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Acute kidney injury (AKI) at admission predicts mortality in patients with severe alcoholic hepatitis (SAH) A manuscript submitted to THE JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY

Published:November 19, 2022DOI:https://doi.org/10.1016/j.jceh.2022.11.008

      Abstract

      Background & Aims

      Severe Alcoholic Hepatitis (SAH) is a grave condition and presence of acute kidney injury (AKI) further jeopardises patient survival. However, impact of AKI on survival in SAH has not been assessed from this region of Asia.

      Materials and Methods

      This study was conducted on consecutive alcohol associated liver disease (ALD) patients hospitalised in Gastroenterology Department, SCB Medical College, Cuttack, India between October 2016 and December 2018. On diagnosis of SAH (mDF score ≥32), demographic, clinical and laboratory parameters were recorded and survival was compared between patients with and without AKI (AKIN criteria). In addition, survival was compared among SAH patients defined by other criteria and prognostic models in presence and absence of AKI.

      Results

      309 (70.71%) of ALD patients had SAH and 201 (65%) of them had AKI. SAH patients with AKI had higher total leucocyte count, total bilirubin, serum creatinine, serum urea, INR, MELD(UNOS), MELD(Na+), CTP score, mDF score, Glasgow score, ABIC score and increased prevalence of acute on chronic liver failure (ACLF) as per EASL-CLIF Consortium criteria(p<0.001). Further they had prolonged hospital stay, increased death during hospitalisation, also at 28 days and 90 days (p<0.001). Significant differences in survival were also seen in SAH (as per MELD, ABIC and GAHS criteria) patients above the marked cut offs in respect to AKI.

      Conclusions

      Over two thirds of ALD patients had SAH and of them about two thirds had AKI. Patients with SAH and AKI had increased prevalence of ACLF, longer hospital stay and increased mortality during hospitalisation, at 28 days and 90 days.

      Lay summary

      Severe Alcoholic Hepatitis (SAH) is a critical condition and the presence of acute kidney injury (AKI) negatively affects their survival. Hence early identification of SAH and AKI, and early initiation of treatment is crucial for better survival. Our study from the coastal part of eastern India is the first to demonstrate the prevalence of SAH among patients with ALD along with prevalence of AKI among SAH patients in this region. This knowledge will be helpful in managing these patients from this region of world.

      Keywords

      Abbreviations

      AH:
      Alcoholic hepatitis
      ALD:
      Alcohol associated liver disease
      mDF:
      Modified Maddrey Discriminant Function
      MELD:
      Model for End-Stage Liver Disease
      ABIC:
      Age serum Bilirubin INR and serum Creatinine
      INR:
      International normalized ratio
      GAHS:
      Glasgow Alcoholic Hepatitis Score
      SAH:
      Severe alcoholic hepatitis
      CS:
      Corticosteroids
      SIRS:
      Systemic inflammatory response syndrome
      AKI:
      Acute Kidney Injury
      AKIN:
      Acute Kidney Injury Network
      SCr:
      Serum creatinine
      ACLF:
      Acute on chronic liver failure
      EASL-CLIF Consortium:
      European Association for the Study of the Liver-Chronic Liver Failure
      PTX:
      Pentoxifylline
      HE:
      Hepatic encephalopathy
      AST:
      Aspartate aminotransferase
      ALT:
      Alanine aminotransferase
      PT:
      Prothrombin time
      CTP:
      Child–Turcotte–Pugh
      MDRI:
      Multidrug-resistant infection

      Funding

      We have not received any funding or external support for our work.
      Alcoholic hepatitis (AH) is a potentially life threatening clinical disorder seen in patients with alcohol associated liver disease (ALD).It is an acute inflammatory condition of the liver due to excessive use of alcohol, and is characterised by rapid onset of jaundice, and is commonly associated with background cirrhosis.
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      Furthermore the presence of SIRS in SAH at admission predicts AKI, irrespective of infection.22Additionally in a retrospective study, Altamirano et al observed that presence of AKI increased 90 day mortality in patients with AH in comparison to patients without AH (65% vs. 7 %, p < 0.0001).
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      The prevalence of AKI in patients with SAH and its impact on survival has not been evaluated earlier from this region. So we conducted this prospective study in our ALD patients with SAH.

