1. Timing of RRT in AKI: The STARRT-AKI Trial Paul M. Palevsky, M.D. Chief, Renal Section VA Pittsburgh Healthcare System Professor of Medicine University of Pittsburgh School of Medicine

2. Indications for Renal Support in Acute Kidney Injury Volume overload Metabolic acidosis Hyperkalemia Uremic state encephalopathy pericarditis Azotemia without uremic manifestations Oliguria

3. Timing of Renal Replacement Therapy in AKI “While there is increasing recognition of the value of earlier dialysis, the published consensus, and the practice in many centers at present, is still to apply dialysis to relatively ill rather than to relatively healthy patients” - Teschan PE, et al: Ann Intern Med 1960; 53:992-1016

4. Timing of Renal Replacement Therapy in AKI “We would urge that dialyses applied to patients who might otherwise survive should not under any circumstances be considered to be superfluous. Rather, the judgment of whether to undertake dialysis should also be made in view of the possible risks of not employing this procedure. We would question both the wisdom and the safety of subjecting patients to several days of avoidable nausea, vomiting, drowsiness and thirst, which not only implies significant discomfort to the patient but may also impose considerable risk of aspiration, pneumonia and other unexpected ‘complications’” - Teschan PE, et al: Ann Intern Med 1960; 53:992-1016

5. Timing of CVVH in Post-Traumatic AKI Gettings LG, et al: Intensive Care Med 1999; 25:805-813 (Mean: 42.6±12.9) (Mean: 94.5±28.3) n=41n=59

6. Timing of CVVH in Post-Cardiac Surgery AKI Elahi MM, et al: Eur J Cardiothorac Surg 2004; 26: 1027-1031 Demirkilic U, et al: J Card Surg 2004; 19: 17-20 BUN ≥ 84 mg/dL, Cr >2.8 mg/dL, or Potassium > 6 mEq/L UOP < 100 mL for 8 hours n=28 n=36 n=27 n=34 Cr >5.0 mg/dL, or Potassium > 5.5 mEq/L

7. Timing of RRT in AKI: PICARD Study Data BUN ≤76 mg/dL (n=122) BUN>76 mg/dL (n=121) Mean BUN47.4 mg/dL114.9 mg/dLp<0.0001 Mean Creatinine3.4 mg/dL4.7 mg/dLp<0.0001 Failed Organ Systems4 (IQR: 3-4)3 (IQR: 2-4)p=0.008 Sepsis37%46%p=0.14 Initial RRT with CRRT69%43%p<0.001 Survival day 14 day 28 80% 65% 75% 59% p=0.09 Adjusted mortality risk adjusted for covariates adjusted for propensity score adjusted for both covariates and propensity 1.85 (95% CI: 1.16-2.96) 2.07 (95% CI: 1.30-3.29) 1.97 (95% CI: 1.21-3.20) Liu K et al. Clin J Am Soc Nephrol 2006; 1: 915-919

8. 2011 Meta-Analysis of Timing of Initiation of RRT in AKI: Survival Karvellas et al. Critical Care 2011 15:R72

9. 2012 Meta-Analysis of Timing of Initiation of RRT in AKI: Survival Wang X, et al. Renal Fail 2012; 34: 396-402

10. Timing of RRT in AKI Patients with Early AKI Early RRT Late RRT Recover without RRT Die without RRT

11. Timing and Dose of CVVH in AKI n=35 SOFA 10.1±2.2 n=35 SOFA 10.3±2.8 Bouman CS, et al. Critical Care Med 2002; 30:2205-2211 n=36 SOFA 10.6±1.9

12. Earlier versus Usual Start of RRT in Community-Acquired AKI Jamale TE, et al. Am J Kidney Dis 2013; 62:1116-1121

13. Earlier versus Usual Start of RRT in Community-Acquired AKI Jamale TE, et al. Am J Kidney Dis 2013; 62:1116-1121 Baseline Data Early StartUsual Start BUN (mg/dL) 71.7±21.7100.9±32.6 Creatinine (mg/dL) 7.4±5.310.4±3.3

14. Standard vs Accelerated initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) RCT comparing strategies of accelerated vs delayed initiation of RRT in critically ill patients with AKI Pilot Phase Completed by Canadian Critical Care Trials Group 100 Patients Evaluated study feasibility Definitive Phase International collaboration led by Ron Wald and Sean Bagshaw Target enrollment 2,866 patients Target US enrollment: 920 patients

15. STARRT-AKI Pilot Eligibility Criteria Presence of severe AKI (2 of the following) Twofold increase in serum creatinine from baseline Urine output <6 ml/kg in the preceding 12 h, or Whole-blood NGAL ≥400 ng/ml) <48 hours since doubling of serum creatinine Absence of urgent indications for RRT initiation (serum K + ≤5.5 mmol/l and HCO 3 - ≥15 mmol/l) Low likelihood of volume-responsive AKI (defined CVP≥8 mm Hg). Exclusions: Lack of commitment to ongoing life support; Presence of an intoxication requiring RRT RRT within the previous 2 months; Clinical suspicion of renal obstruction, RPGN or AIN Pre-hospitalization eGFR<30 ml/min per 1.73 m 2 ; Equipoise among treating team (attending intensivist and nephrologist) Did treating physicians believe that either immediate RRT initiation or RRT deferral was mandated. Wald R, et al. Kidney Int e-published 8 July 2015

