equations would be more accurate in patients with cirrhosis when compared with creatinine clearance.

For example, in a study in liver chirrhotic patients³², a cystatin C-based formulae (developed by Larsson and Hoek) showed significantly lower bias and higher precision than the creatinine-based formulae (Cockroft&Gault or MDRD) for GFR estimation. However, both creatinine and Cystatin C-based equations overestimated the true GFR by 105-154%. Therefore, even in populations in which cystatin C would be expected to outperform creatinine based GFR calculations, cystatin C-based equations are not totally accurate³³.

Also, even if cystatin C proved to be more accurate for the assessment of GFR than serum creatinine in cirrhotics, whether measurement of cystatin C levels would improve patient care is at present unknown, so cystatin C is not at the moment routinely performed in these patients.

Urinary biomarkers, such as neutrophil gelatinaseassociated lipocalin (NGAL), tend to be lower in pre-renal azotaemia and hepatorenal syndrome than in acute tubular necrosis (ATN), but there is considerable overlap between these conditions^34,35.

PRECIPITATING FACTORS²:

– None (in some patients)

– After effective arterial blood volume is decreased by:

Infections other than spontaneous bacterial peritonitis also may cause HRS, but its frequency and severity usually are lower than that of patients with spontaneous bacterial peritonitis.

Gastrointestinal bleeding. The development of kidney failure after gastrointestinal bleeding is not very common in patients who have cirrhosis (10%) and it is almost fully confined to patients with hypovolaemic shock. In most instances, it is associated with ischaemic hepatitis, which implies that the kidney failure most likely is related to ATN and not HRS.

Although diuretics have often been mentioned as precipitants of HRS, diuretics do not cause hepatorenal syndrome. Diuretics can, however, cause azotaemia, which improves with the cessation of therapy and fluid repletion, while in the hepatorenal syndrome kidney function typically worsens inexorably, even after diuretics are stopped.

TREATMENT OF HRS

Type 1 HRS

Treatment of type 1 HRS can be divided into three stages, depending on the severity of the hepatic and renal disease. These stages are: treatment of the hepatorenal syndrome itself, treatment of the acute kidney injury and treatment of the advanced hepatic disease. The first stage, treatment of the hepatorenal syndrome itself, includes pharmacological treatment (with intravenous albumin, to expand intravascular volume, together with vasoconstrictors, to reverse splanchnic vasodilatation) and interventional procedures (transjugular intrahepatic portosystemic shunt – TIPS – and peritoneovenous shunt). The second stage, treatment of the acute kidney injury (with renal replacement therapy) is necessary when the pharmacological treatment is ineffective or is still underway in patients who are candidates to kidney transplant or in whom reversal of the hepatic disease is a possibility. The final stage, treatment of the advanced hepatic disease, either by resolving the hepatic insult or by liver transplant, is the only definite treatment (artificial support of the hepatic and renal function may be temporarily required, in which case the MARS and Prometheus techniques may be of use).

Treatment of the hepatorenal syndrome itself Pharmacological treatment

Albumin and vasoconstrictors

– Administration of albumin: 1 g/kg body weight at day 1 and 2 – maximum 100g – followed by 25-50 g/d.24

– Administration of vasoconstrictor drugs²:

- The dose is increased up to a maximum of 2 mg/4-6 h after 3 days if there is no response to therapy, defined by a decrease in serum creatinine > 25% of pre-treatment values.

- Response to therapy is indicated by a marked decrease in the high serum creatinine levels, to less than 1.5 mg/dL (< 133 μmol/L).

Treatment is usually given from 5-15 days (occasionally longer if there is some but not complete improvement of renal function after two weeks).

- Norepinephrine (given in an ICU): 0.5-3 mg/h as continuous intravenous infusion aimed at increasing mean arterial pressure by 10 mmHg. Treatment is maintained until serum creatinine decreases to < 1.5 mg/dL (< 133 μmol/L).

