Underreporting of acute kidney injury in randomized trials of acute respiratory distress syndrome with mortality endpoints: a systematic review

Passos, Rogerio da Hora; Zawadzki, Bruno; Pinto, Luis Claudio Santos; Melo, Rafael Hortencio; Midega, Thais Dias; Bravim, Bruno de Arruda; Campos Júnior, Vagner Pires de; Silva, Arnaldo Alves da; Nasa, Prashant; Coelho, Fernanda Oliveira

doi:10.62675/2965-2774.20260422

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Original Article • Crit. Care Sci. 38 • 2026 • https://doi.org/10.62675/2965-2774.20260422 linkcopy

Underreporting of acute kidney injury in randomized trials of acute respiratory distress syndrome with mortality endpoints: a systematic review

Authorship SCIMAGO INSTITUTIONS RANKINGS

Objective: To examine how acute kidney injury is represented and reported in randomized controlled trials of acute respiratory distress syndrome with mortality as the primary endpoint.

Methods: This descriptive systematic review included parallel-arm randomized controlled trials enrolling adult patients with acute respiratory distress syndrome, defined by American-European Consensus Conference or Berlin criteria, in which mortality was the primary outcome. The protocol was prospectively registered in PROSPERO (CRD420251043094). Searches were conducted in PubMed^®/MEDLINE^®, Embase, and Scopus for studies published between January 1st, 2005, and April 10, 2025. Two reviewers independently screened studies and extracted data by consensus. Data extraction focused on acute kidney injury reporting, use of standardized definitions, serum creatinine, renal replacement therapy, fluid balance, and kidney-related subgroup analyses.

Results: Twenty-seven randomized controlled trials met inclusion criteria. None applied standardized acute kidney injury definitions such as KDIGO, AKIN, or RIFLE. Serum creatinine was reported in two trials and renal replacement therapy in four, without details on timing or criteria. Organ dysfunction scores were commonly reported, but renal subscores were not specified. Fluid balance was reported in five trials but was not included in the adjusted analyses. No study performed mortality analyses stratified by acute kidney injury or baseline kidney function.

Conclusion: Acute kidney injury is inconsistently represented in randomized trials of acute respiratory distress syndrome evaluating mortality. This inconsistency limits the interpretation of extrapulmonary organ dysfunction. Recognizing the multisystem nature of critical illness may improve the clinical relevance of future trial designs.

Keywords:
Acute kidney injury; Multiple organ failure; Organ dysfunction scores; Respiratory distress syndrome; Renal replacement therapy; Mortality

