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Archived Comments for: Quantification of urinary TIMP-2 and IGFBP-7: an adequate diagnostic test to predict acute kidney injury after cardiac surgery?

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  1. Clinical utilization of TIMP-2 and IGFBP7 for detection of AKI following cardiac surgery

    Eric Hoste, Ghent University Hospital

    16 January 2015

    We read with great interest the study by Wetz et al on the use of the biomarkers tissue inhibitor metalloproteinase-2 (TIMP-2) and insulin growth factor-binding protein-7 (IGFBP7) for prediction of AKI after cardiac surgery [1]. The authors found that measurement of these biomarkers during the first day after surgery could identify patients at risk for AKI, while measurement 4 h after cardiopulmonary bypass (CPB) surgery or at the end of the procedure could not identify patients at risk for AKI.

    As investigators of the first validation studies of these biomarkers we feel that there are a few important issues that need to be mentioned.

    First, the biomarkers were used to identify development of AKI within a 60-h period. This is a very ambitious and unrealistic goal for a biomarker for AKI. In many patients the event that leads to AKI, e.g. haemorrhagic or septic shock, or administration of nephrotoxic drugs such as contrast or aminoglycosides, may have occurred after measurement of the biomarker.

    Second, the authors evaluated occurrence of AKI defined by KDIGO stage 1 or greater. In fact, the majority of AKI patients had AKI stage 1 (81%) and only 3 patients developed AKI stage 2. This is different and a far more sensitive endpoint compared to the endpoint for which the test was validated for and that was used in several large studies including 1670 patients, AKI defined by KDIGO stage 2 or greater within a 12-h period [2-5]. As this single centre study includes only 42 patients, it is certainly not powered to come to meaningful conclusions on this new and more sensitive endpoint. In addition, validating the cut-offs that were derived for the original endpoints for this new endpoint is not accurate.

    Third, the authors included all patients who underwent coronary artery bypass graft surgery regardless of their pre-operation AKI risk category. In addition all patients with valvular surgery, who are considered higher risk category, were excluded. Obviously, this strategy would decrease the pre-test probability of AKI and therefore limits the likelihoods of any test designed for prediction of AKI. In a recent study of CBP patients who were enrolled to evaluate the performance of the TIMP-2 and IGFBP7 test in prediction of AKI, all enrollees had Cleveland Clinic Foundation Score of 6 or more, while in this study only 1 (2.4%) of the patients reached such risk category [6].

    Finally, the authors’ claim regarding patients at increased risk for AKI were identified earlier is hard to ascertain. The authors do not report when AKI occurred, so some patients may already have had AKI at time of measurement of the biomarkers. As it is of no use to predict AKI by a biomarker in patients who are already diagnosed by serum creatinine or urine output, the authors should have restricted their dataset at the different time points to patients without AKI.

    In conclusion, we feel that the study presented by Wetz et al. has important limitations that prohibit drawing meaningful conclusions from the presented data.

     

    Eric Hoste

    Department of Intensive Care Medicine,

    Ghent University Hospital, Ghent University

    Research Foundation-Flanders

    De Pintelaan 185, 9000 Gent, Belgium

     

    Kianoush Banaei-Kashani

    Division of Nephrology and Hypertension, division of Pulmonary and Critical Care Medicine,

    Mayo Clinic

    Rochester, Mn USA

     

     

    References

     

    1.      Wetz AJ, Richardt EM, Wand S, Kunze N, Schotola H, Quintel M, Brauer A, Moerer O: Quantification of urinary TIMP-2 and IGFBP-7 - an adequate diagnostic test to predict acute kidney injury after cardiac surgery? Crit Care 2015, 19: 3.

    2.      Bihorac A, Chawla LS, Shaw AD, Al-Khafaji A, Davison DL, Demuth GE, Fitzgerald R, Gong MN, Graham DD, Gunnerson K, Heung M, Jortani S, Kleerup E, Koyner JL, Krell K, Letourneau J, Lissauer M, Miner J, Nguyen HB, Ortega LM, Self WH, Sellman R, Shi J, Straseski J, Szalados JE, Wilber ST, Walker MG, Wilson J, Wunderink R, Zimmerman J et al.: Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication. Am J Respir Crit Care Med 2014, 189: 932-939.

    3.      Hoste EA, McCullough PA, Kashani K, Chawla LS, Joannidis M, Shaw AD, Feldkamp T, Uettwiller-Geiger DL, McCarthy P, Shi J, Walker MG, Kellum JA: Derivation and validation of cutoffs for clinical use of cell cycle arrest biomarkers. Nephrol Dial Transplant 2014,

    4.      Kashani K, Al-Khafaji A, Ardiles T, Artigas A, Bagshaw SM, Bell M, Bihorac A, Birkhahn R, Cely CM, Chawla LS, Davison DL, Feldkamp T, Forni LG, Gong MNG, Gunnerson KJ, Haase M, Hackett J, Honore PM, Hoste EAJ, Joannes-Boyau O, Joannidis M, Kim P, Koyner JL, Laskowitz DT, Lissauer ME, Marx G, McCullough PA, Mullaney S, Ostermann M, Rimmele T et al.: Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care 2013, 17: R25.

