Liver International ISSN 1478-3223
CIRRHOSIS AND LIVER FAILURE
Evaluation of acute kidney injury and its response to terlipressin in patients with acute-on-chronic liver failure Ankur Jindal1, Ajeet S. Bhadoria2, Rakhi Maiwall1 and Shiv K. Sarin1,3 1 Department of Hepatology, Institute of Liver & Biliary Sciences (ILBS), New Delhi, India 2 Department of Biostatistics and Clinical Reserch, Institute of Liver & Biliary Sciences (ILBS), New Delhi, India 3 Special Centre for Molecular Medicine, Jawaharlal Nehru University (JNU), New Delhi, India
Liver Int. 2016; 36: 59–67. DOI: 10.1111/liv.12895
Abstract Background & aims: Patients with acute-on-chronic liver failure (ACLF) have high mortality. Cirrhotics with acute kidney injury (AKI) have poor outcome but relevance of AKI and response to terlipressin in ACLF is not known. Methods: Consecutive ACLF patients with AKI at admission were compared with those without AKI (controls) for mortality at day 7, month 1 and 3, presence of hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP) and acute variceal bleed (AVB). Patients were also compared based on severity of AKI (mild; S.cr 1.5–3 mg/dl and marked; S.cr >3 mg/dl). Response to terlipressin was also evaluated. Results: Of 241 ACLF patients, 55 (22.8%) had AKI at admission. Patients with AKI had higher mortality at day 7, 1 and 3 month and more often developed HE [54.1% vs. 30.6%; P = 0.001] and SBP [9.1% vs. 5.9%; P = 0.02]. Patients with marked AKI neither had higher mortality or complications in comparison to mild AKI. Presence of AKI [Odds ratio; OR, 2.4], S.bilirubin >20 mg/dl [OR, 3.1] and INR [OR, 2.9] were independent baseline predictors of mortality. Terlipressin was used in 28 of 55 patients with AKI who were volume non-responsive (hepatorenal syndrome, AKI-HRS). Ten (35.7%) of these showed response (S.Cr < 1.5 mg/dl) [median 4 days] and had lower mortality compared to terlipressin non-responders (10% vs. 50%, P = 0.05). There was no difference in terlipressin response in mild vs. marked AKI. Conclusions: Almost one-fourth of the ACLF patients have AKI at admission and presence of AKI, but not its severity predicts complications and high mortality. Terlipressin effectively reverses AKI-HRS within a week in ~35% of ACLF patients resulting in improved survival. Keywords cirrhosis – liver failure – renal dysfunction
ACLF is a common and serious hepatic ailment with high morbidity and short-term mortality (~30–70%) (1). It is characterized by an acute hepatic insult manifesting as jaundice and coagulopathy, complicated within 4 weeks by ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed
chronic liver disease (2). This definition allows early diagnosis before onset of sepsis and extrahepatic organ failure(s). Since acute hepatic insult is short-lived and timely interventions may overcome the crisis, establishment of prognostic factors at initial presentation is the key towards evaluating clinical interventions in
Abbreviations ACLF, Acute-on-chronic liver failure; AKI, acute kidney injury; APACHE II, Acute physiology and chronic health evaluation II; APASL, Asian Pacific Association for the Study of Liver; AVB, acute variceal bleed; DF, discrimination factor; EBL, endoscopic band ligation; G-CSF, Granulocyte colony stimulating factors; HCC, hepatocellular carcinoma; HE, hepatic encephalopathy; HIV, human immunodeficiency virus; HRS, hepatorenal syndrome; ILBS, Institute of Liver and Biliary Sciences; KCH, King’s College criteria; LDLT, living donor liver transplantation; MELD, model for endstage liver disease; S.cr, Serum creatinine; SBP, spontaneous bacterial peritonitis; UGIE, upper gastrointestinal endoscopy. Correspondence Dr Shiv Kumar Sarin, MD, DM, FNASc, Department of Hepatology, Institute of Liver and Biliary Sciences (ILBS), D1, Vasant kunj, New Delhi 110 070, India Tel: +91 11 46300000; Fax: +310 206 8766 e-mail: [email protected] Handling Editor: Stanislas Pol Received 31 March 2015; Accepted 2 June 2015 Additional Supporting Information may be found at onlinelibrary.wiley.com/doi/10.1111/liv.12895/suppinfo
Liver International (2016) © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
59
Jindal et al.
