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.

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.

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.

Analysis of Leukocyte Recruitment in Continuous Veno-Venous Hemofiltration with Regional Citrate vs. Systemic Heparin Anticoagulation.

Acute kidney injury (AKI) is a frequent complication in critically ill patients. Supportive treatment of AKI patients is based on renal-replacement therapy, including continuous veno-venous hemofiltration (CVVH). To limit clotting events on extracorporeal surfaces, anticoagulants are administered, including systemic heparin and local citrate. The differential and comparative effects of these anticoagulants on leukocyte function in acute kidney injury patients are, so far, insufficiently understood. In this bio-add-on-study, AKI patients were randomized as part of a parallel-group trial to either systemic heparin or regional citrate anticoagulation. Patient samples were collected upon inclusion, prior to CVVH initiation at day 0, day 1, day 3 and day 5, following CVVH initiation, and one day after cessation of CVVH, then immediately analyzed. Flow cytometric assessment of surface-receptor molecules was conducted. Whole-blood-perfused human microfluidic chambers were used for the analysis of neutrophil rolling and adhesion. Acute kidney injury was associated with significant changes in the surface expression of CD182 and CD16 throughout CVVH treatment, independent of the anticoagulation regime. AKI furthermore abrogated selectin-induced slow leukocyte rolling and diminished chemokine-induced leukocyte arrest. Subgroup analyses of citrate vs. heparin treatment showed no significant differences between groups, independent of the duration of CVVH treatment. CD182 and CD16 expression remained low in both groups throughout CVVH therapy. These data confirm that AKI impairs selectin-mediated leukocyte slow rolling and chemokine-induced leukocyte arrest in vitro. Systemic heparin or local citrate anticoagulation have no differential effect on the leukocyte recruitment steps examined in this study.

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.

Impact of opioid-free anaesthesia on postoperative nausea, vomiting and pain after gynaecological laparoscopy - A randomised controlled trial.

STUDY OBJECTIVE: Opioid-free anaesthesia may enhance postoperative recovery by reducing opioid-related side effects such as nausea, hyperalgesia or tolerance. The objective was to investigate the impact of multimodal opioid-free general anaesthesia on postoperative nausea, vomiting, pain and morphine consumption compared to the traditional opioid-based approach. DESIGN: This study was conducted as a prospective parallel-group randomised controlled trial. SETTING: Perioperative Care. PATIENTS: 152 adult women undergoing elective inpatient gynaecological laparoscopy. INTERVENTIONS: Patients were randomly assigned for opioid-free anaesthesia (Group OF) with dexmedetomidine, esketamine and sevoflurane or to have opioid-based anaesthesia (Group C) with sufentanil and sevoflurane. MEASUREMENTS: Primary outcome was the occurrence of nausea within 24 h after surgery. Patients were assessed for the incidence and severity of PONV, postoperative pain and morphine consumption and recovery characteristics. MAIN RESULTS: Patients in both groups had comparable clinical and surgical data. 69.7% of patients in the control group and 68.4% of patients in the opioid-free group met the primary endpoint (OR 1.06, 95% Confidence Interval (CI) (0.53; 2.12) p = 0.86). The incidence of clinically important PONV defined by the PONV impact scale was 8.1% (Group C) vs 10.5% (OF); p = 0.57). Antiemetic requirements, pain scores and morphine consumption were equivalent in both groups. Postoperative sedation was significantly increased in group OF (p < 0.001), and the median length of stay at the post-anaesthesia care unit was 69.0 min (46.5-113.0) vs 50.0 (35.3-77.0) minutes in the control group (p < 0.001). CONCLUSIONS: Opioid-free multimodal general anaesthesia is feasible but did not decrease the incidence of PONV, or reduce pain scores and morphine consumption compared to an opioid-containing anaesthetic regimen.

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.

Kinetic Changes of Plasma Renin Concentrations Predict Acute Kidney Injury in Cardiac Surgery Patients.

