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doi:10.1111/jgh.13002
H E PAT O L O G Y
Impact of acute kidney injury on prognosis of patients with liver cirrhosis and ascites: A retrospective cohort study Theresa Bucsics,*,† Mattias Mandorfer,*,† Philipp Schwabl,*,† Simona Bota,*,† Wolfgang Sieghart,*,† Arnulf Ferlitsch,*,† Michael Trauner,* Markus Peck-Radosavljevic*,† and Thomas Reiberger*,† *Division of Gastroenterology, Department of Internal Medicine III and †Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria
Key words acute kidney failure, acute kidney injury, ascites, cirrhosis, liver cirrhosis. Accepted for publication 24 April 2015 Correspondence Dr Thomas Reiberger, Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Email: [email protected] Declaration of conflict of interest: The authors have no conflict of interest. Author contributions: Study design (TB, MM, PS, MPR), data acquisition (TB, SB, MM, AF, TR), statistical analysis (TB, MM, PS, TR), critical revision of intellectual content (TB, MM, PS, SB, AF, MT, MPR, TR).
Abstract Background and Aim: Acute kidney injury (AKI) is a common complication in patients with liver cirrhosis, and its impact on the clinical course is increasingly recognized. Diagnostic classification systems for AKI in cirrhosis have been suggested. The prognostic significance of the respective AKI stages remains to be evaluated in decompensated cirrhosis with ascites. Methods: Data of consecutive patients with cirrhosis and ascites undergoing paracentesis at a tertiary care center were analyzed. AKI was defined as an increase in serum creatinine of ≥ 0.3 mg/dL or by ≥ 50% within 7 days after paracentesis, and classified according to (i) revised Acute Kidney Injury Network (AKIN) criteria and (ii) modified AKI criteria for cirrhosis (C-AKI). In contrast to AKIN, C-AKI stage A discriminates prognosis based on an absolute creatinine cut-off at < 1.5 mg/dL versus C-AKI stage B at ≥ 1.5 mg/dL. Results: The final study cohort included 239 patients. Median transplant-free survival was 768 days (95% confidence interval [CI]: 331–1205 days) without AKI, 198 (0–446) in AKI-1, 91 (0–225) in AKI-2, 19 (0–40) and in AKI-3, whereas it was 89 (20–158) days in C-AKI-A, 384 (0–1063) in C-AKI-B, and 22 (7–776) in C-AKI-C. Mild AKI was already associated with significantly increased 30-day mortality (AKI-1:26.4%, C-AKI-A:33.3%) as compared with patients without AKI (14.3%), even when serum creatinine remained within normal range (< 1.2 mg/dL) we observed a significant 30-day mortality. Conclusion: AKIN criteria—considering small increases in serum creatinine rather than absolute thresholds—seem to be more accurate for estimating prognosis of AKI after paracentesis than C-AKI criteria. Even patients developing AKI-1 with “normal” serum creatinine are at increased risk for mortality.
Introduction Acute kidney injury (AKI) is a common complication in patients with decompensated cirrhosis and represents a major contributor to mortality.1–4 Approximately 20% of hospitalized patients with liver cirrhosis develop renal failure5 and up to 50% of these patients die within 30 days.6 A meta-analysis from 2011 reported a 6.38-fold increased risk for mortality for patients with AKI.6 Moreover, hepatorenal syndrome type 1 (HRS1), which is considered a unique and severe form of AKI,7 is considered one of the most lethal complications in patients with cirrhosis and ascites. However, various diagnostic criteria have been reported for identifying AKI, even among patients with cirrhosis.6,8–10 In 2007, based on the RIFLE (Risk, Injury, Failure, Loss-of-function, Endstage renal disease) criteria from 2004,11 the Acute Kidney Injury Network (AKIN) introduced new criteria for AKI, which is defined by an abrupt reduction in renal function in critically ill patients.12 These criteria classify AKI into three grades, depending on either
a reduction in urine output or a rise in serum creatinine (sCr) within 48 hours with mild (grade 1) to severe (grade 3) stages of renal failure. The AKIN classification considers the prognostic relevance of relative increases in sCr even among patients with low and normal serum levels.12–14 In 2013, Fagundes et al.15 presented a modified version of the AKIN criteria and adapted them for patients with liver cirrhosis (cirrhosis-AKI criteria, C-AKI). Using only sCr as a parameter, the authors introduced a threshold of 1.5 mg/dL to define C-AKI stages “A” and “B” among patients with AKI grade 1 (rise in sCr by ≥ 50% or ≥ .3 mg/dL, but by < 100%), and merged AKI grades 2 and 3 into C-AKI stage “C.” The peak sCr cut-off of 1.5 mg/dL was selected as indicator for a critical decrease in glomerular filtration rate (GFR).16–18 A similar cut-off is also used for diagnosis of HRS.18,19 Most surprisingly, patients with C-AKI stage A (corresponding AKI grade 1 with a peak sCr value < 1.5 mg/dL) showed no higher mortality than patients without AKI.20 A second study performed by Piano et al. obtained similar results.21
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However, many experts still advise being cautious about patients fulfilling the criteria for AKI stage A and suggest treating them according to recommendations for renal failure.20,22 The prognostic significance of the “original” AKI stages (according to AKIN criteria)12 versus the “cirrhosis-specific” C-AKI stages15 (especially for C-AKI stage A) remains to be determined for patients with decompensated cirrhosis and ascites. In this retrospective cohort study, we compared the prognostic significance of (i) the original AKIN classification to (ii) the modified C-AKI criteria for cirrhosis regarding transplant-free survival (TFS), and (iii) of AKI in patients with peak sCr within reference range (< 1.2 mg/dL).
Methods This retrospective cohort study was conducted according to the ethical principles of the revised Declaration of Helsinki and approved by the local Ethics Committee (EK#1008/2011). Similar to a previous study,23 a dataset of all patients undergoing a total of 1731 abdominal paracenteses at the Medical University of Vienna was evaluated. The diagnosis of cirrhosis was established by liver biopsy, transient elastography, radiologically, or by typical clinical signs.24 Hepatocellular carcinoma (HCC) was diagnosed as previously described.25 Patients with HCC, kidney, or orthotopic liver transplantation (OLT) prior to the index paracentesis (see definition below), documented renal parenchymal damage, or chronic kidney disease (CKD) were excluded. Clinical and laboratory data at the time of paracentesis and during follow-up were recorded from medical histories. Patients gave written informed consent to all procedures. Paracenteses and biochemical tests. Paracenteses were performed as clinically indicated.26 Patients undergoing largevolume paracentesis (> 5L) received 8-g human serum albumin per liter of ascites removed.27 The index paracentesis was defined as the first paracentesis at our center. Laboratory parameters were documented from the day of index paracentesis (or up to 7 days before if not available). The baseline value for creatinine was defined as the last stable (maximum variance ± 0.2 mg/dL within three measurements) sCr value < 2 mg/dL within 7–365 days prior to index paracentesis. sCr and sodium values were recorded at baseline and at day of index paracentesis (D0), and then at 24–48 h (D2) and within the first week (W1) after index paracentesis. Methods for determining sCr. Blood samples were collected into heparin-anticoagulated vacuum containers. sCr was measured using the standard assay method of the main laboratory of the Vienna General Hospital (Jaffe method).28 Definition of AKI. AKI was defined as an increase in sCr by ≥ .3 mg/dL or by ≥ 50% either from baseline to the index paracentesis (D0),19 from D0 to 24–4 h afterwards (D2), or from D2 to 3–7 days after paracentesis (W1). AKI was regarded associated with paracentesis when AKI criteria were fulfilled at day 2 (D2) or within 1 week after the paracentesis (W1). The following potential triggers for AKI were documented for 7 days prior to AKI: systemic infections, sepsis, shock, upper gastrointestinal bleeding, 1658
surgery, application of radiocontrast agents, or nephrotoxic drugs (i.e. non-steroidal antiinflammatory drugs or aminoglycosides). AKI episodes were staged according to AKIN or C-AKI criteria: — AKIN1: increase in sCr by either ≥ 50–99% or ≥ 0.3 mg/dL; — AKIN2: increase in sCr by ≥ 100–199%; — AKIN3: increase in sCr by ≥ 200% or ≥ 4 mg/dL or hemodialysis/anuria ≥ 12 h;12 — C-AKI A: increase in sCr by either ≥ 0.3 mg/dL or ≥ 50% to a final value < 1.5 mg/dL; — C-AKI B: increase in sCr by either ≥ 0.3 mg/dL or ≥ 50% to a final value ≥ 1.5 mg/dL; — C-AKI C: whenever criteria for AKIN stages 2 or 3 where fulfilled.15 Resolution of AKI was determined by a reduction in sCr to < 0.3 mg/dL above baseline sCr levels (or lower) within 14 days after AKI onset. HRS was defined by a rise in sCr to > 1.5 mg/dL in the absence of typical trigger events for renal failure.7,27 In order to evaluate the impact of small increases in sCr within normal laboratory ranges, we analyzed TFS in patients with AKI and a peak sCr < 1.2 mg/dL (the upper limit of normal of sCr). Statistical analysis. Statistical analyses were performed using IBM SPSS Statistics (IBM, version 22.0, Armonk, NY, USA). Parametric distribution was assessed by Kolmogorov– Smirnov test. Student t-test or Mann–Whitney U-test was applied for group comparison of continuous variables. Parameters were reported as mean ± standard deviation ( x ± SD ) or median (interquartile range, IQR) as appropriate. Categorical variables were reported as numbers (proportions) and analyzed using Chisquare or Fisher exact test. Kaplan–Meier curves were plotted for TFS. OLT or last follow-up visits were defined as censoring events, and death as event. TFS was reported as median (95% confidential interval, CI). Log–rank test was used to compare TFS between AKIN and C-AKI groups. Univariate analyses were performed to identify independent predictors of overall (cox regression) and 30-day (binary logistic regression) mortality. AKIN stages and variables that showed a trend or were significant in univariate analysis (P < .10) were then entered into multivariate cox regression analysis (overall mortality) and a binary logistic regression analysis (30-day mortality) to assess independent risk factors for death. Variables that were significant at univariate analyses but are already included within scores have not been included into the same multivariate model to omit redundancy.
