Rationale & Objective: Many recent randomized controlled trials (RCTs) for acute kidney injury have incorporated biomarkers as part of their eligibility criteria. The sample size calculation of these trials is often based on prior studies that did not include such criteria. This meta-analysis evaluates the impact of a biomarker-based enrichment strategy on the rate of anticipated versus observed primary events and explores the effect of integrating such biomarkers on statistical power. Study Design: We performed a PRISMA-guided systematic review and methodological meta-analysis of RCTs extracted from 6 databases. Setting & Study Population: The RCTs included patients at risk for or diagnosed with acute kidney injury. Selection Criteria for Studies: Clinical trials with a biomarker-based eligibility criterion and either a renal or mortality primary outcome, published between 2010 and 2023. Data Extraction: Data were extracted independently by 2 reviewers. Analytical Approach: The absolute risk difference between anticipated and observed event rates was measured for all patients and stratified for control and intervention groups. Results: Fourteen RCTs involving 3,817 patients were included. Biomarkers of interest were neutrophil gelatinase-associated lipocalin, TIMP-2∗IGFBP7, proteinuria, serum albumin, NT-pro-BNP, homocysteine, and uric acid. The pooled absolute risk difference between anticipated and observed event rates was 0.12 (95% CI; 0.06-0.17). In the control and interventional groups, the absolute risk differences were 0.10 (95% CI, 0.01-0.19) and 0.12 (95% CI, 0.06-0.18), respectively. For kidney damage biomarkers, the risk difference was 0.13 (95% CI, 0.06-0.20). The mean preplanned and achieved statistical powers were 0.84 ± 0.07 and 0.43 ± 0.28, respectively, with no improvement when extrapolating the preplanned sample size. Limitations: Most RCTs were underpowered for their primary outcome. There was a high level of heterogeneity. Conclusions: There is a difference between expected and observed incidence rates that may be partly attributed to biomarker-based enrichment methods. These findings highlight the need for rigorous validation of biomarkers before their incorporation into the eligibility criteria of RCTs. Plain-Language Summary: Clinical trials in acute kidney injury increasingly use specific biomarkers to determine patient eligibility. These tests are meant to identify patients who are most likely to benefit from the intervention. We systematically reviewed 14 randomized trials to assess how this approach affects study results. We found that the number of primary clinical events observed often differed substantially from what researchers expected when planning the trials. Many studies ended up with fewer events and lower statistical power than anticipated. In addition, the use of biomarkers led to the exclusion of many patients during screening. These findings suggest that biomarkers should be carefully validated before being used to select patients for acute kidney injury trials.

KEY POINTS:Accurate GFR assessment is critical to guiding dosing of cancer therapy and minimizing the risks of toxicity and undertreatment. The role of cystatin C for estimating eGFR for melphalan dosing for multiple myeloma patients undergoing autologous stem cell transplant is poorly investigated. eGFR based on serum creatinine may overestimate melphalan dosing resulting in toxicity in one in five patients undergoing autologous stem cell transplant. BACKGROUND:Accurate renal dosing of high-dose melphalan as conditioning chemotherapy is critical for patients with multiple myeloma (MM) undergoing autologous stem cell transplant (ASCT). In clinical practice, serum creatinine (sCr) is used to eGFR for dosing calculations. The objective of our study was to compare sCr-based eGFR to serum cystatin C-based eGFR (eGFRcys) for melphalan dosing in patients undergoing ASCT for MM to determine discrepancies in dosing and the effect on patient centered outcomes including chemotherapy-related toxicity and hospitalization and to assess International Myeloma Working Group response criteria at 3 and 12 months. METHODS:We conducted a retrospective study including 76 patients with MM who received melphalan conditioning before ASCT. Melphalan dosing in all patients was based on pretransplant eGFR calculated from sCr (200 mg/m 2 for eGFR >50 ml/min, 140 mg/m 2 for eGFR <50 ml/min). We calculated eGFR using both sCr and cystatin C levels before transplantation and observed the 30-day hospitalization from symptoms of melphalan toxicity. We identified a discordant patient group, whose cystatin C eGFR was calculated <50 ml/min compared with sCr eGFR >50 ml/min and would have qualified for a reduced melphalan dose. RESULTS:Of 76 patients, 13 (17%) were identified as having received a higher than intended dose of melphalan when eGFR was estimated using sCr rather than cystatin C (200 mg/m 2 rather than 140 mg/m 2 , discordant dosing). One hundred percent of discordant patients were hospitalized within 30 days of melphalan dosing compared with 60% of the concordant patients whose eGFR was >50 ml/min with both cystatin C and sCr-based eGFR, with melphalan dosing 200 mg/m 2 ( P = 0.006). Furthermore, patients with discordant dosing had a significantly longer hospitalization duration of 7 days compared with 2.5 days in patients with concordant dosing ( P = 0.0014). More patients qualified for dose reduction using eGFRcys compared with combined sCr-cystatin C-based eGFR ( P = 0.02). CONCLUSIONS:Discordance between creatinine and eGFRcys calculations in ASCT patients was linked to inconsistent melphalan dosing and associated with an increase in adverse outcomes.

