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During sterile inflammation, tissue damage induces excessive activation and infiltration of neutrophils into tissues, where they critically contribute to organ dysfunction. Tight regulation of neutrophil migration and their effector functions is crucial to prevent overshooting immune responses. Neutrophils utilize more glutamine, the most abundant free α-amino acid in the human blood, than other leukocytes. However, under inflammatory conditions, the body's requirements exceed its ability to produce sufficient amounts of glutamine. This study investigates the impact of glutamine on neutrophil recruitment and their key effector functions. Glutamine treatment effectively reduced neutrophil activation by modulating β2-integrin activity and chemotaxis in vitro. In a murine in vivo model of sterile inflammation induced by renal ischemia-reperfusion injury, glutamine administration significantly attenuated neutrophil recruitment into injured kidneys. Transcriptomic analysis revealed, glutamine induces transcriptomic reprogramming in murine neutrophils, thus improving mitochondrial functionality and glutathione metabolism. Further, glutamine influenced key neutrophil effector functions, leading to decreased production of reactive oxygen species and formation of neutrophil extracellular traps. Mechanistically, we used a transglutaminase 2 inhibitor to identify transglutaminase 2 as a downstream mediator of glutamine effects on neutrophils. In conclusion, our findings suggest that glutamine diminishes activation and recruitment of neutrophils and thus identify glutamine as a potent means to curb overshooting neutrophil responses during sterile inflammation., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Studies have pointed to a decisive role of autoantibodies in the context of sepsis and severe Coronavirus disease 2019 (COVID-19), which itself often fulfills the criteria for sepsis, including dysregulated immune responses and organ dysfunction. To directly compare and further analyze the autoantibody profiles of sepsis patients with and without COVID-19, the luciferase immunoprecipitation systems (LIPS) assay was used to measure the levels of autoantibodies against a variety of clinically relevant cytokines, lung-associated proteins, other autoantigens, and antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition, cytokine titers were measured with the LEGENDplex™ Human Antivirus Response Panel. We observed significantly increased levels of autoantibodies in 59% of the COVID-19-Sepsis group compared to 48% of the Sepsis group. Significant differences were identified between the groups for the levels of autoantibodies against gATPase. The cytokine levels of interferon (IFN)-λ1 and IP-10 were higher in the COVID-19-Sepsis group compared to the Sepsis group. Additional correlations between autoantibodies, cytokines and 30-day survival could be demonstrated, suggesting varied underlying pathological mechanisms. Elevated levels of cytokines and autoantibodies may serve as prognostic indicators for the survival probability of sepsis patients, highlighting the intricate relationship between immune responses and patient outcomes in the context of both sepsis and COVID-19., (© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

Fluid therapy is an integral component of perioperative management. In light of emerging evidence in this area, the Perioperative Quality Initiative (POQI) convened an international multiprofessional expert meeting to generate evidence-based consensus recommendations for fluid management in patients undergoing surgery. This article provides a summary of the recommendations for perioperative fluid management of surgical patients from the preoperative period until hospital discharge and for all types of elective and emergency surgery, apart from burn injuries and head and neck surgery. Where evidence was lacking, recommendations for future research were generated. Specific recommendations are made for fluid management in elective major noncardiac surgery, cardiopulmonary bypass, thoracic surgery, neurosurgery, minor noncardiac surgery under general anaesthesia, and critical illness. There are ongoing gaps in knowledge resulting in variation in practice and some disagreement with our consensus recommendations. Perioperative fluid management should be individualised, taking into account the type of surgery and important patient factors, including intravascular volume status and acute and chronic comorbidities. Recommendations are made for further research in perioperative fluid management to address important gaps., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Neutrophils, the most abundant white blood cells in the human circulation, play crucial roles in various diseases, including kidney disease. Traditionally viewed as short-lived pro-inflammatory phagocytes that release reactive oxygen species, cytokines and neutrophil extracellular traps, recent studies have revealed their complexity and heterogeneity, thereby challenging this perception. Neutrophils are now recognized as transcriptionally active cells capable of proliferation and reverse migration, displaying phenotypic and functional heterogeneity. They respond to a wide range of signals and deploy various cargo to influence the activity of other cells in the circulation and in tissues. They can regulate the behavior of multiple immune cell types, exhibit innate immune memory, and contribute to both acute and chronic inflammatory responses while also promoting inflammation resolution in a context-dependent manner. Here, we explore the origin and heterogeneity of neutrophils, their functional diversity, and the cues that regulate their effector functions. We also examine their emerging role in infectious and non-infectious diseases with a particular emphasis on kidney disease. Understanding the complex behavior of neutrophils during tissue injury and inflammation may provide novel insights, thereby paving the way for potential therapeutic strategies to manage acute and chronic conditions. By deciphering their multifaceted role, targeted interventions can be developed to address the intricacies of neutrophil-mediated immune responses and improve disease outcomes., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Importance: Supplementing potassium in an effort to maintain high-normal serum concentrations is a widespread strategy used to prevent atrial fibrillation after cardiac surgery (AFACS), but is not evidence-based, carries risks, and is costly., Objective: To determine whether a lower serum potassium concentration trigger for supplementation is noninferior to a high-normal trigger., Design, Setting, and Participants: This open-label, noninferiority, randomized clinical trial was conducted at 23 cardiac surgical centers in the United Kingdom and Germany. Between October 20, 2020, and November 16, 2023, patients with no history of atrial dysrhythmias scheduled for isolated coronary artery bypass grafting (CABG) surgery were enrolled. The last study patient was discharged from the hospital on December 11, 2023., Interventions: Patients were randomly assigned to a strategy of tight or relaxed potassium control (only supplementing if serum potassium concentration fell below 4.5 mEq/L or 3.6 mEq/L, respectively). Patients wore an ambulatory heart rhythm monitor, which was analyzed by a core laboratory masked to treatment assignment., Main Outcomes and Measures: The prespecified primary end point was clinically detected and electrocardiographically confirmed new-onset AFACS in the first 120 hours after CABG surgery or until hospital discharge, whichever occurred first. All primary outcome events were validated by an event validation committee, which was masked to treatment assignment. Noninferiority of relaxed potassium control was defined as a risk difference for new-onset AFACS with associated upper bound of a 1-sided 97.5% CI of less than 10%. Secondary outcomes included other heart rhythm-related events, clinical outcomes, and cost related to the intervention., Results: A total of 1690 patients (mean age, 65 years; 256 [15%] females) were randomized. The primary end point occurred in 26.2% of patients (n = 219) in the tight group and 27.8% of patients (n = 231) in the relaxed group, which is a risk difference of 1.7% (95% CI, -2.6% to 5.9%). There was no difference between the groups in the incidence of at least 1 AFACS episode detected by any means or by ambulatory heart rhythm monitor alone, non-AFACS dysrhythmias, in-patient mortality, or length of stay. Per-patient cost for purchasing and administering potassium was significantly lower in the relaxed group (mean difference, $111.89 [95% CI, $103.60-$120.19]; P <.001)., Conclusions and Relevance: For AFACS prophylaxis, supplementation only when serum potassium concentration fell below 3.6 mEq/L was noninferior to the current widespread practice of supplementing potassium to maintain a serum potassium concentration greater than or equal to 4.5 mEq/L. The lower threshold of supplementation was not associated with any increase in dysrhythmias or adverse clinical outcomes., Trial Registration: ClinicalTrials.gov Identifier: NCT04053816.