16. STARRT-AKI Pilot Wald R, et al. Kidney Int e-published 8 July 2015

17. STARRT-AKI Pilot Wald R, et al. Kidney Int e-published 8 July 2015 Treatment Group90-day Mortality Accelerated Initiation of RRT (n=48)37.5% Standard Initiation of RRT (n=52)36.5% Received RRT (n=33)39.4% Did not receive RRT (n=19)31.6%

18. STARRT-AKI Definitive Phase: Eligibility Criteria Inclusion Criteria Age ≥18 years and receiving care in an ICU Early severe AKI KDIGO stage 2/3 AKI Serum creatinine not >3x baseline for >48 hours Equipoise regarding timing of RRT for the individual patient based on: Absence of metabolic criteria predicting need for RRT within the next 24 hours: Serum potassium>5.5 mmol/L Total CO 2 <15 mmol/L Absence of drug intoxication requiring RRT Agreement by treating physicians that RRT does not need to be initiated immediately but with no objection to the possibility of immediate initiation

19. STARRT-AKI Definitive Phase: Eligibility Criteria Exclusion Criteria Lack of commitment to ongoing life support, including RRT AKI resulting from a potentially treatable etiology History of pre-existing kidney disease defined by: RRT in previous 2 months Kidney transplant within past year; Known advanced CKD with eGFR<20 mL/min/1.73 m 2

20. STARRT-AKI Definitive Phase: Treatment Groups Accelerated RRT Initiation Dialysis Catheter to be placed and RRT initiated as soon as possible within 12 hours of eligibility Delayed RRT Initiation Persistent severe AKI defined as S creat that remains >50% of value at randomization AND at least one of the following: K + ≥ 6.0 mmol/L; pH < 7.20 or tCO 2 ≤ 12 mmol/L; or Evidence of severe respiratory failure based on PaO 2 /FiO 2 < 200 with volume overload or Persistent severe AKI for >72 hours from randomization The decision to initiate RRT in the delayed arm will be made by the treating physicians and not by research personnel

21. STARRT-AKI Definitive Phase: RRT Management Other than timing of initiation of RRT, all other aspects of RRT will be based on usual care guided by accepted clinical practice guidelines RRT will be continued until Death; Withdrawal of life support; or Kidney function recovery as per treating physician’s judgment

22. STARRT-AKI Definitive Phase: Endpoints Primary outcome 90-day all-cause mortality Secondary outcomes Dialysis-dependence at 90 days Patient self-assessment of HRQoL and functional status Tertiary outcomes eGFR among patients alive at day 90 Major adverse kidney events (MAKE) Death RRT dependence eGFR <75% of baseline eGFR at 90 days

23. STARRT-AKI Definitive Phase: Sample Size Assumptions: 40% 90-day all cause mortality in delayed RRT initiation arm 34% 90-day all cause mortality in accelerated RRT initiation arm (absolute risk reduction of 6%; relative risk reduction of 15%) 3% loss to follow-up α=0.05 1-β=0.90 Sample size: 2,866

24. STARRT-AKI Trials Group International Study Chairs Ron Wald (Toronto, ON) Sean Bagshaw (Edmonton, AB) Data Management & Coordinating Center Applied Health Research Center, St. Michael’s Hospital, Toronto International Steering Committee Canada – Ron Wald & Sean Bagshaw United Kingdom – Marlies Ostermann Austria – Michael Joannidis Finland – Ville Pettilä Australia – Rinaldo Bellomo & Martin Gallagher New Zealand – Shay McGuiness United States – Paul Palevsky & Kathleen Liu

25. STARRT-AKI United States Consortium US Steering Committee Paul M. Palevsky, US Study Chair Kathleen D. Liu, US Study Co-Chair US Clinical Sites Beth Israel Deaconess Medical Center, Boston, MA - Ali Poyan Mehr & Daniel Talmor Brigham & Women’s Hospital, Boston, MA – Sushrut Waikar Cleveland Clinic, Cleveland, OH – Sevag Demirjian Massachusetts General Hospital, Boston, MA – John Niles University of Alabama, Birmingham, AL – Ashita Tolwani University of California, San Francisco, CA – Kathleen Liu University of Chicago, Chicago, IL – Jay Koyner University of Miami, Miami, FL – Gabriel Contreras & Roland Schein University of Pittsburgh, Pittsburgh, PA - Raghavan Murugan & Chethan Puttarajappa University of Texas HSC, Houston, TX – Kevin Finkel Vanderbilt University, Nashville, TN – Edward Siew Washington University, St. Louis, MO – Anitha Vijayan