Regional citrate anticoagulation (RCA) is recommended by guidelines over systemic heparinization for continuous renal replacement therapy (CRRT). However, its use in patients with impaired citrate metabolism poses specific challenges and standardized guidance for managing RCA-related metabolic complications remains lacking. A modified Delphi study was conducted according to a predefined protocol and reported in adherence with the CREDES (Conducting and REporting of DElphi Studies) checklist. The international expert panel comprised 29 clinicians and researchers from Europe, United States and Canada, with recognized expertise in RCA for CRRT in critically ill patients. Three iterative survey rounds were conducted to obtain agreement with proposed statements. Twenty-three experts completed all Delphi rounds, achieving consensus on twenty-two statements. RCA was considered feasible in patients with liver dysfunction, severe shock, or hyperlactatemia, with close monitoring and citrate dosing adjustment. Citrate accumulation can be prevented and managed using a stepwise approach, focused on reducing citrate delivery and discontinuing RCA in cases of overt accumulation. Metabolic alkalosis and electrolyte disturbances were identified as relevant but manageable complications, underscoring the need for individualizing CRRT settings. These consensus statements support the use of RCA during CRRT in critically ill patients with impaired citrate metabolism and provide practical guidance for monitoring and management of metabolic complications. However they reflect expert opinion, especially for questions with limited data and low-level evidence.

BACKGROUND:Circulating nucleic acids in blood plasma form an attractive, minimally invasive resource to study human health and disease. In this study, we aimed to identify cell-free RNA alterations that can distinguish cancer patients from cancer-free individuals. METHODS:We first performed mRNA capture sequencing on 266 blood plasma samples from cancer patients and controls, including a discovery set of 208 donors across 25 cancer types and a replication set of 58 donors across three cancer types. We first conducted group-level comparisons and then compared individual patient profiles to a reference control population in a one-versus-many approach. This approach was further evaluated in independent cohorts: a prostate cancer plasma cohort (n = 180), a non-malignant disease plasma cohort (n = 125), a lymphoma plasma cohort (n = 65), and a bladder cancer urine cohort (n = 24), each including both patients and controls. RESULTS:Here we show that cancer patients exhibit both cancer type-specific and general cell-free RNA alterations. However, differentially abundant RNAs vary widely among patients and across cohorts, hampering robust biomarker identification. By comparing individual patient profiles to control populations, we identify so-called biomarker tail genes, which strongly deviate from controls. The number of these genes per sample distinguishes cancer patients from control samples. Independent cohorts also confirm the potential of this approach. CONCLUSIONS:Our findings demonstrate substantial heterogeneity in cell-free RNA alterations among cancer patients and propose that patient-specific changes can be exploited for classification.

Introduction Reports on the epidemiology and outcomes of acute kidney injury in the critically ill provide variable estimates based on differences in populations and underlying exposures. Current and generalisable incidence data are needed along with information on long-term patient and kidney outcomes.The acute kidney injury-epidemiology in intensive care unit patients 2 (AKI-EPI 2) study aims to describe the occurrence and associated outcomes of AKI in critically ill patients worldwide. In addition, in selected centres, it aims to further describe the influence of AKI on long-term kidney and patient outcomes.Methods and analysis This is an international prospective, observational study of patients admitted to the intensive care unit (ICU). Each participating centre will record data from 100 consecutive patients fulfilling the following eligibility criteria: age≥18 years, admission to the ICU for more than 24 hours and informed consent according to the local ethics committee (EC). Exclusion criteria include end-stage kidney disease treated with maintenance renal replacement therapy (RRT), readmission to the ICU or missing AKI-defining data. Particular attention will be paid to recruiting centres from all continents and to ensure geographical diversity and representativeness. The target sample is 10 642 patients. The primary endpoint is the occurrence and maximum severity of AKI within 7 days of ICU admission according to 2012 Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Secondary endpoints include AKI severity, AKI duration, RRT use and hospital survival. In selected centres, health-related quality of life, major adverse kidney events and vital status will also be captured at day 90 and 1 year from admission.Ethics and dissemination AKI-EPI 2 has been approved by the EC of the Ghent University and University Hospital. Approval will be sought by corresponding ECs for all participating centres.Results will be presented at conferences, disseminated in peer-reviewed journals and will guide future research in the field of critical care nephrology.Trial registration NCT07207031.