Background: Cardiac surgery invariably triggers acute kidney stress causing adverse renal outcomes. The AKITA study evaluated the efficacy and safety of RMC-035, a novel analogue of alpha-1-microglobulin, for reducing cardiac surgery-associated kidney injury., Methods: In this randomised double-blind placebo-controlled phase 2a study, we randomly assigned (1:1) adult hospitalised patients undergoing open-chest cardiac surgery at high risk for acute kidney injury (AKI) at 21 sites in North America and Europe to receive either RMC-035 (1.3 or 0.65 mg/kg) or placebo (1:1) for 2 days (5 intravenous infusions), stratified by region and renal function. Eligible patients had at least one pre-defined AKI risk factor. Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m 2 ) were excluded. The co-primary efficacy and safety endpoints were AKI (Kidney Disease: Improving Global Outcomes definition) within 72 h after surgery and nature, frequency, and severity of treatment-emergent adverse events (TEAEs). Secondary endpoints included eGFR and Major Adverse Kidney Events (MAKE) up to Day 90. Randomised patients who had received at least one dose of study drug were analysed for primary and safety analyses. Participants, investigators and sponsor were masked to treatment allocation. This study is registered at ClinicalTrials.gov (NCT05126303) and EudraCT (2021-004040-19)., Findings: Patient enrolment was stopped at interim analysis due to futility. Between March 31, 2022 and July 12, 2023, 177 patients (RMC-035: 89, placebo: 88) were randomised and treated. AKI rate for RMC-035 vs placebo was 50.6% (n = 45) and 39.8% (n = 35) (relative risk [RR]: 1.30, 90% confidence interval [90% CI]: 0.99, 1.71; p = 0.12). A short-lived creatinine increase was observed with the higher RMC-035 dose. Treatment with RMC-035 was associated with improved secondary renal outcomes at Day 90: placebo-adjusted eGFR change from baseline 4.3 mL/min/1.73 m 2 , 90% CI 0.51-8.12, p = 0.06; and MAKE 6.7% (n = 6) vs 15.9% (n = 14); RR: 0.41, 90% CI: 0.19, 0.88, p = 0.05. The most frequently reported TEAEs for RMC-035 were chills (30.3%), nausea (21.3%), anaemia (20.2%); and atrial fibrillation (29.5%), anaemia (20.5%), hypervolemia (14.8%) for placebo. The majority of TEAEs in both treatment groups were mild or moderate in severity. In the RMC-035 group, 26 (29.2%) patients experienced at least one severe or life-threatening TEAE and in the placebo group 16 (18.2%) patients. There were 4 deaths per treatment arm (one treatment-related, in placebo group)., Interpretation: In this proof-of-concept study, RMC-035 did not reduce AKI 72 h after cardiac surgery. Evaluations may have been confounded by a drug-induced transient creatinine increase in a subgroup of patients. RMC-035 was associated with improved secondary renal outcomes. These results merit further investigation and should be interpreted with caution, as the study was not powered for these outcomes., Funding: Guard Therapeutics., Competing Interests: AZ received consulting and lecture fees and grants from German Research Foundation, BioMerieux, Baxter, Fresenius, Paion, Viatris, Bayer, Novartis, AM Pharma, and Alexion, received meeting and travel support from Sphingotec and held leadership and fiduciary roles at the German Interdisciplinary Association for Intensive and Emergency Medicine, the International Anesthesia Research Society and the journal “Der Anästhesist”. JLK received consulting fees from Biomerieux, Baxter, Alexion, SeaStar, Novartis, Guard Therapeutics and research funding from the NIH, Fresenius Medical and Biomerieux. TEL is a shareholder and employee of Guard Therapeutics. MR holds stock options and is a paid consultant to Guard Therapeutics. CDM received consulting fees from Alexion. AB was past-president of the German society for heart, thorax and vascular surgery, served on the DSMB for the INCREASE study and received consulting, lecture and advisory board fees from Guard Therapeutics, Marizyme, Abbott, and Abiomed, Data Monitoring Committee payments from Amopharma and patient fees from Guard Therapeutics. JoB received travel costs payments from Guard Therapeutics for an investigator meeting. DE is president of the ERAS Cardiac Society and was a member of Data Safety Monitoring Boards/Advisory Boards for Arthrex, Edwards Lifescience, Medella, Atricure, Pharmacosmos, Renibus, Alexion, and Genentech. AM, BdV, JaB, KM, ML, MT and NN declare no competing interests., (© 2024 The Author(s).)

Acute kidney injury (AKI) is a multifactorial syndrome with a high risk of short- and long-term complications as well as increased health care costs. The traditional biomarkers of AKI, serum creatinine and urine output, have important limitations. The discovery of new functional and damage/stress biomarkers has enabled a more precise delineation of the aetiology, pathophysiology, site, mechanisms, and severity of injury. This has allowed earlier diagnosis, better prognostication, and the identification of AKI sub-phenotypes. In this review, we summarize the roles and challenges of these new biomarkers in clinical practice and research., (© 2024. The Author(s).)

Purpose: Novel interventions for the prevention or treatment of acute kidney injury (AKI) are currently lacking. To facilitate the evaluation and adoption of new treatments, the use of the most appropriate design and endpoints for clinical trials in AKI is critical and yet there is little consensus regarding these issues. We aimed to develop recommendations on endpoints and trial design for studies of AKI prevention and treatment interventions based on existing data and expert consensus., Methods: At the 31st Acute Disease Quality Initiative (ADQI) meeting, international experts in critical care, nephrology, involving adults and pediatrics, biostatistics and people with lived experience (PWLE) were assembled. We focused on four main areas: (1) patient enrichment strategies, (2) prevention and attenuation studies, (3) treatment studies, and (4) innovative trial designs of studies other than traditional (parallel arm or cluster) randomized controlled trials. Using a modified Delphi process, recommendations and consensus statements were developed based on existing data, with > 90% agreement among panel members required for final adoption., Results: The panel developed 12 consensus statements for clinical trial endpoints, application of enrichment strategies where appropriate, and inclusion of PWLE to inform trial designs. Innovative trial designs were also considered., Conclusion: The current lack of specific therapy for prevention or treatment of AKI demands refinement of future clinical trial design. Here we report the consensus findings of the 31st ADQI group meeting which has attempted to address these issues including the use of predictive and prognostic enrichment strategies to enable appropriate patient selection., (© 2024. The Author(s).)

