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dysfunction31 is supported by recent reports of patients inwhom HRS was successfully treated by reduction of portalpressure by a TIPS.12 Furthermore, occlusion of a TIPS by anangioplasty balloon was associated with acute reduction of renal blood flow.32 Upon release of the balloon, with elimina-tion of portal hypertension, renal blood flow returned to base-line levels. Portal hypertension with portosystemic shuntsand splanchnic dilatation leads to development of hyperdy-

namic circulation with attendant systemic arterial vasodilata-tion and effective arterial underfilling and hence renal hypo-perfusion. However, this is unlikely to be the wholeexplanation. Presinusoidal portal hypertension due to portalvein thrombosis, nodular regenerative hyperplasia, or schis-tosomiasis is associated with hemodynamic changes similar tothose of compensated cirrhosis17,33 but not associated renalsodium retention34 or HRS. Animal studies suggest the impor-tant afferent factor for the development of HRS is sinusoidalportal hypertension. For example, infusion of glutamine intothe portal vein, which induces hepatocyte swelling and henceincreases sinusoidal portal pressure, was associated with asignificant decrease of both renal plasma flow and glomerularfiltration rate. These effects were abolished by sectioning the

renal sympathetic nervous supply.35

Furthermore, increasedintrahepatic pressure resulted in greater efferent renal sympa-thetic nervous activity,36 and renal sympathectomy improvedglomerular filtration rate in cirrhotic rats.37,38 Finally, renalsympathetic block resulted in transient improvement in renalblood flow and function in patients with HRS.39

Bataller et al.14 proposed that renal hypoperfusion in cir-rhosis could also be related to liver dysfunction, which influ-ences the synthesis or release of renal vasodilators such as therenal prostaglandins40,41 from the kidney. In decompensatedcirrhosis but without renal failure, increased renal productionof prostaglandins has been reported.42 In HRS, urinary excre-

tion of prostaglandin E2 (PGE2) and prostacyclin metabolite6-oxo-PGF1 are decreased compared with patients with as-cites alone.43 This may partly result from a fall in glomerularfiltration rate44 and decreased renal production of PGE2 and6-oxo-PGF1.45 In addition, the use of nonsteroidal anti-in-flammatory drugs, which are cyclo-oxygenase inhibitors, inpatients with cirrhosis and ascites can precipitate HRS.46

Another renal vasodilator that could be involved in the

pathogenesis of HRS is nitric oxide.47

In portal hypertensionendothelial nitric oxide synthase (NOS) activity is signifi-cantly increased, leading to increased circulating levels of ni-tric oxide.48 In normal animals and humans, short-term inhi-bition of NOS results in renal vasoconstriction and reducedrenal plasma flow.49,50 In contrast, NOS inhibition in cirrhoticrats with ascites does not affect renal blood flow or func-tion51,52 despite an increased systemic pressor effect.53 Fur-thermore, renal vasoconstriction may occur in the presence ofincreased glomerular nitrite production54 and increased uri-nary nitrate excretion55 in ascitic patients compared withcompensated nonascitic cirrhotics. This suggests that renalmicrocirculation in ascites is less sensitive to nitric oxide.56

However, infusion of nitric oxide substrate L-arginine in cir-

rhotic patients with ascites, in contrast to controls, causesincreased natriuresis with increased urinary nitrate/nitrite ex-cretion.57

Finally, there is a possible role of natriuretic peptides.58 Inexperimental cirrhosis with ascites in rats, blockade of natri-uretic peptide receptors was followed by a significant reduc-tion of both renal blood flow and glomerular filtration rate.59

Renal vasodilatation with acetylcysteine improved renal func-tion in patients with HRS without affecting liver function orsystemic hemodynamics.60 Furthermore, not all patients withseemingly equally severe hepatic dysfunction develop HRS.Therefore, the role of liver dysfunction in the pathogenesis of

FIG. 1. The pathophysiology of hepatorenal syndrome.

HEPATOLOGY Vol. 34, No. 6, 2001 WONG AND BLENDIS 1243



HRS appears to be an important background factor, or “firsthit,” that requires an additional factor, or “second hit,” toinitiate HRS (Fig. 2). In the same way splanchnic and systemicvasodilation and sinusoidal portal hypertension appear to beprimary factors in the pathogenesis, but all require additionalfactors to initiate HRS.

DEFINITION OF HRS—ITS ROLE IN CLARIFYING THE

PATHOGENESIS AND PREVENTION

The recent consensus conference of the International As-cites Club clearly posed the diagnostic criteria of HRS (Table1) and defined types I and II. Although the definition de-scribes renal failure complicating liver failure, and helps in theclinical management of these patients, it is not clear whethertypes I and II HRS are two different stages on the same con-

tinuum of the end-stage cirrhotic process or two distinct en-tities. The definition does not explain what determineswhether a patient with normal serum creatinine will graduallyevolve into type II HRS with progressively worsening glomer-ular filtration rate or acutely develop renal failure with itsgrave prognosis. Finally, the definition does not explain whymost but not all patients with HRS have ascites. We will at-tempt to answer some of these questions while focusing on thetwo types of HRS from a pathogenetic point of view. We alsoare taking the opportunity to suggest certain recommenda-tions in the literature for prevention of HRS.

TYPE I

Gines et al.1 reported that hyponatremia and high plasmarenin activity (PRA) are independent predictors for develop-ment of type 1 HRS in cirrhotic patients with ascites. Theysuggested that it is the extent of the systemic arterial vasodi-latation with consequent effective arterial underfilling (thefirst hit), causing a rise in the PRA that is important in thepathogenesis of type 1 HRS. Indeed, HRS frequently developsas a consequence of precipitating events (the second hit),which exaggerate the effective arterial underfilling. Such

events may include the overzealous use of diuretics,61

largevolume paracentesis, or development of spontaneous bacte-rial peritonitis (SBP) in ascitic patients as well as in patientswith gastrointestinal bleeding. However, at least 24% of pa-tients with type 1 HRS develop renal failure without any ob-vious precipitating factor.62 This suggests that other as yetunrecognized factors may also be involved in the pathogenesisof HRS, which we shall address later.

Diuretics

Patients with refractory ascites have significantly higherPRA63 compared with patients with responsive ascites, sug-

FIG. 2. The first hit and the sec-ond hit hypothesis of hepatorenalsyndrome.