- Midodrine (a systemic vasoconstrictor): 7.5 mg orally at eight-hour intervals, increased to a maximum of 15 mg 3id if needed. Treatment with the combination of terlipressin and albumin is associated with reduced mortality and reversal of HRS in 40%-50% of patients³⁷, making this approach the preferred initial therapy (according to the European Association for the Study of the Liver – EASL – 2010 guidelines)³⁶. However, given the fact that some studies^38,39 found no difference in efficacy and safety between patients treated with terlipressin plus albumin versus noradrenalin plus albumin, and because terlipressin may be significantly more expensive than noradrenalin, noradrenalin is recommended by some authors²⁴ as first line therapy for patients with HRS who are in a ICU (noradrenalin perfusion is not usually available on the general medical ward). However, in Portugal, this price difference may not be always present so an individual approach is warranted. Response to treatment with terlipressin and albumin is associated with a progressive decrease in serum creatinine concentration, increased urine output, and improvement of hyponatremia.

Factors that predict a response to treatment are an increase in arterial pressure during treatment and low baseline creatinine level. After withdrawal of therapy, HRS recurs in < 15% of patients, and in these cases, a second treatment with terlipressin is usually effective. The incidence of side effects (usually ischaemic) that mandate discontinuation of treatment is ~12%. Terlipressin has been associated with an increase of cardiovascular adverse events³⁷.

Alternatives to terlipressin (especially useful in countries where terlipressin is not available, such as the USA) are noradrenaline and midodrine (low cost; broad availability) plus octreotide (100 to 200 μg subcutaneously 3x/d; or as a continuous intravenous infusion – 50 mcg/hr), both in combination with albumin. Octreotide is a somatostatin analogue, which inhibits the release of endogenous vasodilators, producing splanchnic vasoconstriction. The speed with which effective treatment is achieved appears to be important. Thus, some authors²⁴ prefer continuous infusion of octreotide rather than subcutaneous injection and adjustment of each consecutive midodrine dose (every 8 hours) in order to rapidly achieve an increase in blood pressure instead of changing the dose only 24 hours later. In patients who respond to therapy, midodrine is occasionally used indefinitely to maintain a higher mean arterial pressure (or until there is resolution of liver injury or liver transplantation is performed). Also, midodrine may be effective in many patients who recover from type 1 hepatorenal syndrome who continue to have refractory ascites.

Patients treated with vasoconstrictors should be followed up carefully throughout treatment for early detection of side effects, particularly cardiovascular events and pulmonary oedema.

Alternative therapies

Acutely lowering renal sympathetic tone and renal vascular resistance in the early stages of hepatorenal syndrome by the intravenous administration of the sympatholytic agent, clonidine, can raise the GFR by as much as 25 percent⁵⁶. However, this benefit does not appear to be sustained with chronic oral therapy, despite a persistent reduction in sympathetic activity⁵⁷.

Interventional procedures

TIPS

A recent study showed that vasoconstrictor therapy followed by stent placement (TIPS – transjugular intrahepatic portosystemic shunt) was effective in a limited number of patients with type 1 HRS^2,45,46.

This approach is sometimes successful in highly selected patients, who fail to respond to vasoconstrictors and albumin and who are well enough to undergo the procedure. However, this procedure is associated with numerous complications (high incidence of encephalopathy, among others) and, because of the need for intravenous contrast, it may cause acute kidney injury. For this reason, some experts prefer dialysis as a first option (continuous renal replacement therapy) for patients whose serum creatinine remains above 1.5 mg/dL despite medical therapy. Overall, the available results suggest that TIPS should be considered only as a last resort in selected patients²⁴. More studies are required to establish the value of TIPS placement in the treatment of HRS.

Peritoneovenous shunt

Peritoneovenous shunts drain peritoneal fluid from the peritoneum into the internal jugular vein, reinfusing ascites into the vascular space. It is now rarely used because of an appreciable rate of complications and lack of evidence that peritoneovenous shunting prolongs patient survival²⁴.

Goal of therapy

The goal of medical therapy or TIPS in patients with hepatorenal syndrome is reversal of the acute kidney injury (decrease in the high serum creatinine levels, to least < 1.5 mg/dL, < 133 μmol/L). In addition, when patients are treated with norepinephrine, terlipressin, or midodrine plus octreotide, an immediate goal of therapy is to raise the mean arterial pressure by approximately 10 to 15 mmHg²⁴. The magnitude of the increase in mean arterial pressure induced by these vasoconstrictors appears to be significantly associated with the magnitude of the decrease in serum creatinine⁵⁸. As an example, in a systematic review of 501 patients with hepatorenal syndrome from 21 studies, a 9 mmHg increase in mean arterial pressure predicted a 1 mg/dL (88.4 micromol/L) decrease in serum creatinine. If a patient has no improvement in renal function after two weeks, therapy with these drugs can be considered futile²⁴.

