Gut Supplement, 1991, S 12-S 17

Pathogenesis of ascites and hepatorenal syndrome

S P Wilkinson, K P Moore, V Arroyo

Ascites is one of the most common complicationsof cirrhosis and has a one year mortality of up to50%. For fluid to accumulate in any clinicalsituation the amount of sodium ingested mustexceed that excreted by the kidneys and thevirtual absence of sodium from the urine ofascitic patients was first documented by Farns-worth and Krakusin in 1948.' Five years laterChart and Shipley showed such patients to havean excess of a sodium retaining hormone in theirurine (later identified as aldosterone).2 Fourdecades after these discoveries the inter-relation-ship between renal function, hormonal changesand ascites formation remains controversial. Atthe other extreme of functional renal changes upto 85% ofpatients dying with cirrhosis have renalfailure and, where there is no apparent causeother than the liver disease, is termed 'hepato-renal syndrome.' In 1863 Flint noted that pro-teinuria was uncommon and kidney morphologyoften normal, but some patients showed a varietyof renal parenchymal changes.3 Hecker andSherlock confirmed the absence of proteinuriaand normal histology in many patients andreported very low urine sodium concentrations -findings of a prerenal type of uraemia.

Gloucestershire RoyalHospital, GloucesterSP Wilkinson

Department of ClinicalPharmacology,Hammersmith Hospital,LondonKP Moore

Hospital Clinico-Y-Provincial, Barcelona,SpainV ArroyoCorrespondence to:SP Wilkinson.

AscitesRenal function varies enormously in patientswith ascites, values for glomerular filtration rateand renal plasma flow showing a complete spec-trum from twice normal down to those foundwith significant renal impairment. When renalfailure is present, the markedly reduced filtra-tion of sodium may be sufficient alone to explainthe fluid retention, but for those with wellpreserved renal function other factors actingon the renal tubules must be implicated. Itis possible to determine the nephron site forabnormal sodium retention under conditionsof a maximum water diuresis. Although theincreased sodium reabsorption has been shownto occur throughout the nephron the greatestdifference between patients with and withoutsodium retention is in the distal segment (distalconvulted tubule or collecting tubule) (Fig 1).5Hormonal and neural factors affecting thispart of the nephron include aldosterone, atrialnatriuretic hormone and the sympatheticnervous system.

RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEMThe concept has developed that cirrhosis is a

high renin high aldosterone state. This has not,however, been confirmed in many studies inwhich only 35-50% of patients accumulatingascites have increased values (Fig 2)5-8 Further-more, before there is clinical evidence forfluid retention the renin-angiotensin-aldosteronesystem has been reported to be suppressed.5 6

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Figure 1: Comparison ofthe role ofthe different nephronsegments in the pathogenesis ofabnormal sodium retention incirrhosis. These studies were carried out during a water diuresisand all patients diluted their urine to <75 mosmollkg. FromWilkinson et al (ref228). Reprinted with permissionfromClinical Science. Copyright @ 1979 The BiochemicalSociety, London.

In view of the normal values for aldosterone ina number of patients actively retaining sodiumits pathogenic importance has been questioned.Evidence in favour of a dominant role for aldo-sterone include: (a) renal sodium excretion isclosely related to plasma concentration and therenal excretion of aldosterone whatever the stateof sodium balance5; (b) blood volume, andexpression of renal sodium retention, correlateswell with the plasma aldosterone concentration9;(c) the aldosterone antagonist spironolactone oradrenalectomy will almost invariably reverse thesodium retention, provided renal failure is notalready present'° "; (d) during P-adrenergicblockade it was observed that the renal sodiumexcretion increased or decreased exactly as pre-dicted by the changes in aldosterone.'2 Thus ifaldosterone is of major importance one mustimplicate an increase in renal tubular sensitivityto this hormone. It is of further interest that theabnormal aldosterone/sodium excretion relation-ship is 'shifted to the left' compared with controlsubjects and this becomes more marked withadvanced disease.9