Purpose of Review: To provide an overview of the current diagnostic criteria for acute kidney injury (AKI) including their limitations and to discuss prevention and treatment approaches in the perioperative setting., Recent Findings: AKI is common in the perioperative period and is associated with worse short- and long-term outcomes. Current definitions of AKI have several limitations and lead to delayed recognition of kidney dysfunction which is why novel diagnostic approaches by using renal biomarkers may be helpful. In general, prevention of the development and progression of AKI is vital as a causal treatment for AKI is currently not available. Optimization of kidney perfusion and avoidance of nephrotoxic drugs reduce the occurrence of AKI in surgical patients. Angiotensin II as a new vasopressor, the use of remote ischemic preconditioning, and amino acids may be approaches with a positive effect on the kidneys., Summary: Evidence suggests that the implementation of supportive measures in patients at high risk for AKI might reduce the occurrence of AKI. Novel biomarkers can help allocating resources by detecting patients at high risk for AKI., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Urinary Chemokine (C-C motif) ligand 14 (CCL14) is a biomarker associated with persistent severe acute kidney injury (AKI). There is limited data to support the implementation of this AKI biomarker to guide therapeutic actions., Methods: Sixteen AKI experts with clinical CCL14 experience participated in a Delphi-based method to reach consensus on when and how to potentially use CCL14. Consensus was defined as ≥ 80% agreement (participants answered with 'Yes', or three to four points on a five-point Likert Scale)., Results: Key consensus areas for CCL14 test implementation were: identifying challenges and mitigations, developing a comprehensive protocol and pairing it with a treatment plan, and defining the target population. The majority agreed that CCL14 results can help to prioritize AKI management decisions. CCL14 levels above the high cutoff (> 13 ng/mL) significantly changed the level of concern for modifying the AKI treatment plan ( p  < 0.001). The highest level of concern to modify the treatment plan was for discussions on renal replacement therapy (RRT) initiation for CCL14 levels > 13 ng/mL. The level of concern for discussion on RRT initiation between High and Low, and between Medium and Low CCL14 levels, showed significant differences., Conclusion: Real world urinary CCL14 use appears to provide improved care options to patients at risk for persistent severe AKI. Experts believe there is a role for CCL14 in AKI management and it may potentially reduce AKI-disease burden. There is, however, an urgent need for evidence on treatment decisions and adjustments based on CCL14 results.

Purpose: Urinary C-C motif chemokine ligand 14 (CCL14) is a strong predictor of persistent stage 3 acute kidney injury (AKI). Multiple clinical actions are recommended for AKI but how these are applied in individual patients and how the CCL14 test results may impact their application is unknown., Methods: We assembled an international panel of 12 experts and conducted a modified Delphi process to evaluate patients at risk for persistent stage 3 AKI (lasting 72 hours or longer). Using a Likert scale, we rated 11 clinical actions based on international guidelines applied to each case before and after CCL14 testing and analyzed the association between the strength and direction of recommendations and CCL14 results., Results: The strength and direction of clinical recommendations were strongly influenced by CCL14 results (P < 0.001 for the interaction). Nine (82%) recommendations for clinical actions were significantly impacted by CCL14 results (P < 0.001 comparing low to highest CCL14 risk category)., Conclusions: Most recommendations for care of patients with stage 2-3 by an international panel of experts were strongly modified by CCL14 test results. This work should set the stage for clinical practice protocols and studies to determine the effects of recommended actions informed by CCL14., Competing Interests: Declaration of competing interest SB, SD, LF, MJ, JAK, JLK, MO, JP, CR, AS, AT, AZ disclose consulting fees paid by bioMérieux. JPK, TK, and PM were full-time employees of Astute Medical/bioMérieux when this work was conducted. JDLS is a full-time employee of bioMérieux., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose of this review Acute kidney injury (AKI) is a complex syndrome whose development is associated with an increased morbidity and mortality. Recent studies show that this syndrome is a common complication in critically ill and surgical patients the trajectory of which may differ. As AKI can be induced by different triggers, it is complex and therefore challenging to manage patients with AKI. This review strives to provide a brief historical perspective on AKI, elucidate recent developments in diagnosing and managing AKI, and show the current usage of novel biomarkers in both clinical routine and research. In addition, we provide a perspective on potential future developments and their impact of AKI understanding and management. Recent findings/developments Recent studies show the merits of stress and damage biomarkers, highlighting limitations of the current KDIGO definition that only uses the functional biomarkers serum creatinine and urine output. The use of novel biomarkers led to the introduction of the concept of "subclinical AKI". This new classification may allow a more distinct management of affected or at risk patients. Ongoing studies, such as BigpAK-2 and PrevProgAKI, investigate the implementation of biomarker-guided interventions in clinical practice and may demonstrate an improvement in patients' outcome. Summary The ongoing scientific efforts surrounding AKI have deepened our understanding of the syndrome prompting an expansion of existing concepts. A future integration of stress and damage biomarkers in AKI management, may lead to an individualized therapy in this area., Competing Interests: Declaration of competing interest A.Z. has received consulting fees from Astute-Biomerieux, Baxter, Bayer, Novartis, Guard Therapeutics, AM Pharma, Paion, Fresenius, research funding from Astute-Biomerieux, Fresenius, Baxter, and speakers fees from Astute-Biomerieux, Fresenius, Baxter; L. F has received research support and lecture fees from Ortho Clinical Diagnostics, Baxter, Exthera and Biomerieux and consulting fees from La Jolla Pharmaceuticals and Paion; The remaining authors declare no competing interests. C.S. and H.B. do not have any disclosures., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Rhabdomyolysis describes a syndrome characterized by muscle necrosis and the subsequent release of creatine kinase and myoglobin into the circulation. Myoglobin elimination with extracorporeal hemoadsorption has been shown to effectively remove myoglobin from the circulation. Our aim was to provide best practice consensus statements developed by the Hemoadsorption in Rhabdomyolysis Task Force (HRTF) regarding the use of hemadsorption for myoglobin elimination., Methods: A systematic literature search was performed until 11th of January 2023, after which the Rhabdomyolysis RTF was assembled comprising international experts from 6 European countries. Online conferences were held between 18th April - 4th September 2023, during which 37 consensus questions were formulated and using the Delphi process, HRTF members voted online on an anonymised platform. In cases of 75 to 90% agreement a second round of voting was performed., Results: Using the Delphi process on the 37 questions, strong consensus (> 90% agreement) was achieved in 12, consensus (75 to 90% agreement) in 10, majority (50 to 74%) agreement in 13 and no consensus (< 50% agreement) in 2 cases. The HRTF formulated the following recommendations: (1) Myoglobin contributes to the development of acute kidney injury; (2) Patients with myoglobin levels of > 10,000 ng/ml should be considered for extracorporeal myoglobin removal by hemoadsorption; (3) Hemoadsorption should ideally be started within 24 h of admission; (4) If myoglobin cannot be measured then hemoadsorption may be indicated based on clinical picture and creatinine kinase levels; (5) Cartridges should be replaced every 8-12 h until myoglobin levels < 10,000 ng/ml; (6) In patients with acute kidney injury, hemoadsorption can be discontinued before dialysis is terminated and should be maintained until the myoglobin concentration values are consistently < 5000 ng/ml., Conclusions: The current consensus of the HRTF support that adjuvant hemoadsorption therapy in severe rhabdomyolysis is both feasible and safe and may be an effective method to reduce elevated circulating levels of myoglobin., (© 2024. The Author(s).)

