INTRODUCTION• Hepato Renal Syndrome (HRS) is a functional and reversible form of renal failure , in patients with advanced chronic liver disease.• Interactions between systemic and portal hemodynamics causes intense renal vasoconstriction .• May develop spontaneously without known precipitating factors but there are known triggers.• To be diagnosed based on criteria.• Worst prognosis of all the complications of cirrhosis.• Terlipressin is the drug of choice in treatment.• Liver transplantation is the definitive cure for patients.• Recently liver dialysis by means of albumin bound membranes is providing a means of extracorporeal liver support.
History• Frerichs ,Flint - first report of renal failure in the absence of significant renal histologic changes,in chronic liver diseases.• Hecker, Sherlock (1956) – Pathogenesis of hepatorenal syndrome.• Epstein et al - splanchnic ,systemic vasodilation together with intense renal vasoconstriction is the pathophyisological hallmark of HRS.• 1970 s -TERMINAL FUNCTIONAL RENAL FAILURE• 2007 -Molecular Adsorbent Recirculating System.
Case• A 35-year-old male,k/c/o alcoholic cirrhosis, ascites and a history of alcoholic hepatitis presented to casualty for management of his cirrhosis and was diagnosed with new- onset renal insufficiency upon admission.• no history of renal dysfunction ,diabetes mellitus. He had blood transfusions at another hospital 5 days previously after having suffered a gastrointestinal hemorrhage.• No h/o SBP or recent treatment with nephrotoxic drugs. Upon admission, he was taking pentoxifylline 400 mg three times daily (tid) for alcoholic hepatitis, and furosemide 80 mg daily (qd) and spironolactone 200 mg qd for his cirrhosis with ascites.
• Physical examination revealed jaundice, ascites, and spider angiomas on his chest. Viral hepatitis serologies were negative, but ultrasound revealed a nodular liver and splenomegaly. No evidence of chronic renal parenchymal disease or obstructive uropathy. Ascitic fluid analysis demonstrated a SAAG of >1.1g/dl.• Diuretics were discontinued, and intravascular volume replacement was provided by administration of both 1.5 l of isotonic saline and a total of 120 g of human albumin administered over several doses but the patients renal function continued to worsen.• A DIAGNOSIS OF HEPATORENAL SYNDROME WAS MADE.
CAUSES OF RENAL FAILURE IN CIRRHOSIS H• Large volume paracentesis Y• Shock P O• Sepsis T• Nephrotoxic Medications E Renal failure• Intrinsic renal diseases N• Volume depletion secondary S to diuresis. I O N
Diagnostic Approach to Renal Failure in CirrhoticsRenal failure in a pt with cirrhosis hold diuretics,offending medications YES Trial of ntravascularvolumeexpanderECF fluid losses;rapid/excessive diuretics (albumin)if renal function ↑ses , hVomiting,diarrhoea,hemorrhage,recent, Diagnosis of prerenal failure isLVP /hemodynamic changes due to use of madeNSAIDS (or)ACEI YES NO Toxic or ischemic renal failureRecent use of nephrotoxicmedicationsHypotension(sepsis,hemorrhage) YES Suspected glomerular disease NO Depending upon clinical scenario Glomerular proteinuria&hematuria Further workup may include i.e.,dysmorphic RBCs and RBC cast Cryoglobulins C3,C4 and renal NO YES biopsy Imaging (USG,CT scan)shows Suggestive of obstructive uropathy Hydronephrosis,urinary retention Unless long standiing relief of obstruction NO Should lead to improvement in YES renalfunction Patient has evidence of Portal Diagnosis of HRS can be Hypertension & serum made creatinine>1.5mg/dl
IAC verbatim• “Hepatorenal syndrome is a syndrome that occurs in patients with chronic liver disease, portal hypertension and advanced hepatic failure .It is characterised by impaired renal function, marked abnormalities in arterial circulation and activity of endogenous vasoactive systems . In the kidney ,there is marked renal vasoconstriction that results in low GFR. In the extrarenal circulation there is predominance of arteriolar vasodilation , that results in reduction of total systemic vascular resistance and arterial hypotension.A similar syndrome may also occur in the setting of acute live failure”. -IAC ,Chicago 1996
DEFINITION• First systemic attempt to define HRS was made by International Ascites Club(1994)• HEPATORENAL SYNDROME is a distinct form of fucntional acute/sub acute renal failure charecterised by severe renal vasoconstriction which develops in decompensated Cirrhosis or Acute liver failure,in the absence of uderlying renal pathology. (Clinics of North America;Expert consensus;1996)• Recently updated to include Albumin as volume expander.