Acute kidney injury (AKI) is a common and serious complication following cardiothoracic surgery, occurring in up to 30% of patients. Cardiac surgery-associated AKI (CSA-AKI) is associated with increased morbidity, mortality, and progression to chronic kidney disease. Currently, no pharmacological interventions have been approved for clinical use to reduce the incidence or severity of CSA-AKI. It is hypothesized that early modulation of the inflammatory response, triggered by the release of damage-associated molecular patterns during surgery, may improve renal outcomes. Ilofotase alfa, a recombinant human alkaline phosphatase, has demonstrated potential to attenuate renal injury through its immunomodulatory effects in animal studies. This manuscript presents the protocol for a Phase 2 clinical trial evaluating the safety and efficacy of ilofotase alfa in preventing renal damage following cardiac surgery. This is a Phase 2, multi-centre, randomized, double-blinded, placebo-controlled trial employing a two-arm, parallel-group design. Adult patients at risk for CSA-AKI undergoing complex open-heart surgery will be randomized to receive two intravenous doses (2x128 mg) of ilofotase alfa or placebo, just before and after surgery. Ethics and Dissemination The study has been approved by all relevant institutional review boards and independent ethics committees. It will be conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and all applicable regulatory requirements. The results of this trial will inform the potential role of ilofotase alfa in preventing cardiac surgery associated renal injury and improving longer-term clinical outcomes and will be published in a peer-reviewed scientific journal. The primary endpoint is the serum creatinine ratio, defined as the highest serum creatinine level within five days postoperatively relative to the preoperative baseline, with the occurrence of major adverse kidney events up to day 60 as the secondary endpoint. In addition, safety assessments and the AKI as defined by the KDIGO creatinine-criterion will be assessed. Patients will be followed for a total of 60 days. The results of this study will will enable us to assess safety as well as the efficacy of ilofotase alfa in attenuating renal injury and improving long-term renal outcomes. Trial registration numbers EUCT Number:2023-505859-45 US IND Number:117 605 ClinicalTrials.gov ID:NCT06168799

Renal tubular epithelial cells (RTECs) are increasingly recognized as key players in kidney diseases. They integrate metabolic, inflammatory, and fibrotic signals. This article reviews new data suggesting that RTECs could function as central integrators within diagnostic networks, linking cellular stress responses to detectable blood and urine biomarkers. We discuss the latest advances in multi-omics, extracellular vesicles, and single-cell technologies that enable precise identification of RTEC states. Finally, we discuss the potential of RTEC-centric diagnostics and highlight current limitations in early disease recognition, stratification, and the development of personalized therapeutic interventions.