      Materials and Methods

      The present study was conducted on consecutive ALD patients hospitalised in the Gastroenterology Department, SCB Medical College between October 2016 and December 2018. Patients included in the study were diagnosed with AH on the basis of clinical background and biochemical parameters using various laboratory-based models at the time of hospitalization. The following mathematical models were used to detect SAH patients, such as DF score [4.6 × [patient’s prothrombin time-control prothrombin time (s)] + total bilirubin (mg/dL)], ABIC score [(age × 0.1) + [serum bilirubin (mg/dL) × 0.08] + [serum creatinine (mg/dL) × 0.3] + (INR × 0.8)], GAHS score [Age, blood urea nitrogen, white blood cell count, serum bilirubin, and INR; each scored 1-3], and MELD score [MELD = 3.78 ln [bilirubin (mg/dL)] + 11.20ln(INR)+ 9.57ln[creatinine (mg/dL)] + 6.43].
      • Dominguez M.
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      • Abraldes J.G.
      • Miquel R.
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      • Bellot P.
      • et al.
      A new scoring system for prognostic stratification of patients with alcoholic hepatitis.
      ,
      • Maddrey W.C.
      • Boitnott J.K.
      • Bedine M.S.
      • Weber Jr., F.L.
      • Mezey E.
      • White Jr., R.I.
      Corticosteroid therapy of alcoholic hepatitis.
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      • Forrest E.H.
      • Evans C.D.
      • Stewart S.
      • Phillips M.
      • Oo Y.H.
      • Mc Avoy N.C.
      • et al.
      Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score.
      Patients were classified as “severe alcoholic hepatitis” at the time of admission, using cut offs set by various criteria. Recording of demographic, clinical and laboratory parameters were done in SAH patients selected as per mDF criteria. AKI was defined as per the acute kidney injury network (AKIN) criteria, which is “abrupt decline in renal function characterized by absolute increase in serum creatinine (SCr) of 0.3 mg/dL within 48 h or by percentage increase in serum creatinine ≥ 50% from baseline, which is known, or presumed, to have occurred within the previous 7 days”.
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      • Warnock D.G.
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      Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury.
      All patients were screened for presence of acute on chronic liver failure (ACLF) as per European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) Consortium criteria, which is defined as “acute deterioration of preexisting CLD usually related to a precipitating event and associated with increased mortality at 3 months due to multi-system organ failure”.
      • Moreau R.
      • Jalan R.
      • Gines P.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      Patients, who fulfilled the criteria for SAH and having no contraindications to treatment with corticosteroids, were treated with prednisone orally for 4 weeks followed by a 2-week taper period. In patients where steroid was contraindicated, pentoxifylline (PTX) 400mg thrice daily for 28 days was administered (Table 4).
      • Parker R.
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      Systematicreview: pentoxifylline for the treatment of severe alcoholic hepatitis.
      Contraindications for steroid treatment were severe bacterial infections, gastrointestinal bleeding, and presence of AKI.
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      Before initiating steroid, bacterial infection was ruled out by meticulous history and thorough clinical examination, and on hospitalization complete blood count (CBC), urine examination, ascitic fluid analysis along with ascitic fluid/urine culture was done in all patients; further, according to clinical setting, chest radiography, and sonography of abdomen and pelvis were done when indicated. After initiation of prednisolone, we followed up these patients till end of steroid therapy, while repeating all relevant investigations (complete blood count, urine examination, ascitic fluid, chest radiography) whenever infection was suspected. All patients were followed up for 90 days post treatment completion. Patients with other related complications such as ascites, spontaneous bacterial peritonitis or other infections, AKI, hepatic encephalopathy (HE), portal hypertension related gastrointestinal bleed were treated as per standard medical therapy.
