Acute Kidney Injury
Conditions
Keywords
Renal replacement therapy, Acute kidney injury, Dialysis, Hemodialysis, Critical illness
Brief summary
The objectives of this trial are to determine whether, in critically ill patients with severe acute kidney injury (AKI), randomization to accelerated initiation of renal replacement therapy (RRT), compared to standard initiation, leads to: 1. Improved survival (primary outcome); and 2. Recovery of kidney function (principal secondary outcome), defined as independence from RRT at 90 days
Detailed description
Acute kidney injury (AKI) is a common and devastating complication of critical illness. Once AKI is established, treatment is largely supportive and no intervention has been found to restore kidney function or improve overall survival. Renal replacement therapy (RRT), usually in the form of hemodialysis, is frequently needed to manage patients with severe AKI. Such patients have an in-hospital mortality that consistently exceeds 50% with delays in RRT initiation implicated as a possible contributor. A recent meta-analysis suggested that earlier initiation of RRT may improve survival, but this is based on data derived overwhelmingly from observational studies. The investigators recently completed a multi-centre randomized controlled pilot trial that confirmed the feasibility of allocating patients to two different strategies of RRT initiation. Patient recruitment and follow-up, as well as patient safety, were successfully demonstrated during the pilot phase of this research program. The optimal timing of RRT initiation is an existing knowledge gap and a clear priority for investigation.
Interventions
In the absence of kidney function recovery, the initiation of RRT will be permitted if one of the following develops: serum potassium ≥ 6.0 mmol/L; pH ≤ 7.20 or serum bicarbonate ≤ 12 mmol/L; evidence of severe respiratory failure, based on a PaO2/FiO2 ≤ 200 and clinical perception of volume overload; and/or persistent AKI \> 72 hours following the time of randomization.
A dialysis catheter will be placed and RRT initiated as soon as possible and within 12 hours of eligibility. This 12 hour window includes the time needed to obtain consent.
Sponsors
Canadian Institutes of Health Research (CIHR)
National Health and Medical Research Council, Australia
Baxter Healthcare Corporation
The George Institute
National Institute for Health Research, United Kingdom
Medical Research Institute of New Zealand
Health Research Council, New Zealand
Unity Health Toronto
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 18 years 2. Admission to an intensive care unit (ICU) 3. Evidence of kidney dysfunction \[serum creatinine ≥100 µmol/L (women) and ≥ 130 µmol/L (men)\] 4. Evidence of severe AKI defined by at least 1 of the following 3 criteria: i) ≥ 2-fold increase in serum creatinine from a known pre-morbid baseline or during the current hospitalization; OR ii) Achievement of a serum creatinine ≥ 354 µmol/L with evidence of a minimum increase of 27 µmol/L from pre-morbid baseline or during the current hospitalization; OR iii) Urine output \< 6.0 mL/kg over the preceding 12 hours
Exclusion criteria
1. Serum potassium \> 5.5 mmol/L 2. Serum bicarbonate \< 15 mmol/L 3. Presence of a drug overdose that necessitates initiation of RRT 4. Lack of commitment to ongoing life support (including RRT) 5. Any RRT within the previous 2 months (either acute or chronic RRT) 6. Kidney transplant within the past 365 days 7. Known pre-hospitalization advanced chronic kidney disease, defined by an estimated glomerular filtration rate \< 20 mL/min/1.73 m2 8. Presence or clinical suspicion of renal obstruction, rapidly progressive glomerulonephritis, vasculitis, thrombotic microangiopathy or acute interstitial nephritis 9. Clinician(s) caring for patient believe(s) that immediate RRT is mandated 10. Clinician(s) caring for patient believe(s) that deferral of RRT initiation is mandated * at their discretion, clinicians may administer a bolus of intravenous furosemide (ie, furosemide stress test) and evaluate the subsequent urine output to help guide decision making regarding the likelihood of AKI progression
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| All-cause Mortality. | 90 days following study randomization. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Composite of Death or RRT Dependence. | 90 days following study randomization. | — |
| Measurement of Estimated Glomerular Filtration Rate. | 90 days following study randomization. | — |
| Measurement of Albuminuria. | 90 days following study randomization. | — |
| Major Adverse Kidney Outcomes. | 90 days following study randomization. | Defined as death, RRT dependence or sustained reduction in kidney function (defined as eGFR \< 75% baseline eGFR). |
| Mechanical Ventilation-free Days. | Measured from randomization through day 28. | — |
| RRT Dependence | 90 days following study randomization. | — |
| ICU-free Days | Measured from randomization through day 28. | — |
| Hospitalization-free Days | Measured from randomization through day 90. | — |
| Death in ICU | Measured in-hospital and at day 28. | — |
| EuroQoL EQ-5D-5L. | Measured at day 90 and at day 365. | A measure of health-related quality of life and patient utility. |
| Health Care Costs. | Measured from baseline through day 365. | — |
| Vasoactive Therapy-free Days | Measured from randomization through day 28. | — |
Countries
Australia, Austria, Belgium, Brazil, Canada, China, Finland, France, Germany, Ireland, Italy, New Zealand, Switzerland, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Standard RRT Initiation RRT initiation will be guided by the presence of one or more clinical indications. Even in the absence of one of these indications, RRT may be commenced at the discretion of the treating physician.
