Predictive value of plasma proenkephalin and neutrophil gelatinase-associated lipocalin in acute kidney injury and mortality in cardiogenic shock

Toni Jäntti, Tuukka Tarvasmäki, Veli-Pekka Harjola, Kari Pulkki, Heidi Turkia, Tuija Sabell, Heli Tolppanen, Raija Jurkko, Mari Hongisto, Anu Kataja, Alessandro Sionis, Jose Silva-Cardoso, Marek Banaszewski, Salvatore DiSomma, Alexandre Mebazaa, Mikko Haapio, Johan Lassus, CardShock investigators, Veli-Pekka Harjola, Marek Banaszewski, Lars Køber, Johan Lassus, Alexandre Mebazaa, Marco Metra, John Parissis, Jose Silva-Cardoso, Alessandro Sionis, Salvatore Di Somma, Jindrich Spinar, Katerina Koniari, Astrinos Voumvourakis, Apostolos Karavidas, Jordi Sans-Rosello, Montserrat Vila, Albert Duran-Cambra, Michela Bulgari, Valentina Lazzarini, Jiri Parenica, Roman Stipal, Ondrej Ludka, Marie Palsuva, Eva Ganovska, Petr Kubena, Matias G Lindholm, Christian Hassager, Tom Bäcklund, Raija Jurkko, Kristiina Järvinen, Tuomo Nieminen, Kari Pulkki, Leena Soininen, Reijo Sund, Ilkka Tierala, Jukka Tolonen, Marjut Varpula, Tuomas Korva, Anne Pitkälä, Rossella Marino, Alexandra Sousa, Carla Sousa, Mariana Paiva, Inês Rangel, Rui Almeida, Teresa Pinho, Maria Júlia Maciel, Janina Stepinska, Anna Skrobisz, Piotr Góral, Toni Jäntti, Tuukka Tarvasmäki, Veli-Pekka Harjola, Kari Pulkki, Heidi Turkia, Tuija Sabell, Heli Tolppanen, Raija Jurkko, Mari Hongisto, Anu Kataja, Alessandro Sionis, Jose Silva-Cardoso, Marek Banaszewski, Salvatore DiSomma, Alexandre Mebazaa, Mikko Haapio, Johan Lassus, CardShock investigators, Veli-Pekka Harjola, Marek Banaszewski, Lars Køber, Johan Lassus, Alexandre Mebazaa, Marco Metra, John Parissis, Jose Silva-Cardoso, Alessandro Sionis, Salvatore Di Somma, Jindrich Spinar, Katerina Koniari, Astrinos Voumvourakis, Apostolos Karavidas, Jordi Sans-Rosello, Montserrat Vila, Albert Duran-Cambra, Michela Bulgari, Valentina Lazzarini, Jiri Parenica, Roman Stipal, Ondrej Ludka, Marie Palsuva, Eva Ganovska, Petr Kubena, Matias G Lindholm, Christian Hassager, Tom Bäcklund, Raija Jurkko, Kristiina Järvinen, Tuomo Nieminen, Kari Pulkki, Leena Soininen, Reijo Sund, Ilkka Tierala, Jukka Tolonen, Marjut Varpula, Tuomas Korva, Anne Pitkälä, Rossella Marino, Alexandra Sousa, Carla Sousa, Mariana Paiva, Inês Rangel, Rui Almeida, Teresa Pinho, Maria Júlia Maciel, Janina Stepinska, Anna Skrobisz, Piotr Góral

Abstract

Background: Acute kidney injury (AKI) is a frequent form of organ injury in cardiogenic shock. However, data on AKI markers such as plasma proenkephalin (P-PENK) and neutrophil gelatinase-associated lipocalin (P-NGAL) in cardiogenic shock populations are lacking. The objective of this study was to assess the ability of P-PENK and P-NGAL to predict acute kidney injury and mortality in cardiogenic shock.