Craniotomy or decompressive craniectomy are among the therapeutic options to prevent or treat secondary damage after severe brain injury. The choice of procedure depends, among other things, on the type and severity of the initial injury. It remains controversial whether both procedures influence the neurological outcome differently. Thus, estimating the risk of brain herniation and death and consequently potential organ donation remains difficult. All patients at the University Hospital Münster for whom an isolated craniotomy or decompressive craniectomy was performed as a treatment after severe brain injury between 2013 and 2022 were retrospectively included. Proportion of survivors and deceased were evaluated. Deceased were further analyzed regarding anticoagulants, comorbidities, type of brain injury, potential and utilized donation after brain death. 595 patients were identified, 296 patients survived, and 299 deceased. Proportion of decompressive craniectomy was higher than craniotomy in survivors (89% vs. 11%, p < 0.001). Brain death was diagnosed in 12 deceased and 10 donations were utilized. Utilized donations were comparable after both procedures (5% vs. 2%, p = 0.194). Preserved brain stem reflexes as a reason against donation did not differ between decompressive craniectomy or craniotomy (32% vs. 29%, p = 0.470). Patients with severe brain injury were more likely to survive after decompressive craniectomy than craniotomy. Among the deceased, potential and utilized donations did not differ between both procedures. This suggests that brain death can occur independent of the previous neurosurgical procedure and that organ donation should always be considered in end-of-life decisions for patients with a fatal prognosis., (© 2024. The Author(s).)

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., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2024 International Anesthesia Research Society.)

Objective: This article describes the statistical analysis plan for the Biomarker-guided intervention to prevent AKI after major surgery (BigpAK-2) trial., Design: Adaptive trial design with an interim analysis after enrolment of 618 evaluable patients., Setting: The BigpAK.-2 trial is an international, prospective, randomised controlled multicentre study., Participants: The BigpAK-2 study enrols patients after major surgery who are 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 and insulin-like growth factor binding protein 7 ([TIMP-2]∗[IGFBP7]) will be enrolled., Intervention: Patients are randomly and evenly allocated to standard of care (control) group or the implementation of a nephroprotective care bundle (intervention group), as recommended by the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. The KDIGO care bundle recommends discontinuation of nephrotoxic agents if possible, ensuring adequate volume status and perfusion pressure, considering functional haemodynamic monitoring, regular monitoring of serum creatinine and urine output, avoiding hyperglycemia, and considering alternatives to radiocontrast procedures when possible., Results: The BigpAK-2 study investigates whether the biomarker-gudied implementation of the KDIGO care bundle reduces the incidence of moderate or severe AKI (stage 2 or 3), according to the KDIGO 2012 criteria, within 72 h after surgery., Conclusion: AKI is a common and often severe complication after major surgery. As no specific treatments exist, prevention of AKI is of high importance. The BigpAK-2 study investigates a promising approach to prevent AKI after major surgery., Trial Registration: The trial was registered prior to start at clinicaltrials.gov; NCT04647396., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alexander Zarbock reports financial support was provided by bioMérieux Inc. Alexander Zarbock reports a relationship with AM Pharma, Baxter, Bayer, bioMerieux, Fresenius Medical Care, Guard Therapeutics, Novartis, Paion. that includes: funding grants and speaking and lecture fees. Melanie Meersch reports a relationship with Biomériux, Baxter and Fresenius Medical Care that includes: funding grants and speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Purpose: There is evidence that lower activity of the RAF/MEK/ERK network is associated with positive outcomes in mild and moderate courses of COVID-19. The effect of this cascade in COVID-19 sepsis is still undetermined. Therefore, we tested the hypothesis that activity of the RAF/MEK/ERK network in COVID-19-induced sepsis is associated with an impact on 30-day survival., Methods: We used biomaterial from 81 prospectively recruited patients from the multicentric CovidDataNet.NRW-study cohort (German clinical trial registry: DRKS00026184) with their collected medical history, vital signs, laboratory parameters, microbiological findings and patient outcome. ERK activity was measured by evaluating ERK phosphorylation using a Proximity Ligation Assay., Results: An increased ERK activity at 4 days after diagnosis of COVID-19-induced sepsis was associated with a more than threefold increased chance of survival in an adjusted Cox regression model. ERK activity was independent of other confounders such as Charlson Comorbidity Index or SOFA score (HR 0.28, 95% CI 0.10-0.84, p = 0.02)., Conclusion: High activity of the RAF/MEK/ERK network during the course of COVID-19 sepsis is a protective factor and may indicate recovery of the immune system. Further studies are needed to confirm these results., (© 2024. The Author(s).)

Abstract: Pulmonary defense mechanisms are critical for host integrity during pneumonia and sepsis. This defense is fundamentally dependent on the activation of neutrophils during the innate immune response. Recent work has shown that semaphorin 7A (Sema7A) holds significant impact on platelet function, yet its role on neutrophil function within the lung is not well understood. This study aimed to identify the role of Sema7A during pulmonary inflammation and sepsis. In patients with acute respiratory distress syndrome (ARDS), we were able to show a correlation between Sema7A and oxygenation levels. During subsequent workup, we found that Sema7A binds to the neutrophil PlexinC1 receptor, increasing integrins, and L-selectin on neutrophils. Sema7A prompted neutrophil chemotaxis in vitro and the formation of platelet-neutrophil complexes in vivo. We also observed altered adhesion and transmigration of neutrophils in Sema7A-/-animals in the lung during pulmonary inflammation. This effect resulted in increased number of neutrophils in the interstitial space of Sema7A-/- animals but reduced numbers of neutrophils in the alveolar space during pulmonary sepsis. This finding was associated with significantly worse outcome of Sema7A-/- animals in a model of pulmonary sepsis. Sema7A has an immunomodulatory effect in the lung, affecting pulmonary sepsis and ARDS. This effect influences the response of neutrophils to external aggression and might influence patient outcome. This trial was registered at www.ClinicalTrials.gov as #NCT02692118., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The renin-angiotensin system (RAS) constitutes one of the principal mechanisms to maintain hemodynamic and fluid homeostasis. However, most research until now on RAS primarily focuses on its relationship with hypertension and its role in critically ill hypotensive populations is not well understood. With the approval of angiotensin II (Ang II) in the United States and Europe, following a phase 3 randomized controlled trial showing efficacy in catecholamine-resistant vasodilatory shock, there is growing interest in RAS in critically ill patients. Among the fundamental components of RAS, renin acts as the initial stimulus for the entire system. In the context of hypotension, its release increases in response to low blood pressure sensed by renal baroreceptors and attenuated negative Ang II feedback loop. Thus, elevated renin could reflect disease severity and predict poor outcomes. Studies investigating this hypothesis have validated the prognostic accuracy of renin in various critically ill populations, with several reports indicating its superiority to lactate for mortality prediction. Accordingly, renin reduction has been used to assess the effectiveness of Ang II administration. Furthermore, renin holds potential to identify patients who might benefit from Ang II treatment, potentially paving the way for personalized vasopressor management. Despite these promising data, most available evidence is derived from retrospective analysis and necessitates prospective confirmation. The absence of a rapid, point-of-care and reliable renin assay presents another hurdle to its integration into routine clinical practice. This narrative review aims to describe the current understanding and future directions of renin as a biomarker during resuscitation of critically ill patients., (© 2024. The Author(s).)

