Accepted Article
Acute kidney injury and hepatorenal syndrome in cirrhosis1
Mads Egerod Israelsen1, Lise Lotte Gluud2, Aleksander Krag1
1) Department of Gastroenterology, Odense University Hospital, University of Southern Denmark, Odense, Denmark
2) Department of Gastroenterology, Hvidovre University Hospital, University of Copenhagen, Hvidovre, Denmark CORRESPONDING AUTHOR: Aleksander Krag, MD, PhD, Professor Department of Gastroenterology, Entrance 126, 2nd floor Odense University Hospital, University of Southern Denmark Sdr. Boulevard 29, 5000 Odense Denmark
E-mail: [email protected]:
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/jgh.12709
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Accepted Article Abstract
Cirrhosis is the eighth leading cause of “years of lost life” in the US and accounts for approximately 1 to 2% of all deaths in Europe. Patients with cirrhosis have a high risk of developing acute kidney injury. The clinical characteristics of HRS are similar to prerenal uraemia, but the condition does not respond to volume expansion. HRS type 1 is rapidly progressive whereas HRS type 2 has a slower course often associated with refractory ascites. A number of factors can precipitate HRS such as infections, alcoholic hepatitis and bleeding. The monitoring, prevention, early detection and treatment of HRS are essential. This paper reviews the value of early evaluation of renal function based on two new sets of diagnostic criteria. Interventions for HRS type 1 include terlipressin
combined with albumin. In HRS type 2 transjugular intrahepatic portosystemic shunt (TIPS) should be considered. For both types of HRS patients should be evaluated for liver transplantation. Key words: Cirrhosis, hepatorenal syndrome, acute kidney injury, acute-on-chronic-liver-failure, cirrhotic cardiomyopathy, adrenal insufficiency
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Introduction Cirrhosis is a chronic liver disease that accounts for approximately 1 to 2% of all deaths in Europe1. In the US, the number of deaths caused by cirrhosis has increased over the last twenty years and cirrhosis is responsible for more than 1.23 million years of lost life. This makes cirrhosis the eighth
leading cause of “years of lost life” in the US2. Cirrhosis is a global burden and was the cause of 493,300 alcohol-related deaths in 20103. In the UK, hospital admissions due to liver disease are expected to increase to 2 million per year by 20204. The increasing mortality rate from chronic liver disease combined with falling hospital admissions and mortality rates from other chronic diseases, such as stroke and heart disease, calls for increased focus on complication to chronic liver diseases4. Within a period of ten years following the diagnosis of cirrhosis, around 60% will develop ascites5. Cirrhosis and ascites are associated with high morbidity and mortality. Renal failure is one of the most severe complications. More than 50% of patients with renal failure and cirrhosis die within one month after the diagnosis6. Twenty percent of hospitalised patients with cirrhosis and ascites develop acute kidney injury. Twenty percent of these patients have hepatorenal syndrome (HRS)7, a condition that occurs mainly in patients with cirrhosis and ascites8. The clinical characteristics of HRS are similar to prerenal uraemia, but the condition does not respond to volume expansion. Other causes of kidney injury must be excluded to make the diagnosis, e.g. nephrotoxic medications. In recent years, progress has been made in the understanding of the underlying pathophysiology of HRS leading to a number of new diagnostic, therapeutic and prophylactic options. The purpose of this paper is to review the diagnostic criteria, pathophysiology and interventions for HRS and the latest findings on acute kidney injury.
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Definition of hepatorenal syndrome The diagnostic criteria for HRS were defined in 19968 and revised in 20079 (Table 1). Based on the
course of the disease, HRS is divided into two types: HRS type 1 is characterised by acute renal impairment with doubling of serum creatinine to > 226 µmol/l within two weeks9. The condition usually develops secondary to a decrease in blood pressure as part of an inflammatory response caused by e.g., spontaneous bacterial peritonitis, sepsis, severe alcoholic hepatitis or gastrointestinal bleeding9,10. The median survival without treatment is a few weeks11. HRS type 2 is characterised by a slow increase in serum creatinine from 133 to 226 μmol/l9. It is an
expression of a moderate reduction of renal function as a complication to end-stage liver disease and refractory ascites9,12. The median survival is 6 months8. The two types of HRS have different clinical courses and pathophysiology. While HRS type 1 often develops after an acute reduction in the effective arterial blood volume, HRS type 2 develops due to the haemodynamic derangement seen in end-stage liver disease with refractory ascites12.
Pathophysiology The pathophysiology leading to renal dysfunction includes several factors associated with cirrhosis (Figure 1). The main factors are the haemodynamic changes seen in patients with cirrhosis, ascites and portal hypertension. Portal hypertension causes an increased production and release of
endogenous vasodilatation agents such as nitric oxide, carbon monoxide, and cannabinoids mainly into the splanchnic arterial circulation. The consequence is vasodilation, increased plasma volume and blood flow in the splanchnic circulation leading to a reduction in the effective arterial blood volume and a drop in mean arterial pressure (MAP)13. To maintain sufficient perfusion of vital
organs, compensation is initiated by increased cardiac output (CO) and activation of the endogenous
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vasoconstrictors including the renin-angiotensin-aldosterone system, the sympathetic nervous system and release of arginine vasopressin14. In severe cases, the heart cannot longer provide a sufficient cardiac output to maintain an adequate MAP and circulation. The increased activity of the endogenous vasoconstrictors leads to renal vasoconstriction and sodium and water retention. Renal vasoconstriction combined with a reduced MAP may lead to hypoperfusion of the kidneys and renal impairment. Fluid retention leads to the development of ascites in the majority of the patients15. The
translocation of bacteria and bacterial products from the gut is likely to be a main factor in the progression of disease16. Translocation increases with the severity of the underlying liver disease leading to a chronic inflammatory state, spontaneous infections and complications including HRS16,17.