EPIDEMIOLOGY• Incidence of HRS in patients with chronic liver disease is not well studied.• 4% of patients admitted with decompensated cirrhosis.• In a study of 234 non azotemic patients with liver disease who had ascites and cirrhosis,18% developed HRS at 1year and 39% developed by 5 years.• Retrospective studies indicate HRS is present in 17% of pts admitted to hospital with ascites,and in > 50% of cirrhotics dying from liver failure• Some patients without ascites devolped the condition in the setting of acute fulminant hepatic failure.
Pathophysiology• Four interrelated pathways have been implicated in the pathophysiology ..• “Possible impact of each one of these pathways on renal vasoconstrcition and development of HRS varies from one patient to other .”• 1.PERIPHERAL ARTERIAL VASODILATION• 2.STIMULATION OF RENAL SNS• 3.CARDIAC DYSFUNCTION• 4.CYTOKINES ,VASOACTIVE MEDIATORS.
Cont..• 1.PERIPHERAL ARTERIAL VASODILATION :• Rational and simple explanation to the hemodynamic changes that takes place in cirrhosis ,HRS.• Degree of hepatic decompensation degree of hyperdynamic circulation ,• Degree of hepatic decompensation 1/ arterial BP.• Reversal of HRS ,improvement of hemodynamics by systemic vasoconstriction gives support to this hypothesis.
Pathophysiology of HRS CIRRHOSIS splanchnic arterial vasodilation arterial underfilling stimulation of systemic vasoconstrictors renal vasoconstrictionlate stage of cirrhosis early stages of cirrhosis local vasodilators , local vasoconstrictors systemic and local vasodilators HEPATORENAL SYNDROME PRESERVED RENAL PERFUSION
Correlation between clinical features and pathophysiology in HRS HRS diuretic refractory ascites ascitesClinicalPhysiological Portal HTN Splanchnic vasodilation renal vasoconstriction
• 2.stimulation of renal SNS :• sympathetic tone in pts with cirrhosis.• KOSTREVA et al vena caval ligation -- increased intrahepatic pressure -- renal sympathomimetic activity --wears after anterior hepatic nerves are cut.• Severing renal ,hepatic,spinal nerves abolishes the response of decreased GFR ,RPF seen after hepatocyte swelling.
• 3.cardiac dysfunction :• Myocardial contractility impaired.( cirrhosis )• Diastolic dysfunction cirrhosis progression• Hyperdynamic state being present• Cause is diseased liver ,reversible after TRx• BNP , CVP child pugh score ,ventricular wall thickness.• Neurohormonal activity - growth ,fibrosis – disturbed relaxation .• Inhibitory effect of TNF ,NO on ventricular function.
Cardiac dysfunction ismasked by decreasedafterload in cirrhoticpatients .Decreased cardiac output
• 4.cytokines ,vasoactive mediators:• Not a sole player.• NO,TNF ,endothelin , endotoxin,glucagon,increased PG s .• Upregulation of e NOS activity,endotoxin ,inducible.• Reduces pressor effect of vasoconstrictors.• More in cirrhotics ,ascites.• Renal vasoconstriction due to dimethylarginine - a natural NO inhibitor.• Reduced cyclooxygenase activity in renal medullary tissue.
Precipitating factors• In type I HRS ppting event identified in 70-100 % pts.• More than one event in a patient.• Bacterial infections• Large volume paracentesis without albumin infusion. (15%)• GI bleeding• Acute alcoholic hepatitis. (25%)• SBP - 20-30% develop HRS.
