07 Ra Hepatorenal Syndrome

8/20/2019 07 Ra Hepatorenal Syndrome

http://slidepdf.com/reader/full/07-ra-hepatorenal-syndrome 1/7

36 JOURNAL OF THE ASSOCIATION OF PHYSICIANS OF INDIA • VOL 62 • PUBLISHED ON 1ST OF EVERY MONTH 1ST AUGUST, 2014

Abstract

Hepatorenal syndrome is a unique form of acute kidney injury seen in patients with acute liver failure or

chronic liver disease in absence of any other identifiable cause of renal failure. It is primarily a diagnosis

of exclusion. Despite of good pathophysiological understanding and better available therapeutic options

for management of hepatorenal syndrome, it is still associated with significant morbidity and mortality.

Liver transplantation forms the cornerstone for its management. In this review article, we have attempted

to assimilate and summarise the advances made in the previous decade with regards to pathophysiology,

classification and management of this entity.

1Professor and Head,2Assistant Professor, 3Senior

Resident, Department of

Anaesthesiology, Institute of

Liver and Biliary Sciences, New

Delhi-110070

Received; 25.06.2013;

Accepted: 02.09.2013

Hepatorenal Syndrome : A Decade Later

CK Pandey1, ST Karna2, A Singh2, VK Pandey2, M Tandon2, V Saluja3

Introduction

Hepatorenal syndrome (HRS) is a unique form of acute kidney injury seen inpatients with acute liver failure or chronic liver disease in absence of any other

identifiable cause of renal failure. It is primarily a diagnosis of exclusion. We havecome a long way in understanding the pathophysiology and treatment of hepatorenal

syndrome. In this review article, we have attempted to assimilate and summarise theadvances made in the previous decade with regards to pathophysiology, classificationand management of this entity, which was once considered ambiguous.

Diagnostic criteria: The International Ascites Club (IAC) revised the criteria for

diagnosis of HRS in 2007.1,2

These consist of:1. Cirrhosis with ascites

2. Serum creatinine >1.5 mg/dL

3. No improvement of serum creatinine (a decrease in serum < 1.5 mg/dL) after 2days off diuretics and volume expansion with albumin (1g/kg body weight up toa maximum of 100 g/d)

4. Absence of shock

5. No current or recent treatment with nephrotoxic drugs

6. Absence of signs of parenchymal renal disease, as suggested by proteinuria (> 500mg/d) or haematuria (> 50 red blood cells per high-power field) and/or abnormal

renal ultrasound

The main differences from the old diagnostic criteria (1996) are:

1. The use of creatinine clearance has been abandoned for the diagnosis of HRS

2. As long as septic shock is absent, the presence of ongoing bacterial infection doesnot preclude the diagnosis of HRS

3. Albumin is preferred over saline for plasma volume expansion to exclude pre-renalaetiology of acute kidney injury (AKI)

4. Minor diagnostic criteria including low fractional excretion of sodium and oliguriahave now been omitted.

Even the new diagnostic criteria have been scrutinised and criticised in view of thefollowing shortcomings and pitfalls.3,4

REVIEW ARTICLE

696 © JAPI • AUGUST 2014 • VOL. 62



JOURNAL OF THE ASSOCIATION OF PHYSICIANS OF INDIA • VOL 62 • PUBLISHED ON 1ST OF EVERY MONTH 1ST AUGUST, 2014 37

1. Patients with chronic kidney disease (CKD)/Anuric patients cannot be diagnosed with HRS.

2. The discrepancy between acute kidney injurynetwork (AKIN) diagnostic definit ion andclassification of AKI and IAC diagnostic criteriafor HRS prevents early diagnosis of renaldysfunction in cirrhotic patients. A patient

having increase in creatinine of 0.3 mg/dl in 48hrs. will be classified as having AKI but if the

serum creatinine is < 1.5mg/dl, the diagnosisof HRS is not possible. In cirrhotics, where the baseline creatinine is low, this excludes a group ofpatients with impending HRS who may benefit byinstituting specific treatment at an earlier stage.