INTRODUCTION:Greater sodium avidity in acute heart failure (AHF) is associated with worse outcomes, but whether kidney tubule injury is associated with sodium avidity and impaired diuretic responsiveness remains underexplored. METHODS:We evaluated 339 participants from the ROSE-AHF trial, which enrolled patients hospitalized for AHF with kidney dysfunction and randomized them to the dopamine, nesiritide, or placebo group. Urinary kidney injury molecule-1 (KIM-1), N-acetyl-β-D-glucosaminidase (NAG), and neutrophil gelatinase-associated lipocalin (NGAL) were measured at enrolment. Associations between these biomarkers and urinary sodium (uNa) concentration at baseline, fractional excretion of sodium (FeNa), as well as total uNa output and urine output over 72-h were assessed using multivariable regression models. RESULTS:Higher KIM-1 and NAG values at baseline were associated with lower uNa concentration at baseline [-6.1% (-8.5%, -3.7%), P < 0.001 and -5.9% (-9.2%, -2.6%), P & .001, respectively, per two-fold increase in each biomarker]. Higher baseline KIM-1 and NAG were also associated with lower FeNa [-6.1% (-8.5%, -3.6%), P < .001 and -5.2% (-8.6%, -3.6%), P = 0 .001, respectively, per two-fold increase in each biomarker]. Higher baseline KIM-1 was associated with lower total uNa excretion over 72-h [-3.6% (-6.8%, -0.2%), P = 0.037 per two-fold increase]. None of the biomarkers were associated with urine output over 72-h. CONCLUSION:Kidney tubular injury, as assessed by urine KIM-1 and NAG, is associated with greater sodium avidity and higher KIM-1 is associated with impaired diuretic responsiveness in AHF.