Results Patient characteristics. Among all patients undergoing paracentesis at the Vienna General Hospital from 2006 to 2011, 239 patients with cirrhosis and portalhypertensive ascites and without previous liver or kidney transplantation were included (Table 1, Figure 1). Most (90%) of our patients were inpatients (n = 215) and only 10% (n = 24) were outpatients. A total of 78 patients (32.6%) had either AKI at the time of paracentesis or developed AKI within 1 week (paracentesis-associated “AKI group”), whereas 161 patients (67.4%) developed no AKI (“noAKI group”). Thirteen (32%) had already developed kidney failure
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Table 1
Acute kidney injury and liver cirrhosis
Baseline characteristics, and comparison of patients with and without AKI development
Parameter
All patients
No AKI
AKI
Patients (n [%]) Age (years) Sex (m/f [%m]) Etiology (n [%]) Alcohol Viral Mixed alcohol/viral Autoimmune PBC/PSC NASH Cryptogenic Other Child–Pugh A/B/C (n [%])
239 (100.0) 54.9 ± 11.7 160/79 (66.9)
161 (67.4) 54.8 ± 11.9 108/53 (67.1)
78 (32.6) 55.1 ± 11.4 52/26 (66.7)
140 (58.6) 39 (16.3) 21 (8.8) 6 (2.5) 5 (2.1) 10 (4.2) 11 (4.6) 7 (2.59 10/98/131 (4%/41%/55%) 186 (78) 50 (20.9) 17.37 (12.93–23.22) 134.4 ± 4.9 0.92 (0.74–1.10) 3.68 (1.80–7.67) 27.5 ± 5.4 32 (20–53) 64 (42–95) 1.44 (1.27–1.81) 2.5 (1.3–5.0) 7.8 (5.4–11.2) 40 (16)
98 (60.9) 25 (15.5) 12 (7.5) 4 (2.5) 3 (1.9) 6 (3.7) 7 (4.3) 6 (3.7) 8/77/76 (5%/48%/47%)) 126 (78) 35 (21.7) 14.84 (11.58–20.10) 134.6 ± 4.8 0.90 (0.72–1.08) 2.91 (1.53–5.9) 28.3 ± 5.4 31 (20–47) 60 (40–88) 1.39 (1.20–1.70) 2.0 (1.1–3.8) 6.9 (4.9–9.4) 29 (18)
42 (53.8) 14 (17.9) 9 (11.5) 2 (2.6) 2 (2.6) 4 (5.1) 4 (5.1) 1 (1.3) 2/21/55 (3%/27%/71%) 60 (77) 15 (19.2) 22.95 (18.20–28.55) 133.8 ± 5.1 0.96 (0.77–1.18) 4.78 (2.73–12.91) 25.8 ± 5.0 35 (21–60) 78 (46–132) 1.61 (1.37–2.16) 4.1 (2.1–7.4) 10.0 (6.5–14.1) 11 (14)
Gastroesophageal varices (n [%]) Previous variceal bleeding (n [%]) MELD (median [IQR]) Baseline serum sodium (mEq/L) Baseline creatinine (mg/dL) (median [IQR]) Baseline bilirubin (mg/dL) (median [IQR]) Baseline albumin (mg/dL) (mean ± SD) Baseline ALT (U/L) (median [IQR]) Baseline AST (U/L) (median [IQR]) Baseline INR (median [IQR]) Baseline CRP (mg/dL) Baseline Leukocytes (G/L) OLT (n [%])
P n/a 0.834 1.000 0.796
0.003 0.869 0.736 < 0.001 0.235 0.038 < 0.001 0.001 0.151 0.005 0.001 < 0.001 < 0.001 0.580
AKI, acute kidney injury; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; INR, international normalized ratio; IQR, interquartile range; MELD, Model of End-stage Liver Disease; NASH, non-alcoholic steatohepatitis; OLT, orthotopic liver transplantation; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; SD, standard deviation.
Table 2
Mortality and transplant-free survival of patients according to AKI stage
Patients
Number of patients (n)
30 Days mortality (deaths, %)
Median TFS (months)
Median TFS (days)
Total Without AKI All AKI AKIN 1 AKIN 2 AKIN 3 C-AKI A C-AKI B C-AKI C
329 161 78 53 15 10 24 29 25
70 (21.3%) 23 (14.3%) 28 (35.9%) 14 (26.4%) 7 (46.7%) 7 (70.0%) 8 (33.3%) 6 (20.7%) 14 (56.0%)
13.6 25.2 3.0 6.5 3.0 0.6 2.9 12.6 0.7
414 (52–776) 768 (331–1205) 91 (0–234) 198 (0–446) 91 (0–225) 19 (0–40) 89 (20–158) 384 (0–1063) 22 (7–776)
n/a n/a 0.002 0.049 0.034 < 0.001 0.006 NS < 0.001
23 (16.4%) 19 (14.5%) 4 (44.4%) 4 (50.0%) 0 (0%)
25.2 27.5 1.9 0.7 n/a
768 (210–1326) 839 (326–1352) 57 (0–165) 20 (0–77) n/a
n/a n/a 0.001 < 0.001 NS
Patients with peak serum creatinine < 1.2 mg/dL Total 140 Without AKI 131 All AKI 9 AKIN 1 8 AKIN 3 1
P*
*P-values comparing the respective AKI stage to patients without AKI. AKI, acute kidney injury; AKIN, Acute Kidney Injury Network; C-AKI, modified acute kidney injury criteria for cirrhosis; TFS, transplant-free survival; NS, not significant.
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n = 1731 paracenteses n = 606 patients
Included patients: n = 239 (39.4%)
Recorded AKI patients: n = 78 (32.6%)
Excluded: n = 367 (60.6%) No liver cirrhosis (n = 5, 1.4%) Previous OLT/KT (n = 59, 16.1%) Past or current HCC (n = 111, 30.2%) CKD or parenchymal kidney damage (n = 33, 9.0%) Missing data (n = 159, 43.3%)
AKIN:
C-AKI:
1: n = 53 (68%) 2: n = 15 (20%) 3: n = 10 (13%)
1: n = 24 (31%) 2: n = 29 (37%) 3: n = 25 (32%)
Possible trigger events*: n = 37 (47%) Infection*: n = 33 (89%) - SBP: n = 16 - other: n = 21 -of which sepsis: n = 13 (62%) Shock: n = 5 (14%) Toxic: n = 4 (11%) Upper GI bleeding: n = 3 (8%) -of which variceal bleeding: n = 1 (33%) Perioperative setting: n = 2 (5%)
HRS 1 during follow-up: n = 28 (36%)
Paracentesistriggered AKI: n = 28 (36%)
Without external trigger: n = 41 (53%)
Figure 1 Consort flowchart of patients evaluated for study enrollment. Percentages refer to the previous headline if not indicated otherwise. AKI episodes that develop within 7 days after paracentesis and cannot be attributed to an external trigger were considered paracentesistriggered AKI. Abbreviations: AKI, acute kidney injury; OLT, orthotopic liver transplantation; KT, kidney transplantation; HCC, hepatocellular carcinoma; CKD, chronic kidney disease; AKIN, classification according to the Acute Kidney Injury Network; C-AKI, modified AKIN criteria for liver cirrhosis; HRS1, type-1 hepatorenal syndrome; SBP, spontaneous bacterial peritonitis; GI, gastrointestinal. *Some patients may have experienced more than one event.
at the time of paracentesis and 28 (68%) developed AKI within 1 week after paracentesis (at D2 or W1). A total of 28 patients (36%) met the criteria for HRS1. The cumulative incidence rates according to AKIN and C-AKI criteria were as follows: AKIN1: n = 53 (68%), AKIN2: n = 15 (20%), AKIN3: n = 10 (13%); C-AKI A: n = 24 (31%), C-AKI: n = 29 (37%), C-AKI C: n = 25 (32%). Patients developing AKI had more often Child C cirrhosis (71% vs 47%, P = .003) and a higher MELD (22.95 (IQR 18.20–28.55) versus 14.84 (11.58–20.10); P < .001) compared with patients without AKI. More patients in the AKI group suffered from infection (42.3% vs 25.5%; P = .011) or sepsis (16.7% vs 5.6%; P = 0.008) at time of index paracentesis than patients in the control 1660
group. Five patients (6.4%) in the AKI group had developed either septic or hemorrhagic shock, as compared with only one patient (0.6%) in the no-AKI group (P = 0.015). Interestingly, significantly more patients without AKI received potentially nephrotoxic agents prior to index paracentesis than patients with AKI (15.5% vs 5.1%, P = .021). In 41 patients (53%), no trigger event was recorded. Prognosis of AKI after paracentesis. Overall mortality during the observation period 2006–2011 was 57.7% (n = 138/239; median survival: 557 days [IQR: 46 days—end of study]), 65.4% (n = 51/78; median survival: 104 days [IQR: 14 days—end of study]) in patients with AKI and 54% (n = 87/161; median survival: 806 days [IQR: 97 days—end of study]) in the AKI free control group (P = 0.015) (Tables 1 and 2, Figure 2). Median TFS among all groups was 414 days (95% CI: 52–776 days). Among 78 patients with AKI, 28 (35.9%) died within 1 month after the AKI episode and 49 (62.8%) until the end of follow-up, whereas in the control group without AKI (n = 161), 23 patients (14.3%) died within 1 month and 76 (47.2%) until the end of follow-up. Median TFS in the AKI group was significantly lower with only 91 days (95% CI: 0–234 days) compared with 768 days (95% CI: 331–1205 days) in patients without AKI (P = .002). Main causes of death were liverrelated complications in 75 cases (56%), non-hepatic malignancies in 12 (9%), and cardiovascular diseases in 6 cases (5%). Overall, 40 patients (16.7%) underwent OLT: 11 (14%) in the AKI group and 29 (18%) in the no-AKI group (P = not significant (NS)). Independent risk factors for mortality. In univariate analysis, higher age (P = 0.012), Child–Pugh class C (vs B, P < 0.001), high sCr (P = 0.041), high serum bilirubin (P = 0.004), low serum albumin (P = 0.002), high aspartate aminotransferase (P = 0.028), high white blood cell count (WBC count) (P = 0.003), and AKIN stages (P = 0.027, AKIN C in particular: P = 0.054) were possible predictive factors for death in all patients (Table 3). Higher alanine aminotransferase antimouse, C-reactive protein (CRP) and international normalized ratio (INR) indicated increased risk for mortality during follow-up (P = 0.096, P = 0.069, and P = 0.073, respectively). The multivariate Cox-regression model revealed age (odds ratio [OR] 1.027 per year), Child–Pugh class C (OR 1.872 vs Child B), white blood cell count (WBC) (OR 1.041 per G/L increase), and increasing AKIN stage (P = 0.003) as independent risk factors for mortality. AKIN stage 3 increased the risk of death fourfold (OR 4.082). Independent risk factors for 30 days mortality. Regarding 30-day mortality, univariate analyses revealed Child–Pugh C (as compared with class B, P = 0.009), sCr (P = 0.024), WBC (P = 0.008), and increasing AKIN stages (P = 0.019) as possible predictors for death within 30 days after AKI (Table S2, Figure S1). In a binary logistic regression analysis model with death < 30 days as outcome, Child–Pugh Class C (OR 4.588), WBC (OR 1.129, 95% CI: 1.015–1.257, P = 0.025) and increasing AKIN stages (P = 0.046) resulted as independent risk factors for short-term mortality. AKIN stage 3 was the strongest predictor for 30-day mortality (OR 6.134). Interestingly, when we assessed the MELD score by area under the receiver operating
Journal of Gastroenterology and Hepatology 30 (2015) 1657–1665 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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Acute kidney injury and liver cirrhosis
Figure 2 Kaplan–Meier graphs depicting transplant-free survival (TFS) according to development of AKI according to AKIN criteria (a and c: left side) versus C-AKI criteria (b and d: right side) within 1 month (a and b: upper graphs) and within 1 year (c and d: lower graphs). Log–rank tests refer to overall distinctions in TFS within 31 days in (a) and (b), and within total follow-up in (c) and (d), respectively. (c) and (d) depict 12 months survival. Asterisks indicate statistically significant differences between stages.