Rationale:Survivors of ARDS are at risk of persistent physical and psychological impairments, yet reliable prognostic factors for long-term recovery are poorly defined. The aims of the study were to describe changes in health-related quality of life (HRQoL) during the year after discharge from intensive care unit (ICU) in a cohort of ARDS survivors, and to identify factors associated with a favorable recovery trajectory. Methods:This planned secondary analysis used prospectively collected data from the multicenter randomized CONFIDENT trial that enrolled 475 mechanically ventilated COVID-19 ARDS patients. Patients who completed interviews at both day 90 (D90) and one year (Y1) were included. HRQoL was assessed using the EQ-5D-5L utility score (EQ-score) and visual analog scale (EQ-VAS). Baseline status, disease severity, and ICU characteristics were analyzed for associations with HRQoL changes. Results:156 survivors completed follow-up at both D90 and Y1. EQ-score and EQ-VAS significantly improved between D90 and Y1 (p < 0.0001 and p = 0.0002 respectively), but both remained lower than pre-ICU status. Notably, 38 and 43% of patients showed stagnation or deterioration in EQ-score and EQ-VAS over the year. Longer durations of mechanical ventilation, ICU stay, and hospital stay were associated with greater EQ-score and EQ-VAS recovery, whereas shorter stays were linked to less improvement (respectively p = 0.0002 and p = 0.025, p = 0.0002 and p = 0.0035, p = 0.0020 and p = 0.026). Demographics and pre-admission frailty showed no impact on the recovery trajectory. Conclusion:In this multicenter cohort of ARDS survivors, patients with shorter durations of mechanical ventilation, ICU and hospital stay experienced poorer HRQoL recovery, independently of baseline characteristics such as age or frailty. Trial registration:Clinicaltrials.gov registration number NCT04558476. Registered 14 September 2020-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04558476.

Background Acute kidney injury (AKI) is a frequent, severe complication in the intensive care units (ICU). Existing machine learning models are typically inflexible, classification-based (i.e., predicting AKI occurrence as yes/no), and of limited clinical utility. This study proposes and externally validates the first multi-step, multivariate distributional regression model that directly predicts future distributions of serum creatinine (sCr) and urine output across multiple time horizons, thereby enhancing AKI risk stratification and personalized clinical decision support. Methods The model was developed using a training cohort of 4,118 adult ICU stays from the MIMIC-IV dataset and externally validated on four independent, diverse cohorts: MIMIC-IV (N=3,838), UZGent (N=4,442), eICU (N=10,760), and AmsterdamUMC (N=6,129). The model used clinical data to generate multivariate predictive distributions hourly for urine output and sCr (up to 48 hours ahead). Predictors included demographics, vital signs, laboratory results, medications, and recent urine output, with time-varying variables summarized over the preceding 72 hours (recent value, slope, minimum, maximum, variability). Performance was evaluated by comparing our predictive distributions with state-of-the-art tree-based classifiers for 24-hour ahead prediction of KDIGO stages 1-3 AKI and persistent stage 3 AKI. Results Across all external cohorts, the distributional regression model demonstrated high discrimination (mean AUC-PR 0.774 for all stages) and excellent calibration, consistently outperforming the benchmark classifiers. By jointly predicting sCr and urine output distributions, a single model successfully enables flexible risk stratification across all stages, capturing AKI onset and persistence, and allowing changes to stage definitions. Conclusion This multi-step, multivariate distributional regression model is a reliable, more flexible, transparent, and clinically interpretable approach for AKI prediction compared to traditional classification methods. It represents a necessary step toward bedside implementation of predictive models for personalized AKI management in the ICU.

Anticoagulation during extracorporeal membrane oxygenation (ECMO) requires balancing thrombotic and bleeding risks, yet early coagulation dynamics may differ between venovenous (VV) and venoarterial (VA) support. This study prospectively characterized standard coagulation tests and viscoelastic profiles during the first 48 h of ECMO and related these to early bleeding and transfusion need. Multicenter, prospective cohort in four Belgian ICUs (03/2021–01/2023; NCT04912336). Adults initiated on VV- or VA-ECMO were enrolled immediately before cannulation and sampled at inclusion, + 2 h, + 24 h, and + 48 h. Laboratory tests (aPTT, PT/INR, fibrinogen, platelets, anti-Xa, D-dimer, AT), ROTEM, bleeding (BARC, GUSTO), and transfusions were recorded. Forty-three patients were included (23 VV, 20 VA). At inclusion, platelet counts were higher in VV than in VA (median 292 vs. 145·109/L). Thrombocytopenia was present at enrollment in 30