INTRODUCTION:Acute kidney injury (AKI) is common complication in the critically ill. Standard functional biomarkers are limited at predicting persistent severe AKI (PS-AKI) and long-term outcomes. This study evaluated the diagnostic and prognostic performance of a panel of urinary biomarkers (novel and standard) for predicting PS-AKI and major adverse kidney events (MAKEs). METHODS:This was an exploratory post hoc analysis of the prospective Dublin Acute Biomarker Group Evaluation (DAMAGE) multicentred prospective observational cohort study. ICU AKI (KDIGO stages 1-3) patients were included. Sixteen urinary biomarkers were measured on the day of AKI diagnosis. The primary endpoint was PS-AKI (stage 2/3 AKI ≥48 h). Discrimination was assessed using AUC and logistic regression models, and reclassification metrics (IDI, cfNRI). Secondary endpoints included MAKE90 and MAKE365. Tertile trends for CCL14 also evaluated. RESULTS:Among 186 patients with AKI, 80 (43.0%) developed PS-AKI. Albumin (uAlb; AUC = 0.82; 95% CI: 0.76-0.88), albumin/creatinine ratio (uAlb/Cr; AUC = 0.79; 95% CI: 0.72-0.85), urine output (AUC = 0.81; 95% CI: 0.74-0.87), and serum creatinine (AUC = 0.77; 95% CI: 0.70-0.84) demonstrated the highest discrimination. In logistic regression analysis adjusted for a clinical model, IL-18 showed the strongest association with PS-AKI (aOR = 3.09; 95% CI: 1.92-5.30), while uAlb, uAlb/Cr, cystatin C, CCL14, and MCP-1 were also significantly associated. CCL14 and uAlb tertiles showed a significant stepwise increase in PS-AKI. uAlb was the strongest discriminator for MAKE90 (AUC = 0.70; 95% CI: 0.57-0.83). Pi-GST was negatively associated with MAKE365 (aOR = 0.44; 95% CI: 0.21-0.81). CONCLUSION:Urine output, uAlb, and uAlb/Cr outperformed several novel biomarkers and demonstrated strong discrimination for PS-AKI. CCL14 showed moderate discrimination and was associated with early adverse outcomes. These findings support integrating standard and novel biomarkers to personalise AKI management.

BACKGROUND AND HYPOTHESIS:Serum creatinine frequently increases during hospitalizations for acute heart failure (AHF) meeting criteria for acute kidney injury (AKI), but the significance of this increase is variable. We evaluated whether admission levels of kidney tubule and cardiac biomarkers are associated with increases in serum creatinine and adverse in-hospital events. METHODS:In a nested case-control, we identified 214 cases with at least stage 1 AKI defined by the 2012 Kidney Disease Improving Global Outcomes criteria within seven days of admission in the Acute Kidney Injury Neutrophil Gelatinase-Associated Lipocalin Evaluation of Symptomatic Heart Failure Study and matched with 214 controls who did not experience AKI. The primary outcome was the development of AKI within the first seven days; secondary outcomes were the development of severe AKI (stages 2 or 3) and a composite of adverse in-hospital events. Associations of 6 blood and 14 urine biomarkers were assessed with logistic regression and Receiver Operating Characteristic Area Under the Curve (ROC-AUC) curve analysis. RESULTS:Individuals were 71 ± 13 years; 64% were men; with median admission creatinine 1.3 [IQR 1.0-1.8] mg/dL. Among AKI cases, 181 (85%), 16 (8%), and 17 (8%) were stages 1, 2, and 3, respectively. Compared to the lowest tertile, only the highest tertiles of fractional excretion of sodium (FeNa ≥ 3.65; OR 1.7, 95% CI 1.0-2.9) and urinary MCP-1 (≥ 433 ng/g; OR 1.7, 95% CI 1.0-2.8) were associated with AKI risk, though discrimination was poor (ROC-AUC < 0.60). Neither was associated with severe AKI. Only elevated B-type natriuretic peptide (≥ 932 pg/mL) predicted the composite adverse in-hospital event (OR 2.3, 95% CI 1.2-4.2). CONCLUSION:Kidney tubule and cardiac biomarkers at admission for AHF are not associated with risk for increases in creatinine or adverse in-hospital events reaffirming that creatinine changes in AHF are largely functional in nature.

