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IntroductionPrevious studies demonstrated that the implementation of the Kidney Disease Improving Global Outcomes (KDIGO) guideline-based bundle, consisting of different supportive measures in patients at high risk for acute kidney injury (AKI), might reduce rate and severity of AKI after surgery. However, the effects of the care bundle in broader population of patients undergoing surgery require confirmation.Methods and analysisThe BigpAK-2 trial is an international, randomised, controlled, multicentre trial. The trial aims to enrol 1302 patients undergoing major surgery who are subsequently admitted to the intensive care or high dependency unit and are at high-risk for postoperative AKI as identified by urinary biomarkers (tissue inhibitor of metalloproteinases 2*insulin like growth factor binding protein 7 (TIMP-2)*IGFBP7)). Eligible patients will be randomised to receive either standard of care (control) or a KDIGO-based AKI care bundle (intervention). The primary endpoint is the incidence of moderate or severe AKI (stage 2 or 3) within 72 hours after surgery, according to the KDIGO 2012 criteria. Secondary endpoints include adherence to the KDIGO care bundle, occurrence and severity of any stage of AKI, change in biomarker values during 12 hours after initial measurement of (TIMP-2)*(IGFBP7), number of free days of mechanical ventilation and vasopressors, need for renal replacement therapy (RRT), duration of RRT, renal recovery, 30-day and 60-day mortality, intensive care unit length-of-stay and hospital length-of-stay and major adverse kidney events. An add-on study will investigate blood and urine samples from recruited patients for immunological functions and kidney damage.Ethics and disseminationThe BigpAK-2 trial was approved by the Ethics Committee of the Medical Faculty of the University of Münster and subsequently by the corresponding Ethics Committee of the participating sites. A study amendment was approved subsequently. In the UK, the trial was adopted as an NIHR portfolio study. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and will guide patient care and further research.Trial registration numberNCT04647396.

Background Accurate pre-operative evaluation of cardiovascular risk is vital to identify patients at risk for major adverse cardiovascular and cerebrovascular events (MACCE) after noncardiac surgery. Elevated presepsin (sCD14-ST) is associated with peri-operative MACCE in coronary artery disease (CAD) patients after noncardiac surgery. Objectives Validating the prognostic utility of presepsin for MACCE after noncardiac surgery. Design Prospective patient enrolment and blood sampling, followed by post hoc evaluation of pre-operative presepsin for prediction of MACCE. Setting Single university centre. Patients A total of 222 CAD patients undergoing elective, inpatient noncardiac surgery. Intervention Pre-operative presepsin measurement. Main outcome measures MACCE (cardiovascular death, myocardial infarction, myocardial ischaemia and stroke) at 30 days postsurgery. Results MACCE was diagnosed in 23 (10%) patients. MACCE patients presented with increased pre-operative presepsin (median [IQR]; 212 [163 to 358] vs. 156 [102 to 273] pgml, P = 0.023). Presepsin exceeding the previously derived threshold of 184 pg ml was associated with increased 30-day MACCE rate. After adjustment for confounders, presepsin more than 184 pg ml [OR = 2.8 (95% confidence interval 1.1 to 7.3), P = 0.03] remained an independent predictor of peri-operative MACCE. Predictive accuracy of presepsin was moderate [area under the curve (AUC) = 0.65 (0.54 to 0.75), P = 0.023]. While the basic risk model of revised cardiac risk index, high-sensitive cardiac troponin T and N-terminal fragment of pro-brain natriuretic peptide resulted in an AUC = 0.62 (0.48 to 0.75), P = 0.072, addition of presepsin to the model led to an AUC = 0.67 (0.56 to 0.78), P = 0.009 and (ΔAUC = 0.05, P = 0.438). Additive risk predictive value of presepsin was demonstrated by integrated discrimination improvement analysis (integrated discrimination improvement = 0.023, P = 0.022). Net reclassification improvement revealed that the additional strength of presepsin was attributed to the reclassification of no-MACCE patients into a lower risk group. Conclusion Increased pre-operative presepsin independently predicted 30-day MACCE in CAD patients undergoing major noncardiac surgery. Complementing cardiovascular risk prediction by inflammatory biomarkers, such as presepsin, offers potential to improve peri-operative care. However, as prediction accuracy of presepsin was only moderate, further validation studies are needed. Trial registration Clinicaltrials.gov: NCT03105427.

