Abstract
Objective
Acute kidney injury (AKI) in patients with cirrhosis is associated with increased morbidity and mortality in critically ill patients. There is a considerable variation in the reported prevalence of AKI across studies. We provide a unique regional analysis, addressing gaps in AKI data in critically ill cirrhotic patients from the Middle East.
Methods
In this single-center, retrospective cohort study, we included all patients known to have liver cirrhosis admitted to our tertiary care center over 16 years. Data was extracted from the existing database in the intensive care unit (ICU) department at King Abdulaziz Medical City, Riyadh, Saudi Arabia. Subjects were categorized into four groups using the Kidney Disease Improving Global Outcomes criteria. We evaluated the prevalence of AKI and its association on the in-hospital mortality.
Results
From 2002 to 2017, 1197 cirrhotic patients were admitted to our ICU. Among them, 68 (5.7%) had stage 1 AKI, 193 (16.1%) had stage 2 AKI, 475 (39.8%) had stage 3 AKI. Overall, in-hospital mortality was progressively higher with worsening severity of AKI, from non-AKI (42.0%) to stage 3 AKI (72.2%), p-value <0.0001. In addition, ICU mortality, hospital and ICU lengths of stay, use of vasopressors and renal replacement therapy were found to increase with worsening severity of AKI. Multivariate analysis demonstrated the following predictors of hospital mortality, the presence of AKI, age, female sex, vasopressor use, increasing bilirubin and lactic acid, and decreasing Glasgow coma scale and PaO2/FiO2 ratio.
Conclusions
The prevalence of AKI in cirrhotic patients is high and associated with high mortality. Further research is warranted to develop strategies for early detection and management of AKI in this vulnerable population. Future studies integrating national and international data registries could enhance predictive modeling and tailored management for AKI in cirrhotic patients.
Introduction
Liver cirrhosis is a major cause of morbidity and mortality globally. A 2017 study reported more than 1.32 million cirrhosis-related deaths globally. 1 Nearly half the hospitalized patients with end-stage liver disease are predisposed to acute kidney injury (AKI).2–4 AKI among cirrhotic patients is estimated to increase the 1-year odds of death by almost eightfold as compared to cirrhotic patients without AKI. 5 Most AKI in cirrhotic patients is due to pre-renal etiology related to renal hypoperfusion. 6 The diagnostic criteria of AKI in these patients have been constantly revised over the past years. 7 The most recent and dynamic one is an acute increase of serum creatinine to ≥50% from baseline to a final value ≥1.5 mg/dL (133 µmol/L) since the use of urine output as one of the criteria does not apply to patients with cirrhosis (i.e. many patients are oliguric but have preserved kidney function). 7 However, by all the diagnostic criteria, AKI in cirrhosis patients was found to be a strong predictor of in-hospital mortality associated with increasing severity of AKI.8–10 For example, in one prospective study on 192 hospitalized patients with cirrhosis, in-hospital mortality varied from 2% for AKI stage 1, 7% for stage 2, and up to 21% for stage 3. Among these patients, mortality increased significantly when there was a progression of AKI stages during hospital stay, reaching 70% of patients who ultimately reached dialysis. 8 In another study of 162 cirrhotic patients, which used AKIN criteria for identification of AKI, decompensated liver disease and AKI appeared to be independent variables predicting death in patients with cirrhosis. 11 Therefore, it is imperative to explore the common causes of AKI in cirrhosis along with early diagnosis and treatment for improving outcomes. Despite numerous global studies on AKI in cirrhotic patients, there is a paucity of data from the Middle East, where unique etiological and demographic factors could influence outcomes. This study aims to characterize the cirrhotic patients admitted in the intensive care unit (ICU) at a tertiary care center according to the Kidney Disease Improving Global Outcomes (KDIGO) classification and evaluate the association between the stages of AKI and in-hospital mortality.