Background Loop diuretics require functioning kidney tubules to increase the excretion of sodium into urine thereby relieving congestion in patients with acute heart failure (AHF). Whether biomarkers of kidney tubular health are associated with the natriuretic response of loop diuretics in AHF is unknown. Methods Spot urine sodium and 14 urine biomarkers of tubular health were measured after intravenous loop diuretic administration on the day of enrollment in 418 patients with AHF from AKINESIS (Acute Kidney Injury Neutrophil Gelatinase–Associated Lipocalin [NGAL] Evaluation of Symptomatic Heart Failure Study). The association of each biomarker with urine sodium concentration was assessed with multivariable linear regression. Results The mean age was 71±12 years, 64% were men, average estimated glomerular filtration rate was 56±24 mL/min per 1.73 m2, and urine sodium was 94±48 mEq/L. Higher urine concentrations of α‐1‐microglobulin (−5.0 mEq/L [95% CI, −8.3 to −1.6 mEq/L]), insulin‐like growth factor–binding protein‐7 (IGFBP‐7 mEq/L; −4.1 [95% CI, −8.1 to 0.0 mEq/L]), tissue inhibitor of metalloproteinases 2 (TIMP‐2; −3.6 mEq/L [95% CI, −6.5 to −0.7 mEq/L]), IGFBP‐7*TIMP‐2 product (−5.1 mEq/L [95% CI, −6.6 to −3.7 mEq/L]), interleukin 18 (−8.2 mEq/L [95% CI, −13.2 to −3.1 mEq/L]), kidney injury molecule 1 (−2.4 mEq/L [95% CI, −4.4 to −0.3 mEq/L]), and chemokine ligand 14 (−2.3 mEq/L [95% CI, −4.0 to −0.5 mEq/L]) were associated with lower urine sodium concentration after adjustment for confounders including estimated glomerular filtration rate and urine albumin. Conclusions Urine biomarkers of tubular health are associated with lower natriuretic response to loop diuretics in patients with AHF. Kidney tubule health may be an underappreciated contributor to diuretic responsiveness in AHF.

INTRODUCTION:The impact of empiric intraoperative vancomycin and piperacillin-tazobactam (VPT) compared to vancomycin and cefepime (VC) on AKI is equivocal, and renal recovery and infection outcomes have not been studied in this context. Further, this has not been studied in patients undergoing orthotopic heart transplantation (OHT). METHODS:We performed a single-center prospective study in patients undergoing OHT (n = 120), with a change in intraoperative microbial coverage from VPT to VC. Primary outcomes included AKI rates and stage. Secondary outcomes included renal recovery rates, bloodstream bacterial infections, rates of enterococcal infection, ESRD (end-stage renal disease), change in eGFR, and mortality at 12 months post-OHT. RESULTS:Rates of all stages of AKI were similar between groups (p = 0.769), and the majority of AKI in both groups were Stage 1. 27.1% of patients in the pre-intervention arm and 25.0% in the post-intervention arm had a Stage 3 AKI (p = 0.798). Rates of recovery from AKI at 7 days showed a trend toward improved recovery in patients receiving VC compared to VPT (65.1%, 46.7%, p = 0.056), but recovery from RRT at 7 days and recovery from RRT at hospital discharge were not statistically significant between groups (p = 0.140, p = 0.659). Rates of bloodstream infection were similar following the change in empiric antimicrobials (2.08%, 4.17%; p = 0.53), and rates of wound infection were similar following this change (4.2%, 1.4%; p = 0.56). There was no increase in enterococcal infections. CONCLUSION:In patients undergoing OHT and receiving empiric antimicrobial therapy, change from VPT to VC did not affect the incidence or severity of AKI, renal recovery, or infection rates.

