Perioperative point-of-care-testing of plasmacholinesterases identifies older patients at risk for postoperative delirium: an observational prospective cohort study.

BACKGROUND: Postoperative delirium (POD) is a severe perioperative complication that may increase mortality and length-of-stay in older patients. Moreover, POD is a major economic burden to any healthcare system. An altered expression of Acetylcholine- and Butyrylcholinesterases (AChE, BuChE) due to an unbalanced neuroinflammatory response to trauma or an operative stimulus has been reported to play an essential role in the development of POD. We investigated if perioperative measurement of cholinesterases (ChEs) can help identifying patients at risk for the occurrence of POD in both, scheduled and emergency surgery patients. METHODS: This monocentric prospective observational cohort study was performed in a tertiary hospital (departments of orthopaedic surgery and traumatology). One hundred and fifty-one patients aged above 75 years were enrolled for scheduled (n = 76) or trauma-related surgery (n = 75). Exclusion criteria were diagnosed dementia and anticholinergic medication. Plasma samples taken pre- and postoperatively were analysed regarding AChE and BuChE activity. Furthermore, perioperative assessment using different cognitive tests was performed. The type of anaesthesia (general vs. spinal anaesthesia) was analysed. Primary outcome was the incidence of POD assessed by the approved Confusion Assessment Method (CAM) in combination with the expression of AChE and BuChE. RESULTS: Of 151 patients included, 38 (25.2%) suffered from POD; 11 (14%) in scheduled and 27 (36%) in emergency patients. AChE levels showed no difference throughout groups or time course. Trauma patients had lower BuChE levels prior to surgery than scheduled patients (p < 0.001). Decline in BuChE levels correlated positively with the incidence of POD (1669 vs. 1175 U/l; p < 0.001). Emergency patients with BuChE levels below 1556 U/L were at highest risk for POD. There were no differences regarding length of stay between groups or incidence of POD. The type of anaesthesia had no influence regarding the incidence of POD. Only Charlson Comorbidity Index and Mini Nutrition Assessment demonstrated reliable strength in respect of POD. CONCLUSIONS: Perioperative measurement of BuChE activity can be used as a tool to identify patients at risk of POD. As a point-of-care test, quick results may alter the patients' course prior to the development of POD. TRIAL REGISTRATION: https://drks.de/search/de/trial/DRKS00017178 .

A Pilot Study of Renin-Guided Angiotensin-II Infusion to Reduce Kidney Stress After Cardiac Surgery.

BACKGROUND: Vasoplegia is common after cardiac surgery, is associated with hyperreninemia, and can lead to acute kidney stress. We aimed to conduct a pilot study to test the hypothesis that, in vasoplegic cardiac surgery patients, angiotensin-II (AT-II) may not increase kidney stress (measured by [TIMP-2]*[IGFBP7]). METHODS: We randomly assigned patients with vasoplegia (cardiac index [CI] > 2.1l/min, postoperative hypotension requiring vasopressors) and Δ-renin (4-hour postoperative-preoperative value) ≥3.7 µU/mL, to AT-II or placebo targeting a mean arterial pressure ≥65 mm Hg for 12 hours. The primary end point was the incidence of kidney stress defined as the difference between baseline and 12 hours [TIMP-2]*[IGFBP7] levels. Secondary end points included serious adverse events (SAEs). RESULTS: We randomized 64 patients. With 1 being excluded, 31 patients received AT-II, and 32 received placebo. No significant difference was observed between AT-II and placebo groups for kidney stress (Δ-[TIMP-2]*[IGFBP7] 0.06 [ng/mL]2/1000 [Q1-Q3, -0.24 to 0.28] vs -0.08 [ng/mL]2/1000 [Q1-Q3, -0.35 to 0.14]; P = .19; Hodges-Lehmann estimation of the location shift of 0.12 [ng/mL]2/1000 [95% confidence interval, CI, -0.1 to 0.36]). AT-II patients received less fluid during treatment than placebo patients (2946 vs 3341 mL, P = .03), and required lower doses of norepinephrine equivalent (0.19 mg vs 4.18mg, P < .001). SAEs were reported in 38.7% of patients in the AT-II group and in 46.9% of patients in the placebo group. CONCLUSIONS: The infusion of AT-II for 12 hours appears feasible and did not lead to an increase in kidney stress in a high-risk cohort of cardiac surgery patients. These findings support the cautious continued investigation of AT-II as a vasopressor in hyperreninemic cardiac surgery patients.

Acute kidney disease beyond day 7 after major surgery: a secondary analysis of the EPIS-AKI trial.

