Critical Care ClinicsVolume 18 • Number 2 • April 2002Copyright © 2002 W. B. Saunders Company

Hepatorenal syndrome:  Definition, pathophysiology, and intervention

Andrew E. Briglia, DO a , *

Frank A. Anania, MD b

a Division of NephrologyUniversity of MarylandN3W14322 South Greene St.Baltimore, MD 21201, USA

b Division of HepatologyUniversity of MarylandN3W5022 South Greene St.Baltimore, MD 21201, USA

* Corresponding authorE-mail address:  abriglia@medicine.umaryland.edu

PII S0749-0704(01)00003-3

Hepatorenal syndrome (HRS) is defined as functional renal failure in the setting of cirrhosis in the absence of intrinsic renal disease. It is an extreme in the spectrum of liver-related renal insufficiency [6] and is characterized by intense constriction of renal cortical vasculature leading to oliguria and avid sodium retention [13] [52] [77] [106] . HRS usually occurs in patients with alcoholic cirrhosis but can complicate fulminant hepatic failure, acute hepatitis, and hepatic malignancy [13] [77] . The functional nature of HRS must be emphasized, because recovery of renal function has been observed after transplantation of a kidney from a patient with HRS [52] , and normalization of the renal vascular abnormalities associated with HRS has been demonstrated in a pre- and postmortem arteriograph (Fig. 1) [56] . The incidence of HRS in patients with hepatic cirrhosis and ascites is 18% at 1year and 30% at 5 years [69] . After the onset of HRS, patients have minimal chance for recovery of normal renal function and carry an extremely poor prognosis without liver transplantation. Ninety percent of patients with advanced HRS die within 10 weeks, most within the first month after diagnosis [69] . The only established therapy which improves renal failure in this syndrome is liver transplantation [6] [74] . Continuous hemofiltration in an intensive care unit setting is the mainstay of support for these critically ill patients awaiting transplantation. However, because of overwhelming infection, profound hypotension, or multi-system disease, including acute respiratory distress syndrome (ARDS), patients are often not appropriate candidates for organ transplantation by the time an organ becomes available [96] . Transplant organ shortages, which are severe in some regions of the

United States, limit urgent transplantation even for suitable candidates. Several recent reviews of HRS are available [2] [6] [7] [10] [13] [18] [49] [56] [70] [72] [77] [136] [143] . The purpose of this article is to review causes for renal failure in the setting of hepatic disease, to provide salient features of the pathophysiology of HRS, and to discuss the management of this syndrome with emphasis upon extracorporeal blood purification.

Fig. 1.  (A) A selective renal arteriogram performed in a patient with oliguric renal failure and cirrhosis (T.L.). Note the extreme abnormality of the intrarenal vessels,

including primary branches off of the main renal artery and the interlobar arteries. The arcuate and cortical arterial system is not recognizable, nor is a distinct cortical nephrogram present. The arrow indicates the edge of the kidney. (B) Angiogram of the same kidney performed postmortem with the intra-arterial injection of micropaque in gelatin as the contrast agent. Note filling of the renal arterial system throughout the vascular bed to the periphery of the cortex. The peripheral arterial tree that did not opacify in vivo now fills completely. The vascular attenuation and tortuosity are no longer present. The vessels were also histologically normal. (From Epstein M. Hepatorenal syndrome: emerging perspectives. Semin Nephrol 1997;17:563–575; with permission.)

Diagnosis

Two different forms of HRS have been described. Type I HRS is characterized by rapid impairment of renal function and either doubling of the serum creatinine to a concentration >2.5 mg/dL or a 50% reduction in creatinine clearance to <20 ml/min in less than 2 weeks [70] . Type II HRS is characterized by a more gradual decrement in renal function [6] [70] . The International Ascites Club has provided diagnostic criteria for HRS (Table 1) [6] . Causes for acute renal failure in the setting of liver disease are manifold (Table 2) [49] [52] [77] ; therefore, the diagnosis of HRS rests upon the identification of clinical and laboratory features. In general, HRS is characterized by: 1) urine that is relatively hyperosmolar to plasma, 2) a high urine:plasma creatinine ratio (typically >30), and 3) very low urinary sodium concentration (<10 mEq/L) and fractional excretion of sodium (FENa <1%) even in the presence of diuretics [56] [155] [156] . Low urinary sodium excretion is not specific for HUS, since acute glomerulonephritis, contrast nephropathy, and myoglobinuric renal failure can be accompanied by low urinary sodium concentration [UNa] [77] . Although a reduced urinary sodium concentration [UNa] is considered to be pathognomonic for HRS, the syndrome can be associated with elevated [UNa] [47] [77] . Both urinary sodium and chloride should be measured, since the former may increase with urinary excretion of nonreabsorbed anions (penicillin derivatives, ketones, diatrizoate) or excretion of bicarbonate (resolving metabolic or developing respiratory alkalosis and resolving respiratory acidosis) [77] [157] . Because of malnutrition, muscle wasting, and reduced creatinine production in patients with cirrhosis, a normal serum creatinine may be present despite severe renal dysfunction [77] . In addition, serum creatinine may be underestimated by some analyzers due to interference by bilirubin. Bile constituents (bile acids, bilirubin, cholesterol) probably do not produce direct nephrotoxicity but may contribute to renal dysfunction in HRS by producing pre-renal hypoperfusion via extrarenal factors such as reduced systemic vascular resistance [52] [77] . Other plausible mechanisms of renal dysfunction in cholemia include: 1) impaired tubular function via inhibition of the Na+/H+-antiporter and Na+/K+-ATPase [52] [124] ; 2) tubular damage via oxidative stress (e.g., increased F2-isoprostane synthesis) [20] ; and 3) complex interplay with other

mediators including endothelin-1, leukotrienes, and endotoxin [20] [124] . Hyperbilirubinemia in patients with hypoalbuminemia has been associated with decreased urinary sodium excretion, free water clearance, creatinine clearance, and renal blood flow [160] .

Table 1.   International Ascites Club's diagnostic criteria of hepatorenal syndrome

From Arroyo V, Gines P, Gerbes AL, et al: Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis: International Ascites Club. Hepatology 1996;23:164–176; with permission.

