Renal Dysfunction in Cirrhosis: Diagnosis, Treatment, and Prevention

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MedGenMed Gastroenterology

Renal Dysfunction in Cirrhosis: Diagnosis, Treatment, and Prevention

Elaine Yeung, MD; Elaine Yong, MD, FRCPC; Florence Wong, MD, FRCPC Medscape General Medicine 6(4), 2004. © 2004 Medscape

Posted 12/02/2004

Introduction

Renal dysfunction is a common and serious problem in patients with advanced liver disease. In particular, alterations in renal physiology in acute liver failure or cirrhosis with ascites can predispose patients to a specific functional form of renal failure known as hepatorenal syndrome (HRS).[1] The first detailed description of HRS was made by Hecker and Sherlock[2] in 1956. These authors reported 9 patients with cirrhosis or acute hepatitis who developed renal failure without associated proteinuria and with very low urinary sodium excretion. On autopsy, these kidneys showed normal histology. It was later shown that kidneys from patients with HRS regain their function when transplanted into patients without cirrhosis,[3] and that HRS can be reversible following liver transplantation.[4]

Definition

HRS is defined as the development of renal failure in patients with advanced liver failure (acute or chronic) in the absence of any identifiable causes of renal pathology. In 1996, the International Ascites Club published a consensus paper subdividing HRS into 2 types.[5] Type 1 HRS is characterized by a rapid decline in renal function, defined as a doubling of serum creatinine to a level > 2.5 mg/dL or a halving of the creatinine clearance to < 20 mL/min within 2 weeks (Table 1). The clinical presentation is that of acute renal failure. In type 2 HRS, renal function deteriorates more slowly, with serum creatinine increasing to > 1.5 mg/dL or a creatinine clearance of < 40 mL/min. The clinical presentation is that of stable renal failure in a patient with refractory ascites.

Epidemiology

In a large prospective study of cirrhotic patients with ascites, 18% developed type 1 HRS at 1 year and 39% at 5 years.[1] The predictive factors for the development of HRS include a low serum sodium, high plasma rennin, and absence of hepatomegaly.[1] Until the recent development of effective therapies, the median survival following the development of type 1 HRS was 1.7 weeks, with only 10% of patients surviving more than 10 weeks.[1] Survival rate in type 2 HRS is 50% at 5 months and 20% at 1 year.[6]

Pathophysiology

Patients with cirrhosis and portal hypertension develop circulatory dysfunction characterized by disturbances in systemic and renal hemodynamics.[7] It has been shown that the severity of circulatory dysfunction correlates with the severity of cirrhosis.[8]

In compensated cirrhosis (ie, cirrhosis without ascites), the systemic hemodynamics are normal in the upright position, but become hyperdynamic in the supine position -- that is, cardiac output increases and systemic vascular resistance decreases.[9] This is thought to be due to volume expansion secondary to subtle sodium retention in the upright position.[10-12] The renal circulation is frequently vasodilated with glomerular hyperfiltration.[13]

With disease progression, circulatory dysfunction worsens, manifested as vasodilatation and relative intravascular underfilling.[14,15] There is increased activity of the sympathetic nervous and renin-angiotensin systems[16-18] in order to maintain hemodynamic stability. Peripheral edema and ascites can occur as a result of worsening sodium retention despite an increase in natriuretic substances.[19] Despite activation of various vasoconstrictor systems, renal perfusion and glomerular filtration rate (GFR) in the early stages of ascites may be normal or only moderately decreased as a result of increased renal production of prostaglandins.[20,21] Nitric oxide and prostacyclin have also been shown to counteract vasoconstrictors to maintain renal perfusion.[22-24] At this stage of disease, hypersecretion of antidiuretic hormone (ADH) results in decreased free water excretion.[25] Concurrently, increased prostaglandin E2 synthesis by the collecting tubules antagonizes ADH and preserves renal excretion of free water.[26] Therefore, hyponatremia is not common in early ascites.[27]

As systemic vasodilation progresses, the systemic arterial pressure falls. Renal perfusion also decreases, leading to decreased renal blood flow.[28] The renal circulation also becomes hypersensitive to the vasoconstrictive effects of various activated hormonal systems. When the vasoconstrictors overwhelm the compensatory effects of the various renal vasodilators, renal vasoconstriction occurs and GFR falls.[29]