Author	Study period	Sample size (n)	Center (n)	ARDS definition	ARDS severity	Intervention	Outcomes	COVID-19	Definition	Intervention Group	Control Group	Results
Bollen et al.(¹²)	October 1997 to March 2001	61	4 centers from United Kingdom, France, and Germany	PaO₂/FiO₂ < 200mmHg, radiographic evidence of bilateral infiltrates on CXR, and no evidence of atrial hypertension	Moderate to severe	High-frequency oscillatory ventilation	Primary: cumulative survival without MV or oxygen dependency at 30 days; mortality at 30 days; therapy failure; crossover rate; and persisting pulmonary problems defined as oxygen dependency or still being on a ventilator at 30 days	No	30 days	43%	33%	Neutral
Wiedemann et al.(¹³)	June 2000 to October 2005	1,000	20 centers from North America	PaO₂/FiO₂ < 300mmHg (adjusted if the altitude exceeded 1000m), and bilateral infiltrates on CXR consistent with the presence of pulmonary edema without evidence of left atrial hypertension	Mild, moderate, and severe	Conservative strategy of fluid management	Primary: death at 60 days Secondary: number of VFDs and organ-failure-free days and measures of lung physiology	No	60 days	25.5%	28.4%	Neutral
Wheeler et al.(¹⁴)	June 2000 to October 2005	999	20 centers from North America	Bilateral infiltrates on CXR consistent with the presence of pulmonary edema not due to left atrial hypertension, PaO₂/FiO₂ < 300mmHg	Mild, moderate, and severe	Pulmonary artery versus central venous catheter to guide treatment of acute lung injury	Primary: mortality during the first 60 days before discharge; Secondary: number of VFDs in the first 28 days; number of days without various types of organ failure	No	60 days	27.4%	26.3%	Neutral
Villar et al.(¹⁵)	March 1999 to March 2001		8 centers from Spain	ARDS American-European Consensus Conference criteria, PaO₂/FiO₂ ≤ 200mmHg	Moderate to severe	Pressure-controlled with spontaneous ventilation	Primary: ICU mortality Secondary: VFDs, pulmonary complications (barotrauma), extrapulmonary organ failures, and hospital mortality	No	ICU mortality	53.3%	32%	Neutral
Mercat et al.(¹⁶)	September 2002 to December 2005	767	37 ICUs from France	Recent appearance of bilateral pulmonary infiltrates consistent with edema, with no clinical evidence of left atrial hypertension; PaO₂/FIO₂ ≤ 300mmHg	Mild, moderate, and severe	Minimal distension strategy versus increased recruitment strategy	Primary: proportion of patients who died within 28 days after randomization Secondary: 60-day mortality, hospital mortality censored on day 60, numbers of VFDs and organ failure-free days from day 1 to day 28, and proportion of patients who experienced pneumothorax requiring chest tube drainage between day 1 and day 28	No	28 days	31.2%	27.8%	Neutral
Meade et al.(¹⁷)	August 2000 to March 2006	983	30 centers from Canada, Australia, and Saudi Arabia	New respiratory symptoms within 28 days and bilateral opacifications on CXR, PaO₂/FIO₂ ≤ 250 during invasive MV	Moderate to severe	Ventilatory strategy - combining low tidal volume, lung recruitment maneuvers, and high PEEP	Primary: all-cause hospital mortality Secondary: mortality during MV, ICU mortality, and 28-day mortality, and eligible use and total use of rescue therapies in response to refractory hypoxemia, refractory acidosis, or refractory barotrauma	No	Hospital mortality	36.4%	40.4%	Neutral
Taccone et al.(¹⁸)	February 2004 to June 2008	342	25 centers from Italy (23) and Spain (2)	ARDS American-European Consensus Conference criteria, PaO₂/FiO₂ ≤ 200mmHg	Moderate to severe	Prone positioning	Primary: 28-day all-cause mortality Secondary: 6-month mortality and mortality at ICU discharge, organ dysfunctions, and the complication rate related to prone positioning	No	28 days	31%	32.8%	Neutral
Papazian et al.(¹⁹)	March 2006 to March 2008	339	20 centers from France	PaO₂/FiO₂ ≤ 150mmHg with PEEP of 5 cm of water or higher and a tidal volume of 6 to 8mL per kg of predicted body weight, and bilateral pulmonary infiltrates that were consistent with edema	Severe	Cisatracurium continuous infusion	Primary: 90-day in-hospital mortality rate Secondary: day-28 mortality, numbers of days outside the ICU between day 1 and day 28 and between day 1 and day 90, number of days without organ or system failure between day 1 and day 28, rate of barotrauma, rate of ICU-acquired paresis, the MRC scores on day 28 and at the time of ICU discharge, and the numbers of VFDs between day 1 and day 28 and between day 1 and day 90	No	90 days	31.6%	40.7%	Positive
Spragg et al.(²⁰)	November 2003 to March 2008	836	161 centers from 22 countries	PaO₂/FiO₂ < 170mmHg due to aspiration of gastric contents or pneumonia	Severe	Recombinant surfactant protein-C-based surfactant	Primary: percentage of patients alive at Day 28 Secondary: ventilator-free days at Day 28, measures of oxygenation and ventilation, and the number of nonpulmonary organ failure-free days	No	28 days	22.7%	23.8%	Negative
Gao Smith et al.(²¹)	December 2006 to March 2010	324	46 centers from United Kingdom	ARDS American-European Consensus criteria, PaO₂/FiO₂ ≤ 200mmHg	Moderate to severe	Intravenous salbutamol	Primary: 28-day mortality Secondary: mortality in the ICU or hospital before first discharge; ventilator-free and organ failure-free days from randomization to day 28, length of stay in ICU and hospital, and tachycardia, new arrhythmia, or other side-effects sufficient to stop treatment with trial drug	No	28 days	34%	23%	Negative
