---
title: "Proenkephalin A Predicts Hydrocortisone Effect on Kidney Outcomes in Septic Shock (VANISH Post Hoc)"
id: "pubmed-42902572"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42902572"
content_type: "clinical_feed_article"
specialty: "Critical Care"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42902572/"
doi: "10.1097/CCE.0000000000001496"
published_at: "2026-10-21T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Proenkephalin A Predicts Hydrocortisone Effect on Kidney Outcomes in Septic Shock (VANISH Post Hoc)
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42902572
- **Specialty:** [Critical Care](https://medichelpline.com/clinical-feed/critical-care.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42902572/)
- **DOI:** [10.1097/CCE.0000000000001496](https://doi.org/10.1097%2FCCE.0000000000001496)
- **Published At:** 2026-10-21T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- Post hoc analysis of the VANISH randomized trial evaluated whether baseline **proenkephalin A** (PENK), a plasma biomarker of renal function, modified hydrocortisone treatment effects in **septic shock**. - The cohort comprised 173 ICU patients enrolled in the VANISH trial; interventions included vasopressin versus norepinephrine and hydrocortisone versus placebo. - Investigators dichotomized PENK at a threshold of 89 pmol/L to define high versus low baseline PENK. - PENK ≥ 89 pmol/L associated with higher 28-day mortality (odds ratio 3.24; 95% CI, 1.62–6.74), the study team reported. - No interaction was observed between PENK group and assignment to vasopressin versus norepinephrine for outcomes. - In the subgroup who reached the trial's maximum vasopressor threshold (n = 111), authors observed a significant interaction between PENK group and hydrocortisone versus placebo for kidney failure–free days (p = 0.01). - Within that subgroup, patients with high PENK receiving hydrocortisone had the fewest kidney failure–free days compared with high-PENK placebo and low-PENK groups. - There was no statistically significant interaction for 28-day mortality (p = 0.14), although the highest raw mortality occurred in the high-PENK hydrocortisone group (50% vs high-PENK placebo 32%). - The analysis was exploratory and post hoc; the authors stated that the findings require validation in independent, prospective studies. - The source did not report detailed protocolized hydrocortisone dosing, timing of PENK sampling relative to randomization beyond baseline measurement, or additional stratified safety outcomes beyond mortality and kidney failure–free days.
## Clinical Analysis & Structured Key Points
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Affiliations Expand ### Affiliations * 1 Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London, London, United Kingdom. * 2 Intensive Care Unit, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom. * 3 Medical Department, SphingoTec GmbH, Hennigsdorf, Germany. * 4 School of Medicine, University of Surrey and Intensive Care Unit, Royal Surrey Hospital NHS Foundation Trust, Guildford, United Kingdom. * PMID: **42902572** * DOI: [ 10.1097/CCE.0000000000001496 ](https://doi.org/10.1097/cce.0000000000001496) Item in Clipboard Randomized Controlled Trial # Proenkephalin A and Heterogeneity of Hydrocortisone Treatment Effect in Septic Shock: A Post Hoc Analysis of the VANISH Trial David B Antcliffe et al. Crit Care Explor. 2026. Show details Display options Display options Format Abstract PubMed PMID Crit Care Explor Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Crit+Care+Explor%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Crit+Care+Explor%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42902572/) . 2026 Oct 21;8(10):e1496. doi: 10.1097/CCE.0000000000001496. eCollection 2026 Oct 1. ### Authors [David B Antcliffe](https://pubmed.ncbi.nlm.nih.gov/?term=Antcliffe+DB&cauthor_id=42902572)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42902572/#short-view-affiliation-1 "Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London, London, United Kingdom.