Underreporting of Acute Kidney Injury in Randomized Trials of ARDS with Mortality Endpoints: A Systematic Review

Underreporting of Acute Kidney Injury in Randomized Trials of ARDS with Mortality Endpoints: A Systematic Review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Underreporting of Acute Kidney Injury in Randomized Trials of ARDS with Mortality Endpoints: A Systematic Review Rogerio da Hora Passos, Bruno Zawadzki, Luis Claudio Santos Pinto, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7272410/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Acute Kidney Injury (AKI) is a frequent complication among patients with Acute Respiratory Distress Syndrome (ARDS), and its definition has evolved significantly over the past two decades. We conducted a systematic review to evaluate how AKI was defined in randomized controlled trials (RCTs) involving ARDS patients and whether changes in AKI definitions impacted mortality outcomes. Methods This systematic review was registered on PROSPERO (CRD420251043094). We searched PubMed/MEDLINE, Embase, and Cochrane databases up to December 2023 for RCTs that reported AKI in ARDS patients. Studies were grouped according to the AKI definitions used: RIFLE, AKIN, KDIGO, or undefined. Descriptive statistics and mortality trends were assessed across groups. Results A total of 39 RCTs were included. Only 15 studies (38.4%) adopted standardized definitions for AKI—5 used RIFLE, 4 used AKIN, and 6 used KDIGO. The remaining 24 studies (61.5%) did not clearly define AKI. Among studies using KDIGO, mortality rates for AKI patients ranged from 32–56%, whereas those without defined criteria reported broader and less consistent mortality outcomes. There was no consistent trend indicating improved mortality outcomes with more recent definitions. Conclusions Despite the evolution of AKI diagnostic criteria, most RCTs on ARDS still lack standardized definitions for AKI. This heterogeneity limits comparison across trials and impairs the accuracy of clinical interpretations. The implementation of KDIGO criteria should be encouraged in future ARDS-related research to improve standardization and comparability. Figures Figure 1 Introduction Acute respiratory distress syndrome (ARDS) is a major cause of morbidity and mortality in critically ill patients. ( 1 ) Defined by non-cardiogenic pulmonary edema, severe hypoxemia, and reduced lung compliance, ARDS often requires prolonged mechanical ventilation and intensive care. ( 2 ) While the syndrome is primarily pulmonary in presentation, its systemic implications are substantial multiorgan dysfunction is common, and the kidneys are particularly vulnerable. ( 3 ) Acute kidney injury (AKI) occurs frequently in patients with ARDS and is associated with poor outcomes, including longer ICU stays, increased need for renal replacement therapy (RRT), and higher mortality.( 4 ) The interplay between lung and kidney injury involves complex hemodynamic, inflammatory, and neurohormonal mechanisms.( 5 ) Clinical management strategies such as fluid therapy, ventilator settings, and pharmacologic interventions can directly influence both pulmonary and renal function. ( 6 ) As such, the kidney is not just a bystander in ARDS but a key determinant of disease trajectory. ( 7 ) Recent patient-level analyses from over 5,000 participants in 10 ARDS trials revealed a 43.7% incidence of AKI, with stable risk over time and an estimated 15.4% excess 90-day mortality attributable to AKI rising to 20.3% in severe cases. ( 8 ) Most AKI occurred early during critical illness and was linked to factors such as hemodynamic instability, inflammation, and ventilator-associated injury. ( 9 ) Despite advances in ICU care, no improvement in AKI incidence or renal recovery was observed, underscoring the need for consistent reporting and kidney-specific endpoints in ARDS trials. ( 10 ) The aim of this systematic review was to examine how AKI is captured in ARDS RCTs that use mortality as a primary endpoint. Specifically, we sought to determine how often AKI is reported as an outcome, whether standardized definitions are applied, and to what extent trials report RRT use, assess fluid balance, or include kidney-related subgroup analyses. Methods Review registration and reporting guidelines The protocol for this systematic review was registered on PROSPERO (Registration No: CRD420251043094) on June 26, 2024. Reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The completed PRISMA checklist is available in Additional file 1: File A. Objective This review aimed to assess how acute kidney injury (AKI) is represented and reported in randomized controlled trials (RCTs) involving patients with acute respiratory distress syndrome (ARDS) when mortality is the primary outcome. Eligibility criteria Types of studies We included parallel arm randomized controlled trials conducted in adult populations with ARDS, published in English between January 1, 2005, and April 10, 2025. Only trials reporting mortality as a primary endpoint were eligible. Review articles, editorials, observational studies, and non-randomized interventions were excluded. Participants Studies were eligible if they enrolled adult patients (≥ 18 years) diagnosed with ARDS, as defined by either the AECC (American European Consensus Conference) or Berlin criteria. Interventions There were no restrictions regarding intervention type, comparator, or ventilatory strategy. Included studies investigated any therapeutic or supportive intervention in the context of ARDS. Outcomes The primary focus was on the representation and reporting of AKI. This included whether AKI was included as a secondary or exploratory outcome, whether formal definitions (such as KDIGO, AKIN, or RIFLE) were used, whether serum creatinine or renal replacement therapy (RRT) was reported, whether AKI was classified as an adverse event, whether subgroup analyses by AKI status were performed, and whether fluid balance was reported in relation to renal function. Search strategy A comprehensive search was conducted in PubMed, Embase, and Scopus using controlled vocabulary (MeSH) and relevant keywords. The following terms were used: (“Acute Respiratory Distress Syndrome” [Mesh] OR “ARDS” OR “SARA” OR “acute lung injury”) AND (“Mortality” [Mesh] OR mortality OR “Death”) AND (“Randomized Controlled Trial” [Publication Type] OR “Randomized Controlled Trials as Topic”[Mesh] OR “randomized trial” OR “randomized trial”). The search included studies published between January 1, 2005, and April 10, 2025, and was limited to English-language publications involving adult patients. Study selection Two reviewers independently screened all titles and abstracts for eligibility. Full-text articles were retrieved for potentially eligible studies and reviewed in detail. Discrepancies were resolved through discussion and consensus. Data extraction and management Two reviewers independently extracted data using a standardized form. Extracted information included study design, setting, intervention type, ARDS severity, COVID-19 status, AKI definitions, creatinine monitoring, RRT use, fluid balance reporting, and whether AKI was analyzed as an adverse event or stratified subgroup. Risk of bias assessment As no meta-analysis was planned and effect sizes were not pooled, formal risk-of-bias tools were not applied. Instead, methodological completeness and the consistency of AKI-related reporting were qualitatively assessed across trials. Data synthesis Findings were synthesized descriptively. Reporting practices related to AKI were compared across included studies. Trends in AKI representation over time, by intervention type, and by COVID-19 versus non-COVID status were evaluated narratively. Results Study Selection A total of 312 articles were initially identified through database searches. Tables 1 and 2 presents the characteristics of the 27 included RCTs, including sample size, intervention type, ARDS severity and associated Acute Kidney Injury Outcomes. After removal of duplicates and screening of titles and abstracts, 28 randomized controlled trials (RCTs) met the eligibility criteria and were included in the final analysis. Study Characteristics Of the 27 included studies, 25 were conducted as multicenter trials (11-36), and 2 (37-38) were single center. Two studies enrolled patients exclusively with COVID-19 related ARDS (32-35), whereas 25 studies investigated ARDS of other etiologies. The classification of ARDS varied among the included studies. A total of 16 studies specifically enrolled patients with moderate a severe ARDS. Seven studies defined ARDS based on PaO2/FiO2 ,thereby potentially including patients across the mild,moderate, and severe spectrum.