1. Major Clinical Trials in AKI Michael Zappitelli, MD, MSc Montreal Children's Hospital McGill University Health Centre

2. What does “Clinical Trials in AKI” mean? IllnessAKI Reduce AKI Therapeutics Preventative RRT need Reduce RRT need Therapeutics Preventative Good vs. poor outcome RRT intervention evaluation Modality “Dose” Timing Intra/Post-RRT therapeutics?

3. ATN Study 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

4. RENAL study Timing not standardized Modality not addressed

5. 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

6. 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

7. Timing and dose Only 2 actual RCT’s Heterogeneity high

8. Timing and dose: pediatric 20 children: +24 hours PD vs not No differences in biomarkers 22 children: prophylactic PD vs. not

9. Timing and dose: horizon IDEAL study: Early (12 hours from AKI) vs. later (>48 hours from AKI) RRT initiation. N=864 STAART-AKI: NGAL used for eligibility. Accelerated (<12 hours from eligibility) vs. not. Pediatric: Use of biomarkers to trigger /decision on CRRT and fluid management

10. Diuretics: do they help once CRRT stopped? They excreted more sodiumNo difference in renal recovery

11. Can we prevent/treat AKI? Still an elusive goal. Therapeutic hypothermia Off pump versus on pump (cardiac surgery) Statins Sodium bicarbonate Anti-inflammatory agents Fenoldopam, ANP/BNP RIPC, theophylline

12. Remote ischemic pre- conditioning

14. Child Remote Ischemic Preconditioning CreatEstimated GFRPlasma CysC Plasma NGALUrine NGALUrine Output No effect Too low power ?Significance of preventing 50% SCr rise?

15. Theophylline: the only KDIGO recommended drug Recent trials: adult CIN

16. Theophylline: urine output Jenik Bhat

17. Theophylline: GFR BhatBakr

18. AKI treatments: horizon Ongoing or planned or completed Aminophylline Acetaminophen RIPC Intensive glucose control Rewarming

19. 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

20. Summary & Conclusion Clinical trials in pediatrics ARE feasible Need to sort out: Existing practice Best outcome to study Best population to study Balance risk of Rx vs potential benefit Demonstrate clinical equipoise What are the most important first questions we want to answer?

21. THANK YOU pCRRT conference organizers Montreal Children’s Hospital AKI research team Collaborators/mentors: Stuart Goldstein, Prasad Devarajan, Chirag Parikh The Kidney Injury During Membrane Oxygenation group