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42902572/#short-view-affiliation-2 "Intensive Care Unit, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom."), [Florian Uhle](https://pubmed.ncbi.nlm.nih.gov/?term=Uhle+F&cauthor_id=42902572)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42902572/#short-view-affiliation-3 "Medical Department, SphingoTec GmbH, Hennigsdorf, Germany."), [Dominic C Marshall](https://pubmed.ncbi.nlm.nih.gov/?term=Marshall+DC&cauthor_id=42902572)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42902572/#short-view-affiliation-1 "Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London, London, United Kingdom."), [Ashleigh D Green](https://pubmed.ncbi.nlm.nih.gov/?term=Green+AD&cauthor_id=42902572)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42902572/#short-view-affiliation-1 "Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London, London, United Kingdom."), [Anthony C Gordon](https://pubmed.ncbi.nlm.nih.gov/?term=Gordon+AC&cauthor_id=42902572)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42902572/#short-view-affiliation-1 "Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London, London, United Kingdom."), [Lui G Forni](https://pubmed.ncbi.nlm.nih.gov/?term=Forni+LG&cauthor_id=42902572)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42902572/#short-view-affiliation-4 "School of Medicine, University of Surrey and Intensive Care Unit, Royal Surrey Hospital NHS Foundation Trust, Guildford, United Kingdom.") ### Affiliations * 1 Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London, London, United Kingdom. * 2 Intensive Care Unit, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom. * 3 Medical Department, SphingoTec GmbH, Hennigsdorf, Germany. * 4 School of Medicine, University of Surrey and Intensive Care Unit, Royal Surrey Hospital NHS Foundation Trust, Guildford, United Kingdom. * PMID: **42902572** * DOI: [ 10.1097/CCE.0000000000001496 ](https://doi.org/10.1097/cce.0000000000001496) Item in Clipboard Cite Display options Display options Format Abstract PubMed PMID Linked Discoveries ## Abstract **Objectives:** Heterogeneity of treatment effect is thought to drive conflicting results for the benefits of corticosteroids in sepsis. Proenkephalin A (PENK) is a biomarker of renal function. Given the kidney's role in sepsis pathophysiology and corticosteroid metabolism, we hypothesized that baseline renal function, assessed using PENK, would be associated with hydrocortisone efficacy. **Design:** A post hoc analysis of a double-blind, randomized clinical trial in septic shock (Effect of Early Vasopressin vs. Norepinephrine on Kidney Failure in Patients with Septic Shock [VANISH]). **Setting:** ICUs across the United Kingdom. **Patients:** One hundred seventy-three patients admitted to ICU with septic shock. **Interventions:** Norepinephrine vs. vasopressin and hydrocortisone vs. placebo. **Measurements and main results:** PENK was measured in plasma, and patients were dichotomized using a PENK concentration above 89 pmol/L. PENK greater than or equal to 89 pmol/L was associated with 28-day mortality (odds ratio, 3.24; 95% CI, 1.62-6.74). We found no interaction between PENK and randomization to vasopressin or norepinephrine on outcome. However, there was a significant interaction between the PENK groups and hydrocortisone or placebo use in those patients who reached the maximum vasopressor threshold (n = 111) for kidney failure-free days (high PENK [≥ 89 pmol/L] placebo 26 [13-28], hydrocortisone 11 [0-26] and low PENK placebo 28 [15-28], hydrocortisone 28 [28-28]; p = 0.01). Patients with high PENK receiving hydrocortisone had the fewest kidney failure-free days. Although we found no significant interaction for 28-day mortality (p = 0.14), the patients with high PENK who received hydrocortisone had the highest mortality (high PENK hydrocortisone 50%, placebo 32% and low PENK hydrocortisone 14%, placebo 24%). **Conclusions:** This exploratory analysis identified a possible interaction between baseline PENK and hydrocortisone treatment on kidney failure-free days. These findings require validation in independent and prospective studies. **Keywords:** corticosteroids; hydrocortisone; proenkephalin A; renal failure; sepsis; septic shock. Copyright © 2026 The Authors. Published by Wolters Kluwer Health, LLC. on behalf of the Society of Critical Care Medicine. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## References 1. 1. Singer M, Deutschman CS, Seymour CW, et al.: The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016; 315:801–810 2. 1. Bellomo R, Kellum JA, Ronco C, et al.: Acute kidney injury in sepsis. Intensive Care Med 2017; 43:816–828 3. 1. Lin LC, Chuan MH, Liu JH, et al.: Proenkephalin as a biomarker correlates with acute kidney injury: A systematic review with meta-analysis and trial sequential analysis. Crit Care 2023; 27:481 4. 1. Beunders R, Donato LJ, van Groenendael R, et al.: Assessing GFR with proenkephalin. Kidney Int Rep 2023; 8:2345–2355 5. 1. Hollinger A, Wittebole X, François B, et al.: Proenkephalin A 119-159 (Penkid) is an early biomarker of septic acute kidney injury: The Kidney in Sepsis and Septic Shock (Kid-SSS) study. 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