Understanding the circulatory dysfunction The circulatory changes in cirrhosis and portal hypertension affect several organs and compromise the organism’s resistance to haemodynamic instability due to infection, bleeding or surgery. Cardiomyopathy and relative adrenal insufficiency predict renal impairment and death and might be important for the understanding of the pathophysiology and future treatment of HRS. Cardiac hypertrophy, diastolic dysfunction and impaired response to inotropic and chronotropic stimuli are frequent subclinical observations in cirrhosis18-22. Renal failure in cirrhosis is associated with reduced CO18. HRS type 1 is associated with a reduced CO and a decreased cardiopulmonary pressure under hyperactive vasoconstriction systems and reduced MAP19. Cardiac dysfunction is closely related to a poor outcome including in particular renal impairment21,22. These findings
suggest a cardio renal link in advanced cirrhosis23. In theory, renal failure and decreased effective blood volume in HRS type 1 are the consequences of an arterial vasodilatation and an impaired cardiac contractility that compromise an increased CO in response to stress. Relative adrenal insufficiency is a common subclinical condition in patients with cirrhosis diagnosed as an
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inadequate production of cortisol in response to stimulation with synthetic adrenocorticotropic hormone (ACTH)24-26. It is seen in approximately 10 % of all cases of cirrhosis and frequency
increases with the severity of the liver disease27. Cirrhotic patients with adrenal insufficiency increases the risk of bacterial infection, septic shock and HRS26. Cortisol plays an important role in the haemodynamic homeostasis. The heart’s and blood vessels’ response to catecholamines and angiotensin-II is increased by cortisol. Low levels of cortisol lead to an inadequate increase in CO and inadequate vasoconstriction in response to stress28. Accordingly, adrenal insufficiency could be involved in the development of cardiomyopathy and HRS23,26,27. Treatment with hydrocortisone in patients with cirrhosis and sepsis has been investigated, but the results are equivocal and it can only be recommended in selected patients with documented AI29,30.
Acute-on-chronic liver failure Patients who develop HRS or other types of acute kidney dysfunction often present with acute deterioration of their chronic liver disease. Acute-on-chronic liver failure (ACLF) is associated with
a high risk of sequential organ failure and increased mortality31,32. A large-scale observational study was conducted to describe ACLF33. The study evaluated the severity of the organ dysfunction based on a composite score known as the Chronic Liver failure-Sequential Organ Failure Assessment (CLIF-SOFA) score. The score is based on the SOFA score34 which predict mortality in intensive care unit patients. The SOFA score was modified to make it a liver specific score. Based on the observational study, patients with ACLF were classed into four groups, which reflect the underlying mortality; no ACLF or grade 1, grade 2 or grade 3 (Table 2). The study showed that acute kidney failure with serum creatinine > 177 µmol/l and kidney dysfunction with serum creatinine 133 µmol/l to 177 µmol/l were strong predictors of mortality 33.
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Classification of acute kidney injury in cirrhosis The diagnostic criteria for HRS include a serum creatinine above 133 µmol/l. However, patients with cirrhosis often have reduced levels of serum creatinine due to malnutrition and decreased muscle mass35. Serum creatinine may therefore overestimate the renal function. A revised strategy
that is more sensitive to changes in creatinine rather than the absolute creatinine level may improve early detection of HRS and other types of acute kidney injury in patients with severe liver disease. In 2007, the Acute Kidney Injury Network (AKIN) established new criteria for the classification of acute renal failure36 (Table 1). The classification is more sensitive to small changes in serum
creatinine and may improve the assessment of kidney injury in cirrhosis. The Acute Dialysis Quality Initiative Group proposes a new classification of kidney dysfunction in cirrhosis based on
the AKIN criteria (Table 1)37. Several observational studies of patients with cirrhosis and renal insufficiency have evaluated the usefulness of the AKIN classification38-47. The main conclusion in most studies is that the AKIN criteria predict mortality, infection and potentially the risk of progression to HRS (Table 3). Although the AKIN criteria are useful, it has been argued that the criteria specific to HRS are more accurate46. A classification that combines the AKIN criteria with
the classic HRS criteria may provide a better prediction than the AKIN criteria alone40. Consensus
on this issue is not yet reached48_ENREF_44. In addition, no studies have investigated if the use of the AKIN criteria improves patients' overall prognosis.
Prevention and treatment of the triggering event Volume depletion due to infection, severe alcoholic hepatitis, gastrointestinal bleeding can trigger HRS type 15,49.
Spontaneous bacterial peritonitis (SBP) is the predominant infection leading to HRS. It is defined as an infection in the ascites fluid with > 250 neutrophils/mm3-ascites fluid. Patients with cirrhosis
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and ascites have a compromised immune system and an increased risk of translocation of intestinal bacteria49,50. This leads to HRS in approximately 30% of the patients. SBP is often associated with gram-negative aerobic bacteria. Several antibiotics have been recommended for the initial treatment of SBP including cefotaxime or other third-generation cephalosporins, amoxicillin-clavulanic acid
or quinolones49. Ascites puncture should be repeated after 2-3 days to assess the effect of treatment on neutrophil count if a lack of response is suspected. A meta-analysis51 found that albumin
infusion combined with antibiotics reduces the incidence of renal impairment and mortality. Patients with low ascites protein (100 g/day) and
usually after withdrawal of alcohol intake. Symptoms include jaundice, fever, ascites and proximal loss of muscles. Severe cases are often associated with increased serum creatinine and the development of HRS type 153. Standard treatment is prednisolone or pentoxifylline. A double-blind randomised controlled trial on 270 patients with alcoholic hepatitis found no difference in mortality between patients allocated to prednisolone and pentoxifylline versus prednisolone and placebo54. The trial found a potential benefit on HRS in the pentoxifylline-group, which is consistent with the results of a meta-analysis on pentoxifylline55. Thus pentoxifylline may be the preferred first line treatment for patients with alcoholic hepatitis and high risk of HRS, which is in line with a recent multiple treatment comparison meta-analysis56.
Gastrointestinal bleeding may result in blood loss and infections both of which may lead to HRS57. Variceal bleeding is treated according to clinical guidelines including resuscitation, antibiotic prophylaxis, vasoactive drugs and endoscopic therapy57-59_ENREF_58. For bleeding
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oesophageal varices, the administration of terlipressin and antibiotics reduces bleeding, mortality and the risk of HRS59. Oral quinolones are the antibiotic recommended for most patients57.
Intravenous cephalosporins should be considered in patients with severer cirrhosis and patients in previous quinolone prophylaxis58.
Paracentesis with large volume (>5 liters) may affect haemodynamics and thereby result in postparacentesis circulatory dysfunction (PCD)60. This condition is characterised as a reduction in the effective blood volume and may lead to HRS5. A meta-analysis61 found that approximately 73 %
develops PCD after undergoing large volume paracentesis (LVP) if the procedure is not combined with volume supportive treatment. This meta-analyse_ENREF_30 shows that administration of
albumin reduces the incidence of post-paracentesis circulatory dysfunction, HRS type 1 and mortality61. Therefore albumin should be administrated to all patients undergoing LVP (8 grams per liter of drained ascites fluid)5.
