1. Major Published Clinical Trials in AKI: What do they Really Mean? Michael Zappitelli, MD, MSc Montreal Children's Hospital McGill University Health Centre

2. What does “Clinical Trials in AKI” mean? Reduce AKI incidence Therapeutics Preventive Illness – PICU Cardiac surgery Nephrotoxin No AKI AKI

3. What does “Clinical Trials in AKI” mean? Reduce RRT need Therapeutics Preventive Improve outcome Therapeutics Preventive RRT initiation timing Patient develops AKI No RRT need RRT need Good outcome Poor outcome

4. What does “Clinical Trials in AKI” mean? RRT intervention evaluation Modality “Dose” Timing Intra/Post-RRT therapeutics? Survival Renal recovery Complications Cost/Morbidity Patient requires RRT Good outcome Poor outcome

5. Overview Major trials on dose and timing Brief meta-analyses review Selected adult and pediatric trials Brief review of meta-analyses Context of pediatric AKI and future directions

6. Timing not standardized Did it really answer the dose question? Allowed for different modalities No benefit to increase HD dose > 3/week + Kt/V >1.2-1.4 OR CRRT > 20 ml/kg/hr ATN Study

7. RENAL study Timing not standardized Timing not standardized >25 ml/kg/hr no difference Modality not addressed Timing not standardized Timing not standardized >25 ml/kg/hr no difference Modality not addressed

8. Meta-analyses: similar findings Several meta-analyses: intensity and/or renal recovery Casey et al, Renal Failure, 2010 Zhang et al, J of Critical Care, 2010 Jun et al, CJASN, 2010 Negash et al, Cochrane review, updated 2011 Modality - several meta-analyses: IHD vs CRRT Tonelli et al, AJKD, 2002 Rabindranath, Cochrane review, 2008 Bagshaw et al, Crit Care Med, 2008 Highlight: Poor quality evidence, heterogeneity

9. Timing and dose “Early”: within 12 hours of inclusion “Late”: when “standard” RRT criteria used “High”: ~40 ml/kg/hr for 70kg “Low”: ~ 15-20 ml/kg/hr for 70 kg “Early”: within 12 hours of inclusion “Late”: when “standard” RRT criteria used “High”: ~40 ml/kg/hr for 70kg “Low”: ~ 15-20 ml/kg/hr for 70 kg

10. Timing and dose Only 2 RCT’s Publication Bias Heterogeneity – unable to account for lack of consensus on “early” definition Publication Bias Heterogeneity – unable to account for lack of consensus on “early” definition

11. Diuretics: do they help once CRRT stopped? They excreted more sodium No difference in renal recovery

12. AKI prevention: EPO?

13. Extraprocess

14. Biomarker selected sicker patients with worse outcomes

15. AKI prevention: EPO? But EPO did not alter outcome

16. Child Remote Ischemic Preconditioning

17. Plasma Creatinine Estimated GFRPlasma CysC Urine Output Urine NGAL Plasma NGAL No effect Too low power ?Significance of preventing 50% SCr rise? No effect Too low power ?Significance of preventing 50% SCr rise?

18. Fenoldopam: infants, biventricular anatomy Secondary endpoints: Trend towards reduced pRIFLE AKI Less diuretics and vasodilators in Rx group Secondary endpoints: Trend towards reduced pRIFLE AKI Less diuretics and vasodilators in Rx group

19. Fenoldopam MORTALITY

20. ANP/BNP

21. Peak SCr RRT Need X Mortality 2009 Cochrane review: Similar findings More complications with higher dose Useful for “prevention”, not “treatment” 2009 Cochrane review: Similar findings More complications with higher dose Useful for “prevention”, not “treatment” ANP/BNP

22. Must it all be about RCT's right away? Propensity score analysis 30 day mortality 23% 43% 90-day mortality 28% 51% “Early” = latest day after surgery “Late” = 2 days after surgery or later “Early” = latest day after surgery “Late” = 2 days after surgery or later

23. Other avenues with evidence  Therapeutic hypothermia  Off pump versus on pump (cardiac surgery)  Statins  Sodium bicarbonate  Anti-inflammatory agents  Fenoldopam, ANP/BNP

24. Summary & Conclusion  Dose/Intensity of RRT: ATN/RENAL study suggest intensity above ~ 20-25 ml/kg/hr will not improve outcomes No pediatric data, but:  Should we be more aware of the dose we provide?  Are we actually delivering what we think we are?  Modality based on clinical factors  Use of diuretics to enhance water clearance unlikely to improve outcome or prevent RRT need Does not mean they do not play important role  “Earlier” RRT initiation may be beneficial Need to standardize definition Pediatrics: different epidemiology, fluid overload – future trials

25. Summary & Conclusion  Clinical trials in pediatrics ARE feasible We have: Definition (s) Biomarkers Demonstrated importance Need to sort out: Existing practice Best outcome to study Best population to study Balance risk of Rx vs potential benefit Demonstrate clinical equipoise

26. THANK YOU  Composium organizers: Stuart Goldstein Timothy Bunchman  KIDMO colleagues: David Askenazi Geoffrey Fleming Matthew Paden David Selewski Brian Bridges David Cooper  Cincinnati Children's Hospital Medical Centre  ppCRRT members  Montreal Children's Hospital AKI research team