HRS occurs in the latest phases of cirrhosis and is considered the extreme expression of circulatory dysfunction. Renal GFR decreases to < 40 mL/min. Marked renal vasoconstriction occurs due to increased levels of intrarenal vasoconstrictors (renin and angiotensin II).[30] Increasing levels of renal vasoconstrictors such as adenosine,[31] endothelin, leukotrienes,[32] and F2-isoprostanes[32] cause mesangial contraction which further reduces GFR.[33]

Another factor that influences renal hemodynamics is sinusoidal portal hypertension; this is supported by the fact that an acute increase in sinusoidal pressure leads to reduction of renal plasma flow,[34] and a reduction in sinusoidal pressure results in improvement of renal hemodynamics and renal function.[35] Bataller and colleagues[36] proposed that renal hypoperfusion in cirrhosis could also be related to liver dysfunction. However, the mechanism whereby liver dysfunction could directly induce a reduction of renal vasodilators is unclear. It is possible that the liver is involved in the synthesis or release of renal vasodilators such as nitric oxide.[24]

The extremely low urinary sodium in HRS results from decreased filtered sodium (decreased GFR) and increased sodium reabsorption in the proximal renal tubule.[37] This results in a minimal amount of filtered sodium reaching the loop of Henle and the distal nephron. Decreased delivery of diuretics to renal tubules hampers the ability of diuretics to promote natriuresis.[37] Hyponatremia is common[27] and is caused by a further nonosmotically induced increase in antidiuretic hormone and possibly decreased prostaglandin E2 activity, resulting in a decrease in water excretion.[26]

Precipitating Factors

It is important to be aware of precipitating factors in order to reduce the incidence of HRS and related mortality. Watt and colleagues[38] found that the most common predisposing factors for HRS were bacterial infection (48%), gastrointestinal bleed (33%), and aggressive paracentesis (27%). Drugs were the precipitating cause in 7% of cases, and surgery the cause in 7%. Miscellaneous factors accounted for 11% of cases.[38] Twenty-four percent of patients with type 1 HRS develop renal failure without an obvious precipitating factor.[39]

Spontaneous Bacterial Peritonitis

Renal impairment is a frequent event in cirrhotic patients with spontaneous bacterial peritonitis (SBP). It occurs more commonly in patients with preexisting kidney failure, although it can occur in patients with normal renal function. Renal impairment is the most important predictor of hospital mortality in cirrhotic patients with SBP.[40] Renal impairment is related to further deterioration of systemic hemodynamics, possibly brought about by endotoxins and various cytokines induced in SBP, causing further vasodilatation.[41] The incidence of renal impairment is most significant among patients with a serum bilirubin level > 4 mg/dL (68 mcmol/L) and a serum creatinine level > 1 mg/dL (88 mcmol/L).[42]

Gastrointestinal Bleeding

Acute gastrointestinal bleeding leads to acute blood volume contraction, with decreased renal perfusion. In one study, HRS developed in 3 of 85 patients with hepatic cirrhosis hospitalized for upper gastrointestinal bleeding.[43] The occurrence of renal failure is mainly related to the severity of bleeding and to the baseline liver function. In another study, the development of renal failure and hypovolemic shock were independent predictors of in-hospital mortality. Patients with renal failure had a mortality rate of 55% as compared with only 3% in patients without renal failure (P < .01).[44]

Aggressive Paracentesis

Aggressive paracentesis in cirrhotic patients with ascites accentuates the reduction of effective arterial blood volume and further activates vasoconstrictor systems, leading to further renal vasoconstriction.[45] HRS occurs in 10% of patients with ascites treated by total paracentesis.[1]

Drugs

Numerous drugs can precipitate HRS. Overzealous use of diuretics can cause renal failure, although this may be reversible. Patients with ascites and no edema are able to mobilize more than 1 L/day during rapid diuresis but at the expense of plasma volume contraction and renal insufficiency. Aminoglycosides are nephrotoxic in cirrhotic patients, and frequent assessments of beta-2 microglobulin are no guarantee against the development of renal failure. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the synthesis of prostaglandins. Short-term celecoxib administration induces marked decrease in GFR in cirrhotic patients with ascites.[46] Cirrhotic patients are dependent on the activated renin-angiotensin system to maintain systemic blood pressure. Therefore, the use of angiotensin-converting enzyme inhibitors and angiotensin II antagonists can result in arterial hypotension and prerenal failure in these patients.[47-49]