How ppt factor leads to renal failure?• A.cytokine-induced aggravation of the circulatory dysfunction with further stimulation of the RAAS and SNS and worsening renal vasoconstriction.• intrarenal vicious cycle that favors more renal vasoconstrictor release and impairs renal vasodilator synthesis .• will progress to HRS even if the underlying precipitating event has been corrected.• B.secondary to deterioration in cardiac function as a result of either the development of septic cardiomyopathy or worsening of a latent cirrhotic cardiomyopathy
DIAGNOSIS OF HRS• Diagnosis of HRS is made on certain predefined criteria in the appropriate clinical setting• Increasing s.creatinine in patients with cirrhosis and acute fulminant liver failure itself is enough to investigate for Hepatorenal syndrome• All the major criteria are to be met for the diagnosis of HRS and minor criteria are just supportive and are not essential to make the diagnosis
MAJOR DIAGNOSTIC CRITERIA1)Chronic/Acute liver disease with advanced hepatic failure or portal hypertension2)Serum creatinine >1.5mg/dl(reflecting decreased GFR),<40 ml/min3)Absence of shock,bacterial infection,current or recent treatment with nephrotoxic drugs,absence of renal or g.i.t losses4)No increase in renal function after diuretic withdrawal and plasma volume expansion and intravenous albumin(1g/kg bdy wt upto a maximum of 100g)5)Proteinuria <500mg/dl, no USG evidence of renal parenchymal damage (urine analysis) , no obstructive uropathy.
MINOR DIAGNOSTIC CRITERIAUrine volume <500ml/24 hrUrine sodium <10 meq/LUrine plasma osmolality greater than plasma osmolalityUrine blood cells<50 per HPFSerum sodium <130 meq/L
CLASSIFICATION OF HRSClassified based on TIME COURSE and PRECIPITATING FACTORSFour types-HRS type-1: Cirrhosis with rapidly progressive acute renal failureHRS type-2:Cirrhosis with sub acute renal failureHRS type-3:Cirrhosis with type-1 or type-2 HRS superimposed on chronic kidney disease/acute renal injuryHRS type-4:fulminant liver failure with HRS Clinics of North America,2006
TYPE-1 HRSIt is the cirrhosis with rapidly progressive acute renal failureCharacterized by-Rapid elevation of BUN and creatinine:100% increase with a level reaching 2.5mg/dl in 2 weeks or a 50% reduction in initial 24 hr clearance to < 20 ml/minRapidly progressiveMortality reaching 80% with 2 weeksCommonly has precipitating factors-SBP(20%) -variceal hemorrhage -acute alcoholic hepatitis -drug induced(acetaminophen) -acute hepatic injury from viral hepatitisDeeply jaundiced ,coagulopathyDeath by hepatic plus renal failure,variceal bleeding.
TYPE-2 HRSCirrhosis with sub acute renal failureCharacterized by-Slowly increasing serum creatinine levels and slow reduction of GFR(Takes weeks to months)No precipitating factorIt has poorer prognosis and eventually progresses to type -1 due to precipitating factors
TYPE-3 HRSCirrhosis with type 1 or type 2 HRS superimposed on chronic kidney disease or acute renal injury85% of end stage cirrhotics have intrinsic renal disease on renal biopsyDiagnostic markers of HRS are absent
TYPE-4 HRSFulminant liver failure with HRSMore than 50% of acute fulminant liver failure develop HRSPrognosis of HRS is superimposed on already poor prognosis of acute fulminant liver failure.
CLINICAL FEATURES• SYMPTOMS- -distension of the abdomen -change in mental status(confusion,delirium and dementia) -coarse muscle movements or muscle jerks -dark coloured urine -yellow skin -↓sed urine output -nausea and vomiting -weight gain
DIFFERENTIAL DIAGNOSIS• Pre renal causes--- hemorrhage ,diarrhea,hypovolemia• Intra Renal causes --- acute tubular necrosis,interstitial nephritis.• Post renal causes -- uropathy• Diagnosis by exclusion.• it is extreme example of prerenal failure.(Una <20 ,Fna <1, Ucr/Pcr >40 ,Uosm/Posm >1.5 )
LABORATORY STUDIES• Diagnosis depends mainly on s . creatinine levels as no specific tests establish the diagnosis of HRS. (>1.5mg/dl)• Though serum creatinine level is a poor marker of renal function in cirrhosis (low muscle mass) no other validated and reliable non invasive markers exist for monitoring renal function in these patients.• Inulin clearance is cumbersome and is not used clinically.• Low GFR is defined by s cr >1.5 mg/dl without diuretic therapy for at least 5 days.• overestimates GFR by upto 50% .
CBP ,WBC : infection such as SBP if leucocytosis or bands arepresent,a condition known to present with reversibleimpairment in renal functionSerum electrolytes and renal functionLiver function test with PT (although the degree of liver failuredoesn’t correlate with the development of HRS,these areessential for Child-Pugh scoring)Blood cultures- for bacteremia particularly if no precipitant isidentified,is prudent( 20% SBP are culture -ve)Cryoglobulins- in patients with hepatitis B and or C who candevelop renal failure from cryoglobulinemia.