Major criteria

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

     Low glomerular filtration rate as indicated by serum creatinine of >1.5 mg/dL or 24-h creatinine clearance <40 mL/min

     Absence of shock, ongoing bacterial infection, and current or recent treatment with nephrotoxic drugs; absence of gastrointestinal fluid losses (repeated vomiting or intense diarrhea) or renal fluid losses (weight loss >500 g/d for several days in patients with ascites without peripheral edema or 1000 g/d in patients with peripheral edema)

     No sustained improvement in renal function (decrease in serum creatinine to ≤1.5 mg/dL or increase in creatinine clearance to ≥40 mL/min) following diuretic withdrawal and expansion of plasma volume with 1.5 L of isotonic saline

     Proteinuria <500 mg/dL and no ultrasonographic evidence of obstructive uropathy or parenchymal renal disease

Additional criteria

     Urine volume <500 mL/d

     Urine sodium <10 mEq/L

     Urine osmolality greater than plasma osmolality

     Urine red blood cells <50 per high power field

     Serum sodium concentration <130 mEq/L

Table 2.   Conditions causing simultaneous liver and renal failure

Data from references [49] [52] [77] .

Infections

     Sepsis

     Leptospirosis

     Reye's syndrome

     Malaria

     Cytomegalovirus

Toxins

     Methoxyflurane

Table 2.   Conditions causing simultaneous liver and renal failure

     Carbon tetrachloride

     Tetracyclines (especially in third trimester of pregnancy)

     Acetaminophen

     Elemental phosphorus (contained in some rodent poisons)

Circulatory

     Congestive heart failure

     Shock

Neoplasms

     Metastatic

     Hypernephroma

Collagen vascular disease

     Systemic lupus erythematosus

     Polyarteritis nodosa

Genetic

     Polycystic kidney disease

     Sickle cell anemia

Miscellaneous

     Amyloidosis

     Glomerulonephritis associated with hepatitis B, and IgA nephropathy associated with alcoholic cirrhosis

     Hepatorenal syndrome

In patients with hepatic cirrhosis, ascites, renal dysfunction and low fractional sodium excretion (FENa <1%), administration of volume expanders (100 grams albumin in 500 mL normal saline) is recommended to distinguish between pre-renal azotemia and HRS [143] . However, because cirrhotic patients may require massive amounts of colloid and crystalloid solutions to replete intravascular volume, central hemodynamics and other clinical parameters (e.g., urine flow rate, creatinine clearance) should be monitored [57] [77] . In patients with HRS, a sustained response to intravascular volume expansion is unlikely, and other measures such as transjugular intrahepatic portosystemic shunting [TIPS], peritoneovenous shunting [PVS], dialysis, or orthotopic liver transplantation [OLT] may become necessary (see later).

Pathophysiology

Several theories have been advanced to explain the development of ascites and renal dysfunction in HRS (Fig. 2) [53] . The overflow hypothesis postulates that a primary increase in renal sodium retention leads to expansion of the extracellular fluid and, subsequently, ascites formation [71] . The hepatic sinusoids, which are ordinarily freely permeable to albumin, rely on low hydrostatic pressure to maintain fluid within the vascular space [143] . Portal venous hypertension increases the intrasinusoidal hydrostatic pressure, leading to translocation of fluid (lymph) from the sinusoids to the hepatic interstitium [143] . On the other hand, the underfill concept, that proposes aberrations in Starling forces within the hepatic sinusoids and splanchnic capillaries are responsible for ascites formation rather than primary renal sodium retention alone [53] .

As lymph fluid accumulates in the peritoneal space, plasma volume is decreased. This reduction in effective circulating volume, in turn, leads to increased renal sodium and water retention, a failure to escape from the sodium-retaining effect of aldosterone, and renal resistance to atrial natriuretic peptide [53] [119] . The revised underfill theory postulates that peripheral arterial vasodilation is the primary event that spawns renal sodium and water retention [53] [119] [153] . The stimulus for the peripheral vasodilation, which is most pronounced in the splanchnic circulation, is incompletely understood [153] . The ensuing decrease in effective arterial blood volume is sensed by arteriolar baroreceptors.

Fig. 2.  Presumed sequence of events culminating in ascites formation, according to three alternative theories. Refer to text for explanation. From Epstein M.

Hepatorenal syndrome, in Epstein M, editor. The kidney in liver disease, chap 1. Philadelphia:Lippincott, 1996, pp 75–108; with permission.)

The presence of decreased effective arterial blood volume appears to be an important feature of HRS, as head out water immersion, which increases central blood volume, corrects renal sodium and water retention in these patients [119] [175] . Three major vasoconstrictive mechanisms are stimulated: 1) the renin-angiotension-aldosterone system (RAAS), 2) the sympathetic nervous system (SNS), and 3) the nonosmotic release of vasopressin [153] . In addition, an increase in other vasoconstrictors (e.g., leukotrienes, thromboxanes) or a decrease in renal vasodilatory eicosanoids (e.g., PGE2 and PGI2) may partially explain renal vasoconstriction in decompensated cirrhosis with ascites [153] . The observations that nonsteroidal antiinflammatory drugs (NSAIDs) decrease renal blood flow and glomerular filtration rate (GFR) [119] [153] and that a prostaglandin E analog (misoprostol 0.4 mg QID) may improve renal function in patients with alcoholic cirrhosis support the peripheral vasodilation theory [52] [143] . The most severe manifestation of the peripheral vasodilatory state is HRS, a hyperdynamic state with reduced SVR, increased cardiac output, low mean arterial pressure, hyperreninism, and renal vasoconstriction that varies independently of changes in cardiac output [52] [60] [72] . Other neurohormonal mediators contributing to renal ischemia include elevated plasma endothelin levels, endotoxemia, enhanced nitric oxide production, and impaired renal kallikrein production [52] . The discovery that infusion of glutamine into the portal-venous system leads to reduced GFR, renal plasma flow, and urine output has ignited interest in the existence of a hepatorenal depressor reflex [105] [147] .

Intervention

Because no single therapeutic maneuver for HRS is fully effective aside from liver transplantation, prevention and eradication of precipitating factors remain vital. In this regard, avoidance of intravascular volume contraction and nephrotoxic agents is paramount. Overusage of diuretics and lactulose should be discouraged to avoid intravascular volume contraction [52] [77] . Prostaglandin synthetase inhibitors (e.g., NSAIDs) and demeclocycline (used to treat hyponatremia in the syndrome of inappropriate antidiuretic hormone secretion) may induce azotemia in patients with cirrhosis and ascites [28] [52] [77] . NSAIDs also blunt the natriuretic and diuretic response to diuretics in patients with cirrhosis [99] . Aminoglycosides may produce nephrotoxicity in hepatic disease either through interference with a vasodilatory prostaglandin [115] [127] or through enhanced renal uptake of gentamicin in the presence of endotoxemia [52] [77]

[178] . Beta-adrenergic antagonists (e.g., propranolol), which can reduce renal plasma flow and GFR in hypertensive patients, do not appear to produce renal failure in cirrhotic patients [12] [52] [77] .