Standard RRT initiation: In the absence of kidney function recovery, the initiation of RRT will be permitted if one of the following develops:
serum potassium ≥ 6.0 mmol/L; pH ≤ 7.20 or serum bicarbonate ≤ 12 mmol/L; evidence of severe respiratory failure, based on a PaO2/FiO2 ≤ 200 and clinical perception of volume overload; and/or persistent AKI \> 72 hours following the time of randomization. | 1,462 |
| Accelerated RRT Initiation A dialysis catheter will be placed and RRT initiated as soon as possible and within 12 hours of the patient meeting the eligibility criteria.
Accelerated RRT initiation: A dialysis catheter will be placed and RRT initiated as soon as possible and within 12 hours of eligibility. This 12 hour window includes the time needed to obtain consent. | 1,465 |
| Total | 2,927 |
Baseline characteristics
| Characteristic | Standard RRT Initiation | Total | Accelerated RRT Initiation |
|---|---|---|---|
| Admission category - no. (%) - Medical | 989 Participants | 1962 Participants | 973 Participants |
| Admission category - no. (%) - Scheduled surgery | 184 Participants | 391 Participants | 207 Participants |
| Admission category - no. (%) - Unscheduled surgery | 289 Participants | 574 Participants | 285 Participants |
| Age, Continuous | 64.6 years STANDARD_DEVIATION 13.3 | 64.5 years STANDARD_DEVIATION 13.8 | 64.5 years STANDARD_DEVIATION 14.2 |
| Clinical condition at randomization - Mechanical ventilation - no. (%) | 1148 Participants | 2251 Participants | 1103 Participants |
| Clinical condition at randomization- Median cumulative fluid balance (IQR) - ml | 2819 ml/ 24 hr | 2691.5 ml/ 24 hr | 2581 ml/ 24 hr |
| Clinical condition at randomization - Median urinary output (IQR) - ml/24 hr | 478 ml/24 hr | 462 ml/24 hr | 450 ml/24 hr |
| Clinical condition at randomization- Oliguria or anuria - no./total no. (%) | 618 Participants | 1265 Participants | 647 Participants |
| Clinical condition at randomization - SAPS II value | 59.4 units on a scale STANDARD_DEVIATION 17.4 | 58.8 units on a scale STANDARD_DEVIATION 17.4 | 58.1 units on a scale STANDARD_DEVIATION 17.4 |
| Clinical condition at randomization - Sepsis - no. (%) | 834 Participants | 1689 Participants | 855 Participants |
| Clinical condition at randomization - Septic shock - no. (%) | 643 Participants | 1283 Participants | 640 Participants |
| Clinical condition at randomization - Serum bicarbonate - mmol/liter | 19.5 mmol/liter STANDARD_DEVIATION 4.5 | 19.6 mmol/liter STANDARD_DEVIATION 4.6 | 19.7 mmol/liter STANDARD_DEVIATION 4.7 |
| Clinical condition at randomization - Serum creatinine - mg/dl | 3.4 mg/dl STANDARD_DEVIATION 1.6 | 3.5 mg/dl STANDARD_DEVIATION 1.65 | 3.6 mg/dl STANDARD_DEVIATION 1.7 |
| Clinical condition at randomization - Serum potassium - mmol/liter | 4.5 mmol/liter STANDARD_DEVIATION 0.8 | 4.5 mmol/liter STANDARD_DEVIATION 0.8 | 4.5 mmol/liter STANDARD_DEVIATION 0.8 |
| Clinical condition at randomization - SOFA score | 11.8 SOFA score (0-24) STANDARD_DEVIATION 3.6 | 11.7 SOFA score (0-24) STANDARD_DEVIATION 3.6 | 11.6 SOFA score (0-24) STANDARD_DEVIATION 3.6 |
| Clinical condition at randomization - Vasoactive support - no. (%) | 1052 Participants | 2060 Participants | 1008 Participants |
| Estimated glomerular filtration rate - ml/min/1.73 m2 | 67.3 ml/min/1.73 m2 STANDARD_DEVIATION 29.8 | 66.7 ml/min/1.73 m2 STANDARD_DEVIATION 29.8 | 66.0 ml/min/1.73 m2 STANDARD_DEVIATION 29.8 |
| Hospital-acquired risk factor AKI previous wk (no./total no. (%)) - Exposure radiocontrast material | 375 Participants | 757 Participants | 382 Participants |
| Hospital-acquired risk factor for AKI in previous wk - no./total no. (%) - Aortic aneurysm repair | 74 Participants | 145 Participants | 71 Participants |
| Hospital-acquired risk factor for AKI in previous wk - no./total no. (%) - Cardiopulmonary bypass | 118 Participants | 230 Participants | 112 Participants |
| Hospital-acquired risk factor for AKI in previous wk - no./total no. (%) - Major trauma | 55 Participants | 117 Participants | 62 Participants |
| Hospital-acquired risk factor for AKI in previous wk - no./total no. (%) - Obstetric complication | 5 Participants | 10 Participants | 5 Participants |
| Hospital-acquired risk factor for AKI in previous wk - no./total no. (%) - Other vascular surgery | 77 Participants | 153 Participants | 76 Participants |
