Letter on: Pre‐Emptive Initiation of Continuous Renal Replacement Therapy in Patients With Acute Liver Failure With Cerebral Edema Improves Outcomes: A Randomized Controlled Trial

Dear Editor,

1.

We read with great interest the randomized controlled trial by Maiwall et al. [1] evaluating pre‐emptive continuous renal replacement therapy (CRRT) in patients with acute liver failure (ALF) and cerebral edema. This study tackles an important clinical challenge and provides valuable prospective data in a field where randomized evidence is still limited. However, several methodological considerations should be discussed to accurately interpret the reported findings.

Most importantly, the trial failed to demonstrate a benefit for its primary endpoint in the intention‐to‐treat (ITT) analysis. Twenty‐eight–day mortality was similar between the pre‐emptive and standard‐initiation groups (46.7% vs. 44.4%), with no significant difference in overall survival (HR 1.22, 95% CI 0.67–2.23) [2]. Despite this neutral primary result, the title, abstract, and conclusion state that pre‐emptive continuous renal replacement therapy (CRRT) ‘improves outcomes’. Such wording may overstate efficacy, as the ITT analysis is the most reliable method to preserve the benefits of randomization and minimize bias.

A second concern relates to the large number of protocol violations. Thirty‐one protocol deviations occurred, representing more than one‐third of the randomized cohort, and were markedly more frequent in the standard‐initiation arm (55.6% vs. 13.3%). The apparent survival benefit primarily emerged from per‐protocol analyses that excluded these patients. However, many of the crossover events were triggered by worsening hyperammonemia, cerebral edema, or multiorgan dysfunction—conditions that are themselves strongly associated with patient prognosis. Excluding such participants may introduce substantial post‐randomization bias and undermine the comparability established by random allocation [3]. Consequently, the favourable per‐protocol findings should be viewed as exploratory rather than definitive evidence of treatment efficacy.

Furthermore, the reported reduction in early mortality during the first 7 days was derived from a piecewise exponential regression analysis rather than the primary survival analysis. While this interval‐specific benefit is biologically plausible, it comes with a wide confidence interval (HR 0.12, 95% CI 0.02–0.96), indicating considerable statistical uncertainty [4]. Given the pilot nature of the trial and multiple secondary analyses performed, the possibility of a chance finding cannot be excluded.

The study also reported a significant baseline imbalance in total bilirubin levels, which were higher in the standard‐initiation group. While other characteristics were broadly similar, such imbalances may influence outcomes in a relatively small trial [5]. Additionally, the trial registry initially listed a substantially smaller target enrollment than the final recruited population, highlighting the importance of transparent reporting regarding protocol modifications and sample‐size adjustments.

Overall, this pilot trial provides important evidence that early CRRT may improve surrogate markers of cerebral edema and reduce early neurologic deterioration. Nevertheless, because the primary ITT analysis was neutral and the positive findings were driven largely by per‐protocol and exploratory analyses, larger multicenter trials are needed before routine pre‐emptive CRRT can be recommended in ALF patients with cerebral edema.

Author Contributions

Shumaila Ashfaq Ahmed Mangi: conceptualization, investigation, validation, formal analysis, writing – review and editing. Omar Alfauri: writing – original draft, writing – review and editing, validation, methodology. Pawan Kumar: methodology, writing – review and editing. Muhammad Umar: supervision, writing – review and editing.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Linked Articles

This article is linked to Maiwall et al. papers. To view these articles, visit https://doi.org/10.1111/apt.70794 and https://doi.org/10.1111/apt.70889.

Mangi S. A. A., Alfauri O., Kumar P., and Umar M., “Letter on: Pre‐Emptive Initiation of Continuous Renal Replacement Therapy in Patients With Acute Liver Failure With Cerebral Edema Improves Outcomes: A Randomized Controlled Trial,” Alimentary Pharmacology & Therapeutics 64, no. 7 (2026): 1025–1026, 10.1111/apt.70840.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.