TABLE 1. Definition of Hepatorenal Syndrome

Major criteria

Chronic or acute liver disease with liver failure and portal hypertension

Low glomerular filtration rate as indicated by a serum creatinine 1.5

mg/dL or a creatinine clearance of 40 mL/min

Absence of shock, ongoing bacterial infection, and recent treatment with

nephrotoxic drugs. Absence of excessive fluid loss including

gastrointestinal loss

No sustained improvement in renal function following expansion with

1.5 L of isotonic saline

Proteinuria of 0.5 g/d and no ultrasonagraphic evidence of renal tract

disease

Minor criteria

Urine volume 500 mL/d

Urine sodium 10 mmoL/d

Urine osmolality plasma osmolality

Urine red cell count 50 per high power field

Serum sodium 130 mmol/L

1244 WONG AND BLENDIS HEPATOLOGY December 2001



gesting reduction in effective arterial blood volume. Further-more, these patients have a poor natriuretic response to furo-semide.63 Gines et al. reported a significantly higher incidenceof reversible renal impairment in hospitalized patients withtense ascites treated with diuretics compared with thosetreated with large-volume paracentesis,64 which is associatedwith further increases in PRA. These findings support thecontention that diuretics cause a further contraction of intra-vascular volume with compensatory increases in the vasocon-

strictor activities predisposing patients to development of re-nal failure. However, the same investigators also reported thatdiuretics do not increase the incidence of postparacentesiscirculatory dysfunction (defined as an increase in renin of greater than 50% over baseline levels up to a value higher than4 ng/mL/h on the third day after paracentesis).65 The possibil-ity remains that diuretic therapy in nonhospitalized, severelydecompensated patients might induce the onset of HRS. Inhospitalized patients, addition of a colloid solution such asalbumin to diuretic therapy prevented a diuretic-induced risein serum creatinine and blood urea nitrogen despite an un-changed hematocrit and lack of protection from a fall in sys-temic blood pressure,66 indicating an unchanged intravascu-lar volume. Thus albumin may have a local effect on the

physical factors of the tubule.67

This suggests that diureticsmay also induce renal impairment via mechanisms other thanreduction in intravascular volume.67 This may occur via somelocal effects of diuretics on the nephron, as structural changeshave been observed following prolonged diuretic therapy.68

Although overzealous use of loop diuretics in particular cancause a rise in serum urea and creatinine, it is nearly alwaysreversible with cessation of diuretics.69 Furthermore, patientswith peripheral edema appear to be protected by more rapidmobilization of edema fluid.70 Therefore, the indication forthe protective and synergistic use of albumin with diureticsremains controversial.71

Recommendation. In patients with ascites, spironolactoneshould not be increased above 400 mg daily. The pharmaco-

dynamics of loop diuretics in cirrhotic ascitic patients arealtered, and the diminished response to furosemide is notenhanced by large doses.72 These patients should be treatedwith divided doses of furosemide of up to 160 mg daily and befollowed closely with monitoring of electrolytes and serumcreatinine, especially in the absence of peripheral edema. Pa-tients who do not respond to these generally accepted maxi-mal doses of diuretic therapy should not have their diureticdoses increased further, but other treatment options for as-cites should be considered. In the future, simple tests such asthe natriuretic response to an acute intravenous infusion of furosemide63 may help to predict diuretic nonresponsivenessand possibly avoid unrecognized precipitation of HRS, espe-cially in outpatients.

Large-Volume Paracentesis

Ruiz-del-Arbol et al.73 described development of circula-tory dysfunction after large-volume paracentesis that led todeterioration in renal function. They interpreted this as anexaggeration of the arterial vasodilatation already present incirrhotic patients with ascites, with further activation of thealready stimulated vasoconstrictor systems74 leading to fur-ther renal vasoconstriction. The intriguing observation is thatonly 32% of patients had activation of the vasoconstrictorsystems after large-volume paracentesis.74 The answer may liein the extent of the hemodynamic instability before paracen-

tesis. Because PRA is one of the independent predictors fordevelopment of HRS,1 those patients with higher baselinePRA (first hit) are more likely to develop HRS after large-volume paracentesis (second hit). However, use of albumin asa volume expander after large-volume paracentesis does notalways prevent postparacentesis renal failure.

Recommendation. Before starting a course of repeated para-centeses, it is important to measure serum creatinine levelsand, if possible, perform PRA determinations to identify pa-

tients at greatest risk of developing postparacentesis circula-tory dysfunction. Such patients should be maximally pro-tected with 6 to 8 grams of intravenous albumin per liter ofascites.

Gastrointestinal Bleeding

Acute blood loss leads to acute blood volume contractionwith decreased renal perfusion and acute tubular necrosis.However, the pathogenesis of acute renal failure secondary tovariceal bleeding has been poorly documented, and some pa-tients are diagnosed as having (type 1) HRS. For example, in arecent study 46% of 85 patients with decompensated cirrhosis(first hit) and variceal bleeding developed a systemic inflam-

matory response syndrome, manifesting with increased tem-perature, tachycardia, tachypnea, and leukocytosis, with orwithout an infection,75 associated with exacerbation of thehyperdynamic circulation (second hit). The inflammatory re-sponse is associated with activation of many cytokines,76

some of which stimulate production of nitric oxide and othervasodilators.76 Thus, the patient with gastrointestinal bleed-ing is also predisposed to further exaggeration of systemicarterial vasodilation because the accompanying inflammatoryresponse will yield more vasodilators and aggravate the effec-tive arterial underfilling. Superimposition of this systemic in-flammatory response (second hit) on decompenasated liverdisease can lead to organ failure. In one report, 3 patients diedof documented HRS after acute gastrointestinal bleeding.75

However, in such cases, the classic differentiation of acutetubular necrosis from HRS by an active urinary sediment withcasts and urinary sodium concentration greater than 20mmol/L may be blurred. Development of renal failure aftergastrointestinal bleeding is related to an advanced stage ofcirrhosis77 and renal impairment before the bleeding is a pre-dictor of mortality.77 Cirrhotic patients with marked systemicarterial vasodilatation and effective underfilling are less ableto tolerate intravascular volume depletion, predisposing themto development of renal failure and a poor outcome.

Recommendation. Cirrhotic patients with acute gastrointes-tinal bleeding and poor liver function and/or decreased renalfunction should be managed in an intensive care unit where

optimal monitoring can provide maximum protection of theireffective circulating blood volume and renal perfusion. In ad-dition, cirrhotic patients, particularly those with ascites, withacute variceal bleeding, should be given a prophylactic courseof antibiotics.78 Recommended antibiotic regimens includenorfloxicin, 400 mg 12 hourly for a minimum of 7 days, or acombination of ciprofloxacin, 400 mg daily, and amoxicillin-clavulanic acid, 3 g daily, intravenously and then orally andcontinued for 3 days after the bleeding stops. In a meta-anal-ysis of randomized controlled trials,79 prophylactic antibioticssignificantly reduced the incidence of SBP and consequentlymortality from septic shock and renal failure.80




Spontaneous Bacterial Peritonitis

SBP is another common precipitant of HRS. At least 30% of patients with SBP develop HRS despite adequate treatment of infection.81,82 Previous renal impairment and a marked in-flammatory response, indicated by the polymorphonuclearcell count and cytokine concentrations in ascitic fluid, resultin further arterial vasodilatation and are important predictorsfor development of type 1 HRS.83 Sepsis decreases both spon-taneous and agonist-induced vascular contractile activity in

the cirrhotic rat.84 Sort et al.85 postulated that sepsis in cirrho-sis induces an increased production of various cytokines andendotoxins, which in turn stimulate the production of nitricoxide and other vasodilators86 causing further arterial vasodi-latation. Indeed, intestinal decontamination with oral antibi-otics in cirrhotic patients was associated with improvement insystemic hemodynamics and reduction in systemic arterialvasodilatation,87 probably as a result of a reduction of nitricoxide–induced systemic arterial vasodilatation.88 Thus, circu-latory dysfunction in patients with SBP is in many ways sim-ilar to that observed in patients with gastrointestinal bleeding:the inflammatory response leads to further reduction of effec-tive arterial blood volume resulting in incremental activationof the already elevated neurohumoral vasoconstrictor systems

with development of renal vasoconstriction and dysfunc-tion.85 Therefore, it is not surprising that the same investiga-tors reported significant reduction in the incidence of renalimpairment when patients with SBP were given volume ex-pansion in the form of intravenous albumin85 in a randomizedcontrolled study. However, circulatory dysfunction wors-ened, indicated by rising PRA, despite adequate treatment of the infection. It appears that a precipitant will only inducetype I HRS in a susceptible patient. For example, renal impair-ment in patients with SBP only occurred in those with a directbilirubin level greater than 4 mg/dL.85

Recommendation. Patients who develop SBP with evidence of renal impairment or with serum bilirubin levels greater than 4mg/dL should be managed in a setting that allows optimalmonitoring to protect volume status and renal function andshould be treated initially with intravenous albumin 1.5 g/kgper day.