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      Intravascular volume constriction was corrected with intravenous saline/injection albumin, and variceal bleeding was treated with blood transfusions and intravenous terlipressin, followed by endotherapy. All patients presenting with AKI were screened for use of AKI precipitating drugs such as diuretics, nonsteroidal anti-inflammatory drugs, angiotensin converting enzyme inhibiters, angiotensin II receptor blockers, vasodilators, aminoglycoside antibiotics prior to hospitalization or any sepsis or other risk factors that lead to AKI. On diagnosis of AKI, volume expansion was done with intravenous albumin for 48h, and in patients with hepatorenal syndrome; intravenous albumin and terlipressin or noradrenaline was used. Haemodialysis was initiated if patient did not improve. Patients with bacterial infection received empirical intravenous antibiotics and albumin, and antibiotic was later changed according to culture and sensitivity report. In septic shock patients, noradrenaline infusion was added.
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      All subjects were explained in detail about the study and only those who agreed to provide written consent were included in the study.
      Table 4Characteristics of complications in patients with Severe Alcoholic Hepatitis (SAH).
      Sl NoClinical ManifestationsN (%)
      1Acute Kidney Injury (AKI)201 (65%)
      2Infection174 (56.3%)
      3Gastrointestinal Bleeding (GI Bleeding)135 (43.7%)
      4Contraindication to corticosteroid treatment (AKI and/or, Infectionand/or, GI Bleeding)275 (89%)
      SAH, severe alcoholic hepatitis; AKI, acute kidney injury; GI Bleeding, Gastrointestinal Bleeding.
      Period of hospitalisation, inpatient survival and also survival at 28 days as well as 90 days were recorded and compared between patients with and without AKI. Survival at 28 days and 90 days were compared with respect to AKI among SAH patients defined by other prognostic models too.
      In our study, the inclusion criteria were age≥18 years; onset of jaundice within prior 8 weeks; ongoing consumption of alcohol >40g per day (female) or >50g (male) alcohol per day for ≥6 months, with <60 days of abstinence before the onset of jaundice; AST >50 IU/ml and AST/ALT >1.5, and both values <400 IU/L; and serum total bilirubin >3.0 mg/dL.2Patients who were excluded were those with past history of kidney injury, presence underlying liver diseases due to other etiologies like hepatitis B infection, hepatitis C, autoimmune liver diseases, Wilson disease, suspected drug-induced liver injury, presence of hepatocellular carcinoma or other active malignancies, pregnancy, recent hepatotoxic drug exposure and use of either CS or PTX within prior 6 weeks.2Patients without a SCr report within prior 7 days were also excluded from the study. In our study, survival at 28 days was defined as the primary end-point while that at 90 days served as the secondary end-point for our survival analysis. Duration of hospital stay was the other secondary end-point for comparing SAH patients with and without AKI at admission.
      Normally distributed continuous variables were reported as mean and standard deviation and compared using Student t test. Nonnormally distributed continuous variables were reported as median and interquartile range and compared using Mann-Whitney U test. Categorical variables were reported as proportions and compared by chi-square test or Fisher exact test as appropriate. The 28 days and 90 days survival were compared by the Kaplan-Meier analysis and log-rank test. All tests were 2-tailed and p values <0.05 were considered significant. The statistical analysis was performed using SPSS statistical package, version 20.0 (IBM Corp, Armonk, NY). Ethical clearance has been obtained from Institutional Ethics Committee, S.C.B. Medical College, Cuttack-753007, Odisha [Regd. No. ECR/84/Inst/OR/2013].

