Proenkephalin Compared to Conventional Methods to Assess Kidney Function in Critically Ill Sepsis Patients

Abstract

Background: The assessment of renal function in clinical practice remains challenging. Using creatinine to assess the glomerular filtration rate (GFR) is notoriously inaccurate, and determination of the true GFR, e.g., using inulin or iohexol, is laborious and not feasible in daily practice. Proenkephalin (PENK) is a novel candidate biomarker for kidney function that is filtrated in the glomerulus, has shown to represent steady-state GFR in patients with different severities of renal insufficiency. In this pilot study in non-steady-state critically ill patients, we compared plasma PENK concentrations with creatinine-based GFR assessments and validated both against the “true GFR” measured using a gold standard method: iohexol plasma clearance. Methods: Twenty-three critically ill patients with septic shock were included. Kidney function was determined using the Modification of Diet in Renal Disease formula (eGFR MDRD ), Endogenous Creatinine Clearance (GFR ECC ), and iohexol plasma clearance (GFR iohexol ) during a 6-h window. Plasma PENK concentrations were measured using the penKid immunoassay. Results: The eGFR MDRD and GFR ECC correlated with the GFR iohexol ( R 2 = 0.82, P < 0.0001 and R 2 = 0.82, P < 0.0001 respectively); however, bias and variability were considerable: the eGFR MDRD overestimated the true GFR with 31 ± 35% (95% limits of agreement: −37% to 100%) and the GFR ECC with 37 ± 49% (95% limits of agreement: −59% to 133%). Plasma PENK concentrations showed a very strong inverse correlation with the GFR iohexol ( R 2 = 0.90, P < 0.0001) which tended to be better compared with the correlation of eGFR MDRD ( P = 0.06) and GFR ECC ( P = 0.08) with the GFR iohexol . Conclusions: In this pilot study in non-steady-state critically ill sepsis patients, GFR appears to be more accurately reflected by plasma PENK concentrations compared to conventional creatinine-based methods. Therefore, PENK holds promise as an accurate and feasible biomarker to determine kidney function during non-steady-state conditions in the critically ill.

Proenkephalin as a new biomarker for pediatric acute kidney injury – reference values and performance in children under one year of age

“…Remarkably, these higher PENK concentrations were still highly associated with AKI in critically ill children. This is in concordance with a study in adults, where PENK highly correlated with measured GFR in 24 septic ICU patients [26]. Moreover, in another cohort of 101 sepsis patients, PENK was independently associated with RIFLE stages [22].…”

“…Research in healthy and diseased adults supports PENK as an early indicator of AKI and independent predictor of impaired kidney function. Moreover, PENK was strongly correlated with estimated and measured GFR after cardiac surgery and in septic patients [20][21][22][23][24][25][26][27][28][29].…”

Proenkephalin Predicts Organ Failure, Renal Replacement Therapy, and Mortality in Patients With Sepsis

“…Proenkephalin A 119–159 (PENK) is a stable surrogate marker for endogenous enkephalins, and it has been suggested to be a functional kidney marker closely related to the iohexol-determined GFR, which is considered the gold standard [ 12 – 14 ]. PENK has been investigated as a novel biomarker for AKI in various clinical settings, including sepsis and heart failure [ 14 – 22 ]. Further, few recent studies showed that high PENK levels are associated with the deterioration of kidney function and adverse clinical outcomes for critically ill patients.…”

Biomarkers and predicting acute kidney injury

“…Proenkefalin is expressed in many tissues including the kidney 27 . Beunders et al have proposed PENK as a novel biomarker for renal function 28 . Proenkefalin plasma levels showed promise and were highly correlated with iohexol clearance.…”