Ascites

The goal of ascites management is attainment of negative sodium and water balance [14] [143] . Initial measures include bed rest, which increases central volume and reduces SNS and RAAS activity, as well as dietary sodium (90 mEq or approximately 2 grams per day) and fluid (1000–1500 mL per day) restriction [105] [143] . However, most patients with ascites require diuretics [6] [21] [66] [67] [143] . A recent review advocates use of spironolactone alone in patients with initial urinary sodium excretion >30 mEq/L and a combination of spironolactone and furosemide when urinary sodium excretion is 10–30 mEq/L. The usual ratio of spironolactone to furosemide is 100 mg: 40 mg once daily in the morning [143] . The natriuretic activity of spironolactone and its metabolites (e.g., canrenone) depends upon the degree of hyperaldosteronism; therefore, doses of 400–600 mg daily may be required in patients with HRS. Similarly, high doses of furosemide (up to 160 mg daily) may be required, as this agent depends on plasma protein binding in order to be secreted into the tubular lumen and reach its site of action [6] . Large volume paracentesis with volume expanders (6–8 grams albumin per liter of ascitic fluid) is recommended for patients with diuretic-resistant ascites, or patients in whom diuretic therapy has been complicated by hyponatremia, encephalopathy, or azotemia [6] [143] . Patients who require frequent paracentesis (more than once every 2 weeks) may be candidates for TIPS or PVS (see later) [143] . Combined ascitic fluid and furosemide infusion has been found to create greater increases in GFR, urine volume, and urinary sodium excretion than either therapy alone [50] . Other authors have described spontaneous ascites filtration and reinfusion (SAFR) as a means of concentrating ascitic fluid via a polyamide dialysis filter [25] . The concentrate is then reinfused into an antecubital vein [25] [104] or the peritoneal cavity [1] [22] [26] [83] [100] [140] . While this method has been shown to increase urine output and natriuresis [103] [104] and may provide more favorable hemodynamic effects [140] and safer solute removal than hemodialysis [1] , it is rarely, if ever, used in clinical practice.

Pharmacologic manipulation of hemodynamic perturbations in HRS

Nitric oxide causes systemic vasodilation in cirrhotic patients with endotoxemia, which appears to induce one form of nitric oxide synthase [58] [66] . Use of nitric oxide synthase inhibitors (e.g., N-monomethyl-L-arginine) in patients with cirrhosis has received attention recently; however, the use of these agents is currently restricted to investigational settings [58] [66] . Demonstrations of elevated circulating levels of endothelin-1 and endothelin-3 in patients with HRS [126] have provided the rationale for the use of a selective endothelin receptor antagonist (BQ123) to ameliorate renal dysfunction in this syndrome. Dose-related improvements in renal inulin clearance with BQ123 were seen in a small number of patients [162] . Whether endothelin accumulates as an effect of HRS or as a consequence of reduced renal clearance is uncertain [58] N-acetylcysteine (NAC) administration was associated with increased creatinine clearance, urine output, and sodium excretion in 12 patients with HRS. The 1-month and 3-month survival rates of the patients were 67% and 58%, respectively, and two of the patients underwent orthotopic liver transplantation after improvement in renal function [85] . While initial studies on the effect of pressor amines such as metaraminol demonstrated improvement in urine volume, urinary sodium excretion, and attenuation of the hyperdynamic state in patients with HRS [61] [76] [102] , dopamine infusion alone in

patients with HRS revealed inconsistent improvement in urine output and glomerular filtration rate (GFR) [17] [171] . However, combined intravenous dopamine (3.0 mcg/kg/min) and norepinephrine (titrated to maintain SVR ∼800 dyne-sec/cm3) infusions have been found to have favorable effects on urine output, sodium excretion, and systemic hemodynamics. These changes have been attributed to vasodilation of renal afferent arterioles and vasoconstriction of peripheral and splanchnic vessels leading to reversal of renal ischemia [48] . More recent literature has focused upon use of vasopressin analogs, such as 8-ornithin vasopressin (Ornipressin). These agents have preferential affinity for the V1 rather than V2 receptor and, therefore, have vasoconstrictive potency similar to vasopressin but approximately 20% less antidiuretic effect [29] [110] . Increased urine volume, sodium excretion, and creatinine clearance [32] [79]

[110] as well as reversal of the hyperdynamic circulatory state (e.g., increased SVR and renal blood flow, and decreased norepinephrine and renin activity) [111] have been reported utilizing a continuous infusion of ornipressin (6 IU/hr) at a dose of 6 IU/hr. Improvement in renal function has also been demonstrated by combining ornipressin (6I U/hr) with dopamine (2–3 μg/kg/min) [79] . Lower infusion rates (2 IU/hr) have been used successfully for longer periods of time (15 days) in combination with albumin-based plasma volume expansion [78] . While reductions in plasma aldosterone and norepinephrine concentration and increased atrial natriuretic peptide levels have been observed with ornipressin, plasma endothelin levels do not appear to be affected [78] [173]

. In addition, evidence of gastrointestinal, cardiac, and tongue ischemia as well as limited cutaneous necrosis have rarely been associated with this therapy [65] [78] [79] . Other vasopressin analogs such as PLV-2 (Octapressin 0.004–0.5 units/min) and terlipressin (2–6 mg/day) have been used successfully in HRS [29] [33] [65] [81] . Midodrine hydrochloride, an oral α-mimetic agent, has been used in Type II HRS with no effects on renal hemodynamics or renal function [3] . Another study reported use of oral midodrine (7.5–12.5 mg three times daily) combined with octreotide (100–200 μg subcutaneously three times daily) and human albumin (50–100 mL of 20% daily for 20 days) in five of thirteen patients with Type I HRS [4] . These authors found that combining midodrine, a vasoconstrictive agent, with octreotide, an inhibitor of endogenous vasodilators, led to improvement in renal plasma flow, GFR, and urinary sodium excretion [4] . Inhibitors of thromboxane synthesis (e.g., dazoxiben and OKY 046) have been studied as a method of reducing circulating levels of thromboxanes A2 and B2 while allowing continued production of vasodilatory prostaglandins [57] [68] [179] . However, these agents allow for accumulation of the endoperoxides PGG2 and PGH2, which mimic thromboxane A2 via similar receptor interaction. A thromboxane receptor antagonist (ONO-3708) has been evaluated and found to have a favorable renal hemodynamic profile [98] , and initial research involving an adenosine-1 receptor antagonist has also suggested salutary renal effects [67] [164] . Calcium antagonists have been postulated to have a similarly favorable renal hemodynamic profile because of their ability to reduce afferent arteriolar resistance and, possibly, attenuate renal ischemia in HRS [52] [59] . Calcium antagonists may also offer protection against the intrarenal effects of endothelin-1 [139] .

