Urinary biomarkers TIMP-2 and IGFBP7 early predict acute kidney injury after major surgery

Ivan Gocze, Matthias Koch, Philipp Renner, Florian Zeman, Bernhard M Graf, Marc H Dahlke, Michael Nerlich, Hans J Schlitt, John A Kellum, Thomas Bein, Ivan Gocze, Matthias Koch, Philipp Renner, Florian Zeman, Bernhard M Graf, Marc H Dahlke, Michael Nerlich, Hans J Schlitt, John A Kellum, Thomas Bein

Abstract

Objective: To assess the ability of the urinary biomarkers IGFBP7 (insulin-like growth factor-binding protein 7) and TIMP-2 (tissue inhibitor of metalloproteinase 2) to early predict acute kidney injury (AKI) in high-risk surgical patients.

Introduction: Postoperative AKI is associated with an increase in short and long-term mortality. Using IGFBP7 and TIMP-2 for early detection of cellular kidney injury, thus allowing the early initiation of renal protection measures, may represent a new concept of evaluating renal function.

Methods: In this prospective study, urinary [TIMP-2]×[IGFBP7] was measured in surgical patients at high risk for AKI. A predefined cut-off value of [TIMP-2]×[IGFBP7] >0.3 was used for assessing diagnostic accuracy. Perioperative characteristics were evaluated, and ROC analyses as well as logistic regression models of risk assessment were calculated with and without a [TIMP-2]×[IGFBP7] test.

Results: 107 patients were included in the study, of whom 45 (42%) developed AKI. The highest median values of biomarker were detected in septic, transplant and patients after hepatic surgery (1.24 vs 0.45 vs 0.47 ng/l²/1000). The area under receiving operating characteristic curve (AUC) for the risk of any AKI was 0.85, for early use of RRT 0.83 and for 28-day mortality 0.77. In a multivariable model with established perioperative risk factors, the [TIMP-2]×[IGFBP7] test was the strongest predictor of AKI and significantly improved the risk assessment (p<0.001).

Conclusions: Urinary [TIMP-2]×[IGFBP7] test sufficiently detect patients with risk of AKI after major non-cardiac surgery. Due to its rapid responsiveness it extends the time frame for intervention to prevent development of AKI.

Conflict of interest statement

Competing Interests: JAK has received grant support and consulting fees from Astute Medical. IG received honoraria for lectures from Astute Medical. There was no commercial sponsorship or any financial support related to this study. All other authors declare that they have no competing interests. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Study design and flow diagram.
Fig 1. Study design and flow diagram.
1 High Risk for AKI—major surgery and one additional risk factor—critical illness, sepsis, major trauma, chronic renal disease or use of radiocontrast agent.2 AKI was defined according to KDIGO 2012 criteria by creatinine increase of > 0.3 after surgery.
Fig 2. Area under the curve (AUC)…
Fig 2. Area under the curve (AUC) and the best cut-offs for predicting AKI, AKI Stage 2 and 3, early use of RRT and 28-days mortality.