      Results

      A total of 464 ALD patients were hospitalised between October 2016 and December 2018. Twenty seven patients had to be excluded, either because they did not meet the inclusion criteria or they were lost to follow up. 437 patients met the inclusion criteria for alcoholic hepatitis and were enrolled in the study. 70.71 % (n=309) patients had SAH as per mDF criteria and of them 65% (n=201) had AKI as per AKIN criteria. Among these AKI patients, 57.2% (n=115) had stage I AKI, 22.4%(n=45) had stage II AKI, and 20.4% (n=41) had stage III AKI (Figure 1). Comparison of SAH patients with respect to presence and absence of AKI showed that the patients with AKI had higher total leucocyte count per decilitre (dl) (10965±5323 versus 9063±3489; p<0.001), total bilirubin (6.10mg/dl versus 4.70mg/dl, IQR; p<0.001), serum creatinine (1.80mg/dl versus 0.88mg/dl, IQR; p<0.001), serum urea (52mg/dl versus 21mg/dl, IQR; p<0.001), INR (2.20 versus 1.90, IQR; p<0.001),MELD (UNOS) (29.27±8.47 versus 19.72±4.14; p<0.001), MELD (Na+) (30.92±7.61versus 22.90±4.66; p<0.001),CTP score (12.48±1.80 versus 11.80±1.52; p=0.001), mDF score (71.6 versus 53.2, IQR; p<0.001), GLASGOW score (8.94±1.22 versus 8.35±1.01; p<0.001), ABIC score (8.04±1.85 versus 6.75±1.09; p<0.001) (Tables 1 and 2). As per ABIC score criteria, significantly greater proportion of SAH patients with AKI belonged to high risk AH group (21.4% versus 1.9%; p<0.001) and intermediate AH risk group (60.7% versus 50%; p<0.001) as compared to patients without AKI. Further, AKI patients had lower MAP (82.12±11.11mmHg versus 84.68±7.03mmHg; p=0.014), lower serum protein (6.31±0.94g/dl versus 6.58±0.90g/dl; p=0.013) and higher incidence of bacterial infections (63.7% versus 42.6%; p<0.001). They also had longer hospital stay (6 days versus 4 days, IQR; p<0.001) and increased death during hospitalisation (25.4% versus 4.6%; p<0.001) (Tables 1 and 2). In addition, these patients had decreased survival both at 28 days (55.2% versus 80.6%; p<0.001) and 90 days (33.3% versus 59.3%; p<0.001) as compared to patients without AKI (Table 2). Kaplan-Meier survival analysis also showed significant differences in survival with respect to AKI, both at 28 days (log rank p value <0.001) and 90 days (log rank p value <0.001) (Figures 2, 3).
      Figure 1
      Figure 1Schematic flow diagram for the study.
      Table1Comparison of baseline characteristics of patients with severe alcoholic hepatitis (SAH) as per mDF criteria in presence or absence of acute kidney injury (AKI) at admission.
      Sl NoParametersPatients without AKI (n=108)Patients with AKI (n=201)p Value
      1Age (Mean±SD)43.8±10.645.5±9.60.172
      2Male Gender (%)107(99.1%)201(100%)0.350
      3BMI(kg/mt
      • Crabb D.W.
      • Bataller R.
      • Chalasani N.P.
      • et al.
      Standard Definitions and Common Data Elements for Clinical Trials in Patients With Alcoholic Hepatitis: Recommendation From the NIAAA Alcoholic Hepatitis Consortia.
      ) (Mean±SD)
      21.51±3.7022.41±3.840.046
      4MAP(mmHg) (Mean±SD)84.68±7.0382.12±11.110.014
      5Variceal Bleeding (%)45(41.7%)90(44.8%)0.599
      6Infection (%)46(42.6%)128(63.7%)<0.001
      7Serum creatinine(mg/dl) [Median(IQR)]0.88(0.7-1.0)1.80(1.35-2.60)<0.001
      8Urea(mg/dl) [Median(IQR)]21(17-26)52(34-79.5)<0.001
      9Serum bilirubin(total in mg/dl) [Median(IQR)]4.70(2.80-6.94)6.10(3.20-13.20)<0.001
      10INR [Median(IQR)]1.90(1.64-2.24)2.20(1.80-2.69)<0.001
      11Serum protein(g/dl) (Mean±SD)6.58±0.906.31±0.940.013
      12Serum albumin(g/dl) (Mean±SD)2.50±0.472.51±0.420.804
      13Serum sodium(mEq/L) (Mean±SD)131.6±16.61130.84±11.990.674
      14Serum potassium(mEq/L) [Median(IQR)]3.85(3.40-4.30)4.00(3.50-4.70)0.060
      15Total leucocyte count(10
      • O'Shea R.S.
      • Dasarathy S.
      • McCullough A.J.
      • Diseases PGCotAAftSoL
      • PPCotACo Gastroenterology
      Alcoholic liver disease.
      cells/dl) (Mean±SD)
      9063±348910965±5323<0.001
      SAH, severe alcoholic hepatitis; mDF, modified Maddrey Discriminant Function;AKI, acute kidney injury; BMI, body mass index; MAP, mean arterial pressure;INR, International Normalized Ratio;IQR, interquartile range; SD, standard deviation.
      Table 2Comparison of indices for severe liver disease and comparison of outcomes of patients with SAHas per mDF criteriain presence or absence of acute kidney injury (AKI) at admission.
      Sl NoParametersPatients without AKI (n=108)Patients with AKI (n=201)p Value
      1MELD(UNOS)