Although several of these pharmacologic agents appear to offer hemodynamic benefit in HRS, most of the studies involved small numbers of patients and had surrogate rather than hard outcome measures. At present, there is not a standard pharmacologic approach to HRS.

Peritoneovenous shunts and liver transplantation

In 1974, LeVeen and colleagues developed an extracorporeal device, which reinfuses ascitic fluid into the systemic circulation [128] . The peritoneovenous or LeVeen shunt operates on the principle of a pressure difference between the peritoneal cavity and the

superior vena cava. Since their intital report, a number of competing shunts became available (such as the Denver and the Minnesota shunts). All of these act on the same principle, but with modifications. The insertion of peritoneovenous shunts with cirrhosis and ascites results in an expansion of the intravascular volume, an increase in natriuresis, creatinine clearance, renal blood flow, and a decrease in plasma renin activity and aldosterone levels. Before the advent of TIPS, which produces the same alterations in circulatory physiology, the peritoneovenous shunt was offered to cirrhotic patients and patients with refractory ascites, malignant ascites, and hepatic hydrothorax. This shunt has been used in patients with hepatorenal syndrome, but controlled studies have not convincingly shown benefit.

The peritoneovenous shunt should not be offered to patients with ascites infection, congestive heart failure, or severe coagulopathy. This type of shunt is fraught with numerous complications including early shunt occlusion, disseminated intravascular coagulation, sepsis, and late complications including these as well as thrombosis of jugular or superior vena cava, emboli from the catheter tip, intestinal obstruction, and abdominal abscess [95] . In general, the use of such shunts has no role in the treatment of refractory ascites or hepatorenal syndrome in patients awaiting liver transplantation. The use of large volume paracentesis and TIPS has proved to be safer for these complications of cirrhosis and has served as a more effective bridge to liver transplantation.

Transjugular intrahepatic portosystemic shunt

The advent of the transjugular intrahepatic portosystemic (TIPS) shunt has aided patients with end-stage liver disease who have refractory ascites and hepatopleural effusions. In general, TIPS may serve as a bridge to liver transplantation. Its impact has been reviewed in the liver transplantation literature [131] . A TIPS is used to reduce portal hypertension, believed to be one of the major factors responsible for HRS. The placement of a TIPS requires creation of a parenchymal tract between the portal and hepatic veins followed by reinforcement of the tract with a metallic stent under fluoroscopic guidance. Absolute contraindications to TIPS placement include right-sided heart failure with elevated central venous pressure, polycystic liver disease, and severe, or decompensated, hepatic failure. Relative contraindications include active intrahepatic or systemic infection, severe hepatic encephalopathy poorly controlled by medical therapy, and portal vein thrombosis. Acute complications include hemoperitoneum, hemobilia, acute hepatic ischemia, cardiac puncture, pulmonary edema, septicemia, hematoma, hemolytic anemia, fever, and reactions to contrast agents. Chronic complications include portal or splenic vein thrombosis, chronic hemolysis, worsening hepatic function, shunt stenosis, and chronic refractory hepatic encephalopathy. Of interest, a transient increase in serum creatinine is commonly observed following TIPS insertion. This may be related to the large radiocontrast dye load given during the procedure. Thus, careful attention to intravascular volume replacement before and after the procedure is recommended to minimize this risk.

The use of TIPS in HRS

Despite the evidence of isolated reports of improvement of renal function in patients with HRS after portacaval shunts during the 1970s, neither this procedure nor placement of a LeVeen peritoneal shunt is recommended for the treatment of HRS because of the trend toward higher morbidity and mortality. The introduction of TIPS has led to reconsideration of the utility of portal decompression [168] . Patients with

refractory ascites who are at high risk of HRS can be effectively treated by TIPS. However, data on recovery of renal function after TIPS placement in such patients are controversial and limited. One study reported an increase in glomerular filtration rate (GFR) in 6-month survivors [131] . In another small randomized trial comparing TIPS with large volume paracentesis for refractory ascites, GFR improved only marginally after TIPS while natriuresis increased significantly [108] . As refractory ascites and HRS share a similar pathophysiology [6] , TIPS has been tried as a rescue measure in patients with advanced HRS. So far, preliminary short-term data are favorable. However, these series are small (1–7 severe HRS patients) and often lack follow-up data beyond three months [78] [95] [101] [128] [131] [137] [158] [168] . Furthermore, these studies use a variety of definitions of HRS and include patients who are candidates for transplant rescue [101] [131]

[137] [168] , limiting, to some extent, outcome interpretation especially for those patients who are not transplant candidates at the time of HRS diagnosis.

In a recent phase II clinical investigation 41 non-transplantable cirrhotics were prospectively studied following TIPS placement to evaluate feasibility, safety, efficacy, and outcomes [23] . HRS was diagnosed using current criteria [severe (type I) HRS and moderate (type II) HRS]. Thirty-one patients (14 type I, 17 type II) received TIPS; in 10 patients advanced liver failure precluded shunting. The median time for follow-up was 24 months and renal function, complications, and survival by Kaplan-Meier plots were reported. TIPS markedly reduced the portal pressure gradient from 21 ± 5 to 13 ± 4 mmHg (P<0.001) with one procedure-related death (3.2%). Renal function deteriorated without TIPS but improved within two weeks after TIPS with creatinine clearance increasing from 18 ± 15 to 48 ± 42 ml/min (P<0.001), with stabilization thereafter. Following TIPS, 3-, 6-, 12-, and 18-month survival rates were 81%, 71%, 48%, and 35%, respectively. Only 10% of non-TIPS patients survived 3 months, and the total survival rates were 63%, 56%, 39%, and 29%, respectively [23] . The important point to note in this study, however, is that multivariate Cox regression analysis demonstrates two independent predictors of survival after TIPS placement: serum bilirubin and HRS type. These predictors imply that patients with severe end-stage liver failure accompanied by HRS, who are unlikely to survive with or without a liver transplant, will not have improved morbidity or mortality rates by the placement of TIPS for HRS. These data, however, are limited, and larger, prospective studies will need to clarify whether benefits from TIPS in HRS are lacking. In summary, some published studies indicate that TIPS improves renal perfusion and glomerular filtration rates and reduces the activity of vasoconstrictor systems [78] [131] [158] . It is clear that any improvement seen with the placement of TIPS for HRS has been on a case by case basis. At this time the role of TIPS in the management of HRS needs to be established by rigorous randomized controlled clinical trials.