    5.      Koyner JL, Shaw AD, Chawla LS, Hoste EA, Bihorac A, Kashani K, Haase M, Shi J, Kellum JA: Tissue Inhibitor Metalloproteinase-2 (TIMP-2)IGF-Binding Protein-7 (IGFBP7) Levels Are Associated with Adverse Long-Term Outcomes in Patients with AKI. J Am Soc Nephrol 2014,

    6.      Meersch M, Schmidt C, Van Aken H, Martens S, Rossaint J, Singbartl K, Gorlich D, Kellum JA, Zarbock A: Urinary TIMP-2 and IGFBP7 as Early Biomarkers of Acute Kidney Injury and Renal Recovery following Cardiac Surgery. PLoS One 2014, 9: e93460.

     

    Competing interests

    EH and KBK were investigators in Astute Biomedical sponsored studies on TIMP-2 and IGFBP7. EH also received speaker fees from Astute Medical. In 2012-2014 he received an Industrial Research Fund (IOF) of the Ghent University for a clinical validation study on a biomarker for AKI. KBK received a research grant from Astute Biomedical.

     

  2. Quantification of urinary TIMP-2 and IGFBP-7 in cardiac surgery – Applying standards for reporting prognostic accuracy

    Azra Bihorac, University of Florida

    23 January 2015

    We read with interest the results of the study by Wetz at el. examining the predictive performance of a novel urinary biomarker test (tissue-inhibitor of metalloproteinase 2 multiplied with urine insulin like growth factor binding protein 7, NephroCheckR) for the diagnosis of acute kidney injury (AKI) after cardiac surgery [1]. This test is the first FDA approved biomarker for risk stratification for AKI in critically ill patients, validated in two large multicenter trials [2-4]. In this study the definition and timing of outcomes, sample size and the reporting of statistical uncertainty all fall below standards in reporting and extrapolating the results of prognostic tests for clinical use [5, 6]. Measuring the occurrence of any stage of AKI up to sixty hours after surgery, as opposed to the occurrence of moderate to severe AKI twelve hours after the test in previous studies, inevitably leads to the inclusion of patients with less severe tubular damage and lesser urinary excretion of biomarkers as well as patients with secondary postoperative tubular injury in whom urinary biomarkers will appear later in the postoperative course. Achieving appropriate statistical power for this more heterogeneous outcome is problematic, as one would expect that the study would need to include more than forty patients with positive outcome that were necessary to achieve statistical power of 95% in the initial validation study [2]. With only sixteen of forty-three enrolled patients reaching an end-point of AKI this study has power well below 60%, rendering any conclusion regarding test performance statistically meaningless. The consistent omission of confidence intervals in reported results prevents readers from assessing the level of uncertainty in estimates and the variability among the groups. So while we applaud an attempt to externally validate this novel prognostic tool for AKI in different patient populations, future studies should match if not exceed the rigor of the initial discovery and validation studies [2].

      REFERENCES

     1.         Wetz AJ, Richardt EM, Wand S, Kunze N, Schotola H, Quintel M, Brauer A, Moerer O: Quantification of urinary TIMP-2 and IGFBP-7 - an adequate diagnostic test to predict acute kidney injury after cardiac surgery? Crit Care 2015, 19(1):3.

     

    2.         Bihorac A, Chawla LS, Shaw AD, Al-Khafaji A, Davison DL, Demuth GE, Fitzgerald R, Ng Gong M, Graham DD, Gunnerson K et al: Validation of Cell-Cycle Arrest Biomarkers for Acute Kidney Injury Using Clinical Adjudication. Am J Respir Crit Care Med 2014.

     

    3.         Hoste EA, McCullough PA, Kashani K, Chawla LS, Joannidis M, Shaw AD, Feldkamp T, Uettwiller-Geiger DL, McCarthy P, Shi J et al: Derivation and validation of cutoffs for clinical use of cell cycle arrest biomarkers. Nephrol Dial Transplant 2014, 29(11):2054-2061.

     

    4.         Kashani K, Al-Khafaji A, Ardiles T, Artigas A, Bagshaw SM, Bell M, Bihorac A, Birkhahn R, Cely CM, Chawla LS et al: Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care 2013, 17(1):R25.

     

    5.         Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig LM, Moher D, Rennie D, de Vet HCW, Lijmer JG: The STARD Statement for Reporting Studies of Diagnostic Accuracy: Explanation and Elaboration. Ann Intern Med 2003, 138(1):W1-12.

     

    6.         Collins GS, Reitsma JB, Altman DG, Moons KG: Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD): The TRIPOD Statement. Ann Intern Med 2015, 162(1):55-63.

    Competing interests

    AB is supported by Center for Sepsis and Critical Illness Award P50 GM-111152 from the National Institute of General Medical Sciences and has received research grants from Astute Medical, Inc. 

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