Major Published Clinical Trials in AKI: What do they Really Mean?

Michael Zappitelli, MD, MScMontreal Children's HospitalMcGill University Health Centre

What does “Clinical Trials in AKI” mean?

Reduce AKI incidenceTherapeuticsPreventive

Illness – PICU

Cardiac surgery

Nephrotoxin

No AKI

AKI

What does “Clinical Trials in AKI” mean?

Reduce RRT needTherapeutics Preventive

Improve outcomeTherapeuticsPreventiveRRT initiation timing

Patient develops AKI

No RRT need

RRT need

Good outcome

Poor outcome

What does “Clinical Trials in AKI” mean?

RRT intervention evaluationModality“Dose”TimingIntra/Post-RRT therapeutics?

SurvivalRenal recoveryComplicationsCost/Morbidity

Patient requires RRT

Good outcome

Poor outcome

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

Timing not standardizedDid it really answer the dose question? Allowed for different modalities

No benefit to increase HD dose > 3/week + Kt/V >1.2-1.4 ORCRRT > 20 ml/kg/hr

ATN Study

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, 2010Zhang et al, J of Critical Care, 2010Jun et al, CJASN, 2010Negash et al, Cochrane review, updated 2011

Modality - several meta-analyses: IHD vs CRRT

Tonelli et al, AJKD, 2002Rabindranath, Cochrane review, 2008Bagshaw 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

Only 2 RCT’s

Publication Bias

Heterogeneity – unable to account forlack 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

Urine OutputUrine NGALPlasma NGAL

No effect

Too low power

?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

Peak SCr

RRT Need

X

Mortality

2009 Cochrane review:Similar findings

More complications with higher dose

Useful for “prevention”, not “treatment”

ANP/BNP

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

Other avenues with evidence

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: • 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