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Introduction: Troponin elevation after noncardiac surgery is associated with an elevated risk of 30-day mortality. Little is known about relative merit of using a high-sensitivity Troponin T (hsTnT), the fifth-generation assay, vs the nonhigh sensitivity Troponin T (non-hsTnT), the fourth-generation assay, in the noncardiac surgery setting. We aimed to identify whether hsTnT can identify additional patients at risk that would have gone undetected with non-hsTnT measurement., Methods: The VISION Study included 40,004 noncardiac surgery patients with postoperative troponin measurements. Among them, 1,806 patients had both fourth-generation non-hsTnT and fifth-generation hsTnT concomitant measurements (4,451 paired results). We compared the absolute concentrations, the timing, and the impact of different thresholds on predicting 30-day major cardiovascular complications (composite of death, nonfatal cardiac arrest, coronary revascularization, and congestive heart failure)., Results: Based on the manufacturers' threshold of 14 ng/L, 580 (32.1%) patients had postoperative hsTnT concentrations greater than the threshold, while their non-hsTnT concentrations were below the manufacturer's threshold. These 580 patients had higher risk of major cardiovascular events (OR 2.33; CI 95% 1.04-5.23; P = .049) than patients with hsTnT concentrations below the manufacturer threshold. Among patients with myocardial injury after noncardiac surgery, only 50% would be detected by the fourth-generation non-hsTnT assay at 6 to 12 hours postoperative as compared to 85% with the fifth-generation hsTnT assay (P-value < .001)., Conclusions: Within the first 3 postoperative days, fifth-generation hsTnT identified at least 1 in 3 patients with troponin elevation that would have gone undetected by fourth-generation non-hsTnT using published thresholds in this setting. Furthermore, fifth-generation hsTnT identified patients with an elevation earlier than fourth-generation non-hsTnT, indicating potential to improve postoperative risk stratification., Competing Interests: Disclosures FKB holds a Research Early Career Award from Hamilton Health Sciences, and has received grants from Roche Diagnostics and SIEMENS for investigator initiated research grants, and honorarium for lectures or participation in as advisory board from Roche Diagnostics and Novartis. ED reports research grants for investigator-initiated studies and honoraria for participation in advisory board from Roche Diagnostics and research grant for investigator-initiated study from Abbott Laboratories. PK has received grants/reagents/consultant/advisor/ honoraria from Abbott Laboratories, Abbott Point of Care, Beckman Coulter, Ortho Clinical Diagnostics, Quidel, Randox Laboratories, Roche Diagnostics, Siemens Healthcare Diagnostics, and Thermo Fisher Scientific . McMaster University has filed patents with PK listed as an inventor in the acute cardiovascular biomarker field. OB Received research grants from AstraZeneca, Pfizer, Bayer, Amgen, Servier, Novartis, BMS and Boeheringer-Ingelheim unrelated to the submitted work PJD reports grants from Canadian Institutes of Health Research and from Ontario Strategy for Patient Oriented Research Support Unit/Ministry of Health and Long-Term Care during the conduct of the study; and grants from Abbott Diagnostics, Roche Diagnostics, and Siemens, CloudDX, Philips Healthcare, outside the submitted work. Declares to be consultant for Abbott Canada, Renibus, Roche Canada and Trimedic. Declares be a member of advisory board of Bayer, Quidel and speaker for Velocit. DIS, MT, AP, YL, DH, SS, WC, CC, SNO, SP, AK, AT and ACT declare no conflict of interest, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Drug-induced kidney injury (DIKI) refers to kidney damage resulting from the administration of medications. The aim of this project was to identify reliable urinary microRNA (miRNAs) biomarkers that can be used as potential predictors of DIKI before disease diagnosis. This study quantified a panel of six miRNAs (miRs-210-3p, 423-5p, 143-3p, 130b-3p, 486-5p, 193a-3p) across multiple time points using urinary samples from a previous investigation evaluating effects of a nephrotoxicant in cynomolgus monkeys. Exosome-associated miRNA exhibited distinctive trends when compared to miRNAs quantified in whole urine, which may reflect a different urinary excretion mechanism of miRNAs than those released passively into the urine. Although further research and mechanistic studies are required to elucidate how these miRNAs regulate signaling in disease pathways, we present, for the first time, data that several miRNAs displayed strong correlations with histopathology scores, thus indicating their potential use as biomarkers to predict the development of DIKI in preclinical studies and clinical trials. Also, these findings can potentially be translated into other non-clinical species or human for the detection of DIKI., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The following authors are employed in the pharmaceutical industries (at the time of article submission): P.K.M., B.B., A.E., E.V., T.S., D.D.W., A.S, T.R.V. The opinions presented here are those of the authors. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Preliminary data suggest that preoperative N-terminal pro-B-type natriuretic peptide (NT-proBNP) may improve risk prediction in patients undergoing noncardiac surgery., Objective: To determine whether preoperative NT-proBNP has additional predictive value beyond a clinical risk score for the composite of vascular death and myocardial injury after noncardiac surgery (MINS) within 30 days after surgery., Design: Prospective cohort study., Setting: 16 hospitals in 9 countries., Patients: 10 402 patients aged 45 years or older having inpatient noncardiac surgery., Measurements: All patients had NT-proBNP levels measured before surgery and troponin T levels measured daily for up to 3 days after surgery., Results: In multivariable analyses, compared with preoperative NT-proBNP values less than 100 pg/mL (the reference group), those of 100 to less than 200 pg/mL, 200 to less than 1500 pg/mL, and 1500 pg/mL or greater were associated with adjusted hazard ratios of 2.27 (95% CI, 1.90 to 2.70), 3.63 (CI, 3.13 to 4.21), and 5.82 (CI, 4.81 to 7.05) and corresponding incidences of the primary outcome of 12.3% (226 of 1843), 20.8% (542 of 2608), and 37.5% (223 of 595), respectively. Adding NT-proBNP thresholds to clinical stratification (that is, the Revised Cardiac Risk Index [RCRI]) resulted in a net absolute reclassification improvement of 258 per 1000 patients. Preoperative NT-proBNP values were also statistically significantly associated with 30-day all-cause mortality (less than 100 pg/mL [incidence, 0.3%], 100 to less than 200 pg/mL [incidence, 0.7%], 200 to less than 1500 pg/mL [incidence, 1.4%], and 1500 pg/mL or greater [incidence, 4.0%])., Limitation: External validation of the identified NT-proBNP thresholds in other cohorts would reinforce our findings., Conclusion: Preoperative NT-proBNP is strongly associated with vascular death and MINS within 30 days after noncardiac surgery and improves cardiac risk prediction in addition to the RCRI., Primary Funding Source: Canadian Institutes of Health Research.