Acute dialys is qual i ty ini t iat ive (ADQI) intheir 8 th international consensus conference onhepatorenal syndrome5 has tried to address thevarious shortcomings of previous definitions. Theirrecommendations are to be considered as the first step

towards standardisation of the definition of AKI inpatients with cirrhosis.

As the diagnosis of AKI as defined by RIFLEcriteria has been shown to be a predictor of hospitalsurvival. The consensus of the workgroup has beento apply the modified RIFLE criteria to define AKIin patients with cirrhosis irrespective on the cause-structural or functional.

The early identificat ion of change in serumcreatinine in patients with AKI not fulfilling thecriteria for HRS but having low GFR will allow earlyinstitution of therapy for these patients and prevent

rapid progression of the pathology.The workgroup also goes on to suggest the

term hepatorenal disorders be used to describe allpatients with advanced cirrhosis and concurrent

kidney dysfunction encompassing both functionaland structural. The classification of the severity ofdysfunction will be based on the RIFLE criteria.

This will allow cirrhotic patients with renaldysfunction to be properly classified –allowingstudies to be conducted to define their prognosis andto devise treatment options.

Classification of HRSThe classification of hepatorenal syndrome into two

types has remained unchanged even in the updateddiagnostic criteria. It is crucial to differentiate betweenthe 2 types, not just for the clinical management, but al so for appropriate progno sticat io n and risk

assessment.

Type 1 HRS: Defined as doubling of the serum

creatinine to more than 2.5 mg/dl in duration ofless than 2 weeks. It is more acute, associated withprecipitating factors and has a grave prognosis.

Type 2HRS: Defined as a slowly progressive rise inserum creatinine to more than 1.5 mg/dl. It is usuallyassociated with diuretic resistant refractory ascites.

Epidemiology

HRS occurs almost exclusively in patients withascites and the estimated probability of developing

HRS at 1 and 5 years in patients with ascites being 18and 39% respectively.6

In a retrospective multicentric study conducteda decade back by Moreau et al. found that in 423patients with cirrhosis and AKI; Type 1 and 2 HRSwere implicated in 20% and 6.6% cases respectively.7

In a recent study Montoliu et al. assessed theincidence and prognosis of different types of

functional renal failure in 263 consecutive cirrhoticpatients with ascites. All patients were followed upfor 41±3 months after their first incidence of ascites.During the follow-up period, out of the 129 (49%)

patients who developed some type of functionalrenal failure, hepatorenal syndrome was causative inonly 7.6%. The cumulative probability of developingHRS was 11.4%. The independent predictors fordevelopment of functional renal failure were age,Child-Pugh score, and serum creatinine.8 However,another prospective study conducted in a tertiarytransplant centre documented that 40% patient withcirrhosis and kidney failure had HRS.9

Pathogenic Mechanisms

Many interrelated pathophysiological processes

have been implicated in the development of HRSwhich include the diseased liver, portal hypertensionand development of ascites, splanchnic vasodilation,myocardial depression, abnormal systemic and renalneurohumoral regulation, lower renal prostaglandinproduction and adrenal insufficiency.10 The severity ofdeterioration of liver function affects the development

of renal dysfunction.

Arter ia l hypotens ion along with re lat ive ly

insufficient CO (in spite being high) is the keyfactor in development of compensatory mechanismscontributing to development of HRS. The traditional

model of the hepato-renal axis and HRS includessplanchnic hyperaemia and vasodilat ion withcompensatory activation of the renin–angiotensinaldosterone (RAAS) and sympathetic systems (SNS)to maintain blood pressure. Contributory to this isthe non-osmotic release of endogenous vasopressin.The resultant increase in serum catecholamine and

angiotensin levels causes intra-renal vasoconstrictionand hypoperfusion result ing in a decrease inglomerular filtration rate (GFR). With increasingserum creatinine levels, HRS ensues especially whenadditional precipitating factors like- spontaneous

© JAPI • AUGUST 2014 • VOL. 62 697




bacterial peritonit is, upper GI bleeding, large volumeparacentesis, further increase renal vasoconstriction.11