Background: Sepsis, a life-threatening condition caused by the dysregulated host response to infection, is a major global health concern. Understanding the impact of viral or bacterial pathogens in sepsis is crucial for improving patient outcomes. This study aimed to investigate the human cytomegalovirus (HCMV) seropositivity as a risk factor for development of sepsis in patients with COVID-19., Methods: A multicenter observational study enrolled 95 intensive care patients with COVID-19-induced sepsis and 80 post-surgery individuals as controls. HCMV serostatus was determined using an ELISA test. Comprehensive clinical data, including demographics, comorbidities, and 30-day mortality, were collected. Statistical analyses evaluated the association between HCMV seropositivity and COVID-19 induced sepsis., Results: The prevalence of HCMV seropositivity did not significantly differ between COVID-19-induced sepsis patients (78%) and controls (71%, p = 0.382) in the entire cohort. However, among patients aged ≤60 years, HCMV seropositivity was significantly higher in COVID-19 sepsis patients compared to controls (86% vs 61%, respectively; p = 0.030). Nevertheless, HCMV serostatus did not affect 30-day survival., Discussion: These findings confirm the association between HCMV seropositivity and COVID-19 sepsis in non-geriatric patients. However, the lack of an independent effect on 30-day survival can be explained by the cross-reactivity of HCMV specific CD8 + T-cells towards SARS-CoV-2 peptides, which might confer some protection to HCMV seropositive patients. The inclusion of a post-surgery control group strengthens the generalizability of the findings. Further research is needed to elucidate the underlying mechanisms of this association, explore different patient populations, and identify interventions for optimizing patient management., Conclusion: This study validates the association between HCMV seropositivity and severe COVID-19-induced sepsis in non-geriatric patients, contributing to the growing body of evidence on viral pathogens in sepsis. Although HCMV serostatus did not independently influence 30-day survival, future investigations should focus on unraveling the intricate interplay between HCMV, immune responses, and COVID-19. These insights will aid in risk stratification and the development of targeted interventions for viral sepsis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ziehe, Wolf, Rahmel, Nowak, Haberl, Bergmann, Rump, Dyck, Palmowski, Marko, Witowski, Willemsen, Pfaender, Eisenacher, Anft, Babel, Bracht, Sitek, Bayer, Zarbock, von Groote, Putensen, Ehrentraut, Weisheit, Adamzik, Unterberg and Koos.)

Serum renin increases in response to sympathetic nerve activation and hypotension. Recent studies have reported the association of serum renin levels with adverse clinical outcomes in acute care settings. This scoping review aimed to systematically review the available literature on renin as a prognostic marker in intensive care and perioperative patients. We searched for studies published since inception until March 31, 2023, which assessed the association between serum renin levels and clinical outcomes or the effect of synthetic angiotensin II administration on serum renin levels in critically ill and perioperative patients in PubMed, Embase, and the Cochrane Library. The primary outcome was mortality at the longest follow-up; the secondary outcomes were adverse renal outcomes (ie, acute kidney injury, the need for renal replacement therapy, and major adverse kidney events), hemodynamic instability, outcomes to angiotensin II administration, and prognostic performance for mortality when compared with lactate. Among the 2081 studies identified, we included 16 studies with 1573 patients (7 studies on shock, 5 on nonspecific critical illness, 2 on cardiac surgery, 1 on noncardiac surgery, and 1 on coronavirus disease 2019). A significant association between serum renin levels and poor outcomes was identified in 14 studies, with 10 studies demonstrating an association with mortality. One post hoc analysis found that angiotensin II administration reduced mortality in patients with markedly elevated renin values. Two studies showed that renin was superior to lactate as a prognostic marker of mortality. Our scoping review showed that elevated serum renin levels may be associated with clinically relevant outcomes among various perioperative and intensive care populations. Increased serum renin levels may identify patients in which synthetic angiotensin II administration improves clinical outcomes and may outperform serum lactate in predicting mortality., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2023 International Anesthesia Research Society.)

Background: Resuscitation is a team effort, and it is increasingly acknowledged that team cooperation requires training. Staff shortages in many healthcare systems worldwide, as well as recent pandemic restrictions, limit opportunities for collaborative team training. To address this challenge, a learner-centred approach known as flipped learning has been successfully implemented. This model comprises self-directed, asynchronous pre-course learning, followed by knowledge application and skill training during in-class sessions. The existing evidence supports the effectiveness of this approach for the acquisition of cognitive skills, but it is uncertain whether the flipped classroom model is suitable for the acquisition of team skills. The objective of this study was to determine if a flipped classroom approach, with an online workshop prior to an instructor-led course could improve team performance and key resuscitation variables during classroom training., Methods: A single-centre, cluster-randomised, rater-blinded study was conducted on 114 final year medical students at a University Hospital in Germany. The study randomly assigned students to either the intervention or control group using a computer script. Each team, regardless of group, performed two advanced life support (ALS) scenarios on a simulator. The two groups differed in the order in which they completed the flipped e-learning curriculum. The intervention group started with the e-learning component, and the control group started with an ALS scenario. Simulators were used for recording and analysing resuscitation performance indicators, while professionals assessed team performance as a primary outcome., Results: The analysis was conducted on the data of 96 participants in 21 teams, comprising of 11 intervention groups and 10 control groups. The intervention teams achieved higher team performance ratings during the first scenario compared to the control teams (Estimated marginal mean of global rating: 7.5 vs 5.6, p < 0.01; performance score: 4.4 vs 3.8, p < 0.05; global score: 4.4 vs 3.7, p < 0.001). However, these differences were not observed in the second scenario, where both study groups had used the e-learning tool., Conclusion: Flipped classroom approaches using learner-paced e-learning prior to hands-on training can improve team performance., Trial Registration: German Clinical Trials Register ( https://drks.de/search/de/trial/DRKS00013096 )., (© 2024. The Author(s).)