Immune cells drive atherosclerotic lesion progression and plaque destabilization. Coronary heart disease patients undergoing noncardiac surgery are at risk for perioperative major adverse cardiac and cerebrovascular events (MACCE). It is unclear whether differential leukocyte subpopulations contribute to perioperative MACCE and thereby could aid identification of patients prone to perioperative cardiovascular events. First, we performed a hypothesis-generating post hoc analysis of the LeukoCAPE-1 study (n = 38). We analyzed preoperative counts of 6 leukocyte subpopulations in coronary heart disease patients for association with MACCE (composite of cardiac death, myocardial infarction, myocardial ischemia, myocardial injury after noncardiac surgery, thromboembolic stroke) within 30 d after surgery. Regulatory T cells (Tregs) were the only leukocyte subgroup associated with MACCE. We found reduced Tregs in patients experiencing MACCE versus no-MACCE (0.02 [0.01; 0.03] vs. 0.04 [0.03; 0.05] Tregs nl−1, P = 0.002). Using Youden index, we derived the optimal threshold value for association with MACCE to be 0.027 Tregs nl−1. Subsequently, we recruited 233 coronary heart disease patients for the prospective, observational LeukoCAPE-2 study and independently validated this Treg cutoff for prediction of MACCE within 30 d after noncardiac surgery. After multivariate logistic regression, Tregs < 0.027 cells nl−1 remained an independent predictor for MACCE (OR = 2.54 [1.22; 5.23], P = 0.012). Tregs improved risk discrimination of the revised cardiac risk index based on ΔAUC (area under the curve; ΔAUC = 0.09, P = 0.02), NRI (0.26), and IDI (0.06). Preoperative Treg levels below 0.027 cells nl−1 predicted perioperative MACCE and can be measured to increase accuracy of established preoperative cardiac risk stratification in coronary heart disease patients undergoing noncardiac surgery.

BACKGROUND To evaluate the diagnostic and prognostic value of sensitive troponin I (TnI) in patients with acute dyspnea and/or peripheral edema suspected of having acute heart failure (AHF). METHODS This single centre prospective clinical study evaluates 372 patients presenting with acute dyspnea and/or peripheral edema to the emergency department (ED). Measurements of TnI and NT-proBNP were performed at the initial presentation in the ED. All patients were followed up to 5 years. The diagnostic value of TnI compared to NT-proBNP for AHF diagnosis as well as long-term prognostic values for all cause mortality and AHF related rehospitalization were evaluated. RESULTS TnI plus NT-proBNP improved the diagnosis of AHF (improvement of accuracy (75%, 95% CI 71% - 79%), specificity (68%, 95% CI 62% - 74%), PPV (54%, 95% CI 47% - 62%), and NRI +0.15) compared to NT-proBNP alone (p = 0.0001). TnI levels showed independent prognostic value for all-cause mortality and AHF related rehospitalization after 1 and 5 years (range of AUCs 0.64 - 0.72; p = 0.03 or lower). Highest TnI levels of the 4th quartile revealed an up to 5.5 times higher risk of death within 1 and 5 years (range of HRs: 2.5 - 5.5; p = 0.0001). TnI added significantly to multivariable Cox prediction models even after adjusting for NT-proBNP, particularly in AHF patients (range of HRs: 2.1 - 2.7; p ≤ 0.05). CONCLUSIONS TnI improves AHF diagnosis when combined with NT-proBNP. TnI identifies patients with high 1- and 5-year all-cause mortality and AHF-related rehospitalization risk and adds prognostic value to NT-proBNP.

Aims To evaluate the diagnostic and prognostic value of osteopontin in patients with acute dyspnoea and/or peripheral oedema suspected of having acute congestive heart failure (aCHF). Methods and results A total of 401 patients presenting with acute dyspnoea and/or peripheral oedema to the emergency department were prospectively enrolled and followed up for up to 5 years. Blood samples for biomarker measurements were collected on admission to the emergency department. Osteopontin combined with NT-proBNP vs. NT-proBNP alone for diagnosis of aCHF was tested. Additionally, osteopontin vs. NT-proBNP for prognostic outcomes (i.e. all-cause mortality, aCHF-related rehospitalization, and both in combination) was tested. The diagnostic and prognostic capacity of osteopontin was tested by C-statistics, reclassification indices, and multivariable Cox prediction models. Osteopontin plus NT-proBNP improved the diagnostic capacity for aCHF diagnosis [accuracy 76%, 95% confidence interval (CI) 72–80%; specificity 74%, 95% CI 69–79%, net reclassification improvement (NRI) +0.10] compared with NT-proBNP alone in the emergency department (P = 0.0001). Osteopontin independently predicted all-cause mortality and aCHF-related rehospitalization after 1 and 5 years. Compared with NT-proBNP, osteopontin was of superior prognostic value, specifically in aCHF patients and for the prognostic outcome of aCHF-related rehospitalization. Conclusion Osteopontin improves aCHF diagnosis when combined with NT-proBNP. Osteopontin identifies aCHF patients with high 1- and 5-year mortality and rehospitalization risk, and adds prognostic value to NT-proBNP. Trial registration NCT00143793

Congestive heart failure is characterized by an adverse structural remodeling of the myocardium. Osteopontin is a glycoprotein being expressed in cardiomyocytes and fibroblasts. Osteopontin is involved in extracellular matrix formation and acts as a mediator of myocardial remodeling and fibrosis.