T reatment of the acute kidney injury

– when vasoconstrictors are ineffective Renal replacement therapy

RRT is not considered the first-line treatment for patients with type 1 HRS because it does not correct the underlying pathogenesis². RRT should be started when patients with type 1 HRS are unresponsive to vasoconstrictors and when there are signs of uraemia, volume overload, severe metabolic acidosis, or hyperkalaemia.

However, not all patients are candidates for dialysis. Dialysis is useful as a bridge to liver transplantation or until there is liver recovery². Bridging patients to liver transplantation includes patients either waiting for a transplant or being evaluated for liver transplantation. In patients who develop a need for RRT but who are not expected to recover liver function / to receive a liver transplant, long-term RRT is usually not indicated / should be withhold⁴⁰ except as a trial to see if renal function will return⁴².

Haemodialysis is frequently difficult to perform in patients with hepatorenal syndrome since decompensated hepatic function is associated with haemodynamic instability, thrombocytopenia and coagulopathy.

Survival with RRT is poor with only 30–60% of patients surviving to liver transplant⁴². Some success has been accomplished with continuous renal replacement (CRRT) modalities⁴¹, which have potential advantages such as improved cardiovascular stability, more gradual correction of hyponatraemia (necessary to avoid central pontine myelinolysis), less fluctuation in intracranial pressure and removal of inflammatory cytokines, such as TNF-α and IL-6.

Studies, however, do not show superiority of CRRT when compared with conventional intermittent RRT.

However, all trials available are non-randomized with populations considered to be non-comparable to one another. Therefore, the decision of which modality to choose continues to be based on the clinical characteristics of the patient as dictated by haemodynamic stability and severity of illness⁴².

T reatment of the advanced hepatic disease

– looking for a definitive treatment

Although with today’s available therapy there may be reversibility of HRS without liver transplant¹⁸, the definitive treatment of hepatorenal syndrome is improvement of liver function (for example, by recovery of alcoholic hepatitis, treatment of decompensated hepatitis B with effective antiviral therapy or recovery from acute hepatic failure), or liver transplantation.

In patients in which recovery of liver function may be expected or who are candidates for liver transplantation, temporary artificial support of the liver (and renal) function may be considered, using either the MARS (molecular readsorbent recirculating system) or FPSA (fractionated plasma separation and adsorption – the Prometheus system).

MARS and Prometheus

The MARS system is designed to remove albuminbound toxins (including  vasodilators) by albumin dialysis as well as providing standard continuous renal replacement therapy (CRRT). The albumin dialysate is then regenerated utilizing an anion exchange resin and active charcoal adsorption. MARS has been utilized in treatment of HRS and was shown to be superior to CRRT in terms of patient survival, improved haemodynamics and urine output⁴². However, no large-scale trial has been carried out and more recent studies (6 patients) in patients with type 1 HRS not responding to vasoconstrictor therapy found no improvement following MARS therapy in terms of systemic haemodynamics⁴². Also, in a French study with thirty-two patients with type 1 hepatorenal syndrome, MARS therapy improved renal function in only very few patients with type 1 HRS⁴³.

Fractionated plasma separation and adsorption (FPSA) is a method of albumin dialysis that is integrated into an extracorporeal liver support device (Prometheus). In the HELIOS trial, a randomized-controlled European multicenter trial of FPSA therapy, a total of 145 patients with acute-on-chronic liver failure were either treated with standard medical treatment and FPSA eight to 11 times over 21 days or with standard medical treatment alone. There was no statistically significant difference in the overall survival.

However, significant survival benefit was observed under FPSA therapy in a predefined subgroup of patients with type 1 hepatorenal syndrome⁴⁴.

In conclusion, although MARS and Prometheus systems may be used to bridge patients to liver transplant, controlled studies are needed. Until then, these therapies should be considered experimental⁴².

Liver transplant

Liver transplant is the first choice of treatment for patients with cirrhosis and type 1 HRS because of their low survival expectancy². Therefore, patients who are candidates for liver transplant should be referred immediately to transplant centres.

Because kidney failure is reversible after liver transplant, combined liver-kidney transplant is generally considered appropriate only for patients who have been on RRT for more than 8 weeks who have a low likelihood of recovery of kidney function^47,48.