Rationale: The renin-angiotensin-aldosterone system is a major pathway in regulating blood pressure, glomerular filtration, and fluid homeostasis. During inflammatory diseases, generation of angiotensin II might be disturbed, leading to increased renin concentrations. Cardiac surgery and the use of cardiopulmonary bypass both induce inflammatory response and cardiovascular instability, which can contribute to acute kidney injury (AKI).Objectives: To investigate whether renin concentrations are associated with hypotension and AKI.Methods: This is a single-center, prospective, observational study among patients undergoing cardiac surgery.Measurements and Main Results: The primary endpoint was the occurrence of AKI within 72 hours after cardiac surgery. A total of 197 patients were available for the primary analysis. The median renin serum concentration was 40.2 µU/ml (quartile 1 [Q1]-Q3, 9.3-144.4) at baseline and 51.3 µU/ml (Q1-Q3, 19.1-167.0) 4 hours after cardiac surgery, whereas the difference between postoperation and preoperation concentrations (Δ-renin) was 3.7 µU/ml (Q1-Q3, -22.7 to 50.9). Patients with an elevated Δ-renin developed an AKI significantly more often (43% vs. 12.2%; P < 0.001). High Δ-renin after cardiac surgery was associated with a significantly lower mean arterial pressure, longer time on vasopressors, and longer length of ICU and hospital stay. The area under the curve (AUC) of Δ-renin for the prediction of AKI (AUC, 0.817; 95% confidence interval, 0.747-0.887) was significantly greater compared with the AUC of the postoperative renin concentrations (AUC, 0.702; 95% CI, 0.610-0.793; P = 0.007).Conclusions: Elevated renin concentrations were associated with cardiovascular instability and increased AKI after cardiac surgery. Elevated renin concentrations could be used to identify high-risk patients for cardiovascular instability and AKI who would benefit from timely intervention that could improve their outcomes.

Effect of Regional Citrate Anticoagulation vs 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.

Importance: Although current guidelines suggest the use of regional citrate anticoagulation (which involves the addition of a citrate solution to the blood before the filter of the extracorporeal dialysis circuit) as first-line treatment for continuous kidney replacement therapy in critically ill patients, the evidence for this recommendation is based on few clinical trials and meta-analyses. Objective: To determine the effect of regional citrate anticoagulation, compared with systemic heparin anticoagulation, on filter life span and mortality. Design, Setting, and Participants: A parallel-group, randomized multicenter clinical trial in 26 centers across Germany was conducted between March 2016 and December 2018 (final date of follow-up, January 21, 2020). The trial was terminated early after 596 critically ill patients with severe acute kidney injury or clinical indications for initiation of kidney replacement therapy had been enrolled. Interventions: Patients were randomized to receive either regional citrate anticoagulation (n = 300), which consisted of a target ionized calcium level of 1.0 to 1.40 mg/dL, or systemic heparin anticoagulation (n = 296), which consisted of a target activated partial thromboplastin time of 45 to 60 seconds, for continuous kidney replacement therapy. Main Outcomes and Measures: Coprimary outcomes were filter life span and 90-day mortality. Secondary end points included bleeding complications and new infections. Results: Among 638 patients randomized, 596 (93.4%) (mean age, 67.5 years; 183 [30.7%] women) completed the trial. In the regional citrate group vs systemic heparin group, median filter life span was 47 hours (interquartile range [IQR], 19-70 hours) vs 26 hours (IQR, 12-51 hours) (difference, 15 hours [95% CI, 11 to 20 hours]; P < .001). Ninety-day all-cause mortality occurred in 150 of 300 patients vs 156 of 296 patients (Kaplan-Meier estimator percentages, 51.2% vs 53.6%; unadjusted difference, -2.4% [95% CI, -10.5% to 5.8%]; unadjusted hazard ratio, 0.91 [95% CI, 0.72 to 1.13]; unadjusted P = .38; adjusted difference, -6.1% [95% CI, -12.6% to 0.4%]; primary adjusted hazard ratio, 0.79 [95% CI, 0.63 to 1.004]; primary adjusted P = .054). Of 38 prespecified secondary end points, 34 showed no significant difference. Compared with the systemic heparin group, the regional citrate group had significantly fewer bleeding complications (15/300 [5.1%] vs 49/296 [16.9%]; difference, -11.8% [95% CI, -16.8% to -6.8%]; P < .001) and significantly more new infections (204/300 [68.0%] vs 164/296 [55.4%]; difference, 12.6% [95% CI, 4.9% to 20.3%]; P = .002). Conclusions and Relevance: Among critically ill patients with acute kidney injury receiving continuous kidney replacement therapy, anticoagulation with regional citrate, compared with systemic heparin anticoagulation, resulted in significantly longer filter life span. The trial was terminated early and was therefore underpowered to reach conclusions about the effect of anticoagulation strategy on mortality. Trial Registration: ClinicalTrials.gov Identifier: NCT02669589.

Prevention of Acute Kidney Injury.

Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common complication after cardiac surgery and associated with a worse outcome. The pathogenesis of CSA-AKI is complex and multifactorial. Therapeutic options for severe CSA-AKI are limited to renal replacement therapy constituting a supportive measure. Therefore, risk identification, prevention, and early diagnosis are of utmost importance to improve patient outcomes. This review aims to provide an overview of the diagnosis, pathophysiologic mechanisms, and risk factors of CSA-AKI and delineates the strategies for AKI prevention available to improve patient outcomes after cardiac surgery.

Effects of Different Doses of Remote Ischemic Preconditioning on Kidney Damage Among Patients Undergoing Cardiac Surgery: A Single-Center Mechanistic Randomized Controlled Trial.

OBJECTIVES: We have previously shown that remote ischemic preconditioning reduces acute kidney injury (acute kidney injury) in high-risk patients undergoing cardiopulmonary bypass and that the protective effect is confined to patients who exhibit an increased urinary tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein 7 in response to remote ischemic preconditioning. The purpose of this study was to determine the optimal intensity of remote ischemic preconditioning to induce required [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor-binding protein 7] changes and further explore mechanisms of remote ischemic preconditioning. DESIGN: Observational and randomized controlled, double-blind clinical trial. SETTING: University Hospital of Muenster, Germany. PATIENTS: High-risk patients undergoing cardiac surgery as defined by the Cleveland Clinic Foundation Score. INTERVENTIONS: In the interventional part, patients were randomized to receive either one of four different remote ischemic preconditioning doses (3 × 5 min, 3 × 7 min, 3 × 10 min remote ischemic preconditioning, or 3 × 5 min remote ischemic preconditioning + 2 × 10 min remote ischemic preconditioning in nonresponders) or sham-remote ischemic preconditioning (control). MEASUREMENTS AND MAIN RESULTS: The primary endpoint of the interventional part was change in urinary [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor-binding protein 7] between pre- and postintervention. To examine secondary objectives including acute kidney injury incidence, we included an observational cohort. A total of 180 patients were included in the trial (n = 80 observational and n = 100 randomized controlled part [20 patients/group]). The mean age was 69.3 years (10.5 yr), 119 were men (66.1%). Absolute changes in [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor-binding protein 7] were significantly higher in all remote ischemic preconditioning groups when compared with controls (p < 0.01). Although we did not observe a dose-response relationship on absolute changes in [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor-binding protein 7] across the four different remote ischemic preconditioning groups, in the 15 patients failing to respond to the lowest dose, nine (60%) responded to a subsequent treatment at a higher intensity. Compared with controls, fewer patients receiving remote ischemic preconditioning developed acute kidney injury within 72 hours after surgery as defined by both Kidney Disease: Improving Global Outcomes criteria (30/80 [37.5%] vs 61/100 [61.0%]; p = 0.003). CONCLUSIONS: All doses of remote ischemic preconditioning significantly increased [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor-binding protein 7] and significantly decreased acute kidney injury compared with controls. High-dose remote ischemic preconditioning could stimulate [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor-binding protein 7] increases in patients refractory to low-dose remote ischemic preconditioning.

Biomarker-guided implementation of the KDIGO guidelines to reduce the occurrence of acute kidney injury in patients after cardiac surgery (PrevAKI-multicentre): protocol for a multicentre, observational study followed by randomised controlled feasibility trial.

INTRODUCTION: Acute kidney injury (AKI) is a frequent complication after cardiac surgery with adverse short-term and long-term outcomes. Although prevention of AKI (PrevAKI) is strongly recommended, the optimal strategy is uncertain. The Kidney Disease: Improving Global Outcomes (KDIGO) guideline recommended a bundle of supportive measures in high-risk patients. In a single-centre trial, we recently demonstrated that the strict implementation of the KDIGO bundle significantly reduced the occurrence of AKI after cardiac surgery. In this feasibility study, we aim to evaluate whether the study protocol can be implemented in a multicentre setting in preparation for a large multicentre trial. METHODS AND ANALYSIS: We plan to conduct a prospective, observational survey followed by a randomised controlled, multicentre, multinational clinical trial including 280 patients undergoing cardiac surgery with cardiopulmonary bypass. The purpose of the observational survey is to explore the adherence to the KDIGO recommendations in routine clinical practice. The second phase is a randomised controlled trial. The objective is to investigate whether the trial protocol is implementable in a large multicentre, multinational setting. The primary endpoint of the interventional part is the compliance rate with the protocol. Secondary endpoints include the occurrence of any AKI and moderate/severe AKI as defined by the KDIGO criteria within 72 hours after surgery, renal recovery at day 90, use of renal replacement therapy (RRT) and mortality at days 30, 60 and 90, the combined endpoint major adverse kidney events consisting of persistent renal dysfunction, RRT and mortality at day 90 and safety outcomes. ETHICS AND DISSEMINATION: The PrevAKI multicentre study has been approved by the leading Research Ethics Committee of the University of Münster and the respective Research Ethics Committee at each participating site. The results will be used to design a large, definitive trial. TRIAL REGISTRATION NUMBER: NCT03244514.