Evaluation of acute kidney injury in ACLF
Key Points
Impact of AKI in ACLF is significant and it is an important predictor of portal hypertension related complications. Presence of AKI, not its severity based on serum creatinine values is more important in predicting clinical outcomes in ACLF. Presence of AKI along with high bilirubin (>20 mg/dl) and INR (>2) independently predict mortality in ACLF at 3 month. Terlipressin is effective in 35% of patients with ACLF and AKI-HRS and thereby improve outcomes. ACLF. Although liver transplantation can significantly improve survival, it is often limited by donor shortages, lack of finances and access to liver transplant centres. Presence of acute kidney injury (AKI) is a major accompaniment of liver disease progression. Cirrhotics with AKI have poor prognosis with an overall survival rate of 50% at 1 month and 20% at 6 months (3). In a systematic review of 118 studies evaluating predictors of survival in cirrhosis, high serum creatinine was a powerful predictor of death in decompensated cirrhosis (4). Many elegant studies have thrown light upon AKI in cirrhosis, but none has specifically assessed the burden of AKI in ACLF or the role of systemic vasopressor therapy in these patients. Patients and methods Patients
A retrospective clinical record analysis of all consecutive cases of ACLF from the medical record library of the Institute of Liver and Biliary Sciences (ILBS), New Delhi from August 2010 to April 2013 was carried out after the approval from the Institutional ethical committee/ Institutional Review Board (ECR/67/Inst/DL/2013), ILBS. Informed written consent was taken from all the patients at the time of hospital admission. ACLF was defined as per APASL guidelines (2). Exclusion criteria were patients with chronic decompensated cirrhosis, advanced hepatocellular carcinoma (HCC), pregnancy, human immunodeficiency virus infection, ongoing treatment with terlipressin, septic shock or any other severe systemic or mental diseases. Those who underwent liver transplantation or albumin dialysis or had received granulocyte colony stimulating factors (G-CSF) were also excluded. Baseline evaluation
All patients were subjected to detailed history, clinical examination and had haematological tests including complete blood counts and international normalization ratio (INR), kidney and liver function tests at admis-
60
sion. Details pertaining to use of alcohol, hepatotoxic drugs and risk factors for viral hepatitis were recorded. Patient sera was tested for hepatitis B surface antigen and antibody to hepatitis C virus, IgM antibodies to hepatitis A and hepatitis E using commercial ELISA. Appropriate tests for autoimmune liver disease and Wilson’s disease were performed, if needed. Each patient also underwent real time ultrasonography and/or triple phase contrast enhanced CT scan, upper gastrointestinal endoscopy (UGIE) and alfa-feto protein (AFP) estimation. Diagnosis of cirrhosis was based on clinical examination, imaging characteristics and/or presence of varices on UGIE. Complications and follow up
AKI at admission was defined as >50% increase in serum creatinine level from the stable baseline value in 250 cells/mm3 (8). Acute variceal bleed was diagnosed as per Baveno V endoscopic criteria (9). Severity of liver failure was assessed by Child–Turcotte–Pugh (CTP) score and Model for end-stage liver disease (MELD) score. Although, Acute physiology and chronic health evaluation (APACHE II) and sequential organ failure assessment (SOFA) scores are reported as good predictors of ACLF severity (10), we felt that these scores are more adapted to ICU patients, in a late stage of the disease when organ failure has set in. All patients were followed up for the duration of hospitalization and their clinical outcomes were carefully recorded. General management of patients
Every patient received standard medical treatment including barrier nursing, nutritional supplementation including high calorie (35–40 cal/kg/day) and high protein diet (1.2–1.5 g/kg proteins/day), lactulose, bowel wash, antibiotics and intensive care monitoring, as required. Enteral or parenteral nutrition was provided to those patients where caloric requirement was not fulfilled by mouth. Standard guidelines based institutional protocols were followed up for the management of individual complications such as SBP, HE and acute variceal bleed. AKI based classification at admission
All included patients were categorized based on presence of AKI at admission (Group A) or no AKI (Group B). To study the impact of severity of AKI, Group A patients were further subgrouped as: mild AKI (S.creatinine ≤3 mg/dl) or marked AKI (S.creatinine >3 mg/dl). Although this classification is arbitrary, Liver International (2016) © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Jindal et al.