PURPOSE: Acute kidney disease (AKD) is a significant health care burden worldwide. However, little is known about this complication after major surgery. METHODS: We conducted an international prospective, observational, multi-center study among patients undergoing major surgery. The primary study endpoint was the incidence of AKD (defined as new onset of estimated glomerular filtration rate (eCFR) < 60 ml/min/1.73 m2 present on day 7 or later) among survivors. Secondary endpoints included the relationship between early postoperative acute kidney injury (AKI) (within 72 h after major surgery) and subsequent AKD, the identification of risk factors for AKD, and the rate of chronic kidney disease (CKD) progression in patients with pre-existing CKD. RESULTS: We studied 9510 patients without pre-existing CKD. Of these, 940 (9.9%) developed AKD after 7 days of whom 34.1% experiencing an episode of early postoperative-AKI. Rates of AKD after 7 days significantly increased with the severity (19.1% Kidney Disease Improving Global Outcomes [KDIGO] 1, 24.5% KDIGO2, 34.3% KDIGO3; P < 0.001) and duration (15.5% transient vs 38.3% persistent AKI; P < 0.001) of early postoperative-AKI. Independent risk factors for AKD included early postoperative-AKI, exposure to perioperative nephrotoxic agents, and postoperative pneumonia. Early postoperative-AKI carried an independent odds ratio for AKD of 2.64 (95% confidence interval [CI] 2.21-3.15). Of 663 patients with pre-existing CKD, 42 (6.3%) had worsening CKD at day 90. In patients with CKD and an episode of early AKI, CKD progression occurred in 11.6%. CONCLUSION: One in ten major surgery patients developed AKD beyond 7 days after surgery, in most cases without an episode of early postoperative-AKI. However, early postoperative-AKI severity and duration were associated with an increased rate of AKD and early postoperative-AKI was strongly associated with AKD independent of all other potential risk factors.

Personalized acute kidney injury treatment.

PURPOSE OF REVIEW: Acute kidney injury (AKI) is a complex syndrome that might be induced by different causes and is associated with an increased morbidity and mortality. Therefore, it is a very heterogeneous syndrome and establishing a "one size fits all" treatment approach might not work. This review aims to examine the potential of personalized treatment strategies for AKI. RECENT FINDINGS: The traditional diagnosis of AKI is based on changes of serum creatinine and urine output, but these two functional biomarkers have several limitations. Recent research identified different AKI phenotypes based on clinical features, biomarkers, and pathophysiological pathways. Biomarkers, such as Cystatin C, NGAL, TIMP2∗IGFBP7, CCL14, and DKK-3, have shown promise in predicting AKI development, renal recovery, and prognosis. Biomarker-guided interventions, such as the implementation of the KDIGO bundle, have demonstrated an improvement in renal outcomes in specific patient groups. SUMMARY: A personalized approach to AKI treatment as well as research is becoming increasingly important as it allows the identification of distinct AKI phenotypes and the potential for targeted interventions. By utilizing biomarkers and clinical features, physicians might be able to stratify patients into subphenotypes, enabling more individualized treatment strategies. This review highlights the potential of personalized AKI treatment, emphasizing the need for further research and large-scale clinical trials to validate the efficacy of these approaches.

Epidemiology of surgery associated acute kidney injury (EPIS-AKI): a prospective international observational multi-center clinical study.

PURPOSE: The incidence, patient features, risk factors and outcomes of surgery-associated postoperative acute kidney injury (PO-AKI) across different countries and health care systems is unclear. METHODS: We conducted an international prospective, observational, multi-center study in 30 countries in patients undergoing major surgery (> 2-h duration and postoperative intensive care unit (ICU) or high dependency unit admission). The primary endpoint was the occurrence of PO-AKI within 72 h of surgery defined by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Secondary endpoints included PO-AKI severity and duration, use of renal replacement therapy (RRT), mortality, and ICU and hospital length of stay. RESULTS: We studied 10,568 patients and 1945 (18.4%) developed PO-AKI (1236 (63.5%) KDIGO stage 1500 (25.7%) KDIGO stage 2209 (10.7%) KDIGO stage 3). In 33.8% PO-AKI was persistent, and 170/1945 (8.7%) of patients with PO-AKI received RRT in the ICU. Patients with PO-AKI had greater ICU (6.3% vs. 0.7%) and hospital (8.6% vs. 1.4%) mortality, and longer ICU (median 2 (Q1-Q3, 1-3) days vs. 3 (Q1-Q3, 1-6) days) and hospital length of stay (median 14 (Q1-Q3, 9-24) days vs. 10 (Q1-Q3, 7-17) days). Risk factors for PO-AKI included older age, comorbidities (hypertension, diabetes, chronic kidney disease), type, duration and urgency of surgery as well as intraoperative vasopressors, and aminoglycosides administration. CONCLUSION: In a comprehensive multinational study, approximately one in five patients develop PO-AKI after major surgery. Increasing severity of PO-AKI is associated with a progressive increase in adverse outcomes. Our findings indicate that PO-AKI represents a significant burden for health care worldwide.