A Multinational Observational Study Exploring Adherence With the Kidney Disease: Improving Global Outcomes Recommendations for Prevention of Acute Kidney Injury After Cardiac Surgery.

BACKGROUND: The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend a bundle of different measures for patients at increased risk of acute kidney injury (AKI). Prospective, single-center, randomized controlled trials (RCTs) have shown that management in accordance with the KDIGO recommendations was associated with a significant reduction in the incidence of postoperative AKI in high-risk patients. However, compliance with the KDIGO bundle in routine clinical practice is unknown. METHODS: This observational prevalence study was performed in conjunction with a prospective RCT investigating the role of the KDIGO bundle in high-risk patients undergoing cardiac surgery. A 2-day observational prevalence study was performed in all participating centers before the RCT to explore routine clinical practice. The participating hospitals provided the following data: demographics and surgical characteristics, AKI rates, and compliance rates with the individual components of the bundle. RESULTS: Ninety-five patients were enrolled in 12 participating hospitals. The incidence of AKI within 72 hours after cardiac surgery was 24.2%. In 5.3% of all patients, clinical management was fully compliant with all 6 components of the bundle. Nephrotoxic drugs were discontinued in 52.6% of patients, volume optimization was performed in 70.5%, 52.6% of the patients underwent functional hemodynamic monitoring, close monitoring of serum creatinine and urine output was undertaken in 24.2% of patients, hyperglycemia was avoided in 41.1% of patients, and no patient received radiocontrast agents. The patients received on average 3.4 (standard deviation [SD] ±1.1) of 6 supportive measures as recommended by the KDIGO guidelines. There was no significant difference in the number of applied measures between AKI and non-AKI patients (3.2 [SD ±1.1] vs 3.5 [SD ±1.1]; P = .347). CONCLUSIONS: In patients after cardiac surgery, compliance with the KDIGO recommendations was low in routine clinical practice.

Vascular Adhesion Protein-1 Is Associated With Acute Kidney Injury in High-Risk Patients After Cardiac Surgery.

BACKGROUND: Acute kidney injury is a common complication after cardiac surgery, with a high impact on morbidity and mortality. Vascular adhesion protein-1 is involved in inflammation, which, in turn, is part of the development of acute kidney injury after cardiac surgery. METHODS: In this ancillary study to the RENal effects of Remote Ischemic Preconditioning in cardiac surgery trial, we investigated whether vascular adhesion protein-1 might be associated with the development of acute kidney injury in high-risk patients after cardiac surgery. In total, 114 patients were included in this data set. Acute kidney injury was defined by the Kidney Disease: Improving Global Outcomes criteria serum creatinine and/or urine output. Vascular adhesion protein-1 concentrations were measured at baseline (before surgery), 4 hours, and 12 hours after cardiopulmonary bypass. RESULTS: Vascular adhesion protein-1 levels at 12 hours were significantly higher in patients with acute kidney injury (no acute kidney injury, 271 ng/mL [Q1, Q3, 179, 364 ng/mL] versus acute kidney injury, 384 ng/mL [Q1, Q3, 311, 478 ng/mL]; P < .001). Moreover, patients developing acute kidney injury had higher differences in vascular adhesion protein-1 levels between 12 hours and baseline (P < .001) and between 12 and 4 hours (P < .001) after cardiopulmonary bypass. At a cut point difference value of 99 ng/mL (95% CI, 63-133) between 12 hours and baseline, patients with differences >99 ng/mL showed a higher occurrence rate of acute kidney injury (acute kidney injury, 78.6% versus no acute kidney injury, 31.5%; P < .001). Receiver-operating characteristic curve analyses demonstrated best performance for vascular adhesion protein-1 levels at 12 hours for acute kidney injury within 72 hours after surgery, especially in the subgroup of patients with chronic kidney disease (area under the receiver-operating characteristic curve, 0.78; P < .001). CONCLUSIONS: Vascular adhesion protein-1 is elevated in patients developing acute kidney injury assuming that vascular adhesion protein-1 plays a crucial role in the development of acute kidney injury in high-risk patients after cardiac surgery.