Despite major advances in care for patients admitted to the intensive care unit (ICU), mortality remains high and functional outcomes for ICU survivors are often poor. The persistent burden underscores the need for innovative, mechanism-based approaches. Precision medicine has emerged as a promising paradigm in critical illness, and regulated cell death (RCD) may offer a novel entry point for targeted interventions. Among the various RCD pathways, ferroptosis, an iron-dependent form of RCD driven by excessive lipid peroxidation within cellular membranes, has gained increasing attention. Its mechanistic distinctiveness from other RCDs and potential reversibility make it particularly relevant in acute, dynamic disease states. In this narrative review, we explore the role of ferroptosis in critical care, focusing on high-impact conditions such as sepsis, COVID-19, ischaemia–reperfusion injury, and neurological emergencies. We outline the molecular mechanisms of ferroptosis and discuss how it may contribute to organ dysfunction across systems. While most insights to date stem from preclinical models, emerging clinical data suggest translational potential. We highlight key studies, discuss current limitations in detection and therapeutic targeting, and consider how the evaluation of ferroptosis could help shape the future of precision medicine in the ICU.

BACKGROUND:This single center study analyzed epidemiology, outcomes, and three-year quality of life (QoL) of critically ill COVID-19 patients requiring a possibly life-saving VV-ECMO. METHODS:Demographics, clinical and technical data from adult critical COVID-19 VV-ECMO patients were prospectively analyzed (March 2020-January 2022). QoL was yearly assessed by the 'Medical Outcomes Study 36-item Short Form Health Survey' (SF-36) questionnaire. Hospital Anxiety and Depression Scales were measured. Return to work (RTW) was monitored. Multivariate linear regression analyzed factors influencing SF-36 physical (PCS) and mental component summary (MCS) scores. RESULTS:Forty-eight patients were included, median age was 51 [42.8-57.2] years. Clinical Frailty Scores were 1(33%), 2(44%) or 3(23%). At ECMO initiation, median SOFA score was 11.0 [9.0-12.0]. ECMO support lasted for a median duration of 16 [11.8-28.8] days. Median ICU and hospital stay was 32.0 [21.0-45.0] and 67.0 [58.0-130.0] days. One-year mortality was 33.3% without additional mortality after three years. PCS scores were lower than in general healthy population at one (P<0.001), two (P=0.037) and three (P<0.010) years. MCS scores were equivalent and higher at three years (P=0.015). Anxiety was present in 10/29 (34.5%) and 4/29 (13.8%) had symptoms of depression three years after ECMO initiation. RTW was possible in 13 out of 23 (56,5%), working prior to critical COVID-19. CONCLUSIONS:Three-year mortality after VV-ECMO for critical COVID-19 was 33.3%. Physical health was impaired, but mental health remained comparable to the general population, with relatively low anxiety and depression levels. RTW was possible in 56.5%.

Acute kidney injury (AKI) is a common clinical complication of cardiac surgeries. Although urinary particle analysis is useful for differentiating AKI, its value in AKI diagnosis has not yet been well described. We sought to determine the contribution of urinary particle analysis to the diagnosis of AKI. Two-hundred and thirty-nine adult patients were prospectively included after cardiac surgery. The diagnostic performance of urinary particle analysis at different time points after intensive care unit (ICU) admission was evaluated. AKI was diagnosed and classified according to the KDIGO definitions. Urinary particles, including renal tubular epithelial cells (RTEC) and non-hyaline casts, Nephrocheck®, urinary alpha-1-microglobulin and urinary γ-glutamyltransferase (GGT) levels were measured at 4, 12 and 24 h after ICU admission and evaluated against different endpoints. Of the 239 patients included, 39 (16.3