Evaluation of Proenkephalin A 119-159 for liberation from renal replacement therapy: an external, multicenter pilot study in critically ill patients with acute kidney injury.

INTRODUCTION: Recent evidence suggests an association of plasma Proenkephalin A 119-159 (penKid) with early and successful liberation from continuous renal replacement therapy (CRRT) in critically ill patients with acute kidney injury. However, these exploratory results are derived from a monocentric trial and therefore require external validation in a multicenter cohort. METHODS: Data and plasma samples from the "Effect of Regional Citrate Anticoagulation versus Systemic Heparin Anticoagulation During Continuous Kidney Replacement Therapy on Dialysis Filter Life Span and Mortality Among Critically Ill Patients With Acute Kidney Injury-A Randomized Clinical Trial" (RICH Trial) were used for this validation study. PenKid was measured in all plasma samples available at CRRT initiation and at day 3 of CRRT. Patients were categorized into low and high penKid groups with a cutoff at 100 pmol/l. Competing-risk time-to-event analyses were performed. Competing risk endpoints were successful and unsuccessful liberation from CRRT, the latter meaning death or initiation of a new RRT within one week of discontinuation of primary CRRT. Then penKid was compared to urinary output. RESULTS: Low pre-CRRT penKid levels at CRRT initiation were not associated with early and successful liberation from CRRT compared to patients with high pre-CRRT penKid levels [subdistribution hazard ratio (sHR) 1.01, 95% CI 0.73-1.40, p = 0.945]. However, the landmark analysis on day 3 of ongoing CRRT demonstrated an association between low penKid levels and successful liberation from CRRT (sHR 2.35, 95% CI 1.45-3.81, p < 0.001) and an association between high penKid levels and unsuccessful liberation (sHR 0.46, 95% CI 0.26-0.80, p = 0.007). High daily urinary output (> 436 ml/d) was even stronger associated with successful liberation (sHR 2.91, 95% CI 1.80-4.73, p < 0.001) compared to penKid. DISCUSSION: This study suggests that penKid may be a competent biomarker to monitor the recovery of kidney function during CRRT. This is in line with previous findings and investigated this concept in a multicenter cohort. Again, low penKid was associated with early and successful CRRT liberation, but was outperformed by high daily urinary output. The findings of this study now warrant further evaluation in prospective studies or a randomized controlled trial. Trial registration The RICH Trial was registered at clinicaltrials.gov: NCT02669589. Registered 01 February 2016.

Recombinant Alpha-1-Microglobulin (RMC-035) to Prevent Acute Kidney Injury in Cardiac Surgery Patients: Phase 1b Evaluation of Safety and Pharmacokinetics.

Introduction: Acute kidney injury (AKI) is a common complication in cardiac surgery patients and prevention is needed to improve clinical outcomes. Alpha-1-microglobulin (A1M) is a physiological antioxidant with strong tissue-protective and cell-protective properties that has demonstrated renoprotective effects. RMC-035, a recombinant variant of endogenous human A1M, is being developed for the prevention of AKI in cardiac surgery patients. Methods: In this phase 1b, randomized, double-blind, and parallel group clinical study, 12 cardiac surgery patients undergoing elective, open-chest, on-pump coronary artery bypass graft and/or valve surgery with additional predisposing AKI risk factors were enrolled to receive in total 5 intravenous doses of either RMC-035 or placebo. The primary objective was to evaluate the safety and tolerability of RMC-035. The secondary objective was to evaluate its pharmacokinetic properties. Results: RMC-035 was well tolerated. The nature and frequency of adverse events (AEs) were consistent with the expected background rates in the underlying patient population with no AEs reported as related to study drug. No clinically relevant changes were observed for vital signs or laboratory parameters except for renal biomarkers. Several established AKI urine biomarkers were reduced at 4 hours after first dose administration in the treatment group, indicating a reduced perioperative tubular cell injury following RMC-035 treatment. Conclusion: Multiple intravenous doses of RMC-035 were well tolerated in patients undergoing cardiac surgery. Observed RMC-035 plasma exposures were safe and in the range of expected pharmacological activity. Furthermore, urine biomarkers suggest reduced perioperative kidney cell injury, warranting further investigation of RMC-035 as a potential renoprotective treatment.

