Incidence and Outcome of Subclinical Acute Kidney Injury Using penKid in Critically Ill Patients

Am J Respir Crit Care Med. 2020 Sep 15;202(6):822-829. doi: 10.1164/rccm.201910-1950OC.


Rationale: Subclinical acute kidney injury (sub-AKI) refers to patients with low serum creatinine but elevated alternative biomarkers of AKI. Its incidence and outcome in critically ill patients remain, however, largely unknown. Plasma proenkephalin A 119-159 (penKid) has been proposed as a sensitive biomarker of glomerular function.Objectives: In this ancillary study of two cohorts, we explored the incidence and outcome of sub-AKI based on penKid.Methods: A prospective observational study in ICUs was conducted. FROG-ICU (French and European Outcome Registry in ICUs) enrolled 2,087 critically ill patients, and AdrenOSS-1 (Adrenomedullin and Outcome in Severe Sepsis and Septic Shock-1) enrolled 583 septic patients. The primary endpoint was 28-day mortality after ICU admission. Sub-AKI was defined by an admission penKid concentration above the normal range (i.e., >80 pmol/L) in patients not meeting the definition of AKI. A sensitivity analysis was performed among patients with estimated glomerular filtration rate above 60 ml/min/1.73 m2 at ICU admission.Measurements and Main Results: In total, 6.1% (122/2,004) and 6.7% (39/583) of patients from the FROG-ICU and AdrenOSS-1 cohorts met the definition of sub-AKI (11.6% and 17.5% of patients without AKI). In patients without AKI or with high estimated glomerular filtration rate, penKid was associated with higher mortality (adjusted standardized hazard ratio [HR], 1.4 [95% confidence interval, 1.1-1.8]; P = 0.010; and HR, 1.6 [95% confidence interval, 1.3-1.8]; P < 0.0001, respectively) after adjustment for age, sex, comorbidities, diagnosis, creatinine, diuresis, and study. Patients with sub-AKI had higher mortality compared with no AKI (HR, 2.4 [95% confidence interval, 1.5-3.7] in FROG-ICU and 2.5 [95% confidence interval, 1.1-5.9] in AdrenOSS-1).Conclusions: Sub-AKI defined using penKid occurred in 11.6-17.5% of patients without AKI and was associated with a risk of death close to patients with AKI.

Keywords: acute kidney injury; biomarker; penKid; proenkephalin; renal recovery.

Publication types

  • Observational Study

MeSH terms

  • Acute Kidney Injury / diagnosis*
  • Acute Kidney Injury / epidemiology
  • Acute Kidney Injury / mortality*
  • Aged
  • Biomarkers / blood*
  • Cohort Studies
  • Critical Illness / therapy*
  • Decision Making
  • Enkephalins / blood*
  • Europe / epidemiology
  • Female
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Prospective Studies
  • Protein Precursors / blood*
  • Risk Factors


  • Biomarkers
  • Enkephalins
  • Protein Precursors