Management of patients with cirrhosis, ascites and renal impairment Renal impairment in patients with cirrhosis and ascites should be evaluated quickly. Correct handling of renal impairment is required to avoid further deterioration and reduce the risk of renal failure and death62. Table 4 describes a proposal for primary investigation of patients with cirrhosis, ascites and renal impairment. The initial evaluation should include volume expansion by infusion of human albumin and discontinuation of diuretics and nephrotoxic drugs (Table 5). Other causes that can lead to renal impairment (e.g. obstructive uropathy) should also be excluded.
Evidence-based intervention for treatment of HRS Vasoconstrictors and albumin
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Terlipressin and albumin is the recommended treatment for patients with HRS type 1. The treatment improves the MAP and thereby the renal perfusion. Terlipressin, which is an analogue of vasopressin, induces vasoconstriction by stimulating vasopressin-receptors in the smooth muscle cells in the vessel wall63. Intravenous administration of albumin combined with terlipressin increases the effective arterial blood volume and thereby preload to the heart64. This improves the
circulation and stabilises MAP as a result of an increased preload and CO13. The treatment of HRS type 1 should be initiated rapidly, as early diagnosis and treatment improves the prognosis65. The effect of terlipressin and albumin has been assessed in several randomised clinical trials. When the results are combined in a meta-analysis, terlipressin and albumin reduce the mortality and improve renal function in patients with HRS type 166. There is little evidence for this treatment of HRS type 2. A few small studies have compared the effect of terlipressin with norepinephrine or other vasoconstrictors. Since the trials have low statistical power, it is not possible to assess whether other vasoconstrictors are as effective as terlipressin. There is no standardised dose of terlipressin, but the efficacy in HRS has been established in studies using an initial bolus injection of 1 mg 4-6 times daily and titrated to a maximum of 2 mg 6 times daily based on the effect on creatinine (Table 6)5.
Terlipressin is considered effective if S-creatinine is reduced > 25 % after 3 days of intervention. Treatment should be continued until S-creatinine is below 133 μmol/l. The treatment is effective in
up to 40% of the patients using current the diagnostic criteria and dose regime37. An ongoing RCT (NCT01530711) is currently evaluating terlipressin titrated according to the haemodynamic response. The dose of terlipressin is increased every 8 hours until the arterial blood pressure is increased with more than 10 mmHg or S-creatinine is reduced with more than 25 %. Adverse events Approximately 30% of patients develop adverse events on terlipressin. In 4% of patients treatment with terlipressin has to be stopped due to adverse events63. Most adverse events reflect
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vasoconstrictor effects with mild degrees of peripheral ischemia including cyanotic fingers and toes. Arrhythmias, most commonly bradycardia, are seen in approximately 7% of patients. Sixteen percent of patients develop abdominal pain and diarrhoea probably due to splanchnic ischemia. There has been one case of intestinal ischemic necrosis. Rarely, ischemic necrosis is seen63. Dealing with adverse events
There is no specific antidote to terlipressin. Careful selection of patients without contraindications, close surveillance of adverse events and daily adjustments of the dose and duration of therapy is recommended to prevent serious adverse events and treatment withdrawals. Myocardial infarctions and malignant arrhythmias are absolute contraindications to continued therapy. The efficacy of terlipressin is established in studies with bolus infusion66, however continuous infusion may be as
effective as bolus and have fewer adverse events67. This is being examined in an on-going equivalence trial (NCT00742690). Continuous low dose infusion can therefore, until further data document non-inferiority to bolus infusion, only be recommended in patients with an increased risk of adverse events or in case of moderate AEs. Less severe side effects such as skin cyanosis without necrosis can usually be managed by a reduction in dose and oxygen therapy or shifting from bolus to continuous infusion therapy. Abdominal pain and loose stools are usually self-limiting. In patients with mild to moderate atherosclerotic cardiovascular disease, terlipressin can be administered at a low dose or as continuous infusion with careful titration and monitoring.
Alternative vasoconstrictors In some countries, including USA, terlipressin is not available. The American Association for the Study of Liver Diseases’ guidelines on management of ascites suggest albumin infusion plus midodrine and octreotid or norepinephrine in the treatment of HRS type 168. Even though some
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studies found benefits in these treatments additional randomised controlled trials are still needed as the evidence to support these recommendations are weak69.
Transjugular intrahepatic portosystemic shunt HRS type 2 develops in patients with ascites refractory to treatment with diuretics. Therapeutic paracentesis and Transjugulær Intrahepatic Porto-systemic Shunt (TIPS) have been studied and both are considered effective treatments. Randomised controlled trials suggest that TIPS improves survival compared with therapeutic paracentesis70. TIPS can cause heart failure and increases the
risk of hepatic encephalopathy. Therefore, cardiac function should be examined and a history of hepatic encephalopathy should be included when assessing the treatment strategy70,71. The Model of End-stage Liver Disease (MELD) score predicts the survival in patients treated with elective TIPS72. Therefore the MELD score should be included in monitoring of patients to better select the patients who would benefit from TIPS placement. Liver Transplantation Liver transplantation should be considered in all patients with advanced liver disease, if there are no obvious contraindications such as ongoing excessive use of alcohol or malignant disease. A successful liver transplantation will completely reverse HRS73. The 5-year post-transplant mortality
is 32% in patients with advanced liver disease and prerenal dysfunction74. Simultaneous liverkidney transplantation should be considered when renal failure reflects chronic kidney disease with GFR < 30 mL/min or acute kidney injury with dialysis > 8 weeks75.
Conclusion Cirrhosis is a growing global problem. World-wide death caused by cirrhosis is increasing. Acute kidney injury is an important prognostic marker in cirrhosis. HRS is seen in approximately 20 % of cirrhotic patients hospitalised with renal impairment. A number of well-known factors can trigger 12 This article is protected by copyright. All rights reserved.