Implementation of the Kidney Disease Improving Global Outcomes guidelines for the prevention of acute kidney injury after cardiac surgery: An international cohort survey.

BACKGROUND: Increasing evidence from randomised controlled trials supports the implementation of a six-measure care bundle proposed by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines in patients at high risk for acute kidney injury (AKI) to reduce its incidence after cardiac surgery. OBJECTIVE: To assess compliance with the KDIGO bundle in clinical practice. DESIGN: Prospective observational multinational study. SETTING: Six international tertiary care centres, from February 2021 to November 2021. PATIENTS: Five hundred and thirty-seven consecutive patients undergoing cardiac surgery during a 1-month observational period. INTERVENTIONS: All patients were assessed for the postoperative implementation of the following measures: avoidance of nephrotoxic medication and radiocontrast agents whenever possible, strict glycaemic control, close monitoring of renal function, optimisation of haemodynamic and volume status and functional monitoring of haemodynamic status. MAIN OUTCOME MEASURES: The primary endpoint was the proportion of patients receiving fully compliant care. Secondary outcomes were occurrence of AKI and major adverse kidney event rate at day 30. RESULTS: The full care bundle was applied to 0.4% of patients. There was avoidance of nephrotoxic drugs in 15.6%, radiocontrast agents in 95.3% and hyperglycaemia in 39.6%. Close monitoring of urine output and serum creatinine was achieved in 6.3%, 57.4% underwent optimisation of volume and haemodynamic status, and 43.9% received functional haemodynamic monitoring. 27.2% developed AKI within 72 h after surgery. The average number of implemented measures was 2.6 ±â€Š1.0 and did not differ between AKI or non-AKI patients ( P  = 0.854). CONCLUSION: Adherence with the KDIGO bundle was very low in cardiac surgery patients. Initiatives to improve guideline compliance might provide a strategy to mitigate the burden of AKI. TRIAL REGISTRATION: www.drks.de DRKS00024204.

Biomarker-guided intervention to prevent acute kidney injury after major surgery (BigpAK-2 trial): study protocol for an international, prospective, randomised controlled multicentre trial.

INTRODUCTION: Previous 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 ANALYSIS: The 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 DISSEMINATION: The 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 NUMBER: NCT04647396.

Predicting the Development of Renal Replacement Therapy Indications by Combining the Furosemide Stress Test and Chemokine (C-C Motif) Ligand 14 in a Cohort of Postsurgical Patients.

OBJECTIVES: Optimal timing of renal replacement therapy (RRT) initiation in severe acute kidney injury (AKI) remains controversial. Initiation of treatment early in the course of AKI may lead to some patients undergoing unnecessary RRT, whereas delayed treatment is associated with increased mortality. This study aims to investigate whether the combination of the furosemide stress test (FST) and AKI-associated biomarkers can predict the development of indications for RRT. DESIGN: Single-center, prospective, observational study. SETTING: University Hospital of Muenster, Germany. PATIENTS: Critically ill, postoperative patients with moderate AKI (Kidney Disease: Improving Global Outcomes stage 2) and risk factors for further progression (vasopressors and/or mechanical ventilation) receiving an FST. INTERVENTIONS: Sample collection and measurement of different biomarkers (chemokine [C-C motif] ligand 14 [CCL14], neutrophil gelatinase-associated lipocalin, dipeptidyl peptidase 3). MEASUREMENT AND MAIN RESULTS: The primary endpoint was the development of greater than or equal to one predefined RRT indications (hyperkalemia [≥ 6 mmol/L], diuretic-resistant hypervolemia, high urea serum levels [≥ 150 mg/dL], severe metabolic acidosis [pH ≤ 7.15], oliguria [urinary output < 200 mL/12 hr], or anuria). Two hundred eight patients were available for the primary analysis with 108 having a negative FST (urine output < 200 mL in 2 hr following FST). Ninety-eight patients (47%) met the primary endpoint, 82% in the FST negative cohort. At the time of inclusion, the combination of a negative FST test and high urinary CCL14 levels had a significantly higher predictive value for the primary endpoint with an area under the receiver operating characteristic curve (AUC) of 0.87 (95% CI, 0.82-0.92) compared with FST or CCL14 alone (AUC, 0.79; 95% CI, 0.74-0.85 and AUC, 0.83; 95% CI, 0.77-0.89; p < 0.001, respectively). Other biomarkers showed lower AUCs. CONCLUSIONS: The combination of the FST with the renal biomarker CCL14 predicts the development of indications for RRT.

Effect of Glutamine Administration After Cardiac Surgery on Kidney Damage in Patients at High Risk for Acute Kidney Injury: A Randomized Controlled Trial.

