The strong performance of this urinary TIMP2•IGFBP7 test was observed in the surgical cohorts of each individual study as well as when the patients from both cohorts are combined (Figs. 2–3). This is demonstrated by the AUC (95% CI) for the Sapphire (0.80 [95% CI, 0.69–0.92], p < 0.0001) and Topaz (0.88 [95% CI, 0.81–0.96], p < 0.0001) studies and for when cohorts are combined (0.84 [95% CI, 0.76–0.90], p < 0.0001). In comparison, neither urine output nor serum creatinine predicted the development of AKI during the same period as well. Of note, the cohorts were not heterogeneous, as evidenced by the heterogeneity tests for the AUCs between Sapphire and Topaz: Higgin's I2 = 29%; Cochran's Q statistic for measuring heterogeneity is not significant (p = 0.23).
To provide further assessment of the ability of the biomarker to enhance clinical risk prediction, we performed IDI and cfNRI analyses as described in Table 2. The addition of the biomarker to the clinical model resulted in a significant increase in overall ability to predict AKI: IDI = 0.15 (0.09–0.21), p < 0.001; and cfNRI = 0.95 (0.59–1.30), p < 0.001 (Table 2) (see also eFigure 1 in Supplemental Digital Content 1, http://links.lww.com/TA/A693).
To our knowledge, this is the first report using the cell cycle arrest biomarkers TIMP-2 and IGFBP7 to predict the development of moderate-to-severe AKI in a large cohort of heterogeneous, critically ill, postoperative surgical patients. In our study, we used a single measurement of urinary TIMP2•IGFBP7 soon after ICU admission and found an AUC-ROC of 0.84 for development of moderate-to-severe AKI within 12 hours. Using a prespecified cutoff value of 0.3, we found sensitivity and specificity of 89% (77–97%) and 49% (43–54%), respectively; using a prespecified cutoff value of 2.0, we found sensitivity and specificity of 40% (23–57%) and 94% (92–96%). We have demonstrated reassuringly robust performance of a new biomarker test in the prediction of an important clinical outcome and further shown that it is able to significantly enhance clinical risk prediction techniques alone. Importantly, we have also shown that the results of this test remain robust in cardiac and noncardiac surgery and in elective as well as emergent surgery.
The performance of AKI biomarkers can sometimes be diminished in the presence of chronic disease states and also in circumstances where there is activation of the inflammatory cascade.32–39 However, TIMP2•IGFBP7 seems to retain its performance in this surgical cohort and also specifically in the cardiac surgery subgroup (Fig. 2). Current mechanistic thinking in AKI is moving toward the concept of AKI as a secondary injury occurring as danger- and pathogen-associated molecular pattern (DAMP, PAMP) molecules are delivered to the renal tubule via both glomerular filtration and the bloodstream.37 These molecules are detected by pattern recognition receptors on the tubular cell surface where they signal a number of cell responses including alterations in cell cycle progression. When prolonged, cell cycle arrest may lead to senescence and/or apoptosis. However, cell cycle arrest is, itself, a protective mechanism that prevents cells from dividing when they may be injured. The fact that these biomarkers perform so well in surgical patients, and that they are seemingly robust to type and urgency of surgery, suggests that this mechanism of AKI is determined much more by the host response to stress rather than by the type of operation itself.
In addition to TIMP-2 and IGFBP7, a host of other AKI biomarkers has been previously investigated within the context of surgery.45–50 The majority of these studies have been conducted in post–cardiac surgery patients,45,48 the most comprehensive being the National Institutes of Health–sponsored TRIBE AKI trial wherein multiple AKI biomarkers were tested in more than 1,200 post–cardiac surgery patients.47 These studies have demonstrated that plasma NGAL, urinary NGAL, and urinary IL-18 all performed modestly well in the prediction of AKI, with AUC-ROC values between 0.67 and 0.74. When the biomarkers were added to a clinical model, its performance improved to 0.73 to 0.76. These results are consistent with other cohorts of cardiac and noncardiac surgery patients.
Our study has several limitations. First, our limited sample size only permits exploratory analysis within different surgical subgroups, such as those undergoing cardiac or noncardiac surgery. Second, although consistent with other reports, our overall event rate does not permit large multivariate analyses that may uncover the contribution of other important risk factors such as blood transfusion, fluid administration, or different hemodynamic management strategies. These questions are the focus of our ongoing studies. Despite these limitations, we believe that our data provide busy clinicians caring for surgical patients with reassuring evidence that the TIMP2•IGFBP7 test is able to improve their clinical decision making in the context of AKI risk assessment and stratification. In the future, it will be important to demonstrate which clinical interventions and therapeutic maneuvers are associated with good (and bad) outcomes in patients stratified by biomarker test results. If confirmed in prospective trials, these candidate interventions may then be considered therapeutic goals in patients classified as high risk.
We have previously shown that the TIMP2•IGFBP7 test accurately identifies a cohort of critically ill adult patients who are at increased risk for developing AKI within the subsequent 12 to 24 hours. Here we provide evidence that this finding is just as accurate, in fact more so, in surgical patients. This is important both because of unique exposures and the presence of several potentially modifiable risk factors in this patient population. Future interventional trials focused on AKI prevention using urinary TIMP2•IGFBP7 as an early marker of renal cellular stress are warranted.
K.J.G., A.D.S., L.S.C., A.B., A.A.-K., K.K., M.L., and J.A.K. conducted the literature search. J.A.K., K.J.G., A.B., A.D.S., L.S.C., A.A.-K., and K.K. designed the study. K.J.G., A.D.S., L.S.C., A.B., A.A.-K., K.K., M.L., and J.A.K. collected data on behalf of the Sapphire and Topaz investigators. J.S. and M.G.W. performed data analysis. J.A.K., K.J.G., A.D.S., L.S.C., A.B., A.A.-K., K.K., M.L., J.S., and M.G.W. contributed to data interpretation. K.J.G., J.A.K., A.D.S., L.S.C., A.B., A.A.-K., K.K., M.L.,J.S., and M.G.W. wrote and critically revised the manuscript.
This study was sponsored by Astute Medical.
K.K., A.A.-K., A.B., M.L., J.S., and M.W. declare no conflicts of interest. L.C. has consulting agreements with Abbott Medical, Affymax Medical, Alere Medical, AM Pharma, Astute Medical, Covidien Medical, Gambro Medical, Nxstage, Sanofi, and Bonner Kiernana Law Offices. L.C. has applied for research support from Eli Lilly and owns stock in MAKO Corporation for an orthopedic surgical robot. K.G. has received research grants from Spectral Diagnostics. A.S. has received fees for expert testimony from Abbott Laboratories and is a Medical Advisory Board member for FAST diagnostics for Optical GFR measurement and a Scientific Advisory Board member for NxStage Medical for CRRT in the ICU. J.K. has received consulting fees from Astute Medical, Alere, Opsona, Aetholon, AM Pharma, Cytosorbents, VenBio, Gambro, Baxter, Abbott, Roche, Spectral Diagnostics, Sangart, and Siemens. J.K. has also received research grants from Astute Medical, Alere, Cytosorbents, Gambro, Baxter, Kaneka, Grifols, CR Bard, and Spectral Diagnostics and has a license in unrelated technologies through the University of Pittsburgh to Astute Medical, Cytosorbents, and Spectral Diagnostics.
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