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HRS. The risk of developing HRS can be reduced by prevention of these events as well as adequate treatment. HRS type 2 is associated with end-stage liver disease and patients should be evaluated for TIPS or liver transplantation. For HRS Type 1 the first line treatment is the combination of terlipressin and albumin. This treatment is effective in up to 40 % of the patients under current diagnostic criteria and dose regime, which is why a more aggressive dose titration as well as earlier detection of renal impairment is under evaluation. The SOFA-CLIF score is a prognostic tool to estimate the survival in patients with cirrhosis and acute deterioration. In this scoring system kidney dysfunction is associated with very poor outcome. The AKI criteria is suggested to detect those patients earlier who have an increased risk of developing HRS and death by use of small changes in serum creatinine. However, there is not at this stage a consensus on the application of the criteria and
more research is needed in this area. Conflict of interest The authors declare that they have no competing interests. Acknowledgement Figure 1 is made in a collaboration of designer Jalte Windum and the authors. 1. Blachier M, Leleu H, Peck-Radosavljevic M, Valla DC, Roudot-Thoraval F. The burden of liver disease in Europe: a review of available epidemiological data. Journal of hepatology 2013;58:593-608. 2. Collaborators USBoD. The state of US health, 1990-2010: burden of diseases, injuries, and risk factors. JAMA : the journal of the American Medical Association 2013;310:591-608. 3. Rehm J, Samokhvalov AV, Shield KD. Global burden of alcoholic liver diseases. Journal of hepatology 2013;59:160-8. 4. Williams R, Horton R. Liver disease in the UK: a Lancet Commission. Lancet 2013;382:1537-8. 5. European Association for the Study of the L. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. Journal of hepatology 2010;53:397-417. 6. Fede G, D'Amico G, Arvaniti V, et al. Renal failure and cirrhosis: a systematic review of mortality and prognosis. Journal of hepatology 2012;56:810-8. 7. Garcia-Tsao G, Parikh CR, Viola A. Acute kidney injury in cirrhosis. Hepatology 2008;48:206477. 8. Arroyo V, Gines P, Gerbes AL, et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology 1996;23:164-76. 9. Salerno F, Gerbes A, Gines P, Wong F, Arroyo V. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007;56:1310-8.
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53. European Association for the Study of L. EASL clinical practical guidelines: management of alcoholic liver disease. Journal of hepatology 2012;57:399-420. 54. Mathurin P, Louvet A, Duhamel A, et al. Prednisolone with vs without pentoxifylline and survival of patients with severe alcoholic hepatitis: a randomized clinical trial. JAMA : the journal of the American Medical Association 2013;310:1033-41. 55. Parker R, Armstrong MJ, Corbett C, Rowe IA, Houlihan DD. Systematic review: pentoxifylline for the treatment of severe alcoholic hepatitis. Alimentary pharmacology & therapeutics 2013;37:845-54. 56. Thiele M, Del Giovane, C, Askgaard, G & Krag, A. Pentoxifylline is superior to corticosteroids and n-acetylcysteine in alcoholic hepatitis: A multiple-treatment comparison meta-analysis. Hepatology 2013 2014;58:(Suppl): 581A. 57. Bendtsen F, Krag A, Moller S. Treatment of acute variceal bleeding. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 2008;40:328-36. 58. de Franchis R, Baveno VF. Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension. Journal of hepatology 2010;53:762-8. 59. Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W, Practice Guidelines Committee of the American Association for the Study of Liver D, Practice Parameters Committee of the American College of G. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007;46:922-38. 60. Ruiz-del-Arbol L, Monescillo A, Jimenez W, Garcia-Plaza A, Arroyo V, Rodes J. Paracentesisinduced circulatory dysfunction: mechanism and effect on hepatic hemodynamics in cirrhosis. Gastroenterology 1997;113:579-86. 61. Bernardi M, Caraceni P, Navickis RJ, Wilkes MM. Albumin infusion in patients undergoing large-volume paracentesis: a meta-analysis of randomized trials. Hepatology 2012;55:1172-81. 62. Moreau R, Lebrec D. Acute renal failure in patients with cirrhosis: perspectives in the age of MELD. Hepatology 2003;37:233-43. 63. Krag A, Borup T, Moller S, Bendtsen F. Efficacy and safety of terlipressin in cirrhotic patients with variceal bleeding or hepatorenal syndrome. Advances in therapy 2008;25:1105-40. 64. 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. The New England journal of medicine 1999;341:403-9. 65. Sanyal AJ, Boyer T, Garcia-Tsao G, et al. A randomized, prospective, double-blind, placebocontrolled trial of terlipressin for type 1 hepatorenal syndrome. Gastroenterology 2008;134:1360-8. 66. Gluud LL, Christensen K, Christensen E, Krag A. Terlipressin for hepatorenal syndrome. The Cochrane database of systematic reviews 2012;9:CD005162. 67. Gerbes AL, Huber E, Gulberg V. Terlipressin for hepatorenal syndrome: continuous infusion as an alternative to i.v. bolus administration. Gastroenterology 2009;137:1179; author reply -81. 68. Runyon BAAPGC. Management of adult patients with ascites due to cirrhosis: update 2012. Wiley Online Library - update based on Hepatology 2009;49:2087-107 2012. 69. Gluud LL, Christensen K, Christensen E, Krag A. Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome. Hepatology 2010;51:576-84. 70. Salerno F, Camma C, Enea M, Rossle M, Wong F. Transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis of individual patient data. Gastroenterology 2007;133:825-34. 71. Rossle M, Gerbes AL. TIPS for the treatment of refractory ascites, hepatorenal syndrome and hepatic hydrothorax: a critical update. Gut 2010;59:988-1000. 72. Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, ter Borg PC. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology 2000;31:864-71. 73. Boyer TD, Sanyal AJ, Garcia-Tsao G, et al. Impact of liver transplantation on the survival of patients treated for hepatorenal syndrome type 1. Liver transplantation : official publication of the
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American Association for the Study of Liver Diseases and the International Liver Transplantation Society 2011;17:1328-32. 74. Sharma P, Welch K, Eikstadt R, Marrero JA, Fontana RJ, Lok AS. Renal outcomes after liver transplantation in the model for end-stage liver disease era. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 2009;15:1142-8. 75. Martin PD, A. Feng, S. Brown, Jr. Fallon, M. Evaluation for Liver Transplantation in Adults: 2013 Practice Guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology 2014;59:22.
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Diagnostic criteria of hepatorenal syndrome:
Acute Kidney Injury Networks classification of acute kidney injury:
• Cirrhosis with ascites
Grade I
Increase in serum creatinine 50 100% from baseline or 26.4 µmol/l within 48 hours.
