Major Clinical Trials in AKI

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

What does “Clinical Trials in AKI” mean?

Illness AKI

Reduce AKITherapeuticsPreventative

RRT need

Reduce RRT needTherapeutics Preventative

Good vs. poor outcome

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

ATN Study

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

RENAL study

Timing not standardized

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 actual RCT’s

Heterogeneity high

Timing and dose: pediatric

20 children: +24 hours PD vs not

No differences in biomarkers

22 children: prophylactic PD vs. not

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

Diuretics: do they help once CRRT stopped?

They excreted more sodium No difference in renal recovery

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

Remote ischemic pre-conditioning

Remote ischemic pre-conditioning

Child Remote Ischemic Preconditioning

Creat Estimated GFR Plasma CysC

Plasma NGAL Urine NGAL Urine OutputNo effect

Too low power

?Significance of preventing 50% SCr rise?

Theophylline: the only KDIGO recommended drug

Recent trials: adult CIN

Theophylline: urine outputJenik

Bhat

Theophylline: GFRBhat Bakr

AKI treatments: horizon

Ongoing or planned or completed

Aminophylline

Acetaminophen

RIPC

Intensive glucose control

Rewarming

Summary & ConclusionDose/Intensity of RRT:

ATN/RENAL study suggest intensity above ~ 20-25 ml/kg/hr willnot 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 improveoutcome or prevent RRT need

Does not mean they do not play important role

“Earlier” RRT initiation may be beneficialNeed to standardize definitionPediatrics: different epidemiology, fluid overload – future trials

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?

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