Others

Surgery, acute alcoholic hepatitis, and cholestasis can also act as precipitating factors of HRS. Acute biliary obstruction is associated with the development of renal impairment and oxidative stress. The F2-isoprostanes, formed during oxidant injury, are renal vasoconstrictors acting via thromboxane-like receptors. Antioxidants such as N-acetylcysteine have been shown to improve renal function.[50,51]

Diagnosis of HRS

The presence of renal dysfunction is often missed in patients with cirrhosis. Because of a reduction in muscle mass in these patients, serum creatinine may be within the normal range, even with a very low GFR. The use of blood urea nitrogen (BUN) concentration as a measure of renal function is even less reliable, because BUN levels can be affected by the presence of gastrointestinal bleeding or by the amount of protein in the diet. It has been suggested that serum creatinine concentrations of 71 mcmol/L, 88 mcmol/L, 160 mcmol/L, 195 mcmol/L, and 354 mcmol/L, would reflect steady-state GFRs of 100 mL/min, 50 mL/min, 25 mL/min, 12 mL/min, and 6 mL/min, respectively.[52] Therefore, a creatinine level > 88 mcmol/L in a patient with cirrhosis should alert the clinician to the presence of renal dysfunction.

HRS should only be diagnosed in patients with decreased renal function in the presence of advanced cirrhosis, chronic liver disease with severe liver failure and portal hypertension, or acute liver failure. Other forms of organic renal disease must be ruled out. Some patients with primary liver diseases are at higher risk for developing certain forms of kidney diseases (Table 2), while some systemic processes can affect both the liver and the kidney (Table 3).[53-55]

The International Ascites Club requires major criteria to be fulfilled for the diagnosis of HRS. These criteria include serum creatinine > 1.5 mg/dL (133 mcmol/L) or 24-hour creatinine clearance < 40 mL/min in the absence of diuretic therapy and excluding other causes of renal failure (Table 1). Despite the existence of these criteria, arriving at an accurate diagnosis can be challenging.[38]

Approach to Renal Failure in Cirrhosis

The diagnostic approach to renal failure in a patient with cirrhosis is outlined in Table 4 and Table 5. Patients with type 2 HRS are at particularly high risk for type 1. A thorough history and physical exam can detect intravascular volume depletion and arterial hypotension. A careful assessment of the patient's history should identify preceding events such as gastrointestinal bleeding, overdiuresis, or aggressive paracentesis. Sepsis should be suspected in any cirrhotic patient with renal deterioration, even in the absence of symptoms. Fever and leukocytosis may not be present. Appropriate cultures should be obtained, including examination of the ascitic fluid to rule out SBP. Recent exposure to nephrotoxins such as NSAIDs, aminoglycosides, or radiocontrast dyes prior to the increase in serum creatinine level should be ruled out. If proteinuria and/or hematuria are present, additional investigations should be undertaken to rule out renal parenchymal diseases. Renal biopsy should be considered if there is a strong suspicion of glomerulonephritis. An abdominal ultrasound should be performed to determine whether the patient has postobstructive renal failure.

Differentiating HRS from acute tubular necrosis (ATN) is often difficult. Distinguishing the 2 entities is important when considering therapy and for prognostication purposes. Typically, urine sodium is < 10 mmol/L in HRS and > 20 mmol/L in ATN due to impaired reabsorption of sodium from damaged renal tubules, but this feature is not always reliable. Heme-granular casts may be seen in ATN. And ATN should be considered when renal failure develops abruptly following hypovolemia, septic shock, or exposure to nephrotoxins. A recent study suggested that fractional excretion of urea ([urine urea nitrogen/ blood urea nitrogen)/(urine creatinine/plasma creatinine)] X 100) < 35% is specific for prerenal azotemia, and > 50% is specific for ATN.[56] Because this study included only 7 patients with hepatic failure, its significance in distinguishing ATN from HRS awaits further investigation.

It is interesting to note that in a recent multicenter retrospective study involving 355 patients with cirrhosis and acute renal failure, 58% had prerenal failure, with one third of patients fulfilling the definition of type 1 HRS.[57] Acute tubular necrosis was present in 41.7%. Only 1 patient had obstructive or postrenal failure. There were no cases of glomerulonephritis. However, preliminary reports from an ongoing prospective study of renal failure in patients with cirrhosis revealed a frequency of 32% infection-induced renal failure, 24% parenchymal renal disease, 22% prerenal failure, 11% ATN, 8% HRS, and 3% nephrotoxic renal failure.[52]

Management of HRS -- Prevention

The most important aspect in management of HRS is to prevent its occurrence. The latter is achieved by avoidance, prophylaxis, early recognition, and treatment or removal of precipitating factors.