Grade II
Increase in serum creatinine > 100200% from baseline
Grade III
Increase in serum creatinine to > 200% from baseline or acute increase of 44 µmol/l to 354 µmol/l
• S-creatinine> 133 µmol/l • No improvement in serum creatinine (i.e. Screatinine
Acute kidney injury and hepatorenal syndrome in cirrhosis1
Mads Egerod Israelsen1, Lise Lotte Gluud2, Aleksander Krag1
1) Department of Gastroenterology, Odense University Hospital, University of Southern Denmark, Odense, Denmark
2) Department of Gastroenterology, Hvidovre University Hospital, University of Copenhagen, Hvidovre, Denmark CORRESPONDING AUTHOR: Aleksander Krag, MD, PhD, Professor Department of Gastroenterology, Entrance 126, 2nd floor Odense University Hospital, University of Southern Denmark Sdr. Boulevard 29, 5000 Odense Denmark
E-mail: [email protected]:
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/jgh.12709
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Accepted Article Abstract
Cirrhosis is the eighth leading cause of “years of lost life” in the US and accounts for approximately 1 to 2% of all deaths in Europe. Patients with cirrhosis have a high risk of developing acute kidney injury. The clinical characteristics of HRS are similar to prerenal uraemia, but the condition does not respond to volume expansion. HRS type 1 is rapidly progressive whereas HRS type 2 has a slower course often associated with refractory ascites. A number of factors can precipitate HRS such as infections, alcoholic hepatitis and bleeding. The monitoring, prevention, early detection and treatment of HRS are essential. This paper reviews the value of early evaluation of renal function based on two new sets of diagnostic criteria. Interventions for HRS type 1 include terlipressin
combined with albumin. In HRS type 2 transjugular intrahepatic portosystemic shunt (TIPS) should be considered. For both types of HRS patients should be evaluated for liver transplantation. Key words: Cirrhosis, hepatorenal syndrome, acute kidney injury, acute-on-chronic-liver-failure, cirrhotic cardiomyopathy, adrenal insufficiency
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Introduction Cirrhosis is a chronic liver disease that accounts for approximately 1 to 2% of all deaths in Europe1. In the US, the number of deaths caused by cirrhosis has increased over the last twenty years and cirrhosis is responsible for more than 1.23 million years of lost life. This makes cirrhosis the eighth
leading cause of “years of lost life” in the US2. Cirrhosis is a global burden and was the cause of 493,300 alcohol-related deaths in 20103. In the UK, hospital admissions due to liver disease are expected to increase to 2 million per year by 20204. The increasing mortality rate from chronic liver disease combined with falling hospital admissions and mortality rates from other chronic diseases, such as stroke and heart disease, calls for increased focus on complication to chronic liver diseases4. Within a period of ten years following the diagnosis of cirrhosis, around 60% will develop ascites5. Cirrhosis and ascites are associated with high morbidity and mortality. Renal failure is one of the most severe complications. More than 50% of patients with renal failure and cirrhosis die within one month after the diagnosis6. Twenty percent of hospitalised patients with cirrhosis and ascites develop acute kidney injury. Twenty percent of these patients have hepatorenal syndrome (HRS)7, a condition that occurs mainly in patients with cirrhosis and ascites8. The clinical characteristics of HRS are similar to prerenal uraemia, but the condition does not respond to volume expansion. Other causes of kidney injury must be excluded to make the diagnosis, e.g. nephrotoxic medications. In recent years, progress has been made in the understanding of the underlying pathophysiology of HRS leading to a number of new diagnostic, therapeutic and prophylactic options. The purpose of this paper is to review the diagnostic criteria, pathophysiology and interventions for HRS and the latest findings on acute kidney injury.
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Definition of hepatorenal syndrome The diagnostic criteria for HRS were defined in 19968 and revised in 20079 (Table 1). Based on the
course of the disease, HRS is divided into two types: HRS type 1 is characterised by acute renal impairment with doubling of serum creatinine to > 226 µmol/l within two weeks9. The condition usually develops secondary to a decrease in blood pressure as part of an inflammatory response caused by e.g., spontaneous bacterial peritonitis, sepsis, severe alcoholic hepatitis or gastrointestinal bleeding9,10. The median survival without treatment is a few weeks11. HRS type 2 is characterised by a slow increase in serum creatinine from 133 to 226 μmol/l9. It is an
expression of a moderate reduction of renal function as a complication to end-stage liver disease and refractory ascites9,12. The median survival is 6 months8. The two types of HRS have different clinical courses and pathophysiology. While HRS type 1 often develops after an acute reduction in the effective arterial blood volume, HRS type 2 develops due to the haemodynamic derangement seen in end-stage liver disease with refractory ascites12.
Pathophysiology The pathophysiology leading to renal dysfunction includes several factors associated with cirrhosis (Figure 1). The main factors are the haemodynamic changes seen in patients with cirrhosis, ascites and portal hypertension. Portal hypertension causes an increased production and release of
endogenous vasodilatation agents such as nitric oxide, carbon monoxide, and cannabinoids mainly into the splanchnic arterial circulation. The consequence is vasodilation, increased plasma volume and blood flow in the splanchnic circulation leading to a reduction in the effective arterial blood volume and a drop in mean arterial pressure (MAP)13. To maintain sufficient perfusion of vital
organs, compensation is initiated by increased cardiac output (CO) and activation of the endogenous
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vasoconstrictors including the renin-angiotensin-aldosterone system, the sympathetic nervous system and release of arginine vasopressin14. In severe cases, the heart cannot longer provide a sufficient cardiac output to maintain an adequate MAP and circulation. The increased activity of the endogenous vasoconstrictors leads to renal vasoconstriction and sodium and water retention. Renal vasoconstriction combined with a reduced MAP may lead to hypoperfusion of the kidneys and renal impairment. Fluid retention leads to the development of ascites in the majority of the patients15. The
translocation of bacteria and bacterial products from the gut is likely to be a main factor in the progression of disease16. Translocation increases with the severity of the underlying liver disease leading to a chronic inflammatory state, spontaneous infections and complications including HRS16,17.