Young et al.(²²)	December 2007 to July 2012	795	29 centers from England, Wales, and Scotland	PaO₂/FiO₂ ≤ 200mmHg with PEEP of 5cm of water or greater, if bilateral pulmonary infiltrates were visible on CXR without evidence of left atrial hypertension	Moderate to severe	High-frequency oscillatory ventilation	Primary: all-cause mortality 30 days after randomization; Secondary: all-cause mortality at the time of discharge from the ICU and the hospital, duration of MV, and use of antimicrobial, sedative, vasoactive, and neuromuscular-blocking drugs	No	30 days	41.7%	41.1%	Neutral
Guérin et al.(²³)	January 2008 to July 2011	466	27 centers from France (26) and Spain (1)	ARDS American-European Consensus Conference criteria, PaO₂/FiO₂ < 150mmHg, with an FiO₂ of ≥ 0.6, a PEEP of ≥ 5cm of water, and a tidal volume of about 6mL per kg of predicted body weight	Severe	Prone positioning	Primary: mortality at day 28 Secondary: mortality at day 90, rate of successful extubation, time to successful extubation, length of stay in ICU, complications, use of noninvasive ventilation, tracheotomy rate, number of days free from organ dysfunction, and ventilator settings, measurements of arterial blood gases, and respiratory-system mechanics during the first week after randomization	No	28 days	16%	32.8%	Positive
Truwit et al.(²⁴)	March 2010 to September 2013	745	The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome and the Clinical Trials Network	Bilateral infiltrates on CXR that were consistent with pulmonary edema, without evidence of left atrial hypertension, PaO₂/FiO₂ ≤ 300mmHg.	Mild, moderate, and severe	Rosuvastatin	Primary: mortality before hospital discharge, home, or until study day 60 if the patient was still in a health care facility Secondary: VFDs to day 28, organ-failure-free days to day 14, ICU-free days to day 28, changes in the PaO₂/FiO₂ ratio and the oxygenation index during the first 7 days, hospital mortality to day 28, hospital-free days at day 60, VTE at day 14, composite end-point of myocardial infarction, bowel ischemia or ischemic stroke to day 28, arrhythmias during ICU stay or day 14, development of AKI, changes in plasma concentrations of CRP from day 0 to day 6 and 14	No	60 days	28.5%	24.9%	Negative
Willson et al.(²⁵)	July 2008 to July 2011	427	34 centers from 6 countries	ARDS American-European Consensus Conference criteria, PaO₂/FiO₂ ≤ 200mmHg	Mild, moderate, and severe	Instilled calfactant	Primary: all-cause mortality at 90 days after study entry; Secondary: VFDs at 90 days, durations of ICU, hospital stay, and oxygen use, and changes in oxygenation after the study intervention	No	90 days	27.8%	25.5%	Negative
Cavalcanti et al.(²⁶)	November 2011 to April 2017	1,010	120 centers from Brazil, Argentina, Colombia, Italy, Poland, Portugal, Malaysia, Spain, and Uruguay	ARDS American- European Consensus Conference criteria	Moderate to severe	Lung recruitment associated with PEEP titration according to the best respiratory system compliance	Primary: mortality until 28 days Secondary: length of ICU and hospital stay; VFDs from day 1 until day 28; pneumothorax requiring drainage within 7 days; barotrauma within 7 days; and ICU, in-hospital, and 6-month mortality	No	28 days	55.3%	49.3%	Negative
Combes et al.(²⁷)	Until April 2017	249	60 centers from France, 1 from Australia, 2 from the USA and 1 from Canada	ARDS American-European Consensus Conference definition, PaO₂/FiO₂ < 50mmHg for > 3 hours, PaO₂/FiO₂ < 80mmHg for > 6 hours, or an arterial blood pH of < 7.25 with a PaCO₂ of ≥ 60mmHg for > 6 hours, with the respiratory rate increased to 35 breaths per minute and MV settings adjusted to keep a plateau pressure of ≤ 32cm of water) despite ventilator optimization	Severe	ECMO	Primary: mortality at 60 days Secondary: treatment failure, mortality at other time points, the time to death until day 60, and a per-treatment analysis in which mortality was compared among patients who received ECMO and those who did not	No	60 days	35%	46%	Neutral
Moss et al.(²⁸)	January 2016 to April 2018	1,006	48 centers from United States	PaO₂/FiO₂ ≤ 150mmHg with a PEEP of 8cm or more of water; bilateral pulmonary opacities on CXR or on computed tomography that could not be explained by effusions, pulmonary collapse, or nodules; and respiratory failure that could not be explained by cardiac failure or fluid overload	Moderate to severe	Cisatracurium continuous infusion	Primary: in-hospital death from any cause at 90 days Secondary: organ dysfunction (as assessed on the basis of the SOFA score, in-hospital death at day 28, days free of organ dysfunction, days not in the ICU, days free of MV, and days not in the hospital at day 28, long-term endpoints at 3, 6, and 12 months	No	90 days	35%	41.1%	Neutral
Beitler et al.(²⁹)	October 2012 to September 2017	200	14 centers from United States and Canada	ARDS Berlin definition, PaO₂/FiO₂ ≤ 200mmHg	Moderate to severe	PEEP titration guided by esophageal pressure	Primary: ranked composite score that incorporated death and days free from MV through day 28 Secondary: all-cause mortality at 28 days, 60 days, and 1 year; VFDs through day 28; ICU and hospital lengths of stay through day 28 and day 60; protocol failure requiring rescue therapy; and functional status at 1 year	No	28 days	32.4%	30.6%	Neutral
