Evaluation of Proenkephalin A 119-159 for liberation from renal replacement therapy: an external, multicenter pilot study in critically ill patients with acute kidney injury

Crit Care. 2023 Jul 10;27(1):276. doi: 10.1186/s13054-023-04556-w.


Introduction: Recent evidence suggests an association of plasma Proenkephalin A 119-159 (penKid) with early and successful liberation from continuous renal replacement therapy (CRRT) in critically ill patients with acute kidney injury. However, these exploratory results are derived from a monocentric trial and therefore require external validation in a multicenter cohort.

Methods: Data and plasma samples from the "Effect of Regional Citrate Anticoagulation versus Systemic Heparin Anticoagulation During Continuous Kidney Replacement Therapy on Dialysis Filter Life Span and Mortality Among Critically Ill Patients With Acute Kidney Injury-A Randomized Clinical Trial" (RICH Trial) were used for this validation study. PenKid was measured in all plasma samples available at CRRT initiation and at day 3 of CRRT. Patients were categorized into low and high penKid groups with a cutoff at 100 pmol/l. Competing-risk time-to-event analyses were performed. Competing risk endpoints were successful and unsuccessful liberation from CRRT, the latter meaning death or initiation of a new RRT within one week of discontinuation of primary CRRT. Then penKid was compared to urinary output.

Results: Low pre-CRRT penKid levels at CRRT initiation were not associated with early and successful liberation from CRRT compared to patients with high pre-CRRT penKid levels [subdistribution hazard ratio (sHR) 1.01, 95% CI 0.73-1.40, p = 0.945]. However, the landmark analysis on day 3 of ongoing CRRT demonstrated an association between low penKid levels and successful liberation from CRRT (sHR 2.35, 95% CI 1.45-3.81, p < 0.001) and an association between high penKid levels and unsuccessful liberation (sHR 0.46, 95% CI 0.26-0.80, p = 0.007). High daily urinary output (> 436 ml/d) was even stronger associated with successful liberation (sHR 2.91, 95% CI 1.80-4.73, p < 0.001) compared to penKid.

Discussion: This study suggests that penKid may be a competent biomarker to monitor the recovery of kidney function during CRRT. This is in line with previous findings and investigated this concept in a multicenter cohort. Again, low penKid was associated with early and successful CRRT liberation, but was outperformed by high daily urinary output. The findings of this study now warrant further evaluation in prospective studies or a randomized controlled trial. Trial registration The RICH Trial was registered at clinicaltrials.gov: NCT02669589. Registered 01 February 2016.

Keywords: Acute kidney injury; Biomarker; Critical illness; Proenkephalin; Renal replacement therapy.

Publication types

  • Randomized Controlled Trial
  • Multicenter Study

MeSH terms

  • Acute Kidney Injury* / therapy
  • Anticoagulants
  • Continuous Renal Replacement Therapy*
  • Critical Illness / therapy
  • Humans
  • Pilot Projects
  • Prospective Studies
  • Renal Dialysis
  • Renal Replacement Therapy


  • proenkephalin
  • Anticoagulants

Associated data

  • ClinicalTrials.gov/NCT02669589