ATRIAL NATRIURETIC PEPTIDEIt is now established that a 28 amino acid peptide(atrial natriuretic peptide) synthesised by theatrial wall has a major role in the regulation ofsodium excretion. It is released in response tocentral volume expansion. Atrial natriuretic pep-tide concentrations in cirrhosis are variable, butmost studies have shown plasma values to beincreased or normal when ascites is present."' 14Furthermore, in contrast with aldosterone, thereappears to be a reduced renal sensitivity to its

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Pathogenesis ofascites and hepatorenalsyndrome

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Wilkinson et al WFigure 2: Plasma renin activity and aldosteronein patients with cirrhosis and without clinical evretention. Stippled areas indicate the normal ranfrom Wilkinson et al[216, 223, 2281(1977-79

natriuretic effects.'5 16 Whether thiinsensitivity or down regulation ofremains to be determined.

SYMPATHETIC ACTIVITYIncreased renal sympathetic activitysodium reabsorption. Plasma noradrecentrations (an indirect index of s3activity) are raised in cirrhotics with aare inversely related to sodium excretirecent studies in cirrhotic animal mshown marked amelioration of sodiunwhen the renal sympathetic systemvated. 1"

WATER RETENTIONThe kidney retains water secondary tcorder to maintain osmotic equilibriascites, however, excess water isretained resulting in hyponatraerstudies point to increased antidiuretilevels as the dominant pathogenicRecent studies using a thromboxaneinhibitor have suggested that thismay also affect renal water excretion irwith ascites.20

Synthesis of available data relating tpathogenesis of ascitesAscitic fluid is derived from hesplanchnic lymph, the formation

* increases consequent to portal hypertension, andaccentuated by hypoalbuminaemia. Tradition-ally renal sodium and water retention is thoughtof as a homeostatic mechanism to restore'effective' extracellular fluid volume and blood

* volumes (the components available to the intra-thoracic volume receptors). The initial deficitswere said to arise as a result of loss of extra-cellular fluid into the peritoneal compartment asascites, and from sequestration of blood in thesplanchnic circulation secondary to portal hyper-

s tension. It is now realised, however, that sodium: retention precedes ascites formation.2' This con-

cept has therefore been modified with peripheralvasodilatation, characteristic of many patientswith cirrhosis, as the initiating factor causing alow effective arterial blood volume.22 The site ofvasodilatation is likely to be the splanchniccirculation and/or that supplying the skin andmuscles. Although this 'underfill' concept mayindeed be valid for the one-third of patientswith a stimulated renin-angiotensin-aldosteronesystem it is incompatible with the findings ofnormal values for those with normal plasmaaldosterone, and with increased plasma atrialnatriuretic peptide. In order to explain themechanisms involved in the other patients anumber of findings must be taken into account.These include suppression of the renin-angio-

ernze et al tensin system before clinical evidence of fluidconcentration retention, and possible altered renal tubular,idence offluid sensitivity to aldosterone and atrial natriureticrge. Modified peptide.)- Consideration of patients before ascites has

developed may help interpretation. Whatever itsexplanation the aldosterone/sodium excretion

is is true relationship is abnormal at this stage of thef receptors disease and sodium excretion appears to be

related to aldosterone. Presumably, as theabnormality develops the previously normalaldosterone levels result in some degree offluid retention which account for the expanded

promotes plasma volume observed at this stage of thenaline con- disease. If the fluid remains within the 'effective'ympathetic compartments this could explain the suppressioniscites, and of the renin-angiotensin-aldosterone systemion. 17 More which would result in a return to sodium balancetodels have at a higher concentration of total body sodium.n retention The process would be accentuated by reducedi is dener- renal sensitivity to atrial natriuretic hormone.

An alternative explanation to the traditionalconcept for ascites formation is 'the overflowtheory.'23 Renal sodium and water retention aresaid to be the primary abnormalities with the

sodium in expanded extracellular fluid localising to theium. With peritoneal cavity when factors such as portalsometimes hypertension and reduced plasma oncoticnia. Most pressure favour ascites formation. For theic hormone 35% of patients in whom the renin-angiotensin-- factors.'9 aldosterone system is not stimulated andk2 synthase natriuretic hormone concentrations are in-compound creased the findings fit well with this concept.n cirrhotics There is evidence that splanchnic haemo-

dynamics may be fundamentally different forthese two groups of ascitic patients. In one studypatients were divided into those readily respond-

o the ing to diuretics without complication and thosewith resistant ascites is which diuretics readily

patic and precipitated renal impairment.24 Although theof which components of the renin-angiotensin-aldo-