INTRODUCTION:Haemodynamic adverse events related to renal replacement therapy are a complication of all RRT modalities used in the ICU, including intermittent haemodialysis (IHD), sustained low efficiency dialysis (SLED) and continuous renal replacement therapy (CRRT). At present it is unclear which risk factors predispose to HAE and whether these contribute to adverse patient outcomes. METHODS:We performed a secondary analysis of the multinational STARRT-AKI trial to assess factors associated with the occurrence of haemodynamic adverse events (HAE) in patients receiving RRT and whether these HAE were associated with less favourable clinical outcomes. The primary analysis was a multivariable Cox proportional hazards model based on the least absolute shrinkage and selection operator (LASSO), which included time to HAE as the dependent variable. RESULTS:Factors significantly associated with an increased hazard ratio (HR) for HAE during RRT were a higher SOFA score at RRT initiation (HR 1.05; 95% 1.00-1.10), use of IHD as the initial RRT modality in comparison to CRRT (HR 1.74; 95% CI 1.28-2.37) and use of SLED as the initial RRT modality in comparison to CRRT (HR 2.73; 95% CI 1.65-4.51). In a multivariable analysis, adjusted for baseline patient characteristics and RRT initiation covariates, there was no significant association between the occurrence of a HAE during RRT and mortality, dialysis dependence, length of stay, RRT-free days, ventilator-free days or vasoactive-free days, respectively. There was, however, a significant association between multiple haemodynamic adverse events and all-cause mortality at 90 days. CONCLUSIONS:In this secondary analysis of the STARRT-AKI trial, the use of intermittent RRT modalities and higher severity of illness were associated with HAE during RRT. These events were not significantly associated with adverse clinical outcomes, apart from a significant association between multiple HAE and all-cause mortality at 90 days.

INTRODUCTION:The management of severe traumatic brain injury (sTBI) in the intensive care unit (ICU) is focused on preventing secondary brain insults, by ensuring adequate cerebral perfusion, oxygenation and substrate delivery. Despite optimisation of intracranial pressure (ICP) and cerebral perfusion pressure (CPP) using evidence-based guidelines, brain tissue hypoxia can still occur and is strongly associated with adverse functional outcomes post sTBI. METHODS AND ANALYSIS:The Brain Oxygen Neuromonitoring in Australia and New Zealand Assessment - Global Trial (BONANZA-GT) is an international, two-arm, open-label, parallel group, randomised controlled trial comparing sTBI management incorporating early brain tissue oxygen (PbtO2) monitoring and optimisation, with ICP/CPP-based management alone. A total of 860 adults admitted to participating institutions with non-penetrating sTBI and requiring insertion of an ICP monitor (as determined by the treating neurosurgeon) will be enrolled. The primary outcome is the proportion of patients with favourable neurological outcomes, as defined by a Glasgow Outcome Score-Extended (GOS-E) >4, at 6 months following injury. Key secondary outcomes include all-cause mortality at ICU discharge, hospital discharge, adverse events, as well as hospital and ICU length of stay and GOS-E at 12 months. The BONANZA-GT will determine whether a protocolised therapeutic strategy guided by continuous PbtO2 monitoring in addition to ICP/CPP targets results in improved neurological outcomes when compared with standard care using ICP/CPP-guided management alone. ETHICS AND DISSEMINATION:Approval has been obtained from relevant ethics boards in every jurisdiction that is participating in the trial. Inclusion of adults who lack capacity for informed consent will be governed in accordance with the legal requirements of each participating site. Study findings will be presented at scientific meetings and disseminated via peer-review publications. TRIAL REGISTRATION NUMBER:Australian and New Zealand Clinical Trials Registry (ACTRN 12619001328167).

Cardiac procedures, particularly those requiring cardiopulmonary bypass (CPB), are associated with the development of cardiac surgery-associated acute kidney injury (CSA-AKI). Development of CSA-AKI occurs as a result of inflammation, uncontrolled complement activation, and kidney cell damage. In patients with preoperative renal impairment, such as those with chronic kidney disease (CKD), there is an increased risk of both CSA-AKI and poorer clinical outcomes. Currently, there are limited effective, targeted pharmacological interventions for the prevention or treatment of CSA-AKI, although emerging therapies are being investigated, particularly in patients with existing CKD. The ARTEMIS (RAvulizumab to PRotect PaTients with Chronic Kidney DisEase froM CSA-AKI and Subsequent Major Adverse Kidney Events) trial will assess the efficacy and safety of ravulizumab (a complement C5 inhibitor) in reducing the risk of major adverse kidney events (MAKE) in patients with preoperative CKD undergoing non-emergent cardiac surgery with CPB. This trial is currently recruiting patients with CKD who have planned cardiac surgery requiring CPB including coronary artery bypass grafting, valve replacement or repair, or combined procedures. This is a phase 3, randomized, double-blind, placebo-controlled, global study assessing the efficacy and safety of a single preoperative dose of ravulizumab. These outcomes will be assessed using the occurrence of MAKE and its components, as well as the occurrence and severity of CSA-AKI throughout the study period. Complement activation is known to occur during and after cardiac procedures as a result of CPB and ischemia–reperfusion injury, leading to a cycle of cell damage and death. Therefore, it is hypothesized that preoperative administration of ravulizumab will provide immediate and complete complement inhibition, which will be sustained throughout the surgical period, preventing the uncontrolled complement activation associated with the development of CSA-AKI, thus minimizing poor outcomes for patients. ClinicalTrials.gov NCT05746559. Registered on February 27, 2023.