Cholestasis

The presence of cholestatic jaundice may be an unrecog-nized factor in the development of type 1 HRS. This is notsurprising because historically obstructive jaundice can be animportant factor (first hit) in patients subjected to circulatorychanges, such as surgery (second hit), and can lead to renalfailure.89 It is now well accepted that cholestasis per se, in theabsence of portal hypertension, causes vasodilatation and ahyperdynamic circulation associated with impaired vascular

responsiveness to circulating vasoconstrictors.90

Therefore,cholestasis superimposed on cirrhosis and portal hyperten-sion is likely to compound the circulatory changes,91 thuspredisposing the patient to HRS. It is not surprising to findboth elevated bilirubin levels as a major component of prog-nostic indexes, such as the Child-Pugh score, and creatinineclearance frequently decreased to 60% of normal with biliaryobstruction.92 The mechanism is still unknown, but couldinclude endotoxemia, nephrotoxic effects of elevated levels of bile acids,93 and/or disturbances of renal prostaglandin/ thromboxane synthesis.94 Holt et al. observed that acute bili-ary obstruction was associated with the development of renal

impairment.95 They postulated that the increased productionof F2-isoprostanes in cholestasis was responsible for the de-velopment of renal failure because F2-isoprostanes are potentrenal vasoconstrictors, and administration of antioxidantsthat reduced F2-isoprostanes levels was associated with im-provement of renal function.95 HRS is also a common cause ofdeath in patients with severe acute alcohol-induced hepati-tis96 in whom sinusoidal portal hypertension is exacerbatedand liver function deteriorates further. Severity in this context

can be defined using the Maddrey discriminant function97

: 1of the 2 components is serum bilirubin level and the other isprothrombin time, i.e., 4.6 (prothrombin time controltime in seconds) serum bilirubin in mg/dL. Therefore, theonset of cholestatic jaundice in advanced cirrhosis may be aless well recognized second hit, contributing to the develop-ment of type 1 HRS in patients.

Recommendation. Cirrhotic patients who as a consequenceof decompensation have developed significant cholestasis,e.g., serum bilirubin greater than 4 mg/dL, should be consid-ered at increased risk for developing HRS in the presence of asecond hit, SBP, or variceal bleeding and treated accordingly.In patients with severe acute alcohol-induced hepatitis and jaundice, further control trials are needed to confirm the use

of pentoxifylline to prevent onset of HRS and to reduce mor-tality96 in these patients.

TYPE II

Type II HRS has been regarded as an extension of the stageof refractory ascites in cirrhosis and shares the same patho-physiology, namely, splanchnic and systemic vasodilatationwith renal vasoconstriction, leading to progressive deteriora-tion in renal function.4 However, Papper et al. reported on aseries of 200 patients with HRS, in which only 75% of thepatients had massive ascites.98 Furthermore, in the only long-term follow-up study of Gines et al.1 assessing the naturalhistory of a cohort of ascitic cirrhotic patients, the presence ofascites was not an independent predictor for development of

HRS. Newer predictive factors such as renal-resistive index,measured by doppler ultrasound,99,100 or the Mayo End-StageLiver Disease Index (MELD),101 based on the initial elevationof serum creatinine together with total bilirubin and a reduc-tion in prothrombin time, may increase our ability to predictthe onset of HRS in these patients. Despite this, patients withrefractory ascites are poised to develop renal failure. Subtlefactors such as a further deterioration in liver function withincreasing cholestatic jaundice, which in itself causes sys-temic vasodilatation,90 further compromises the pathophysi-ology of refractory ascites and triggers development of renalfailure.96

It is clear that while the definition separates HRS into twoclinically distinct entities, for some patients both types of HRS

are a continuum of the same condition: type II HRS can evolveinto type I HRS, especially in the presence of precipitatingfactors.

NEW THERAPIES FOR HRS

Although liver transplantation remains the only effectivepermanent treatment for HRS,5,6 preoperative renal dysfunc-tion frequently reduces patient and graft survival after livertransplantation.6-8,102 Therefore, medical treatments have at-tempted to reverse HRS, either definitively or to improve renalfunction sufficiently to allow liver transplantation to proceed.All manipulate some aspects of the pathophysiology of HRS,




with varying degrees of success. We therefore will examinevarious nonsurgical treatments for HRS from a pathophysio-logic standpoint with the aim of improving prevention andoverall management of HRS.

Vasopressin Analogues

The rationale for using vasopressin analogues as a treat-ment for HRS is based on the observation that the vasopres-sin-1 receptor agonist, 8-ornithin vasopressin or ornipressin,

a vasoconstrictor, increased splanchnic and systemic vascularresistance in cirrhotic patients with impaired renal function,resulting in redistribution of circulating blood volume. Thisimproved systemic blood pressure and therefore renal perfu-sion pressure, thereby increasing renal plasma flow and glo-merular filtration rate after only 4 hours of intravenous infu-sion.103,104 Infusion longer than 48 hours further improvedrenal function, resulting in a suppression of the renin-angio-tensin and sympathetic activities with consequent further im-provement in renal plasma flow and glomerular filtration rate. When ornipressin was infused for up to 15 days, together withplasma volume expansion with intravenous albumin, the im-provement in renal function was even more impressive, butserious life-threatening ischemic complications limited the

use of this therapy.11

In contrast, infusion of another vaso-pressin analogue, terlipressin, over 48 hours improved renalfunction, suppressed PRA and aldosterone levels, and in-creased the atrial natriuretic factor levels without increasingsodium excretion, all without serious side effects.105 Lack of anatriuretic response after improvement of renal function maybe related to severe liver dysfunction in these patients, asonset of natriuresis has been shown to be related to a thresh-old of liver function.106-109 When terlipressin was combinedwith either intravenous albumin110 or a renal vasodilator suchas low-dose dopamine,10 the result was even more encourag-ing, with suppression of the renin-angiotensin activity andnormalization of serum creatinine in a number of patientswithout serious ischemic side effects. These observations fur-

ther support the concept that both splanchnic and systemicarterial vasodilatation with effective arterial underfilling, re-sulting in increased circulating levels of vasoconstrictors, playpathogenetic roles in the development of HRS. However, insome patients improvement in renal function persisted de-spite discontinuation of the vasopressin analogue, yet vaso-constrictor levels returned to their previously elevated lev-els.11

-Adrenergic Agonists

In HRS, systemic vasoconstrictors such as metaraminol im-proved urinary sodium excretion but not renal function,111

whereas norepinephrine112 or dopamine10 were ineffective.Oral administration of an -adrenergic agonist, midodrine,

improved systemic and renal hemodynamics in nonazotemiccirrhotic patients but had no effect in patients with HRS.113

However, when midodrine was combined with plasma vol-ume expansion and octreotide, a nonspecific inhibitor of therelease of endogenous vasodilators, there was significant im-provement in both the systemic and renal hemodynamics andurinary sodium excretion9 although renal function did notreturn to normal despite suppression of all measured neuro-hormonal systems to within the normal range. This may bebecause of continued renal hypoperfusion, maintained as aresult of persistent intrarenal activation of vasoconstric-tors.114

Endothelin Antagonists

Endothelin has been postulated as one such mediator ofintrarenal vasoconstriction in HRS. Therefore, an endothelinantagonist was assessed in a preliminary study to determineits efficacy in reversing HRS. Consecutive and increasingdoses of an endothelin antagonist, BQ123, were infused for 60minutes in 3 patients with HRS.115 All patients showed a dose-related increase in both glomerular filtration rate and renalplasma flow that approached 100% with the highest dose.