Translocation of bacteria from the intestinal lumen to

mesenteric lymph nodes (MLNs) and then into thesystemic circulation lead to an inflammatory state andvasodilation.10,12 Recent studies have shown the roleof the Renin–angiotensin–aldosterone system (RAAS)not only in propagating renal injury through intra-renal vasoconstriction but also as a cause for hepaticfibrosis.13 For pathophysiological phases responsiblefor the development of ascites and HRS is summarisedin Table 1.14

Precipitating Factors for HRS

In 50% cas e s , t he de v e lo pm e nt o f HRS i sspontaneous, whereas in other half 1 or moreidentifiable triggers may be found which include.15

1. Bacterial infections–Ascitic fluid, respiratorysystem, urinary tract, GI tract infections and

infections of the biliary tract.

2. Diarrhoea and vomiting

3. Diuretics

4. Gastrointestinal bleeding-variceal bleeding

5. Large volume paracentesis (LVP)–more than 5litres without adequate blood volume expansion.

Prevention of HRSThe development of HRS is associated with

significantly increased morbidity and mortality.With better understanding of the pathophysiology ofHRS, certain specific strategies have been identified

to prevent HRS in specific clinical situations. Asystematic literature review was conducted by acutedialysis quality initiative (ADQI) in 2010, where theexperts developed a consensus recommendationfor standardised care of cirrhotics with HRS.16 Thepreventive strategies outlined by ADQI are mentioned

below along with the review of other literature forprevention of HRS:

1. Careful assessment , close monitori ng andprevention of precipitating factors in cirrhoticswith ascites.

2. Consider covert hypoadrenalism in patients withcirrhosis to improve response to vasopressors and

survival.17

3. Drugs which reduce renal perfusion and thosecausing nephrotoxicity have been reported toprecipitate HRS, should be avoided.

4. Antibiotic prophylaxis has shown to reducespontaneous bacterial peritonitis (SBP). Studiesusing norfloxacin have reported not only a

reduction in SBP (7 versus 61%) but also areduction in the incidence of HRS (28 versus41%).18

5. Albumin infusion s have been reported todecrease the incidence of HRS in patients withSBP.19Consecutive trials have shown that incontext of SBP, albumin infusion is more effectivethan other plasma expanders. 20 In severelyill cirrhotic patients, volume expansion withalbumin has been shown to reduce plasma renin,

suggesting an improvement in the effectivecirculating volume. In randomised controlledclinical trials, albumin infusions reduced boththe incidence of HRS and mortality19

6. Prophylactic pentoxifyll ine, a tumour necrosisfactor-α antagonist, reduces complications inpatients with advanced cirrhosis including renal

dysfunction.21

7. Large volume paracentesis (LVP) may induceparacentesis induced circulatory dysfunction(PICD) leading to development or exacerbation ofAKI and HRS. Administration of albumin 8 g/ litre

of fluid aspirated (specially if the aspiration ismore than or equal to 5 litres) leads to preventionof PICD.22

General Management

Once the diagnosis of HRS is confirmed, it is

important to classify the disease into either of the twotypes. Patients with Type 1 HRS need to be managedin an intensive care unit, in view of the associatedinherent risk of multi-organ failure. Patients withType 2 HRS may be managed on an outpatient basiswith thorough workup and supportive care.

Monitoring

Patients with type 1 HRS should be monitoredcarefully. Parameters to be monitored include urineoutput, fluid balance, and arterial pressure, andstandard vital signs. Ideally central venous pressure

Table 1 : Pathophysiological phases in the development of

ascites and HRS14

Phase Term Ascites Na+ andH

2O

Increased inRAAS and

SNS

DecreasedRBF and

GFR

Pre-asciticcirrhosis

No No/Yes No No

Mild-

ModerateAscites

Yes Yes No/Yes No

Moderate-TenseAscites

Yes Yes Yes No/Yes

Type 2 HRS Yes Yes Yes Yes

Type 1 HRS Yes Yes Yes Yes

Abbreviations : RAAS-Renin–angiotensin–aldosterone system; SNS-sympathetic nervous system; RBF-renal blood ow; GFR-glomerularltration rate; HRS-hepatorenal syndrome

698 © JAPI • AUGUST 2014 • VOL. 62




should be monitored to help with the management offluid balance and prevent volume overload.