However, one must consider that the exact duration of pre-liver transplant kidney dysfunction or dialysis that is amenable to recovery is not known. Retrospective studies from single centres have shown the importance of the duration of > 12 weeks of SCr ≥ 1.5 mg/dL and dialysis ≤ 4 weeks pre-transplant on post-transplant renal outcomes^49-52. The duration of pre-transplant dialysis may be variable according to the physician/centre considered, so these results must be viewed with caution. The decision for combined liver-kidney versus liver transplant alone should be undertaken with consideration of duration of HRS, AKI and CKD and risk factors for progression of CKD present at the time of liver transplant such as hypertension, diabetes and obesity⁴⁰. In summary, the 8^th international consensus conference of the Acute Dialysis Quality Initiative (ADQI) Group⁴⁰, suggest liver transplantation alone for candidates with type-1 HRS for less than four weeks and simultaneous liver-kidney (SLK) for those at risk for nonrecovery of renal function (2D).

Provision of intra-operative continuous RRT during liver transplant may be indicated to help control volume and electrolytes⁴². Use of vasoconstrictors before liver transplant with the aim of performing transplant on patients with normal or near-normal kidney function remains an open question, because studies are scarce and include a small number of patients. However, excellent survival has been reported with the 2 approaches (“transplant-without treating HRS” or “treat HRS before transplant”) ^53,54,55.

Decisions about the management of patients who are not candidates for transplant or who have important comorbid conditions should be made on an individual basis2. In these patients, therapy with vasoconstrictors should be individualized and RRT probably be reserved for particular cases (potentially reversible chronic liver diseases – alcoholic hepatitis, acute-on-chronic liver failure, etc. – with no important associated comorbid conditions) in order to avoid futilities.

Type 2 HRS

– Usually managed as outpatients

– Spironolactone and other potassium-sparing diuretics should generally be avoided because of the risk of hyperkalaemia, whereas loop diuretics, such as furosemide, usually lack efficacy.

However, diuretics can be given to patients without adverse reactions to diuretics who have a sodium excretion under diuretic treatment of > 30 mEq/d².

– Treatment of ascites is based on repeated largevolume paracentesis and albumin administration (8 g/1 L of ascites removed)^36,59.

– More studies are required to more fully understand the role that vasoconstrictors plus albumin and TIPS may have in treating type 2 HRS. Some algorithms propose the use of vasoconstrictors in patients with type 2 HRS who are candidates for liver transplant and in whom there is a rise in serum creatinine².

– Renal replacement therapy is not indicated in the management of patients with type 2 HRS because of the lack of a severe decrease in kidney function.

Prevention of HRS^2,24,36:

– Administration of IV albumin to all patients with cirrhosis and spontaneous bacterial peritonitis (1.5 g/kg body weight at diagnosis and 1 g/kg 48 hours later) – as proposed in the guidelines of the European Association for the Study of the Liver (EASL) – reduces kidney impairment and improves survival.

– Long-term oral administration of norfloxacin (400 mg/d) in patients with ascitic fluid protein < 15 g/L and associated decreased liver and/or kidney function (bilirubin > 3 mg/dL [> 51.3 μmol/L], Child-Pugh score > 10, serum sodium < 130 mEq/L [< 130 mmol/L], and/or serum creatinine > 1.2 mg/dL [> 106.1μmol/L]) reduces the risk of HRS and improves survival. These effects probably are related to prevention of bacterial translocation, suppression of pro-inflammatory cytokines, and improvement in circulatory function.

– One report suggested that the reduction in intrahepatic pressure induced by transjugular intrahepatic portosystemic shunt (TIPS) placement may prevent the development of the hepatorenal syndrome. This retrospective study evaluated 204 patients with variceal bleeding who were treated with either a portasystemic shunt or sclerotherapy (or other non-shunt modalities) 60. Portasystemic shunting was associated with a lower incidence of ascites (15 versus 73%) and hepatorenal syndrome (4 versus 21%), a higher incidence of encephalopathy, and no difference in overall patient survival⁶⁰.

Prognosis

– If untreated, median survival of type 1 HRS is only 2 weeks. In type 2, average median survival is 6 months. The best hope for reversal of the renal failure is an improvement in hepatic function due to partial resolution of the primary disease or to successful liver transplantation.

The rate of recovery of kidney function following recovery of liver failure is uncertain. However, a substantial proportion of patients who have progressed to dialysis and survive to receive a liver transplant do recover kidney function⁶¹.

References