characteristics curve (AUROC) analysis in its predictive value for mortality, and calculated the Youden’s index for a relevant cut-off, a Model of End-stage Liver Disease (MELD) score of 22 had the best specificity and sensitivity.
Outcomes in C-AKI stage A versus stage B. Although patients with C-AKI stage B had a significantly higher baseline sCr value before development of AKI than C-AKI A patients (1.18 [IQR 0.98–1.32] mg/dL vs 0.78 [IQR 0.68–0.91]
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Table 3
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Independent predictors for overall survival
Variable
Survival (n = 114)
Death (n = 125)
Univariate P
OR
Cox-regression analysis 95% CI
Age (years) Child–Pugh C versus B Serum sodium (mmol/L) Serum creatinine (mg/dL) Serum bilirubin (mg/dL) Serum albumin (mg/dL) Serum ALT (U/L) Serum AST (U/L) Serum CRP (mg/dL) WBC (G/L) INR AKI (n [%])† —AKIN 1† —AKIN 2† —AKIN 3†
52.9 ± 10.7 B: 67 (62%) C: 47 (36%) 134.3 ± 5.8 0.98 (0.77–1.26) 2.75 (1.30–6.21) 28.6 ± 5.4 31 (17–48) 59 (37–89) 2.13 (1.20–4.49) 6.52 (4.86–10.17) 1.41 (1.21–4.74) 29 (37%) 21 (40%) 6 (40%) 2 (20%)
56.7 ± 12.3 B: 41 (38%) C: 84 (64%) 133.2 ± 6.7 1.11 (0.86–1.45) 4.32 (2.17–8.97) 26.5 ± 5.2 35 (24–57) 68 (48–99) 3.03 (1.46–5.47) 8.38 (5.95–12.62) 1.48 (1.31–1.91) 49 (63%) 32 (60%) 9 (60%) 8 (80%)
0.012 < 0.001 0.174 0.041 0.004 0.002 0.096 0.028 0.069 0.003 0.073 0.027 0.114 0.422 0.054
M-variate P
1.027 1.872
1.010–1.045 1.244–2.818
0.001 0.003
1.002 0.999 1.016 1.041
1.000–1.004 0.996–1.002 0.988–1.044 1.003–1.080
0.054 0.664 0.270 0.033
1.119 1.786 4.082
0.718–1.743 0.885–3.602 1.864–8.937
0.003 0.619 0.105 < 0.001
†
Versus patients without AKI. Variables that showed a trend or were significant in univariate analysis P ≤ 0.010) were entered into the multivariate model. AKI, acute kidney injury; AKIN, Acute Kidney Injury Network; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; CRP, C-reactive protein; WBC, white blood cell count.
mg/dL; P < 0.001), other patient characteristics were equally distributed between C-AKI A and B patients (P = NS) (Table S1, Figure 2). Mortality increased with each AKIN stage—especially in the short-term (Figure 2a,b), however, higher C-AKI stages were not associated with impaired TFS. Most interestingly, C-AKI A patients (sCr remained < 1.5 mg/dL) showed a significantly worse prognosis both in the short and long term than patients without AKI development (P < .05; Figure 2c,d). Median TFS was lowest in patients with AKI progression, AKIN stage 3 and C-AKI stage C (respectively 6 days, 95% CI: 3–12 days; 19 days, 95%: CI 0–40 days and 22 days, 95% CI: 7–37 days). Impact of AKI in patients with “normal” sCr. In total, 140 patients had a peak sCr value below the upper limit of our reference laboratory ranges (< 1.2 mg/dL) between D0 and W1 (Table 2, Figure 3). Nine (6.4%) of these patients developed AKI (any stage) according to AKIN criteria. Among these nine AKI patients, eight developed AKI 1, none AKI 2 and one AKI 3. Strikingly, median TFS among AKI patients with “normal” sCr was only 57 (95% CI: 0–165) days. This is significantly lower than the 839 (326–1352) days median TFS of the remaining 131 patients without AKI and “normal” sCr (P = 0.001). Figure 3 Comparison of patients with serum creatinine levels within reference laboratory ranges (< 1.2 mg/dL) with versus without development of AKI. Log–rank test refers to total follow-up survival.
Discussion In our study we found an AKI incidence of 33% among cirrhotic patients with ascites at or within one week of paracentesis—a similar incidence as reported in previous studies.1,3,21 Development of AKI was strongly associated with subsequent mortality (both when assessing overall mortality or TFS), underlining its important prognostic significance in patients with ascites.4,6,29,30 We were also able to demonstrate that even small increases within “normal” 1662
laboratory ranges of sCr are of substantial prognostic relevance.14,31 In our study, mortality gradually increased with each AKIN stage, and both development of AKI and the severity of AKIN stage were identified as independentors predictor mortality.
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Moreover, even “mild” AKI in patients with cirrhosis and ascites, whose peak sCr remained below 1.5 mg/dL (C-AKI stage A) was already indicative of an increased risk for mortality as compared with patients without C-AKI. As a result, our study provides evidence that the implementation of the 1.5 mg/dL cut-off in sCr (which has been used for defining HRS23,32 and the “conventional” AKI criterion, defined as an increase in sCr by ≥ 50% to ≥ 1.5 mg/ dL)33,34 in order to discriminate C-AKI A and B does not improve the prognostic assessment of patients with cirrhosis and ascites. Indeed, it might suggest that C-AKI A is a less severe form of kidney injury than C-AKI B and might preclude important therapeutic measures. In our cohort, the surprisingly high mortality rate of the nine patients with AKI within “normal” sCr underlines the prognostic importance of AKI diagnosis in cirrhotic patients with ascites undergoing paracentesis. However, AKI itself might not be the sole reason for poor outcome in the cohort with “normal” creatinine levels: A recent study assessed prognostic value ACLF (acute-on-chronic liver failure) criteria to predict short-term mortality.35 The authors of this study conclude that ACLF criteria performed better than AKIN criteria because the ACLF score also considers other organ failures rather than only renal failure in patients with decompensated cirrhosis. Although we want to encourage the use of ACLF criteria in decompensated patients (who do not always present with ascites), our study focused on the prognostic value of C-AKI versus AKIN to stage prognosis in patients with ascites who are most prone to develop renal failure. However, the ACLF criteria [34] might have been able to predict mortality in our nine patients with AKI in low sCr levels. Indeed, most of these patients with AKIN grade 1 and low sCr levels were diagnosed with infections and some progressed to sepsis, and two patients died from septic shock. Interestingly, next to AKI (staged according to AKIN) as independent risk factor or mortality, WBC also emerged as independent risk factor—indicating infections and/or inflammation as a relevant prognostic factor in patients with ascites. Interestingly, a MELD score of 22 had the best specificity and sensitivity for predicting mortality. This particular MELD cut-off at 22 points has also been identified by previous studies as a critical treshold in decompensated patients with ascites.36–38 The two main assets of our current study are the application of strict exclusion criteria and detailed documentation of our patients’ medical histories. Many patients with cirrhosis are of higher age and suffer from additional medical conditions, such as HCC, cardiovascular diseases, or CKD. These conditions may cause renal dysfunction not related to the underlying liver disease and may per se affect prognosis and mortality. Although previous studies often included those patients, we intended to limit our analyses to patients without those potential confounders. The main downside of this study is its retrospective nature. In daily routine, baseline creatinine values are not always available 48 h previous to an AKI episode. Because up to 20% of patients hospitalized for decompensation of cirrhosis present with AKI already at admission, we used the last stable creatinine value (prior to admission) as “baseline” for AKI diagnosis. Patients with cirrhosis and ascites are often exposed to potential triggers that eventually can result in renal injury such as nephrotoxic drugs, infections (i.e. spontaneous bacterial peritonitis), repeated imaging scans using radio-contrast agents, or surgery. In order to assess the prognostic value of AKI according to its poten-
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tial trigger, we thoroughly recorded potential factors influencing kidney and liver function from medical histories. sCr is an inexpensive and widely established marker for renal function in clinical practice—including in patients with cirrhosis. However, there are clear limitations that clinicians should be aware of:34,39 there is a range when sCr levels do not reflect a drop of renal function by up to 50%—so minor or beginning renal failure might be missed. Moreover, patients with compensated cirrhosis often present with lower sCr levels than agematched healthy controls. As a consequence, GFR is often overestimated in cirrhosis when using creatinine-based models. This suggests that kidney function might already be severely impaired in patients with cirrhosis when sCr rises above the upper limit of normal and that renal failure may be overlooked when it remains within reference limits.31,40 We confirmed AKI as an important predictor of TFS with gradually increasing mortality rates for each stage. However, we could not validate all findings by Fagundes et al. and Piano et al., who argued that kidney damage associated with C-AKI stage A (AKI without “reaching” absolute sCr values above 1.5 mg/dL) had only minor (if at all) influence on prognosis and survival of patients with cirrhosis. In the present study, however, patients with C-AKI stage A showed a significantly worse prognosis compared with patients without AKI, whereas this was not the case in patients with C-AKI stage B (mild AKI with peak sCr surpassing 1.5 mg/dL). These results are in contrast to the aforementioned studies. However, our finding is supported by a study recently published by Tsien et al.29 who demonstrated a significantly decreased survival in outpatients with cirrhosis and ascites developing AKI despite absolute sCr levels remaining within “normal” ranges. A letter by Thalheimer and Burroughs also warned to regard C-AKI stage A as a benign condition, but rather to treat as aggressively as in any other renal failure, since an overlooked AKI may result in death of the patient.22 Our results fully support this opinion to encourage special caution with regard to patients with cirrhosis and ascites who show a rise in sCr levels despite low absolute values. In summary, management of AKI represents a clinical priority in patients with cirrhosis. We want to emphasize that relative, rather than absolute, increases in sCr should be preferred for diagnosing AKI. Special attention should be paid to increases in sCr despite low or moderate levels, as early stages (C-AKI A) of AKI may be overlooked in patients with cirrhosis. Further prospective studies are warranted to assess the prognosis of AKI in patients with decompensated cirrhosis and ascites, and effective interventions for “hepatic” AKI in patients with cirrhosis and ascites should be investigated.