      (Mean±SD)
      19.72±4.1429.27±8.47<0.001
      2MELD(Na+)

      (Mean±SD)
      22.90±4.6630.92±7.61<0.001
      3CTP score (Mean±SD)11.80±1.5212.48±1.800.001
      4mDF Score [Median(IQR)]53.2(42.3-68.1)71.6(49.4-100.3)<0.001
      5GLASGO Score (Mean±SD)8.35±1.018.94±1.22<0.001
      6ABIC Score (Mean±SD)6.75±1.098.04±1.85<0.001
      7ABIC Risk Score (%)Low Risk (<6.71)52(48.1%)36(17.9%)<0.001
      Intermediate Risk (6.71-8.99)54(50%)122(60.7%)
      High Risk (≥ 9)2(1.9%)43(21.4%)
      8ACLF [EASL-CLIF Consortium criteria] (%)34(31.5%)135(67.2%)<0.001
      9Duration of Hospital Stay in days [Median(IQR)]4 (3-5)6 (4-8)<0.001
      10Death During Hospitalisation5(4.6%)51(25.4%)<0.001
      1128 days Survival (%)87(80.6%)111(55.2%)<0.001
      1290 days Survival (%)64(59.3%)67(33.3%)<0.001
      SAH, severe alcoholic hepatitis; mDF, modified Maddrey Discriminant Function;AKI, acute kidney injury; MELD, model for end-stage liver disease; UNOS, The United Network for Organ Sharing;CTP,Child-Turcotte-Pugh; GAHS, Glasgow Alcoholic Hepatitis score; ABIC score, Age, serum Bilirubin, INR, and serum Creatinine; ACLF, Acute on chronic liver failure; IQR, interquartile range; SD, standard deviation.
      Figure 2
      Figure 2Kaplan–Meier survival curves showed significant differences in survival in SAH between acute kidney injury (AKI) and without acute kidney injury at 28 days (log rank P value<0.001).(),Without AKI;(),With AKI.
      Figure 3
      Figure 3Kaplan–Meier survival curves showed significant differences in survival in SAH patients between acute kidney injury (AKI) and without acute kidney injury at 90 days (log rank P value<0.001). (),Without AKI; (), With AKI.
      Survival analysis was done at 28 days and 90 days for all patients of alcoholic hepatitis as identified by various criteria (MELD, ABIC and GAHS) with respect to the defined cut offs and also in SAH patients with respect to AKI. Significant differences in survival were observed at below and above the cut offs and as well in presence or absence of AKI (Table 3). At a cut off MELD score of 20, survival differences were seen both at 28 days (89.7% versus 57.1%; p<0.001) and 90 days (74.6% versus 35.3%; p<0.001). Again, on comparison between patients with MELD score ≥20 with respect to AKI, decreased survival was noted in patients with AKI both at 28 days (53.2% versus 72.5%; p=0.013) and 90 days (31.8% versus 49%; p=0.022). Similarly, on comparison of patients with GAHS cut off of 9, differences in survival both at 28 days (85.1% versus 52.1%; p<0.001) and 90 days (68.3% versus 30.3%; p<0.001) were observed. Likewise on evaluation of patients with GAHS of ≥9, decreased survival was observed in patients with AKI both at 28 days (45.3% versus 70.6%; p=0.002) and 90 days (24.8% versus 45.1%; p=0.007). At a cut off ABIC risk score of 6.71, differences in survival were observed both at 28 days (86.1% versus 61.8%; p<0.001) and 90 days (70.9% versus 40.4%; p<0.001)and also decreased survival was seen in patients at ABIC risk score ≥6.7 with AKI, both at 28 days (56.2% versus 77.5%; p=0.002) and 90 days (36.6% versus 52.1%; p=0.002) (Table 3) in comparison to patients without AKI.
      Table 3Comparison of prognostic models of severe alcoholic hepatitis for survival at 28 days and 90 days.
      Sl NoPrognostic ModelsSurvival at 28 daysP ValueSurvival at 90 daysP Value
      1mDFx_Score (cut off 32)<32 (n=128)112(87.5%)<0.00196(75%)<0.001
      ≥ 32 (n=309)198(64.1%)131(42.4%)
      ≥ 32 without AKI (n=108)87(80.6%)<0.00164(59.3%)<0.001
      ≥ 32 with AKI (n=201)111(55.2%)67(33.3%)
      2MELD (cut off 20)MELD <20 (n=185)166(89.7%)<0.001138(74.6%)<0.001
      MELD ≥ 20 (n=252)144(57.1%)89(35.3%)
      MELD ≥ 20 without AKI (n=51)37(72.5%)0.01325(49%)0.022
      MELD ≥ 20 with AKI (n=201)107(53.2%)64(31.8%)
      3GLASGO RISK SCORE (cut off 9)<9 (n=249)212(85.1%)<0.001170(68.3%)<0.001
      ≥ 9 (n=188)98(52.1%)57(30.3%)
      ≥ 9 without AKI (n=51)36(70.6%)0.00223(45.1%)0.007
      ≥ 9 with AKI (n=137)62(45.3%)34(24.8%)
      4ABIC RISK SCORE (cut off 6.71)<6.71 (n=165)142(86.1%)<0.001117(70.9%)<0.001
      ≥6.71 (n=272)168(61.8%)110(40.4%)
      ≥6.71without AKI (n=71)55(77.5%)0.00237(52.1%)0.002
      ≥6.71 with AKI (n=201)113(56.2%)73(36.6%)
      SAH, severe alcoholic hepatitis; mDF score, modified Maddrey Discriminant Function score;AKI, acute kidney injury; MELD score, model for end-stage liver disease score; UNOS, The United Network for Organ Sharing; GLASGO score, Glasgow Alcoholic Hepatitis score; ABIC score, Age, serum Bilirubin, INR, and serum Creatinine.