Introduction: Herpes simplex virus (HSV) is frequently detected in the respiratory tract of mechanically ventilated patients and is associated with a worse outcome. The aim of this study is to determine whether antiviral therapy in HSV-positive patients improves outcome., Methods and Analysis: Prospective, multicentre, open-label, randomised, controlled trial in parallel-group design. Adult, mechanically ventilated patients with pneumonia and HSV type 1 detected in bronchoalveolar lavage (≥10 5 copies/mL) are eligible for participation and will be randomly allocated (1:1) to receive acyclovir (10 mg/kg body weight every 8 hours) for 10 days (or until discharge from the intensive care unit if earlier) or no intervention (control group). The primary outcome is mortality measured at day 30 after randomisation (primary endpoint) and will be analysed with Cox mixed-effects model. Secondary endpoints include ventilator-free and vasopressor-free days up to day 30. A total of 710 patients will be included in the trial., Ethics and Dissemination: The trial was approved by the responsible ethics committee and by Germany's Federal Institute for Drugs and Medical Devices. The clinical trial application was submitted under the new Clinical Trials Regulation through CTIS (The Clinical Trials Information System). In this process, only one ethics committee, whose name is unknown to the applicant, and Germany's Federal Institute for Drugs and Medical Devices are involved throughout the entire approval process. Results will be published in a journal indexed in MEDLINE and CTIS. With publication, de-identified, individual participant data will be made available to researchers., Trial Registration Number: NCT06134492., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Adsorption-based extracorporeal therapies have been subject to technical developments and clinical application for close to five decades. More recently, new technological developments in membrane and sorbent manipulation have made it possible to deliver more biocompatible extracorporeal adsorption therapies to patients with a variety of conditions. There are several key rationales based on physicochemical principles and clinical considerations that justify the application and investigation of such therapies as evidenced by multiple ex-vivo, experimental, and clinical observations. Accordingly, unspecific adsorptive extracorporeal therapies have now been applied to the treatment of a wide array of conditions from poisoning to drug overdoses, to inflammatory states and sepsis, and acute or chronic liver and kidney failure. In response to the rapidly expanding knowledge base and increased clinical evidence, we convened an Acute Disease Quality Initiative (ADQI) consensus conference dedicated to such treatment. The data show that hemoadsorption has clinically acceptable short-term biocompatibility and safety, technical feasibility, and experimental demonstration of specified target molecule removal. Pilot studies demonstrate potentially beneficial effects on physiology and larger studies of endotoxin-based hemoadsorption have identified possible target phenotypes for larger randomized controlled trials (RCTs). Moreover, in a variety of endogenous and exogenous intoxications, removal of target molecules has been confirmed in vivo. However, some studies have raised concerns about harm or failed to deliver benefits. Thus, despite many achievements, modern hemoadsorption remains a novel and experimental intervention with limited data, and a large research agenda., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: The peripheral perfusion index is the ratio of pulsatile to nonpulsatile static blood flow obtained by photoplethysmography and reflects peripheral tissue perfusion. We investigated the association between intraoperative perfusion index and postoperative acute kidney injury in patients undergoing major noncardiac surgery and receiving continuous vasopressor infusions., Methods: In this exploratory post hoc analysis of a pragmatic, cluster-randomised, multicentre trial, we obtained areas and cumulative times under various thresholds of perfusion index and investigated their association with acute kidney injury in multivariable logistic regression analyses. In secondary analyses, we investigated the association of time-weighted average perfusion index with acute kidney injury. The 30-day mortality was a secondary outcome., Results: Of 2534 cases included, 8.9% developed postoperative acute kidney injury. Areas and cumulative times under a perfusion index of 3% and 2% were associated with an increased risk of acute kidney injury; the strongest association was observed for area under a perfusion index of 1% (adjusted odds ratio [aOR] 1.32, 95% confidence interval [CI] 1.00-1.74, P=0.050, per 100%∗min increase). Additionally, time-weighted average perfusion index was associated with acute kidney injury (aOR 0.82, 95% CI 0.74-0.91, P<0.001) and 30-day mortality (aOR 0.68, 95% CI 0.49-0.95, P=0.024)., Conclusions: Larger areas and longer cumulative times under thresholds of perfusion index and lower time-weighted average perfusion index were associated with postoperative acute kidney injury in patients undergoing major noncardiac surgery and receiving continuous vasopressor infusions., Clinical Trial Registration: NCT04789330., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: An increasing amount of longitudinal health data is available on critically ill septic patients in the age of digital medicine, including daily sequential organ failure assessment (SOFA) score measurements. Thus, the assessment in sepsis focuses increasingly on the evaluation of the individual disease's trajectory. Machine learning (ML) algorithms may provide a promising approach here to improve the evaluation of daily SOFA score dynamics. We tested whether ML algorithms can outperform the conventional ΔSOFA score regarding the accuracy of 30-day mortality prediction., Methods: We used the multicentric SepsisDataNet.NRW study cohort that prospectively enrolled 252 sepsis patients between 03/2018 and 09/2019 for training ML algorithms, i.e. support vector machine (SVM) with polynomial kernel and artificial neural network (aNN). We used the Amsterdam UMC database covering 1,790 sepsis patients for external and independent validation., Results: Both SVM (AUC 0.84; 95% CI: 0.71-0.96) and aNN (AUC 0.82; 95% CI: 0.69-0.95) assessing the SOFA scores of the first seven days led to a more accurate prognosis of 30-day mortality compared to the ΔSOFA score between day 1 and 7 (AUC 0.73; 95% CI: 0.65-0.80; p = 0.02 and p = 0.05, respectively). These differences were even more prominent the shorter the time interval considered. Using the SOFA scores of day 1 to 3 SVM (AUC 0.82; 95% CI: 0.68 0.95) and aNN (AUC 0.80; 95% CI: 0.660.93) led to a more accurate prognosis of 30-day mortality compared to the ΔSOFA score (AUC 0.66; 95% CI: 0.58-0.74; p < 0.01 and p < 0.01, respectively). Strikingly, all these findings could be confirmed in the independent external validation cohort., Conclusions: The ML-based algorithms using daily SOFA scores markedly improved the accuracy of mortality compared to the conventional ΔSOFA score. Therefore, this approach could provide a promising and automated approach to assess the individual disease trajectory in sepsis. These findings reflect the potential of incorporating ML algorithms as robust and generalizable support tools on intensive care units., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Palmowski et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Acute kidney injury (AKI) often complicates sepsis and is associated with high morbidity and mortality. In recent years, several important clinical trials have improved our understanding of sepsis-associated AKI (SA-AKI) and impacted clinical care. Advances in sub-phenotyping of sepsis and AKI and clinical trial design offer unprecedented opportunities to fill gaps in knowledge and generate better evidence for improving the outcome of critically ill patients with SA-AKI. In this manuscript, we review the recent literature of clinical trials in sepsis with focus on studies that explore SA-AKI as a primary or secondary outcome. We discuss lessons learned and potential opportunities to improve the design of clinical trials and generate actionable evidence in future research. We specifically discuss the role of enrichment strategies to target populations that are most likely to derive benefit and the importance of patient-centered clinical trial endpoints and appropriate trial designs with the aim to provide guidance in designing future trials., (© 2024. The Author(s).)