Screening for Sepsis

Bacterial infection should be identified early, by blood, urine and ascitic fluid cultures, and treatedwith antibiotics. Patients who do not have signs

of infection should continue taking prophylacticantibiotics, if previously prescribed.

Use of Paracentesis

There are few data on the use of paracentesis inpatients with type 1 HRS. Nevertheless, if patientshave tense ascites, large-volume paracentesis withalbumin may be useful.23

Volume Resuscitation

Excessive administration of fluids should be

avoided to prevent volume overload due to thepresence of kidney injury and development orprogression of dilutional hyponatraemia. Use ofFunctional haemodynamic monitoring to assess

the dynamic response to a fluid volume bolus isdesirable.5All diuretics should be stopped in patientsat the initial evaluation and diagnosis of HRS. Thereare no data to support the use of furosemide inpatients with ongoing type 1 HRS. Neverthelessfurosemide may be useful to maintain urine outputand treat central volume overload if present .Spironolactone is contraindicated because of high riskof life-threatening hyperkalaemia. Patients with HRS

should be optimally resuscitated, with intravenousadministration of albumin (initially 1 g of albumin/kgof body weight up to a maximum of 100 g, followed by20-40 g/day) in combination with vasopressor therapy,for up to 14 days.16,23

Pharmacological Treatment of HRS

Most o f these therapies have targeted thehaemodynamic perturbations that are thought tounderlie the pathophysiology of HRS, includingsystemic and splanchnic vasodilation.

Vasopressin Analogues

Vasopress in analogues form the f i rs t l inemanagement of type 1 HRS as a bridge to transplant.Among all vasopressin analogues, the drug mostwidely used for treatment of type1 HRS is terlipressin

(three glycyl residues and lysine-VP). Followingintravenous administration, the glycyl residues are

cleaved by endothelial peptidases allowing slow,prolonged release of lysine-VP. This mechanismprolongs the half-l i fe of terl ipressin, enabling

administration in divided doses without the need foran infusion, and minimises systemic toxicity.24

Terlipressin has a preferential effect on V1receptors, which are densely located in the splanchnic bed. The improvement in renal perfusion is attributedto splanchnic vasoconstriction, rise in the effectivecirculating volume, mean arterial pressure, and

decrease in the plasma renin and aldosterone andoverall improvement in renal perfusion pressure.25 Terlipressin is not yet approved by the Food and DrugAdministration (FDA) in the USA for use in HRS,though it is commonly used in Europe and Asia. In arecent meta-analysis of randomised controlled trials,it was observed that the therapy with terlipressinand albumin improves the renal function in patientswith cirrhosis and HRS type 1. This improvement wassustained in most of the patients for the duration offollow-up (90 to 180 days) leading to an improvement

in overall and transplant-free survival. The pooledpercentage of HRS reversal was 46% and recurrencein 8%.26

In recent randomised, prospective, placebo-controlled clinical trials, terlipressin was foundsignificantly more effective than placebo in reversingtype 1 HRS with a similar safety profile. 27Caraceniet al. reported their experience with terlipressin andalbumin treatment as a bridge to liver transplantationin three patients with cirrhosis and recurrent HRS.

They concluded that terlipressin prevents irreversiblerenal failure and the need for dialysis until anorgan becomes available.28Though most studieson terlipressin have been conducted in patients

with Type 1 HRS, but recently its use has also beenevaluated in patients with type 2 HRS. This studydemonstrated a combined reversal rate for type 2 HRSwith terlipressin and albumin of about 80% which,recurred after discontinuation of therapy.29