BACKGROUND: Acute kidney injury (AKI) is a common complication after cardiac surgery and is associated with increased morbidity and mortality. However, no specific treatment options are available, emphasizing the need for preventive measures. The aim of this study was to clarify the effect of glutamine on [TIMP2]*[IGFBP7] levels at the end of the intervention period. METHODS: In a randomized clinical, double-blind pilot study, 64 eligible cardiac surgery patients at high risk for AKI identified by high urinary [TIMP2]*[IGFBP7] were randomized, and body weight-adapted intravenous glutamine or saline-control was administered continuously for 12 hours postoperatively. The primary outcome was urinary [TIMP2]*[IGFBP7] at the end of the 12-hour study period. Secondary outcomes included kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) at 12 hours, overall AKI rates at 72 hours, free days through day 28 of mechanical ventilation and vasoactive medication, renal recovery at day 90, requirement of renal replacement therapy and mortality each at days 30, 60, and 90, length of intensive care unit (ICU) and hospital stay, and major adverse kidney events consisting of mortality, dialysis dependency, and persistent renal dysfunction (serum creatinine ≥2× compared to baseline value) at day 90 (major adverse kidney event; MAKE 90 ). RESULTS: Sixty-four patients (mean age, 68.38 [standard deviation {SD} ± 10.48] years; 10 of 64 women) were enrolled and randomized. Patients received coronary artery bypass graft surgery (32/64), valve surgery (18/64), coronary artery bypass graft and valve surgery (6/64), or other procedures (8/64). Mean on-pump time was 68.38 (standard deviation ± 10.48) minutes. After glutamine administration, urinary [TIMP-2]*[IGFBP7] was significantly lower in the glutamine compared to the control group (primary end point, intervention: median, 0.18 [Q1, Q3; 0.09, 0.29], controls: median, 0.44 [Q1, Q3; 0.14, 0.79]; P = .01). In addition, [KIM-1] and [NGAL] were also significantly lower in the glutamine group. The overall AKI rate within 72 hours was not different among groups: (intervention 11/31 [35.5%] versus control 8/32 [25.0%]; P = .419; relative risk [RR], 0.86% [95% confidence interval {CI}, 0.62-1.20]). There were no differences regarding secondary end points. CONCLUSIONS: Glutamine significantly decreased markers of kidney damage in cardiac surgery patients at high risk for AKI. Future trials have to be performed to investigate whether the administration of glutamine might be able to reduce the occurrence of AKI after cardiac surgery.

Comparison of C-C motif chemokine ligand 14 with other biomarkers for adverse kidney events after cardiac surgery.

OBJECTIVE: Outcomes after acute kidney injury are affected by both the severity and the duration of the insult. Patients with persistent acute kidney injury have higher major adverse kidney events, including 90-day mortality, renal replacement therapy, and persistent kidney dysfunction. Methods to identify these patients are urgently needed to improve outcomes. The purpose of this study was to evaluate whether biomarkers, including C-C motif chemokine ligand 14, were able to predict persistent acute kidney injury and major adverse kidney events after cardiac surgery. METHODS: This study was a single-center, prospective, observational study. Patients who developed moderate or severe acute kidney injury (Kidney Disease Improving Global Outcomes 2 or 3) within 72 hours after cardiac surgery were enrolled with a primary end point of persistent severe acute kidney injury (Kidney Disease Improving Global Outcomes 3) lasting 72 hours or more. RESULTS: A total of 100 patients were available for the primary analysis, and 37 met the primary end point. C-C motif chemokine ligand 14 was the most predictive biomarker for the primary end point with an area under the curve of 0.930 (95% confidence interval, 0.881-0.979). The area under the curve of C-C motif chemokine ligand 14 was significantly higher than the area under the curve for the other biomarkers analyzed. C-C motif chemokine ligand 14 was significantly higher in end point positive patients at enrollment (4.47 ng/mL [2.35-11.5] vs 0.67 ng/mL [0.38-1.07]; P = .001). Sensitivity and specificity were 78% and 95% at a cutoff value of 2.21 ng/mL, respectively. C-C motif chemokine ligand 14 was also highly accurate for predicting renal replacement therapy within 7 days (area under the curve, 0.915; 95% confidence interval, 0.858-0.972; P < .001). CONCLUSIONS: Elevated C-C motif chemokine ligand 14 levels predict persistent acute kidney injury in cardiac surgery patients with moderate or severe acute kidney injury. This new biomarker may help stratify patients destined to receive renal replacement therapy and identify patients who may benefit from novel therapeutic approaches to acute kidney injury.