Background Whether variability of B-type natriuretic peptide (BNP) values between races affects its clinical integration as a marker for congestion and predictor of prognosis in acute heart failure (AHF) remains unknown. We aimed to investigate the relationship between diuretic therapy, change in BNP value, and prognosis in AHF in relation to racial differences. Methods This analysis combined data from the AKINESIS and REALITY-AHF studies. We included White, Black, and Asian individuals admitted with AHF requiring intravenous diuretic therapy. We examined the relative change in BNP values at 48 h post hospital admission, and its association with diuretic therapy and one-year mortality. Results Of 1380 participants, 29 % were White, 12 % were Black, and 58 % were Asian. Admission BNP values were highest in Black, followed by Asian and White individuals. After adjusting for confounding factors, Black individuals had significantly higher admission BNP values compared to White individuals. During the first 48 h of hospitalization, Asian individuals received the lowest diuretic dose but demonstrated the greatest diuretic response and BNP decrease. After adjustment for confounding factors, Asian individuals were more likely to have a BNP decrease compared to White individuals. Higher admission BNP values predicted higher one-year mortality in White and Asian but not in Black individuals (p for interaction = 0.021). BNP decrease was associated with a lower one-year mortality without a significant interaction by race. Conclusions In AHF patients, admission BNP was higher in Black, and its decrease after diuretic therapy was greater in Asian individuals. A BNP decrease predicted a better prognosis, regardless of race.

Introduction: We evaluated a panel of novel urinary and serum biomarkers (BMs) for early and sensitive detection of cisplatin drug-induced kidney injury (DIKI) in patients with cancer, comparing their diagnostic accuracy with standard BMs (SBMs). Methods: In this prospective exploratory observational study, 105 patients treated with cisplatin (“treated” with > 65 mg/m2/cycle), 20 non-cisplatin treated cancer controls (“nontreated”), and 34 “healthy” controls were enrolled. The treated group’s serum and urine samples were collected predose, after 12 hours, and on days 1, 2, 4, 7, 14, and 21. SBMs and novel BMs (NBMs; 8 urinary, 1 serum) were measured, comparing accuracy, percent changes from baseline (PCFBs), and median time to peak values between treated patients and nontreated cancer controls. Blinded adjudication of the treated group’s BM profiles occurred at 2 stages for DIKI diagnosis. Results: All urinary NBMs had significant PCFBs in the treated group compared with the nontreated cancer control group; most accurately detected cisplatin exposure (area under the receiver operating characteristics [ROC] curve [AUROC] > 0.8). NBMs peaked earlier. In stage 1 adjudication (SBMs) of the treated group, PCFB of urinary NBMs showed no difference between DIKI (n = 24) and no-DIKI (n = 71) groups except for neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C (CYSC). In treated participants, all BMs showed greater PCFBs than control groups, regardless of stage 1 DIKI adjudication. Stage 2 (SBMs and NBMs), DIKI incidence (n = 63) increased by 41%, with most BMs having an AUROC > 0.80 compared with the nontreated cancer control group. Conclusion: NBMs accurately and timely detected cisplatin exposure and identified “sub-clinical” DIKI undetected by standard acute kidney injury (AKI) criteria, highlighting the limitations of current functional BMs in estimating the true DIKI incidence.