Constantin et al.(³⁰)	June 2014 to Feb 2017	400	20 centers from France	ARDS Berlin definition, PaO₂/FiO₂ ≤ 200mmHg	Moderate to severe	Personalized MV to lung morphology	Primary: all-cause mortality at day 90 Secondary: mortality at 28 days, 30 days, 180 days, and 365 days, ICU mortality, number of VFDs at day 30, ARDS resolution, length of stay in the ICU, the number of patients with VAP, and barotrauma	No	90 days	27%	27%	Neutral
Barrot et al.(³¹)	June 2016 to September 2018	201	13 centers from France	ARDS Berlin definition), PaO₂/FiO₂ ≤ 300mmHg	Mild, moderate, and severe	Conservative oxygen therapy (target PaO₂, 55 to 70mmHg; oxygen saturation as measured by pulse oximetry [SpO₂], 88 to 92%)	Primary: 28-day mortality Secondary: death in the ICU and at day 90; the SOFA scores (calculated without the respiratory component) at days 0, 3, and 7; VAP during the first 28 days; septicemia during the first 28 days; cardiovascular complications over the first 7 days; respiratory weaning success at days 28 and 90; RASS neurologic status, seizures, new cerebral stroke on imaging, administration of neuroleptics, and delirium	No	28 days	34.3%	26.5%	Neutral
Kumar et al.(³²)	May 2020 to July 2020	30	4 centers from India	Moderate to severe ARDS; PaO₂/FiO₂ ratio of < 200 or more than 25% deterioration from the immediate previous value	Moderate to severe	Itolizumab	Primary: mortality 1 month after randomization, proportion of patients with deteriorating lung functions, proportion of patients who needed NIV, invasive MV/endotracheal intubation, and high flow nasal oxygen, and inflammatory markers: Ferritin, D-dimer, LDH, CRP Secondary: biomarkers such as IL-6, TNF-α, IL-17A, Absolute lymphocyte count, PaO₂/FiO₂ ratio, and number of participants with treatment-related side effects	Yes	30 days	0%	30%	Positive
He et al.(³³)	November 2018 to September 2020	117	Single-center from China	ARDS Berlin definition, PaO₂/FiO₂ < 300mmHg	Mild, moderate, and severe	Electrical impedance tomography-guided PEEP	Primary: all-cause mortality within 28 days after randomization Secondary: number of VFDs at day 28, ICU length of stay, and new onset barotrauma during MV	No	28 days	21%	27%	Neutral
McNamee et al.(³⁴)	May 2016 to December 2019	405	51 centers from United Kingdom	Moderate to severe hypoxemic respiratory; were receiving invasive MV using at least 5cmH₂O of PEEP; PaO₂/FiO₂ < 150mmHg	Moderate to severe	Lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal	Primary: all-cause mortality 90 days after randomization; Secondary: tidal volume at day 2 and day 3, VFDs at day 28, duration of invasive MV in survivors, need for ECMO up to day 7, mortality at day 28, and adverse event rate	No	90 days	41.5%	39.5%	Neutral
Misset et al.(³⁵)	September 2020 to March 2022	475	17 centers from Belgium	ARDS Berlin definition	Mild, moderate, and severe	Convalescent plasma	Primary: death by day 28 after randomization; Secondary: adverse events, inflammatory and anti-SARS-CoV-2 antibody responses, the SOFA score, the use of organ support, the length of hospital stay, and death by day 90 and 365	Yes	28 days	35.4%	45%	Positive
Richard et al.(³⁶)	February 2013 to October 2018	699	22 centers from France	ARDS Berlin definition, PaO₂/FiO₂ ≤ 200mmHg	Moderate to severe	Pressure-controlled strategy allowing non-synchronized unassisted spontaneous ventilation (pressure-controlled with spontaneous ventilation)	Primary: in-hospital death from any cause at day 60 after randomization Secondary: mortality at day 28, numbers of VFDs, organ failure-free days, and vasoactive drugs-free days at day 28, total amounts of vasoactive drugs and fluids received during the first 7 days after inclusion, incidence of refractory hypoxemia during the first 7 days of treatment, proportion of patients requiring adjunctive treatment of hypoxemia during the first 7 days, number of days alive without sedation at day 28, total amounts of sedative drugs and NMBA during the first seven days after inclusion, mean sedation level from day 1 to day 7, duration of ventilation and ICU stay	No	60 days in hospital	34.6%	33.5%	Neutral
Tiwari et al.(³⁷)	Not reported	30	Single center from India	Tested positive for Plasmodium falciparum, Plasmodium vivax, or both on a peripheral smear or rapid antigen test, with an acute onset of respiratory failure, bilateral infiltrates on CXR sparing the costophrenic angles, partial pressure of oxygen PaO₂/FiO₂ < 300mmHg, and lack of clinical evidence of left ventricular failure	Mild, moderate, and severe	Corticosteroid - pulse methylprednisolone therapy	Primary: death of the patient or discharge from the hospital Secondary: duration of stay in the medical ICU, the number of days for which MV was required, and the rate of secondary infections	No	Hospital mortality	40%	26.7%	Positive
Tongyoo et al.(³⁸)	December 2010 to December 2014	197	Single center from Thailand	ARDS American-European Consensus definition, as later reclassified based on ARDS Berlin criteria	Mild, moderate, and severe	Hydrocortisone	Primary: all-cause mortality at study day 28 Secondary: patients alive without organ support (ventilator, renal replacement therapy, and vasopressors) on day 28, VFDs up to day 28, vasopressor-free days up to day 28, and mortality at study day 60	No	28 days	22.5%	27.3%	Neutral