Critically ill patients admitted to the intensive care unit (ICU) frequently suffer from sepsis and severe multiple organ dysfunction with underlying widespread cell death. Pyroptosis and ferroptosis are regulated cell death forms that may serve as potential therapeutic targets. Pyroptosis is a major detrimental factor driving sepsis, which typically results in excessive oxidative stress potentially inducing ferroptotic organ injury. Here, we show that ICU patients with simultaneous pyro- and ferroptosis-positive signatures have the lowest survival probability. This is reflected by significantly elevated levels of pyroptosis-related biomarkers interleukin-1 receptor antagonist (IL-1Ra), IL-18, and growth and differentiation factor-15 (GDF15), as well as the ferroptosis-related biomarkers malondialdehyde (MDA) and catalytic iron (Fec). Moreover, combining these biomarkers with IL-1α, IL-6, IL-10, TNF, and chitinase-3-like protein 1 further improves clinical outcome prediction. The daily monitoring of pyro- and ferroptosis signatures reveals potential intervention opportunities, such as anakinra, tadekinig alfa, lead ferroptosis inhibitors, or a combination thereof. In summary, our findings demonstrate that a targeted biomarker panel enables predictive enrichment of ICU patients, paving the way for timely intervention strategies against pyroptosis or ferroptosis.

PURPOSE OF REVIEW:Acute kidney injury (AKI) is a common but complex clinical syndrome, especially among critically ill patients. Current consensus definitions for AKI rely only on changes in serum creatinine and urine output, which limits timely detection of renal injury and recovery. This review summarizes the recent literature on AKI biomarkers and digital tools investigated to optimize AKI care. RECENT FINDINGS:There is a growing body of literature on the use of biochemical, imaging, and functional biomarkers to detect AKI prior to changes in creatinine and urine output, ideally to provide a window for potential intervention and prevention of worsening renal injury. Biomarkers have also been shown to help prognosticate progression, need for dialysis, or recovery. Additionally, machine learning models have been developed and studied with similar goals. This review summarizes various biomarkers and machine learning models investigated to predict and prognosticate AKI in several critical care populations. Furthermore, this review discusses other digital tools such as electronic alerts and remote monitoring programs implemented to optimize AKI care. SUMMARY:The studies included in this review provide optimism for an abundance of novel resources to improve AKI care. Further validation is needed prior to utilization in clinical practice.

Abstract Background Convalescent plasma (CP) reduced the mortality in COVID-19 induced ARDS (C-ARDS) patients treated in the CONFIDENT trial. As patients are immunologically heterogeneous, we hypothesized that clusters may differ in their treatment responses to CP. Methods We measured 20 cytokines, chemokines and cell adhesion markers using a multiplex technique at the time of inclusion in the CONFIDENT trial in patients of centers having accepted to participate in this secondary study. We performed descriptive statistics, unsupervised hierarchical cluster analysis, and examined the association between the clusters and CP effect on day-28 mortality. Results Of the 475 patients included in CONFIDENT, 391 (82%) were sampled, and 196/391 (50.1%) had been assigned to CP. We identified four sub-phenotypes representing 89 (22.8%), 178 (45.5%), 38 (9.7%), and 86 (22.0%) patients. The most contributing biomarkers in the principal component analysis were IL-1β, IL-12p70, IL-6, IFN-α, IL-17A, IFN-γ, IL-13, TFN-α, total IgG, and CXCL10. Sub-phenotype-1 displayed a lower immune response, sub-phenotype-2 a higher adaptive response, sub-phenotype-3 the highest innate antiviral, pro and anti-inflammatory response, and adhesion molecule activation, and sub-phenotype-4 a higher pro and anti-inflammatory response, migration protein and adhesion molecule activation. Sub-phenotype-2 and sub-phenotype-4 had higher severity at the time of inclusion. The effect of CP treatment on mortality appeared higher than standard care in each sub-phenotype, without heterogeneity between sub-phenotypes (p = 0.97). Conclusion In patients with C-ARDS, we identified 4 sub-phenotypes based on their immune response. These sub-phenotypes were associated with different clinical profiles. The response to CP was similar across the 4 sub-phenotypes. Trial registration: Ethics Committee of the University Hospital of Liège CE 2020/239. Clinicaltrials.gov NCT04558476. Registered 2020-09-11, https://www.clinicaltrials.gov/study/NCT04558476.