      Discussion

      In our cohort, we observed that patients with SAH and AKI had significantly decreased survival both at 28 days and 90 days (Tables 2 and 3) compared to not only ALD patients without SAH, but also SAH patients without AKI. This is similar to the observations from three prospective studies, who showed a mortality of 35% to 50% at one month in patients with mDF score ≥32 and by Carithers et al, who observed increased survival at 28-days in patients with mDF score < 32 (93% versus 68% in those with a score ≥32).
      • Ramond M.J.
      • Poynard T.
      • Rueff B.
      • Mathurin P.
      • Théodore C.
      • Chaput J.C.
      • et al.
      A randomized trial of prednisolone in patients with severe alcoholic hepatitis.
      ,
      • Maddrey W.C.
      • Boitnott J.K.
      • Bedine M.S.
      • Weber Jr., F.L.
      • Mezey E.
      • White Jr., R.I.
      Corticosteroid therapy of alcoholic hepatitis.
      ,
      • Carithers J.R.L.
      • Herlong H.F.
      • Diehl A.M.
      • et al.
      Methylprednisolone therapy in patients with severe alcoholic hepatitis: a randomized multicenter trial.
      ,
      • Phillips M.
      • Curtis H.
      • Portmann B.
      • et al.
      Antioxidants versus corticosteroids in the treatment of severe alcoholic hepatitis—a randomized clinical trial.
      In a Danish study, Sandahl et al observed 28-day mortality of 15%, 84-day mortality of 24%, and 5-year mortality of 56% with a further increase of mortality in cirrhotic patients.
      • Sandahl T.D.
      • Jepsen P.
      • Thomsen K.L.
      • Vilstrup H.
      Incidence and mortality of alcoholic hepatitis in Denmark 1999–2008: a nationwide population based cohort study.
      Kollipara et al in their study reported 40% mortality in their patients with SAH at day 30. High CTP scores along with presence of renal dysfunction or hepatorenal syndrome at the time of admission have also been associated with increased 30-day mortality.
      • Kollipara R.K.
      • Geetha S.
      • Rao K.P.R.
      Clinical determinants of thirty-day mortality in a cohort of patients with severe alcoholic hepatitis.
      In our study, 28-day and 90-day survival were 64% (n=198) and 41% (n=131) respectively. We found higher inpatient mortality (19%) in our study as compared to a population based study by Yang et al who reported mortality between 6.6 % and 6.8 % in their patients with AH.
      • Liangpunsakul S.
      Clinical characteristics and mortality of hospitalized alcoholic hepatitis patients in the United States.
      ,
      • Yang A.L.
      • Vadhavkar S.
      • Singh G.
      • Omary M.B.
      Epidemiology of alcohol-related liver and pancreatic disease in the United States.
      (Table 5) Besides, increased 90-day mortality was also observed in our SAH and AKI patients (66.7%) in comparison to earlier studies by Michelena J et al (62.1%) and Altamirano Jet al (65%); however Sujan R et al reported lower mortality (45%).
      • Michelena J.
      • Altamirano J.
      • Abraldes J.G.
      • Affò S.
      • Morales-Ibanez O.
      • Sancho-Bru P.
      • et al.
      Systemic inflammatory response and serum lipopolysaccharide levels predict multiple organ failure and death in alcoholic hepatitis.
      ,
      • Altamirano J.
      • Fagundes C.
      • Dominguez M.
      • García E.
      • Michelena J.
      • Cárdenas A.
      • et al.
      Acute kidney injury is an early predictor of mortality for patients with alcoholic hepatitis.
      ,
      • Sujan R.
      • Cruz-Lemini M.
      • Altamirano J.
      • Simonetto D.
      • Maiwall R.
      • Axley P.
