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AKI In Alcohol-Related Hepatitis

AKI In Alcohol-Related Hepatitis

The prevalence, prediction, and impact of acute kidney injury (AKI) in alcohol-related hepatitis (AH) remain uncertain. AH is the most severe form of alcohol-related liver disease (ARLD) with a 30% mortality rate within 90 days, often aggravated by AKI, either as a primary or secondary cause.

Research suggests that severe AH commonly accompanies AKI in about 30% of cases, yet lacks a detailed characterization. AKI can manifest upon hospital admission or develop during the stay (‘incident AKI’), which carries a higher mortality risk and is preventable in 20% of instances.

Unlike cirrhosis patients, AH patients follow a distinct disease course, making the relationship between AKI and mortality less consistent and potentially independent of liver disease severity. Consequently, therapeutic focus in AH leans toward liver function restoration, with limited attention to AKI prevention or treatment.

Novel biomarkers, including serum cystatin C, NGAL, B2M, and various interleukins, along with TNF-α and Transforming Growth Factors β1 and β2, have been proposed for early AKI prediction. However, these biomarkers remain untested in AH.

To address these uncertainties, a study using data from the largest AH randomized controlled trial aimed to determine AKI incidence, and its association with mortality, identify clinical risk factors, and evaluate novel biomarkers for early AKI detection. This research strives to enhance our understanding of AKI in AH, potentially improving patient outcomes through early intervention.

Study Objective 

The primary objectives of the research were to determine the incidence of acute kidney injury (AKI) in the context of alcohol-related hepatitis (AH) and to analyze its association with mortality rates. Additionally, they conducted a thorough assessment of various serum biomarkers within the largest AH cohort recorded to date. 

Furthermore, the study aimed to explore how the administration of prednisolone and pentoxifylline, both considered potential therapeutic agents in AH, might influence the occurrence and consequences of AKI in this specific cohort. This research endeavors to provide a comprehensive understanding of AKI in the context of AH and explore potential strategies for its management.

Study Methods 

This study involved 1092 participants from the STOPAH trial, utilizing a 2×2 factorial design with four treatment groups: prednisolone, pentoxifylline, placebo, and prednisolone plus pentoxifylline. Ethical approval was obtained, and participants met severe alcoholic hepatitis criteria, excluding those with high creatinine or undergoing renal replacement therapy. The previous STOPAH trial did not show significant effects on D90 mortality, although prednisolone reduced D28 mortality without statistical significance.

The International Club of Ascites (ICA) definition of acute kidney injury (AKI) is commonly used for cirrhosis patients, emphasizing a dynamic approach based on serum creatinine. This is crucial because cirrhosis can mask AKI with normal creatinine levels due to various factors. Fixed creatinine cut-offs may underestimate AKI. ICA’s definition excludes urine output due to its unreliability in cirrhosis. 

In the STOPAH study, pre-admission creatinine values were unavailable. The study used the Modification of Diet in Renal Disease (MDRD) equation inversely, although this isn’t ideal for cirrhosis. Comparing this with the lowest recorded creatinine during follow-up revealed formula-based overestimation. Using the lowest recorded creatinine was considered the best measure despite not being a perfect baseline indicator.

Outcome Measures

This study placed a strong emphasis on evaluating the outcomes of patients at specific time points, with a primary focus on mortality at day 90 (D90) and a secondary interest in mortality at day 28 (D28). Notably, the study accounted for three participants who underwent liver transplantation after the D90 time point, ensuring that all relevant data were considered.

To shed light on the impact of acute kidney injury (AKI) in this context, the study employed several comparisons. Firstly, it contrasted individuals who experienced AKI at day zero (D0) with those who did not encounter this complication. Secondly, it delved into the group of participants who did not have AKI at D0 but developed it by day seven (D7) and compared them to those who remained free of AKI at both D0 and D7. Additionally, the study explored a subgroup within the D0-AKI cohort, examining those who had persistent AKI at D7 against those who had successfully resolved their AKI condition by that time, although this particular analysis had limited statistical power.

By conducting these comparisons and considering outcomes at distinct time intervals, the study aimed to provide a comprehensive understanding of how AKI influences the prognosis of individuals with alcohol-related hepatitis (AH). This approach allows for a nuanced examination of the temporal aspects of AKI in AH, enhancing our insights into its clinical significance and potential implications for patient management.

Statistical Analysis 

The study employed various statistical methods for analysis. Survival was assessed at D90 using Kaplan-Meier analysis with Breslow (Generalized Wilcoxon) testing. Mortality associations were explored through univariate and multivariate Cox regression. AKI and incident infection associations were investigated using binary logistic regression, while biomarkers were assessed via receiver operating characteristic (AUROC) analysis. 

Demographic and clinical characteristics were compared using t-tests, Mann-Whitney U, and χ2 tests. False discovery rate control was applied, and missing data were addressed using pairwise deletion. MicroRNA differential expression analysis was conducted in R. Differential expression was determined if gene expression differed by more than 1.


In the study, 19% of participants had acute kidney injury (AKI) at day zero (D0), while an additional 21% developed incident AKI. Those with D0-AKI had a higher 90-day mortality rate (32% vs. 25%). Similarly, participants with incident AKI had significantly higher mortality (47% vs. 25%). Incident AKI was independently associated with increased 90-day mortality, whereas D0-AKI was not.

Prednisolone therapy reduced the occurrence of incident AKI but did not impact mortality. Biomarkers like D0 bilirubin, IL-8, miR-6826-5p, and miR-6811-3p showed promise in predicting incident AKI. These findings highlight the importance of preventing incident AKI in alcohol-related hepatitis (AH) to reduce mortality, potentially through the evaluation of novel therapies.

Final Thoughts 

To sum up, the study’s findings underscore the critical role of incident acute kidney injury (AKI) as a robust predictor of 90-day mortality in patients with alcohol-related hepatitis (AH), and this association holds true irrespective of their liver function. Additionally, an intriguing discovery emerged from the study – the administration of prednisolone was linked to a decreased likelihood of individuals developing incident AKI. 

This suggests that prednisolone, a potential therapeutic agent in AH, may not only affect liver-related outcomes but also play a protective role against the development of AKI in these patients. These findings provide valuable insights into the management of AH, suggesting that interventions targeted at preventing AKI could potentially have a positive impact on patient outcomes in the short term. Further research and clinical exploration are warranted to better understand the mechanisms underlying this relationship and to optimize treatment strategies for AH patients, with a focus on mitigating the risk of AKI and improving their overall prognosis.

Promising biomarkers, including D0 bilirubin, IL-8, miR-6826-5p, and miR-6811-3p, could help predict the onset of AKI. Future research should focus on developing and evaluating novel therapies to prevent incident AKI in AH, ultimately aiming to reduce mortality in this patient population.

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