References 1 Belcher JM, Garcia-Tsao G, Sanyal AJ et al. Association of AKI with mortality and complications in hospitalized patients with cirrhosis. Hepatology 2013; 57: 753–62. 2 Cholongitas E, Senzolo M, Patch D, Shaw S, O’Beirne J, Burroughs AK. Cirrhotics admitted to intensive care unit: the impact of acute renal failure on mortality. Eur. J. Gastroenterol. Hepatol. 2009; 21: 744–50. 3 Wong F, O’Leary JG, Reddy KR et al. New consensus definition of acute kidney injury accurately predicts 30-day mortality in patients with cirrhosis with infection. Gastroenterology 2013; 145: 1280–8.
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4 Du Cheyron D, Bouchet B, Parienti J-J, Ramakers M, Charbonneau P. The attributable mortality of acute renal failure in critically ill patients with liver cirrhosis. Intensive Care Med. 2005; 31: 1693–9. 5 Garcia-Tsao G, Parikh CR, Viola A. Acute kidney injury in cirrhosis. Hepatology 2008; 48: 2064–77. 6 Fede G, D’Amico G, Arvaniti V et al. Renal failure and cirrhosis: A systematic review of mortality and prognosis. J. Hepatol. 2011; 56: 810–18. 7 Salerno F, Gerbes A, Ginès P, Wong F, Arroyo V. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007; 56: 1310–18. 8 Kellum JA, Levin N, Bouman C, Lameire N. Developing a consensus classification system for acute renal failure. Curr. Opin. Crit. Care 2002; 8: 509–14. 9 Ostermann M, Chang RWS. Challenges of defining acute kidney injury. QJM 2011; 104: 237–43. 10 Lameire N. The definitions and staging systems of acute kidney injury and their limitations in practice. Arab J. Nephrol. Transplant. 2013; 6: 145–52. 11 Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit. Care 2004; 8: R204–12. 12 Mehta RL, Kellum JA, Shah SV et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit. Care 2007; 11: R31. 13 Lassnigg A, Schmidlin D, Mouhieddine M et al. Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: a prospective cohort study. J. Am. Soc. Nephrol. 2004; 15: 1597–605. 14 Praught ML, Shlipak MG. Are small changes in serum creatinine an important risk factor? Curr. Opin. Nephrol. Hypertens. 2005; 14: 265–70. 15 Fagundes C, Barreto R, Guevara M et al. A modified acute kidney injury classification for diagnosis and risk stratification of impairment of kidney function in cirrhosis. J. Hepatol. 2013; 59: 474–81. 16 Bataller R, Ginès P, Guevara M, Arroyo V. Hepatorenal syndrome. Semin. Liver Dis. 1997; 17: 233–47. 17 Francoz C, Glotz D, Moreau R, Durand F. The evaluation of renal function and disease in patients with cirrhosis. J. Hepatol. 2010; 52: 605–13. 18 Arroyo V, Ginès P, Gerbes A, Dudley FJ. Special article: definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology 1996; 23: 164–76. 19 Wong F, Nadim MK, Kellum JA et al. Working party proposal for a revised classification system of renal dysfunction in patients with cirrhosis. Gut 2011; 60: 702–9. 20 Piano S, Morando F, Angeli P. Reply to: “To close the stable door before the horse has bolted. J. Hepatol. 2014; 60: 680–1. 21 Piano S, Rosi S, Maresio G et al. Evaluation of the Acute Kidney Injury Network criteria in hospitalized patients with cirrhosis and ascites. J. Hepatol. 2013; 59: 482–9. 22 Thalheimer U, Burroughs AK. To close the stable door before the horse has bolted. J. Hepatol. 2014; 60: 678–9. 23 Mandorfer M, Bota S, Schwabl P et al. Nonselective β blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis. Gastroenterology 2014; 146: 1680–90, e1. 24 Reiberger T, Ferlitsch A, Payer BA et al. Noninvasive screening for liver fibrosis and portal hypertension by transient elastography—a large single center experience. Wien. Klin. Wochenschr. 2012; 124: 395–402.
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25 Hucke F, Sieghart W, Schöniger-Hekele M, Peck-Radosavljevic M, Müller C. Clinical characteristics of patients with hepatocellular carcinoma in Austria—is there a need for a structured screening program? Wien. Klin. Wochenschr. 2011; 123: 542–51. 26 De Franchis R. Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension. J. Hepatol. 2010; 53: 762–8. 27 Peck-Radosavljevic M, Angermayr B, Datz C et al. Austrian consensus on the definition and treatment of portal hypertension and its complications (Billroth II). Wien. Klin. Wochenschr. 2013; 125: 200–19. 28 Bartels H, Böhmer M, Heierli C. [Serum creatinine determination without protein precipitation]. Clin. Chim. Acta 1972; 37: 193–7. 29 Tsien CD, Rabie R, Wong F. Acute kidney injury in decompensated cirrhosis. Gut 2013; 62: 131–7. 30 Tandon P, Garcia-Tsao G. Renal dysfunction is the most important independent predictor of mortality in cirrhotic patients with spontaneous bacterial peritonitis. Clin. Gastroenterol. Hepatol. 2011; 9: 260–5. 31 Francoz C, Prie D, Abdelrazek W et al. Inaccuracies of creatinine and creatinine-based equations in candidates for liver transplantation with low creatinine: impact on the model for end-stage liver disease score. Liver Transplant. 2010; 16: 1169–77. 32 Nadim MK, Kellum JA, Davenport A et al. Hepatorenal syndrome: the 8th international consensus conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit. Care 2012; 16: R23. 33 Arroyo V. Acute kidney injury (AKI) in cirrhosis: Should we change current definition and diagnostic criteria of renal failure in cirrhosis? J. Hepatol. 2013; 59: 415–17. 34 Angeli P, Sanyal A, Moller S et al. Current limits and future challenges in the management of renal dysfunction in patients with cirrhosis: report from the International Club of Ascites. Liver Int. 2013; 33: 16–23. 35 Angeli P, Rodríguez E, Piano S et al. Acute kidney injury and acute-on-chronic liver failure classifications in prognosis assessment of patients with acute decompensation of cirrhosis. Gut 2014; 0: 1–7. 36 Tandon P, Kumar D, Seo YS et al. The 22/11 risk prediction model: a validated model for predicting 30-day mortality in patients with cirrhosis and spontaneous bacterial peritonitis. Am. J. Gastroenterol. 2013; 108: 1473–9. 37 Kim JJ, Tsukamoto MM, Mathur AK et al. Delayed paracentesis is associated with increased in-hospital mortality in patients with spontaneous bacterial peritonitis. Am. J. Gastroenterol. 2014; 109: 1–7. 38 Schwabl P, Bucsics T, Soucek K et al. Risk factors for development of spontaneous bacterial peritonitis and subsequent mortality in cirrhotic patients with ascites. Liver Int. 2015 Feb 2. doi: 10.1111/liv.12795. 39 Demirtas¸ S, Bozbas¸ A, Akbay A, Yavuz Y, Karaca L. Diagnostic value of serum cystatin C for evaluation of hepatorenal syndrome. Clin. Chim. Acta 2001; 311: 81–9. 40 Cerdá J, Cerdá M, Kilcullen P, Prendergast J. In severe acute kidney injury, a higher serum creatinine is paradoxically associated with better patient survival. Nephrol. Dial. Transplant. 2007; 22: 2781–4.
Supporting information Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Figure S1 Kaplan–Meier graphs depicting transplant-free survival (TFS) according to development of AKI versus no AKI development within (a) 1 month and (b) 1 year. Log–rank tests refer to TFS within 31 days in (a) and within 12 months in (b).
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Figure S2 AUROC an analyses showing the AUC for MELD score for predicting 30-day mortality in patients with ascites developing AKI. The AUC for a MELD score cut-off at 22 for predicting 30day mortality was 0.774 (95%CI: 0.662–0.887). Patients with MELD ≥ 22 had a 30-day mortality of 56% (n = 22/39), while patients with a MELD < 22 showed only 13% (n = 4/31) 30-day mortality (P < .001). The MELD 22 cut-off had a sensitivity of 88.5% and a specificity of 61.4% to predict death 30days after AKI development.