However, these results have only appeared in the form of aLetter to the Editor and therefore cannot be recommendedoutside a clinical trial setting.

Antioxidants

Another group of intrarenal vasoconstrictors, the productsof lipid peroxidation such as F2-isoprostanes, have been im-plicated in the pathogenesis of HRS.28,116 The synthesis ofF2-isoprostanes is regulated through products of lipid peroxi-dation. In a recent study, 12 patients received continuousinfusion of N-acetylcysteine, an antioxidant, for 5 days. Cre-atinine clearance improved from 24 3 mL/min to 43 4mL/min without any change in liver function or systemic he-modynamics,60 suggesting that it was the reduction in oxidantstress per se that caused the improvement in renal function.Again, these are preliminary data and they need to be con-firmed by clinical controlled trials. We cannot recommendthis therapy outside the setting of a clinical trial.

Moleculular Adsorbent Recirculating System

Molecular adsorbent recirculating system (MARS) is amodified dialysis method that uses an albumin-containing di-alysate that selectively removes albumin-bound substances.The device consists of a dialysis module with an asymmetricpermeable polysulfone-saturated membrane with human al-bumin on both the patient and dialysate sides of the mem-brane. During dialysis, a closed loop dialysate circuit allows

the transfer of albumin-bound toxins from plasma onto themembrane. The membrane-bound albumin plus toxin is recy-cled by continuous deligandization. Water-soluble toxins canalso be removed by using charcoal columns and ion-exchangeresins as the adsorbents. The system is connected to a contin-uous venovenous hemofiltration system to remove most mol-ecules except those with a molecular weight greater than 50kd. Although conventional dialysis has not been shown to beeffective in the treatment of HRS,117,118 the use of albumin-enriched dialysate fluid seems to help in the management ofHRS. In a randomized controlled trial of MARS-assisted dial-ysis versus conventional hemodialysis and standard medicaltherapy,119 the patients who received MARS-assisted dialysishad a significant reduction in serum bilirubin and creatinine

(from 3.8 1.6 mg/dL to 2.3 1.5 mg/dL) that was associ-ated with a prolongation of survival; however, survival wasstill low (40%) at 2 weeks. Although hemodynamic measure-ments were not performed, mean arterial pressure did notchange in the MARS patients. MARS dialysate removes cyto-kines, such as tumor necrosis factors and interleukin 6,120,121

among other substances, that have been implicated in theproduction of various vasodilators.76 Therefore, excessivetoxins such as cytokines appear to be important in the patho-genesis of HRS but only via the intermediary of arterial vaso-dilatation. At the very least, MARS appears to have potential asbridging therapy for HRS patients awaiting definitive treat-




ment. In addition, it may open up new avenues of researchinto the pathogenesis of HRS. We must await further confir-matory trials of this exciting approach. Therefore, MARSshould not be used in the treatment of patients with HRSexcept in the context of a clinical trial.

TIPS

Successful insertion of a TIPS, which lowers portal pres-sure, was associated with improved renal function in patients

with HRS,11,12,122-124

thereby supporting a central role of sinu-soidal portal hypertension in the pathogenesis of renal dys-function in these patients. From a pathophysiologic point of view, TIPS returns a significant portion of the splanchnic vol-ume into the systemic circulation, suppressing various vaso-active neurohormones, and thus improves renal hemodynam-ics.125 However, TIPS does not reverse every case of HRS, andeven in those patients who do respond, it does not completelynormalize renal function. This may be related to the fact thatTIPS acutely exacerbates the hyperdynamic circulation.125,126

Many of the systemic vasoconstrictors such as ET1 also re-mained elevated post-TIPS despite refilling of the systemiccirculation122; this can also explain the slow recovery of renalfunction. In the first small controlled trial of TIPS for 25 pa-

tients with refractory ascites, a forerunner of HRS, that in-cluded 8 jaundiced Child class C patients, the mortality rateafter 2 years in patients treated with TIPS was 56%, which wassignificantly greater than in patients treated with repeat large-volume paracentesis (29%).127 This finding was recently re-versed, with TIPS significantly improving the chances of sur-vival in patients with refractory ascites compared withparacentesis.128 However, the second study excluded chole-static patients with serum bilirubin greater than 5 mg/dL andserum creatinine greater than 3 mg/dL. In the largest study of TIPS for HRS to date, the survivalrate at 2 years was 35%.12 Of further interest, the patients were separated into types I and IIHRS. Survival was 70% at 1 year for type II HRS patients andsignificantly greater than the 20% for type I HRS patients.

Thus, Cox regression analysis found both HRS type (P .05)and serum bilirubin (P .001) to be independent survivalpredictors post-TIPS. It still remains to be seen whether fur-ther correction of the pathophysiology, such as reduction of portal pressure into the normal range or infusion of volumeexpanders, such as albumin, in the post-TIPS period, mayhelp to return renal function to normal.

We obviously still do not understand every pathophysio-logic change that occurs after TIPS nor do we know whatdetermines which patients will or will not respond to TIPSplacement. Perhaps there are critical levels of renal dysfunc-tion and cholestatic jaundice that determine no response nomatter what medical treatment is provided. The answers tothese questions will have to await the results of randomized

controlled trials. After that, we may be able to select the idealcandidates for TIPS insertion.129

Recommendation. TIPS therapy for HRS should only be per-formed in the setting of a clinical trial, optimally with types Iand II patients being studied separately.

SUMMARY

Recent advances made in the understanding of the patho-physiology of HRS have improved the prognosis of many pa-tients. However, there is still a great deal to be learned aboutHRS. Treatments now available prolong the survival of manyof these patients and allow liver transplantation to proceed

more electively. Furthermore, by improving renal functionbefore liver transplantation, we may improve patient and graftsurvival after transplantation6,102 and avoid the necessity ofliver-kidney transplants.8 Alternatively, by identifying pa-tients at risk earlier in the natural history of HRS, by usingpredictive indices such as the renal arteriolar-resistive indexor MELD,101 we may be able to develop management strate-gies to further prevent development of HRS and thereby re-duce the morbidity and mortality of these severely ill patients.

Finally, future clinical trials in HRS should separate types Iand II patients to clarify the therapeutic responses for bothgroups. These considerations are important because clinicalinvestigators will find randomized placebo-controlled trialsdifficult to conduct ethically in this group of patients becauseof the virtual 100% mortality of HRS type I.

REFERENCES

1. Gines A, Escorsell, Gines P, Salo J, Jimenez W, Inglada L, Navasa M, etal. Incidence, predictive factors and prognosis of the hepatorenal syn-drome in cirrhosis and ascites. Gastroenterology 1993;105:229-236.