Extracorporeal blood purification

Dialysis has traditionally been considered to be ineffective in patients with HRS because of the high mortality rate (86.5–92%) despite institution of dialytic therapy [51] [77] [136] . Indeed, some advocate a limited trial of hemodialysis solely as a bridge to hepatic transplantation, since dialytic support beyond 2 weeks is associated with poor survival in those who undergo transplantation beyond this time frame [24] [149] . Others believe that dialysis is warranted in HRS patients and those with concomitant renal failure and a reversible hepatic insult [94] [136] . One must consider the observation that recovery of renal failure depends on the severity of liver damage and that the outcome of HRS is generally fatal if orthotopic liver transplantation (OLT) is not offered [49] . For these reasons, withholding renal replacement therapy may be justified for patients with HRS who are not candidates for OLT [49] [77] . In addition, there continues to be

controversy over the time at which to commence renal replacement therapy as well as the best modality [116] .

The indications for initiating renal replacement therapy include correction of solute disturbances (acidemia, hyperkalemia, uremia, hyperphosphatemia) and volume overload (pulmonary edema, parenteral administration of hyperalimentation, blood products, and medications) [24] [49] [77] [94] . Furthermore, there is an emerging role for extracorporeal blood purification methodologies in addition to hemodialysis as support measures for patients with hepatic failure (Table 3) [94] .

Table 3.   Extracorporeal blood purification for hepatic failure

From Kaplan AA, Epstein M: Extracorporeal blood purification in the management of patients with hepatic failure. Semin Nephrol 1997;17:576–58; with permission.

Systems

     Hemodialysis

     Continuous renal replacement therapy (e.g., CAVH, CAVHD, CVVHD)

     Therapeutic plasma exchange

     Sorbent systems

          Hemoperfusion

          Combined filter-sorbent systems

     Hybrid organ systems

          Hepatocyte-lined filters

     Extracorporeal liver perfusion

Indications

     Temporary support for fulminant, reversible liver failure

     Reversal of hepatic coma

     Treatment for intracranial hypertension

     Intraoperative fluid management during hepatic transplantation

     Reversal of hepatorenal syndrome

     Bridge to hepatic transplantation

Choice of extracorporeal modality

No single extracorporeal modality can adequately remove all of the toxins associated with hepatic failure, due mainly to the range in their molecular weights (Table 4) [94] . Moreover, currently available toxin removal systems do not replace the synthetic (e.g., clotting factors, albumin) and metabolic (e.g., maintenance of serum glucose) functions of the liver and may, in fact, remove potentially regenerative substances [94] . Of the major modalities, hemodialysis is capable of removing small molecular weight substances with large volumes of distribution, while larger “middle molecules” (MW 15,000–20,000 daltons) are better removed by hemofiltration. Still, other modalities such as therapeutic plasma exchange (TPE) are needed to remove endotoxin and albumin-bound substances [94] .

Table 4.   Toxins associated with hepatic failure: relation to blood purification techniques

      b Phenolic acids, fatty acids, and mercaptans have been shown to inhibit Na+/K+-ATPase activity and may contribute to the cerebral edema associated with severe hepatic encephalopathy.      a Albumin-bound.

From Kaplan AA, Epstein M: Extracorporeal blood purification in the management of patients with hepatic failure. Semin Nephrol 1997;17:576–582; with permission.

Small–molecular-weight toxins removable by hemodialysis

     Ammonia

     False neurotransmitters

     γ-Aminobutyric acid (GABA)

     Octopamine (false neurotransmitter)

Middle–molecular-weight substances removable by hemofiltration

     Cytokines (IL-6, IL-1, TNF-α)

     Middle moleculesb

Albumin-bound or large–molecular-weight toxins removable by plasma exchange

     Aromatic amino acidsa

     Bile acidsa

     Bilirubina

     Endotoxin

     Endotoxin-induced substances: nitrous oxide, cytokines (IL-6, IL-1, TNF-α)

     Indolsa

     Mercaptansa,b

     Phenolsa,b

     Short chain fatty acids†

Substances removable by hemoperfusion

     Bile Acidsa

     Bilirubin (conjugated and unconjugated)a

     Cytokines (IL-6, IL-1, TNF-α)

     Mercaptansa,b

     Phenolsa,b

Hemodialysis (HD) and peritoneal dialysis (PD) have been utilized in patients with hepatic cirrhosis. Some authors have described the successful application of PD in patients with chronic renal failure and liver disease [118] , and others have described use of this modality in patients with fulminant hepatic failure [138] . However, in a series of four studies compiled by Perez et al., patients with fulminant hepatic failure and HRS demonstrated poor outcome with PD [136] . These authors have illustrated similar results with HD, underscoring the overall dismal prognosis of HRS despite dialytic therapy [136] . PD may offer a more favorable hemodynamic profile than HD, allow for control of ascites formation, and be performed without anticoagulation [118] . However, arguments posed against the use of PD in this situation include diminution of solute clearance imposed by the presence of ascites [55] [77] [136] and augmentation of protein losses [136] .

Ultimately, the decision to use PD versus intermittent HD may be based upon the experience of the institution.

Continuous renal replacement therapy (CRRT) is the preferred approach in patients with combined hepatic and renal failure [34] . Because of increased cardiac output and reduced systemic vascular resistance, patients with hepatic failure are particularly prone to hypotension during intermittent HD. Intradialytic hypotension normally occurs in 20–50% [34] [117] [136] of patients despite using cooled (35.5°C) dialysate with variable sodium concentration, priming the lines with albumin, and monitoring intradialytic plasma volume [34] . CRRTs have been shown to confer greater hemodynamic and cerebrovascular stability than either intermittent HD or intermittent hemofiltration (HF) [35] [36] [39] [43] [151] . One study demonstrated that intermittent hemofiltration (3.5–4.5 hours and average fluid exchange 17 L per treatment) created greater reductions in cerebral perfusion pressure and MAP and, hence, greater increases in intracranial pressure (ICP) than either continuous arteriovenous or venovenous hemodialysis (CAVHD or CVVHD, respectively) [35] . These changes were most pronounced within the first hour of treatment, when significant changes in serum osmolality had not yet occurred, and were independent of changes in plasma volume (as evidenced by stable hematocrit) and SVR (which remained unchanged from already reduced baseline levels) [35] . These findings are particularly relevant to patients with hepatic failure since such patients are at risk for cerebral edema [39] . These individuals may experience paradoxical acidemia of the cerebrospinal fluid (CSF) due to the loss of CSF bicarbonate during dialysis. This, in turn, is accompanied by an increase in brain osmole content due to accumulation of idiogenic osmoles and, ultimately, cerebral edema [5] . Importantly, increased intracranial pressure is likely the result of decreased cerebral perfusion pressure, which leads to rebound vasodilatation. This acute ischemic insult, which is superimposed on already impaired cerebral autoregulation in fulminant hepatic failure, is believed to be the most plausible explanation for increased ICP [35] . In addition to its ability to mitigate changes in ICP, CRRT is also postulated to improve cerebral stability by removing a cardiodepressant or vascular endothelial vasodilatory factor [34] . Moreover, CRRT provides improved solute clearance over PD and has the potential to provide more efficient urea transfer than intermittent HD over a long period of time [34] [117] .

