STandard versus Accelerated initiation of Renal Replacement Therapy in Acute Kidney Injury

BACKGROUND The optimal timing of RRT initiation in critically ill patients with AKI is still uncertain No consensus to guide clinical practice of acute RRT Wide variability in the timing of RRT initiation This is an important knowledge gap in the support of critically ill patients with AKI NICE identified the “optimal timing of RRT” as a research priority. 2

International multi-centre RCT (NCT02568722) Principal question: Does accelerated initiation of RRT in critically ill patients with AKI reduce 90-day all-cause mortality and non-recovery of kidney function compared to standard initiation? Target: 2,866 critically ill patients with AKI who do not have an urgent indication for RRT 3

Intent of the trial: To identify and enroll patients with severe AKI who have an increased likelihood of needing RRT at some point during their hospitalization but who do NOT need immediate RRT.

Protocol Inclusion criteria: Age ≥18 years Admission to a critical care unit serum creatinine ≥100 µmol/L (women) and ≥130 µmol/L (men) Evidence of severe AKI based on at least 1 of the following criteria: i) ≥ 2-fold increase in serum creatinine (sCr) from baseline ii) sCr ≥ 354 µmol/L with minimum rise of 27 µmol/L from baseline sCr iii) urine output < 6.0 mL/kg over the preceding 12 hours 5

Presence of a drug overdose that necessitates initiation of RRT Exclusion criteria 1-8: Potassium > 5.5 mmol/L Bicarbonate <15 mmol/L (note: these metabolic criteria are dynamic and if corrected, patient may be reconsidered) Presence of a drug overdose that necessitates initiation of RRT Lack of commitment to provide RRT Any RRT within the previous 2 months Kidney transplant within the past 365 days Known advanced CKD, i.e., eGFR < 20 mL/min/1.73 m2 Presence or strong clinical suspicion of renal obstruction, rapidly progressive glomerulonephritis, vasculitis, thrombotic microangiopathy or acute interstitial nephritis 6

Clinician believes that immediate RRT is mandated If patient meets all inclusion criteria and none of exclusion criteria 1-8, then the patient is deemed provisionally eligible. The attending clinician will be approached to confirm his/her equipoise with enrolling the patient in the trial. Potential outcomes: Clinician believes that immediate RRT is mandated -> patient will not be enrolled (but limited data will be collected) b) Clinician believes that deferral of RRT is mandated -> patient will not be enrolled (but limited data will be collected) Clinician has equipoise (exclusions above do not apply) -> patient can be enrolled and randomized 7

Key points about exclusions by clinical team The research team is asking the clinician(s) if there are any compelling reasons to either start RRT immediately or take a watchful waiting approach Patients initially excluded by clinician decision can be re- evaluated later Assuming inclusion criteria are still met and exclusions 1-8 are still ruled out, the clinician may change his/her mind and have equipoise. In this case, the patient is eligible again. 8

Concealed Random Block Allocation Stratified by Center Standard RRT initiation RRT discouraged unless ≥1 of: K≥ 6.0 mmol/L pH ≤7.20 or HCO3 ≤12 mmol/L PaO2/FiO2 ≤200 or clinically significant volume overload persistent AKI for >72 hr Accelerated RRT initiation Start RRT no more than 12 hr after becoming eligible All aspects of prescribed RRT (i.e., modality, dose, anticoagulation) will follow current best practice guidelines and local standards of care The Clock starts ticking 1. 12 hour window to obtain consent 2. if participant is randomized to the accelerated arm, RRT also needs to started within this window RRT continued in both arms until death, withdrawal of care or evidence of kidney recovery

Patients in accelerated group Patients in standard group Final patient groups: Patients in accelerated group Patients in standard group Patients treated as per clinician decision We plan to include all 3 groups in the analysis. Patients in all groups (incl group 3) will be asked for consent for data collection and analysis. 10

Primary outcome: Secondary outcomes: all-cause mortality at 90 days Kidney-specific outcomes: dialysis dependence at 90 days among survivors; composite of death or dialysis dependence at 90 days; eGFR among patients alive at 90 days; albuminuria at 90 days; and Major Adverse Kidney Events (MAKE) at 90 days; dialysis dependence at 1-year. Patient-centered outcomes: mortality at 28 days; ICU; hospital; and 1-year; health-related quality of life (EQ-5D-5L) at 90 days Resource utilization outcomes: changes in organ dysfunction in the 7 days after randomization; mechanical ventilation-free days through 28 days; vasoactive therapy-free days through 28 days; ICU-free days through 28 days; and hospital-free days through 90 days Cost evaluation: Health care costs through 90 days and 1-year; cost-effectiveness analysis 11

Chief Investigators: Prof Ron Wald, Toronto, Canada Prof Sean Bagshaw, Edmonton, Canada Participating institutions: Centers in Canada, Australia, New Zealand, Finland, Ireland, Austria, Belgium, UK, USA, China Funding applications were supported by NICE UK Study has been adopted as portfolio study 12