Glutamine prevents acute kidney injury by modulating oxidative stress and apoptosis in tubular epithelial cells.

Acute kidney injury (AKI) represents a common complication in critically ill patients that is associated with increased morbidity and mortality. In a murine AKI model induced by ischemia/reperfusion injury (IRI), we show that glutamine significantly decreases kidney damage and improves kidney function. We demonstrate that glutamine causes transcriptomic and proteomic reprogramming in murine renal tubular epithelial cells (TECs), resulting in decreased epithelial apoptosis, decreased neutrophil recruitment, and improved mitochondrial functionality and respiration provoked by an ameliorated oxidative phosphorylation. We identify the proteins glutamine gamma glutamyltransferase 2 (Tgm2) and apoptosis signal-regulating kinase (Ask1) as the major targets of glutamine in apoptotic signaling. Furthermore, the direct modulation of the Tgm2-HSP70 signalosome and reduced Ask1 activation resulted in decreased JNK activation, leading to diminished mitochondrial intrinsic apoptosis in TECs. Glutamine administration attenuated kidney damage in vivo during AKI and TEC viability in vitro under inflammatory or hypoxic conditions.

Effect of Intraoperative Handovers of Anesthesia Care on Mortality, Readmission, or Postoperative Complications Among Adults: The HandiCAP Randomized Clinical Trial.

Importance: Intraoperative handovers of anesthesia care are common. Handovers might improve care by reducing physician fatigue, but there is also an inherent risk of losing critical information. Large observational analyses report associations between handover of anesthesia care and adverse events, including higher mortality. Objective: To determine the effect of handovers of anesthesia care on postoperative morbidity and mortality. Design, Setting, and Participants: This was a parallel-group, randomized clinical trial conducted in 12 German centers with patients enrolled between June 2019 and June 2021 (final follow-up, July 31, 2021). Eligible participants had an American Society of Anesthesiologists physical status 3 or 4 and were scheduled for major inpatient surgery expected to last at least 2 hours. Interventions: A total of 1817 participants were randomized to receive either a complete handover to receive anesthesia care by another clinician (n = 908) or no handover of anesthesia care (n = 909). None of the participating institutions used a standardized handover protocol. Main Outcomes and Measures: The primary outcome was a 30-day composite of all-cause mortality, hospital readmission, or serious postoperative complications. There were 19 secondary outcomes, including the components of the primary composite, along with intensive care unit and hospital lengths of stay. Results: Among 1817 randomized patients, 1772 (98%; mean age, 66 [SD, 12] years; 997 men [56%]; and 1717 [97%] with an American Society of Anesthesiologists physical status of 3) completed the trial. The median total duration of anesthesia was 267 minutes (IQR, 206-351 minutes), and the median time from start of anesthesia to first handover was 144 minutes in the handover group (IQR, 105-213 minutes). The composite primary outcome occurred in 268 of 891 patients (30%) in the handover group and in 284 of 881 (33%) in the no handover group (absolute risk difference [RD], -2.5%; 95% CI, -6.8% to 1.9%; odds ratio [OR], 0.89; 95% CI, 0.72 to 1.10; P = .27). Nineteen of 889 patients (2.1%) in the handover group and 30 of 873 (3.4%) in the no handover group experienced all-cause 30-day mortality (absolute RD, -1.3%; 95% CI, -2.8% to 0.2%; OR, 0.61; 95% CI, 0.34 to 1.10; P = .11); 115 of 888 (13%) vs 136 of 872 (16%) were readmitted to the hospital (absolute RD, -2.7%; 95% CI, -5.9% to 0.6%; OR, 0.80; 95% CI, 0.61 to 1.05; P = .12); and 195 of 890 (22%) vs 189 of 874 (22%) experienced serious postoperative complications (absolute RD, 0.3%; 95% CI, -3.6% to 4.1%; odds ratio, 1.02; 95% CI, 0.81 to 1.28; P = .91). None of the 19 prespecified secondary end points differed significantly. Conclusions and Relevance: Among adults undergoing extended surgical procedures, there was no significant difference between the patients randomized to receive handover of anesthesia care from one clinician to another, compared with the no handover group, in the composite primary outcome of mortality, readmission, or serious postoperative complications within 30 days. Trial Registration: ClinicalTrials.gov Identifier: NCT04016454.

Remote ischemic preconditioning causes transient cell cycle arrest and renal protection by a NF-κB-dependent Sema5B pathway.