Results: P-PENK and P-NGAL were measured at different time points between baseline and 48 h in 154 patients from the prospective CardShock study. The outcomes assessed were AKI defined by an increase in creatinine within 48 h and all-cause 90-day mortality. Mean age was 66 years and 26% were women. Baseline levels of P-PENK and P-NGAL (median [interquartile range]) were 99 (71-150) pmol/mL and 138 (84-214) ng/mL. P-PENK > 84.8 pmol/mL and P-NGAL > 104 ng/mL at baseline were identified as optimal cut-offs for AKI prediction and independently associated with AKI (adjusted HRs 2.2 [95% CI 1.1-4.4, p = 0.03] and 2.8 [95% CI 1.2-6.5, p = 0.01], respectively). P-PENK and P-NGAL levels at baseline were also associated with 90-day mortality. For patients with oliguria < 0.5 mL/kg/h for > 6 h before study enrollment, 90-day mortality differed significantly between patients with low and high P-PENK/P-NGAL at baseline (5% vs. 68%, p < 0.001). However, the biomarkers provided best discrimination for mortality when measured at 24 h. Identified cut-offs of P-PENK24h > 105.7 pmol/L and P-NGAL24h > 151 ng/mL had unadjusted hazard ratios of 5.6 (95% CI 3.1-10.7, p < 0.001) and 5.2 (95% CI 2.8-9.8, p < 0.001) for 90-day mortality. The association remained significant despite adjustments with AKI and two risk scores for mortality in cardiogenic shock.

Conclusions: High levels of P-PENK and P-NGAL at baseline were independently associated with AKI in cardiogenic shock patients. Furthermore, oliguria before study inclusion was associated with worse outcomes only if combined with high baseline levels of P-PENK or P-NGAL. High levels of both P-PENK and P-NGAL at 24 h were found to be strong and independent predictors of 90-day mortality.

Trial registration: NCT01374867 at www.clinicaltrials.gov , registered 16 Jun 2011-retrospectively registered.

Keywords: AKI; Acute kidney injury; Cardiogenic shock; Mortality; NGAL; PENK; Proenkephalin; Prognosis.

Conflict of interest statement

VPH: advisory board fees from Roche Diagnostics, research grant from Abbott, speaker fees from Orion. KP: advisory board fees from Roche Diagnostics. JSC has consulted and received speaker fees, or advisory boards’ participation fees, or investigational grants for Abbott, Astra-Zeneca Pharmaceuticals, Bial, Boehringer Ingelheim, Menarini, Merck Serono, Merck Sharp & Dohme, Novartis, Orion, Pfizer, Sanofi, Servier and Vifor. AM: lecture fees from Novartis, Orion, and Abbott, research grants from Roche, consultant fees from Servier and Sanofi and fees as a member of the advisory board and/or steering committee from Cardiorentis, Adrenomed, Sphingotec, Sanofi, Roche, Abbott, and Bristol-Myers Squibb. JL: Speakers bureau and consultancy fees: Astra-Zeneca, Bayer, Boehringer-Ingelheim, Novartis, Orion, Pfizer, Roche Diagnostics, and ViforPharma. All other authors report that they have no relationships with industry to disclose.

Figures

Fig. 1
Fig. 1
Biomarker medians at different time points separated by occurrence of AKI within 48 h. a P-PENK. b P-NGAL. c Creatinine. Error bars = 95% confidence interval
Fig. 2
Fig. 2
P-PENK and P-NGAL median levels at different time points separated by 90-day mortality. a P-PENK. b P-NGAL. Error bars = 95% confidence interval
Fig. 3
Fig. 3
Kaplan–Meier curves for occurrence of acute kidney injury by P-PENK and P-NGAL levels at baseline. a Lines separated by P-PENK > 84.8 pmol/mL at baseline. b Lines separated by P-NGAL > 104 ng/mL at baseline
Fig. 4
Fig. 4
Venn diagram of P-PENK, P-NGAL at baseline, acute kidney injury and 90-day mortality. PENK high = P-PENK  104 ng/mL at baseline. For illustrative purposes. Areas not proportional, unable to show all overlaps
Fig. 5
Fig. 5
Kaplan–Meier survival curves for patients with and without AKI separated by P-PENK and P-NGAL levels. a P-PENK higher or lower than 84.8 pmol/mL at baseline. b P-NGAL higher or lower than 104 ng/mL at baseline. §p = 0.07, *p < 0.05, **p < 0.001. AKI acute kidney injury

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