(12,14,15,16,22,27,37,38) Three studies included patients with mild to moderate ARDS (13,23,33) and only two studies explicity focused on severe ARDS. (22,27). The included randomized controlled trials investigated a wide range of interventions for ARDS (As detailed in Table 1, ventilatory strategies were the most frequently studied intervention.). Ventilatory strategies were the most frequently studied, appearing in 12 trials (11,14,15,16,21,24.26,29,30,33,34,36). Neuromuscular blockade was evaluated in 2 trials (17,24), and prone positioning was investigated in 2 studies (28,29), including one that focused specifically on patients with severe ARDS. Corticosteroids were assessed in 2 studies (37,38), and immunomodulatory agents such as itolizumab (32) and rosuvastatin (23) were included in 1 trial each. Fluid management strategies (12) and liberal oxygen therapy (31) were each evaluated in 1 study. Extracorporeal support with ECMO (27) was studied in 1 trial, while convalescent plasma (15) was assessed in another. Other pharmacologic interventions included intratracheal calf actant (25), recombinant surfactant protein C–based surfactant (19), and intravenous salbutamol (20), each studied in 1 trial. One trial also compared pulmonary artery versus central venous catheterization (13) for the management of acute lung injury. Reporting of AKI and Related Renal Variables Acute kidney injury (AKI) was reported as a predefined secondary outcome in two studies (Table 2 summarizes how AKI and related renal variables were reported across included trials.). (12,23) No study reported AKI as an adverse event. No study employed formal AKI definitions, such as those proposed by KDIGO, AKIN, or RIFLE. Serum creatinine values were reported in two studies (12,23), either at baseline or during the follow-up period. Among the included studies, 18 trials reported using the SOFA (12,13,15,17,18,21,22,26,27,28,29,30,31,32,33,34,35,36) score as the definition for AKI; however, none of them specified the use or individual components of the renal SOFA sub score. Renal replacement therapy (RRT) use was reported in two studies (12,33). In these, RRT was presented as the proportion of patients receiving therapy in each arm, without additional details regarding modality, timing, or criteria for initiation. No study reported the proportion of patients with AKI at enrollment or the incidence of AKI during the study follow-up. Similarly, none of the included studies reported a specific mortality analysis for the AKI subgroup Reporting of Fluid Balance Fluid balance data were available in three studies (As shown in Table 2 , only three studies reported early fluid balance data within 48 hours of randomization.). In most cases, fluid balance was reported at early time points, such as within 24 to 48 hours after randomization (12,13,36). None of the included studies incorporated fluid balance into adjusted analyses or explored its association with mortality or organ dysfunction. Mortality Outcomes The mortality endpoint was consistently reported across all included studies, with time frames ranging from 28 to 90 days , and in some cases, hospital mortality was used as the primary outcome. The most frequently used time point was 28-day mortality (13,17,19,20,22,24,26,29,31,33,35,37,38) , reported in 14 studies , followed by 90-day mortality in 6 studies (15,18,25,28,30,34) , and 60-day mortality in 5 studies (11,12,23,27,36), and 30-day mortality in one study (32) . Two studies reported hospital mortality (14,16) as the outcome. Despite this consistency in mortality reporting, the heterogeneity in time frames and the absence of standardized mortality subgroup analyses (e.g., by AKI status) highlight variability in outcome assessment across trials. Discussion This systematic review highlights a persistent and clinically relevant omission in the design of randomized controlled trials (RCTs) in ARDS. Although acute kidney injury (AKI) is a frequent complication in moderate to severe ARDS and independently contributes to worse outcomes, kidney-specific endpoints were rarely incorporated. Most trials did not apply standardized AKI definitions—such as KDIGO—and reporting of renal outcomes, including serum creatinine trajectories or use of renal replacement therapy, was inconsistent or absent. This lack of structured renal assessment limits the interpretability of multiorgan effects and hinders efforts to advance organ-supportive strategies in this population. None of the included trials employed standardized AKI definitions such as KDIGO, despite their broad acceptance and incorporation into ICU research since 2012. (39) Instead, several studies referred to the SOFA score but failed to clarify whether or how the renal subscore was utilized. This ambiguity limits the clinical interpretability of renal dysfunction and precludes valid cross-trial comparisons. (40) Furthermore, reporting of serum creatinine and renal replacement therapy (RRT) was often incomplete, lacking key clinical details such as timing, modality, and initiation thresholds. These methodological gaps are particularly concerning given the well-established prognostic value of renal function and RRT parameters in critically ill populations. (41,42) Fluid balance—a key determinant of both pulmonary and renal outcomes in critical illness—was infrequently reported. Fewer than 20% of trials included data on cumulative fluid status, and only a minority incorporated it into adjusted analyses. This omission is particularly notable given evidence from the FACTT trial and subsequent cohort studies demonstrating that fluid overload contributes to both pulmonary edema and acute kidney injury. (43) Failure to account for fluid dynamics may obscure the renal consequences of lung-targeted interventions and limit the detection of potential harm in susceptible subgroups. (44) None of the included trials conducted stratified analyses based on AKI status or examined potential heterogeneity of treatment effect according to baseline kidney function. This represents a missed opportunity to evaluate whether patients with impaired renal reserve respond differently to interventions in ARDS. Renal dysfunction is known to alter drug pharmacokinetics, modulate systemic inflammation, and influence hemodynamic responses—all of which may interact with therapies such as lung-protective ventilation, corticosteroids, or extracorporeal modalities.(45) Moreover, mechanical ventilation itself—particularly when associated with ventilator-induced lung injury (VILI)—can propagate kidney injury through biotrauma and altered hemodynamics.