Renal failure in patients with cirrhosis: hepatorenal syndrome and renal support strategies Current opinion in anaesthesiology [0952-7907] Meltzer Ano:2010 Vol:23 Nr:2 Pág:139 -144 Meltzer, Josepha,b,c; Brentjens, Tricia Ed,e,f Abstract Purpose of review: The development of hepatorenal syndrome in liver cirrhosis leads to an increased morbidity and mortality in patients with cirrhosis. Currently, there are no proven methods for the treatment or prevention of hepatorenal syndrome except to maintain adequate hemodynamics and intravascular volume in this patient population. These patients will frequently require renal replacement therapy when presenting for hepatic transplantation. Recent findings: New consensus definitions have been published in order to create uniform standards for classifying and diagnosing acute kidney injury. Two such groups are the Acute Dialysis Quality Initiative (ADQI) and the Acute Kidney Injury Network (AKIN), which have proposed approaches to defining criteria for acute kidney injury. Recent literature supports not only the role of splanchnic vasodilation and systemic vasoconstriction but also heart failure in the pathogenesis of hepatorenal syndrome. The practice of using vasoconstrictor and intravenous albumin therapy for the treatment of hepatorenal syndrome is ongoing with a growing body of recent data supporting the use of vasopressin analogs as the first-line therapy in the ICU setting with knowledge of the possible cardiovascular side-effects. Summary: Hepatorenal syndrome, HRS, is a diagnosis of exclusion. There are two forms of hepatorenal syndrome: type 1 hepatorenal syndrome and type 2 hepatorenal syndrome. Type 1 HRS is rapidly progressive and portends a very poor prognosis and has a high mortality rate. Type 2 is more indolent while still associated with an overall poor prognosis. Treatment of HRS is largely still supportive. It is imperative to maintain euvolemia and hemodynamics in this patient population to optimize renal perfusion and preserve renal function. Renal replacement therapy may be necessary in this chronically ill patient population, if renal function deteriorates such that the kidneys cannot maintain metabolic and volume homeostasis. Further research is still necessary as to the prevention and effective treatment for hepatorenal syndrome. Introduction Acute renal failure (ARF), more recently termed acute kidney injury (AKI) , is a common and major complication of advanced liver cirrhosis. Kidney function, as evinced by serum creatinine (SCr) and blood urea nitrogen (BUN), is a powerful predictor of death in patients with decompensated cirrhosis . It is also an important risk factor when considering orthotopic liver transplantation (OLT), in that it increases mortality while on the waiting list and increases the frequency of complications after transplantation [3••,4,5]. In fact, SCr is one of only three variables used in the calculation of the model of end-stage liver disease (MELD) score, a good predictor of 3- month mortality in cirrhotic patients without OLT, and is currently used to allocate organs to patients awaiting transplantation. The other variables are bilirubin and international normalized ratio. The use of the MELD score in organ allocation has also increased the number of patients with ARF who present for transplantation . Pretransplant kidney function has been shown to be a predictor of survival post-OLT [7•]. As there is a powerful interconnection between kidney and liver dysfunction, AKI in patients with cirrhosis must be identified, understood and treated. Definitions of acute renal failure and acute kidney injury Acute kidney injury is a common and complex disorder without a standardized, accepted definition. Recently, groups of experts have assembled in order to create uniform standards for classifying and diagnosing AKI. Two such groups are the Acute Dialysis Quality Initiative (ADQI) and the Acute Kidney Injury Network (AKIN), which have proposed similar approaches to defining criteria for AKI that are more specific, sensitive and evidence based than the older ‘gestalt method’ of simply looking for a rising creatinine [1,8]. These consensus definitions of AKI take into account reductions in kidney function manifested by absolute elevations in SCr, percentage increases in SCr or changes in urine output over defined periods of time. Table 1 shows the AKIN consensus definition of AKI (based upon the ADQI RIFLE criteria for AKI). A recent study demonstrated the RIFLE classification of AKI as a predictive factor of mortality in patients with cirrhosis admitted to the ICU . This is an active area of collaborative clinical and translational research, which needs further validation. Etiology of acute kidney injury in cirrhosis Usually, three broad classifications of ARF/AKI are identified. First, AKI