Understanding the circulatory dysfunction The circulatory changes in cirrhosis and portal hypertension affect several organs and compromise the organism’s resistance to haemodynamic instability due to infection, bleeding or surgery. Cardiomyopathy and relative adrenal insufficiency predict renal impairment and death and might be important for the understanding of the pathophysiology and future treatment of HRS. Cardiac hypertrophy, diastolic dysfunction and impaired response to inotropic and chronotropic stimuli are frequent subclinical observations in cirrhosis18-22. Renal failure in cirrhosis is associated with reduced CO18. HRS type 1 is associated with a reduced CO and a decreased cardiopulmonary pressure under hyperactive vasoconstriction systems and reduced MAP19. Cardiac dysfunction is closely related to a poor outcome including in particular renal impairment21,22. These findings
suggest a cardio renal link in advanced cirrhosis23. In theory, renal failure and decreased effective blood volume in HRS type 1 are the consequences of an arterial vasodilatation and an impaired cardiac contractility that compromise an increased CO in response to stress. Relative adrenal insufficiency is a common subclinical condition in patients with cirrhosis diagnosed as an
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inadequate production of cortisol in response to stimulation with synthetic adrenocorticotropic hormone (ACTH)24-26. It is seen in approximately 10 % of all cases of cirrhosis and frequency
increases with the severity of the liver disease27. Cirrhotic patients with adrenal insufficiency increases the risk of bacterial infection, septic shock and HRS26. Cortisol plays an important role in the haemodynamic homeostasis. The heart’s and blood vessels’ response to catecholamines and angiotensin-II is increased by cortisol. Low levels of cortisol lead to an inadequate increase in CO and inadequate vasoconstriction in response to stress28. Accordingly, adrenal insufficiency could be involved in the development of cardiomyopathy and HRS23,26,27. Treatment with hydrocortisone in patients with cirrhosis and sepsis has been investigated, but the results are equivocal and it can only be recommended in selected patients with documented AI29,30.
Acute-on-chronic liver failure Patients who develop HRS or other types of acute kidney dysfunction often present with acute deterioration of their chronic liver disease. Acute-on-chronic liver failure (ACLF) is associated with
a high risk of sequential organ failure and increased mortality31,32. A large-scale observational study was conducted to describe ACLF33. The study evaluated the severity of the organ dysfunction based on a composite score known as the Chronic Liver failure-Sequential Organ Failure Assessment (CLIF-SOFA) score. The score is based on the SOFA score34 which predict mortality in intensive care unit patients. The SOFA score was modified to make it a liver specific score. Based on the observational study, patients with ACLF were classed into four groups, which reflect the underlying mortality; no ACLF or grade 1, grade 2 or grade 3 (Table 2). The study showed that acute kidney failure with serum creatinine > 177 µmol/l and kidney dysfunction with serum creatinine 133 µmol/l to 177 µmol/l were strong predictors of mortality 33.
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Classification of acute kidney injury in cirrhosis The diagnostic criteria for HRS include a serum creatinine above 133 µmol/l. However, patients with cirrhosis often have reduced levels of serum creatinine due to malnutrition and decreased muscle mass35. Serum creatinine may therefore overestimate the renal function. A revised strategy
that is more sensitive to changes in creatinine rather than the absolute creatinine level may improve early detection of HRS and other types of acute kidney injury in patients with severe liver disease. In 2007, the Acute Kidney Injury Network (AKIN) established new criteria for the classification of acute renal failure36 (Table 1). The classification is more sensitive to small changes in serum
creatinine and may improve the assessment of kidney injury in cirrhosis. The Acute Dialysis Quality Initiative Group proposes a new classification of kidney dysfunction in cirrhosis based on
the AKIN criteria (Table 1)37. Several observational studies of patients with cirrhosis and renal insufficiency have evaluated the usefulness of the AKIN classification38-47. The main conclusion in most studies is that the AKIN criteria predict mortality, infection and potentially the risk of progression to HRS (Table 3). Although the AKIN criteria are useful, it has been argued that the criteria specific to HRS are more accurate46. A classification that combines the AKIN criteria with
the classic HRS criteria may provide a better prediction than the AKIN criteria alone40. Consensus
on this issue is not yet reached48_ENREF_44. In addition, no studies have investigated if the use of the AKIN criteria improves patients' overall prognosis.
Prevention and treatment of the triggering event Volume depletion due to infection, severe alcoholic hepatitis, gastrointestinal bleeding can trigger HRS type 15,49.
Spontaneous bacterial peritonitis (SBP) is the predominant infection leading to HRS. It is defined as an infection in the ascites fluid with > 250 neutrophils/mm3-ascites fluid. Patients with cirrhosis
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and ascites have a compromised immune system and an increased risk of translocation of intestinal bacteria49,50. This leads to HRS in approximately 30% of the patients. SBP is often associated with gram-negative aerobic bacteria. Several antibiotics have been recommended for the initial treatment of SBP including cefotaxime or other third-generation cephalosporins, amoxicillin-clavulanic acid
or quinolones49. Ascites puncture should be repeated after 2-3 days to assess the effect of treatment on neutrophil count if a lack of response is suspected. A meta-analysis51 found that albumin
infusion combined with antibiotics reduces the incidence of renal impairment and mortality. Patients with low ascites protein (100 g/day) and
usually after withdrawal of alcohol intake. Symptoms include jaundice, fever, ascites and proximal loss of muscles. Severe cases are often associated with increased serum creatinine and the development of HRS type 153. Standard treatment is prednisolone or pentoxifylline. A double-blind randomised controlled trial on 270 patients with alcoholic hepatitis found no difference in mortality between patients allocated to prednisolone and pentoxifylline versus prednisolone and placebo54. The trial found a potential benefit on HRS in the pentoxifylline-group, which is consistent with the results of a meta-analysis on pentoxifylline55. Thus pentoxifylline may be the preferred first line treatment for patients with alcoholic hepatitis and high risk of HRS, which is in line with a recent multiple treatment comparison meta-analysis56.
Gastrointestinal bleeding may result in blood loss and infections both of which may lead to HRS57. Variceal bleeding is treated according to clinical guidelines including resuscitation, antibiotic prophylaxis, vasoactive drugs and endoscopic therapy57-59_ENREF_58. For bleeding
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oesophageal varices, the administration of terlipressin and antibiotics reduces bleeding, mortality and the risk of HRS59. Oral quinolones are the antibiotic recommended for most patients57.
Intravenous cephalosporins should be considered in patients with severer cirrhosis and patients in previous quinolone prophylaxis58.