(46) Identifying such cross-organ interactions is essential to advancing precision medicine and should be prioritized in future trial designs. (47) The broader issue reflected in these findings is the persistence of a single-organ approach in critical care trials. ARDS continues to be framed primarily as a pulmonary condition, despite growing recognition of its systemic implications. Lung–kidney crosstalk is well established, involving mechanical, inflammatory, and neurohormonal pathways. By neglecting kidney-specific endpoints, current RCTs risk overlooking meaningful effects or unintended harms, especially in patients with overlapping vulnerabilities. (48,49) RRT, a high-cost and high-stakes intervention, was rarely analyzed despite being recorded in several trials. Without reporting RRT timing or stratifying mortality by its use, trial conclusions may mask differences in severity or misattribute outcomes. This omission weakens both internal validity and external applicability, particularly for ICU clinicians managing patients with evolving multiorgan failure. (50,51) Strengths and Limitations This review has several strengths. It is, to our knowledge, the first to systematically assess how AKI is reported in RCTs of ARDS with mortality endpoints. The methodology followed PRISMA guidelines, included three major biomedical databases, and spanned two decades of trial activity. By focusing on mortality-powered studies, we prioritized trials with high clinical impact and relevance to bedside care. However, some limitations must be acknowledged. We limited inclusion to English-language studies, which may have excluded relevant international trials. We did not perform a formal risk-of-bias assessment, as the review was descriptive and not focused on treatment efficacy. Additionally, our analysis relied on reported data; some studies may have collected renal variables but chose not to report them due to space constraints or prioritization of respiratory endpoints. Finally, given the heterogeneity in ARDS definitions over time, some variation in population severity and trial design was inevitable. Conclusion AKI is a frequent and clinically meaningful complication in ARDS, yet it remains consistently underreported in randomized trials—even those explicitly designed to evaluate mortality. This gap limits the interpretability and applicability of trial results, particularly in high-risk patients. Future ARDS trials should adopt standardized AKI definitions, routinely report RRT and fluid balance, and perform subgroup analyses by renal function. Recognizing the multisystem nature of critical illness is essential to designing trials that are both scientifically sound and clinically useful. Abbreviations ARDS Acute Respiratory Distress Syndrome AKI Acute Kidney Injury RCT Randomized Controlled Trial N Number of patients included PEEP Positive End–Expiratory Pressure PaO₂/FiO₂ Ratio of arterial oxygen partial pressure to inspired oxygen fraction CVP Central Venous Pressure RRT Renal Replacement Therapy ICU Intensive Care Unit CKD Chronic Kidney Disease KDIGO Kidney Disease: Improving Global Outcomes Cr Creatinine UO Urine Output CXR Chest X–ray FiO₂ Fraction of Inspired Oxygen PaO₂ Arterial Partial Pressure of Oxygen MAP Mean Arterial Pressure Declarations Ethical Approval and Consent to Participate Not applicable, as this study is a systematic review and did not involve human participants, data, or animals requiring ethical approval. Consent for Publication Not applicable . Availability of Supporting Data All data generated or analyzed during this study are included in this published article. Competing Interests The authors declare that they have no competing interests. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Authors' contributions (CRediT Taxonomy) R.H.P.: Conceptualization, Supervision, Formal analysis, Writing – Review & Editing; B.Z: Data curation, Investigation, Writing; L. C. S. P: Methodology, Investigation, Formal analysis; R. H. M: Formal analysis, Data curation, Writing – Review & Editing; T.D.M: Methodology, Project administration, Writing – Review & Editing; B.A.B: Validation, Investigation, Writing – Review & Editing; V. P. C. J. : Formal analysis; A. A. S. : Formal analysis; P.N: Resources, Writing – Review & Editing, Visualization; F.O.C: Data curation, Resources, Project administration. All authors reviewed the manuscript Acknowledgements Not applicable. References Bos LDJ, Ware LB. Acute respiratory distress syndrome: causes, pathophysiology, and phenotypes. Lancet. 2022 Oct 1;400(10358):1145-1156. doi: 10.1016/S0140-6736(22)01485-4. 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Joannidis M, Forni LG, Klein SJ, Honore PM, Kashani K, Ostermann M, Prowle J, Bagshaw SM, Cantaluppi V, Darmon M, Ding X, Fuhrmann V, Hoste E, Husain-Syed F, Lubnow M, Maggiorini M, Meersch M, Murray PT, Ricci Z, Singbartl K, Staudinger T, Welte T, Ronco C, Kellum JA. Lung-kidney interactions in critically ill patients: consensus report of the Acute Disease Quality Initiative (ADQI) 21 Workgroup. Intensive Care Med. 2020 Apr;46(4):654-672. Kellum, J.A., Romagnani, P., Ashuntantang, G. et al. Acute kidney injury. Nat Rev Dis Primers 7 , 52 (2021). Benites, M.H., Suarez-Sipmann, F., Kattan, E. et al. Ventilation-induced acute kidney injury in acute respiratory failure: Do PEEP levels matter?. Crit Care 29 , 130 (2025). Meersch M, Mayerhöfer T, Joannidis M. Acute kidney injury subphenotyping and personalized medicine. Curr Opin Crit Care. 2024 Dec 1;30(6):555-562. Nasa P, Bos LD, Estenssoro E, van Haren FM, Serpa Neto A, Rocco PR, Slutsky AS, Schultz MJ. Consensus statements on the utility of defining ARDS and the utility of past and current definitions of ARDS-protocol for a Delphi study. BMJ Open. 2024 Apr 25;14(4):e082986. Nasa, PrashantAryal, Diptesh et al. Defining and subphenotyping ARDS: insights from an international Delphi expert panel The Lancet Respiratory Medicine, Volume 0, Issue 0 Naorungroj T, Neto AS, Wang A, Gallagher M, Bellomo R. Renal outcomes according to renal replacement therapy modality and treatment protocol in the ATN and RENAL trials. Crit Care. 2022 Sep 6;26(1):269 Wald, R., Gaudry, S., da Costa, B.R. et al. Initiation of continuous renal replacement therapy versus intermittent hemodialysis in critically ill patients with severe acute kidney injury: a secondary analysis of STARRT-AKI trial. Intensive Care Med 49 , 1305–1316 (2023) Tables Tables 1 to 2 are available in the Supplementary Files section. PRISMA Checklist Additional File 1: FIle A: Completed PRISMA checklist is not available with this version. Additional Declarations No competing interests reported. Supplementary Files Table1.pdf Table1: Summary of Randomized Controlled Trials Investigating Acute Respiratory Distress Syndrome and Mortality or Primary Outcome. Abbreviations: ARDS – Acute Respiratory Distress Syndrome, AKI – Acute Kidney Injury,RCT – Randomized Controlled Trial, N – Number of patients included, PEEP – Positive End-Expiratory Pressure,PaO₂/FiO₂ – Ratio of arterial oxygen partial pressure to inspired oxygen fraction,CVP – Central Venous Pressure,RRT – Renal Replacement Therapy,ICU – Intensive Care Unit,CKD – Chronic Kidney Disease,KDIGO – Kidney Disease: Improving Global Outcomes,Cr – Creatinine,UO – Urine Output,CXR – Chest X-ray,FiO₂ – Fraction of Inspired Oxygen,PaO₂ – Arterial Partial Pressure of Oxygen,MAP – Mean Arterial Pressure Table2.pdf Table 2. Summary of Randomized Controlled Trials Investigating Acute Respiratory Distress Syndrome and Associated Acute Kidney Injury Outcomes Abbreviations: AKI: Acute Kidney Injury, ARDS: Acute Respiratory Distress Syndrome, RCT: Randomized Controlled Trial, N: Number of participants included in the study, RRT: Renal Replacement Therapy, MV: Mechanical Ventilation, PEEP: Positive End-Expiratory Pressure, ICU: Intensive Care Unit, Cr: Creatinine, PaO₂/FiO₂: Ratio of partial pressure of oxygen in arterial blood to the fraction of inspired oxygen, KDIGO: Kidney Disease: Improving Global Outcomes, NC or NR: Not clearly defined or not calculated, SOFA: Sequential Organ Failure Assessment, MODS: Multiple Organ Dysfunction Syndrome, LODS: Logistic Organ Dysfunction System, APACHE: Acute Physiology and Chronic Health Evaluation, CRRT: Continuous Renal Replacement Therapy, IRRT: Intermittent Renal Replacement Therapy, CVVHDF: Continuous Veno-Venous Hemodiafiltration, CRS: Cardio-Renal Syndrome, VFD: Ventilator-Free Days, ECMO: Extracorporeal Membrane Oxygenation Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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1","display":"","copyAsset":false,"role":"figure","size":59916,"visible":true,"origin":"","legend":"\u003cp\u003eUnnumbered image in the Method section.