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Wilkinson, Moore, Arroyo

sterone system were not specifically determinedone might predict that the diuretic responsivegroup are more likely to have ascites forming asan overflow mechanism than those in whom theeffective extracellular fluid was already depleted(diuretics in the latter group presumably result-ing in further depletion with renal impairmentand thus diuretic resistance). Those comprisingthe latter group had significantly less spontan-eous portasystemic shunting and a tendency toa higher postsinusoidal vascular resistance. Theauthors concluded that collateral vascular resist-ance must also be higher. Taken together thesechanges would encourage intrahepatic lymphformation with consequent accumulation ofascites. Thus, ascites would be developing asa primary abnormality independent of the effec-tive extracellular fluid volume which eventuallyfalls.

Hepatorenal syndromeThe aetiology of hepatorenal syndrome is stillincompletely understood. To date most empha-sis has centred on the hypothesis that it is causedby severe renal arterial and arteriolar vasocon-striction causing reduced renal blood flow andthence renal failure. This has been based onmany studies which have shown reduced renalblood flow, but was given extra impetus by thoseof Epstein et al in which renal angiographyshowed marked vasoconstriction of the arterialvasculature.2' Studies by Ring-Larsen andothers, however, have shown that many patientswith ascites but relatively intact renal functionhave renal blood flows comparable with thoseobserved in many subjects with hepatorenalsyndrome.26 This suggests that other factorsmodulating glomerular filtration rate must beimportant.2728 This is likely to involve mesangialcells which have similar properties to smoothmuscle. These cells invaginate the glomerularcapillary tuft and contract in response to manymediators. Mesangial cells appear to dynamic-ally regulate the surface area available for ultra-filtration, and thus the ultrafiltration co-efficient.2526Renal blood flow is dependent on renal

vascular resistance and renal perfusion pressure(mean arterial pressure minus renal venouspressure). Many patients with decompensatedliver disease have a moderately low mean arterialpressure, and increased renal venous pressure.Furthermore, liver failure is characterised byincreased sympathetic tone which appears toshift the autoregulatory curve such that renalblood flow is more dependent on renal perfusionpressure. Thus, even patients with a modestdecrease in renal perfusion pressure may exhibita significant fall in renal blood flow. No studiesconstructing a scattergram of the perfusionpressure/renal blood flow relationship in patientswith liver disease or hepatorenal syndrome haveyet been carried out.

MECHANISMS FOR VASOCONSTRICTIONMost research over the last 10-20 years hasfocused on identifying increased production ofvasoactive mediators of vasoconstriction. Inter-

|* Limulus positiveDE Limulus negative

251

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10'

5.

0]Without renal With renal

failure failureFigure 3: Relationship ofhepatorenal syndrome toendotoxaemia as measured by the limulus assay. FromWilkinson et al (ref220). Reprinted with kind permissionfrom the British Medical Journal. Copyright @ 1976.

estingly, many of these mediators also modulatemesangial cell function, causing contraction ofthis smooth muscle like cell, and may thereforemodulate not only renal blood flow through thearterioles but also through the glomerularcapillary bed.

PERIPHERAL ARTERIAL VASODILATATIONHYPOTHESISThe most recent proposal to explain renal vaso-constriction is the vasodilatation hypothesis ofSchrier et al,22 and suggests that systemic vaso-dilatation is the initiating event. This, in itsextreme form results in a reduction of effectivearterial blood volume with moderate hypoten-sion. The cause of systemic vasodilatation isunknown, but recent studies on the role ofendothelium derived relaxing factor (nitricoxide) in animal models of cirrhosis have sug-gested that this may be an important factor.29Systemic vasodilatation activates homeostaticmechanisms causing rises in plasma renin, aldos-terone, noradrenaline, and vasopressin concen-trations which cause sodium retention and renalvasoconstriction. Procedures which augmentplasma volume, such as head out of waterimmersion or plasma expansion, result in asmall transient increase in renal blood flow andglomerular filtration rate in many subjects, butthis is rapidly offset by redistribution of fluid orenhanced vasodilatation. Fernandez-Seara et alhave reported an interesting study in which theyobserved a decrease in systemic vascular resist-ance, a decrease in renal blood flow, and inpatients with ascites there was an initial increasein femoral blood flow (to twice normal), indica-tive of participation of the extra-splanchnic