2. Helwig FC, Schutz CB. A liver kidney syndrome. Clinical pathologicaland experimental studies. Surg Gynecol Obstet 1932;55:570-580.

3. Hecker R, Sherlock S. Electrolyte and circulatory changes in terminalrenal failure. Lancet 1956;2:1121-1125.

4. Arroyo V, Gines P, Gerbes AL, Dudley FJ, Gentilini P, Laffi G, ReynoldsTB, et al. Definition and diagnostic criteria of refractory ascites andhepatorenal syndrome in cirrhosis. HEPATOLOGY 1996;23:164-176.

5. Iwatsuki S, Popovtzer MM, Corman JL, Ishikawa M, Putnam CW, KatzFH, Starzl TE. Recovery from hepatorenal syndrome after orthotopicliver transplantation. N Engl J Med 1973;289:1155-1159.

6. Gonwa TA, Morris CA, Goldstein RM, Husberg BS, Klintmalm GB.Long-termsurvival and renal function following liver transplantation inpatients with and without hepatorenal syndrome—experience in 300patients. Transplantation 1991;51:428-430.

7. Brown RS, Lombardero M, Lake JR. Outcome of patients with renalinsufficiency undergoing liver or liver-kidney transplantation. Trans-plantation 1996;62:1788-1793.

8. Jeyarajah DR, Gonwa TA, McBride M, Testa G, Abbasoglu O, HusbergBS, LevyMF, et al. Hepatorenal syndrome: combined liver kidney trans-plants versus isolated liver transplant. Transplantation 1997;64:1760-1765.

9. Angeli P, Volpin R, Gerunda G, Craighero R, Merenda R, Bottaro S,Amodio P, et al. Reversal of type 1 hepatorenal syndrome with theadministration of midodrine and octreotide. HEPATOLOGY 1999;29:1690-1697.

10. Gulberg V, Bilzer M, Gerbes AL. Long-term therapy and retreatment ofhepatorenal syndrome type 1 with ornipressin and dopamine. HEPATOL-OGY 1999;30:870-875.

11. Guevara M, Gines P, Fernandez-Esparrach G, Sort P, Salmeron JM, JimenezW, Arroyo V, Rodes J. Reversibility of hepatorenal syndromebyprolonged administration of ornipressin and plasma volume expansion.HEPATOLOGY 1998;27:35-41.

12. Brensing KA, Textor J, Perz J, Schiedermaier P, Raab P, Strunk H, KlehrHU, et al. Long term outcome after transjugular intrahepatic portosys-temic stent-shunt in non-transplant cirrhotics with hepatorenal syn-drome: a phase II study. Gut 2000;47:288-295.

13. Cardenas A, Uriz J, Gines P, Arroyo V. Hepatorenal syndrome. Livertransplantation 2000;6(suppl 1):S63-S71.

14. BatallerR, Sort P, Gines P, ArroyoV. Hepatorenal syndrome: definition,pathophysiology, clinical features and management. Kidney Int 1998;53(suppl 66):S47-S53.

15. BernardiM, Fornale L, Di Marco C, Trevisani F, Baraldini M, GasbarriniA, De Collibus C, et al. Hyperdynamiccirculationof advancedcirrhosis:a re-appraisal based on posture-induced changes in hemodynamics.

J Hepatol 1995;22:309-318.16. Groszmann, RJ. Hyperdynamic circulation of liver disease 40 years

later: pathophysiology and clinical consequences. HEPATOLOGY 1994;20:1359-1363.

17. Albillos A, Colombato LA, Groszmann RJ. Vasodilatation and sodiumretention in prehepatic portal hypertension. Gastroenterology 1992;102:931-935.

18. Schrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen JH, Rodes J.Peripheral arterial vasodilation hypothesis: a proposal for the initiation




of renal sodium and water retention in cirrhosis. HEPATOLOGY 1988;8:1151-1157.

19. SteinJ. Regulation of the renal circulation. Kidney Int 1990;38:571-576.20. Maroto A, Gines P, Arroyo V, Gines A, Salo J, Claria J, Jimenez W, et al.

Brachial and femoral artery blood flow in cirrhosis: relationship to kid-ney dysfunction. HEPATOLOGY 1993;17:788-793.

21. Moore K. Hepatorenal syndrome. Clin Sci 1997;92:433-443.22. Ring-Larsen H. Renal blood flow in relation to systemic and portal

hemodynamics and liver function.Scand J ClinLab Invest 1977;37:635-642.

23. Dagher L, Patch D, Marley R, Moore K, Burrough A. Review article:

pharmacological treatment of hepatorenal syndrome in cirrhotic pa-tients. Aliment Pharmacol Ther 2000;14:515-521.24. Uchihara M, Izumi N, Sato C, Marumo F. Clinical significance of ele-

vated plasma endothelin concentration in patients with cirrhosis. HEPA-TOLOGY 1992;16:95-99.

25. Moore K, Wendon J, Frazer M, Karani J, Williams R, Badr K. Plasmaendothelin immunoreactivity in liver disease and the hepatorenal syn-drome. N Engl J Med 1992;327:1774-1778.

26. Huber M, Kastner S, Scholmerich J, Gerok W, Keppler D. Analysis of cysteinyl leukotrienes in human urine: enhanced excretion in patientswith liver cirrhosis and hepatorenal syndrome. Eur J Clin Invest 1989;19:53-60.

27. Uemura M, Buchholz U, Kojima H, Keppler A, Hafkemeyer P, Fukui H,Tsujii T, et al. Cysteinyl leukotrienes in the urine of patients with liverdiseases. HEPATOLOGY 1994;20:804-812.

28. Morrow JD, Moore KP, Awad JA, Ravenscraft MD, Marini G, Badr K, Williams R, et al. Marked overproduction of non-cyclo-oxygenase de-

rived prostanoids (F2-isoprostanes) in the hepatorenal syndrome. JLipid Mediators 1993;6:417-420.

29. Salo J, Fernandez-Esparrach G, Gines P, Gines A, Guevara M, Sort P, Jimenez W, et al. Urinary endothelin like immunoreactivity in patientswith cirrhosis. J Hepatol 1997;27:810-816.

30. Guevara M, Gines P, Bandi JC, Gilabert R, Sort P, Jimenez W, Garcia-Pagan JC, et al. Transjugular intrahepatic portosystemic shunt in hepa-torenal syndrome: effect on renal function and vasoactive systems.HEPATOLOGY 1998;28:416-422.

31. Campbell V, Greig PD, Cranford J, Langer B, Silverman M, Blendis LM.A comparison of acute reversible pre- and post-sinusoidal portal hyper-tension on salt and water retention in the dog. HEPATOLOGY 1982;2:54-58.

32. Jalan R, Forrest EH, Redhead DN, Dillon JF, Hayes PC. Reduction inrenal blood flow following acute increase in the portal pressure: evi-dence for the existence of a hepatorenal reflex in man? Gut 1997;40:

664-670.33. Lebrec D, Bataille C, Bercoff E, Valla D. Hemodynamic changes in pa-tients with portal venous obstruction. HEPATOLOGY 1983;3:550-553.

34. Rayner BL,Robson SC,Kirsch RE,VoigtM. Renalfunction, sodiumandwater homeostasis in patients with idiopathic extrahepatic portal veinthrombosis compared with normal healthy controls. S Afr Med J 2001;91:61-65.

35. Lang F, Tschernko E, Schulze E, Ottl I, Ritter M, Valkl H, et al. Hepa-torenal reflex regulating kidney function. HEPATOLOGY 1991;14:590-594.