\u003c/p\u003e","description":"","filename":"prisma1.png","url":"https://assets-eu.researchsquare.com/files/rs-7272410/v1/df52b132efdf5a2a5a1f5312.png"},{"id":95193805,"identity":"d1d3e0c1-c4d4-428b-8102-09755a8844ce","added_by":"auto","created_at":"2025-11-05 10:54:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1084014,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7272410/v1/a7c5ba5f-b610-4c8f-a0f5-14e78868e2f3.pdf"},{"id":91963503,"identity":"0f2da9b8-baae-4be2-b69b-98a1331b600e","added_by":"auto","created_at":"2025-09-23 08:07:11","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":488813,"visible":true,"origin":"","legend":"\u003cp\u003eTable1: Summary of Randomized Controlled Trials Investigating Acute Respiratory Distress Syndrome and Mortality or Primary Outcome.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e\u003cbr\u003e\n \u003cstrong\u003eARDS\u003c/strong\u003e – Acute Respiratory Distress Syndrome, \u003cstrong\u003eAKI\u003c/strong\u003e – Acute Kidney Injury,\u003cstrong\u003eRCT\u003c/strong\u003e – Randomized Controlled Trial, \u003cstrong\u003eN\u003c/strong\u003e – Number of patients included, \u003cstrong\u003ePEEP\u003c/strong\u003e – Positive End-Expiratory Pressure,\u003cstrong\u003ePaO₂/FiO₂\u003c/strong\u003e – Ratio of arterial oxygen partial pressure to inspired oxygen fraction,\u003cstrong\u003eCVP\u003c/strong\u003e – Central Venous Pressure,\u003cstrong\u003eRRT\u003c/strong\u003e – Renal Replacement Therapy,\u003cstrong\u003eICU\u003c/strong\u003e – Intensive Care Unit,\u003cstrong\u003eCKD\u003c/strong\u003e – Chronic Kidney Disease,\u003cstrong\u003eKDIGO\u003c/strong\u003e – Kidney Disease: Improving Global Outcomes,\u003cstrong\u003eCr\u003c/strong\u003e – Creatinine,\u003cstrong\u003eUO\u003c/strong\u003e – Urine Output,\u003cstrong\u003eCXR\u003c/strong\u003e – Chest X-ray,\u003cstrong\u003eFiO₂\u003c/strong\u003e – Fraction of Inspired Oxygen,\u003cstrong\u003ePaO₂\u003c/strong\u003e – Arterial Partial Pressure of Oxygen,\u003cstrong\u003eMAP\u003c/strong\u003e – Mean Arterial Pressure\u003c/p\u003e","description":"","filename":"Table1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7272410/v1/d5a313c68711e0cb8b9526a8.pdf"},{"id":91965336,"identity":"b735a454-b54a-4b0b-886a-ff568bbe9fd6","added_by":"auto","created_at":"2025-09-23 08:23:11","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":546930,"visible":true,"origin":"","legend":"\u003cp\u003eTable 2. Summary of Randomized Controlled Trials Investigating Acute Respiratory Distress Syndrome and Associated Acute Kidney Injury Outcomes\u003c/p\u003e\n\u003cp\u003eAbbreviations:\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAKI\u003c/strong\u003e: Acute Kidney Injury, \u003cstrong\u003eARDS\u003c/strong\u003e: Acute Respiratory Distress Syndrome, \u003cstrong\u003eRCT\u003c/strong\u003e: Randomized Controlled Trial, \u003cstrong\u003eN\u003c/strong\u003e: Number of participants included in the study, \u003cstrong\u003eRRT\u003c/strong\u003e: Renal Replacement Therapy, \u003cstrong\u003eMV\u003c/strong\u003e: Mechanical Ventilation, \u003cstrong\u003ePEEP\u003c/strong\u003e: Positive End-Expiratory Pressure, I\u003cstrong\u003eCU\u003c/strong\u003e: Intensive Care Unit, \u003cstrong\u003eCr\u003c/strong\u003e: Creatinine, \u003cstrong\u003ePaO₂/FiO\u003c/strong\u003e₂: Ratio of partial pressure of oxygen in arterial blood to the fraction of inspired oxygen, \u003cstrong\u003eKDIGO\u003c/strong\u003e: Kidney Disease: Improving Global Outcomes, \u003cstrong\u003eNC or NR\u003c/strong\u003e: Not clearly defined or not calculated, \u003cstrong\u003eSOFA\u003c/strong\u003e: Sequential Organ Failure Assessment, \u003cstrong\u003eMODS\u003c/strong\u003e: Multiple Organ Dysfunction Syndrome, \u003cstrong\u003eLODS\u003c/strong\u003e: Logistic Organ Dysfunction System, \u003cstrong\u003eAPACHE\u003c/strong\u003e: Acute Physiology and Chronic Health Evaluation, \u003cstrong\u003eCRRT\u003c/strong\u003e: Continuous Renal Replacement Therapy, \u003cstrong\u003eIRRT\u003c/strong\u003e: Intermittent Renal Replacement Therapy, \u003cstrong\u003eCVVHDF\u003c/strong\u003e: Continuous Veno-Venous Hemodiafiltration, \u003cstrong\u003eCRS\u003c/strong\u003e: Cardio-Renal Syndrome, \u003cstrong\u003eVFD\u003c/strong\u003e: Ventilator-Free Days, \u003cstrong\u003eECMO\u003c/strong\u003e: Extracorporeal Membrane Oxygenation\u003c/p\u003e","description":"","filename":"Table2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7272410/v1/ae1eb82677c7e772bdd5b209.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Underreporting of Acute Kidney Injury in Randomized Trials of ARDS with Mortality Endpoints: A Systematic Review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAcute respiratory distress syndrome (ARDS) is a major cause of morbidity and mortality in critically ill patients. (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) Defined by non-cardiogenic pulmonary edema, severe hypoxemia, and reduced lung compliance, ARDS often requires prolonged mechanical ventilation and intensive care. (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) While the syndrome is primarily pulmonary in presentation, its systemic implications are substantial multiorgan dysfunction is common, and the kidneys are particularly vulnerable. (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eAcute kidney injury (AKI) occurs frequently in patients with ARDS and is associated with poor outcomes, including longer ICU stays, increased need for renal replacement therapy (RRT), and higher mortality.(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) The interplay between lung and kidney injury involves complex hemodynamic, inflammatory, and neurohormonal mechanisms.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) Clinical management strategies such as fluid therapy, ventilator settings, and pharmacologic interventions can directly influence both pulmonary and renal function. (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) As such, the kidney is not just a bystander in ARDS but a key determinant of disease trajectory. (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e Recent patient-level analyses from over 5,000 participants in 10 ARDS trials revealed a 43.7% incidence of AKI, with stable risk over time and an estimated 15.4% excess 90-day mortality attributable to AKI rising to 20.3% in severe cases. (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) Most AKI occurred early during critical illness and was linked to factors such as hemodynamic instability, inflammation, and ventilator-associated injury. (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) Despite advances in ICU care, no improvement in AKI incidence or renal recovery was observed, underscoring the need for consistent reporting and kidney-specific endpoints in ARDS trials. (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eThe aim of this systematic review was to examine how AKI is captured in ARDS RCTs that use mortality as a primary endpoint. Specifically, we sought to determine how often AKI is reported as an outcome, whether standardized definitions are applied, and to what extent trials report RRT use, assess fluid balance, or include kidney-related subgroup analyses.