Differences were examined between male and female Sprague-Dawley rats in basal levels of a wide range of urinary biomarkers, including 7 recently qualified biomarkers. The data were generated from urine samples collected on 3 occasions from untreated rats included in a study of the effect of gentamicin nephrotoxicity on urinary renal biomarkers, reported in a companion article in this journal (Gautier et al. 2014). The performance of multiple assays (9 singleplex assays and 2 multiplex platforms from Rules Based Medicine [RBM] and Meso Scale Discovery [MSD]) was evaluated, and normal ranges and variability estimates were derived. While variability was generally greater on the RBM platform than other assays, the more striking difference in the results from different assays was in magnitude. Where differences were observed between assays for an individual biomarker, they were seen in both sexes and consistent across samples collected at different time points. Differences of up to 15-fold were observed for some biomarker values between assays indicating that results generated using different assays should not be compared. For 8 biomarkers, there was compelling evidence for a sex difference. Baseline values in males were significantly higher than in females for total protein, β2-microglobulin, clusterin, cystatin-C, glutathione-S-transferase (GST-α), tissue inhibitor of metalloproteinases (TIMP-1), and vascular endothelial growth factor (VEGF); female values were significantly higher than that of males for albumin. The largest sex differences (male greater than female by 2- to 11-fold) were seen with β2-microglobulin, GST-α, and TIMP-1. These data add substantially to the limited body of knowledge in this area and provide a useful framework for evaluation of the potential relevance of sex differences in the diagnostic performance of these biomarkers., (© 2014 by The Author(s).)

Differences were examined between male and female Sprague-Dawley rats in the response of 16 urinary biomarkers (measured using several assay platforms) to renal injury produced by gentamicin administered subcutaneously for 10 days at a dosage of 75 mg/kg. Urinary biomarkers expressed as fold difference from contemporaneous controls and renal histopathology were assessed after 3 and 10 doses. On day 4, minimal proximal tubular changes were observed microscopically in all males but no females; on day 11, more extensive and more severe injury was observed to a similar extent in all animals of both sexes. Modest increases (maximum 5-fold) in all urinary biomarkers (except epidermal growth factor [EGF], which was decreased) on day 4 and marked elevations (maximum 271-fold) on day 11 were seen consistently in both sexes. However, the magnitude of the increases differed between the sexes. On day 4, despite the lack of tubular injury, many biomarkers were more elevated in females than males but this rarely led to statistically significant sex differences; only 2 biomarkers (β2-microglobulin and total protein) showed a greater increase in males than females in line with the histopathology. On day 11, there were many more biomarkers that showed a statistically significant difference between the sexes in fold change with treatment; in line with the results on day 4, the majority of biomarkers were more increased in females than males. It remains unresolved if sex differences in the magnitude of biomarker response at injury threshold would lead to any difference in diagnostic interpretation between the sexes. These data highlight the need for publication of more studies using animals of both sexes to fully explore the influence of sex on the diagnostic performance of the novel biomarkers., (© 2014 by The Author(s).)