Acute kidney injury (AKI) is a common complication after surgery and the more complex the surgery, the greater the risk. During surgery, patients are exposed to a combination of factors all of which are associated with the development of AKI. These include hypotension and hypovolaemia, sepsis, systemic inflammation, the use of nephrotoxic agents, tissue injury, the infusion of blood or blood products, ischaemia, oxidative stress and reperfusion injury. Given the risks of AKI, it would seem logical to conclude that early identification of patients at risk of AKI would translate into benefit. The conventional markers of AKI, namely serum creatinine and urine output are the mainstay of defining chronic kidney disease but are less suited to the acute phase. Such concerns are compounded in surgical patients given they often have significantly reduced mobility, suboptimal levels of nutrition and reduced muscle bulk. Many patients may also have misleadingly low serum creatinine and high urine output due to aggressive fluid resuscitation, particularly in intensive care units. Over the last two decades, considerable information has accrued with regard to the performance of what was termed "novel" biomarkers of AKI, and here, we discuss the most examined molecules and performance in surgical settings. We also discuss the application of biomarkers to guide patients' postoperative care., Competing Interests: Dr Alexander Zarbock reports consulting and/or lecture fees from Baxter, BioMerieux, Guard Therapeutics, Bayer, Fresenius, Novartis, AM Pharma, Paion, during the conduct of the study. Professor Lui Forni reports grants note directly related to this work from Baxter, grants for biomarkers integrated as part of a multicentre research study from Biomerieux, personal fees for lectures on biomarkers from Ortho clinical diagnostics, during the conduct of the study. The authors report no other conflicts of interest in this work., (© 2024 Singh et al.)

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 m 2 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., (© 2024. The Author(s).)

Purpose of Review: Patients undergoing cardiac surgery are at high risk to develop cardiac surgery-associated acute kidney injury (CS-AKI) postoperatively. CS-AKI is associated with an increased risk for persistent renal dysfunction, morbidity and mortality. This review summarizes the epidemiology and pathophysiology of CS-AKI, as well as current treatment and prevention strategies., Recent Findings: As AKI is a syndrome with complex pathophysiology, no causative treatment strategies exist. Recent advances in the field of AKI biomarkers offer new perspectives on the issue and the implementation of biomarker-guided preventive strategies may reduce rates of CS-AKI. Finally, nephroprotective treatments and angiotensin II as a novel vasopressor may offer new opportunities for high-risk patients undergoing cardiac surgery., Summary: Based on the described novel approaches for early detection, prevention and management of CS-AKI, a precision-medicine approach should be implemented in order to prevent the development of AKI in patients undergoing cardiac surgery., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Acute kidney injury (AKI) is a common clinical condition with various causes and is associated with increased mortality. Despite advances in supportive care, AKI increases not only the risk of premature death compared with the general population but also the risk of developing chronic kidney disease and progressing towards kidney failure. Currently, no specific therapy exists for preventing or treating AKI other than mitigating further injury and supportive care. To address this unmet need, novel therapeutic interventions targeting the underlying pathophysiology must be developed. New and well-designed clinical trials with appropriate end points must be subsequently designed and implemented to test the efficacy of such new interventions. Herein, we discuss predictive and prognostic enrichment strategies for patient selection, as well as primary and secondary end points that can be used in different clinical trial designs (specifically, prevention and treatment trials) to evaluate novel interventions and improve the outcomes of patients at a high risk of AKI or with established AKI., (© 2023. Springer Nature Limited.)

Sepsis is a common life-threatening disease caused by dysregulated immune response and metabolic acidosis which lead to organ failure. An abnormal expression of aquaporins plays an important role in organ failure. Additionally, genetic variants in aquaporins impact on the outcome in sepsis. Thus, we investigated the polymorphism (rs17553719) and expression of aquaporin-3 ( AQP3 ) and correlated these measurements with the survival of sepsis patients. Accordingly, we collected blood samples on several days (plus clinical data) from 265 sepsis patients who stayed in different ICUs in Germany. Serum plasma, DNA, and RNA were then separated to detect the promotor genotypes of AQP3 mRNA expression of AQP3 and several cytokines. The results showed that the homozygote CC genotype exhibited a significant decrease in 30-day survival (38.9%) compared to the CT (66.15%) and TT genotypes (76.3%) ( p = 0.003). Moreover, AQP3 mRNA expression was significantly higher and nearly doubled in the CC compared to the CT ( p = 0.0044) and TT genotypes ( p = 0.018) on the day of study inclusion. This was accompanied by an increased IL-33 concentration in the CC genotype (day 0: p = 0.0026 and day 3: p = 0.008). In summary, the C allele of the AQP3 polymorphism (rs17553719) shows an association with increased AQP3 expression and IL-33 concentration accompanied by decreased survival in patients with sepsis.

Sepsis involves an immunological systemic response to a microbial pathogenic insult, leading to a cascade of interconnected biochemical, cellular, and organ-organ interaction networks. Potential drug targets can depict aquaporins, as they are involved in immunological processes. In immune cells, AQP3 and AQP9 are of special interest. In this study, we tested the hypothesis that these aquaporins are expressed in the blood cells of septic patients and impact sepsis survival. Clinical data, routine laboratory parameters, and blood samples from septic patients were analyzed on day 1 and day 8 after sepsis diagnosis. AQP expression and cytokine serum concentrations were measured. AQP3 mRNA expression increased over the duration of sepsis and was correlated with lymphocyte count. High AQP3 expression was associated with increased survival. In contrast, AQP9 expression was not altered during sepsis and was correlated with neutrophil count, and low levels of AQP9 were associated with increased survival. Furthermore, AQP9 expression was an independent risk factor for sepsis lethality. In conclusion, AQP3 and AQP9 may play contrary roles in the pathophysiology of sepsis, and these results suggest that AQP9 may be a novel drug target in sepsis and, concurrently, a valuable biomarker of the disease.