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eReview registration and reporting guidelines\u003c/h2\u003e\u003cp\u003eThe protocol for this systematic review was registered on PROSPERO (Registration No: CRD420251043094) on June 26, 2024. Reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The completed PRISMA checklist is available in Additional file 1: File A.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eObjective\u003c/h3\u003e\n\u003cp\u003eThis review aimed to assess how acute kidney injury (AKI) is represented and reported in randomized controlled trials (RCTs) involving patients with acute respiratory distress syndrome (ARDS) when mortality is the primary outcome.\u003c/p\u003e\n\u003ch3\u003eEligibility criteria\u003c/h3\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eTypes of studies\u003c/h2\u003e\u003cp\u003eWe included parallel arm randomized controlled trials conducted in adult populations with ARDS, published in English between January 1, 2005, and April 10, 2025. Only trials reporting mortality as a primary endpoint were eligible. Review articles, editorials, observational studies, and non-randomized interventions were excluded.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eParticipants\u003c/h3\u003e\n\u003cp\u003eStudies were eligible if they enrolled adult patients (\u0026ge;\u0026thinsp;18 years) diagnosed with ARDS, as defined by either the AECC (American European Consensus Conference) or Berlin criteria.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eInterventions\u003c/h2\u003e\u003cp\u003eThere were no restrictions regarding intervention type, comparator, or ventilatory strategy. Included studies investigated any therapeutic or supportive intervention in the context of ARDS.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eThe primary focus was on the representation and reporting of AKI. This included whether AKI was included as a secondary or exploratory outcome, whether formal definitions (such as KDIGO, AKIN, or RIFLE) were used, whether serum creatinine or renal replacement therapy (RRT) was reported, whether AKI was classified as an adverse event, whether subgroup analyses by AKI status were performed, and whether fluid balance was reported in relation to renal function.\u003c/p\u003e\n\u003ch3\u003eSearch strategy\u003c/h3\u003e\n\u003cp\u003eA comprehensive search was conducted in PubMed, Embase, and Scopus using controlled vocabulary (MeSH) and relevant keywords. The following terms were used: (\u0026ldquo;Acute Respiratory Distress Syndrome\u0026rdquo; [Mesh] OR \u0026ldquo;ARDS\u0026rdquo; OR \u0026ldquo;SARA\u0026rdquo; OR \u0026ldquo;acute lung injury\u0026rdquo;) AND (\u0026ldquo;Mortality\u0026rdquo; [Mesh] OR mortality OR \u0026ldquo;Death\u0026rdquo;) AND (\u0026ldquo;Randomized Controlled Trial\u0026rdquo; [Publication Type] OR \u0026ldquo;Randomized Controlled Trials as Topic\u0026rdquo;[Mesh] OR \u0026ldquo;randomized trial\u0026rdquo; OR \u0026ldquo;randomized trial\u0026rdquo;). The search included studies published between January 1, 2005, and April 10, 2025, and was limited to English-language publications involving adult patients.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eStudy selection\u003c/h2\u003e\u003cp\u003eTwo reviewers independently screened all titles and abstracts for eligibility. Full-text articles were retrieved for potentially eligible studies and reviewed in detail. Discrepancies were resolved through discussion and consensus.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eData extraction and management\u003c/h2\u003e\u003cp\u003eTwo reviewers independently extracted data using a standardized form. Extracted information included study design, setting, intervention type, ARDS severity, COVID-19 status, AKI definitions, creatinine monitoring, RRT use, fluid balance reporting, and whether AKI was analyzed as an adverse event or stratified subgroup.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eRisk of bias assessment\u003c/h2\u003e\u003cp\u003eAs no meta-analysis was planned and effect sizes were not pooled, formal risk-of-bias tools were not applied. Instead, methodological completeness and the consistency of AKI-related reporting were qualitatively assessed across trials.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eData synthesis\u003c/h2\u003e\u003cp\u003eFindings were synthesized descriptively. Reporting practices related to AKI were compared across included studies. Trends in AKI representation over time, by intervention type, and by COVID-19 versus non-COVID status were evaluated narratively.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eStudy Selection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 312 articles were initially identified through database searches. Tables 1 and 2 presents the characteristics of the 27 included RCTs, including sample size, intervention type, ARDS severity and associated Acute Kidney Injury Outcomes. After removal of duplicates and screening of titles and abstracts, 28 randomized controlled trials (RCTs) met the eligibility criteria and were included in the final analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOf the 27 included studies, 25 were conducted as multicenter trials (11-36), and 2 (37-38) were single center. Two studies enrolled patients exclusively with COVID-19 related ARDS (32-35), whereas 25 studies investigated ARDS of other etiologies. The classification of ARDS varied among the included studies. A total of 16 studies specifically enrolled patients with moderate a severe ARDS. Seven studies defined ARDS based on PaO2/FiO2 ,thereby potentially including patients across the mild,moderate, and severe spectrum.(12,14,15,16,22,27,37,38) Three studies included patients with mild to moderate ARDS (13,23,33) and only two studies explicity focused on severe ARDS. (22,27).\u003c/p\u003e\n\u003cp\u003eThe included randomized controlled trials investigated a wide range of interventions for ARDS (As detailed in Table 1, ventilatory strategies were the most frequently studied intervention.).\u0026nbsp;Ventilatory strategies were the most frequently studied, appearing in\u0026nbsp;12 trials (11,14,15,16,21,24.26,29,30,33,34,36).\u0026nbsp;Neuromuscular blockade\u0026nbsp;was evaluated in\u0026nbsp;2 trials (17,24), and\u0026nbsp;prone positioning\u0026nbsp;was investigated in\u0026nbsp;2 studies (28,29), including one that focused specifically on patients with severe ARDS.\u0026nbsp;Corticosteroids\u0026nbsp;were assessed in\u0026nbsp;2 studies (37,38), and\u0026nbsp;immunomodulatory agents\u0026nbsp;such as itolizumab (32) and rosuvastatin (23) were included in\u0026nbsp;1 trial\u0026nbsp;each.\u0026nbsp;Fluid management strategies\u0026nbsp;(12)\u0026nbsp;and\u0026nbsp;liberal oxygen therapy\u0026nbsp;(31) were each evaluated in\u0026nbsp;1 study.\u0026nbsp;Extracorporeal support\u0026nbsp;with\u0026nbsp;ECMO (27)\u0026nbsp;was studied in\u0026nbsp;1 trial, while\u0026nbsp;convalescent plasma (15)\u0026nbsp;was assessed in another. Other pharmacologic interventions included\u0026nbsp;intratracheal calf actant (25),\u0026nbsp;recombinant surfactant protein C–based surfactant (19), and\u0026nbsp;intravenous salbutamol (20), each studied in\u0026nbsp;1 trial. One trial also compared\u0026nbsp;pulmonary artery versus central venous catheterization\u0026nbsp;(13) for the management of acute lung injury.