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Pathogenesis ofascites and hepatorenal syndrome

system in the vasodilatation.38 On the otherhand, patients with hepatorenal syndromeexhibited femoral blood flow close to normalsubjects suggesting that splanchnic vasodilata-tion was extreme causing intense activation ofthe pressor systems.There is marked activation of the sympatho-

adrenal system in advanced liver disease, andthe degree of activation follows the degree ofdecompensation.3' The kidneys are richly in-nervated by the sympathetic system which,when activated, increase renal vascular resist-ance. Early studies of a-adrenergic blockade byphentolamine infusion produced no improve-ment in renal function, although any beneficialeffect was offset by a fall in mean arterialpressure.32 More recently, a novel approach hasused lumbar sympathetic blockade of the sym-pathetic nerves, which produced an increase inrenal blood flow in all eight subjects studied, butonly five subjects showed an improvement inglomerular filtration rate, and three showed anactual deterioration.33 Thirdly, studies in whichhead out ofwater immersion have followed serialchanges in glomerular filtration rate and plasmanoradrenaline concentrations did not observesuppression of noradrenaline in nine out of 15subjects in whom there was an improvementin glomerular filtration rate.34 Thus, increasedsympathetic activity may be an important factorreducing glomerular filtration rate in some butnot all patients with hepatorenal syndrome.As already discussed the renin-angiotensin

system is activated in decompensated liverdisease.6'8 Increased renin formation may besecondary to renal hypoperfusion or a decreasein effective blood volume. Activation of reninformation increases angiotensin II formationwithin the kidney. Angiotensin II predomin-antly increases efferent arteriolar tone and thusthe filtration fraction. Although this reducesrenal blood flow and increases renal vascularresistance, it maintains glomerular filtrationrate. Thus, in conditions such as hypovoalemiaor shock, it is often regarded as a mechanismprotecting glomerular filtration rather than theconverse. This important principal was demon-strated by Schroeder et al who infused angio-tensin II into patients with cirrhosis.35 This studyobserved that in four of five patients with thelowest renal blood flow there was an actualincrease in glomerular filtration rate despite afurther fall in renal blood flow.

CIRCULATING OR INTRARENAL VASOCONSTRICTOR.ROLE OF ENDOTOXINSAlthough activation of the above homeostaticmechanisms are undoubtedly responsible forsome degree of renal vasoconstriction otherfactors are likely to be important.

Endotoxins are the lipopolysaccharide com-ponents of the cell wall of gram negative bacilli.They are thought to be responsible for many ofthe manifestations of gram negative septicaemiain man, and are known to be vasoconstrictor inthe renal circulation in animals. In advancedliver disease, there appears to be failure of thereticuloendotheliac system to remove endotoxinsabsorbed from the gut, and direct absorption

through portasystemic collaterals into thesystemic circulation. Several studies have showna higher incidence of endotoxaemia in the sys-temic circulation in hepatorenal syndrome36 38(Fig 3). Other toxins such as staphylococcaltoxin may act synergistically with endotoxinsand may account for some of the discrepantresults reported by other groups. Supportiveevidence is also provided by more recent studiesin which daily culture of blood, urine, sputum,ascites, as well as daily nasopharyngeal/vaginalswabs, have shown a higher incidence of bac-terial infection and fungal infection in patientswith fulminant hepatic failure developing hepa-torenal syndrome.39