The ADQI recommends that patients with Type 1

HRS should be optimally resuscitated with albumin(initially 1 g of albumin/kg of body weight for 2days, up to a maximum of 100 g/day, followed by20-40 g/day) in combination with a vasoconstrictor,preferentially terlipressin. The terlipressin treatmentprotocol comprises an init ial dose of 0.5-1 mg

terlipressin applied by intravenous injection every4-6 h or continuous intravenous infusion startingat an initial dose of 2 mg/d. The therapy is aimedto improve renal function and to decrease serum

creatinine to less than 1.5 mg/dl (complete response).If serum creatinine does not decrease at least 25% ofits base value or < 133 µmol/L after 3 days, the doseof terlipressin should be increased in a stepwisemanner up to a maximum of 2 mg/4 hour. For patientswith partial response (serum creatinine does notdecrease < 133 µmol/L) or in those patients withoutreduction of serum creatinine, treatment should

© JAPI • AUGUST 2014 • VOL. 62 699




be discontinu ed with in 14 days . If terl ipress in isnot available, alternative vasoconstrictors, such asnorepinephrine or combination octreotide/midodrine,together with albumin should be considered.Therapy should be discontinued after 14 days innon-responders and only continued thereafter inpartial responders while awaiting the outcome of

salvage techniques.16 Contraindications to terlipressintherapy include ischaemic cardiovascular diseases.Patients on terlipressin should be carefully monitoredfor development of cardiac arrhythmias or signsof splanchnic or digital ischaemia, and treatmentmodified or stopped accordingly. Recurrence of type1 HRS after discontinuation of terlipressin therapyis relatively uncommon. Treatment with terlipressinshould be repeated and is frequently successful.23

Norepinephrine

Norepinephrine, an α-1 adrenergic agonist drug,

has been found to be effective in the treatment ofHRS.29 Noradrenaline (0.5-3 mg/h) is administeredas a continuous infusion and the dose is increasedto achieve a raise in arterial pressure and alsoimproves renal function in patients with type 1 HRS.In a prospective, randomised study of 46 patients,the safety and efficacy of norepinephrine wascompared with terlipressin in treatment of type 1HRS. Albumin was administered in both the groups.Noradrenaline was found to be as safe and effectiveas terlipressin, but less expensive in the treatment

of HRS. On multivariate analysis, only baseline CTPscore was found to be predictive of response.30It is

also recommended by ADQI as an alternative toterlipressin along with albumin for the treatment ofHRS.16 A recent meta analysis also confirmed that norepinephrine and terlipressin are equivalent in efficacyand side effect profile in reversing HRS.31

Midodrine and Octreotide

Midodrine, an α-1 agonist has been used in bothtype 1 and 2 HRS. It causes vascular smooth muscleconstriction and the availability of an oral preparationmakes administration of this drug on an outpatient ba si s fea si bl e. St ud ie s ha ve sh own th at it is th e

combination of thrice daily midodrine (7.5- 12.5 mg)with octreotide (100- 200 µg subcutaneously) andalbumin, which actually improves renal plasma flow,GFR, urinary sodium excretion along with a reductionin renin, vasopressin and glucagon after 3 weeks oftreatment.32 In a recent study of 162 patients with HRStype 1 and type 2, the effect of octreotide, midodrine,and albumin on survival and renal function wascompared with a cohort that did not receive this

therapy. Transplantation could be performed in 45%of patients in the treatment group as compared with

26% of patients in the control group. It was concludedthat the therapeutic regimen of octreotide, midodrine,and albumin significantly improved short-termsurvival and renal function in both HRS type 1 andtype 2 and provided a significant benefit as a bridgeto liver transplantation in HRS type 1 and preventprogression of HRS type 2 to HRS type 1.33

Transjugular Intrahepatic PortosystemicShunt (TIPS)

In a recent study, 61 TIPS patients who had asubsequent liver transplantation were evaluatedand compared with 591 patients transplanted withcirrhosis without TIPS. It was shown that TIPSimproves post-transplant graft and patient survivalsignificantly, possibly due to an improved pre-transplant renal function and portal blood supply ofthe graft.34 EASL guidelines recommend that thoughthe insertion of TIPS may improve renal function in

some patients, there are insufficient data to supportthe use of TIPS as a treatment of patients with type 1HRS.23 Recent ADQI editorial reviews recommend useof TIPS as a treatment option for patients with type-2HRS with refractory ascites who require large-volumeparacentesis.5

Renal replacement therapy (RRT)