      • et al.
      A Validated Score Predicts Acute Kidney Injury and Survival in Patients with Alcoholic Hepatitis: A Multicentric International Prospective Cohort Study.
      (Table 5) O’Shea et al and Philips et al suggest that AH often presents as acute deterioration of chronic liver disease thereby leading to ACLF.
      • O’Shea R.S.
      • Dasarathy S.
      • McCullough A.J.
      Practice Guideline Committee of the American Association for the Study of Liver D, Practice Parameters Committee of the American College of G. Alcoholic liver disease.
      ,
      • Philips C.A.
      • Augustine P.
      • Yerol P.K.
      • Rajesh S.
      • Mahadevan P.
      Severe alcoholic hepatitis: current perspectives.
      An interesting observation in our study was the higher proportions of ACLF (67.2% versus 31.5%; p<0.001) with increased short term mortality in patients of SAH with AKI when compared to patients without AKI (Table 2). Philips et al had earlier observed that the presence of infections and higher grades of liver disease negatively affect ACLF patients, which further leads to progressive worsening of clinical events, lower rates of response to corticosteroid use and a poor outcome.
      • Philips C.A.
      • Augustine P.
      • Yerol P.K.
      • Rajesh S.
      • Mahadevan P.
      Severe alcoholic hepatitis: current perspectives.
      In our study, more than half of patients had associated infection at the time of hospitalisation and higher number of patients had advanced liver disease as evidenced by raised MELD and CTP score (Tables 2 and 4).
      Table 5Comparison of prevalence of AKI in patients with Alcoholic Hepatitis (AH) and its outcomes in different studies.
      Sl NoAuthorsPeriod of StudyTotal Patients with AH/SAHPatients with AKI (%Patients with AKI
      Died during Hospitalisation28days mortality90days mortality
      1Suthat Liangpunsakul
      • Liangpunsakul S.
      Clinical characteristics and mortality of hospitalized alcoholic hepatitis patients in the United States.
      200756,80911,384(20%)3,881 (6.8%)**
      2Michelena J, Altamirano J, Abraldes JG, et al
      • Michelena J.
      • Altamirano J.
      • Abraldes J.G.
      • Affò S.
      • Morales-Ibanez O.
      • Sancho-Bru P.
      • et al.
      Systemic inflammatory response and serum lipopolysaccharide levels predict multiple organ failure and death in alcoholic hepatitis.
      (Multi-organ failure)
      2000-201216258 (35.8%)**62.1%
      3Altamirano J, Fagundes C, Dominguez M, et al
      • Altamirano J.
      • Fagundes C.
      • Dominguez M.
      • García E.
      • Michelena J.
      • Cárdenas A.
      • et al.
      Acute kidney injury is an early predictor of mortality for patients with alcoholic hepatitis.
      201210329 (28%)**65%
      4Sujan R, Cruz-Lemini M, Altamirano J, et al
      • Sujan R.
      • Cruz-Lemini M.
      • Altamirano J.
      • Simonetto D.
      • Maiwall R.
      • Axley P.
      • et al.
      A Validated Score Predicts Acute Kidney Injury and Survival in Patients with Alcoholic Hepatitis: A Multicentric International Prospective Cohort Study.
      2018773248 (32%)**45%
      5Present Study2016-2018309 (SAH)201 (65%)51 (25.4%)90 (44.8%)134 (66.7%)
      AH, alcoholic hepatitis; SAH, severe alcoholic hepatitis; AKI, acute kidney injury.