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Table S1 Comparison of patients with C-AKI stages A vs B. *P-values indicate significant differences between C-AKI stages A and B. Table S2 30 days mortality in cirrhotic patients with ascites developing AKI
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doi:10.1111/jgh.13002
H E PAT O L O G Y
Impact of acute kidney injury on prognosis of patients with liver cirrhosis and ascites: A retrospective cohort study Theresa Bucsics,*,† Mattias Mandorfer,*,† Philipp Schwabl,*,† Simona Bota,*,† Wolfgang Sieghart,*,† Arnulf Ferlitsch,*,† Michael Trauner,* Markus Peck-Radosavljevic*,† and Thomas Reiberger*,† *Division of Gastroenterology, Department of Internal Medicine III and †Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria
Key words acute kidney failure, acute kidney injury, ascites, cirrhosis, liver cirrhosis. Accepted for publication 24 April 2015 Correspondence Dr Thomas Reiberger, Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Email: [email protected] Declaration of conflict of interest: The authors have no conflict of interest. Author contributions: Study design (TB, MM, PS, MPR), data acquisition (TB, SB, MM, AF, TR), statistical analysis (TB, MM, PS, TR), critical revision of intellectual content (TB, MM, PS, SB, AF, MT, MPR, TR).
Abstract Background and Aim: Acute kidney injury (AKI) is a common complication in patients with liver cirrhosis, and its impact on the clinical course is increasingly recognized. Diagnostic classification systems for AKI in cirrhosis have been suggested. The prognostic significance of the respective AKI stages remains to be evaluated in decompensated cirrhosis with ascites. Methods: Data of consecutive patients with cirrhosis and ascites undergoing paracentesis at a tertiary care center were analyzed. AKI was defined as an increase in serum creatinine of ≥ 0.3 mg/dL or by ≥ 50% within 7 days after paracentesis, and classified according to (i) revised Acute Kidney Injury Network (AKIN) criteria and (ii) modified AKI criteria for cirrhosis (C-AKI). In contrast to AKIN, C-AKI stage A discriminates prognosis based on an absolute creatinine cut-off at < 1.5 mg/dL versus C-AKI stage B at ≥ 1.5 mg/dL. Results: The final study cohort included 239 patients. Median transplant-free survival was 768 days (95% confidence interval [CI]: 331–1205 days) without AKI, 198 (0–446) in AKI-1, 91 (0–225) in AKI-2, 19 (0–40) and in AKI-3, whereas it was 89 (20–158) days in C-AKI-A, 384 (0–1063) in C-AKI-B, and 22 (7–776) in C-AKI-C. Mild AKI was already associated with significantly increased 30-day mortality (AKI-1:26.4%, C-AKI-A:33.3%) as compared with patients without AKI (14.3%), even when serum creatinine remained within normal range (< 1.2 mg/dL) we observed a significant 30-day mortality. Conclusion: AKIN criteria—considering small increases in serum creatinine rather than absolute thresholds—seem to be more accurate for estimating prognosis of AKI after paracentesis than C-AKI criteria. Even patients developing AKI-1 with “normal” serum creatinine are at increased risk for mortality.
Introduction Acute kidney injury (AKI) is a common complication in patients with decompensated cirrhosis and represents a major contributor to mortality.1–4 Approximately 20% of hospitalized patients with liver cirrhosis develop renal failure5 and up to 50% of these patients die within 30 days.6 A meta-analysis from 2011 reported a 6.38-fold increased risk for mortality for patients with AKI.6 Moreover, hepatorenal syndrome type 1 (HRS1), which is considered a unique and severe form of AKI,7 is considered one of the most lethal complications in patients with cirrhosis and ascites. However, various diagnostic criteria have been reported for identifying AKI, even among patients with cirrhosis.6,8–10 In 2007, based on the RIFLE (Risk, Injury, Failure, Loss-of-function, Endstage renal disease) criteria from 2004,11 the Acute Kidney Injury Network (AKIN) introduced new criteria for AKI, which is defined by an abrupt reduction in renal function in critically ill patients.12 These criteria classify AKI into three grades, depending on either
a reduction in urine output or a rise in serum creatinine (sCr) within 48 hours with mild (grade 1) to severe (grade 3) stages of renal failure. The AKIN classification considers the prognostic relevance of relative increases in sCr even among patients with low and normal serum levels.12–14 In 2013, Fagundes et al.15 presented a modified version of the AKIN criteria and adapted them for patients with liver cirrhosis (cirrhosis-AKI criteria, C-AKI). Using only sCr as a parameter, the authors introduced a threshold of 1.5 mg/dL to define C-AKI stages “A” and “B” among patients with AKI grade 1 (rise in sCr by ≥ 50% or ≥ .3 mg/dL, but by < 100%), and merged AKI grades 2 and 3 into C-AKI stage “C.” The peak sCr cut-off of 1.5 mg/dL was selected as indicator for a critical decrease in glomerular filtration rate (GFR).16–18 A similar cut-off is also used for diagnosis of HRS.18,19 Most surprisingly, patients with C-AKI stage A (corresponding AKI grade 1 with a peak sCr value < 1.5 mg/dL) showed no higher mortality than patients without AKI.20 A second study performed by Piano et al. obtained similar results.21
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However, many experts still advise being cautious about patients fulfilling the criteria for AKI stage A and suggest treating them according to recommendations for renal failure.20,22 The prognostic significance of the “original” AKI stages (according to AKIN criteria)12 versus the “cirrhosis-specific” C-AKI stages15 (especially for C-AKI stage A) remains to be determined for patients with decompensated cirrhosis and ascites. In this retrospective cohort study, we compared the prognostic significance of (i) the original AKIN classification to (ii) the modified C-AKI criteria for cirrhosis regarding transplant-free survival (TFS), and (iii) of AKI in patients with peak sCr within reference range (< 1.2 mg/dL).
Methods This retrospective cohort study was conducted according to the ethical principles of the revised Declaration of Helsinki and approved by the local Ethics Committee (EK#1008/2011). Similar to a previous study,23 a dataset of all patients undergoing a total of 1731 abdominal paracenteses at the Medical University of Vienna was evaluated. The diagnosis of cirrhosis was established by liver biopsy, transient elastography, radiologically, or by typical clinical signs.24 Hepatocellular carcinoma (HCC) was diagnosed as previously described.25 Patients with HCC, kidney, or orthotopic liver transplantation (OLT) prior to the index paracentesis (see definition below), documented renal parenchymal damage, or chronic kidney disease (CKD) were excluded. Clinical and laboratory data at the time of paracentesis and during follow-up were recorded from medical histories. Patients gave written informed consent to all procedures. Paracenteses and biochemical tests. Paracenteses were performed as clinically indicated.26 Patients undergoing largevolume paracentesis (> 5L) received 8-g human serum albumin per liter of ascites removed.27 The index paracentesis was defined as the first paracentesis at our center. Laboratory parameters were documented from the day of index paracentesis (or up to 7 days before if not available). The baseline value for creatinine was defined as the last stable (maximum variance ± 0.2 mg/dL within three measurements) sCr value < 2 mg/dL within 7–365 days prior to index paracentesis. sCr and sodium values were recorded at baseline and at day of index paracentesis (D0), and then at 24–48 h (D2) and within the first week (W1) after index paracentesis. Methods for determining sCr. Blood samples were collected into heparin-anticoagulated vacuum containers. sCr was measured using the standard assay method of the main laboratory of the Vienna General Hospital (Jaffe method).28 Definition of AKI. AKI was defined as an increase in sCr by ≥ .3 mg/dL or by ≥ 50% either from baseline to the index paracentesis (D0),19 from D0 to 24–4 h afterwards (D2), or from D2 to 3–7 days after paracentesis (W1). AKI was regarded associated with paracentesis when AKI criteria were fulfilled at day 2 (D2) or within 1 week after the paracentesis (W1). The following potential triggers for AKI were documented for 7 days prior to AKI: systemic infections, sepsis, shock, upper gastrointestinal bleeding, 1658
surgery, application of radiocontrast agents, or nephrotoxic drugs (i.e. non-steroidal antiinflammatory drugs or aminoglycosides). AKI episodes were staged according to AKIN or C-AKI criteria: — AKIN1: increase in sCr by either ≥ 50–99% or ≥ 0.3 mg/dL; — AKIN2: increase in sCr by ≥ 100–199%; — AKIN3: increase in sCr by ≥ 200% or ≥ 4 mg/dL or hemodialysis/anuria ≥ 12 h;12 — C-AKI A: increase in sCr by either ≥ 0.3 mg/dL or ≥ 50% to a final value < 1.5 mg/dL; — C-AKI B: increase in sCr by either ≥ 0.3 mg/dL or ≥ 50% to a final value ≥ 1.5 mg/dL; — C-AKI C: whenever criteria for AKIN stages 2 or 3 where fulfilled.15 Resolution of AKI was determined by a reduction in sCr to < 0.3 mg/dL above baseline sCr levels (or lower) within 14 days after AKI onset. HRS was defined by a rise in sCr to > 1.5 mg/dL in the absence of typical trigger events for renal failure.7,27 In order to evaluate the impact of small increases in sCr within normal laboratory ranges, we analyzed TFS in patients with AKI and a peak sCr < 1.2 mg/dL (the upper limit of normal of sCr). Statistical analysis. Statistical analyses were performed using IBM SPSS Statistics (IBM, version 22.0, Armonk, NY, USA). Parametric distribution was assessed by Kolmogorov– Smirnov test. Student t-test or Mann–Whitney U-test was applied for group comparison of continuous variables. Parameters were reported as mean ± standard deviation ( x ± SD ) or median (interquartile range, IQR) as appropriate. Categorical variables were reported as numbers (proportions) and analyzed using Chisquare or Fisher exact test. Kaplan–Meier curves were plotted for TFS. OLT or last follow-up visits were defined as censoring events, and death as event. TFS was reported as median (95% confidential interval, CI). Log–rank test was used to compare TFS between AKIN and C-AKI groups. Univariate analyses were performed to identify independent predictors of overall (cox regression) and 30-day (binary logistic regression) mortality. AKIN stages and variables that showed a trend or were significant in univariate analysis (P < .10) were then entered into multivariate cox regression analysis (overall mortality) and a binary logistic regression analysis (30-day mortality) to assess independent risk factors for death. Variables that were significant at univariate analyses but are already included within scores have not been included into the same multivariate model to omit redundancy.