BACKGROUND:Kidney dysfunction, defined by measures of glomerular health, in patients hospitalized with acute heart failure (HF) is associated with death and HF readmission. We aimed to determine if kidney tubule damage and dysfunction are associated with these outcomes in acute HF. METHODS:In AKINESIS (Acute Kidney Injury Neutrophil Gelatinase-Associated Lipocalin [NGAL] Evaluation of Symptomatic Heart Failure Study), 218 individuals admitted with acute HF experiencing acute kidney injury were matched with 218 individuals without acute kidney injury. Fourteen urine tubular damage and dysfunction biomarkers were measured at hospital admission in this case-control cohort. Associations between biomarkers and the composite outcome of death or HF readmission, death alone, and HF readmission alone were evaluated adjusting for confounders including kidney and cardiac biomarkers. RESULTS:The mean age was 71±12 years, 64% were men, and mean admission estimated glomerular filtration rate was 55±23 mL/min per 1.73 m2. There were 156 deaths or HF readmissions, 87 deaths, and 92 HF readmissions over 1 year. Each 2-fold higher level of IGFBP-7 (insulin-like growth factor binding protein-7), IGFBP-7*TIMP-2 (tissue inhibitor of metalloproteinases-2) product, KIM-1 (kidney injury molecule-1), and MCP-1 (monocyte chemoattractant protein-1) was associated with a 1.36 (95% CI, 1.13-1.64), 1.08 (95% CI, 1.01-1.14), 1.12 (95% CI, 1.02-1.24), and 1.18 (95% CI, 1.03-1.34) higher risk of death or HF readmission, respectively. IGFBP-7 was associated with death alone, whereas MCP-1 and CCL-14 (C-C motif chemokine ligand-14) were associated with HF readmission alone. CONCLUSIONS:Biomarkers of kidney tubular health are associated with risk of death and HF readmission among people admitted with acute HF independent of measures of glomerular function and cardiac risk.

Introduction: Patients with severe acute kidney injury (AKI) with associated acute hypoxemic respiratory failure (AHRF) experience poorer outcomes, including higher rates of in-hospital mortality, relative to patients with less severe AKI, or those without associated AHRF. Zegocractin is a calcium release-activated calcium (CRAC) channel inhibitor with potent anti-inflammatory and pulmonary endothelial protective properties. Preclinical and early phase clinical studies suggest that zegocractin may be an effective agent for the treatment of AKI. Methods: KOURAGE (NCT06374797) is a multicenter, phase 2, randomized, double blind, placebo-controlled trial that aims to enroll approximately 150 patients with severe AKI and AHRF. Eligible patients will be randomized 1:1 to receive a total of five daily doses of zegocractin intravenous emulsion (Auxora™) or matching placebo. The objective was to evaluate the safety and efficacy of Auxora in patients with severe AKI, with the primary efficacy endpoint defined as the number of days alive, ventilator-free and kidney replacement therapy-free from the start of the first infusion of the study drug through day 30. A key secondary efficacy endpoint is the proportion of patients with major adverse kidney events at day 90. Conclusion: The KOURAGE trial will investigate the safety and efficacy of Auxora in patients with severe AKI and AHRF. .

[This corrects the article DOI: 10.1016/j.ekir.2025.01.035.].