If endotoxins or indeed other bacterial toxinsare important in the pathogenesis of hepatorenalsyndrome, what is the mechanism? Several linesof investigation have shown that endotoxinsactivate formation of the eicosanoids. This iseither through a direct effect on circulatingmonocytes or tissue resident macrophages.Eicosanoids comprise in part the prostaglandins,thromboxane A2, and the cysteinyl-leukotrienes(LTC4, LTD4, and LTE4). These may be classi-fied into renal vasodilators (PGE2, and prosta-cyclin) and renal vasoconstrictors (TXA2, andLTC4 and LTD4), as well as causing relaxationor contraction of the mesangium respectively.The role of thromboxane A2 is controversial.Some studies have reported increased renal pro-duction while others have suggested that there isnormal or decreased production of thromboxaneA2 as assessed by urinary excretion rate orconcentration of its stable metabolite TXB2(40-43). More recent studies have suggested thatwhile there is increased renal and systemicproduction of thromboxane A2 in hepatorenalsyndrome,"4 this was not significantly greaterthan that in subjects appropriately controlledfor severity of hepatic dysfunction but withrelatively normal renal function. Thus,increased production appears to primarily reflectthe severity of liver disease.The vasodilatory prostaglandins are important

in maintaining renal function in patients withdecompensated liver disease. Renal productionof PGE2 and prostacyclin is increased in patientswith ascites,31 41 43 and several studies have shownthat administration of non-steroidal anti-inflammatory drugs to such subjects causesa marked reduction in glomerular filtrationrate.445 Studies have shown that urinary excre-tion of PGE2 is decreased in hepatorenal syn-drome. This may indicate decreased renalproduction of this prostanoid or may reflectglomerular filtration rate dependent excretion.Recent immunocytochemistry studies suggest,however, that medullary endoperoxide synthasewas decreased in renal biopsy samples fromsubjects with hepatorenal syndrome compatiblewith decreased production.' There is no goodevidence, however, to suggest that decreasedproduction of prostacyclin is responsible forhepatorenal syndrome.44Two studies have now shown increased

cysteinyl-leukotriene production in hepatorenalsyndrome.2847 Cysteinyl-leukotrienes are pro-duced by inflammatory cells, lung, vasculartissue, and probably kidney. We recently re-

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300- ported markedly increased cysteinyl-leukotriene. production in hepatorenal syndrome compared

200- with appropriate controls suggesting that leuko-trienes may be important in the aetiology of this

<x5 - - condition28 (Fig 4).] Other mediators such as adenosine may also

X 100 * be important because this may cause systemico j vasodilatation and renal vasoconstriction.m 65- Synthesis may be increased by tissue hypoxia

which is well recognised in advanced livero - failure. Recent studies with dipyridamole (which

f inhibits adenosine uptake) in cirrhotic patientsa 60- have shown that this compound produces renalw impairment suggesting that this may also be an

important mediator.41 Studies with theophylline40 .(an adenosine antagonist) in cirrhotic patients,* . however, showed little systemic effect.49 Trials20- .. using the newer and more specific adenosine

g.§ * | * antagonists are needed. Platelet activating factor0 *;' - . and endothelin are also potent modulators of

Norm CLD Asc Sev hep HRS CRF renal function, and studies on these are awaitedClinical group with interest.

Figure 4: Urinary L TE4excretion in decompensated liver Thus, current concepts on the aetiology ofdisease and hepatorenal syndrome. Highest values wereobserved in hepatorenal syndrome, indicative of increased hepatorenal syndrome are that it iS a multifac-production. CLD=compensated liver disease. torial condition caused by reduced renal bloodAsc=Ascites. Sev hep=Severe hepaticfailure. flow and altered ultrafiltration coefficient as aCRF=Chronic renalfailure.Reprinted by courtesy ofJ Hepatol (Ref44). result of mesangial cell contracton. Reduced

renal blood flow is caused by a moderate decreasein renal perfusion pressure caused by systemic8ctive Sympathetict vasodilatation and increased renal venous pres-

3 Volumef dIrive sure. This is probably exacerbated by a shift inthe renal autoregulatory curve because of in-creased sympathetic activity. This, together withincreased renovascular resistance and mesangial

eral il|cell contraction induced by a combination ofendotoxaemia, altered eicosanoid production,and possibly increased adenosine production

v , gives rise to the functional renal impairmentinini * - 2 Renal afferent known as hepatorenal syndrome (Fig 5).+<arteriole constriction

Unresolved problemsThe most intriguing unresolved issue relating

ins/'/Renin t to renal sodium retention is the apparently(ijnss l / / retention increased renal tubular sensitivity toxins ?/Aaldosterone, apparent resistance to atrial

natriuretic hormone, and the mechanismsunderlying the peripheral vasodilatation.Clarification of these abnormalities might be