Results Patient characteristics. Among all patients undergoing paracentesis at the Vienna General Hospital from 2006 to 2011, 239 patients with cirrhosis and portalhypertensive ascites and without previous liver or kidney transplantation were included (Table 1, Figure 1). Most (90%) of our patients were inpatients (n = 215) and only 10% (n = 24) were outpatients. A total of 78 patients (32.6%) had either AKI at the time of paracentesis or developed AKI within 1 week (paracentesis-associated “AKI group”), whereas 161 patients (67.4%) developed no AKI (“noAKI group”). Thirteen (32%) had already developed kidney failure
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Table 1
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Baseline characteristics, and comparison of patients with and without AKI development
Parameter
All patients
No AKI
AKI
Patients (n [%]) Age (years) Sex (m/f [%m]) Etiology (n [%]) Alcohol Viral Mixed alcohol/viral Autoimmune PBC/PSC NASH Cryptogenic Other Child–Pugh A/B/C (n [%])
239 (100.0) 54.9 ± 11.7 160/79 (66.9)
161 (67.4) 54.8 ± 11.9 108/53 (67.1)
78 (32.6) 55.1 ± 11.4 52/26 (66.7)
140 (58.6) 39 (16.3) 21 (8.8) 6 (2.5) 5 (2.1) 10 (4.2) 11 (4.6) 7 (2.59 10/98/131 (4%/41%/55%) 186 (78) 50 (20.9) 17.37 (12.93–23.22) 134.4 ± 4.9 0.92 (0.74–1.10) 3.68 (1.80–7.67) 27.5 ± 5.4 32 (20–53) 64 (42–95) 1.44 (1.27–1.81) 2.5 (1.3–5.0) 7.8 (5.4–11.2) 40 (16)
98 (60.9) 25 (15.5) 12 (7.5) 4 (2.5) 3 (1.9) 6 (3.7) 7 (4.3) 6 (3.7) 8/77/76 (5%/48%/47%)) 126 (78) 35 (21.7) 14.84 (11.58–20.10) 134.6 ± 4.8 0.90 (0.72–1.08) 2.91 (1.53–5.9) 28.3 ± 5.4 31 (20–47) 60 (40–88) 1.39 (1.20–1.70) 2.0 (1.1–3.8) 6.9 (4.9–9.4) 29 (18)
42 (53.8) 14 (17.9) 9 (11.5) 2 (2.6) 2 (2.6) 4 (5.1) 4 (5.1) 1 (1.3) 2/21/55 (3%/27%/71%) 60 (77) 15 (19.2) 22.95 (18.20–28.55) 133.8 ± 5.1 0.96 (0.77–1.18) 4.78 (2.73–12.91) 25.8 ± 5.0 35 (21–60) 78 (46–132) 1.61 (1.37–2.16) 4.1 (2.1–7.4) 10.0 (6.5–14.1) 11 (14)
Gastroesophageal varices (n [%]) Previous variceal bleeding (n [%]) MELD (median [IQR]) Baseline serum sodium (mEq/L) Baseline creatinine (mg/dL) (median [IQR]) Baseline bilirubin (mg/dL) (median [IQR]) Baseline albumin (mg/dL) (mean ± SD) Baseline ALT (U/L) (median [IQR]) Baseline AST (U/L) (median [IQR]) Baseline INR (median [IQR]) Baseline CRP (mg/dL) Baseline Leukocytes (G/L) OLT (n [%])
P n/a 0.834 1.000 0.796
0.003 0.869 0.736 < 0.001 0.235 0.038 < 0.001 0.001 0.151 0.005 0.001 < 0.001 < 0.001 0.580
AKI, acute kidney injury; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; INR, international normalized ratio; IQR, interquartile range; MELD, Model of End-stage Liver Disease; NASH, non-alcoholic steatohepatitis; OLT, orthotopic liver transplantation; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; SD, standard deviation.
Table 2
Mortality and transplant-free survival of patients according to AKI stage
Patients
Number of patients (n)
30 Days mortality (deaths, %)
Median TFS (months)
Median TFS (days)
Total Without AKI All AKI AKIN 1 AKIN 2 AKIN 3 C-AKI A C-AKI B C-AKI C
329 161 78 53 15 10 24 29 25
70 (21.3%) 23 (14.3%) 28 (35.9%) 14 (26.4%) 7 (46.7%) 7 (70.0%) 8 (33.3%) 6 (20.7%) 14 (56.0%)
13.6 25.2 3.0 6.5 3.0 0.6 2.9 12.6 0.7
414 (52–776) 768 (331–1205) 91 (0–234) 198 (0–446) 91 (0–225) 19 (0–40) 89 (20–158) 384 (0–1063) 22 (7–776)
n/a n/a 0.002 0.049 0.034 < 0.001 0.006 NS < 0.001
23 (16.4%) 19 (14.5%) 4 (44.4%) 4 (50.0%) 0 (0%)
25.2 27.5 1.9 0.7 n/a
768 (210–1326) 839 (326–1352) 57 (0–165) 20 (0–77) n/a
n/a n/a 0.001 < 0.001 NS
Patients with peak serum creatinine < 1.2 mg/dL Total 140 Without AKI 131 All AKI 9 AKIN 1 8 AKIN 3 1
P*
*P-values comparing the respective AKI stage to patients without AKI. AKI, acute kidney injury; AKIN, Acute Kidney Injury Network; C-AKI, modified acute kidney injury criteria for cirrhosis; TFS, transplant-free survival; NS, not significant.
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n = 1731 paracenteses n = 606 patients
Included patients: n = 239 (39.4%)
Recorded AKI patients: n = 78 (32.6%)
Excluded: n = 367 (60.6%) No liver cirrhosis (n = 5, 1.4%) Previous OLT/KT (n = 59, 16.1%) Past or current HCC (n = 111, 30.2%) CKD or parenchymal kidney damage (n = 33, 9.0%) Missing data (n = 159, 43.3%)
AKIN:
C-AKI:
1: n = 53 (68%) 2: n = 15 (20%) 3: n = 10 (13%)
1: n = 24 (31%) 2: n = 29 (37%) 3: n = 25 (32%)
Possible trigger events*: n = 37 (47%) Infection*: n = 33 (89%) - SBP: n = 16 - other: n = 21 -of which sepsis: n = 13 (62%) Shock: n = 5 (14%) Toxic: n = 4 (11%) Upper GI bleeding: n = 3 (8%) -of which variceal bleeding: n = 1 (33%) Perioperative setting: n = 2 (5%)
HRS 1 during follow-up: n = 28 (36%)
Paracentesistriggered AKI: n = 28 (36%)
Without external trigger: n = 41 (53%)
Figure 1 Consort flowchart of patients evaluated for study enrollment. Percentages refer to the previous headline if not indicated otherwise. AKI episodes that develop within 7 days after paracentesis and cannot be attributed to an external trigger were considered paracentesistriggered AKI. Abbreviations: AKI, acute kidney injury; OLT, orthotopic liver transplantation; KT, kidney transplantation; HCC, hepatocellular carcinoma; CKD, chronic kidney disease; AKIN, classification according to the Acute Kidney Injury Network; C-AKI, modified AKIN criteria for liver cirrhosis; HRS1, type-1 hepatorenal syndrome; SBP, spontaneous bacterial peritonitis; GI, gastrointestinal. *Some patients may have experienced more than one event.
at the time of paracentesis and 28 (68%) developed AKI within 1 week after paracentesis (at D2 or W1). A total of 28 patients (36%) met the criteria for HRS1. The cumulative incidence rates according to AKIN and C-AKI criteria were as follows: AKIN1: n = 53 (68%), AKIN2: n = 15 (20%), AKIN3: n = 10 (13%); C-AKI A: n = 24 (31%), C-AKI: n = 29 (37%), C-AKI C: n = 25 (32%). Patients developing AKI had more often Child C cirrhosis (71% vs 47%, P = .003) and a higher MELD (22.95 (IQR 18.20–28.55) versus 14.84 (11.58–20.10); P < .001) compared with patients without AKI. More patients in the AKI group suffered from infection (42.3% vs 25.5%; P = .011) or sepsis (16.7% vs 5.6%; P = 0.008) at time of index paracentesis than patients in the control 1660
group. Five patients (6.4%) in the AKI group had developed either septic or hemorrhagic shock, as compared with only one patient (0.6%) in the no-AKI group (P = 0.015). Interestingly, significantly more patients without AKI received potentially nephrotoxic agents prior to index paracentesis than patients with AKI (15.5% vs 5.1%, P = .021). In 41 patients (53%), no trigger event was recorded. Prognosis of AKI after paracentesis. Overall mortality during the observation period 2006–2011 was 57.7% (n = 138/239; median survival: 557 days [IQR: 46 days—end of study]), 65.4% (n = 51/78; median survival: 104 days [IQR: 14 days—end of study]) in patients with AKI and 54% (n = 87/161; median survival: 806 days [IQR: 97 days—end of study]) in the AKI free control group (P = 0.015) (Tables 1 and 2, Figure 2). Median TFS among all groups was 414 days (95% CI: 52–776 days). Among 78 patients with AKI, 28 (35.9%) died within 1 month after the AKI episode and 49 (62.8%) until the end of follow-up, whereas in the control group without AKI (n = 161), 23 patients (14.3%) died within 1 month and 76 (47.2%) until the end of follow-up. Median TFS in the AKI group was significantly lower with only 91 days (95% CI: 0–234 days) compared with 768 days (95% CI: 331–1205 days) in patients without AKI (P = .002). Main causes of death were liverrelated complications in 75 cases (56%), non-hepatic malignancies in 12 (9%), and cardiovascular diseases in 6 cases (5%). Overall, 40 patients (16.7%) underwent OLT: 11 (14%) in the AKI group and 29 (18%) in the no-AKI group (P = not significant (NS)). Independent risk factors for mortality. In univariate analysis, higher age (P = 0.012), Child–Pugh class C (vs B, P < 0.001), high sCr (P = 0.041), high serum bilirubin (P = 0.004), low serum albumin (P = 0.002), high aspartate aminotransferase (P = 0.028), high white blood cell count (WBC count) (P = 0.003), and AKIN stages (P = 0.027, AKIN C in particular: P = 0.054) were possible predictive factors for death in all patients (Table 3). Higher alanine aminotransferase antimouse, C-reactive protein (CRP) and international normalized ratio (INR) indicated increased risk for mortality during follow-up (P = 0.096, P = 0.069, and P = 0.073, respectively). The multivariate Cox-regression model revealed age (odds ratio [OR] 1.027 per year), Child–Pugh class C (OR 1.872 vs Child B), white blood cell count (WBC) (OR 1.041 per G/L increase), and increasing AKIN stage (P = 0.003) as independent risk factors for mortality. AKIN stage 3 increased the risk of death fourfold (OR 4.082). Independent risk factors for 30 days mortality. Regarding 30-day mortality, univariate analyses revealed Child–Pugh C (as compared with class B, P = 0.009), sCr (P = 0.024), WBC (P = 0.008), and increasing AKIN stages (P = 0.019) as possible predictors for death within 30 days after AKI (Table S2, Figure S1). In a binary logistic regression analysis model with death < 30 days as outcome, Child–Pugh Class C (OR 4.588), WBC (OR 1.129, 95% CI: 1.015–1.257, P = 0.025) and increasing AKIN stages (P = 0.046) resulted as independent risk factors for short-term mortality. AKIN stage 3 was the strongest predictor for 30-day mortality (OR 6.134). Interestingly, when we assessed the MELD score by area under the receiver operating
Journal of Gastroenterology and Hepatology 30 (2015) 1657–1665 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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Figure 2 Kaplan–Meier graphs depicting transplant-free survival (TFS) according to development of AKI according to AKIN criteria (a and c: left side) versus C-AKI criteria (b and d: right side) within 1 month (a and b: upper graphs) and within 1 year (c and d: lower graphs). Log–rank tests refer to overall distinctions in TFS within 31 days in (a) and (b), and within total follow-up in (c) and (d), respectively. (c) and (d) depict 12 months survival. Asterisks indicate statistically significant differences between stages.