      In the present study out of 309 patients, 275 (89%) had contraindication for corticosteroid therapy, as either they had AKI [65%(n=201)], and/or infection [56.3%(n=174)], and/or variceal bleeding [43.7%(n=135)]. Furthermore, a higher number of SAH patients with AKI had ACLF (67.2% versus 31.5%; <0.001), which is associated with increased short term mortality (Table 2).The results indicate that a large number of patients had multiple contraindications for corticosteroid at the time of hospitalisation (Table 4). Thus, only a miniscule of eligible SAH patients were treated with corticosteroids which may possibly have contributed to poor outcome.
      In our institution biomarker estimation to detect bacterial infection, and estimation of AKI markers like FeNa%, urine routine, uNGAL, sNGAL, Cystatin C were not done as this facility were not available. Further there are no local facilities available for liver transplantation nor can our patients afford transplantation at other distant centres. The absence of liver transplantation facility in our centre fortuitously turned out to be the strength of our study as we could study the natural outcome of SAH patients. Further we have shown how presence of AKI in SAH patients adversely impacts survival of these patients. Resource constraints, and nonavailability of trans-jugular liver biopsy facility at our centre led to selection of patients using prognostic models only and all patients received only medical therapy as per current guidelines. None of the patients underwent liver transplantation. These were major limitations of our study.
      In the present study more than two thirds of ALD patients had SAH and about two thirds of them had AKI. There was increased association of AKI with infection and ACLF in comparison to SAH patients without AKI. SAH patients with AKI had decreased survival during hospitalisation, and also at 28 days and 90 days. This underscores the importance of early detection and treatment of infective focus and AKI along with advice for strict alcohol abstinence for better outcome in SAH patients. The importance of our study is the fact that AKI was found to be highly prevalent in our SAH patients. This could be due to two reasons. Firstly, it could be due to the differences in criteria used for identifying AKI, though a similar result was shown in our previous study, and secondly, multidrug-resistant infection (MDRI) is very common in our region as has been reported in the global study.
      • Khatua C.R.
      • Sahu S.K.
      • Meher D.
      • Nath G.
      • Singh S.P.
      Acute kidney injury in hospitalized cirrhotic patients: Risk factors, type of kidney injury, and survival.
      ,
      • Piano S.
      • Singh V.
      • Caraceni P.
      • Maiwall R.
      • et al.
      International Club of Ascites Global Study Group. Epidemiology and Effects of Bacterial Infections in Patients With Cirrhosis Worldwide.
      Another important message from our study is that it highlights the importance of AKI in patients with SAH; AKI was found to be a very robust predictor of outcome and mortality, obviating the need for other prognostic scoring assessments, making them redundant.

      Author contributions

      CK has contributed in conception and design, collection and assembly of data, data analysis and interpretation, statistical analysis and manuscript writing. MP has contributed in manuscript writing and final approval. AC has contributed in manuscript writing and final approval. GN has contributed in collection and assembly of data. RK has contributed in manuscript writing and final approval. PA has contributed in manuscript writing and final approval. SS has contributed in conception and design, data analysis and interpretation, manuscript writing and final approval.

      Conflict of Interest (COI)

      The authors have no conflict of interests.

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