References

    1. Hoste EA, Schurgers M. Epidemiology of acute kidney injury: how big is the problem? Crit Care Med. 2008;36:S146–51 10.1097/CCM.0b013e318168c590
    1. Susantitaphong P, Cruz DN, Cerda J, Abulfaraj M, Alqahtani F, Koulouridis I, et al. (2013) Acute Kidney Injury Advisory Group of the American Society of Nephrology. World incidence of AKI: a meta-analysis. Clin J Am Soc Nephrol. 2013;8(9):1482–932. 10.2215/CJN.00710113
    1. Bihorac A, Yavas S, Subbiah S, Hobson CE, Schold JD, Gabrielli A, et al. Long-term risk of mortality and acute kidney injury during hospitalization after major surgery. Ann Surg. 2009; 249(5):851–8 10.1097/SLA.0b013e3181a40a0b
    1. White LE, Hassoun HT, Bihorac A, Moore LJ, Sailors RM, McKinley BA, et al. Acute kidney injury is surprisingly common and a powerful predictor of mortality in surgical sepsis. J Trauma Acute Care Surg. 2013;75(3):432–8 10.1097/TA.0b013e31829de6cd
    1. Rewa O, Bagshaw SM. Acute kidney injury-epidemiology, outcomes and economics. Nat Rev Nephrol. 2014;(Epub ahead of print)
    1. Kim CS, Oak CY, Kim HY, Kang YU, Choi JS, Bae EH, et al. Incidence, predictive factors, and clinical outcomes of acute kidney injury after gastric surgery for gastric cancer. PLoS One 2013; 9;8(12)
    1. Murray PT, Mehta RL, Shaw A, Ronco C, Endre Z, Kellum JA, et al. Potential use of biomarkers in acute kidney injury: report and summary of recommendations from the 10th Acute Dialysis Quality Initiative consensus conference. Kidney Int. 2015;85(3):513–21.
    1. Haase M, Kellum JA, Ronco. AKI—an emerging syndrome with important consequences. Nat Rev Nephrol. 2012;8(12):735–9. 10.1038/nrneph.2012.197
    1. Price PM, Safirstein RL, Megyesi J. The cell cycle and acute kidney injury. Kidney Int. 2009; 76(6):604–13 10.1038/ki.2009.224
    1. Boonstra J, Post JA. Molecular events associated with reactive oxygen species and cell cycle progression in mammalian cells. Gene. 2014;337:1–13 10.1182/asheducation-2014.1.337
    1. Seo DW, Li H, Qu CK, Oh J, Kim YS, Diaz T, et al. Shp-1 mediates the antiproliferative activity of tissue inhibitor of metalloproteinase-2 in human microvascular endothelial cells. J Biol Chem. 2006;281:3711–3721.
    1. Rodier F, Campisi J, Bhaumik D. Two faces of p53: aging and tumor suppression. Nucleic Acids Res. 2007;35:7475–7484
    1. Yang QH, Liu DW, Long Y, Liu HZ, Chai WZ, Wang XT. Acute renal failure during sepsis: potential role of cell cycle regulation. J Infect. 2009;58:459–464 10.1016/j.jinf.2009.04.003
    1. Seo DW, Li H, Guedez L, Wingfield PT, Diaz T, Salloum R, et al. TIMP-2 mediated inhibition of angiogenesis: an MMP- independent mechanism. Cell. 2003;114:171–180
    1. Wajapeyee N, Serra RW, Zhu X, Mahalingam M, Green MR. Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell. 2008;132:363–374 10.1016/j.cell.2007.12.032
    1. Kashani K, Al-Khafaji A, Ardiles T, Artigas A, Bagshaw SM, Bell M, et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care. 2013;6:17(1)
    1. Bihorac A, Chawla LS, Shaw AD, Al-Khafaji A, Davison DL, Demuth GE et al. Validation of Cell-Cycle Arrest Biomarkers for Acute Kidney Injury Using Clinical Adjudication. Am J Respir Crit Care Med. 2014;Feb 21. [Epub ahead of print]
    1. Meersch M, Schmidt C, Van Aken H, Martens S, Rossaint J, Singbartl K, et al. Urinary TIMP-2 and IGFBP7 as early biomarkers of acute kidney injury and renal recovery following cardiac surgery. PloS One. 2014; 9(3).
    1. Kellum JA, Lameire N, Aspelin P, Barsoum RS, Burdmann EA, Goldstein SL, et al. KDIGO Clinical Practice Guideline for Acute Kidney Injury 2012. Kidney Int. 2012; suppl 2(1):1–138.
    1. Macedo E, Malhotra R, Bouchard J, Wynn SK, Mehta RL. Oliguria is an early predictor of higher mortality in critically ill patients. Kidney Int. 2011;80(7):760–7 10.1038/ki.2011.150
    1. RENAL Replacement Therapy Study Investigators, Bellomo R, Cass A, Cole L, Finfer S, Gallagher M, et al. An observational study fluid balance and patient outcomes in the Randomized Evaluation of Normal vs. Augmented Level of Replacement Therapy trial. Crit Care Med. 2012;40(6):1753–60 10.1097/CCM.0b013e318246b9c6
    1. Bartels K, Karhausen J, Clambey ET, Grenz A, Eltzschig HK. Perioperative organ injury. Anesthesiology. 2013;119(6):1474–89. 10.1097/ALN.0000000000000022
    1. Walsh M, Garg AX, Devereaux PJ, Argalious M, Honar H, Sessler DI. The association between perioperative hemoglobin and acute kidney injury in patients having noncardiac surgery. Anesth Analg. 2013;117(4):924–31. 10.1213/ANE.0b013e3182a1ec84
    1. Asfar P, Meziani F, Hamel JF, Grelon F, Megarbane B, Anguel N, et al. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014;24;370(17)
    1. Murugan R., Kellum JA. Acute kidney injury: what's the prognosis? Nat Rev Nephrol. 2011;7(4), 209–217 10.1038/nrneph.2011.13
    1. Jones RM, Moulton CE, Hardy KJ. Central venous pressure and its effect on blood loss during liver resection. Br J Surg. 1998;85(8):1058–60.
    1. Spolverato G, Ejaz A, Hyder O, Kim Y, Pawlik TM. Failure to rescue as a source of variation in hospital mortality after hepatic surgery. Br J Surg. 2014;101(7):836–46. 10.1002/bjs.9492
    1. Hobson C, Ozrazgat-Baslanti T, Kuxhausen A, Thottakkara P, Efron PA, Moore FA et al. Cost and Mortality Associated With Postoperative Acute Kidney Injury. Ann Surg. 2014; [Epub ahead of print]
    1. Brienza N, Giglio MT, Marucci M, Fiore T. Does perioperative hemodynamic optimization protect renal function in surgical patients? A meta-analytic study. Crit Care Med. 2009;37(6):2079–90 10.1097/CCM.0b013e3181a00a43

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