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eReporting of AKI and Related Renal Variables\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAcute kidney injury (AKI) was reported as a predefined secondary outcome in two studies (Table 2 summarizes how AKI and related renal variables were reported across included trials.). (12,23) No study reported AKI as an adverse event. No study employed formal AKI definitions, such as those proposed by KDIGO, AKIN, or RIFLE. Serum creatinine values were reported in two studies (12,23), either at baseline or during the follow-up period. Among the included studies,\u0026nbsp;18 trials\u0026nbsp;reported using the\u0026nbsp;SOFA (12,13,15,17,18,21,22,26,27,28,29,30,31,32,33,34,35,36) score\u0026nbsp;as the definition for AKI; however, none of them specified the use or individual components of the\u0026nbsp;renal SOFA sub score.\u003c/p\u003e\n\u003cp\u003eRenal replacement therapy (RRT) use was reported in two studies (12,33). In these, RRT was presented as the proportion of patients receiving therapy in each arm, without additional details regarding modality, timing, or criteria for initiation. No study reported the proportion of patients with AKI at enrollment or the incidence of AKI during the study follow-up. Similarly, none of the included studies reported a specific mortality analysis for the AKI subgroup\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eReporting of Fluid Balance\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFluid balance data were available in three studies (As shown in Table 2 , only three studies reported early fluid balance data within 48 hours of randomization.). In most cases, fluid balance was reported at early time points, such as within 24 to 48 hours after randomization (12,13,36). None of the included studies incorporated fluid balance into adjusted analyses or explored its association with mortality or organ dysfunction.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMortality Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe mortality endpoint was consistently reported across all included studies, with time frames ranging from \u003cstrong\u003e28 to 90 days\u003c/strong\u003e, and in some cases, \u003cstrong\u003ehospital mortality\u003c/strong\u003e was used as the primary outcome. The most frequently used time point was \u003cstrong\u003e28-day mortality (13,17,19,20,22,24,26,29,31,33,35,37,38)\u003c/strong\u003e, reported in \u003cstrong\u003e14 studies\u003c/strong\u003e, followed by \u003cstrong\u003e90-day mortality\u003c/strong\u003e in \u003cstrong\u003e6 studies (15,18,25,28,30,34)\u003c/strong\u003e, and \u003cstrong\u003e60-day mortality\u003c/strong\u003e in 5\u003cstrong\u003e\u0026nbsp;studies (11,12,23,27,36), and 30-day mortality in one study (32)\u003c/strong\u003e.\u003cstrong\u003e\u0026nbsp;\u003cstrong\u003eTwo studies\u003c/strong\u003e\u003c/strong\u003e reported \u003cstrong\u003ehospital mortality\u003c/strong\u003e (14,16) as the outcome. Despite this consistency in mortality reporting, the heterogeneity in time frames and the absence of standardized mortality subgroup analyses (e.g., by AKI status) highlight variability in outcome assessment across trials.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis systematic review highlights a persistent and clinically relevant omission in the design of randomized controlled trials (RCTs) in ARDS. Although acute kidney injury (AKI) is a frequent complication in moderate to severe ARDS and independently contributes to worse outcomes, kidney-specific endpoints were rarely incorporated. Most trials did not apply standardized AKI definitions\u0026mdash;such as KDIGO\u0026mdash;and reporting of renal outcomes, including serum creatinine trajectories or use of renal replacement therapy, was inconsistent or absent. This lack of structured renal assessment limits the interpretability of multiorgan effects and hinders efforts to advance organ-supportive strategies in this population.\u003c/p\u003e\n\u003cp\u003eNone of the included trials employed standardized AKI definitions such as KDIGO, despite their broad acceptance and incorporation into ICU research since 2012. (39) Instead, several studies referred to the SOFA score but failed to clarify whether or how the renal subscore was utilized. This ambiguity limits the clinical interpretability of renal dysfunction and precludes valid cross-trial comparisons. (40) Furthermore, reporting of serum creatinine and renal replacement therapy (RRT) was often incomplete, lacking key clinical details such as timing, modality, and initiation thresholds. These methodological gaps are particularly concerning given the well-established prognostic value of renal function and RRT parameters in critically ill populations. (41,42)\u003c/p\u003e\n\u003cp\u003eFluid balance\u0026mdash;a key determinant of both pulmonary and renal outcomes in critical illness\u0026mdash;was infrequently reported. Fewer than 20% of trials included data on cumulative fluid status, and only a minority incorporated it into adjusted analyses. This omission is particularly notable given evidence from the FACTT trial and subsequent cohort studies demonstrating that fluid overload contributes to both pulmonary edema and acute kidney injury. (43) Failure to account for fluid dynamics may obscure the renal consequences of lung-targeted interventions and limit the detection of potential harm in susceptible subgroups. (44)\u003c/p\u003e\n\u003cp\u003eNone of the included trials conducted stratified analyses based on AKI status or examined potential heterogeneity of treatment effect according to baseline kidney function. This represents a missed opportunity to evaluate whether patients with impaired renal reserve respond differently to interventions in ARDS. Renal dysfunction is known to alter drug pharmacokinetics, modulate systemic inflammation, and influence hemodynamic responses\u0026mdash;all of which may interact with therapies such as lung-protective ventilation, corticosteroids, or extracorporeal modalities.(45) Moreover, mechanical ventilation itself\u0026mdash;particularly when associated with ventilator-induced lung injury (VILI)\u0026mdash;can propagate kidney injury through biotrauma and altered hemodynamics.(46) \u0026nbsp;Identifying such cross-organ interactions is essential to advancing precision medicine and should be prioritized in future trial designs. (47)\u003c/p\u003e\n\u003cp\u003eThe broader issue reflected in these findings is the persistence of a single-organ approach in critical care trials. ARDS continues to be framed primarily as a pulmonary condition, despite growing recognition of its systemic implications. Lung\u0026ndash;kidney crosstalk is well established, involving mechanical, inflammatory, and neurohormonal pathways. By neglecting kidney-specific endpoints, current RCTs risk overlooking meaningful effects or unintended harms, especially in patients with overlapping vulnerabilities. (48,49)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRRT, a high-cost and high-stakes intervention, was rarely analyzed despite being recorded in several trials. Without reporting RRT timing or stratifying mortality by its use, trial conclusions may mask differences in severity or misattribute outcomes. This omission weakens both internal validity and external applicability, particularly for ICU clinicians managing patients with evolving multiorgan failure. (50,51)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrengths and Limitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis review has several strengths. It is, to our knowledge, the first to systematically assess how AKI is reported in RCTs of ARDS with mortality endpoints. The methodology followed PRISMA guidelines, included three major biomedical databases, and spanned two decades of trial activity. By focusing on mortality-powered studies, we prioritized trials with high clinical impact and relevance to bedside care.