Acute kidney injury increases morbidity and mortality, and previous studies have shown that remote ischemic preconditioning (RIPC) reduces the risk of acute kidney injury after cardiac surgery. RIPC increases urinary high mobility group box protein-1 (HMGB1) levels in patients, and this correlates with kidney protection. Here, we show that RIPC reduces renal ischemia-reperfusion injury and improves kidney function in mice. Mechanistically, RIPC increases HMGB1 levels in the plasma and urine, and HMGB1 binds to TLR4 on renal tubular epithelial cells, inducing transcriptomic modulation of renal tubular epithelial cells and providing renal protection, whereas TLR4 activation on nonrenal cells was shown to contribute to renal injury. This protection is mediated by activation of induction of AMPKα and NF-κB; this induction contributes to the upregulation of Sema5b, which triggers a transient, protective G1 cell cycle arrest. In cardiac surgery patients at high risk for postoperative acute kidney injury, increased HMGB1 and Sema5b levels after RIPC were associated with renal protection after surgery. The results may help to develop future clinical treatment options for acute kidney injury.

The Association Between Angiotensin II and Renin Kinetics in Patients After Cardiac Surgery.

BACKGROUND: Hyperreninemia after cardiac surgery is associated with cardiovascular instability. Angiotensin II (AT-II) could potentially attenuate hyperreninemia while maintaining target blood pressure. This study assesses the association between AT-II usage and renin levels in cardiac surgery patients with postoperative hyperreninemia and vasoplegia. METHODS: Between September 2020 and March 2021, we retrospectively identified 40 cardiac surgery patients with high Δ-renin levels (4 hours after cardiopulmonary bypass [CPB] minus preoperative levels) (defined as higher than 3.7 µU/mL) and vasopressor use who received a vasopressor therapy with either AT-II or continued norepinephrine alone. The primary outcome was the renin plasma level at 12 hours after surgery, adjusted by the renin plasma level at 4 hours after surgery. RESULTS: Overall, the median renin plasma concentration increased from a baseline with median of 44.3 µU/mL (Q1-Q3, 14.6-155.5) to 188.6 µU/mL (Q1-Q3, 29.8-379.0) 4 hours after CPB. High Δ-renin (difference between postoperation and preoperation) patients (higher than 3.7 µU/mL) were then treated with norepinephrine alone (median dose of 3.25 mg [Q1-Q3, 1.00-4.75]) or with additional AT-II (norepinephrine dose: 1.33 mg [Q1-Q3, 0.78-2.04]; AT-II dose: 0.34 mg [Q1-Q3, 0.29-0.78]). At 12 hours after surgery, AT-II patients had lower renin levels than standard of care patients (71.7 µU/mL [Q1-Q3, 21.9-211.4] vs 130.6 µU/mL [Q1-Q3, 62.9-317.0]; P = .034 adjusting for the renin plasma level at 4 hours after surgery). CONCLUSIONS: In cardiac surgery patients with hypotonia and postoperative high Δ-renin levels, AT-II was associated with reduced renin plasma levels for at 12 hours and significantly decreased norepinephrine use, while norepinephrine alone was associated with increased renin levels. Further studies of AT-II in cardiac surgery appear justified.

Prediction of cardiac surgery associated - acute kidney injury (CSA-AKI) by healthcare professionals and urine cell cycle arrest AKI biomarkers [TIMP-2]*[IGFBP7]: A single center prospective study (the PREDICTAKI trial).

PURPOSE: Cardiac surgery associated acute kidney injury (CSA-AKI) is a contributor to adverse outcomes. Preventive measures reduce AKI incidence in high risk patients, identified by biomarkers [TIMP-2]*[IGFBP7] (Nephrocheck®). This study investigate clinical AKI risk assessment by healthcare professionals and the added value of the biomarker result. MATERIALS AND METHODS: Adult patients were prospectively included. Healthcare professionals predicted CSA-AKI, with and without biomarker result knowledge. Predicted outcomes were AKI based on creatinine, AKI stage 3 on urine output, anuria and use of kidney replacement therapy (KRT). RESULTS: One-hundred patients were included. Consultant and ICU residents were best in AKI prediction, respectively AUROC 0.769 (95% CI, 0.672-0.850) and 0.702 (95% CI, 0.599-0.791). AUROC of NephroCheck® was 0.541 (95% CI, 0.438-0.642). AKI 3 occurred in only 4 patients; there was no anuria or use of KRT. ICU nurses and ICU residents had an AUROC for prediction of AKI 3 of respectively 0.867 (95% CI, 0.780-0.929) and 0.809 (95% CI, 0.716-0.883); for NephroCheck® this was 0.838 (95% CI, 0.750-0.904). CONCLUSIONS: Healthcare professionals performed poor or fair in predicting CSA-AKI and knowledge of Nephrocheck® result did not improved prediction. No conclusions could be made for prediction of severe AKI, due to limited number of events.