Methods
This retrospective cohort study was conducted in the ICU at King Abdulaziz Medical City, Riyadh, Saudi Arabia, between January 2002 and December 2017. The study was approved by the Institutional Review Board of National Guard Health Affairs, Riyadh (RC20/522R). The need for informed consent was waived due to the non-interventional retrospective design of the study. The study was conducted in accordance with the Declaration of Helsinki (1975) and its latest revision (2024). All patient data were de-identified to ensure privacy and confidentiality. All consecutive patients aged ≥ 18 years admitted with cirrhosis were included in the study. A formal sample size calculation was not performed, as this retrospective study included all eligible ICU admissions over the 16-year period. Patients were labeled as cirrhotic, confirmed by liver biopsy or any signs of liver disease, episodes of past upper gastrointestinal bleeding or varices attributed to portal hypertension, or previous episodes of hepatic failure, coma or hepatic encephalopathy. 12 Exclusion criteria included patients with end-stage renal disease who underwent dialysis. We included the first admission only for patients admitted to the ICU more than once during the same hospital admission. The patients were grouped into three groups based on the KDIGO criteria. 13 Since our study was retrospective, the baseline serum creatinine was not available before hospitalization, so we used an estimated value of sCr as the baseline. We calculated sCr by the reverse application of the MDRD formula, using a predetermined value of GFR (75 mL/min). 14 Urine output data were not consistently available in the database and were thus excluded from AKI classification.
All other cirrhotic patients who did not fall into these three groups were grouped as no-AKI patients. Data was extracted from the ICU database, which included all consecutive admissions during the study period. We included the variables like age, gender, acute physiology and chronic health evaluation (APACHE) II score, admission diagnosis category, chronic comorbidities (as defined by APACHE II system), body mass index (BMI), history of diabetes, Glasgow coma scale (GCS), mechanical ventilation requirement in the first 24 h of ICU admission, the ratio of partial pressure of oxygen to the fraction of inspired oxygen (PaO2 /FiO2), the requirement for vasopressors (defined as the use of any vasopressor infusion except dopamine <5 μ g/kg/min), admission bilirubin, creatinine, lactate, and international normalized ratio (INR). The primary outcome was hospital mortality. The secondary outcome included ICU and hospital lengths of stay and mechanical ventilation duration. This study was reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.
Statistical analysis
Analysis was carried out using Statistical analysis software (SAS, version 9.0; SAS Institute, Cary, NC, USA). All categorical variables were presented as frequencies and percentages. All continuous variables were presented as median and interquartile (Q1, Q3). The four groups were compared using the Chi-square for categorical variables and one-way analysis of variance for continuous variables. To determine the predictors of hospital mortality in cirrhotic patients with AKI and evaluate the independent association between worsening of AKI and mortality, multivariate logistic regression analyses were performed using the variables identified in the univariate analysis with p-value < 0.05 and those that were clinically significant. The variables entered in the model were age, sex, vasopressors, bilirubin, lactic acid, INR, GCS and PaO2/FiO2 ratio. The data were presented as odds ratios and 95% confidence intervals. Values of p < 0.05 were considered statistically significant.
Results
Patient characteristics
During the study period, 1197 were found eligible and were included. Most of these patients were males (56.7%), diabetic (41.2%), mechanically ventilated (64.7%) and were on vasopressors (53.8%), with a median APACHE II score of 26 (Q1, Q3:20,32). The overall ICU mortality rate was 39.7%, and the hospital mortality was 57%. The median mechanical ventilation duration was 2 days (Q1, Q3: 0, 8).
Among the study groups, 461(38.5%) patients did not have AKI, 68 (5.7%) patients had AKI stage 1, 193 (16.1%) had AKI stage 2, and 475 (39.8%) had AKI stage 3. The study groups’ demographic characteristics and physiological parameters are presented in Table 1. The patients in the AKI groups were older than the non-AKI group. The BMI was higher in the AKI groups, with the median BMI in stage 3 (29.1 (Q1, Q3: (25.3, 34.2)) in comparison to the non-AKI group (25.6 (Q1, Q3: 22.2, 25.6). The prevalence of diabetes followed by chronic cardiac disease was higher in the AKI groups (Stage 3 AKI: 205 (43.2%) and 78 (16.6)) in comparison to the non-AKI group (171 (37.1%) and 53 (11.6%)), respectively. The need for mechanical ventilation and vasopressors also increased in AKI patients (Stage 3 AKI: 333 (70.1%) and 345 (72.6%)) when compared with the non-AKI patients (282 (61.2%) and 171 (37.1%)), respectively.
Comparison of baseline characteristics of cirrhotic patients admitted to the intensive care unit without and with acute kidney injury (AKI) of different stages.
AKI: acute kidney injury; ICU: intensive care unit; SD: standard deviation; Q1: first quartile, Q3: third quartile.
GCS: Glasgow coma score; APACHE-II: Acute Physiology and Chronic Health Evaluation II; PaO2/FiO2 ratio: the ratio of the partial pressure of oxygen to the fraction of inspired oxygen; INR: International normalized ratio; Q1: first quartile, Q3: third quartile
The body mass index is the weight in kilograms divided by the square of the height in meters. For all percentages, the denominator is the total number of subjects in the group.