characteristics curve (AUROC) analysis in its predictive value for mortality, and calculated the Youden’s index for a relevant cut-off, a Model of End-stage Liver Disease (MELD) score of 22 had the best specificity and sensitivity.
Outcomes in C-AKI stage A versus stage B. Although patients with C-AKI stage B had a significantly higher baseline sCr value before development of AKI than C-AKI A patients (1.18 [IQR 0.98–1.32] mg/dL vs 0.78 [IQR 0.68–0.91]
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Table 3
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Independent predictors for overall survival
Variable
Survival (n = 114)
Death (n = 125)
Univariate P
OR
Cox-regression analysis 95% CI
Age (years) Child–Pugh C versus B Serum sodium (mmol/L) Serum creatinine (mg/dL) Serum bilirubin (mg/dL) Serum albumin (mg/dL) Serum ALT (U/L) Serum AST (U/L) Serum CRP (mg/dL) WBC (G/L) INR AKI (n [%])† —AKIN 1† —AKIN 2† —AKIN 3†
52.9 ± 10.7 B: 67 (62%) C: 47 (36%) 134.3 ± 5.8 0.98 (0.77–1.26) 2.75 (1.30–6.21) 28.6 ± 5.4 31 (17–48) 59 (37–89) 2.13 (1.20–4.49) 6.52 (4.86–10.17) 1.41 (1.21–4.74) 29 (37%) 21 (40%) 6 (40%) 2 (20%)
56.7 ± 12.3 B: 41 (38%) C: 84 (64%) 133.2 ± 6.7 1.11 (0.86–1.45) 4.32 (2.17–8.97) 26.5 ± 5.2 35 (24–57) 68 (48–99) 3.03 (1.46–5.47) 8.38 (5.95–12.62) 1.48 (1.31–1.91) 49 (63%) 32 (60%) 9 (60%) 8 (80%)
0.012 < 0.001 0.174 0.041 0.004 0.002 0.096 0.028 0.069 0.003 0.073 0.027 0.114 0.422 0.054
M-variate P
1.027 1.872
1.010–1.045 1.244–2.818
0.001 0.003
1.002 0.999 1.016 1.041
1.000–1.004 0.996–1.002 0.988–1.044 1.003–1.080
0.054 0.664 0.270 0.033
1.119 1.786 4.082
0.718–1.743 0.885–3.602 1.864–8.937
0.003 0.619 0.105 < 0.001
†
Versus patients without AKI. Variables that showed a trend or were significant in univariate analysis P ≤ 0.010) were entered into the multivariate model. AKI, acute kidney injury; AKIN, Acute Kidney Injury Network; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; CRP, C-reactive protein; WBC, white blood cell count.
mg/dL; P < 0.001), other patient characteristics were equally distributed between C-AKI A and B patients (P = NS) (Table S1, Figure 2). Mortality increased with each AKIN stage—especially in the short-term (Figure 2a,b), however, higher C-AKI stages were not associated with impaired TFS. Most interestingly, C-AKI A patients (sCr remained < 1.5 mg/dL) showed a significantly worse prognosis both in the short and long term than patients without AKI development (P < .05; Figure 2c,d). Median TFS was lowest in patients with AKI progression, AKIN stage 3 and C-AKI stage C (respectively 6 days, 95% CI: 3–12 days; 19 days, 95%: CI 0–40 days and 22 days, 95% CI: 7–37 days). Impact of AKI in patients with “normal” sCr. In total, 140 patients had a peak sCr value below the upper limit of our reference laboratory ranges (< 1.2 mg/dL) between D0 and W1 (Table 2, Figure 3). Nine (6.4%) of these patients developed AKI (any stage) according to AKIN criteria. Among these nine AKI patients, eight developed AKI 1, none AKI 2 and one AKI 3. Strikingly, median TFS among AKI patients with “normal” sCr was only 57 (95% CI: 0–165) days. This is significantly lower than the 839 (326–1352) days median TFS of the remaining 131 patients without AKI and “normal” sCr (P = 0.001). Figure 3 Comparison of patients with serum creatinine levels within reference laboratory ranges (< 1.2 mg/dL) with versus without development of AKI. Log–rank test refers to total follow-up survival.
Discussion In our study we found an AKI incidence of 33% among cirrhotic patients with ascites at or within one week of paracentesis—a similar incidence as reported in previous studies.1,3,21 Development of AKI was strongly associated with subsequent mortality (both when assessing overall mortality or TFS), underlining its important prognostic significance in patients with ascites.4,6,29,30 We were also able to demonstrate that even small increases within “normal” 1662
laboratory ranges of sCr are of substantial prognostic relevance.14,31 In our study, mortality gradually increased with each AKIN stage, and both development of AKI and the severity of AKIN stage were identified as independentors predictor mortality.
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Moreover, even “mild” AKI in patients with cirrhosis and ascites, whose peak sCr remained below 1.5 mg/dL (C-AKI stage A) was already indicative of an increased risk for mortality as compared with patients without C-AKI. As a result, our study provides evidence that the implementation of the 1.5 mg/dL cut-off in sCr (which has been used for defining HRS23,32 and the “conventional” AKI criterion, defined as an increase in sCr by ≥ 50% to ≥ 1.5 mg/ dL)33,34 in order to discriminate C-AKI A and B does not improve the prognostic assessment of patients with cirrhosis and ascites. Indeed, it might suggest that C-AKI A is a less severe form of kidney injury than C-AKI B and might preclude important therapeutic measures. In our cohort, the surprisingly high mortality rate of the nine patients with AKI within “normal” sCr underlines the prognostic importance of AKI diagnosis in cirrhotic patients with ascites undergoing paracentesis. However, AKI itself might not be the sole reason for poor outcome in the cohort with “normal” creatinine levels: A recent study assessed prognostic value ACLF (acute-on-chronic liver failure) criteria to predict short-term mortality.35 The authors of this study conclude that ACLF criteria performed better than AKIN criteria because the ACLF score also considers other organ failures rather than only renal failure in patients with decompensated cirrhosis. Although we want to encourage the use of ACLF criteria in decompensated patients (who do not always present with ascites), our study focused on the prognostic value of C-AKI versus AKIN to stage prognosis in patients with ascites who are most prone to develop renal failure. However, the ACLF criteria [34] might have been able to predict mortality in our nine patients with AKI in low sCr levels. Indeed, most of these patients with AKIN grade 1 and low sCr levels were diagnosed with infections and some progressed to sepsis, and two patients died from septic shock. Interestingly, next to AKI (staged according to AKIN) as independent risk factor or mortality, WBC also emerged as independent risk factor—indicating infections and/or inflammation as a relevant prognostic factor in patients with ascites. Interestingly, a MELD score of 22 had the best specificity and sensitivity for predicting mortality. This particular MELD cut-off at 22 points has also been identified by previous studies as a critical treshold in decompensated patients with ascites.36–38 The two main assets of our current study are the application of strict exclusion criteria and detailed documentation of our patients’ medical histories. Many patients with cirrhosis are of higher age and suffer from additional medical conditions, such as HCC, cardiovascular diseases, or CKD. These conditions may cause renal dysfunction not related to the underlying liver disease and may per se affect prognosis and mortality. Although previous studies often included those patients, we intended to limit our analyses to patients without those potential confounders. The main downside of this study is its retrospective nature. In daily routine, baseline creatinine values are not always available 48 h previous to an AKI episode. Because up to 20% of patients hospitalized for decompensation of cirrhosis present with AKI already at admission, we used the last stable creatinine value (prior to admission) as “baseline” for AKI diagnosis. Patients with cirrhosis and ascites are often exposed to potential triggers that eventually can result in renal injury such as nephrotoxic drugs, infections (i.e. spontaneous bacterial peritonitis), repeated imaging scans using radio-contrast agents, or surgery. In order to assess the prognostic value of AKI according to its poten-
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tial trigger, we thoroughly recorded potential factors influencing kidney and liver function from medical histories. sCr is an inexpensive and widely established marker for renal function in clinical practice—including in patients with cirrhosis. However, there are clear limitations that clinicians should be aware of:34,39 there is a range when sCr levels do not reflect a drop of renal function by up to 50%—so minor or beginning renal failure might be missed. Moreover, patients with compensated cirrhosis often present with lower sCr levels than agematched healthy controls. As a consequence, GFR is often overestimated in cirrhosis when using creatinine-based models. This suggests that kidney function might already be severely impaired in patients with cirrhosis when sCr rises above the upper limit of normal and that renal failure may be overlooked when it remains within reference limits.31,40 We confirmed AKI as an important predictor of TFS with gradually increasing mortality rates for each stage. However, we could not validate all findings by Fagundes et al. and Piano et al., who argued that kidney damage associated with C-AKI stage A (AKI without “reaching” absolute sCr values above 1.5 mg/dL) had only minor (if at all) influence on prognosis and survival of patients with cirrhosis. In the present study, however, patients with C-AKI stage A showed a significantly worse prognosis compared with patients without AKI, whereas this was not the case in patients with C-AKI stage B (mild AKI with peak sCr surpassing 1.5 mg/dL). These results are in contrast to the aforementioned studies. However, our finding is supported by a study recently published by Tsien et al.29 who demonstrated a significantly decreased survival in outpatients with cirrhosis and ascites developing AKI despite absolute sCr levels remaining within “normal” ranges. A letter by Thalheimer and Burroughs also warned to regard C-AKI stage A as a benign condition, but rather to treat as aggressively as in any other renal failure, since an overlooked AKI may result in death of the patient.22 Our results fully support this opinion to encourage special caution with regard to patients with cirrhosis and ascites who show a rise in sCr levels despite low absolute values. In summary, management of AKI represents a clinical priority in patients with cirrhosis. We want to emphasize that relative, rather than absolute, increases in sCr should be preferred for diagnosing AKI. Special attention should be paid to increases in sCr despite low or moderate levels, as early stages (C-AKI A) of AKI may be overlooked in patients with cirrhosis. Further prospective studies are warranted to assess the prognosis of AKI in patients with decompensated cirrhosis and ascites, and effective interventions for “hepatic” AKI in patients with cirrhosis and ascites should be investigated.