Acute Kidney Injury in Cardiac Surgery.

Acute kidney injury (AKI) occurs frequently after cardiac surgery and is associated with high morbidity and mortality. Although the number of cardiac surgical procedures is constantly growing worldwide, incidence of cardiac surgery-associated AKI is still around 40% and has a significant impact on global health care costs. Numerous trials attempted to identify strategies to prevent AKI and attenuate its detrimental consequences. Effective options remained elusive. Current evidence supports a multimodal risk-stratification approach with biomarker-guided management of high-risk patients, perioperative administration of dexmedetomidine, and implementation of a care bundle as recommended by the Kidney Disease: Improving Global Outcomes group.

Prevention of Cardiac Surgery-Associated Acute Kidney Injury by Implementing the KDIGO Guidelines in High-Risk Patients Identified by Biomarkers: The PrevAKI-Multicenter Randomized Controlled Trial.

BACKGROUND: Prospective, single-center trials have shown that the implementation of the Kidney Disease: Improving Global Outcomes (KDIGO) recommendations in high-risk patients significantly reduced the development of acute kidney injury (AKI) after surgery. We sought to evaluate the feasibility of implementing a bundle of supportive measures based on the KDIGO guideline in high-risk patients undergoing cardiac surgery in a multicenter setting in preparation for a large definitive trial. METHODS: In this multicenter, multinational, randomized controlled trial, we examined the adherence to the KDIGO bundle consisting of optimization of volume status and hemodynamics, functional hemodynamic monitoring, avoidance of nephrotoxic drugs, and prevention of hyperglycemia in high-risk patients identified by the urinary biomarkers tissue inhibitor of metalloproteinases-2 [TIMP-2] and insulin growth factor-binding protein 7 [IGFBP7] after cardiac surgery. The primary end point was the adherence to the bundle protocol and was evaluated by the percentage of compliant patients with a 95% confidence interval (CI) according to Clopper-Pearson. Secondary end points included the development and severity of AKI. RESULTS: In total, 278 patients were included in the final analysis. In the intervention group, 65.4% of patients received the complete bundle as compared to 4.2% in the control group (absolute risk reduction [ARR] 61.2 [95% CI, 52.6-69.9]; P < .001). AKI rates were statistically not different in both groups (46.3% intervention versus 41.5% control group; ARR -4.8% [95% CI, -16.4 to 6.9]; P = .423). However, the occurrence of moderate and severe AKI was significantly lower in the intervention group as compared to the control group (14.0% vs 23.9%; ARR 10.0% [95% CI, 0.9-19.1]; P = .034). There were no significant effects on other specified secondary outcomes. CONCLUSIONS: Implementation of a KDIGO-derived treatment bundle is feasible in a multinational setting. Furthermore, moderate to severe AKI was significantly reduced in the intervention group.

EPIdemiology of Surgery-Associated Acute Kidney Injury (EPIS-AKI): study protocol for a multicentre, observational trial.

INTRODUCTION: More than 300 million surgical procedures are performed each year. Acute kidney injury (AKI) is a common complication after major surgery and is associated with adverse short-term and long-term outcomes. However, there is a large variation in the incidence of reported AKI rates. The establishment of an accurate epidemiology of surgery-associated AKI is important for healthcare policy, quality initiatives, clinical trials, as well as for improving guidelines. The objective of the Epidemiology of Surgery-associated Acute Kidney Injury (EPIS-AKI) trial is to prospectively evaluate the epidemiology of AKI after major surgery using the latest Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI. METHODS AND ANALYSIS: EPIS-AKI is an international prospective, observational, multicentre cohort study including 10 000 patients undergoing major surgery who are subsequently admitted to the ICU or a similar high dependency unit. The primary endpoint is the incidence of AKI within 72 hours after surgery according to the KDIGO criteria. Secondary endpoints include use of renal replacement therapy (RRT), mortality during ICU and hospital stay, length of ICU and hospital stay and major adverse kidney events (combined endpoint consisting of persistent renal dysfunction, RRT and mortality) at day 90. Further, we will evaluate preoperative and intraoperative risk factors affecting the incidence of postoperative AKI. In an add-on analysis, we will assess urinary biomarkers for early detection of AKI. ETHICS AND DISSEMINATION: EPIS-AKI has been approved by the leading Ethics Committee of the Medical Council North Rhine-Westphalia, of the Westphalian Wilhelms-University Münster and the corresponding Ethics Committee at each participating site. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and used to design further AKI-related trials. TRIAL REGISTRATION NUMBER: NCT04165369.