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

Major Published Clinical Trials in
AKI: What do they Really Mean?
Michael Zappitelli, MD, MSc
Montreal Children's Hospital
McGill University Health Centre
What does “Clinical Trials in AKI” mean?
No AKI
Illness – PICU
Cardiac surgery
Nephrotoxin
AKI
Reduce AKI incidence
Therapeutics
Preventive
What does “Clinical Trials in AKI” mean?
No RRT need
RRT need
Patient develops AKI
Reduce RRT need
Therapeutics
Preventive
Good outcome
Improve outcome
Therapeutics
Preventive
RRT initiation timing
Poor outcome
What does “Clinical Trials in AKI” mean?
Good outcome
Patient requires RRT
Poor outcome
RRT intervention evaluation
Modality
“Dose”
Timing
Intra/Post-RRT therapeutics?
Survival
Renal recovery
Complications
Cost/Morbidity
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
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
RENAL study
Timing not standardized
>25 ml/kg/hr no difference
Modality not addressed
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
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
Timing and dose
Publication Bias
Only 2 RCT’s
Heterogeneity – unable to account for
lack of consensus on “early” definition
Diuretics: do they help once CRRT stopped?
They excreted more sodium
No difference in renal recovery
AKI prevention: EPO?
Extra
process
AKI prevention: EPO?
Biomarker selected sicker patients with worse outcomes
AKI prevention: EPO?
But EPO did not alter outcome
Child Remote Ischemic Preconditioning
Child Remote Ischemic Preconditioning
Plasma Creatinine
Estimated GFR
Plasma CysC
No effect
Plasma NGAL
Too low
power
Urine NGAL
Urine Output
?Significance of preventing 50% SCr rise?
Fenoldopam: infants, biventricular anatomy
Secondary endpoints:
Trend towards reduced pRIFLE AKI
Less diuretics and vasodilators in Rx group
Fenoldopam
MORTALITY
ANP/BNP
ANP/BNP
Peak SCr
RRT Need
2009 Cochrane review:
Similar findings
More complications with higher dose
Useful for “prevention”, not “treatment”
Mortality
X
Must it all be about RCT's right away?
30 day mortality
23%
43%
28%
51%
Propensity score analysis
“Early” = latest day after surgery
“Late” = 2 days after surgery or later
90-day mortality
Other avenues with evidence
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Therapeutic hypothermia
Off pump versus on pump (cardiac surgery)
Statins
Sodium bicarbonate
Anti-inflammatory agents
Fenoldopam, ANP/BNP
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
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
THANK YOU
 Composium organizers:
• Stuart Goldstein
• Timothy Bunchman
 KIDMO colleagues:
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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