BACKGROUND:Differentiating functional acute kidney injury (AKI) from structural/intrinsic AKI with tubular injury remains a clinical challenge. Urinary NGAL (uNGAL) has shown promise in distinguishing these conditions. This study evaluated the implementation of uNGAL in a heterogeneous medical cohort at an academic tertiary care center in Ireland over a three-year period. METHODS:A retrospective audit was conducted from 2020-2023. Standard clinical data around the time of AKI and uNGAL request were recorded. Blinded case adjudication of the differential diagnosis of AKI cause using the standard clinical information (but not urine NGAL results) was performed by two expert Nephrologists. Analysis of uNGAL focused on the accuracy in differentiating adjudicated (Intra-renal) AKI from Non-intrinsic AKI (Pre-renal & Post-renal). RESULTS:A total of 323 uNGAL tests were performed, with 292 AKI cases adjudicated. Intrinsic AKI cases had significantly higher uNGAL and uNGAL/Cr levels than non-intrinsic cases (p < 0.001), including after excluding UTI cases. uNGAL (AUC 0.71; 95% CI: 0.65-0.77) and uNGAL/Cr (AUC 0.73; 95% CI: 0.67-0.79) showed moderate discriminative performance. uNGAL (threshold 150 ng/ml) had high sensitivity (0.87) and negative predictive value (0.82). uNGAL/Cr was similar at the 288 ng/mg threshold. Discriminative performance improved for uNGAL and uNGAL/Cr, but not for serum creatinine, fractional excretion of sodium (FENa), or serum urea, after excluding UTI cases. Both uNGAL (aOR 2.05; 95% CI: 1.59-2.71) and uNGAL/Cr (aOR 2.07; 95% CI: 1.64-2.68) were independently associated with intrinsic AKI. Adding these biomarkers to a logistic regression model significantly improved discrimination performance (AUC 0.79; 95% CI: 0.76-0.84; p = 0.0116). CONCLUSIONS:The use of uNGAL improved the discriminative accuracy of differential diagnosis of AKI in clinical practice by differentiating intrinsic AKI from non-intrinsic. Specificity was low at the manufacturer's recommended threshold (150ng/ml), but the sensitivity and NPV were high in all analyses. These findings support the clinical utility of uNGAL at the 150ng/ml threshold as a "rule-out" test for intrinsic AKI, thereby helping to direct management toward functional (pre-renal) or obstructive (post-renal) causes when uNGAL is negative.

BACKGROUND:Worsening renal function (WRF) is common in hospitalized patients being treated for acute heart failure. However, discriminating clinically significant WRF remains challenging. In patients hospitalized with acute heart failure, we evaluated if blood and urine biomarkers of cardiac and kidney dysfunction were associated with adverse outcomes. METHODS:We identified 175 of 927 participants in the AKINESIS study (Acute Kidney Neutrophil Gelatinase-Associated Lipocalin Evaluation of Symptomatic Heart Failure Study) who met criteria for stage 1 or 2 Kidney Disease: Improvement Global Outcomes acute kidney injury during the first 3 days of hospitalization. We measured 24 blood and urine biomarkers from specimens collected within 24 hours of meeting acute kidney injury criteria. The primary composite outcome consisted of worsening WRF (higher acute kidney injury stage), need for dialysis, or death at 30 days. Biomarkers' association with the composite outcome was assessed with logistic regression by tertiles and area under the curve (AUC). RESULTS:Of the 175 participants, 32 (18%) developed the primary composite outcome. Only history of chronic kidney disease was significantly different between those with and without the composite outcome. The highest tertile of plasma Gal-3 (galectin-3) and urine epidermal growth factor were associated with increased odds of the composite outcome compared with the lowest tertile in unadjusted analyses. After adjusting for serum creatinine, systolic blood pressure, and blood urea nitrogen, only the highest tertile of Gal-3 was associated with greater odds of the composite outcome (odds ratio, 4.6 [95% CI, 1.4-16.0). Gal-3 had the highest AUC (0.70 [95% CI, 0.58-0.82]), while epidermal growth factor had a lower AUC (0.63 [95% CI, 0.53-0.74]). Notably, urine biomarkers of kidney tubule injury were not associated with the composite outcome. CONCLUSIONS:Tubular injury does not occur in most patients with acute heart failure experiencing WRF, consistent with the functional mechanisms of WRF in this patient population. REGISTRATION:URL: https://www.clinicaltrials.gov/study/NCT01291836?term=NCT01291836&rank=1; Unique identifier: NCT01291836.