Although there is a preference for continuousrenal replacement therapy (CRRT) over intermittenthaemodialys is in haemodynamical ly unstablepatients, analysis of the currently published studies

does not provide enough evidence for the selectionof RRT as a modality for the treatment of AKI in thesetting of HRS.35 CRRT use may be advantageous inthe management of HRS patients with AKI who arehaemodynamically unstable or those patients at riskof elevated intracranial pressure such as patients withacute fulminant liver failure or acute on chronic liverfailure. In type-1 HRS, RRT should be avoided unlessthere is either an acute reversible component or a planfor liver transplantation.5 EASL recommends thatrenal replacement therapy may be useful in patientswho do not respond to vasoconstrictor therapy, and

who fulfill criteria for renal support.23

Artificial Liver Support Systems

There are very limited data on artificial liver supportsystems, and further studies are needed before its usein clinical practice can be recommended.16,23

Transplantation

HRS is a marker of poor hepatic function, whichwill recover only when there is some degree ofimprovement in liver function. In most patients, this

700 © JAPI • AUGUST 2014 • VOL. 62




will occur only after liver transplantation, which isthe best treatment for both type 1 and type 2 HRS.HRS should be treated before liver transplantation,s ince this may improve post - l iver t ransplantoutcome.23 Patients with HRS who do not respond tovasopressor therapy, and who require renal supportshould generally be treated by liver transplantation

alone, since the majority will achieve a recoveryof renal function post-liver transplantation. Thereis a subgroup of patients who require prolongedrenal support (> 12 weeks), and it is this group thatshould be considered for co mbined liver and kidneytransplantation.23 Nadim et al. have suggested livertransplantation alone for candidates with type 1HRS for less than 4 weeks and simultaneous liver-kidney (SLK) for those at risk of non recovery of

renal function.5 The united network of organ sharing(UNOS) recommendations for SLK transplant inpatients with AKI include those with hepatorenalsyndrome with creatinine ≥ 2 mg/dl and duration of

dialysis more than 8 weeks.36

For any given value of MELD or MELD-Na score,patients with HRS have a shorter survival expectancythan patients with chronic liver disease who arecandidates for LT.37 However, patients with HRS arenot given priority to liver transplantation as per the

policy of ‘‘exceptions to the MELD score’’ that arecurrently used in several Western countries.38 In arecent article, Angelli et al. suggested that to optimisethe results of the pharmacological treatment of HRS,responders should receive the right priority in thewaiting list, taking into account not only the value of

HRS per se on three-month mortality beyond the MELDscore, but also considering that the pharmacologicaltreatment of HRS can reduce the baseline MELD scorein these patients.39

Prognosis

The median survival of patients with type 1 HRSis only 10% at 90 days, whereas for type 2 HRS it is

6 months without treatment. Prognosis is howeverimproved with treatment with the 3 month survivalof 20 and 40% respectively for type 1 and 2 HRS.40

The survival in these groups of patients is dictated by the deterioration in l iver function, and theresponse to pharmacological treatment. If there is noimprovement with treatment of vasoconstrictors for10-14 days, it indicates a poor prognosis.

Conclusion

Despite of good pathophysiological understandingand bet ter avai lable therapeut ic opt ions formanagement of hepatorenal syndrome, it is stillassociated with significant morbidity and mortality.Liver transplantation forms the cornerstone for its

management. Timely identification, prioritisationfor transplant, and early initiation of vasoconstrictortherapy may contribute to better management plan.

References

1. Salerno F, Gerbes A, Gine`s P et al. Diagnosis, prevention and

treatment of hepatorenal syndrome in cirrhosis. Gut 2007;56:1310-

18.

2. Arroyo V, Ginès P, Gerbes AL, et al. Definiti on and diagnostic

criteria of refractory ascites and hepatorenal syndrome in cirrhosis.

International Ascites Club. Hepatology 1996;23:164–76.

3. Wong F, Nadim MK, Kellum JA, et al. Working Party proposal for a

revised classification system of renal dysfunction in patients with

cirrhosis. Gut 2011;60:702–9.

