Tissue Inhibitor Metalloproteinase-2·IGF-Binding Protein 7 for the Prediction of Acute Kidney Injury following Cardiac Surgery.

Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common complication associated with increased morbidity and mortality. Tissue inhibitor metalloproteinase-2·insulin-like growth factor-binding protein 7 (TIMP-2·IGFBP7) determines tubular stress markers, which may occur prior to tubular damage. Previous studies on the use of TIMP-2·IGFBP7 for the prediction of CSA-AKI showed divergent results. Therefore, this study aimed to explore the predictive value of TIMP-2·IGFBP7 measurements for the early detection of acute kidney injury (AKI) and short-term adverse outcomes after cardiac surgery. In the prospective cohort study, blood and urine samples were collected 6-12 h after cardiac surgery. Blood samples to monitor serum creatinine levels were additionally extracted from days 1 to 7. AKI was defined based on the KDIGO consensus guidelines. AKI within 7 days following surgery was the primary outcome. The initiation of renal replacement therapy, in intensive care unit mortality, and the combination of both were secondary outcomes. A total of 557 patients were enrolled; 134 (24.06%) of them developed AKI and 33 (5.9%) had moderate or severe AKI. AKI developed more frequently in elderly patients with diabetes or with higher baseline serum creatinine levels. Patients with AKI had higher EuroSCORE II, Cleveland Clinic Score, and simplified renal index (SRI) than those without AKI. Urinary TIMP-2·IGFBP7 was significantly higher in patients with AKI. The area under the curve was 0.66 in predicting all AKI and 0.70 in predicting stages 2 and 3 AKI. The resulting sensitivity and specificity were 44.0% and 83.9%, respectively, for a calculated threshold TIMP-2·IGFBP7 value of 0.265 (ng/mL)2/1,000. The TIMP-2·IGFBP7 values, SRI score, and age were significantly associated with AKI within 7 days postoperatively. A total of 33 patients reached the composite endpoint; the percentage of patients who reached the composite endpoint in the TIMP-2·IGFBP7 of >0.265 (ng/ml)2/1,000 group was significantly higher than that of ≤0.265 (ng/mL)2/1,000 group. Postoperative implementation of TIMP-2·IGFBP7 improved the prediction of CSA-AKI and may aid in identifying patients at risk of short-term adverse outcomes. We identified an ideal calculated cutoff value of 0.265 (ng/mL)2/1,000 for the prediction of CSA-AKI among all AKI patients.

Xie Y ，Guo Q ，Yang B ，Xie P ，Zhang J ，Lu W ，Ronco C ，Jiang G ... -  《-》

Urine Biomarkers of Tubular Renal Cell Damage for the Prediction of Acute Kidney Injury After Cardiac Surgery-A Pilot Study.

To evaluate the perioperative course of urine levels of the renal damage biomarkers tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) and to evaluate the predictive value of elevated TIMP-2 × IGFBP7 concentrations to predict acute kidney injury (AKI) early after cardiac on-pump surgery. Prospective, observational cohort study. University hospital. The study comprised 110 consecutive patients undergoing elective cardiac surgery with cardiopulmonary bypass (CPB) between January and March 2014. None. Urinary TIMP-2 × IGFBP7 levels were quantified using a commercially available kit at the following measurement points: before surgery, 1 hour after starting CPB, 4 hours after weaning from CPB, and 24 hours after weaning from CPB (time points 1-4). Postoperative AKI was defined according to Kidney Disease Improving Global Outcomes criteria. AKI after cardiac surgery was diagnosed in 9 patients (8%). The perioperative course of TIMP-2 × IGFBP7 was significantly different in patients with and without postoperative AKI (p < 0.001). TIMP-2 × IGFBP7 levels were significantly higher in patients with AKI 1 hour after CPB start and 24 hours after weaning from CPB (p < 0.05). TIMP-2 × IGFBP7 levels >0.40 (ng/mL)2/1,000 measured at 1 hour after starting CPB were found to be the optimal cut-off, with a sensitivity of 0.778 and a specificity of 0.641. The negative predictive value was 0.972. Urine levels of TIMP-2 × IGFBP7 are predictive for AKI at an early time point (1 hour after starting CPB). Renal damage biomarkers such as TIMP-2 and IGFBP7 might be recommended as a supplement to traditionally used criteria of AKI prediction.

Mayer T ，Bolliger D ，Scholz M ，Reuthebuch O ，Gregor M ，Meier P ，Grapow M ，Seeberger MD ，Fassl J ... -  《-》

Intraoperative prediction of cardiac surgery-associated acute kidney injury using urinary biomarkers of cell cycle arrest.