resulting from renal hypoperfusion without glomerular or tubular injury is called prerenal failure or prerenal azotemia and is rapidly reversible with correction of the underlying etiology. Second, renal dysfunction related to an obstructed urinary outflow tract is called postrenal failure, or postrenal azotemia. It is very important to rapidly identify this as the potential for recovery of renal function is often inversely related to the duration of obstruction. Third, intrinsic renal failure results from injury to renal tubules (i.e. ischemic or toxic), interstitium (i.e. autoimmune or allergic), vessels or glomerulus . Patients with cirrhosis are at risk for all types of renal failure; however, they can uniquely develop hepatorenal syndrome (HRS), a form a prerenal failure that, unlike most forms of prerenal failure, is unresponsive to fluid resuscitation. Hepatorenal syndrome is a unique and sometimes reversible form of prerenal failure that occurs in patients with advanced cirrhosis. Circulatory dysfunction is at the heart of HRS. Splanchnic vasodilation leads to decreased blood pressure and reduced central arterial blood volume, which in turn leads to renin–angiotensin release, sympathetic stimulation and extreme renal vasoconstriction, low glomerular filtration rate (GFR) and low renal perfusion . Low cardiac output probably exacerbates this hemodynamic picture [12,13]. Recent data seem to support that renal and cardiac dysfunction are tightly related in cirrhosis and that this relationship may be the result of chronic circulatory stress combined with an acute ‘decompensating’ event leading to a systemic response and even worsened circulatory dysfunction The diagnosis of hepatorenal syndrome Differentiating hepatorenal syndrome from acute tubular necrosis (ATN) can be difficult . The diagnosis of HRS must be based on the exclusion of other disorders that cause AKI in cirrhosis, as there are no specific tests for the syndrome . HRS is diagnosed on the basis of a serum creatinine concentration of more than 1.5 mg/dl which is not reduced with the administration of albumin (1 g/kg of body weight) and after a minimum of 2 days without diuretic therapy, along with the absence of current or recent treatment of potentially nephrotoxic drugs, the absence of shock, and the absence of findings suggestive of renal parenchymal disease (urinary excretion of more than 500 mg of protein/day, more than 50 red cells/high-power field, or abnormal kidneys on ultrasonography) [3••]. Major diagnostic criteria of HRS  are as follows: 1. hepatic failure and ascites, 2. creatinine more than 1.5 mg/dl, 3. no shock, ongoing bacterial infection, nephrotoxic agents or fluid losses, 4. no improvement after diuretic withdrawal and fluid resuscitation, 5. proteinuria less than 500 mg/day, normal renal sonography. The diagnosis is made after ruling out infection, often spontaneous bacterial peritonitis (SBP), shock, hypovolemia, parechymal disease, and/or drug-induced renal failure. The subtypes of hepatorenal syndrome There are two types of HRS with different characteristics and prognostic implications. Type 1 is rapidly progressive with SCr doubling to more than 2.5 mg/dl or a 50% reduction in creatinine clearance to less than 20 ml/min in a period of less than 2 weeks. This form often occurs in the inpatient setting after a precipitating event. Type 2 is notable for a steady and slowly progressive rise in SCr in the outpatient setting in the cirrhotic patient with ascites [14•]. This more ‘chronic’ form does not meet the definition of ARF/AKI and, therefore, may be considered a form of chronic kidney disease. Patients with type 1 HRS often have concurrent bacterial infection, gastrointestinal bleeding, recent surgery, acute hepatitis and signs and symptoms of severe hepatic insufficiency with jaundice, coagulopathy, encephalopathy and circulatory dysfunction [17••]. The prognosis for patients with concurrent cirrhosis and renal failure is poor. The overall survival rate is about 50% at 1 month and 20% at 6 months [3••]. Mortality is higher with type 1 HRS than with type 2 HRS, with a median survival of 2–4 weeks vs. 5–6 months respectively [18,19]. Management of acute kidney injury in cirrhosis Treatment of AKI in cirrhosis depends on its cause and severity. Prerenal azotemia should be treated with isotonic intravenous fluid resuscitation and the discontinuation of diuretics in order to restore renal blood flow and euvolemia. The cause of hypoperfusion should be sought and addressed. In patients with gastrointestinal bleeding, red blood cell transfusion and plasma expanders should be administered aggressively with an eye towards maintaining hemodynamic stability. All nephrotoxic drugs (i.e. nonsteroidal anti-inflammatory agents and aminoglycosides) should be discontinued and radiocontrast