Author	Study period	Sample size (n)	Creatinine levels	Coluna 1	Coluna 2	Coluna 3	AKI as a secondary outcome	AKI as an adverse event	AKI definition	AKI subgroup	RRT reported
Wiedemann et al.(¹³)	June 2000 to October 2005	1,000	No	Dependence on dialysis	NA	Yes	No	There were no significant differences between groups in the percentage of patients receiving kidney-replacement therapy (14% in the PAC group versus 11% in the CVC group, p = 0.15)	NA	No	Not reported
Meade et al.(¹⁷)	August 2000 to March 2006	983	No	No	NA	Yes	No	Not reported	NA	No	Not reported
Spragg et al.(²⁰)	November 2003 to March 2008	836	No	No	NA	Yes	Organ failure-free days	Not reported	NA	No	Not reported
Truwit et al.(²⁴)	March 2010 to September 2013	745	Yes	Dialysis requirement	Dialysis requirement	Yes	Number of organ failure-free days at 7 and 28 days after enrollment; dialysis to day 60	Not reported	Organ failure is defined as present on any date when the most abnormal vital signs/abnormal lab values meet the definition of clinically significant organ failure according to the Brussels organ failure table	No	Yes
Willson et al.(²⁵)	July 2008 to July 2011	427	No	Other organ failure	NA	Yes	No	Renal failure	Renal failure	No	Not reported
Constantin et al.(³⁰)	June 2014 to Feb 2017	400	No	No	Baseline 1% x 2%; RRT baseline 6% and 7%	Yes	No	Not reported	NA	No	Not reported
Misset et al.(³⁵)	September 2020 to March 2022	475	No	No	NA	Yes	The number of organ failure-free days was defined as the number of days alive and free of organ failure	Not reported	Organ failures were defined using the Organ Dysfunctions and/or INfection score	No	Not reported

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[TFN1] ARDS - acute respiratory distress syndrome; PaO₂/FiO₂ - ratio of arterial oxygen partial pressure to inspired oxygen fraction; CXR - chest X-ray; MV - mechanical ventilation; VFD - ventilator-free day; ICU – intensive care unit; PEEP - positive end-expiratory pressure; VTE - venous thromboembolism; ECMO - extracorporeal membrane oxygenation; SOFA - Sequential Organ Failure Assessment; VAP - ventilator-associated pneumonia; SpO2 - peripheral capillary oxygen saturation; RASS - Richmond Agitation-Sedation Scale; LDH - lactate dehydrogenase; CRP - C-reactive protein; IL - interleukin; TNF-α - tumor necrosis factor-alpha; SARS-CoV-2 - Severe Acute Respiratory Syndrome Coronavirus 2; NMBA - neuromuscular blocking agent.