Prophylaxis Against Bacterial Infections

Prophylaxis with antibiotics is recommended in patients presenting with gastrointestinal bleeding or those with a history of SBP. Patients with severe cirrhosis who are admitted for gastrointestinal bleeding have a higher risk of developing bacterial infection during their hospitalization;[58] the incidence of bacterial infection is 6.7% to 20%.[59-65] Also, proven bacterial infection or antibiotic use are independent prognostic factors for failure to control bleeding.[66] Short-term antibiotic prophylaxis increases the survival rate at 19 days in cirrhotic patients with gastrointestinal bleeding.[64] The overall probability of SBP recurrence in cirrhotic patients after 1 episode at 1 year of follow-up is 68%.[67] Among cirrhotic patients admitted with SBP, renal impairment occurs in 33%, mainly in those with kidney failure before infection, and is the most important predictor of mortality in hospital.[40] After 1 episode of SBP, patients with cirrhosis should receive antibiotic prophylaxis.

Volume Expansion

The use of albumin to prevent the development of HRS is still controversial. Plasma volume expansion with intravenous albumin has been shown in 1 study to reduce the incidence of renal impairment in cirrhotic patients admitted with SBP. It also reduces in-hospital and 3-month mortality.[42] However, the same study has been criticized in that the patients who did not receive albumin did not receive any other fluid support. Therefore, it is not clear at present whether fluid support with crystalloids or other colloids would have produced the same results. Intravenous albumin infusion has also been shown to prevent activation of endogenous vasoactive systems in cirrhotic patients with ascites who are treated with repeated large-volume paracentesis.[68] Because postparacentesis circulatory dysfunction is not always spontaneously reversible, it then follows that albumin should be able to prevent the development of HRS after large-volume paracentesis. Albumin seems to be the best plasma expander to prevent this complication.[69] However, those patients who receive albumin for their large-volume paracentesis did not demonstrate any survival benefits.

Judicious Use of Diuretics

Diuretic-induced renal impairment occurs in 20% of patients with ascites. The latter occurs when the rate of diuresis exceeds the rate of ascites reabsorption, resulting in intravascular volume depletion. The renal failure is nearly always reversible with cessation of the diuretics. Patients with ascites and no edema are able to mobilize > 1 L/day during rapid diuresis, but at the expense of plasma volume contraction and renal insufficiency. Patients with peripheral edema appear to be protected from these effects because of the preferential mobilization of edema, and they may safely undergo diuresis at a rapid rate (> 2 kg/day) until edema disappears.[70]

Avoidance of Nephrotoxic Agents

Patients with cirrhosis and ascites are predisposed to ATN with use of aminoglycosides; therefore, these agents should be avoided.[71] NSAIDs should also be avoided because renal failure occurs in 33% of this population compared with in 3% to 5% of the general population. NSAIDs inhibit formation of intrarenal prostaglandins, causing a decline in renal function and sodium excretion. Short-term celecoxib administration also induces a marked decrease in GFR in patients with cirrhosis and ascites.[46] Angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists result in arterial hypotension and cause prerenal failure in cirrhotic patients.[47-49]

Management of HRS -- Treatment

Initial Management

Initial management of these patients requires exclusion of reversible or treatable conditions. Patients should be supported until liver recovery or transplantation. A diligent search should be made for precipitating factors (infection, gastrointestinal bleeding) and treated accordingly. Likewise, nephrotoxic drugs should be removed. Patients should be initially challenged with fluid to assess response and to treat subclinical hypovolemia. Cirrhotic patients with an acute gastrointestinal bleed and poor liver function and/or decreased renal function should be managed in intensive care units to protect effective circulating blood volume and renal perfusion.[72] In patients with cirrhosis and SBP, treatment with intravenous albumin in addition to an antibiotic has been shown in one study to reduce the incidence of renal impairment and death compared with treatment with an antibiotic alone.[42]

Pharmacologic Therapy

The aim of pharmacologic therapy is to increase renal blood flow. This can be accomplished either by improving the renal perfusion pressure or by inducing renal vasodilatation. Splanchnic vasoconstriction redistributes some of the intravascular volume to the systemic circulation and improves circulatory function and effective arterial volume, thereby improving renal perfusion and GFR. Such agents can be used as a bridge to liver recovery or liver transplantation.