36. Kostreva D, Castaner A, Kampine J. Reflex effects of hepatic barorecep-tors on renal andcardiac sympathetic nerve activity.Am J Physiol 1980;238:R390-R394.

37. Di Bona GF. Renal nerve activity in hepatorenal syndrome. Kidney Int1984;25:841-853.

38. KoepkeJP, Jones S, Di Bona GF.Renal nervesmediate blunted natriure-sis to atrial natriuretic peptide in cirrhotic rats. Am J Physiol 1987;252:

R1019-R1023.39. Solis-Herruzo JA, Duran A, Favela G, Castellano G, Madrid JL, Munoz-

Yague MT, Morillas JD, et al. Effects of lumbar sympathetic block onkidney function in cirrhotic patients with hepatorenal syndrome.

J Hepatol 1987;5:167-173.40. Epstein M. Renal prostaglandins and the control of renal function in

liver disease. Am J Med 1986;80:46-61.41. Guarner C, Colina I, Guarner F, Corzo J, Prieto J, Vilardi F. Renal

prostaglandins in cirrhosis of the liver. Clin Sci 1986;70:477-484.42. Laffi G, La Villa G, Pinzani M, Ciabattoni G, Patrignani P, Mannelli M,

Cominelli F, et al. Altered renal and platelet arachidonic acid metabo-lism in cirrhosis. Gastroenterology 1986;90:274-282.

43. Rimola A, Gines P, Arroyo V, Camps J, Peres-Ayuso RM, Quintero E, etal. Urinary excretion of 6-keto-prostaglandin F1alpha, thromboxane B2

andprostaglandin E2 in cirrhosiswith ascites:relationshipto functionalrenal failure (hepatorenal syndrome). J Hepatol 1986;3:111-117.

44. MooreK, Ward PS,Taylor GW, WilliamsR. Systemicand renal produc-tion of thromboxane A2 and prostacyclin in decompensated liver dis-ease and hepatorenal syndrome. Gastroenterology 1991;100:1069-1077.

45. Govindarajan S, Nast CC, Smith WL, Koyle MA, Daskalopoulos G,Zipser RD. Immunohistochemical distribution of renal prostaglandinendoperoxidase synthase and prostacyclin synthase: diminshed en-doperoxidasesynthasein the hepatorenal syndrome.HEPATOLOGY 1987;7:654-659.

46. Boyer T, ZiaP, Reynolds T. Effect of indomethacin andprostaglandin A,on renal function and plasma renin activity in alcoholic liver disease.Gastroenterology 1979;77:215-222.

47. Bomzon A, Blendis LM. The nitric oxide hypothesis and the hyperdy-namic circulation in cirrhosis. HEPATOLOGY 1994;20:1343-1350.

48. Guarner C, Soriano G, Tomas A, Bulbena O, Novella MT, Balanzo J,Vilardell F, et al. Increased serum nitrite and nitrate levels in patientswith cirrhosis: relationship to endotoxemia. HEPATOLOGY 1993;18:1139-1143.

49. Raij L, BaylisC. Glomerular actions of nitricoxide. Kidney Int1995;4820-32.

50. Bech JN, Nielsen CB, Pedersen EB. Effects of systemic nitric oxide syn-thesis inhibition on renal plasma flow, glomerular filtration rate, uri-nary sodium excretion, and vasoactive hormones in healthy humans.Am J Physiol 1996;270:F845-F851.

51. Ros J, Claria J, Jimenez W, Bosch-Marce M, Angeli P, Arroyo V, RiveraF, et al. Role of nitric oxide and prostacyclin in the control of renal

perfusion in experimental cirrhosis. HEPATOLOGY 1995;22:915-920.52. Arucha NM, Garcia-Estan J, Ramirez A, Perez MC, Quesada T, Romero JC. Renal effects of nitric oxide synthesis inhibition in cirrhotic rats.Am J Physiol 1994;267: R1454-R1460.

53. ClariaJ, Jimenez W,Ros J,Asbert M,Castro A,ArroyoV, RiveraF, etal.Pathogenesisof arterialhypotensionin cirrhoticrats withascites: roleofendogenous nitric oxide. HEPATOLOGY 1992;15:343-349.

54. Criado M, Flores O, Ortiz MC, Hidalgo F, Rodriguez-Lopez AM, ElenoN, Atucha NM, et al. Elevated glomerular and blood mononuclear lym-phocye nitric oxide production in rats with chronic bile duct ligation:role of inducible nitric oxide sythase activation. HEPATOLOGY 1997;26:268-276.

55. Campillo B, Bories PN, Benvenuti C, Dupeyon C. Serum and urinarynitrate levels in liver cirrhosis: endotoxemia, renal function and hyper-dynamic circulation. J Hepatol 1996;24:707-714.

56. Martin PY, Gines P, Schrier RW. Nitric oxide as a mediator of hemody-namic abnormalities and sodium and water retention in cirrhosis.

N Engl J Med 1998;339:533-541.57. Tajiri K, Miyakawa H, Izumi N, Marumo F, Sato C. Systemic hypoten-

sion and diuresis by L-arginine in cirrhotic patients with ascites: role ofnitric oxide. HEPATOLOGY 1995;22:1430-1435.

58. Gulberg V, Moller S, HenriksenAL, GerbesAL. Increasedrenalproduc-tion of C-type natriuretic peptide (CNP) in patients with cirrhosis andfunctional renal failure. Gut 2000;47:852-857.

59. Angeli P, Jimenez W, Arroyo V, Mackenzie HS, Zhang PL, Claria J,Rivera F, et al. Renal effects of natriuretic peptide receptor blockade incirrhotic rats with ascites. HEPATOLOGY 1994;20:948-954.

60. Holt S, Goodier D, Marley R, Patch D, Burroughs A, Fernando B, HarryD, Moore K. Improvement in renal function in hepatorenal syndromewith N-acetylcysteine. Lancet 1999;353:294-295.

61. Rasool A, Palevsky PM. Treatment of edematous disorders with diuret-ics. Am J Med Sci 2000;319:25-37.

62. Papper S. The hepatorenal syndrome. In: Epstein M, ed. The Kidney inLiver Disease. 2nd Edition. New York: Elsevier Biomedical 1983:87-

106.63. Spahr L, Villeneuve JP, Tran HK, Pomier-Layrargues G. Furosemide-

induced natriuresis as a test to identify cirrhotic patients withrefractoryascites. HEPATOLOGY 2001;33:28-31.

64. Gines P, ArroyoV, QuinteroE, PlanasR, BoryF, Cabrera J, RimolaA, etal. Comparison of paracentesis and diuretics in the treatment of cirrhot-ics with tense ascites. Results of a randomized study. Gastroenterology1987;93:234-241.

65. Fernandez-Esparrach G, Guevara M, Sort P, Pardo A, Jimenez W, GinesP, Planas R, et al. Diureticrequirementsafter therapeutic paracentesisinnon-azotemic patients with cirrhosis. A randomized double-blind trialof spironolactone versus placebo. J Hepatol 1997;26:614-620.

66. Gentilini P, Casini-Raggi V, Di Fiore G, Romanelli RG, Buzzelli G,Pinzani M, La Villa G, Laffi G. Albumin improves the response to di-




uretics in patients with cirrhosis and ascites. Results of a randomizedcontrol trial. J Hepatol 1999;30:639-645.