Association between urinary dickkopf-3, acute kidney injury, and subsequent loss of kidney function in patients undergoing cardiac surgery: an observational cohort study.

BACKGROUND: Cardiac surgery is associated with a high risk of postoperative acute kidney injury (AKI) and subsequent loss of kidney function. We explored the clinical utility of urinary dickkopf-3 (DKK3), a renal tubular stress marker, for preoperative identification of patients at risk for AKI and subsequent kidney function loss. METHODS: This observational cohort study included patients who had cardiac surgery in a derivation cohort and those who had cardiac surgery in a validation cohort (RenalRIP trial). The study comprised consecutive patients who had elective cardiac surgery at the Saarland University Medical Centre (Homburg, Germany; derivation cohort) and those undergoing elective cardiac surgery (selected on the basis of a Cleveland Clinical Foundation score of 6 or higher) who were enrolled in the prospective RenalRIP multicentre trial (validation cohort) and who were randomly assigned to remote ischaemic preconditioning or a sham procedure. The association between the ratio of preoperative urinary concentrations of DKK3 to creatinine (DKK3:creatinine) and postoperative AKI, defined according to the Kidney Disease Improving Global Outcomes criteria, and subsequent kidney function loss, as determined by estimated glomerular filtration rate, was assessed. FINDINGS: In the 733 patient in the derivation cohort, urinary concentrations of DKK3 to creatinine that were higher than 471 pg/mg were associated with significantly increased risk for AKI (odds ratio [OR] 1·65, 95% CI 1·10-2·47, p=0·015), independent of baseline kidney function. Compared with clinical and other laboratory measurements, urinary concentrations of DKK3:creatinine significantly improved AKI prediction (net reclassification improvement 0·32, 95% CI 0·23-0·42, p<0·0001). High urinary DKK3:creatinine concentrations were independently associated with significantly lower kidney function at hospital discharge and after a median follow-up of 820 days (IQR 733-910). In the RenalRIP trial, preoperative urinary DKK3:creatinine concentrations higher than 471 pg/mg were associated with a significantly higher risk for AKI (OR 1·94, 95% CI 1·08-3·47, p=0·026), persistent renal dysfunction (OR 6·67, 1·67-26·61, p=0·0072), and dialysis dependency (OR 13·57, 1·50-122·77, p=0·020) after 90 days compared with DKK3:creatinine concentrations of 471 pg/mg or less. Urinary DKK3:creatinine concentrations higher than 471 pg/mg were associated with significantly higher risk for AKI (OR 2·79, 95% CI 1·45-5·37) and persistent renal dysfunction (OR 3·82, 1·32-11·05) only in patients having a sham procedure, but not remote ischaemic preconditioning (AKI OR 1·35, 0·76-2·39 and persistent renal dysfunction OR 1·05, 0·12-9·45). INTERPRETATION: Preoperative urinary DKK3 is an independent predictor for postoperative AKI and for subsequent loss of kidney function. Urinary DKK3 might aid in the identification of patients in whom preventive treatment strategies are effective. FUNDING: No study funding.

Regional citrate versus systemic heparin anticoagulation for continuous renal replacement therapy in critically ill patients with acute kidney injury (RICH) trial: study protocol for a multicentre, randomised controlled trial.