MANAGEMENT GENERAL MANAGEMENT:• Type I HRS - hospitalization, type 2 - outpatient.• CVP for assessing fluid status.• Stop diuretics• Tense ascites -paracentesis• If > 5l of fluid removed ,then albumin is good as volume expander.• low salt diet,free water restriction -hyponatremia cases.• HRS type-1 & 4 need intensive management
DOPAMINELow dose dopamine(2-5µgm/kg /min) is prescribed in the hope that its vasodilatory properties may improve renal blood flowMISOPROSTOLA synthetic analogue of PG E1, use was based on the observation of low urinary levels of vasodilatory PGs.The use of both the above drugs was not substanciated by any studiesRENAL VASOCONSTRICTOR ANTAGONISTSarlasin used in attempt to reverse renal vasoconstriction.This inhibits the hemostatic response to hypotension and led to further worsening of renal function .N-ACETYLCYSTEINEMechanism of action is unknown but studies encourage optimism for medical management where option for liver transplant is not present
• None of the studies that used renal vasodilators showed imrpovement in renal perfusion or GFR. -- Barnado et al , Benette et al .• Because of adverse effects ,lack of benefit the use of renal vasodilators has been abandoned.
Systemic vasoconstrictors• Most promising agents.• Interruption of splanchnic vasodilation will relieve the intense renal vasoconstriction.• VASOPRESSIN ANALOGUES -ORNIPRESSIN ,TERLIPRESSIN• SOMATOSTATIN ANALOGUE -OCTREOTIDE.• ADRENERGIC AGONISTS - MIDODRINE, NOREPINEPHRINE.
VASOPRESSIN ANALOGUES:• Marked vasoconstrictor effect.• V1receptors on smooth muscle of arterial wall .• Rx of acute variceal hemorrhage.• Ornipressin -- ischemic adverse effects. (30% )• Terlipressin – most common used drug now.• Better response in type 2 HRS than in type 1 HRS.• 17-50% recurrence rate of HRS. – reversible.• Duration of therapy is unclear.• 60-80% improvement in type IHRS• To be given until s creatinine< 1.5 mg/dl ,or 15days.• Liver disease occurs in 3 months of therapy if not TRx.
OCTREOTIDE:• An inhibitor of glucagon.• Ineffective in type 2 HRS Alpha ADRENERGIC AGONISTS - MIDODRINE,NE• Both are ineffective in type 2 HRS .• Better response in type I HRS. DRUG DOSE DURATION SIDE EFFECTSTERLIPRESSIN 0.5-2mg every 4 hrs as 15 days Peripheral,cardiac,splanchnic IV bolus ishemiaNOREPINEPHRINE 0.5-3.0 mg/hr IV 15 days same infusion MIDODRINE 7.5-12.5 mg every 8 hrs ?? Not reported oral
• High HRS recovery rate with vasopressin and improved survival ,more likely to recieve a liver transplant compared to octreotide - Kiser et al.• Norepinephrine role is paradox - levels are elevated in pts with HRS.Significant improvement with
TREATMENT PROTOCOL OF NORADRENALINE/TERLIPRESSIN PLUS AIBUMIN FOR HRS:• NA –Initial dose 0.146µg/kg/min iv infusion,if no increase in MAP by 10mm Hg, dose by 0.05µg/kg/min every 4thhrly up to dose of 0.7µg/kg/min• Terlipressin- 1mg iv bolus every 4th hrly.At day 3 if baseline s. creatinine not reduced ≥25% , the dose up to 2mg every 4thhrly
MIDODRINE WITH OCTREOTIDEMidodrine(alpha adrenergic blocker) and octreotide (somatostatin analogue)Rx protocol of midodrine plus octreotide therapyOctreotide initial dose:100µgm t.i.d SC goal to increase upto 200µgm t.i.d SCMidodrine Initial dose:5mg,7.5mg,10mg t.i.d orally goal to ↑dose upto 12.5mg to 15mg t.i.d if necessaryBecause of oral and subcutaneous route of the drug suitable for use in outpatient deparment
TIPS• Insertion causes reduction of portal pressure.• Beneficial in patients with cirhhosis and refractory ascites.• M.O.A- suppression of putative hepatorenal reflex, improvement in circulatory volume,ameiloration of cardiac function.• Guevara et al• Unanswered observations• 1 . Parameters improve,but not normalize. After TIPS.• 2.maximum renal recovery is 2-4 wks.• 3.advanced cirrhotic patients are not benefited.• 4.ppts underlying acute heart failure.
TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT(TIPS)Is theoretically attractive therapyIt dramatically lowers portal pressure leading to ↓ pooling of blood in splanchnic bedBut ↑venous return is inappropriately handledAnd many patients do not meet the criteria for TIPS insertion(i.e serum bilirubin <5mg/dl,INR <2 and Child-Pugh score <12)When these conditions are not met TIPS insertion may lead to liver failure or intractable hepatic encephalopathyDone only in patients with Child-Pughs A/B with criteria and who do not respond to vasoconstrictor therapyPatients with refractory ascites often proceed to the development of HRS type -2 and TIPS in these patients may lead better survival(metaanalysis)
SURGICAL CAREPERITONEOVENOUS SHUNTINGtheoretically seems attractive because it leads to plasma volume expansion and improvement of circulatory functionHas no role in type-1 HRSImportant for patients type-2HRS who have refractory ascites and are not candidates for orthotopic liver transplant and do not tolerate frequent LVPs
ARTIFICIAL LIVER SUPPORTEliminates circulating mediators of splanchnic vasodilatation & renal vasoconstrictionProvides hemodynamic benefit and decreases s. creatinineContinous venovenous hemofilteration is better.In Acute liver failure patients treated with porcine hepatocyte based bioartificial liver reported renal failure no details providedCurrently these are being used in HRS but are not advocated for its treatment.
ALBUMIN DIALYSIS• Currently three systems are available for albumin dialysis.• 1.MARS• 2.PROMETHEUS• 3.SINGLE PASS ALBUMIN DIALYSIS (SPAD)
MOLECULAR ADSORBENT RECIRCULATING SYSTEM (MARS)• Designed by Stange and Mitzner from Germany in 1993.• Cell free ,modified dialysis technique.• Three circuits - blood,albumin,renal.• 600 ml of 20% albumin acts as dialysate• Removes both albumin bound,water soluble substances by using a combination of albumin enriched dialysate,CRRT.• Removal of albumin bound bile acids (detrimental to hepatocytes) ,kidney –stabilizes liver function.• Removes water soluble TNF A , IL6 and NO.• Substance . 50 KDa are not removed . Artif Organs 1993 ;17:809-13
PROMETHEUS• First described in 1999 .• Principle of fractioned plasma seperation and adsorption.• Albumin permeable membrane ,size of 250kDa.• Albumin passes through the membrane and adsorbers that remove toxins.• Reduction of both bilirubin,urea more > MARS. Rifai K, Kretschmer U ,et al. J.Hepatol 2003 ; 39:984-90
SINGLE PASS ALBUMIN DIALYSIS(SPAD)• Dialyses blood/plasma against a 4.4% solution of albumin,disposed after a sinlge pass.• A standard renal replacement machine is used with out any additional perfusion pump system• With regard to bilirubin,ammonia it is greater than MARS in its detoxifying capacity.• In vivo useful in fulminant hepatic failure.• Further experience required for routine use. Kreymann B, Schweigart U et al. J.Hepatol 1999;31:1080-5
RENAL REPLACEMENT THERAPY• Controversial role in pts with type I HRS ,not undergoing liver TRx.• To be individualized.• Indications:• 1.waiting for liver TRx• 2.developed volume overload• 3.intractable metabolic acidosis.• 4.hyperkalemia.• Bridge to liver TRx.• CRRT > HD - removes inflammatory cytokines - TNF A,IL-6• FUTILE IN pts on mechanical ventilator.
LIVER TRANSPLANTATION• Best treatment for suitable patients with HRS.• RENAL SODIUM excretion,hemodynamic abnormalities normalize in 1 month.• Renal resistance index normalize in 1 year post transplantation.• Allocation is by MELD score.• Alessandra et al MELD score not beneficial for HRS pts.• Prolonged hospitalizations required• Renal failure persists for weeks post TRx.• Post TRx reversal of HRS is 58%.