67. Blendis L, WongF. Intravenous albumin with diuretics. Protean lessonsto be learnt? J Hepatol 1999;30:727-730.

68. Loon NR, Wilcox CS, Unwin RJ. Mechanism of impaired response tofurosemide during prolonged therapy. J Clin Invest 1989;83:113-126.

69. Gregory PB, Broekelschen PH, Hill MD, Lipton AB, Knauer CM, EggerM, Miller R. Complications of diuresis in the alcoholic patient withascites: a controlled trial. Gastroenterology 1977;73:534-538.

70. Pockros PJ, Reynolds TB. Rapid diuresis in patients with ascites fromchronic liver disease: the importance of peripheral edema. Gastroenter-

ology 1986;90:1827-1833.71. Gines P, Arroyo V. Is there still a need for albumin infusions to treatpatients with liver disease? Gut 2000;46:588-590.

72. Brater DC. Diuretic therapy. N Engl J Med 1998;339:387-395.73. Ruiz-del-Arbol L, Monescillo A, Jimenez W, Garcia-Plaza A, Arroyo V,

Rodes J. Paracentesis-induced circulatory dysfunction: mechanism andthe effect on hepatic hemodynamics in cirrhosis. Gastroenterology1997;113:579-586.

74. Salo J, Gines A, Gines P, Piera C, Jimenez W, Guevara M, Fernandez-Esparrach G, et al. Effect of therapeutic paracentesis on plasma volumeand transvascular escape rate of albumin in patients with cirrhosis.

J Hepatol 1997;27:645-653.75. Afessa B, Kublis PS. Upper gastrointestinal bleeding in patients with

hepatic cirrhosis: clinicalcourse and mortality prediction. Am J Gastro-enterology 2000;95:484-489.

76. Paterson RL, Webster NR. Sepsis and the systemic inflammatory re-sponse syndrome. J R Coll Surg Edinb 2000;45:178-182.

77. Del Olmo JA, Pena A, Serra MA, Wassel AH, Benages A, Rodrigo JM.Predictors of morbidity and mortality after the first episode of uppergastrointestinal bleeding in liver cirrhosis. J Hepatol 2000;32:19-24.

78. Rimola A, Garcia-Tsao G, Navasa M, Piddock LJ, Planas R, Bernard B,Inadomi JM. Diagnosis, treatment and prophylaxis of spontaneous bac-terial peritonitis: a consensus document. International Ascites Club.

J Hepatol 2000;32:142-153.79. Bernard B, Grange JD, Khac EN, Amiot X, Opolon P, Poynard T. Anti-

biotic prophylaxis for the prevention of bacterial infections in cirrhoticpatients with gastrointestinal bleeding: a meta-analysis. HEPATOLOGY

1999;29:1655-1661.80. Pauwels A, Mostefa-Kara N, Debenes B, Degoutte E, Florent C, Levy

VG. Antimicrobial prophylaxis after gastrointestinal hemorrhage forcirrhotic patients with a high risk of infection. HEPATOLOGY 1996;24:802-806.

81. Follo A, Llovet JM, Navasa M, Planas R, Forns X, Francitorra A, RimolaA, et al. Renal impairment after spontaneous bacterial peritonitis in

cirrhosis: incidence, clinical course, predictive factors and prognosis.HEPATOLOGY 1994;20:1495-1501.

82. Navasa M, Rodes J. Management of ascites in the patient with portalhypertension with emphasis on spontaneous bacterial peritonitis. Se-min Gastrointest Dis 1997;8:200-209.

83. Navasa M, Follo A, Filella X, Jimenez W, Francitorra A, Planas R,Rimola A, et al. Tumor necrosis factor and interleukin-6 in spontaneousbacterial peritonitis in cirrhosis. Relationship with the development of renal impairment and mortality. HEPATOLOGY 1998;27:1227-1232.

84. Mastrangelo D, Frossard JL, Hadengue A, Pastor CM. Sepsis decreasesthe spontaneous and agonist-induced contractile activities in the ratportal vein. J Hepatol 2000;33:933-940.

85. Sort P, Navasa M, Arroyo V, Aldeguer X, Planas R, Ruiz-del-Arbol,Castells L, et al. Effect of intravenous albumin on renal impairment andmortality in patients with cirrhosis and spontaneous bacterial peritoni-tis. N Engl J Med 1999;341:403-409.

86. Jimenez W, Ros J, Morales-RuizM, NavasaM, Sole M, Colmenero J, Sort

P, et al. Nitric oxide production and inducible nitric oxide synthaseexpression in peritoneal macrophages of cirrhoticpatients. HEPATOLOGY

1999;30:670-676.87. Rasaratnam B, Kaye D, Chin-Dusting J, Gennings G, Dudley F. Effect of

selective intestinal decontimation on the peripheral arterial vasodilata-tion in cirrhosis [Abstract]. HEPATOLOGY 2000;32(part 2 of 2):310A.

88. Chin-Dusting J, Rasaratnam B, Gennings G, Dudley F. Effect of fluoro-quinolone on the enhanced nitric oxide induced peripheral arterial va-sodilatation seen in cirrhosis. Ann Int Med 1997;127:985-988.

89. Dixon JM, Armastrong CP, Duffey, Davies GC. Factors affecting mor-bidity and mortality after surgery for obstructive jaundice: a review of 373 patients. Gut 1983;24:845-852.

90. Bomzon A, Rosenberg M, Gali D, Binah O, Mordechovitz D, Better OS,Greig PD, Blendis LM. Systemic hypotension and decreased pressor

response in dogs with chronic bile duct ligation. HEPATOLOGY 1986;6:595-600.

91. Lee SS, Girod C, Braillon A, Hadengue A, Lebrec D. Hemodynamiccharacterization of chronic bile duct-ligated rats: effect of pentobarbitalsodium. Am J Physiol 1986;251:G176-G180.

92. Thompson JN, Edwards WH, Winearls CG, Blenkharn JI, Benjamin IS,BlumgartLH. Renal impairment followingbiliary tract surgery. Br J Surg1987;74:843-847.

93. Bomzon A, Green J, Better OS. Jaundice and the kidney. In: Epstein M,ed. The Kidney in Liver Disease. Philadelphia: Hanley & Belfast 1996;423-446.

94. Kramer HJ, Scharting K, Backer A. Impaired renal function in obstruc-tive jaundice. Clin Sci & Mol Med 1995;88:39-45.95. Holt S, Marley R, Fernando B, Harry D, Anand R, Goodier D, Moore K.

Acute cholestasis-induced renal failure: effects of antioxidants and li-gands for the thromboxane A2 receptor. Kidney Int 1999;55:271-277.

96. Akriviadis E, Botla R, Briggs W, Han S, Reynolds T, Shakil O. Pentoxi-fylline improves short-term survival in severe acute alcoholic hepatitis:a double-blind, placebo-controlled trial. Gastroenterology 2000;119:1637-1648.

97. Maddrey WC, Boitnott JK, Bedline MS, Weber FLJ, Mezey E, Whire RI.Corticosteroid therapy of alcoholic hepatitis. Gastroenterology 1978;75:193-199.

98. Papper S, Belsky JL, Bleifer KH. Renal failure in Laennecis cirrhosis ofthe liver: (1) Description of clinical and laboratory features. Ann IntMed 1959;51:759-773.