it may fulfil our need of recognizing a distinct group of ACLF patients with more severe degree of renal dysfunction at earliest, on the day of admission. All parameters were compared between each group. Survival outcome and end-points
Patient survival at different time frames [7 days, 1 and 3 month] was compared based on the presence of AKI at admission and severity of AKI. The primary endpoint was patient mortality and secondary outcomes were response to terlipressin and treatment related adverse effects. Terlipressin and response rates
In the absence of specific guidelines for terlipressin use in ACLF patients with AKI, patients with failure to decrease serum creatinine
CIRRHOSIS AND LIVER FAILURE
Evaluation of acute kidney injury and its response to terlipressin in patients with acute-on-chronic liver failure Ankur Jindal1, Ajeet S. Bhadoria2, Rakhi Maiwall1 and Shiv K. Sarin1,3 1 Department of Hepatology, Institute of Liver & Biliary Sciences (ILBS), New Delhi, India 2 Department of Biostatistics and Clinical Reserch, Institute of Liver & Biliary Sciences (ILBS), New Delhi, India 3 Special Centre for Molecular Medicine, Jawaharlal Nehru University (JNU), New Delhi, India
Liver Int. 2016; 36: 59–67. DOI: 10.1111/liv.12895
Abstract Background & aims: Patients with acute-on-chronic liver failure (ACLF) have high mortality. Cirrhotics with acute kidney injury (AKI) have poor outcome but relevance of AKI and response to terlipressin in ACLF is not known. Methods: Consecutive ACLF patients with AKI at admission were compared with those without AKI (controls) for mortality at day 7, month 1 and 3, presence of hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP) and acute variceal bleed (AVB). Patients were also compared based on severity of AKI (mild; S.cr 1.5–3 mg/dl and marked; S.cr >3 mg/dl). Response to terlipressin was also evaluated. Results: Of 241 ACLF patients, 55 (22.8%) had AKI at admission. Patients with AKI had higher mortality at day 7, 1 and 3 month and more often developed HE [54.1% vs. 30.6%; P = 0.001] and SBP [9.1% vs. 5.9%; P = 0.02]. Patients with marked AKI neither had higher mortality or complications in comparison to mild AKI. Presence of AKI [Odds ratio; OR, 2.4], S.bilirubin >20 mg/dl [OR, 3.1] and INR [OR, 2.9] were independent baseline predictors of mortality. Terlipressin was used in 28 of 55 patients with AKI who were volume non-responsive (hepatorenal syndrome, AKI-HRS). Ten (35.7%) of these showed response (S.Cr < 1.5 mg/dl) [median 4 days] and had lower mortality compared to terlipressin non-responders (10% vs. 50%, P = 0.05). There was no difference in terlipressin response in mild vs. marked AKI. Conclusions: Almost one-fourth of the ACLF patients have AKI at admission and presence of AKI, but not its severity predicts complications and high mortality. Terlipressin effectively reverses AKI-HRS within a week in ~35% of ACLF patients resulting in improved survival. Keywords cirrhosis – liver failure – renal dysfunction
ACLF is a common and serious hepatic ailment with high morbidity and short-term mortality (~30–70%) (1). It is characterized by an acute hepatic insult manifesting as jaundice and coagulopathy, complicated within 4 weeks by ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed
chronic liver disease (2). This definition allows early diagnosis before onset of sepsis and extrahepatic organ failure(s). Since acute hepatic insult is short-lived and timely interventions may overcome the crisis, establishment of prognostic factors at initial presentation is the key towards evaluating clinical interventions in
Abbreviations ACLF, Acute-on-chronic liver failure; AKI, acute kidney injury; APACHE II, Acute physiology and chronic health evaluation II; APASL, Asian Pacific Association for the Study of Liver; AVB, acute variceal bleed; DF, discrimination factor; EBL, endoscopic band ligation; G-CSF, Granulocyte colony stimulating factors; HCC, hepatocellular carcinoma; HE, hepatic encephalopathy; HIV, human immunodeficiency virus; HRS, hepatorenal syndrome; ILBS, Institute of Liver and Biliary Sciences; KCH, King’s College criteria; LDLT, living donor liver transplantation; MELD, model for endstage liver disease; S.cr, Serum creatinine; SBP, spontaneous bacterial peritonitis; UGIE, upper gastrointestinal endoscopy. Correspondence Dr Shiv Kumar Sarin, MD, DM, FNASc, Department of Hepatology, Institute of Liver and Biliary Sciences (ILBS), D1, Vasant kunj, New Delhi 110 070, India Tel: +91 11 46300000; Fax: +310 206 8766 e-mail: [email protected] Handling Editor: Stanislas Pol Received 31 March 2015; Accepted 2 June 2015 Additional Supporting Information may be found at onlinelibrary.wiley.com/doi/10.1111/liv.12895/suppinfo
Liver International (2016) © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
59
Jindal et al.