INTRODUCTION: Acute kidney injury (AKI) is a well-recognised complication of critical illness which is of crucial importance for morbidity, mortality and health resource utilisation. Renal replacement therapy (RRT) inevitably entails an escalation of treatment complexity and increases costs for those patients with severe AKI. However, it is still not clear whether regional citrate anticoagulation or systemic heparin anticoagulation for continuous RRT (CRRT) is most appropriate. We hypothesise that, in contrast to systemic heparin anticoagulation, regional citrate anticoagulation for CRRT prolongs filter life span and improves overall survival in a 90-day follow-up period (coprimary endpoints). METHODS AND ANALYSIS: We will conduct a prospective, randomised, multicentre, clinical trial including up to 1450 critically ill patients with AKI requiring CRRT. We suggest to investigate the effect of regional citrate anticoagulation for CRRT as compared with systemic heparin anticoagulation. The two coprimary outcomes are filter life span and overall survival in a 90-day follow-up period. Secondary outcomes are length of stay in the intensive care unit; length of hospitalisation; duration of CRRT; recovery of renal function at days 28, 60, 90 and 1 year; requirement for RRT after days 28, 60, 90 and 1 year; 28 days, 60 days, 90 days and 1-year all-cause mortality; major adverse kidney events at days 28, 60, 90 and 1 year; bleeding complications; transfusion requirements; infection rate and costs of RRT. Additionally, in an add-on study involving several of the participating centres, blood samples from recruited patients will be collected at different time points to analyse whether the anticoagulation strategy has an impact on immune response as evidenced by leucocyte recruitment and function. ETHICS AND DISSEMINATION: The RICH trial has been approved by the Federal Institute for Drugs and Medical Devices, the leading Ethics Committee of the University of Münster and the corresponding Ethics Committee at each participating site. TRIAL REGISTRATION NUMBER: NCT02669589.

C-Reactive Protein Stimulates Nicotinic Acetylcholine Receptors to Control ATP-Mediated Monocytic Inflammasome Activation.

Blood levels of the acute phase reactant C-reactive protein (CRP) are frequently measured as a clinical marker for inflammation, but the biological functions of CRP are still controversial. CRP is a phosphocholine (PC)-binding pentraxin, mainly produced in the liver in response to elevated levels of interleukin-1ß (IL-1ß) and of the IL-1ß-dependent cytokine IL-6. While both cytokines play important roles in host defense, excessive systemic IL-1ß levels can cause life-threatening diseases such as trauma-associated systemic inflammation. We hypothesized that CRP acts as a negative feedback regulator of monocytic IL-1ß maturation and secretion. Here, we demonstrate that CRP, in association with PC, efficiently reduces ATP-induced inflammasome activation and IL-1ß release from human peripheral blood mononuclear leukocytes and monocytic U937 cells. Effective concentrations are in the range of marginally pathologic CRP levels (IC50 = 4.9 µg/ml). CRP elicits metabotropic functions at nicotinic acetylcholine (ACh) receptors (nAChRs) containing subunits α7, α9, and α10 and suppresses the function of ATP-sensitive P2X7 receptors in monocytic cells. Of note, CRP does not induce ion currents at conventional nAChRs, suggesting that CRP is a potent nicotinic agonist controlling innate immunity without entailing the risk of adverse effects in the nervous system. In a prospective study on multiple trauma patients, IL-1ß plasma concentrations negatively correlated with preceding CRP levels, whereas inflammasome-independent cytokines IL-6, IL-18, and TNF-α positively correlated. In conclusion, PC-laden CRP is an unconventional nicotinic agonist that potently inhibits ATP-induced inflammasome activation and might protect against trauma-associated sterile inflammation.

Alpha-1 Antitrypsin Inhibits ATP-Mediated Release of Interleukin-1ß via CD36 and Nicotinic Acetylcholine Receptors.

While interleukin (IL)-1ß is a potent pro-inflammatory cytokine involved in host defense, high levels can cause life-threatening sterile inflammation including systemic inflammatory response syndrome. Hence, the control of IL-1ß secretion is of outstanding biomedical importance. In response to a first inflammatory stimulus such as lipopolysaccharide, pro-IL-1ß is synthesized as a cytoplasmic inactive pro-form. Extracellular ATP originating from injured cells is a prototypical second signal for inflammasome-dependent maturation and release of IL-1ß. The human anti-protease alpha-1 antitrypsin (AAT) and IL-1ß regulate each other via mechanisms that are only partially understood. Here, we demonstrate that physiological concentrations of AAT efficiently inhibit ATP-induced release of IL-1ß from primary human blood mononuclear cells, monocytic U937 cells, and rat lung tissue, whereas ATP-independent IL-1ß release is not impaired. Both, native and oxidized AAT are active, suggesting that the inhibition of IL-1ß release is independent of the anti-elastase activity of AAT. Signaling of AAT in monocytic cells involves the lipid scavenger receptor CD36, calcium-independent phospholipase A2ß, and the release of a small soluble mediator. This mediator leads to the activation of nicotinic acetylcholine receptors, which efficiently inhibit ATP-induced P2X7 receptor activation and inflammasome assembly. We suggest that AAT controls ATP-induced IL-1ß release from human mononuclear blood cells by a novel triple-membrane-passing signaling pathway. This pathway may have clinical implications for the prevention of sterile pulmonary and systemic inflammation.