99. Maroto A, Gines A, Salo J, Claria J, Gines P, Anibarro L, Jimenez W, etal. Diagnosis of functional kidney failure of cirrhosis with Doppler

sonography: prognostic value of resistive index. HEPATOLOGY 1994;20:839-844.100. Platt JF, Ellis JH,RubinJM, Merion RM, Lucey MR. Renal duplexdopp-

ler ultrasonography: a non invasivepredictor of kidney dysfunction andhepatorenal failure in liver disease. HEPATOLOGY 1994;20:362-369.

101. Kamath PS, Wiesner RH, Malinchoc M, Kremers W, Therneau TM,Kosberg C, D’AmicoG, et al. A modelto predict survivalin patientswithend-stage liver disease. HEPATOLOGY 2001;33:464-470.

102. Lafayette RA, Pare G, Schmid CH, King AJ, Rohrer RJ, Nasraway SA.Pre-transplant renal dysfunction predictspoorer outcome in liver trans-plantation. Clin Nephrol 1997;48:159-164.

103. Lenz K, Hortnagl H, Druml W, Grimm G, Laggner A, Schneeweisz B,Kleinberger G. Beneficial effects of 8-ornithin vasopressin on renal dys-function in decompensated cirrhosis. Gut 1989;30:90-96.

104. Lenz K, Hortnagl H, Druml W, Reither H, Schmid R, Schneeweisz B,Laggner A, et al. Ornipressin in the treatment of functional renal failurein decompensated liver cirrhosis, effects on renal hemodynamics and

atrial natriuretic factor. Gastroenterology 1991;101:1060-1067.105. Hadengue A, Gadano A, Moreau R, Giostra E, Durand F, Vella D, Er-

linger S, Lebrec D. Beneficial effects of the 2-day administration ofterlipressin in patients with cirrhosis and hepatorenal syndrome.

J Hepatol 1998;29:565-570.106. Wong F, Massie D, Hsu P, Dudley F. The renal response to a saline load

in well compensated alcoholiccirrhosis. HEPATOLOGY 1994;20:873-881107. Wensing G, Sabra R, Branch RA. Renal and systemic hemodynamics in

experimental cirrhosis in rats: relation to hepatic function. HEPATOLOGY

1990;12:13-19.108. Wensing G, Sabra R, Branch RA. The onset of sodium retention in

experimental cirrhosis in rats is related to a critical threshold of liverfunction. HEPATOLOGY 1990;11:779-786.

109. Jalan R, Hayes PC. Sodium handling in patients with well compensatedcirrhosis is dependent on the severity of liver disease and portal pres-sure. Gut 2000;46:527-533.

110. Uriz J, Gines P, Cardenas A, Sort P, Jimenez W, SalmeronJM, Bataller R,

et al. Terlipressin plus albumin infusion: an effective and safetherapy ofhepatorenal syndrome. J HEPATOLOGY 2000;33:43-48.

111. Lancestremere RG, Klinger EL Jr, Frisch E, Papper S. Simultaneousdeterminations of cardiac output and renal function in patients withLaennec’s cirrhosis during the administration of the pressor amine,metaraminol. J Lab Clin Med 1963;61:820-825.

112. Badalamenti S, Borroni G, Lorenzano E, Incerti P, Salerno F. Renaleffects in cirrhotic patients with avid sodium retention of atrial natri-uretic factor injection during norepinephrine infusion. HEPATOLOGY

1992;15:824-829.113. Angeli P, Volpin R, Piovan D, Bortoluzzi A, Craighero R, Bottaro S,

Finucci GF, et al. Acute effects of the oral administration of midodrine,an -adrenergic agonist, on renal hemodynamics and renal function incirrhotic patients with ascites. HEPATOLOGY 1998;28:937-943.




114. Arroyo V, Jimenez W. Complications of cirrhosis. II. Renal and circu-latory dysfunction. Lights and shadows in an important clinical prob-lem. J Hepatol 2000;32(suppl 1):157-170.

115. Soper CP, Latif AB, Bending MR. Amelioration of hepatorenalsyndromewith selective endothelin-A antagonist [Letter]. Lancet 1996;347:1842-1843.

116. Holt S, Marley R, Goodier D, Harry D, Fernando B, Moore K. Oxidantstress and renal dysfunction in cholestasis. Gut 1998;43:153.

117. Wilkinson SP, Weston MJ, Parsons V, Williams R. Dialysis in the treat-ment of renal failure in liver disease. Clin Nephrol 1977;8:287-292.

118. Perez GO, Oster JR. A critical review of the role of dialysis in the treat-ment of liver disease. In: Epstein M, ed. The Kidney in Liver Disease.First Edition. New York: Elsevier 1978;325-335.

119. Mitzner SR, Stange J, Klammt S, Risler T, Erley CM, Bader BD, BergerED, et al. Improvement of hepatorenal syndrome with extracorporealalbumin dialysis MARS: results of a prospective randomized, controlledclinical trial. Liver Transpl 2000;6:277-286.

120. Awad SS, Sawada S, Soldes OS, Ricj PB, Klein R, Alarcon WH, BartlettRH. Can the clearance of tumor necrosis factor and interleukin 6 beenhanced using an albumin dialysate hemodiafiltration system? ASAIO

J 1999;45:47-49.121. Rahman TM, Hodgson HJF. Liver support systems in acute hepatic

failure. Aliment Pharmacol Ther 1999;13:1255-1272.122. Brensing KA, Textor J, Strunk H, Klehr HU, Schild H, Saverbruch T, et

al. Transjugular intrahepatic portosystemic stent-shunt for hepatorenalsyndrome. Lancet 1997;349:697-698.

123. Lake JR, Ring EJ, LaBerge JM, Gordon R, Roberts J, Ascher N. Trans- jugular intrahepatic portasystemic stent shunts in patients with renalinsufficiency. Transplant Proc 1993;25:1766-1767.

124. Spahr L, Fenyves D, Nguyen VV, Roy L, Legault L, Dufresne MP,Pomier-Layrarques G, et al. Improvement of hepatorenal syndrome bytransjugular intrahepatic portosystemic shunt. Am J Gastroenterology1995;90:1169-1171.

125. Wong F, Sniderman K, Liu P, Allidina Y, Sherman M, Blendis LM. Theeffects of transjugular intrahepatic portasystemicshunt on systemicandrenal hemodynamics and sodium homeostasis in cirrhotic patients withrefractory ascites. Ann Int Med 1995;122:816-822.

126. Azoulay D, Casting D, Dennison A, Martino W, Eyraud D, Bismuth H.Transjugular intrahepatic portosystemic shunt worsens the hyperdy-namic circulation state of the cirrhotic: preliminary report of a prospec-tive study. HEPATOLOGY 1994;19:129-132.

127. Lebrec D, Giuily N, Hadenque A, Vilgrain V, Moreau R, Poynard T,Gadano A, et al. Transjugular intrahepatic portosystemic shunt: com-parison with paracentesis in patients with cirrhosis and refractory as-cites: a randomized trial. J Hepatol 1996;25:135-144.

128. Rossle M, Ochs A, Gulberg V, Siegerstetter V, Holl J, Deibert P, Ol-schewski M, et al. A comparison of paracentesis and transjugular intra-hepatic portosystemic shunting in patients with ascites. N Engl J Med2000;342;1701-1707.

129. Boyer TD. Is transjugular intrahepatic portosystemic shunt a panaceafor the complications of portal hypertension. HEPATOLOGY 1998;28:590-592.


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