The nomenclature for CRRTs is based upon the blood access used to drive the extracorporeal circuit (AV: arteriovenous; VV: venovenous) as well as the method of solute removal (diffusion, convection, or both) [24] [144] . A detailed description of CRRTs is provided elsewhere in this volume. A comparison of extracorporeal modalities in HRS is made difficult by the small numbers of patients in these trials and by the lack of uniform etiology of combined hepatic and renal disease in these subjects. CRRTs have been utilized intraoperatively during the anhepatic phase of orthotopic liver transplantation, and CRRT in combination with other modalities such as therapeutic plasma exchange (TPE) and charcoal hemoperfusion has also been described (see later) [73] [116] [142] [148] [150] . Continuous arteriovenous hemofiltration (CAVH) has been favored as the leading extracorporeal support modality because it allows for removal of fluid, electrolytes, and medium-size molecules (MW<50,000 D) by convection and is driven by the patient's mean arterial pressure (MAP) [37] [92] [107] [136] [142] . Slow continuous ultrafiltration (SCUF) using either arteriovenous or venovenous blood access may be applied to patients with liver disease who require fluid removal only. Continuous arteriovenous ultrafiltration (CAVU) is one form of this methodology [54] [55] . Because the technique requires central venous access for blood return, insertion of a catheter into either the femoral, subclavian, or internal jugular vein is necessary. If the technique is to be used intraoperatively, the preferred site of venous access may be the latter since clamping of the inferior vena cava during OLT increases femoral venous pressure and reduces MAP, thus reducing the arterial-to-venous pressure gradient that drives the

circuit [73] . Pump-assisted CAVH has been described as a means of circumventing this problem [73] . The hemorrhagic and ischemic risks imposed by CAVH and CAVU stem mainly from the arteriotomy required for temporary access and the potential need for anticoagulation of the circuit [142] . In contrast, continuous venovenous hemofiltration (CVVH) requires insertion of one dual lumen catheter into a central vein [136] , but requires a blood pump in order to maintain the transmembrane pressure gradient necessary for convection. With any form of hemofiltration, replacement fluid can be given in the form of Ringer's lactate solution and/or saline or Plasmalyte (Baxter). The solution may be administered postfilter, in which case urea clearance approximates ultrafiltrate removal, [136] [141] or prefilter, which potentially reduces anticoagulation requirements [34] but increases ultrafiltration requirements by ∼15% [117] . Bicarbonate-based replacement fluid and dialysate are favored over lactate- or acetate-based solutions due to the potential for impaired hepatic conversion of these substances to bicarbonate in the presence of hepatic disease [11] [34] [121] . Moreover, accumulation of lactate may be associated with vasodilation [35] [36] , potentially contributing to the hemodynamic instability in these patients. Because of clotting factor deficiencies and thrombocytopenia in hepatic failure, anticoagulation may not be needed to maintain the CRRT circuit [34] [161] . However, in some patients with liver failure, clotting of the CRRT circuit may occur because of activation of the intrinsic pathway (factor VII) and generation of thrombin. These aberrations may occur as a consequence of decreased levels of natural anticoagulants and perturbations within the tissue factor pathway [27] . Moreover, reduced circulating levels of antithrombin III and heparin cofactor II may render heparin ineffective [34] . Trisodium citrate, a widely used anticoagulant, may produce hypernatremia and has been known to create metabolic alkalosis in patients with hepatic dysfunction [122] . Hypocalcemia is a known complication of trisodium citrate anticoagulation; however, hypercalcemia associated with low ionized calcium concentration and calcium-citrate complexing has been reported in a patient with combined hepatic and renal failure [130] . Recently, attention has focused on other anticoagulation strategies including prostacyclin, which may increase cerebral oxygen uptake, [34] [170] and the serine protease inhibitors nafamostat mesilate and gabexate mesilate [55] .

The characteristics of the dialyzer membrane impact substrate removal and may affect cognitive function in patients with HRS. Dialyzer membranes used for hemofiltration and hemodialysis can be described in terms of their biocompatibility, or their ability to activate peripheral blood cells and plasma proteins upon contact with plasma in the extracorporeal circuit [31] [135] . The prototype of bioincompatible membranes is Cuprophane, which is a cellulosic material that has been found to cause neutropenia as a result of neutrophil sequestration within the pulmonary microcirculation. This event is believed to be mediated by activation of complement proteins [31] , such as the anaphylatoxins C3a and C5a, which can be measured by commercial C3a(desArg) and C5a(desArg) radioimmunoassay. In addition to sequestration, neutrophils release proinflammatory mediators (e.g., reactive oxygen species and intragranular proteases) on contact with the dialyzer membrane. In contrast, biocompatible membranes, which are composed of synthetic materials such as polysulfone, polyamide, and polyacrylonitrile [PAN], possess properties which attenuate complement activation. AN69 membranes, which are composed of PAN and sodium methallyl sulfonate, are known to adsorb cationic peptides and allow binding and activation of factor XII, which results in conversion of kininogen to kinin. Angiotensin converting enzyme (ACE), a kininase, can catalyze this reaction. Therefore, the potential for bradykinin accumulation and anaphylactoid reactions exists when AN69 membranes and ACE-inhibitors are used concurrently [31] [109] [134] [169] . While there is evidence to suggest greater survival, increased recovery of renal function, and need for fewer dialysis sessions with synthetic versus celluosic membranes [82] [152] , some controversy still exists [91] over the benefit of dialyzer membrane composition. Recent literature favors

the use of synthetic membranes, however [38] [45] [84] [92] [120] [133] [142] [159] [165] . Polyacrylonitrile membranes, in particular, have been touted for use in hemodialysis and hemofiltration in combined renal and hepatic failure, because they are highly permeable and, thus, allow for the filtration of large molecular weight substances (limit 35,000–40,000 Daltons) [45] [133] [159] [165] . One study found that PAN membranes produced no leukopenia and reduced cerebral perfusion pressure less than polyamide membranes despite similar hemofiltration prescriptions [38] . Patients who underwent hemofiltration with polyamide membranes, on the other hand, experienced significant reductions in cardiac output, pulmonary artery occlusive pressure, tissue oxygen delivery, and mean arterial pressure [38] . Importantly, while biocompatible membranes may produce less monocyte activation and release of proinflammatory cytokines (IL-1β, IL-6, TNF-α), they may be permeable enough to allow backdiffusion or backfiltration of “toxic” substances from the dialysate into the plasma space [30] [31] .