agents avoided. Bacterial infections should be prevented and, when present, treated quickly and aggressively . Some suggest third-generation cephalosporins as the initial treatment of choice for bacterial infections, but region and hospital-specific antibiograms may also guide therapy [21•]. Patients should have ongoing nutritional support. The possibility that sepsis is a causative factor should be investigated and, if suspected, treated aggressively in an intensive care environment [21•]. Consideration should be given to early goal-directed therapy , the avoidance of hypoglycemia and hyperglycemia , lung-protective ventilation for those with acute respiratory distress syndrome (ARDS) or at risk for ARDS , and steroid therapy for possible adrenal insufficiency [25,26]. There is little evidence-based data to support the use of natural/artificial colloids over crystalloids other than that 6% hydroxyethylstarch (HES) should be avoided in patients with sepsis and/or AKI [27– 29]. There may be a role for vasoconstrictor therapy in AKI secondary to ATN. A recent study showed a benefit of terlipressin infusion in patients with cirrhosis, ascites and ATN . The reversal of mesenteric vasodilation with the treatment of vasopressin analogs and resultant increase in blood pressure, central blood volume and renal blood flow is the proposed mechanism of action. If hepatorenal syndrome progresses to frank renal failure, renal replacement therapy will be required. Renal replacement therapy Hepatorenal syndrome that has decompensated, resulting in metabolic acidosis, electrolyte imbalance, metabolic disarray and volume overload should be treated with renal replacement therapy. There are essentially three usual processes for dialysis: intermittent hemodialysis, continuous veno-venous hemodialysis (CVVHD), and peritoneal dialysis. Perintoneal dialysis is contraindicated in the setting of cirrhosis, as ascites is frequently present. There is a paucity of data in regards to intensity, dose and timing of renal replacement therapy but continuous veno-venous hemodialysis is preferable to standard hemodialysis in patients with a tenuous hemodynamic profile. There are also a number of forms of artificial support systems designed to support the patient with combined liver and kidney failure. These systems include the molecular absorbent recirculating system (MARS), the fractioned plasma separation, adsorption and dialysis system, single-pass albumin dialysis (SPAD) and single-pass albumin extended dialysis [31••]. These artificial hepatic support systems require further investigation at this time and are beyond the scope of this review but have been reviewed elsewhere Surgical treatment of hepatorenal syndrome Liver transplantation is the treatment of choice for advanced cirrhosis with or without HRS. Kidney function often recovers after hepatic transplantation. A liver–kidney transplant may be necessary for those with severe or prolonged hepatorenal syndrome . Often there is a further worsening of renal function in the immediate perioperative period necessitating renal replacement therapy about 35% of the time . Owing to ongoing AKI, cyclosporine, tacrolimus and other nephrotoxic agents should be avoided until there is evidence of renal recovery. The hemodynamic and neurohormonal changes associated with HRS disappear within the first month after hepatic transplantation and patients regain their ability to handle sodium and water . Liver transplantation in the face of HRS leads to an increased number of complications, ICU length of stay and mortality when compared with hepatic transplantation without HRS. Patients who undergo hepatic transplantation with HRS have a significantly reduced 5-year survival as compared with patients without HRS . The issue of whether to transplant a kidney in addition to a liver is also important . Hepatorenal syndrome itself is not an indication for combined liver–kidney transplantation. Combined transplant is reserved for those with irreversible kidney injury, requiring hemodialysis for longer than 8 weeks, or progressive primary kidney disease [37,38]. As hepatic transplantation is a complex, lengthy procedure associated with major alterations in systemic hemodynamics, metabolic derangements, bleeding and coagulopathy, intraoperative renal support via CVVHD may be required to successfully transplant patients with preoperative renal failure . Intraoperative CVVHD is well tolerated, feasible, associated with neutral or negative fluid balance during the procedure, and does not require anticoagulation . Transjugular intrahepatic portosystemic shunt (TIPS) lowers portal pressure and may be useful in treating HRS in patients who are poor transplantation candidates. TIPS, in these select patients, may improve SCr and GFR [40,41]. Further research is needed in this