Dopamine. This agent has renal vasodilator effects when given in subpressor doses, but no studies have shown convincing benefit. and colleagues[73] showed that urine flow rate and GFR did not consistently improve with 12- to 24-hour intravenous infusions. Moreover, in cirrhotic patients without HRS, dopamine has been shown to decrease arterial pressure and accentuate portal hypertension.[74]

Noradrenaline. In a study by Duvoux and colleagues,[75] noradrenaline with albumin and furosemide were used in the management of patients with type 1 HRS. Reversal of HRS was seen in 10 of 12 patients after a median of 7 days. There were also associated increases in mean arterial pressure and reductions in active renin and aldosterone. A similar earlier study did not find noradrenaline to be effective for type 1 HRS.[76] Therefore, the use of noradrenaline in patients with HRS awaits further confirmatory investigations.

Midodrine and octreotide. Midodrine is an oral alpha-adrenergic agent and a sympathomimetic drug. Octreotide is a long-acting analogue of somatostatin. Combined long-term administration of oral midodrine and subcutaneous octreotide, in addition to albumin infusion, led to improvement in renal function compared with nonpressor doses of dopamine after 20 days of treatment.[77] This is accompanied by a significant reduction in plasma renin activity, plasma vasopressin, and plasma glucagon levels. No side effects occurred.[77] The latter has recently been confirmed in another study using oral midodrine and intravenous octreotide, together with intravenous albumin.[78] Fifty percent of patients survived for more than 6 months, with or without liver transplantation. Octreotide alone has been shown to be ineffective for treatment of HRS.[79] The use of this therapeutic combination is common in countries where terlipressin is not available, and evidence is accumulating that this may offer an alternative to terlipressin (see below).

Misoprostol. The role of this synthetic analogue of prostaglandin E1 and renal vasodilator was examined by Fevery and colleagues[80] in 4 patients with HRS who were also treated with albumin infusions. All responded with diuresis, a fall in creatinine level, and normalization of hyponatremia. However, it is not clear whether the improvement in renal function was due to the misoprostol or the albumin infusion. Gines and colleagues[81] found in their group of 16 patients that neither oral misoprostol nor infusion of prostaglandin E2 led to improvement in renal function.

Ornipressin. This vasopressin analogue is a nonselective agonist of the V1 vasopressin receptors; it preferentially causes vasoconstriction of the splanchnic vasculature, thus increasing systemic pressure and renal perfusion pressure. There has been evidence of benefit to renal function shown with the use of ornipressin.[82,83] However, Salo and colleagues[84] showed that despite an increase in arterial pressure and suppression of plasma renin activity during ornipressin and ornipressin plus dopamine administration, there was no significant improvement in renal function. Another series showed improvement in urine volume, creatinine clearance, urinary sodium excretion, and serum creatinine with ornipressin in 4 of 7 patients with type 1 HRS who had failed a previous course of albumin plus dopamine therapy.[85] Guevara and colleagues[86] found that prolonged use of ornipressin plus albumin for 15 days of therapy normalized serum creatinine, was associated with a marked increase in renal plasma flow and GFR, and suppressed vasoconstrictor system activity -- but with an increased risk of ischemic complications. Because of the side-effect profile, the use of ornipressin for HRS is rather limited.

Terlipressin. This agent is a synthetic analogue of vasopressin, with intrinsic vasoconstrictor activity. It is also a nonselective V1 vasopressin agonist, but with a lower incidence of ischemic complications than vasopressin. This agent also has the advantage over vasopressin of a longer half-life, allowing administration as a 4-hourly bolus. Terlipressin is used in Europe for management of variceal bleeding and is associated with a decrease in portal pressure.[87] This agent has been shown to improve systemic hemodynamics[88-90] and to improve renal function[88-91] in patients with type 1 HRS.[57] Ischemia is less common, with no patients developing signs of ischemia in 1 study[89]; only 2 of 99 patients in another study developed lower limb ischemia.[57] Other adverse effects were noted in 23 of 99 of these patients. In addition to improving renal function, the use of terlipressin has also been found to be associated with improved survival.[57,90] The use of volume support in addition to terlipressin is debatable, because albumin made no difference in the outcome,[57] while patients in 2 other studies needed volume support in addition to terlipressin to improve their renal function.[92,93] One suggested protocol consists of 0.5 mg every 4 hours with a titration upward by 0.5 mg every 3 days up to 2 mg every 4 hours.