4. Davenport A, Cholongitas E, Xirouchakis E, Burroughs AK. Pitfalls

in assessing renal function in patients with cirrhosis-potential

inequity for access to treatment of hepatorenal failure and liver

transplantation. Nephrol Dial Transplant 2011; 26: 2735-42.

5. Mitra K, Nadim A, Kellum JA, et al. The ADQI Workgroup. Hepatorenal

syndrome: the 8th international consensus conference of the Acute

Dialysis Quality Initiative (ADQI) Group. Crit Care 2012;16:R23.

6. Ginès A, Escorsell A, Ginès P, et al. Incidence, predictive factors, and

prognosis of the hepatorenal syndrome in cirrhosis with ascites.

Gastroenterology 1993;105:229–36.

7. Moreau R, Durand F, Poynard T, et al. Terlipressin in patients

with cirrhosis and type 1 hepatorenal syndrome: a retrospective

multicenter study. Gastroenterology 2002;122:923–30.

8. Montoliu S, Ballesté B, Planas R, et al. Incidence and prognosis of

different types of functional renal failure in cirrhotic patients with

ascites. Clin Gastroenterol Hepatol 2010;8:616-22.

9. Schepke M. Hepatorenal syndrome: current diagnostic and

therapeutic concepts. Nephrol Dial Transplant 2007;22(Suppl8):viii2-4.

10. Wadei HM. Hepatorenal syndrome: a critical update. Semin Respir

Crit Care Med 2012;33:55–69.

11. Wong F. Recent advances in our understanding of hepatorenal

syndrome. Nat Rev Gastroenterol Hepatol 2012;9:382–391.

12. Bellot P, Frances R, Such J. Pathological bacterial translocation in

cirrhosis: pathophysiology, diagnosis and clinical implications. Liver

Int 2013;33:31–39.

13. Grace JA, Herath CB, Mak KY, et al. Update on new aspects of the

renin– angiotensin system in liver disease: clinical implications and

new therapeutic options. Clin Sci 2012;123: 225–39.

14. Arroyo V, Colmenero J. Ascites and hepatorenal syndrome in cirrhosis:

pathophysiological basis of therapy and current management. J

Hepatol 2003;38(Suppl1):S69–S89.

15. Hartleb M, Gutkowski K. Kidneys in chronic liver diseases. World J

Gastroenterol 2012;18:3035-49.

16. Davenport A, Ahmad J, Al-Khafaji A, Kellum JA, Genyk YS, Nadim

MK. Medical management of hepatorenal syndrome. Nephrol Dial

Transplant 2012;27:34-41.

17. Fernandez J, Escorsell A, Zabalza M et al. Adrenal insufficiency in

patients with cirrhosis and septic shock: effect of treatment with

hydrocortisone on survival. Hepatology 2006;44:1288–95.

18. Fernandez J, Navasa M, Planas R et al. Primary prophylaxis of

spontaneous bacterial peritonitis delays hepatorenal syndrome and

improves survival in cirrhosis. Gastroenterology 2007;133:818–24.

19. Sort P, Navasa M, Arroyo V et al. Effect of intravenous albumin on renal

impairment and mortality in patients with cirrhosis and spontaneous

bacterial peritonitis. N Engl J Med 1999;341:403–9.

© JAPI • AUGUST 2014 • VOL. 62 701




20. Fernández J, Monteagudo J, Bargallo X, et al. A randomized unblinded

pilot study comparing albumin versus hydroxyethyl starch in

spontaneous bacterial peritonitis. Hepatology 2005;42:627-34.

21. Lebrec D, Thabut D, Oberti F et al. Pentoxifylline does not decrease

short-term mortality but does reduce complications in patients with

advanced cirrhosis. Gastroenterology 2010;138:1755–1762

22. Nasr G, Hassan A, Ahmed S, Serwah A. Predictors of large volume

paracentesis induced circulatory dysfunction in patients with

massive hepatic ascites. J Cardiovasc Dis Res. 2010;1:136-44.23. European Association for the Study of the Liver. EASL clinical practice

guidelines on the management of ascites, spontaneous bacterial

peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatology

2010;53:397–417.

