1. Critical Care Clinics
Volume 18 • Number 2 • April 2002
Copyright © 2002 W. B. Saunders Company
Hepatorenal syndrome: Definition, pathophysiology, and intervention
Andrew E. Briglia, DO a , *
Frank A. Anania, MD b
a
Division of Nephrology
University of Maryland
N3W143
22 South Greene St.
Baltimore, MD 21201, USA
b
Division of Hepatology
University of Maryland
N3W50
22 South Greene St.
Baltimore, MD 21201, USA
*
Corresponding author
E-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

2. 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

3. 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
Carbon tetrachloride

4. Table 2. Conditions causing simultaneous liver and renal failure
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

5. 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

6. 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

7. 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

8. 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.

9. 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] .

10. 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] .

11. 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] .

12. 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

13. 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

14. 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

15. 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

16. 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.,

17. 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.

18. I was so high I did not recognize
The fire burning in her eyes
The chaos that controlled my mind
Whispered goodbye and she got on a plane
Never to return again
But always in my heart
This love has taken its toll on me
She said Goodbye too many times before
And her heart is breaking in front of me
I have no choice cause I won't say goodbye anymore
I tried my best to feed her appetite
Keep her coming every night
So hard to keep her satisfied
Kept playing love like it was just a game
Pretending to feel the same
Then turn around and leave again
This love has taken its toll on me
She said Goodbye too many times before
And her heart is breaking in front of me
I have no choice cause I won't say goodbye anymore
I'll fix these broken things
Repair your broken wings
And make sure everything's alright
My pressure on your hips
Sinking my fingertips
Into every inch of you
Cause I know that's what you want me to do