| Hospital-acquired risk factor for AKI in previous wk - no./total no. (%) - Receipt of aminoglycoside | 148 Participants | 302 Participants | 154 Participants |
| Hospital-acquired risk factor for AKI in previous wk - no./total no. (%) - Receipt of amphotericin B | 12 Participants | 21 Participants | 9 Participants |
| Preexisting conditions - no./total no. (%) - Chronic kidney disease | 626 Participants | 1284 Participants | 658 Participants |
| Preexisting conditions - no./total no. (%) - Coronary artery disease | 328 Participants | 648 Participants | 320 Participants |
| Preexisting conditions - no./total no. (%) - Diabetes mellitus | 459 Participants | 898 Participants | 439 Participants |
| Preexisting conditions - no./total no. (%) - Heart failure | 204 Participants | 408 Participants | 204 Participants |
| Preexisting conditions - no./total no. (%) - Hematologic cancer | 83 Participants | 170 Participants | 87 Participants |
| Preexisting conditions - no./total no. (%) - HIV infection or AIDS | 13 Participants | 26 Participants | 13 Participants |
| Preexisting conditions - no./total no. (%) - Hypertension | 823 Participants | 1637 Participants | 814 Participants |
| Preexisting conditions - no./total no. (%) - Liver disease | 165 Participants | 337 Participants | 172 Participants |
| Preexisting conditions - no./total no. (%) - Metastatic cancer | 84 Participants | 161 Participants | 77 Participants |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment Australia | 198 participants | 391 participants | 193 participants |
| Region of Enrollment Brazil | 4 participants | 8 participants | 4 participants |
| Region of Enrollment China | 111 participants | 226 participants | 115 participants |
| Region of Enrollment Europe | 572 participants | 1146 participants | 574 participants |
| Region of Enrollment New Zealand | 80 participants | 162 participants | 82 participants |
| Region of Enrollment North America | 497 participants | 994 participants | 497 participants |
| Serum creatinine - mg/dl | 1.3 mg/dl STANDARD_DEVIATION 1 | 1.3 mg/dl STANDARD_DEVIATION 1 | 1.4 mg/dl STANDARD_DEVIATION 1 |
| Sex: Female, Male Female | 467 Participants | 937 Participants | 470 Participants |
| Sex: Female, Male Male | 995 Participants | 1990 Participants | 995 Participants |
| Weight - kg | 87.9 kg STANDARD_DEVIATION 25.1 | 87.8 kg STANDARD_DEVIATION 25.8 | 87.8 kg STANDARD_DEVIATION 26.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 639 / 1,462 | 643 / 1,465 |
| other Total, other adverse events | 245 / 1,489 | 346 / 1,503 |
| serious Total, serious adverse events | 8 / 1,489 | 15 / 1,503 |
Outcome results
Primary
All-cause Mortality.
Time frame: 90 days following study randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard RRT Initiation | All-cause Mortality. | 639 Participants |
| Accelerated RRT Initiation | All-cause Mortality. | 643 Participants |
Secondary
Composite of Death or RRT Dependence.
Time frame: 90 days following study randomization.
Secondary
Composite of Death or RRT Dependence.
Time frame: Measured at day 365.
Secondary
Death in ICU
Time frame: Measured in-hospital and at day 28.
Secondary
EuroQoL EQ-5D-5L.
A measure of health-related quality of life and patient utility.
Time frame: Measured at day 90 and at day 365.
Secondary
Health Care Costs.
Time frame: Measured from baseline through day 365.
Secondary
Hospitalization-free Days
Time frame: Measured from randomization through day 90.
Secondary
ICU-free Days
Time frame: Measured from randomization through day 28.
Secondary
Major Adverse Kidney Outcomes.
Defined as death, RRT dependence or sustained reduction in kidney function (defined as eGFR \< 75% baseline eGFR).
Time frame: 90 days following study randomization.
Secondary
Measurement of Albuminuria.
Time frame: 90 days following study randomization.
Secondary
Measurement of Estimated Glomerular Filtration Rate.
Time frame: 90 days following study randomization.
Secondary
Mechanical Ventilation-free Days.
Time frame: Measured from randomization through day 28.
Secondary
RRT Dependence
Time frame: 90 days following study randomization.
Secondary
Vasoactive Therapy-free Days
Time frame: Measured from randomization through day 28.