Endothelin antagonists. Endothelin, a potent endogenous vasoconstrictor, is increased in patients with HRS.[94] Endothelin a (ETa) is important in the pathogenesis of renal failure that occurs in the setting of acute liver failure, as demonstrated in a rat model of acute liver failure.[95] In this model, plasma endothelin 1 (ET-1) levels were increased and ETa receptors were upregulated. Despite the latter, renal failure was prevented by an endothelin antagonist, bosentan.[95] In an assessment of ET-1 levels before and after orthotopic liver transplantation, reduction of ET-1 levels was seen with improvement of liver function after liver transplantation. This finding preceded improvement in renal function, suggesting ET-1 as one of the causative factors in HRS.[96] A pilot study of an ETa antagonist, BQ123, in 3 cirrhotic patients with HRS showed a dose-related improvement in GFR.[97]

N-acetylcysteine. The effects of N-acetylcysteine, a drug with antioxidant properties, were evaluated in a nonrandomized study of 12 patients with HRS.[50] Nine of 12 patients had alcoholic cirrhosis and/or alcoholic hepatitis. Treatment was well tolerated and renal function improved. High survival rates of 67% at 1 month and 58% at 3 months were observed.

Pentoxifylline. This inhibitor of tumor necrosis factor improves short-term survival in patients with severe alcoholic hepatitis.[98] This benefit appears to be due to a reduction in the risk of developing HRS.

Renal Support

Dialysis. Renal support in the form of dialysis should only be offered in select cases if there is a real chance of liver transplantation in the short term. Dialysis in these patients is fraught with difficulties because of coagulopathy and hemodynamic instability, as well as risk of sepsis. This support is usually given as continuous hemofiltration because of the labile systemic blood pressure during dialysis in these patients. The effectiveness of dialysis in the treatment of HRS has not been proven.

Molecular adsorbent recirculating system. This system is a modified form of dialysis using albumin-containing dialysate that is recirculated and perfused online through charcoal and anion exchanger columns. It enables the removal of water-soluble and albumin-bound substances. Results of one study conducted in patients with type 1 HRS and bilirubin level >/= 15 mg/dL demonstrated a decrease in bilirubin and creatinine as well as mortality rate in the albumin-dialysis treatment group compared with the hemofiltration-alone group.[99] These results were again seen in another study conducted in 8 type 1 HRS patients treated with the molecular adsorbent recirculating system.[100] It is believed that this system removes some of the vasoactive substances that mediate the hemodynamic changes that lead to HRS, thereby improving systemic hemodynamics and, hence, renal perfusion.

Transjugular Intrahepatic Portosystemic Shunt

In the early 1990s, the transjugular intrahepatic portosystemic shunt (TIPS) was developed for the treatment of bleeding varices. In this procedure, a self-expandable metal stent is inserted between the hepatic vein and the intrahepatic portion of the portal vein using a transjugular approach, with a resulting decrease in portal pressure. In certain cases, ascites disappeared after TIPS insertion.[101] Urinary sodium excretion increased 1-2 weeks after TIPS,[102-104] with an associated decrease in plasma renin activity and serum aldosterone levels[105,106] and an improvement in renal function.[102,103] Initial reports have suggested that TIPS may improve renal function in HRS[107-109] and may reduce the risk of progression from type 2 to type 1 HRS.[35,110-114]

In a study by Guevara and colleagues,[106] GFR and renal blood flow improved significantly 30 days after TIPS insertion in patients with type 1 HRS. These beneficial effects on renal function were associated with a reduction in plasma renin activity, aldosterone, and norepinephrine levels. Mean survival was 4.7 ± 2 months (range, 0.3-17 months). In a larger study evaluating TIPS in patients with type 1 and type 2 HRS not eligible for liver transplantation, renal function initially deteriorated but improved within 2 weeks.[35] There was marked suppression of plasma renin activity, vasopressin level, and catecholamines. Survival at 3, 6, and 12 months was 48%, 38%, and 16%, respectively. One-year survival was 20%. Subgroup analysis suggested better survival for those patients with better baseline liver function and those with HRS type 2. One-year survival of type 2 HRS patients was 70%.