Continuous variables were compared using analysis of variance (ANOVA) and categorical value using Chi-square test.
Primary outcome
The AKI subgroups of the KDIGO classification and the association with the primary outcome are presented in Table 2. Hospital mortality was found to increase with the severity of AKI, the highest being in Stage 3 AKI (342 (72.2%)) when compared to the non-AKI group (193 (42.0%)).
Data on intensive care unit (ICU) interventions and outcomes for cirrhotic patients admitted without and with acute kidney injury (AKI) of different stages.
ICU: intensive care unit; LOS: length of stay.
Continuous variables were compared using analysis of variance (ANOVA) and categorical value using Chi-square test.
Secondary outcomes
ICU mortality was also found to increase in a stepwise manner, by the severity of AKI. The AKI group with stage 3 showed the highest ICU mortality (53.8%) in comparison to the non-AKI group (34.3%). In addition, hospital and ICU lengths of stay, use of vasopressors and renal replacement therapy (RRT) were found to increase with worsening severity of AKI.
Multivariate analysis to predict hospital mortality among cirrhotic patients admitted to the ICU with acute kidney injury
On multivariate logistic regression analysis of AKI subgroups, the odds of death in stage 1 and stage 3 seem to be higher than the non-AKI group. Other significant predictors were older age (OR 1.02, 95% CI: 1.01 to 1.04, p-value < 0.001), female sex (OR 1.45, 95% CI: 1.08 to 1.94, p-value = 0.01), vasopressor use (OR 2.18, 95% CI 1.62 to 2.93, p-value≤0.001), higher bilirubin (OR 1.04 95% CI 1.03–1.06), higher lactic acid (OR 1.08, 95% CI 1.04–1.13), lower GCS (for every 1-unit decrease, OR 1.18, 95%CI 1.13, 1.23) and lower PaO2/FiO2 ratio (OR 1.48 95% CI 1.08–2.03). Table 3.
Predictors of hospital mortality cirrhotic patients admitted to the intensive care unit.
PaO2/FiO2 ratio: the ratio of the partial pressure of oxygen to the fraction of inspired oxygen; INR: international normalized ratio.
The assumptions of logistic regression model were met as checked by the likelihood ratio (p-value ≤ 0.0001) of correlated multivariate samples.
OR: Odd ratio. The model included the following variables: AKI stages, age, sex, vasopressor therapy, bilirubin, lactic acid, INR, GCS and PaO2/FiO2 ratio. AKI: acute kidney injury; INR: international normalized ratio.
Discussion
Our study demonstrates that the prevalence of AKI in cirrhotic patients is high and associated with high mortality. New onset AKI in patients with liver cirrhosis carries high mortality.1,15 This is especially evident in critically ill patients. 16 In our study, we investigated the outcomes of this group of patients.
The overall mortality was higher than what is in the literature.16,17 This could be explained by higher severity caused by the etiology of underlying liver disease among our patients. 18 Studies in Saudi Arabia showed that the commonest cause of cirrhosis is acute and chronic viral hepatitis secondary to hepatitis B and C, rather than alcohol liver disease. 19 Baseline characteristics were similar in all groups of AKI. However, cardiac diseases seem to be higher in AKI group 2. Predictors of in-hospital mortality at admission indicated progressive worsening with each group of AKI.