References 1 Belcher JM, Garcia-Tsao G, Sanyal AJ et al. Association of AKI with mortality and complications in hospitalized patients with cirrhosis. Hepatology 2013; 57: 753–62. 2 Cholongitas E, Senzolo M, Patch D, Shaw S, O’Beirne J, Burroughs AK. Cirrhotics admitted to intensive care unit: the impact of acute renal failure on mortality. Eur. J. Gastroenterol. Hepatol. 2009; 21: 744–50. 3 Wong F, O’Leary JG, Reddy KR et al. New consensus definition of acute kidney injury accurately predicts 30-day mortality in patients with cirrhosis with infection. Gastroenterology 2013; 145: 1280–8.
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4 Du Cheyron D, Bouchet B, Parienti J-J, Ramakers M, Charbonneau P. The attributable mortality of acute renal failure in critically ill patients with liver cirrhosis. Intensive Care Med. 2005; 31: 1693–9. 5 Garcia-Tsao G, Parikh CR, Viola A. Acute kidney injury in cirrhosis. Hepatology 2008; 48: 2064–77. 6 Fede G, D’Amico G, Arvaniti V et al. Renal failure and cirrhosis: A systematic review of mortality and prognosis. J. Hepatol. 2011; 56: 810–18. 7 Salerno F, Gerbes A, Ginès P, Wong F, Arroyo V. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007; 56: 1310–18. 8 Kellum JA, Levin N, Bouman C, Lameire N. Developing a consensus classification system for acute renal failure. Curr. Opin. Crit. Care 2002; 8: 509–14. 9 Ostermann M, Chang RWS. Challenges of defining acute kidney injury. QJM 2011; 104: 237–43. 10 Lameire N. The definitions and staging systems of acute kidney injury and their limitations in practice. Arab J. Nephrol. Transplant. 2013; 6: 145–52. 11 Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit. Care 2004; 8: R204–12. 12 Mehta RL, Kellum JA, Shah SV et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit. Care 2007; 11: R31. 13 Lassnigg A, Schmidlin D, Mouhieddine M et al. Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: a prospective cohort study. J. Am. Soc. Nephrol. 2004; 15: 1597–605. 14 Praught ML, Shlipak MG. Are small changes in serum creatinine an important risk factor? Curr. Opin. Nephrol. Hypertens. 2005; 14: 265–70. 15 Fagundes C, Barreto R, Guevara M et al. A modified acute kidney injury classification for diagnosis and risk stratification of impairment of kidney function in cirrhosis. J. Hepatol. 2013; 59: 474–81. 16 Bataller R, Ginès P, Guevara M, Arroyo V. Hepatorenal syndrome. Semin. Liver Dis. 1997; 17: 233–47. 17 Francoz C, Glotz D, Moreau R, Durand F. The evaluation of renal function and disease in patients with cirrhosis. J. Hepatol. 2010; 52: 605–13. 18 Arroyo V, Ginès P, Gerbes A, Dudley FJ. Special article: definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology 1996; 23: 164–76. 19 Wong F, Nadim MK, Kellum JA et al. Working party proposal for a revised classification system of renal dysfunction in patients with cirrhosis. Gut 2011; 60: 702–9. 20 Piano S, Morando F, Angeli P. Reply to: “To close the stable door before the horse has bolted. J. Hepatol. 2014; 60: 680–1. 21 Piano S, Rosi S, Maresio G et al. Evaluation of the Acute Kidney Injury Network criteria in hospitalized patients with cirrhosis and ascites. J. Hepatol. 2013; 59: 482–9. 22 Thalheimer U, Burroughs AK. To close the stable door before the horse has bolted. J. Hepatol. 2014; 60: 678–9. 23 Mandorfer M, Bota S, Schwabl P et al. Nonselective β blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis. Gastroenterology 2014; 146: 1680–90, e1. 24 Reiberger T, Ferlitsch A, Payer BA et al. Noninvasive screening for liver fibrosis and portal hypertension by transient elastography—a large single center experience. Wien. Klin. Wochenschr. 2012; 124: 395–402.
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25 Hucke F, Sieghart W, Schöniger-Hekele M, Peck-Radosavljevic M, Müller C. Clinical characteristics of patients with hepatocellular carcinoma in Austria—is there a need for a structured screening program? Wien. Klin. Wochenschr. 2011; 123: 542–51. 26 De Franchis R. Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension. J. Hepatol. 2010; 53: 762–8. 27 Peck-Radosavljevic M, Angermayr B, Datz C et al. Austrian consensus on the definition and treatment of portal hypertension and its complications (Billroth II). Wien. Klin. Wochenschr. 2013; 125: 200–19. 28 Bartels H, Böhmer M, Heierli C. [Serum creatinine determination without protein precipitation]. Clin. Chim. Acta 1972; 37: 193–7. 29 Tsien CD, Rabie R, Wong F. Acute kidney injury in decompensated cirrhosis. Gut 2013; 62: 131–7. 30 Tandon P, Garcia-Tsao G. Renal dysfunction is the most important independent predictor of mortality in cirrhotic patients with spontaneous bacterial peritonitis. Clin. Gastroenterol. Hepatol. 2011; 9: 260–5. 31 Francoz C, Prie D, Abdelrazek W et al. Inaccuracies of creatinine and creatinine-based equations in candidates for liver transplantation with low creatinine: impact on the model for end-stage liver disease score. Liver Transplant. 2010; 16: 1169–77. 32 Nadim MK, Kellum JA, Davenport A et al. Hepatorenal syndrome: the 8th international consensus conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit. Care 2012; 16: R23. 33 Arroyo V. Acute kidney injury (AKI) in cirrhosis: Should we change current definition and diagnostic criteria of renal failure in cirrhosis? J. Hepatol. 2013; 59: 415–17. 34 Angeli P, Sanyal A, Moller S et al. Current limits and future challenges in the management of renal dysfunction in patients with cirrhosis: report from the International Club of Ascites. Liver Int. 2013; 33: 16–23. 35 Angeli P, Rodríguez E, Piano S et al. Acute kidney injury and acute-on-chronic liver failure classifications in prognosis assessment of patients with acute decompensation of cirrhosis. Gut 2014; 0: 1–7. 36 Tandon P, Kumar D, Seo YS et al. The 22/11 risk prediction model: a validated model for predicting 30-day mortality in patients with cirrhosis and spontaneous bacterial peritonitis. Am. J. Gastroenterol. 2013; 108: 1473–9. 37 Kim JJ, Tsukamoto MM, Mathur AK et al. Delayed paracentesis is associated with increased in-hospital mortality in patients with spontaneous bacterial peritonitis. Am. J. Gastroenterol. 2014; 109: 1–7. 38 Schwabl P, Bucsics T, Soucek K et al. Risk factors for development of spontaneous bacterial peritonitis and subsequent mortality in cirrhotic patients with ascites. Liver Int. 2015 Feb 2. doi: 10.1111/liv.12795. 39 Demirtas¸ S, Bozbas¸ A, Akbay A, Yavuz Y, Karaca L. Diagnostic value of serum cystatin C for evaluation of hepatorenal syndrome. Clin. Chim. Acta 2001; 311: 81–9. 40 Cerdá J, Cerdá M, Kilcullen P, Prendergast J. In severe acute kidney injury, a higher serum creatinine is paradoxically associated with better patient survival. Nephrol. Dial. Transplant. 2007; 22: 2781–4.
Supporting information Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Figure S1 Kaplan–Meier graphs depicting transplant-free survival (TFS) according to development of AKI versus no AKI development within (a) 1 month and (b) 1 year. Log–rank tests refer to TFS within 31 days in (a) and within 12 months in (b).
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Figure S2 AUROC an analyses showing the AUC for MELD score for predicting 30-day mortality in patients with ascites developing AKI. The AUC for a MELD score cut-off at 22 for predicting 30day mortality was 0.774 (95%CI: 0.662–0.887). Patients with MELD ≥ 22 had a 30-day mortality of 56% (n = 22/39), while patients with a MELD < 22 showed only 13% (n = 4/31) 30-day mortality (P < .001). The MELD 22 cut-off had a sensitivity of 88.5% and a specificity of 61.4% to predict death 30days after AKI development.
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Table S1 Comparison of patients with C-AKI stages A vs B. *P-values indicate significant differences between C-AKI stages A and B. Table S2 30 days mortality in cirrhotic patients with ascites developing AKI
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