\u003c/p\u003e\n\u003cp\u003eHowever, some limitations must be acknowledged. We limited inclusion to English-language studies, which may have excluded relevant international trials. We did not perform a formal risk-of-bias assessment, as the review was descriptive and not focused on treatment efficacy. Additionally, our analysis relied on reported data; some studies may have collected renal variables but chose not to report them due to space constraints or prioritization of respiratory endpoints. Finally, given the heterogeneity in ARDS definitions over time, some variation in population severity and trial design was inevitable.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAKI is a frequent and clinically meaningful complication in ARDS, yet it remains consistently underreported in randomized trials\u0026mdash;even those explicitly designed to evaluate mortality. This gap limits the interpretability and applicability of trial results, particularly in high-risk patients. Future ARDS trials should adopt standardized AKI definitions, routinely report RRT and fluid balance, and perform subgroup analyses by renal function. Recognizing the multisystem nature of critical illness is essential to designing trials that are both scientifically sound and clinically useful.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eARDS\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAcute Respiratory Distress Syndrome\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eAKI\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAcute Kidney Injury\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eRCT\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eRandomized Controlled Trial\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eN\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNumber of patients included\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003ePEEP\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePositive End\u0026ndash;Expiratory Pressure\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003ePaO₂/FiO₂\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eRatio of arterial oxygen partial pressure to inspired oxygen fraction\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eCVP\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCentral Venous Pressure\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eRRT\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eRenal Replacement Therapy\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eICU\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eIntensive Care Unit\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eCKD\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eChronic Kidney Disease\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eKDIGO\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eKidney Disease: Improving Global Outcomes\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eCr\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCreatinine\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eUO\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eUrine Output\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eCXR\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eChest X\u0026ndash;ray\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eFiO₂\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eFraction of Inspired Oxygen\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003ePaO₂\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eArterial Partial Pressure of Oxygen\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eMAP\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMean Arterial Pressure\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical Approval and Consent to Participate\u003c/strong\u003e\u003cstrong\u003e\u003cbr\u003e\u003c/strong\u003eNot applicable, as this study is a systematic review and did not involve human participants, data, or animals requiring ethical approval.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e\u003cstrong\u003e\u003cbr\u003e\u003c/strong\u003eNot applicable\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Supporting Data\u003c/strong\u003e\u003cstrong\u003e\u003cbr\u003e\u003c/strong\u003eAll data generated or analyzed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003cstrong\u003e\u003cbr\u003e\u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003cstrong\u003e\u003cbr\u003e\u003c/strong\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAuthors\u0026apos; contributions\u0026nbsp;(CRediT Taxonomy)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eR.H.P.: Conceptualization, Supervision, Formal analysis, Writing \u0026ndash; Review \u0026amp; Editing; B.Z: Data curation, Investigation, Writing; L. C. S. P: Methodology, Investigation, Formal analysis; R. H. M: Formal analysis, Data curation, Writing \u0026ndash; Review \u0026amp; Editing; \u0026nbsp;T.D.M: Methodology, Project administration, Writing \u0026ndash; Review \u0026amp; Editing; B.A.B: Validation, Investigation, Writing \u0026ndash; Review \u0026amp; Editing; V. P. C. J. : Formal analysis; A. A. S. : Formal analysis; P.N: Resources, Writing \u0026ndash; Review \u0026amp; Editing, Visualization; F.O.C: Data curation, Resources, Project administration. All authors reviewed the manuscript\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBos LDJ, Ware LB. Acute respiratory distress syndrome: causes, pathophysiology, and phenotypes. Lancet. 2022 Oct 1;400(10358):1145-1156. doi: 10.1016/S0140-6736(22)01485-4. Epub 2022 Sep 4. 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Prone positioning in patients with moderate and severe acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2009 Nov 11;302(18):1977-84.\u003c/li\u003e\n\u003cli\u003ePapazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, Jaber S, Arnal JM, Perez D, Seghboyan JM, Constantin JM, Courant P, Lefrant JY, Gu\u0026eacute;rin C, Prat G, Morange S, Roch A; ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010 Sep 16;363(12):1107-16\u003c/li\u003e\n\u003cli\u003eSpragg RG, Taut FJ, Lewis JF, Schenk P, Ruppert C, Dean N, Krell K, Karabinis A, G\u0026uuml;nther A. Recombinant surfactant protein C-based surfactant for patients with severe direct lung injury. Am J Respir Crit Care Med. 2011 Apr 15;183(8):1055-61.\u003c/li\u003e\n\u003cli\u003eGao Smith F, Perkins GD, Gates S, Young D, McAuley DF, Tunnicliffe W, Khan Z, Lamb SE; BALTI-2 study investigators. 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A two-arm, randomized, controlled, multi-centric, open-label phase-2 study to evaluate the efficacy and safety of Itolizumab in moderate to severe ARDS patients due to COVID-19. Expert Opin Biol Ther. 2021 May;21(5):675-686\u003c/li\u003e\n\u003cli\u003eHe H, Chi Y, Yang Y, Yuan S, Long Y, Zhao P, Frerichs I, Fu F, M\u0026ouml;ller K, Zhao Z. Early individualized positive end-expiratory pressure guided by electrical impedance tomography in acute respiratory distress syndrome: a randomized controlled clinical trial. Crit Care. 2021 Jun 30;25(1):230.\u003c/li\u003e\n\u003cli\u003eMcNamee JJ, Gillies MA, Barrett NA, Perkins GD, Tunnicliffe W, Young D, Bentley A, Harrison DA, Brodie D, Boyle AJ, Millar JE, Szakmany T, Bannard-Smith J, Tully RP, Agus A, McDowell C, Jackson C, McAuley DF; REST Investigators. Effect of Lower Tidal Volume Ventilation Facilitated by Extracorporeal Carbon Dioxide Removal vs Standard Care Ventilation on 90-Day Mortality in Patients With Acute Hypoxemic Respiratory Failure: The REST Randomized Clinical Trial. JAMA. 2021 Sep 21;326(11):1013-1023\u003c/li\u003e\n\u003cli\u003eMisset B, Piagnerelli M, Hoste E, Dardenne N, Grimaldi D, Michaux I, De Waele E, Dumoulin A, Jorens PG, van der Hauwaert E, Vallot F, Lamote S, Swinnen W, De Schryver N, Fraipont V, de Mey N, Dauby N, Layios N, Mesland JB, Meyfroidt G, Moutschen M, Compernolle V, Gothot A, Desmecht D, Taveira da Silva Pereira MI, Garigliany M, Najdovski T, Bertrand A, Donneau AF, Laterre PF. Convalescent Plasma for Covid-19-Induced ARDS in Mechanically Ventilated Patients. N Engl J Med. 2023 Oct 26;389(17):1590-1600. doi: 10.1056/NEJMoa2209502.