Paracentesis with large volume (>5 liters) may affect haemodynamics and thereby result in postparacentesis circulatory dysfunction (PCD)60. This condition is characterised as a reduction in the effective blood volume and may lead to HRS5. A meta-analysis61 found that approximately 73 %
develops PCD after undergoing large volume paracentesis (LVP) if the procedure is not combined with volume supportive treatment. This meta-analyse_ENREF_30 shows that administration of
albumin reduces the incidence of post-paracentesis circulatory dysfunction, HRS type 1 and mortality61. Therefore albumin should be administrated to all patients undergoing LVP (8 grams per liter of drained ascites fluid)5.
Management of patients with cirrhosis, ascites and renal impairment Renal impairment in patients with cirrhosis and ascites should be evaluated quickly. Correct handling of renal impairment is required to avoid further deterioration and reduce the risk of renal failure and death62. Table 4 describes a proposal for primary investigation of patients with cirrhosis, ascites and renal impairment. The initial evaluation should include volume expansion by infusion of human albumin and discontinuation of diuretics and nephrotoxic drugs (Table 5). Other causes that can lead to renal impairment (e.g. obstructive uropathy) should also be excluded.
Evidence-based intervention for treatment of HRS Vasoconstrictors and albumin
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Terlipressin and albumin is the recommended treatment for patients with HRS type 1. The treatment improves the MAP and thereby the renal perfusion. Terlipressin, which is an analogue of vasopressin, induces vasoconstriction by stimulating vasopressin-receptors in the smooth muscle cells in the vessel wall63. Intravenous administration of albumin combined with terlipressin increases the effective arterial blood volume and thereby preload to the heart64. This improves the
circulation and stabilises MAP as a result of an increased preload and CO13. The treatment of HRS type 1 should be initiated rapidly, as early diagnosis and treatment improves the prognosis65. The effect of terlipressin and albumin has been assessed in several randomised clinical trials. When the results are combined in a meta-analysis, terlipressin and albumin reduce the mortality and improve renal function in patients with HRS type 166. There is little evidence for this treatment of HRS type 2. A few small studies have compared the effect of terlipressin with norepinephrine or other vasoconstrictors. Since the trials have low statistical power, it is not possible to assess whether other vasoconstrictors are as effective as terlipressin. There is no standardised dose of terlipressin, but the efficacy in HRS has been established in studies using an initial bolus injection of 1 mg 4-6 times daily and titrated to a maximum of 2 mg 6 times daily based on the effect on creatinine (Table 6)5.
Terlipressin is considered effective if S-creatinine is reduced > 25 % after 3 days of intervention. Treatment should be continued until S-creatinine is below 133 μmol/l. The treatment is effective in
up to 40% of the patients using current the diagnostic criteria and dose regime37. An ongoing RCT (NCT01530711) is currently evaluating terlipressin titrated according to the haemodynamic response. The dose of terlipressin is increased every 8 hours until the arterial blood pressure is increased with more than 10 mmHg or S-creatinine is reduced with more than 25 %. Adverse events Approximately 30% of patients develop adverse events on terlipressin. In 4% of patients treatment with terlipressin has to be stopped due to adverse events63. Most adverse events reflect
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vasoconstrictor effects with mild degrees of peripheral ischemia including cyanotic fingers and toes. Arrhythmias, most commonly bradycardia, are seen in approximately 7% of patients. Sixteen percent of patients develop abdominal pain and diarrhoea probably due to splanchnic ischemia. There has been one case of intestinal ischemic necrosis. Rarely, ischemic necrosis is seen63. Dealing with adverse events
There is no specific antidote to terlipressin. Careful selection of patients without contraindications, close surveillance of adverse events and daily adjustments of the dose and duration of therapy is recommended to prevent serious adverse events and treatment withdrawals. Myocardial infarctions and malignant arrhythmias are absolute contraindications to continued therapy. The efficacy of terlipressin is established in studies with bolus infusion66, however continuous infusion may be as
effective as bolus and have fewer adverse events67. This is being examined in an on-going equivalence trial (NCT00742690). Continuous low dose infusion can therefore, until further data document non-inferiority to bolus infusion, only be recommended in patients with an increased risk of adverse events or in case of moderate AEs. Less severe side effects such as skin cyanosis without necrosis can usually be managed by a reduction in dose and oxygen therapy or shifting from bolus to continuous infusion therapy. Abdominal pain and loose stools are usually self-limiting. In patients with mild to moderate atherosclerotic cardiovascular disease, terlipressin can be administered at a low dose or as continuous infusion with careful titration and monitoring.
Alternative vasoconstrictors In some countries, including USA, terlipressin is not available. The American Association for the Study of Liver Diseases’ guidelines on management of ascites suggest albumin infusion plus midodrine and octreotid or norepinephrine in the treatment of HRS type 168. Even though some
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studies found benefits in these treatments additional randomised controlled trials are still needed as the evidence to support these recommendations are weak69.
Transjugular intrahepatic portosystemic shunt HRS type 2 develops in patients with ascites refractory to treatment with diuretics. Therapeutic paracentesis and Transjugulær Intrahepatic Porto-systemic Shunt (TIPS) have been studied and both are considered effective treatments. Randomised controlled trials suggest that TIPS improves survival compared with therapeutic paracentesis70. TIPS can cause heart failure and increases the
risk of hepatic encephalopathy. Therefore, cardiac function should be examined and a history of hepatic encephalopathy should be included when assessing the treatment strategy70,71. The Model of End-stage Liver Disease (MELD) score predicts the survival in patients treated with elective TIPS72. Therefore the MELD score should be included in monitoring of patients to better select the patients who would benefit from TIPS placement. Liver Transplantation Liver transplantation should be considered in all patients with advanced liver disease, if there are no obvious contraindications such as ongoing excessive use of alcohol or malignant disease. A successful liver transplantation will completely reverse HRS73. The 5-year post-transplant mortality
is 32% in patients with advanced liver disease and prerenal dysfunction74. Simultaneous liverkidney transplantation should be considered when renal failure reflects chronic kidney disease with GFR < 30 mL/min or acute kidney injury with dialysis > 8 weeks75.
Conclusion Cirrhosis is a growing global problem. World-wide death caused by cirrhosis is increasing. Acute kidney injury is an important prognostic marker in cirrhosis. HRS is seen in approximately 20 % of cirrhotic patients hospitalised with renal impairment. A number of well-known factors can trigger 12 This article is protected by copyright. All rights reserved.
