We thank Mangi and colleagues for their interest in our recently published work and for their thoughtful comments on the trial methodology [1]. The concerns they raised regarding the trial conclusions were addressed in the manuscript. As stated in the discussion, a pre‐emptive approach to continuous renal replacement therapy (CRRT) did not show a survival advantage over standard CRRT initiation in the intention‐to‐treat (ITT) analysis [2]. However, piece‐wise exponential regression showed that pre‐emptive CRRT was associated with reduced early mortality during the first week, largely driven by cerebral edema. This conclusion was also reflected in the abstract.
The study was designed as a pilot randomized controlled trial (RCT) because conducting RCTs in patients with acute liver failure (ALF) and cerebral edema is especially challenging [3]. The rarity and heterogeneity of ALF, its rapid clinical deterioration, and its dynamic course make interventions difficult to define and standardize [4]. These challenges may also explain the limited availability of RCTs on CRRT in ALF, despite society recommendations supporting early CRRT initiation based on retrospective studies [4, 5, 6, 7]. Our center manages a large volume of ALF cases and has both a dedicated liver intensive care unit and a living donor liver transplantation program [8, 9]. The protocol allowed for violations, which inevitably occurred despite randomization because of changes in clinical condition which included either spontaneous recovery, worsening, or need of liver transplantation. Most violations occurred in the standard‐initiation group and tended to favour earlier CRRT initiation. Notably, significantly more patients in this group died from refractory intracranial hypertension during the first week (9 [22%] vs. 2 [4.8%]; p = 0.015). For this reason, piece‐wise Cox proportional hazards analysis was used to evaluate these effects. Although the difference between randomized groups was statistically significant, the wide confidence intervals likely reflect the small number of participants within each time frame. The overall multivariable per‐protocol analysis, adjusted for multiorgan failure using the Sequential Organ Failure Assessment score and for sepsis, also supported the benefit of pre‐emptive CRRT initiation; as noted, these factors also influenced outcomes. The bilirubin though significantly different, was not a independent predictor after adjusting for other factors. Although the ITT analysis did not show a 28‐day survival difference, early CRRT led to faster improvement by Day 3 in ammonia levels, optic nerve sheath diameter, hemodynamic parameters, and SOFA scores, all of which are surrogate markers of poor outcomes in this population. Enrolment beyond the initially planned sample size was permitted to account for the higher‐than‐expected number of protocol violations.
We agree that our trial suggests potential benefits of early CRRT initiation on clinical outcomes and highlights the need for larger multicentric randomized controlled trials to validate these findings.
Author Contributions
Rakhi Maiwall: conceptualization, methodology, validation, investigation, funding acquisition, writing – original draft, writing – review and editing, visualization, data curation, supervision. Meenu Bajpai: writing – review and editing. Neha Chauhan: validation, formal analysis. Sherin Thomas: visualization. Rajendra Prasad Mathur: writing – review and editing. Shiv Kumar Sarin: resources, supervision. Mohit Prajapati: data curation. Prashant Agarwal: data curation. Samba Siva Rao Pasupuleti: validation, formal analysis. Manya Prasad: 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.70840 and https://doi.org/10.1111/apt.70794.
Maiwall R., Bajpai M., Pasupuleti S. S. R., et al., “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. Authors' Reply,” Alimentary Pharmacology & Therapeutics 64, no. 7 (2026): 1027–1028, 10.1111/apt.70889.
Handling Editor: Daniel Huang
Contributor Information
Rakhi Maiwall, Email: rakhi_2011@yahoo.co.in.
Shiv Kumar Sarin, Email: shivsarin@gmail.com.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.