The survival benefits of TIPS vs repeated paracentesis plus intravenous albumin in patients with refractory ascites, a population at high risk for type 1 HRS, is controversial.[110,113,114-116] It has also been argued that the predicted survival without TIPS was no different from observed survival with TIPS.[117,118] The majority of patients in these studies had alcoholic cirrhosis. The main limitation to using TIPS in HRS includes worsening encephalopathy and liver failure from reduced liver venous perfusion, thereby causing relative liver ischemia.[119] However, in those patients whose main problem is one of hemodynamic instability and renal failure rather than severe liver dysfunction, TIPS may be a viable option, at least as a bridge to liver transplantation.

Liver Transplantation

The only effective and permanent treatment for end-stage cirrhosis and HRS is liver transplantation. Patients with severe impairment in renal or circulatory function, such as in refractory ascites and spontaneous bacterial peritonitis, should be evaluated and given priority for liver transplantation. GFR improves in patients with HRS after transplantation.[120] However, patients who are transplanted with HRS have a lower probability of both graft and patient survival after liver transplantation compared with patients without HRS. Additionally, patients with HRS are sicker and require longer stays in intensive care, longer hospitalization, and more dialysis treatments after liver transplantation.[78,121]

Summary

Renal failure is a common complication of cirrhosis and is a poor prognostic indicator. Patients with severe liver dysfunction can develop HRS, characterized by a marked reduction in renal blood flow and hemodynamic disturbances. HRS is now subdivided into 2 types. Type 1 HRS carries a worse prognosis than type 2; these patients also do worse after liver transplantation. Precipitants of HRS need to be sought out and managed early. It is also important to rule out other organic causes of renal disease that can occur in these patients. The most common precipitants are bacterial infection, gastrointestinal bleeding, and aggressive paracentesis. Antibiotic prophylaxis should be used in patients with a history of SBP and in those admitted to hospital for gastrointestinal bleeding. Any nephrotoxic drugs should be removed and volume status of the patient should be maintained. Albumin infusions may be used in patients admitted with SBP and those undergoing large-volume paracentesis. Diuretic use in patients with ascites needs to be monitored, and these agents should be stopped if renal function worsens.

Many treatment options are now showing promise for patients with HRS. Numerous studies have shown the benefit of terlipressin in this setting, with fewer side effects; however, there is also some evidence for the combination of midodrine and octreotide when terlipressin is not available. Intravenous albumin should be considered in adjunct. If there is no response to these therapies, TIPS or the molecular adsorbent recirculating system could be considered. Orthotopic liver transplantation is the most effective strategy for treatment of HRS. Unfortunately, some patients with HRS are not candidates for liver transplantation. For those patients who are to receive liver transplantation, their chances for survival are improved if their renal function is optimized before transplantation.

Tables

Table 1. Hepatorenal Syndrome: Diagnostic Criteria

Major criteria (all must be present)

Chronic or acute liver disease with advanced hepatic failure and portal hypertension

Low GFR as indicated by a 24-hr creatinine clearance of < 40 mL/min or serum creatinine > 1.5 mg/dL

Absence of shock, sepsis, volume depletion, exposure to nephrotoxins

No sustained improvement in renal function (to creatinine > 1.5 mg/dL or 24-hr CrCl to > 40 mL/min) following diuretic withdrawal or plasma volume expansion with 1.5 L of normal saline

Proteinuria < 500 mg/dL

No ultrasonographic findings of obstructive uropathy or parenchymal renal disease

Additional criteria (not necessary but would support diagnosis)

Urine volume < 500 mL/day Urine sodium < 10 mEq/L Urine osmolality greater than plasma osmolality Urine red blood cells < 50 per high-power field Serum sodium < 130 mEq/L

GFR = glomerular filtration rate; CrCl = creatinine chloride

Table 2. Renal Disease Associated With Major Types of Liver Disease

Hepatitis B

Membranous glomerulonephritis (GN), membranoproliferative GN, IgA nephropathy, focal segmental glomerulosclerosis, minimal change disease, polyarteritis nodosum, essential mixed cryoglobulinemia