area. Pharmacologic treatment of hepatorenal syndrome The best approach to the pharmacologic management of HRS is the administration of vasoconstrictor medications. The physiologic rationale for the administration of vasoconstrictors is to reverse the splanchnic vasodilation that initiates HRS. Many vasoconstrictors have been studied in uncontrolled trials in HRS including the vasopressin analogs terlipressin, ornipressin and vasopressin, somatostatin analogs, octreotide, and alpha-adrenergic analogs, midodrine and norepinephrine. Of note, in most of these studies, intravenous albumin therapy was coadministered with the vasoconstrictor medication and seems to enhance their benefit. It appears that vasopressin analogs are most effective, probably due to their profound splanchnic vasoconstrictor effect, and should be considered first-line therapy [3••,42–44,45••,46••]. Two recent randomized controlled trials add to our understanding of vasopressin analog therapy in type 1 HRS. In the first, Sanyal and the Terlipressin Study Group evaluated the safety and efficacy of terlipressin plus albumin vs. albumin alone in patients with HRS type 1 in a multinational study. Although significantly more patients in the terlipressin group achieved HRS reversal than in the placebo group, there was no difference in 6-month survival. More patients in the terlipressin group experienced serious adverse events such as nonfatal myocardial infarction, nonsustained supraventricular tachycardia and arrhythmias [46••]. In the second study, Martin-Llahi and the TAHRS investigators used the same drug in both type 1 and type 2 HRS. Similarly, in this trial, the terlipressin group experienced a significantly higher rate of improved renal function but a nonsignificant improvement in 3-month survival. There was, again, an increased rate of cardiovascular complications in the terlipressin group including myocardial ischemia, intestinal ischemia, arrhythmias and volume overload . The data supporting the use of oral midodrine and subcutaneous octreotide are from small nonrandomized and retrospective studies. However, the studies support the use of these drugs in combination as they have been associated with improved renal function and survival and may be a more convenient option for less ill patients such as those with type 2 HRS, as they do not require intravenous administration [38,47]. Attempts at pharmacological renal–arterial vasodilation with fenoldapam, dopamine or prostaglandins have not been shown to be effective . Prevention of hepatorenal syndrome The best prevention of hepatorenal syndrome is to maintain normovolemia and hemodynamics to optimize renal perfusion to preserve renal function. Subacute bacterial peritonitis (SBP) can cause HRS by inducing proinflammatory cytokines that lead to vasodilation and hypovolemia . It appears that, when SBP is treated with cefotaxime and albumin rather than albumin alone, HRS is less likely to develop and mortality rates are significantly improved . Long-term antibiotic prophylaxis in certain patients may also reduce the incidence of SBP and HRS . Hepatorenal syndrome is a mortal development in cirrhotic patients with severe alcoholinduced hepatitis. The administration of pentoxifylline, a tumor necrosis factor-[alpha] synthesis inhibitor, in patients with alcoholic hepatitis appears to reduce mortality . The avoidance of nephrotoxic agents, when possible, may also help prevent HRS. Prophylaxis should be used in patients with cirrhosis who are at risk for hepatorenal syndrome when they are to receive radio-contrast dye for imaging studies. These strategies include isotonic crystalloid prehydration , oral or intravenous Nacetylcysteine [53,54], intravenous isotonic sodium bicarbonate infusion  as well as the alteration of volume, dose and type of contrast medium. Intravenous precontrast hydration is considered the standard of care but multimodal prophylaxis protocols for high-risk patients, such as those with severe cirrhosis and ascites, may reduce the incidence of contrast-induced AKI and HRS Conclusion The development of hepatorenal syndrome in the presence of cirrhosis is a devastating complication that affects morbidity and mortality in this pa ient population. There are currently no effective pharmacologic agents available for the prevention or definitive treatment of HRS. However, vasopressin analogs and treatment with a combination of midodrine and octreotide have shown some promise. Further research is desperately needed in this area. If hepatorenal syndrome progresses to frank renal failure, renal replacement therapy in the form of intermittent hemodialysis or continuous venovenous hemodialysis in hemodynamically unstable patients is necessary. The definitive therapy for hepatic cirrhosis with the development of HRS is hepatic transplantation.