Interestingly, mortality was increasing for each stage of AKI, but stage 1 AKI had higher mortality than stage 2 AKI in both in-hospital and ICU mortality (64.7%, 47.1 VS 52.9%, 33.3%). While this deviates from the expected stepwise increase in mortality seen with higher KDIGO stages as previously reported by Belcher et al., this may be attributed to multiple factors. 8 First, the stage 1 group had a smaller sample size, making outcome rates more susceptible to fluctuation. Second, a higher proportion of stage 1 patients were designated as Do-Not-Resuscitate, potentially limiting the escalation of critical care therapy with advanced organ support and attributing to other unmeasured cofounding factors. Third, the use of estimated baseline creatinine via the reverse MDRD equation may have resulted in under-estimation of more severe renal dysfunction to stage 1. These factors shed focus on the limitations of serum creatinine-based staging in cirrhotic ICU populations and caution against assuming a linear relationship between KDIGO stage and mortality risk. 13
Our results demonstrated that AKI in cirrhotic patients is associated with significantly prolonged ICU and hospital stays, reflecting the substantial healthcare burden posed by this condition. These findings are consistent with existing literature, which highlights that AKI in cirrhosis exacerbates systemic inflammation and hemodynamic instability, contributing to worse outcomes and extended hospitalization durations. 12 The development of AKI in this population often necessitates more intensive interventions, such as RRT, further escalating healthcare resource utilization. 18
Patient characteristics such as age, sex, BMI and cardiovascular comorbidities were associated with higher mortality rates in our cohort. This aligns with previous studies that underscore how pre-existing conditions like cardiovascular disease exacerbate renal dysfunction in cirrhotic patients, amplifying mortality risks. Additionally, advanced age has been shown to compound the effects of systemic inflammation and reduced hepatic reserve, further elevating mortality in cirrhotic patients with AKI. 16 Moreover, obesity and higher BMI and diabetes not only increase cardiovascular strain but also contribute to altered renal hemodynamics, predisposing patients to more severe AKI and associated complications. 15 These findings emphasize the critical need to identify and manage these comorbidities early to improve outcomes in this high-risk population.
Our research identified age, and bilirubin levels as independent predictors of in-hospital mortality among cirrhotic patients with AKI. Elevated bilirubin, indicative of advanced liver dysfunction, has been recognized as a key predictor of poor outcomes in this population. 17 Similarly, severity of illness has been shown to strongly correlate with mortality risk in critically ill cirrhotic patients. 20 These findings underscore the critical need for early detection and tailored management of AKI in cirrhotic patients to improve outcomes. Future studies should focus on developing predictive models that account for the unique pathophysiology of AKI in cirrhosis, incorporating factors such as hepatic dysfunction, hemodynamic alterations, and systemic inflammation. Early intervention strategies targeting these pathways may reduce the length of ICU and hospital stays and improve survival in this high-risk population.
These findings highlight the need for advanced predictive tools to enhance early detection and risk stratification of AKI in cirrhotic ICU patients. Such approaches may enhance individualized management strategies, particularly when linked to multicenter live registries.
Our study has some limitations. Due to the nature of our database, baseline sCr was estimated using a formula. These formulas are validated for use in other settings but not for AKI in cirrhosis. 13 The implications of this would be that some of the patients presumed to have no AKI might have had AKI stage I, and patient with AKI I & II may have fallen into AKI II & III Category. Additionally, KDIGO guidelines classify initiation of RRT as Stage 3 AKI, regardless of serum creatinine or urine output. 13 However, our study relied on creatinine-based criteria alone and did not incorporate RRT initiation into AKI staging. This may have resulted in under-estimation of AKI prevalence and misclassification of some RRT-treated patients as non-AKI. Also, we did not look into the etiological cause of cirrhosis of the liver in our study, but this could be explored in future research about AKI and variable liver cirrhosis etiologies. The study did not separately look into subgroup analysis of the outcomes of patients with cirrhosis of the liver who had AKI and did not need RRT (51.26% of AKI III Group).
Conclusions
In this single-center, retrospective cohort study of ICU patients with hepatic cirrhosis, AKI was associated with significantly higher mortality, with mortality rates escalating alongside the severity of AKI stages. These findings highlight the critical importance of early detection, risk stratification, and tailored management strategies to mitigate the impact of AKI in this high-risk population. By focusing on a Middle Eastern cohort, this study also sheds light on a region that remains underrepresented in global AKI literature. Future multicenter studies and the integration of real-time predictive tools with data registries are warranted to enhance early intervention, optimize resource utilization and improve survival outcomes in critically ill cirrhotic patients with AKI. This study highlights the importance of targeted research in this area to improve patient outcomes and also contribute to a more comprehensive understanding of AKI in this population.
Footnotes
Author contributions
SW contributed to conception, design of the study, data collection, interpretation of data, drafting of the manuscript and critical revision of the manuscript for important intellectual content. AR, FA, MHT, MS, FH, AM, MD, YZ and YS contributed to data collection, interpretation of data and critical revision of the manuscript for important intellectual content. HT contributed to statistical analysis, interpretation of data and critical revision of the manuscript for important intellectual content. YA contributed to conception, design of the study, interpretation of data, manuscript drafting and critical revision of the manuscript for important intellectual content. All authors approved the final version of the manuscript.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.The authors acknowledge that this manuscript follows the STORBE guidelines for observational research
Data availability statement
The datasets generated during and/or analyzed during the current study are not publicly available but will be made available from the corresponding author on reasonable request