To compare the short-term effects on acid base, electrolyte status and urine output of a single fluid bolus of saline to that of the balanced solution Plasmalyte® in critically ill patients. Prospective, randomized, controlled trial. Adult patients (≥ 18 years) admitted to the ICU receiving a fluid bolus were randomized to receive 1 L of saline (NaCl 0.9

INTRODUCTION:Sepsis, the leading cause of acute kidney injury (AKI), is associated with a high morbidity and mortality. Alkaline phosphatase (ALP) is an endogenous detoxifying enzyme. A recombinant human ALP compound, ilofotase alfa, showed no safety or tolerability concerns in a phase 2 trial. Renal function improvement over 28 days was significantly greater in the ilofotase alfa group. Moreover, a significant relative reduction in 28-day all-cause mortality of >40% was observed. A follow-up trial has been designed to confirm these findings.METHODS AND ANALYSIS:This is a phase 3, global, multi-centre, randomised, double-blind, placebo-controlled, sequential design trial in which patients are randomly assigned to either placebo or 1.6 mg/kg ilofotase alfa. Randomisation is stratified by baseline modified Sequential Organ Failure Assessment (mSOFA) score and trial site. The primary objective is to confirm the survival benefit with ilofotase alfa by demonstrating a reduction in 28-day all-cause mortality in patients with sepsis-associated AKI requiring vasopressors. A maximum of 1400 patients will be enrolled at ∼120 sites in Europe, North America, Japan, Australia and New Zealand. Up to four interim analyses will take place. Based on predefined decision rules, the trial may be stopped early for futility or for effectiveness. In addition, patients with COVID-19 disease and patients with 'moderate to severe' chronic kidney disease are analysed as 2 separate cohorts of 100 patients each. An independent Data Monitoring Committee evaluates safety data at prespecified intervals throughout the trial.ETHICS AND DISSEMINATION:The trial is approved by relevant institutional review boards/independent ethics committees and is conducted in accordance with the ethical principles of the Declaration of Helsinki, guidelines of Good Clinical Practice, Code of Federal Regulations and all other applicable regulations. Results of this study will determine the potential of ilofotase alfa to reduce mortality in critically ill patients with sepsis-associated AKI and will be published in a peer-reviewed scientific journal.TRIAL REGISTRATION NUMBER:EudraCT CT Number 2019-0046265-24. US IND Number 117 605 Pre-results.CLINICALTRIALS:gov number: NCT04411472.

INTRODUCTION:AKI is a frequent complication of critical illness and portends poor outcome. CCL14 is a validated predictor of persistent severe AKI in critically ill patients. We examined the association of CCL14 with urine output within 48 h. METHODS:In pooled data from 2 studies of critically ill patients with KDIGO stage 2-3 AKI, CCL14 was measured by NEPHROCLEAR™ CCL14 Test on the Astute 140® Meter (low, intermediate, and high categories [1.3 and 13 ng/mL]). Average hourly urine output over 48 h, stage 3 AKI per urine output criterion on day 2, and composite of dialysis or death within 7 days were examined using multivariable mixed and logistic regression models. RESULTS:Of the 497 subjects with median age of 65 (56-74) years, 49% (242/497) were on diuretics. CCL14 concentration was low in 219 (44%), intermediate in 217 (44%), and high in 61 (12%) patients. In mixed regression analysis, hourly urine output over time was different within each CCL14 risk category based on diuretic use due to significant three-way interaction (p &lt; 0.001). In logistic regression analysis, CCL14 risk category was independently associated with low urine output on day 2 per KDIGO stage 3 (adjusted for diuretic use and baseline clinical variables), and composite of dialysis or death within 7 days (adjusted for urine output within 48 h of CCL14 measurement). CONCLUSIONS:CCL14 measured in patients with moderate to severe AKI is associated with urine output trajectory within 48 h, oliguria on day 2, and dialysis within 7 days.