\u003c/li\u003e\n\u003cli\u003eRichard JM, Beloncle FM, B\u0026eacute;duneau G, Mortaza S, Ehrmann S, Diehl JL, Prat G, Jaber S, Rahmani H, Reignier J, Boulain T, Yonis H, Richecoeur J, Thille AW, Declercq PL, Antok E, Carteaux G, Vielle B, Brochard L, Mercat A; REVA network. Pressure control plus spontaneous ventilation versus volume assist-control ventilation in acute respiratory distress syndrome. A randomised clinical trial. Intensive Care Med. 2024 Oct;50(10):1647-1656. doi: 10.1007/s00134-024-07612-3. \u003c/li\u003e\n\u003cli\u003eTiwari S, Kursange S, Goyal A, Safi D. Efficacy of Pulse Methylprednisolone in Treatment of Acute Respiratory Distress Syndrome due to Malaria: A Randomized Controlled Clinical Trial. J Assoc Physicians India. 2023 Nov;71(11):36-39\u003c/li\u003e\n\u003cli\u003eTongyoo S, Permpikul C, Mongkolpun W, Vattanavanit V, Udompanturak S, Kocak M, Meduri GU. Hydrocortisone treatment in early sepsis-associated acute respiratory distress syndrome: results of a randomized controlled trial. Crit Care. 2016 Oct 15;20(1):329.\u003c/li\u003e\n\u003cli\u003eOstermann M, Lumlertgul N, Jeong R, See E, Joannidis M, James M. Acute kidney injury. Lancet. 2025 Jan 18;405(10474):241-256.\u003c/li\u003e\n\u003cli\u003eda Hora Passos R, Ramos JGR, Gobatto A, Caldas J, Macedo E, Batista PB. Inclusion and definition of acute renal dysfunction in critically ill patients in randomized controlled trials: a systematic review. Crit Care. 2018 Apr 24;22(1):106\u003c/li\u003e\n\u003cli\u003ePickkers P, Darmon M, Hoste E, Joannidis M, Legrand M, Ostermann M, Prowle JR, Schneider A, Schetz M. Acute kidney injury in the critically ill: an updated review on pathophysiology and management. Intensive Care Med. 2021 Aug;47(8):835-850.\u003c/li\u003e\n\u003cli\u003eBirkelo BC, Koyner JL, Ostermann M, Bhatraju PK. The Road to Precision Medicine for Acute Kidney Injury. Crit Care Med. 2024 Jul 1;52(7):1127-1137.\u003c/li\u003e\n\u003cli\u003eSbaraini Zernini, I.; Nocera, D.; D\u0026rsquo;Albo, R.; Tonetti, T. Acute Respiratory Distress Syndrome and Fluid Management: Finding the Perfect Balance. \u003cem\u003eJ. Clin. Med.\u003c/em\u003e \u003cstrong\u003e2025\u003c/strong\u003e, \u003cem\u003e14\u003c/em\u003e, 2067.\u003c/li\u003e\n\u003cli\u003eJoannidis M, Forni LG, Klein SJ, Honore PM, Kashani K, Ostermann M, Prowle J, Bagshaw SM, Cantaluppi V, Darmon M, Ding X, Fuhrmann V, Hoste E, Husain-Syed F, Lubnow M, Maggiorini M, Meersch M, Murray PT, Ricci Z, Singbartl K, Staudinger T, Welte T, Ronco C, Kellum JA. Lung-kidney interactions in critically ill patients: consensus report of the Acute Disease Quality Initiative (ADQI) 21 Workgroup. Intensive Care Med. 2020 Apr;46(4):654-672.\u003c/li\u003e\n\u003cli\u003eKellum, J.A., Romagnani, P., Ashuntantang, G. \u003cem\u003eet al.\u003c/em\u003e Acute kidney injury. \u003cem\u003eNat Rev Dis Primers\u003c/em\u003e \u003cstrong\u003e7\u003c/strong\u003e, 52 (2021).\u003c/li\u003e\n\u003cli\u003eBenites, M.H., Suarez-Sipmann, F., Kattan, E. \u003cem\u003eet al.\u003c/em\u003e Ventilation-induced acute kidney injury in acute respiratory failure: Do PEEP levels matter?. \u003cem\u003eCrit Care\u003c/em\u003e \u003cstrong\u003e29\u003c/strong\u003e, 130 (2025).\u003c/li\u003e\n\u003cli\u003eMeersch M, Mayerh\u0026ouml;fer T, Joannidis M. Acute kidney injury subphenotyping and personalized medicine. Curr Opin Crit Care. 2024 Dec 1;30(6):555-562.\u003c/li\u003e\n\u003cli\u003eNasa P, Bos LD, Estenssoro E, van Haren FM, Serpa Neto A, Rocco PR, Slutsky AS, Schultz MJ. Consensus statements on the utility of defining ARDS and the utility of past and current definitions of ARDS-protocol for a Delphi study. BMJ Open. 2024 Apr 25;14(4):e082986. \u003c/li\u003e\n\u003cli\u003eNasa, PrashantAryal, Diptesh et al. Defining and subphenotyping ARDS: insights from an international Delphi expert panel The Lancet Respiratory Medicine, Volume 0, Issue 0\u003c/li\u003e\n\u003cli\u003eNaorungroj T, Neto AS, Wang A, Gallagher M, Bellomo R. Renal outcomes according to renal replacement therapy modality and treatment protocol in the ATN and RENAL trials. Crit Care. 2022 Sep 6;26(1):269\u003c/li\u003e\n\u003cli\u003eWald, R., Gaudry, S., da Costa, B.R. \u003cem\u003eet al.\u003c/em\u003e Initiation of continuous renal replacement therapy versus intermittent hemodialysis in critically ill patients with severe acute kidney injury: a secondary analysis of STARRT-AKI trial. \u003cem\u003eIntensive Care Med\u003c/em\u003e \u003cstrong\u003e49\u003c/strong\u003e, 1305\u0026ndash;1316 (2023)\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 2 are available in the Supplementary Files section.\u003c/p\u003e"},{"header":"PRISMA Checklist","content":"\u003cp\u003eAdditional File 1: FIle A: Completed PRISMA checklist is not available with this version.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7272410/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7272410/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eAcute Kidney Injury (AKI) is a frequent complication among patients with Acute Respiratory Distress Syndrome (ARDS), and its definition has evolved significantly over the past two decades. We conducted a systematic review to evaluate how AKI was defined in randomized controlled trials (RCTs) involving ARDS patients and whether changes in AKI definitions impacted mortality outcomes.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis systematic review was registered on PROSPERO (CRD420251043094). We searched PubMed/MEDLINE, Embase, and Cochrane databases up to December 2023 for RCTs that reported AKI in ARDS patients. Studies were grouped according to the AKI definitions used: RIFLE, AKIN, KDIGO, or undefined. Descriptive statistics and mortality trends were assessed across groups.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eA total of 39 RCTs were included. Only 15 studies (38.4%) adopted standardized definitions for AKI\u0026mdash;5 used RIFLE, 4 used AKIN, and 6 used KDIGO. The remaining 24 studies (61.5%) did not clearly define AKI. Among studies using KDIGO, mortality rates for AKI patients ranged from 32\u0026ndash;56%, whereas those without defined criteria reported broader and less consistent mortality outcomes. There was no consistent trend indicating improved mortality outcomes with more recent definitions.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eDespite the evolution of AKI diagnostic criteria, most RCTs on ARDS still lack standardized definitions for AKI. This heterogeneity limits comparison across trials and impairs the accuracy of clinical interpretations. The implementation of KDIGO criteria should be encouraged in future ARDS-related research to improve standardization and comparability.\u003c/p\u003e","manuscriptTitle":"Underreporting of Acute Kidney Injury in Randomized Trials of ARDS with Mortality Endpoints: A Systematic Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-23 08:07:06","doi":"10.21203/rs.3.rs-7272410/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"89c22951-9ecb-4e80-959a-da356d92c2cc","owner":[],"postedDate":"September 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-05T10:54:11+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-23 08:07:06","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7272410","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7272410","identity":"rs-7272410","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}