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HRS. The risk of developing HRS can be reduced by prevention of these events as well as adequate treatment. HRS type 2 is associated with end-stage liver disease and patients should be evaluated for TIPS or liver transplantation. For HRS Type 1 the first line treatment is the combination of terlipressin and albumin. This treatment is effective in up to 40 % of the patients under current diagnostic criteria and dose regime, which is why a more aggressive dose titration as well as earlier detection of renal impairment is under evaluation. The SOFA-CLIF score is a prognostic tool to estimate the survival in patients with cirrhosis and acute deterioration. In this scoring system kidney dysfunction is associated with very poor outcome. The AKI criteria is suggested to detect those patients earlier who have an increased risk of developing HRS and death by use of small changes in serum creatinine. However, there is not at this stage a consensus on the application of the criteria and
more research is needed in this area. Conflict of interest The authors declare that they have no competing interests. Acknowledgement Figure 1 is made in a collaboration of designer Jalte Windum and the authors. 1. Blachier M, Leleu H, Peck-Radosavljevic M, Valla DC, Roudot-Thoraval F. The burden of liver disease in Europe: a review of available epidemiological data. Journal of hepatology 2013;58:593-608. 2. Collaborators USBoD. The state of US health, 1990-2010: burden of diseases, injuries, and risk factors. JAMA : the journal of the American Medical Association 2013;310:591-608. 3. Rehm J, Samokhvalov AV, Shield KD. Global burden of alcoholic liver diseases. Journal of hepatology 2013;59:160-8. 4. Williams R, Horton R. Liver disease in the UK: a Lancet Commission. Lancet 2013;382:1537-8. 5. European Association for the Study of the L. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. Journal of hepatology 2010;53:397-417. 6. Fede G, D'Amico G, Arvaniti V, et al. Renal failure and cirrhosis: a systematic review of mortality and prognosis. Journal of hepatology 2012;56:810-8. 7. Garcia-Tsao G, Parikh CR, Viola A. Acute kidney injury in cirrhosis. Hepatology 2008;48:206477. 8. Arroyo V, Gines P, Gerbes AL, et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology 1996;23:164-76. 9. Salerno F, Gerbes A, Gines P, Wong F, Arroyo V. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007;56:1310-8.
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10. Arroyo V, Fernandez J, Gines P. Pathogenesis and treatment of hepatorenal syndrome. Seminars in liver disease 2008;28:81-95. 11. Gines A, Escorsell A, Gines P, et al. Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites. Gastroenterology 1993;105:229-36. 12. Salerno F, Guevara M, Bernardi M, et al. Refractory ascites: pathogenesis, definition and therapy of a severe complication in patients with cirrhosis. Liver international : official journal of the International Association for the Study of the Liver 2010;30:937-47. 13. Brinch K, Moller S, Bendtsen F, Becker U, Henriksen JH. Plasma volume expansion by albumin in cirrhosis. Relation to blood volume distribution, arterial compliance and severity of disease. Journal of hepatology 2003;39:24-31. 14. Gines P, Schrier RW. Renal failure in cirrhosis. The New England journal of medicine 2009;361:1279-90. 15. Moller S, Bendtsen F, Henriksen JH. Pathophysiological basis of pharmacotherapy in the hepatorenal syndrome. Scandinavian journal of gastroenterology 2005;40:491-500. 16. Wiest R, Lawson M, Geuking M. Pathological bacterial translocation in liver cirrhosis. Journal of hepatology 2013. 17. Madsen BS, Havelund T, Krag A. Targeting the Gut-Liver Axis in Cirrhosis: Antibiotics and Non-Selective beta-Blockers. Advances in therapy 2013;30:659-70. 18. Ruiz-del-Arbol L, Urman J, Fernandez J, et al. Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology 2003;38:1210-8. 19. Ruiz-del-Arbol L, Monescillo A, Arocena C, et al. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology 2005;42:439-47. 20. Wong F. Cirrhotic cardiomyopathy. Hepatology international 2009;3:294-304. 21. Krag A, Bendtsen F, Henriksen JH, Moller S. Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites. Gut 2010;59:105-10. 22. Ruiz-Del-Arbol L, Achecar L, Serradilla R, et al. Diastolic dysfunction is a predictor of poor outcomes in patients with cirrhosis, portal hypertension and a normal creatinine. Hepatology 2013. 23. Krag A, Bendtsen F, Burroughs AK, Moller S. The cardiorenal link in advanced cirrhosis. Medical hypotheses 2012;79:53-5. 24. Triantos CK, Marzigie M, Fede G, et al. Critical illness-related corticosteroid insufficiency in patients with cirrhosis and variceal bleeding. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 2011;9:595-601. 25. Fede G, Spadaro L, Tomaselli T, et al. Assessment of adrenocortical reserve in stable patients with cirrhosis. Journal of hepatology 2011;54:243-50. 26. Acevedo J, Fernandez J, Prado V, et al. Relative adrenal insufficiency in decompensated cirrhosis. relationship to short-term risk of severe sepsis, hepatorenal syndrome and death. Hepatology 2013. 27. Theocharidou E, Krag A, Bendtsen F, Moller S, Burroughs AK. Cardiac dysfunction in cirrhosis - does adrenal function play a role? A hypothesis. Liver international : official journal of the International Association for the Study of the Liver 2012;32:1327-32. 28. Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. The New England journal of medicine 2003;348:727-34. 29. 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. 30. Arabi YM, Aljumah A, Dabbagh O, et al. Low-dose hydrocortisone in patients with cirrhosis and septic shock: a randomized controlled trial. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 2010;182:1971-7. 31. Jalan R, Williams R. Acute-on-chronic liver failure: pathophysiological basis of therapeutic options. Blood purification 2002;20:252-61.
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Accepted Article
Diagnostic criteria of hepatorenal syndrome:
Acute Kidney Injury Networks classification of acute kidney injury:
• Cirrhosis with ascites
Grade I
Increase in serum creatinine 50 100% from baseline or 26.4 µmol/l within 48 hours.
Grade II
Increase in serum creatinine > 100200% from baseline
Grade III
Increase in serum creatinine to > 200% from baseline or acute increase of 44 µmol/l to 354 µmol/l
• S-creatinine> 133 µmol/l • No improvement in serum creatinine (i.e. Screatinine