LIVER TRANSPLANTLong term survival following liver transplant is goodMortality of individuals with HRS was as high as 25% within the first month after transplantation(HRS patients with grater hepatic dysfunction MELD score >36 are at greater risk of early mortality)high priority is given to type-1But these patients are not transplanted because of the precipitating event which initiated HRS and are extremely ill with multiorgan failure and rapid course of the disease providing insufficient time
In patients with HRS type -2 liver transplant is more practical because of the absence of precipitating factors,longer clinical course & less severe renal failureIn type-3 HRS both liver and kidney transplant in these extremely ill patients is a dilemma. only liver transplant may be beneficial given the prospect of post op RRTPatients with low MELD score and successful vasoconstrictor therapy have lower post op complications.Further deterioration of renal function after liver transplantation is transient and is thought to be due to use of immunosuppressants that are nephrotoxic(tacrolimus, cyclosporin)
Renal function beforeliver TRx is an independentpredictor of both shortterm and long term posttransplantation patient andgraft survival…Gonwa et al
Predictors of renal recovery• Younger recipients• Nonalcoholic liver disease• Low posttransplantation bilirubin• Age of the donor
LKT• Prolonged duration of RRT pretransplantation.• h/o previous renal failure• CKD on biopsy.
SPECIFIC THERAPYTYPE OF HRS TREATMENTTYPE I HRS Vasoconstrictors,albumin,TIPS,liver TrxTYPE 2 HRS Vasoconstrictors ,LVP,TIPS(ref),Liver TrxTYPE 3 HRS CRRT, LKT TYPE 4 HRS idealy LTx
PREVENTIONPrompt treatment of precipitating factors of type-1 HRS like sepsis, shock, variceal hemorrhage,acute alcoholic hepatitis and nephrotoxic drugs according to standard guidelinesA trial has shown norfloxacin as prophylaxis for SBP decreases HRS to 28% compared to 41%Albumin administration at diagnosis and day 3 in patients with SBP decreases HRS. (10%)Pentoxyphylline 400mg tid for 28 days in alcoholic hepatitis decreases HRS.( 24%)However these are not proved in recent studies
prognosis• Worst prognosis of all complications of cirrhosis.• Type 1 HRS without Rx < 2 weeks• All pts in 8-10 weeks after onset of RF.• Type 2 HRS - 6 months . Lancet 2003 ;362:1819-1827
Unanswered questions….• 1.best modality of therapy• 2.predictability of LKT versus a liver only transplant.• 3.how are vasoconstrictors compare with TIPS,MARS• 4.best to use vasoconstrictor?• 5.whether there is an independent beneficial effect of albumin in HRS?• 6.why renal recovery rate is variable between centers.
TRIALSFabrizi F et al – meta analysis (2007) of terlipressin therapy for HRSSanyal A,boyer T,Teuber P(2007)-Randomised double blind placebo controlled trail for terlipressin therapyIn both the trials showed that terlipressin is more effective than placebo in reversing HRSNakaeh,Igarashi T,Tajimi K et al-case report of hepatorenal syndrome treatment with plasma differentiation(2007)Rimola A,Navasa M,Grande et al-liver transplantation for cirrhosis and ascitis(2005)
Take home message• 1.HRS is a functional reversible renal failure in cirrhotic, fulminant liver failure patients.• 2. patients with SBP ,who underwent LVP , had GI hemorrhage should be carefully followed up as they are more prone for HRS.• 3 .diagnosis by exclusion ,based on major criteria.• 4.type I HRS has high mortality ,HRS 2 prolonged survival ,type3 in CKD ,type 4 HRS - fulminant hepatic failure.
• 7.MARS is an upcoming procedure.• 8.Liver TRx is treatment of choice .• 9.MELD score does not work out for HRS patients• 10.recovery depends on age,s bilirubin,non alcoholic liver disease.• 11.role of LKT in patients with HRS to be checked out.• 12.albumin infusion in patients with SBP
REFERENCES• MEDICINE UPDATE ,vol 17 , 2007• HEPATORENAL syndrome :pathophysiology and management :Amercian Society Of Nephrology ,2006• Emedicine .com• Clinics of North America ,2006,2007 – care of cirrhotic patients ,hepatic emergencies in cirrhosis.• Mayoclinic.com• HARRISON’S PRINCIPLES OF INTERNAL MEDICINE ,18th ed• World journal of gastroenterology ,2007:4046-4055,