Substrate removal in renal replacement therapy is dependent upon several factors including plasma concentration, dialyzer membrane porosity, modality (CRRT versus intermittent therapy), dialysate and ultrafiltration rate, and blood flow. In general, hemodialysis and hemofiltration effectively remove water-soluble substances, particularly lower molecular weight toxins such as urea, ammonia, gamma-aminobutyric acid (GABA), and octopamine (a false neurotransmitter). However, the actual daily removal of toxins such as ammonia and GABA is small compared with the total body pool and overall rates of generation [40] [94] . One study combined CVVH with plasma exchange in sixteen patients with acute hepatic failure and ≥ grade II encephalopathy. These authors demonstrated removal of “middle molecular weight” substances (>600–4500 <15,000 D) with a polysulfone (synthetic, high permeability) dialyzer membrane [120] . These middle molecules have been shown to inhibit brain Na+/K+-ATPase, leading to coma and cerebral edema [120] [154] . Other toxins which may be able to inhibit Na+/K+-ATPase include bile constituents, free fatty acids, digoxin-like immunoreactive substances, mercaptans, and phenols [174] . Changes in serum high performance liquid chromatography (HPLC) profile and coma grade for one patient are shown. [120] . The HPLC spikes produced by middle molecules were gradually removed by continuous hemofiltration [120] . Similar middle molecule removal was not achieved by plasma exchange alone. Of this cohort, 50% (8/16) showed improved level of consciousness, 3/16 survived the acute illness, and 5/16 survived > 3 weeks [120] . Another study demonstrated similar recovery of consciousness in 59% (13/22) of patients [133] . Removal of proinflammatory cytokines (IL-1β, IL-6, TNF-α) has recently received attention. Some researchers suggest removal of both proinflammatory and antiinflammatory cytokines (IL-10, soluble TNF receptors I and II, IL-1 receptor antagonist) with CVVH [45] , while others suggest no significant removal [84] . There is additional evidence for cytokine removal via adsorption to an AN69 dialyzer membrane. The greatest reductions in cytokine levels occurred within the first hour of initiating CVVH and immediately after changing the membrane [45] . Greater adsorption was also noted when blood flows were increased from 100 to 200 ml/min, which may increase the membrane hydrogel surface area available for adsorption [45] . Other researchers provide evidence for hemofiltration of immunomodulatory substances, which are capable of stimulating peripheral blood monocyte TNF-α release [84] , and clearance of hepatotoxic substances which suppress proliferation of in vitro hepatic cells (HepG2) and are capable of stimulating an acute phase response [142] . Hepatocyte growth factor (MW 35,000–70,000 Daltons), which is not likely to be filtered, also possesses an antiproliferative effect on HepG2 cells [142] .

Daily change in the HPLC profile of sera, coma grade, and prothrombin time (PT) during continuous hemofiltration in a patient with fulminant hepatic failure. (From

Matsubara S, Okabe K, Ouchi K, Miyazaki Y, Yajima Y, Suzuki H, Otsuki M, Matsuno

S. Continuous removal of middle molecules by hemofiltration in patients with acute liver failure. Crit Care Med 1990;18:1331–1338; with permission.)

Nutrient and drug removal with CRRT

Removal of amino acids tends to be greater with continuous hemodialysis (6–16 grams/day) than with CVVH (5–8 grams/day) or intermittent dialysis (5–13 grams/treatment) [117] . Amino acid clearances depend upon dialysate flow rate (Qd) and can represent from 8.9 ± 1.2% (Qd = 1 L/hr) to 12.1 ± 2.2% (Qd = 2 L/hr) of the daily protein input [44] . General recommendations for amino acid supplementation include provision of 500 mg per liter filtrate/dialysate or an additional 0.2 gm/kg/day of amino acids in patients on continuous therapies [46] [93] . Infusion of essential and nonessential amino acids in addition to glucose has been proposed to maintain serum levels of these compounds in individuals receiving standard hemodialysis [172] . Exact removal of specific amino acids varies according to study [41] [42] [64] [88] [89] [97] ; however, of the essential amino acids, valine, isoleucine, and leucine (all branched) do not appear to be significantly removed by PAN hemodialysis, whereas significant decreases in plasma levels of methionine and phenylalanine (branched) as well as lysine and threonine have been observed [80] [133] . Trace amounts of cholesterol and/or triglycerides have been detected in the ultrafiltrate from patients receiving continuous hemodiafiltration [15] [117] . Use of dextrose-containing replacement solutions may result in large net uptake of glucose during continuous hemofiltration and hemodiafiltration (11.9 ± 3.1 g/hr and 8.1 ± 2.1 mg/kg/min, respectively) [63] [125] . Dextrose-free solutions, on the other hand, are associated with a small, but predictable, glucose loss during CRRT [63] . The pharmacokinetics of drug dosing with CRRT is described elsewhere [16] [24] [93] [166] .

Therapeutic plasma exchange (TPE)/hemoperfusion/filter-sorbent systems/hybrid bioartificial liver

Therapeutic plasma exchange (TPE) has been utilized for its ability to remove albumin-bound, macromolecular substances that are confined to the intravascular space, such as endotoxin, aromatic amino acids, and certain bile constituents (Table 4) [94] [120] . This is distinctly different from hemofiltration, which removes substances that are not protein-bound and have large volumes of distribution. TPE was initially described as a means of removing putative nondialyzable substances responsible for hepatic coma [114]

. Later experience revealed little impact of TPE alone on survival [112] [113] ; however, improved neurologic status and survival have been described with combined TPE and continuous hemofiltration or hemodiafiltration [90] [120] [176] [177] . It is possible that use of plasmapheresis may supplement ordinary hemodialysis and hemofiltration by allowing replacement of plasma components that are depleted in hepatic failure, particularly clotting factors [86] .

Hemoperfusion (HP) is a sorbent-based technique which utilizes either activated charcoal (e.g., DHP-1 from Kuraray Co. Ltd., Osaka, Japan and Adsorba 150C from Gambro Ltd., Sidcup, Kent, UK) or an albumin-coated ion exchange resin such as Amberlite XAD-7 (Rohm and Haas Ltd., Croydon, Surey, UK) [19] [129] [136] . The former effectively removes water-soluble substances (e.g., GABA, inhibitors of Na+/K+- ATPase, mercaptans) while the latter removes protein-bound (e.g., bile acids, aromatic amino acids) and lipid-soluble substances [8] [19] [86] [132] [136] [159] . The largest study of

hemoperfusion evaluated patients with fulminant hepatic failure from several etiologies (viral hepatitis, acetominophen overdose, halothane / other drug exposure) and found no survival benefit with daily HP regardless of treatment time (grade III encephalopathy: 5 hrs = 51%: 10 hrs = 50%:: grade IV encephalopathy: no HP = 39.3%: 10 hrs = 34.5%) [132] . In addition, hemoperfusion has been associated with platelet losses, platelet aggregation within the extracorporeal circuit [86] [132] , and loss of coagulation factors [8] . A smaller, more recent trial involving 31 patients with acute hepatic failure reported a 50% survival rate in only four patients undergoing HP compared with hemofiltration (6/9: 67% survival), TPE (3/8: 37%), and hemodialysis (3/10: 30%) [163] .