Tissue inhibitor of metalloproteinases 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) are postoperative urinary biomarkers of renal stress and acute kidney injury (AKI). We conducted this study to test the hypothesis that intraoperative concentrations of urinary [TIMP-2]·[IGFBP7] are associated with postoperative AKI. We measured urinary [TIMP-2]·[IGFBP7] at 8 perioperative timepoints in 400 patients who participated in a randomized controlled trial of atorvastatin for AKI in cardiac surgery. We compared [TIMP-2]·[IGFBP7] between subjects who did and did not develop KDIGO stage 2 or 3 AKI within 48 hours of surgery, adjusted for AKI risk factors. Fourteen patients (3.5%) met the primary endpoint of stage 2 or 3 AKI within 48 hours of surgery, and an additional 77 patients (19.3%) developed stage 1 AKI. Patients who developed stage 2 or 3 AKI displayed bimodal elevations of [TIMP-2]·[IGFBP7], with a first elevation (median, 0.45 [ng/mL]2/1000) intraoperatively and a second elevation (1.45 [ng/mL]2/1000) 6 hours postoperatively. Patients who did not develop AKI did not have any elevations in [TIMP-2]·[IGFBP7]. Each 10-fold increase in intraoperative [TIMP-2]·[IGFBP7] was independently associated with a 290% increase in the odds of stage 2 or 3 AKI (P = .01), and each 10-fold increase in the 6 hours postoperative [TIMP-2]·[IGFBP7] was independently associated with a 650% increase in the odds of stage 2 or 3 AKI (P < .001). The maximum [TIMP-2]·[IGFBP7] between these 2 timepoints provided an area under the receiver operating characteristic curve of 0.82 (95% confidence interval [CI], 0.73-0.90), 100% sensitivity, and 100% negative predictive value using the >0.3 cutoff to predict stage 2 or 3 AKI. Intraoperative elevations of [TIMP-2]·[IGFBP7] can predict moderate or severe AKI and could provide an opportunity to alter postoperative management to prevent kidney injury.

Cummings JJ ，Shaw AD ，Shi J ，Lopez MG ，O'Neal JB ，Billings FT 4th ... -  《-》

A combined approach for the early recognition of acute kidney injury after adult cardiac surgery.

Cardiac surgery-associated acute kidney injury (CSA-AKI) is a frequent complication. The current criteria to detect CSA-AKI rise only when organic dysfunction has occurred. The Doppler Renal Resistive Index (RRI) and the urinary G1 cell cycle arrest proteins (TIMP-2 and IGFBP7) have been advocated to predict CSA-AKI at an early stage after cardiac surgery. The primary objective was to determine the predictive value of these new markers to detect CSA-AKI after elective heart surgery in patients at risk to develop AKI. In a prospective observational trial, we studied 50 patients scheduled for elective on-pump heart surgery at high risk for CSA-AKI. The primary outcome was the incidence of AKI according to the KDIGO criteria recording the urine output every hour until ICU discharge and measuring the serum creatinine levels on each postoperative day until the post-procedure peak values were reached or until the 7th postoperative day. The RRI and the urinary proteins [TIMP-2]*[IGFBP7] were measured concomitantly: before surgery, 1hour (H1), 4-hour (H4), 12-hour (H12), and 24-hour (H24) after surgery. Thirty-seven patients (74%) developed CSA-AKI. Urinary [TIMP-2]*[IGFBP7] at H12 were significantly higher in patients that developed AKI (0.62, [interquartile] [0.20-1.18] vs. 0.30 [0.07-0.47] P=0.044) with an area under the receiver-operating characteristic curve of 0.69 [0.53-0.84]. The best sensitivity (65%) and specificity (62%) was achieved for a cutoff value of 0.3 (ng.mL-1)2.1000-1. The H12 time-point was the only in which the RRI values measured showed a trend toward statistical significance in patients that developed AKI (0.72 (Standard deviation)±(0.06) vs. 0.68±(0.07) P=0.065). The combination of the two markers ([TIMP-2]*[IGFBP7]+RRI) at H12 showed an increased performance of the accuracy with an area under the receiver-operating characteristic curve of 0.78 [0.62-0.93]. In a population at risk of developing CSA-AKI, neither the RRI nor urinary [TIMP-2]*[IGFBP7] detect CSA-AKI occurring in the first post-operative week within the first 24 postoperative hours.

Zaouter C ，Potvin J ，Bats ML ，Beauvieux MC ，Remy A ，Ouattara A ... -  《-》

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

Meersch M ，Schmidt C ，Van Aken H ，Martens S ，Rossaint J ，Singbartl K ，Görlich D ，Kellum JA ，Zarbock A ... -  《PLoS One》