24. Moller S, Hansen EF, Becker U, Brinch K, Henriksen JH, Bendtsen F.

Central and systemic hemodynamic effects of terlipressin in portal

hypertensive patients. Liver 2000;20:51–9.

25. Halimi C, Bonnard P, Bernard B et al. Effect of terlipressin (Glypressin)

on hepatorenal syndrome in cirrhotic patients: results of a

multicentre pilot study. Eur J Gastroenterol Hepatol 2002;14:153-8.

26. Sagi SV, Mittal S, Kasturi KS, Sood GK. Terlipressin therapy for reversal

of type 1 hepatorenal syndrome: a meta-analysis of randomized

controlled trials. J. Gastroenterol. Hepatol 2010;25:880–5.

27. Sanyal AJ, Boyer T, Garcia-Tsao G et al . A randomized, prospective,

double-blind, placebo-controlled trial of Terlipressin for type 1

hepatorenal syndrome. Gastroenterology 2008;134:1360–8.

28. Caraceni P, Santi L, Mirici F, Montanari G, Bevilacqua V, Pinna AD,

Bernardi M..Long-term treatment of hepatorenal syndrome as a

bridge to liver transplantation. Dig Liver Dis 2011;43:242-5.

29. Alessandria C, Ottobrelli A, Debernardi-Venon W et al . Noradrenaline

vs Terlipressin in patients with hepatorenal syndrome: a prospective

randomized unblinded pilot study. J Hepatol 2007;47:499–505.

30. Singh V, Ghosh S, Singh B, et al. Noradrenaline vs. terlipressin in the

treatment of hepatorenal syndrome: a randomized study. J Hepatol

2012;56:1293-8.

31. Dobre M, Demirjian S, Sehgal AR, Navaneethan SD. Terlipressin in

hepatorenal syndrome: a systematic review and meta-analysis. Int

Urol Nephrol 2011;43:175–84.

32. Pomier-Layrargues G, Paquin SC, Hassoun Z et al. Octreotide in

hepatorenal syndrome: a randomized, double-blind, placebo-

controlled, crossover study. Hepatology 2003;38:238–43.

33. Skagen C, Einstein M, Lucey MR, Said A. Combination treatment with

octreotide, midodrine, and albumin improves survival in patients

with type 1 and type 2 hepatorenal syndrome. J Clin Gastroenterol 2009;43:680-5.

34. Guerrini GP, Pleguezuelo M, Maimone S, et al. Impact of tips pre

liver transplantation for the outcome post transplantation. Am J

Transplant 2009;9:192-200.

35. Palevsky PM, Zhang JH, O’Connor TZ, et al. Intensity of renal support

in critically ill patients with acute kidney injury. N Engl J Med

2008;359:7–20.

36. Eason JD, Gonwa TA, Davies CL, Sung RS, Gerber D, Bloom RD.

Proceedings of consensus conference on simultaneous liver–kidney

transplantation [SLK]. Am J Transplant2008;8:2243–51.

37. Alessandria C, Ozdogan O, Guevara M, et al. MELD score and clinical

type predict prognosis in hepatorenal syndrome: relevance to liver

transplantation. Hepatology 2005;41:1282-9.

38. Freeman Jr RB, Gish RG, Harper A, et al. Model for end-stage liver

disease [MELD] exception guidelines: results and recommendations

from the MELD Exception Study Group and Conference [MESSAGE]

for the approval of patients who need liver transplantation with

diseases not considered by the standard MELD formula. Liver Transpl

2006;12:S128–36.

39. Paolo Angeli, Pere Gines. Hepatorenal syndrome, MELD score and

liver transplantation: An evolving issue with relevant implications

for clinical practice. J Hepatology 2012;57:1135-40.

40. Salerno F, Cazzaniga M, Merli M, et al. Diagnosis, treatment and

survival of patients with hepatorenal syndrome: a survey on daily

medical practice. J Hepatol 2011;55:1241–48.

702 © JAPI • AUGUST 2014 • VOL. 62

Documents

07 Ra Hepatorenal Syndrome