A \1 t A ldos eronefundamental to understanding the initiation

rD ..-tAldos/erone! of sodium retention. Further clarification ofsplanchnic haemodynamic changes is alsorequired. In particular whether there really are

Renal efferentfundamental differences between patients who

)\(g/ PGE2/PG12 Renal etferent might form ascites as an 'overflow' mechanismfrom those who appear to have effectivecentral hypovolaemia. Longitudinal studies arerequired to establish whether the former group

Glomerular 0 Filtrationt progresses to the latter or vice versa.filtration rate fraction With respect to hepatorenal syndrome the role

of reduced renal perfusion pressure needsfurther evaluation, and accurate data on the renalblood flow/pressure relationship in liver disease

I ~~~~~~willbe fundamental to this area. More definitive

Figure5: This extends the peripinterrelationships between toxin.their potential modulatory role iiATII=angiotensin II.

Hepatorenal studies on the role of cysteinyl-leucotrienes usingsyndrome specific LTD4 antagonists are needed, and the

role of other mediators of increased vascular tonePheral vasodilatation hypothesis and illustrates the possible and mesangial cell function such as endothelinslendotoxins as well as other horrnones and the eicosanoids andrenal haemodynamics and glomerular function. and plateletactivatig factor may also turn out to

be important contributory factors.

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Pathogenesis ofascites and hepatorenal syndrome S17

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2 Chart JJ, Shipley SS. The mechanism of sodium retention incirrhosis of the liver [Abstract]. J Clin Invest 1953; 32: 560.

3 Flint A. Clinical report on hydroperitoneum, based on ananalysis of forty-six cases. AmJ Med Psy 1863; 45: 306-39.

4 Hecker R, Sherlock S. Electrolyte and circulatory changes interminal liver failure. Lancet 1956; ii: 1121-5.

5 Wilkinson SP, Jowett TP, Slater JDH, et al. Renal sodiumretention in cirrhosis: relation to aldosterone and nephronsite. Clin Sci 1979; 56: 169-77.

6 Wilkinson SP, Smith IK, Williams R. Changes in plasma reninactivity in cirrhosis: a reappraisal based on studies in 67patients with 'low-renin' cirrhosis. Hypertension 1979; 1:521-4.

7 Wernze H-, Spech HJ, Muller G. Studies on the activity of therenin-angiotensin-aldosterone system (RAAs) in patientswith cirrhosis ofthe liver. Klin Wochenschr 1978; 56: 389-97.

8 Arroyo V, Bosch J, Mauri M, et al. Renin, aldosterone andrenal haemodynamics in cirrhosis with ascites. Eur3r ClinInvest 1979; 9: 69-73.

9 Bernardi M, Trevisani F, Santini C, et al. Aldosterone relatedblood volume expansion in cirrhosis before and during theearly phase of ascites formation. Gut 1983; 24: 761-6.

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11 Marson FGW. Total adrenalectomy in hepatic cirrhosis withascites. Lancet 1954; ii: 847-8.

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35 Schroeder ET, Shear L, Sancetta SM, Gasbuzda GJ. Renalfailure in patients with cirrhosis ofthe liver. II. Evaluation ofintrarenal blood flow by paraaminohippurate extraction andresponse to angiotensin. AmJ Med 1967; 43: 887-96.

36 Wilkinson SP, Moodie H, Stamatakis JD, et al. Endotoxaemiaand renal failure in cirrhosis and obstructive jaundice.BrMedJ 1976; ii: 1415-8.

37 Tachiyama G, Sakon M, Kambayashi S, Iijima T, TsujinakaT, Mori T. Endogenous endotoxemia in patients with livercirrhosis. A quantitative analysis of endotoxin in portal andperipheral blood. Jpn J Surg 1988; 18: 403-8.

38 Coratelli P, Passavanti G, Munno I, Fumarola D, Amerio A.New trends in hepatorenal syndrome. Kidney int 1985; 28(Suppl 17): S143-7.

39 Rolando N, Harvey F, Brahm J, et al. Prospective study ofbacterial infection in acute liver failure: an analysis of 50patients. Hepatology 1990; 11: 49-53.

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