Combination filter-sorbent systems provide another form of extracorporeal blood purification for patients awaiting liver transplantation. One such system is the Biologic-DT (HemoCleanse, Inc., West Lafayette, IN), which combines a sorbent-based system with standard hemodialysis [8] [87] . Similar to the Biologic-HD system (Ash Medical Systems, West Lafayette, IN), which utilizes a sorbent column to regenerate dialysate [9] , the Biologic-DT system performs dialysis with a cellulosic plate dialyzer and a dialysate solution containing both powdered activated charcoal (300,000 m2 surface area) and a cation exchanger. This allows removal of middle molecules (100–5000 Daltons) as well as cations such as ammonium [8] . A study which used this system evaluated 15 patients with acute hepatic failure, 11 of whom had concomintant renal failure. All but two experienced neurologic improvement. Four patients recovered liver function without transplantation (two survived), and four received liver transplantation (two survived) with 1–12 daily treatments of 8–12 hours duration [8] . Less favorable results were found in a prospective evaluation of 10 patients with fulminant hepatic failure, in which one of five patients treated with sorbent-based dialysis survived [87] . The Molecular Adsorbent Recirculating System (MARS) has also been recently described [123] [124] . This liver support system utilizes either intermittent (6–8 hours daily) or continuous hemodialysis with dialysate enriched with 20% human serum albumin as a means to remove albumin-bound toxins (bilirubin, bile acids, fatty acids, tryptophan, aromatic amino acids, and copper) [124] . Improvement in hepatic encephalopathy, decreases in serum creatinine and bilirubin concentration, and increases in serum sodium concentration and prothrombin activity were observed with MARS therapy in patients with hepatic cirrhosis and Type I HRS [123] . In HRS, MARS may facilitate removal of nitric oxide, albumin-bound uremic toxins, bile components, and vasoactive hormones (e.g., renin, angiotensin) [124] .

The hybrid bioartificial liver (BAL) is a novel liver assist strategy that utilizes primary hepatocytes derived from either human or animal sources [167] . One group has used a clonally derived human liver cell line (C3A) and cultured them by inoculating 5–10 grams of cells into a dialyzer membrane. The cells exhibit many properties of hepatic cells in vivo such as conversion of ammonia to urea and glutamine, metabolism of aromatic amino acids (phenylalanine, tyrosine), synthesis of clotting factors, expression of P-450 enzymes, and proliferation in glucose-free medium (indicative of gluconeogenesis). Moreover, these cells exhibit contact inhibition. Each dialyzer carries approximately 2 × 1011 cells (metabolic equivalent 200 grams hepatocytes) [167] . Liver regeneration, as documented by increasing organ size and increasing α-fetoprotein, has been observed with this technique [167] . Others have combined hybrid extracorporeal liver support with hemoperfusion and plasmapheresis in an effort to mitigate the risk of bleeding associated with hemoperfusion-induced platelet losses [146] . A similar approach using sequential total plasma volume exchange and artificial liver treatment (7 hr per treatment) has been used successfully to control intracranial pressure in a patient during the transition period (14 hr) from total hepatectomy to OLT [145] . While xenogenically derived hepatocytes are readily available, disadvantages imposed by their use include effects of animal proteins in human circulation (e.g.,

antibody formation, complement activation, and induction of proinflammatory cytokines) as well as viral transfer [124] [167] . In addition, the hepatocyte cell mass required to sustain metabolic support and life in humans remains uncertain, but has been targeted at 20% [167] . Other researchers have described extracorporeal liver perfuson (ECLP) in patients with terminal hepatic disease and advanced (stage III or IV) hepatic coma [62] . This methodology involves perfusion of the patient's blood through a donor liver which otherwise would be considered unacceptable for transplantation. A report on three patients demonstrated decrements in serum bilirubin and arterial ammonia toward normal and clear neurologic improvement in two of the three subjects. Trends toward improved prothrombin time were also noted [62] .

Orthotopic liver transplantation (OLT)

OLT remains the ultimate treatment for hepatorenal syndrome. Delaying liver transplantation, whether intentionally or as an unintended consequence of the liver organ donor shortage, with the onset of HRS imposes great risk to the patient and any chance for survival even with transplantation. OLT recipients with HRS have a significantly decreased survival at 5 years compared with those without HRS (60% vs. 68%) [75] . In addition, both pre- and post-transplantation liver patients with HRS have longer hospitalizations including prolonged intensive care unit stays. Clearly, an increase in liver organ donation and early transplantation in patients with advanced liver disease that do not yet have HRS or significant renal insufficiency is the best life-saving and cost-effective course.

Summary

Hepatorenal syndrome is a well characterized entity in which vasodilation of splanchnic vessels and intense constriction of the renal cortical vasculature occur in concert. The condition is often fatal unless orthotopic liver transplantation (OLT) is performed. Many extracorporeal blood purification techniques exist which can be offered to patients awaiting OLT. Continuous hemofiltration, with or without other modalities such as therapeutic plasma exchange and hemoperfusion, may be helpful in improving the level of consciousness of these patients. Unfortunately, mortality and hepatic regeneration do not appear to be affected by such interventions. The development of a hybrid bioartifical liver support system and pharmacologic manipulation of the hemodynamic perturbations that occur in HRS provide particularly appealing prospects as a means of providing a bridge to liver transplantation in the future.

I was so high I did not recognizeThe fire burning in her eyesThe chaos that controlled my mindWhispered goodbye and she got on a planeNever to return againBut always in my heart

This love has taken its toll on meShe said Goodbye too many times beforeAnd her heart is breaking in front of meI have no choice cause I won't say goodbye anymore

I tried my best to feed her appetiteKeep her coming every nightSo hard to keep her satisfiedKept playing love like it was just a gamePretending to feel the sameThen turn around and leave again

This love has taken its toll on meShe said Goodbye too many times beforeAnd her heart is breaking in front of meI have no choice cause I won't say goodbye anymore

I'll fix these broken thingsRepair your broken wingsAnd make sure everything's alrightMy pressure on your hipsSinking my fingertipsInto every inch of youCause I know that's what you want me to do