Proenkephalin A 119-159 (Penkid) Is an Early Biomarker of Septic Acute Kidney Injury: The Kidney in Sepsis and Septic Shock (Kid-SSS) Study

Alexa Hollinger, Xavier Wittebole, Bruno François, Peter Pickkers, Massimo Antonelli, Etienne Gayat, Benjamin Glenn Chousterman, Jean-Baptiste Lascarrou, Thierry Dugernier, Salvatore Di Somma, Joachim Struck, Andreas Bergmann, Albertus Beishuizen, Jean-Michel Constantin, Charles Damoisel, Nicolas Deye, Stéphane Gaudry, Vincent Huberlant, Gernot Marx, Emanuelle Mercier, Haikel Oueslati, Oliver Hartmann, Romain Sonneville, Pierre-François Laterre, Alexandre Mebazaa, Matthieu Legrand, Alexa Hollinger, Xavier Wittebole, Bruno François, Peter Pickkers, Massimo Antonelli, Etienne Gayat, Benjamin Glenn Chousterman, Jean-Baptiste Lascarrou, Thierry Dugernier, Salvatore Di Somma, Joachim Struck, Andreas Bergmann, Albertus Beishuizen, Jean-Michel Constantin, Charles Damoisel, Nicolas Deye, Stéphane Gaudry, Vincent Huberlant, Gernot Marx, Emanuelle Mercier, Haikel Oueslati, Oliver Hartmann, Romain Sonneville, Pierre-François Laterre, Alexandre Mebazaa, Matthieu Legrand

Abstract

Introduction: Sepsis is the leading cause of acute kidney injury (AKI) in critically ill patients. The Kidney in Sepsis and Septic Shock (Kid-SSS) study evaluated the value of proenkephalin A 119-159 (penkid)-a sensitive biomarker of glomerular function, drawn within 24 hours upon intensive care unit (ICU) admission and analyzed using a chemiluminescence immunoassay-for kidney events in sepsis and septic shock.

Methods: The Kid-SSS study was a substudy of Adrenomedullin and Outcome in Severe Sepsis and Septic Shock (AdrenOSS) (NCT02393781), a prospective, observational, multinational study including 583 patients admitted to the intensive care unit with sepsis or septic shock and a validation cohort of 525 patients from the French and euRopean Outcome reGistry in Intensive Care Units (FROG-ICU) study. The primary endpoint was major adverse kidney events (MAKEs) at day 7, composite of death, renal replacement therapy, and persistent renal dysfunction. The secondary endpoints included AKI, transient AKI, worsening renal function (WRF), and 28-day mortality.

Results: Median age was 66 years (interquartile range 55-75), and 28-day mortality was 22% (95% confidence interval [CI] 19%-25%). Of the patients, 293 (50.3%) were in shock upon ICU admission. Penkid was significantly elevated in patients with MAKEs, persistent AKI, and WRF (median = 65 [IQR = 45-106] vs. 179 [114-242]; 53 [39-70] vs. 133 [79-196] pmol/l; and 70 [47-121] vs. 174 [93-242] pmol/l, all P < 0.0001), also after adjustment for confounding factors (adjusted odds ratio = 3.3 [95% CI = 1.8-6.0], 3.9 [95% CI = 2.1-7.2], and 3.4 [95% CI = 1.9-6.2], all P < 0.0001). Penkid increase preceded elevation of serum creatinine with WRF and was low in renal recovery.

Conclusion: Admission penkid concentration was associated with MAKEs, AKI, and WRF in a timely manner in septic patients.

Keywords: acute kidney injury; biomarker; diagnosis; sepsis.

Figures

Figure 1
Figure 1
Proenkephalin A 119-159 (penkid) values from the Adrenomedullin and Outcome in Severe Sepsis and Septic Shock (AdrenOSS) cohort at admission (boxplots) in (a) patients with or without major adverse kidney events (MAKEs) at day 7, (b) patients with acute kidney injury (AKI) and patients without, (c) patients with worsening renal function (WRF) and patients without, and (d) patients with or without renal replacement therapy (RRT).
Figure 2
Figure 2
Standardized odds ratio (OR) for proenkephalin A 119-159 (penkid) from the Adrenomedullin and Outcome in Severe Sepsis and Septic Shock (AdrenOSS) cohort, unadjusted (unadj.) and adjusted (adj.) for age, sex, admission diagnosis, history of chronic kidney disease, history of diabetes, history of hypertension, urine output, and estimated glomerular filtration rate on admission, and in patients with low creatinine (i.e., renal Sequential Organ Failure Assessment [SOFA] ≤1 [other subgroups not reported due to low event numbers]); endpoints major adverse kidney events (MAKEs), worsening renal function (WRF), and acute kidney injury (AKI). Odds ratios are standardized to 1 interquartile range (IQR); all P < 0.05.
Figure 3
Figure 3
Bar graphs showing incidence of (a) major adverse kidney events (MAKEs) and (b) worsening renal function (WRF) with respect to proenkephalin A 119-159 (penkid) concentration upon admission above or below the predefined cut-off value of 84.2 pmol/l (population median) across renal Sequential Organ Failure Assessment (SOFA) score stage on admission. Median serum creatinine (Screat) values are 0.8, 1.5, 2.6, 2.7, and 2.6 mg/dl for renal SOFA score categories 0, 1, 2, 3, and 4, respectively.
Figure 4
Figure 4
Proenkephalin A 119-159 (penkid) at admission, day 1, and day 2 in patients with low serum creatinine (renal Sequential Organ Failure Assessment [SOFA] score of 0 or 1) upon admission (a) according to worsening renal function (WRF) occurrence and (b) according to major adverse kidney events (MAKEs).
Figure 5
Figure 5
Twenty-eight-day Kaplan−Meier survival curves of low versus high proenkephalin A 119-159 (penkid) concentrations at admission, (a) based upon the cut-off value of 84.2 pmol/l (population median) in all patients from the Adrenomedullin and Outcome in Severe Sepsis and Septic Shock (AdrenOSS) study cohort, and (b) based upon the cut-off value of 85 pmol/l (population median) in all patients from the French and euRopean Outcome reGistry in Intensive Care Units (FROG-ICU) study cohort.
Figure S1
Figure S1
Penkid values from the FROG-ICU cohort at admission (boxplots) in (A) patients with or without major adverse kidney events (MAKEs) at day 7, (B) patients with acute kidney injury (AKI) and patients without, (C) patients with worsening renal function (WRF) and patients without, and (D) patients with or without renal replacement therapy (RRT).
Figure S2
Figure S2
Penkid values at admission (boxplot) according to AKI staging (P < 0.001).
Figure S3
Figure S3
Standardized odds ratio for penkid from the FROG-ICU cohort, unadjusted and adjusted for age, sex, history of CKD, history of diabetes, history of hypertension and eGFR on admission, and in patients with low creatinine (i.e., renal SOFA ≤1); endpoints MAKE, WRF and AKI. OR are standardized to 1 IQR; all P < 0.05.
Figure S4
Figure S4
Penkid values at admission (boxplot) according to rapid recovery from AKI and transient AKI (P < 0.001).

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