Urinary TIMP-2 and IGFBP7 as early biomarkers of acute kidney injury and renal recovery following cardiac surgery

Melanie Meersch, Christoph Schmidt, Hugo Van Aken, Sven Martens, Jan Rossaint, Kai Singbartl, Dennis Görlich, John A Kellum, Alexander Zarbock, Melanie Meersch, Christoph Schmidt, Hugo Van Aken, Sven Martens, Jan Rossaint, Kai Singbartl, Dennis Görlich, John A Kellum, Alexander Zarbock

Abstract

Background: Difficulties in prediction and early identification of (acute kidney injury) AKI have hindered the ability to develop preventive and therapeutic measures for this syndrome. We tested the hypothesis that a urine test measuring insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in acute kidney injury (AKI), could predict AKI in cardiac surgery patients.

Methods: We studied 50 patients at high risk for AKI undergoing cardiac surgery with cardiopulmonary bypass (CPB). Serial urine samples were analyzed for [TIMP-2]*[IGFBP7] concentrations. The primary outcome measure was AKI as defined by international consensus criteria following surgery. Furthermore, we investigated whether urine [TIMP-2]*[IGFBP7] could predict renal recovery from AKI prior to hospital discharge.

Results: 26 patients (52%) developed AKI. Diagnosis based on serum creatinine and/or oliguria did not occur until 1-3 days after CPB. In contrast, urine concentration of [TIMP-2]*[IGFBP7] rose from a mean of 0.49 (SE 0.24) at baseline to 1.51 (SE 0.57) 4 h after CPB in patients who developed AKI. The maximum urinary [TIMP-2]*[IGFBP7] concentration achieved in the first 24 hours following surgery (composite time point) demonstrated an area under the receiver-operating characteristic curve of 0.84. Sensitivity was 0.92, and specificity was 0.81 for a cutoff value of 0.50. The decline in urinary [TIMP-2]*[IGFBP7] values was the strongest predictor for renal recovery.

Conclusions: Urinary [TIMP-2]*[IGFBP7] serves as a sensitive and specific biomarker to predict AKI early after cardiac surgery and to predict renal recovery.

Clinical trial registration information: www.germanctr.de/, DRKS-ID: DRKS00005062.

Conflict of interest statement

Competing Interests: The authors have read the journal's policy and the following conflicts exist: JAK has received grant support and consulting fees from Astute Medical and Alere. This does not alter their adherence to PLOS One policies on sharing data and materials. Alexander Zarbock is a PLOS ONE Editorial Board member. This does not alter the authors' adherence to PLOS ONE Editorial policies and criteria. The remaining authors declare no potential conflicts of interest.

Figures

Figure 1. CONSORT 2010 Flow Diagram.
Figure 1. CONSORT 2010 Flow Diagram.
Figure 2. Analysis of urine [TIMP-2]*[IGFBP7].
Figure 2. Analysis of urine [TIMP-2]*[IGFBP7].
(A) Graph shows mean urine [TIMP-2]*[IGFBP7] concentrations at various time points before and after cardiopulmonary bypass. (B) Graph shows urine [TIMP-2]*[IGFBP7] corrected for urine creatinine excretion. (C) Graph shows mean urine NGAL concentrations at various time points before and after cardiopulmonary bypass. Error bars are SE. Asterisks (*) denote significant differences (p≤0.05) between groups (AKI, non-AKI) at the respective time point.
Figure 3. ROC curves for the maximum…
Figure 3. ROC curves for the maximum early composite and the 4
(A) This figure displays the receiver operating characteristic (ROC) curve for the maximum early composite (maximum value from the first 24 postoperative hours) for [TIMP-2]*[IGFBP7]. (B) This figure displays the receiver operating characteristic (ROC) curves for the 4 h values of [TIMP-2]*[IGFBP7] (black solid line) and NGAL (gray dashed line).
Figure 4. ROC curve for recovery from…
Figure 4. ROC curve for recovery from AKI after cardiac surgery.
This figure displays the area under the curve (AUC) for predicting renal recovery. [TIMP-2]*[IGFBP7] (black solid line) and urine neutrophil gelatinase-associated lipocalin (NGAL, gray dashed line).

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