Evaluation of acute kidney injury in ACLF
Key Points
Impact of AKI in ACLF is significant and it is an important predictor of portal hypertension related complications. Presence of AKI, not its severity based on serum creatinine values is more important in predicting clinical outcomes in ACLF. Presence of AKI along with high bilirubin (>20 mg/dl) and INR (>2) independently predict mortality in ACLF at 3 month. Terlipressin is effective in 35% of patients with ACLF and AKI-HRS and thereby improve outcomes. ACLF. Although liver transplantation can significantly improve survival, it is often limited by donor shortages, lack of finances and access to liver transplant centres. Presence of acute kidney injury (AKI) is a major accompaniment of liver disease progression. Cirrhotics with AKI have poor prognosis with an overall survival rate of 50% at 1 month and 20% at 6 months (3). In a systematic review of 118 studies evaluating predictors of survival in cirrhosis, high serum creatinine was a powerful predictor of death in decompensated cirrhosis (4). Many elegant studies have thrown light upon AKI in cirrhosis, but none has specifically assessed the burden of AKI in ACLF or the role of systemic vasopressor therapy in these patients. Patients and methods Patients
A retrospective clinical record analysis of all consecutive cases of ACLF from the medical record library of the Institute of Liver and Biliary Sciences (ILBS), New Delhi from August 2010 to April 2013 was carried out after the approval from the Institutional ethical committee/ Institutional Review Board (ECR/67/Inst/DL/2013), ILBS. Informed written consent was taken from all the patients at the time of hospital admission. ACLF was defined as per APASL guidelines (2). Exclusion criteria were patients with chronic decompensated cirrhosis, advanced hepatocellular carcinoma (HCC), pregnancy, human immunodeficiency virus infection, ongoing treatment with terlipressin, septic shock or any other severe systemic or mental diseases. Those who underwent liver transplantation or albumin dialysis or had received granulocyte colony stimulating factors (G-CSF) were also excluded. Baseline evaluation
All patients were subjected to detailed history, clinical examination and had haematological tests including complete blood counts and international normalization ratio (INR), kidney and liver function tests at admis-
60
sion. Details pertaining to use of alcohol, hepatotoxic drugs and risk factors for viral hepatitis were recorded. Patient sera was tested for hepatitis B surface antigen and antibody to hepatitis C virus, IgM antibodies to hepatitis A and hepatitis E using commercial ELISA. Appropriate tests for autoimmune liver disease and Wilson’s disease were performed, if needed. Each patient also underwent real time ultrasonography and/or triple phase contrast enhanced CT scan, upper gastrointestinal endoscopy (UGIE) and alfa-feto protein (AFP) estimation. Diagnosis of cirrhosis was based on clinical examination, imaging characteristics and/or presence of varices on UGIE. Complications and follow up
AKI at admission was defined as >50% increase in serum creatinine level from the stable baseline value in 250 cells/mm3 (8). Acute variceal bleed was diagnosed as per Baveno V endoscopic criteria (9). Severity of liver failure was assessed by Child–Turcotte–Pugh (CTP) score and Model for end-stage liver disease (MELD) score. Although, Acute physiology and chronic health evaluation (APACHE II) and sequential organ failure assessment (SOFA) scores are reported as good predictors of ACLF severity (10), we felt that these scores are more adapted to ICU patients, in a late stage of the disease when organ failure has set in. All patients were followed up for the duration of hospitalization and their clinical outcomes were carefully recorded. General management of patients
Every patient received standard medical treatment including barrier nursing, nutritional supplementation including high calorie (35–40 cal/kg/day) and high protein diet (1.2–1.5 g/kg proteins/day), lactulose, bowel wash, antibiotics and intensive care monitoring, as required. Enteral or parenteral nutrition was provided to those patients where caloric requirement was not fulfilled by mouth. Standard guidelines based institutional protocols were followed up for the management of individual complications such as SBP, HE and acute variceal bleed. AKI based classification at admission
All included patients were categorized based on presence of AKI at admission (Group A) or no AKI (Group B). To study the impact of severity of AKI, Group A patients were further subgrouped as: mild AKI (S.creatinine ≤3 mg/dl) or marked AKI (S.creatinine >3 mg/dl). Although this classification is arbitrary, Liver International (2016) © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Jindal et al.
it may fulfil our need of recognizing a distinct group of ACLF patients with more severe degree of renal dysfunction at earliest, on the day of admission. All parameters were compared between each group. Survival outcome and end-points
Patient survival at different time frames [7 days, 1 and 3 month] was compared based on the presence of AKI at admission and severity of AKI. The primary endpoint was patient mortality and secondary outcomes were response to terlipressin and treatment related adverse effects. Terlipressin and response rates
In the absence of specific guidelines for terlipressin use in ACLF patients with AKI, patients with failure to decrease serum creatinine