Context: Of the 200 million adults worldwide who undergo noncardiac surgery each year, more than 1 million will die within 30 days., Objective: To determine the relationship between the peak fourth-generation troponin T (TnT) measurement in the first 3 days after noncardiac surgery and 30-day mortality., Design, Setting, and Participants: A prospective, international cohort study that enrolled patients from August 6, 2007, to January 11, 2011. Eligible patients were aged 45 years and older and required at least an overnight hospital admission after having noncardiac surgery., Main Outcome Measures: Patients' TnT levels were measured 6 to 12 hours after surgery and on days 1, 2, and 3 after surgery. We undertook Cox regression analysis in which the dependent variable was mortality until 30 days after surgery, and the independent variables included 24 preoperative variables. We repeated this analysis, adding the peak TnT measurement during the first 3 postoperative days as an independent variable and used a minimum P value approach to determine if there were TnT thresholds that independently altered patients' risk of death., Results: A total of 15,133 patients were included in this study. The 30-day mortality rate was 1.9% (95% CI, 1.7%-2.1%). Multivariable analysis demonstrated that peak TnT values of at least 0.02 ng/mL, occurring in 11.6% of patients, were associated with higher 30-day mortality compared with the reference group (peak TnT ≤ 0.01 ng/mL): peak TnT of 0.02 ng/mL (adjusted hazard ratio [aHR], 2.41; 95% CI, 1.33-3.77); 0.03 to 0.29 ng/mL (aHR, 5.00; 95% CI, 3.72-6.76); and 0.30 ng/mL or greater (aHR, 10.48; 95% CI, 6.25-16.62). Patients with a peak TnT value of 0.01 ng/mL or less, 0.02, 0.03-0.29, and 0.30 or greater had 30-day mortality rates of 1.0%, 4.0%, 9.3%, and 16.9%, respectively. Peak TnT measurement added incremental prognostic value to discriminate those likely to die within 30 days for the model with peak TnT measurement vs without (C index = 0.85 vs 0.81; difference, 0.4; 95% CI, 0.2-0.5; P < .001 for difference between C index values). The net reclassification improvement with TnT was 25.0% (P < .001)., Conclusion: Among patients undergoing noncardiac surgery, the peak postoperative TnT measurement during the first 3 days after surgery was significantly associated with 30-day mortality.

Cisplatin is an anticancer agent that induces renal proximal tubule lesions in many species. Studies were conducted in Sprague-Dawley and Han-Wistar rats to evaluate the utility of novel preclinical biomarkers of nephrotoxicity for renal lesions caused by this compound. Groups of 10 males of each strain were given a single intraperitoneal injection of 0.3, 1, or 3 mg/kg cisplatin and were sacrificed on days 2, 3, and 5. The novel biomarkers α-glutathione-S-transferase (α-GST) (for proximal tubular injury), μ-glutathione-S-transferase (μ-GST) (for distal tubular injury), clusterin (for general kidney injury), and renal papillary antigen-1 (RPA-1) (for collecting duct injury) were measured in urine by enzyme immunoassay. Histologically, degeneration and necrosis of the S3 segment of the renal proximal tubule were observed on day 2 (Han-Wistar) and days 3 and 5 (both strains) at 1 and 3 mg/kg. Results showed that in both strains of rats, urinary α-GST and clusterin can be detected in urine soon after injury, are more sensitive than BUN and serum creatinine, and therefore are usable as noninvasive biomarkers of proximal tubule injury. Changes in both μ-GST or RPA-1 were considered to represent secondary minor effects of proximal tubular injury on distal segments of the nephron.

We investigated the kinetics of circulating biomarker elevation, specifically correlated with morphology in acute myocardial injury. Male Hanover Wistar rats underwent biomarker and morphologic cardiac evaluation at 0.5 to seventy-two hours after a single subcutaneous isoproterenol administration (100 or 4000 microg/kg). Dose-dependent elevations of serum cardiac troponins I and T (cTnI, cTnT), and heart fatty acid-binding protein (H-FABP) occurred from 0.5 hour, peaked at two to three hours, and declined to baseline by twelve hours (H-FABP) or forty-eight to seventy-two hours (Serum cTns). They were more sensitive in detecting cardiomyocyte damage than other serum biomarkers. The Access 2 platform, an automated chemiluminescence analyzer (Beckman Coulter), showed the greatest cTnI fold-changes and low range sensitivity. Myocardial injury was detected morphologically from 0.5 hour, correlating well with loss of cTnI immunoreactivity and serum biomarker elevation at early time points. Ultrastructurally, there was no evidence of cardiomyocyte death at 0.5 hour. After three hours, a clear temporal disconnect occurred: lesion scores increased with declining cTnI, cTnT, and H-FABP values. Serum cTns are sensitive and specific markers for detecting acute/active cardiomyocyte injury in this rat model. Heart fatty acid-binding protein is a good early marker but is less sensitive and nonspecific. Release of these biomarkers begins early in myocardial injury, prior to necrosis. Assessment of cTn merits increased consideration for routine screening of acute/ongoing cardiomyocyte injury in rat toxicity studies.