Hepatitis C

Membranoproliferative GN, membranous GN, cryoglobulinemia, fibrillary GN, IgA nephropathy, tubulointerstitial nephritis

Alcoholic liver disease

IgA nephropathy

Obstructive jaundice

Prerenal azotemia/acute tubular necrosis from hypovolemia, decreased cardiac output, sepsis; acute tubular necrosis from toxic bile acids

Primary biliary cirrhosis

Membranous GN, antineutrophil cytoplasmic autoantibody-positive vasculitis, antiglomerular basement membrane disease, renal tubular acidosis, tubulointerstitial nephritis

Primary sclerosing cholangitis

Membranous GN, membranoproliferative GN, antineutrophil cytoplasmic autoantibody-positive vasculitis, tubulointerstitial nephritis

's disease

Renal tubular acidosis (Type 1) secondary to copper deposition

Alpha-1 antitrypsin deficiency

Membranoproliferative GN, antiglomerular basement membrane disease

Table 3. Systemic Diseases Involving Both Liver and Kidney

Drug toxicity -- acetaminophen, acetylsalicylic acid, carbon tetrachloride, etc.

Granulomatous diseases (sarcoidosis, drug-induced)

Infectious -- malaria, leptospirosis

Infiltrative -- amyloidosis

Inflammatory -- lupus, Sjogren's syndrome

Nonalcoholic fatty liver disease and diabetic nephropathy

Preeclampsia/HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome

Polycystic kidney/liver disease (autosomal dominant/autosomal recessive forms)

Sickle cell disease

Shock states (congestive heart failure, sepsis, hypovolemia)

Table 4. Work-up for Patients With Suspected HRS

Cirrhosis/chronic liver disease and severe liver failure/acute liver failure and creatinine > 133 mcmol/L:History

Fluid losses -- vomiting, diarrhea, diuretic use Gastrointestinal bleeding Infection -- fever, cough, dysuria, abdominal discomfort Exposure to nephrotoxins -- drugs (aminoglycosides, NSAIDs), radiocontrast agentsPhysical exam

Heart rate, blood pressure (including orthostatic), temperature Signs of infection (pulmonary, abdominal, cellulitis, etc.) Other causes of renal failure -- purpuric rash may suggest cryoglobulinemiaInvestigations

Complete blood count, electrolytes, creatinine level Urine sodium, osmolality Urinalysis for protein, cells, and casts Renal ultrasound

HRS diagnosed if all other causes of renal failure have been excluded and if renal failure persists after correction of hypovolemia or sepsis.

Table 5. Differentiating HRS From Other Forms of Renal Failure in Liver Disease

Prerenal failure

Acute tubular necrosis

Hepatorenal syndrome

Primary renal disorder

Urine sodium

< 10 mmol/L

> 20 mmol/L

< 10 mmol/L

> 30 mmol/L

Urine creatinine/plasma creatinine

> 20

< 15

> 30

< 20

Proteinuria

--

< 500 mg/day

< 500 mg/day

> 500 mg/day

Urine sediment

Bland

Heme-granular casts

None

RBC/WBC casts

Precipitants

Decreased effective circulating volume

Decreased effective circulating volume, nephrotoxic agents, sepsis

Advanced liver disease, refractory ascites, gastrointestinal bleed, SBP

Dependent on type of renal disease

Effect of volume expansion

Immediate improvement in renal function

No immediate effect, but must maintain euvolemia

No effect

Must maintain euvolemia

RBC = red blood cell; WBC = white blood cell

References

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Elaine Yeung, MD, Gastroenterology Fellow, Department of Medicine, Division of Gastroenterology, Toronto General Hospital, University of Toronto, Toronto, Ontario, CanadaElaine Yong, MD, FRCPC, Therapeutic Endoscopy Fellow, Department of Medicine, Division of Gastroenterology, St. 's Hospital, University of Toronto, Toronto, Ontario, CanadaFlorence Wong, MD, FRCPC, Associate Professor, Department of Medicine, Division of Gastroenterology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada

Disclosure: Elaine Yeung, MD, has no significant financial interests or relationships to disclose.Disclosure: Elaine Yong, MD, FRCPC, has no significant financial interests or relationships to disclose.Disclosure: Florence Wong, MD, FRCPC, has disclosed that she has received grants for clinical research and educational activities, and has served as an advisor or consultant for Sanofi-Aventis, Schering Canada, Roche Canada, and Idenix.