K 2P 2.1 (TREK1), a two-pore domain potassium channel, has emerged as regulator of leukocyte transmigration into the central nervous system. In the context of skeletal muscle, immune cell infiltration constitutes the pathogenic hallmark of idiopathic inflammatory myopathies (IIMs). However, the underlying mechanisms remain to be elucidated. In this study, we investigated the role of K 2P 2.1 in the autoimmune response of IIMs. We detected K 2P 2.1 expression in primary skeletal muscle and endothelial cells of murine and human origin. We observed an increased pro-inflammatory cell response, adhesion and transmigration by pharmacological blockade or genetic deletion of K 2P 2.1 in vitro and in in vivo myositis mouse models. Of note, our findings were not restricted to endothelial cells as skeletal muscle cells with impaired K 2P 2.1 function also demonstrated a strong pro-inflammatory response. Conversely, these features were abrogated by activation of K 2P 2.1 and improved the disease course of a myositis mouse model. In humans, K 2P 2.1 expression was diminished in IIM patients compared to non-diseased controls arguing for the translatability of our findings. In summary, K 2P 2.1 may regulate the inflammatory response of skeletal muscle. Further research is required to understand whether K 2P 2.1 could serve as novel therapeutic target., Competing Interests: Declaration of competing interest The authors report no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The development of new extracorporeal blood purification (EBP) techniques has led to increased application in clinical practice but also inconsistencies in nomenclature and misunderstanding. In November 2022, an international consensus conference was held to establish consensus on the terminology of EBP therapies. It was agreed to define EBP therapies as techniques that use an extracorporeal circuit to remove and/or modulate circulating substances to achieve physiological homeostasis, including support of the function of specific organs and/or detoxification. Specific acute EBP techniques include renal replacement therapy, isolated ultrafiltration, hemoadsorption, and plasma therapies, all of which can be applied in isolation and combination. This paper summarizes the proposed nomenclature of EBP therapies and serves as a framework for clinical practice and future research., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Purpose: Ilofotase alfa is a human recombinant alkaline phosphatase with reno-protective effects that showed improved survival and reduced Major Adverse Kidney Events by 90 days (MAKE90) in sepsis-associated acute kidney injury (SA-AKI) patients. REVIVAL, was a phase-3 trial conducted to confirm its efficacy and safety., Methods: In this international double-blinded randomized-controlled trial, SA-AKI patients were enrolled < 72 h on vasopressor and < 24 h of AKI. The primary endpoint was 28-day all-cause mortality. The main secondary endpoint was MAKE90, other secondary endpoints were (i) days alive and free of organ support through day 28, (ii) days alive and out of the intensive care unit (ICU) through day 28, and (iii) time to death through day 90. Prior to unblinding, the statistical analysis plan was amended, including an updated MAKE90 definition., Results: Six hundred fifty patients were treated and analyzed for safety; and 649 for efficacy data (ilofotase alfa n = 330; placebo n = 319). The observed mortality rates in the ilofotase alfa and placebo groups were 27.9% and 27.9% at 28 days, and 33.9% and 34.8% at 90 days. The trial was stopped for futility on the primary endpoint. The observed proportion of patients with MAKE90A and MAKE90B were 56.7% and 37.4% in the ilofotase alfa group vs. 64.6% and 42.8% in the placebo group. Median [interquartile range (IQR)] days alive and free of organ support were 17 [0-24] and 14 [0-24], number of days alive and discharged from the ICU through day 28 were 15 [0-22] and 10 [0-22] in the ilofotase alfa and placebo groups, respectively. Adverse events were reported in 67.9% and 75% patients in the ilofotase and placebo group., Conclusion: Among critically ill patients with SA-AKI, ilofotase alfa did not improve day 28 survival. There may, however, be reduced MAKE90 events. No safety concerns were identified., (© 2024. The Author(s).)

Sepsis is a host's deleterious response to infection, which could lead to life-threatening organ dysfunction. Sepsis-associated acute kidney injury (SA-AKI) is the most frequent organ dysfunction and is associated with increased morbidity and mortality. Sepsis contributes to ≈50% of all AKI in critically ill adult patients. A growing body of evidence has unveiled key aspects of the clinical risk factors, pathobiology, response to treatment and elements of renal recovery that have advanced our ability to detect, prevent and treat SA-AKI. Despite these advancements, SA-AKI remains a critical clinical condition and a major health burden, and further studies are needed to diminish the short and long-term consequences of SA-AKI. We review the current treatment standards and discuss novel developments in the pathophysiology, diagnosis, outcome prediction and management of SA-AKI., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Objectives: Sepsis is a life-threatening condition implicating an inadequate activation of the immune system. Platelets act as modulators and contributors to immune processes. Indeed, altered platelet turnover, thrombotic events, and changes in thrombopoietin levels in systemic inflammation have been reported, but thrombopoietin-levels in sepsis and septic-shock have not yet been systematically evaluated. We therefore performed a meta-analysis of thrombopoietin (TPO)-levels in patients with sepsis., Methods: Two independent reviewers screened records and full-text articles for inclusion. Scientific databases were searched for studies examining thrombopoietin levels in adult sepsis and septic-shock patients until August 1st 2022., Results: Of 95 items screened, six studies met the inclusion criteria, including 598 subjects. Both sepsis and severe sepsis were associated with increased levels of thrombopoietin (sepsis vs. control: standardized mean difference 3.06, 95 % CI 1.35-4.77; Z=3.50, p=0.0005) (sepsis vs. severe sepsis: standardized mean difference -1.67, 95 % CI -2.46 to -0.88; Z=4.14, p<0.0001). TPO-levels did not show significant differences between severe sepsis and septic shock patients but differed between sepsis and inflammation-associated non-septic controls. Overall, high heterogeneity and low sample size could be noted., Conclusions: Concluding, increased levels of thrombopoietin appear to be present both in sepsis and severe sepsis with high heterogeneity but thrombopoietin does not allow to differentiate between severe sepsis and septic-shock. TPO may potentially serve to differentiate sepsis from non-septic trauma and/or tissue damage related (systemic) inflammation. Usage of different assays and high heterogeneity demand standardization of methods and further large multicenter trials., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Purpose of Review: This review aims to explore the relationship between the renin angiotensin system (RAS) and sepsis-associated acute kidney injury (SA-AKI), a common complication in critically ill patients associated with mortality, morbidity, and long-term cardiovascular complications. Additionally, this review aims to identify potential therapeutic approaches to intervene with the RAS and prevent the development of AKI., Recent Findings: Recent studies have provided increasing evidence of RAS alteration during sepsis, with systemic and local RAS disturbance, which can contribute to SA-AKI. Angiotensin II was recently approved for catecholamine resistant vasodilatory shock and has been associated with improved outcomes in selected patients., Summary: SA-AKI is a common condition that can involve disturbances in the RAS, particularly the canonical angiotensin-converting enzyme (ACE) angiotensin-II (Ang II)/angiotensin II receptor 1 (AT-1R) axis. Increased renin levels, a key enzyme in the RAS, have been shown to be associated with AKI and may also guide vasopressor therapy in shock. In patients with high renin levels, angiotensin II administration may reduce renin concentration, improve intra-renal hemodynamics, and enhance signaling through the angiotensin II receptor 1. Further studies are needed to explore the role of the RAS in SA-AKI and the potential for targeted therapies., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

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., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)