Stuart L. Goldstein, MDProfessor of Pediatrics

Baylor College of Medicine

Pediatric Acute Kidney Injury and Biomarkers

6th PCRRT Conference, Rome 2010

Acknowledgements

Baylor College of Medicine/Texas Children’s AKI Study Group

Laura Loftis, MDAnnabelle Chua, MD

Ayse Arikan, MDMichael Zappitelli, MD

Alyssa Riley-Kothari, MDYue Du, PhD

Leticia Castillo, MD

Jack Price, MDDavid Nelson, MD

John Lynn Jeffries, MDJoshua Blinder, MDJeffrey Towbin, MD

Anjan Shah, MD

Brady Moffett, RPh

Outline

AKI Epidemiology – Old DefinitionsRisk Factor AssessmentNew AKI DefinitionsTreatmentPrognosisNew Advancements - Biomarkers

AKI Definitions to 2002

Over 30 definitions in published literatureNearly all based on absolute or change in serum

creatinine concentrationPediatric AKI definitions – All AKI is created

equal100% rise in SCreCCL < 75 ml/min/1.73m2

SCr twice normal for patient age

Few prospective pediatric studiesRetrospective studies assess AKI causesControl group without AKI not assessed to

determine risk factors for AKI

Pediatric AKI Epidemiology until 2002: What was Out There?

Most original data all single centerPredate current ICU technology and practicePredate recent disease therapies

Bone marrow transplantationCardiac transplantationCongenital heart surgery

Cite Hemolytic-Uremic Syndrome/primary renal disease as most common causes

Most articles after 1995 are literature review

Patient Selection Reviewed all admissions to Texas Children’s

Hospital from January 1998 through June 2001 Selected patients <20 years of age with ARF

listed as diagnosis on discharge or death summary

Reviewed list and defined ARF as GFR by Schwartz < 75 ml/min/1.73m2 (n=254)

Most Common ARF Causes ATN-Dehydration (21%) Nephrotoxic drugs (16%) Sepsis (11%) Unknown (14%) Primary Renal Disease (7%)

Patient Survival 176/254 patients (70%) 110/185 patients with ICU care (60%) 43/77 patients receiving renal replacement therapy

(56%)

Pediatric AKI Epidemiology

Author YearTime span

Cohort AKI Cause

Williams 20021978-1998

All hospital

1978-88: HUS 38%, Oncology 8%

1988-98: HUS 22%

Oncology 17%

Hui-Stickle 20051999-2001

All hospital

Ischemic 21%

Nephrotoxins 16%

Primary Renal 7%

Akcan-Arikan 20072005-2006

PICU

Pneumonia (33%)

SIRS/sepsis(27%)

Cardiogenic (10%)

Pediatric AKI Risk Factors

Few comparative data of populations with versus without AKI to determine who is truly at risk

Most data examine only patients with AKI and report causes (previous slides)

AKI Risk Factors – Assessment IssuesRetrospective

aminoglycoside studyAKI defined as 50%

decreaseHeme/Onc and Pulm

with highest AKISurgery with lowest

AKIHeme/Onc and Pulm

assessed SCr significantly more often than Surgery

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Peds H-Onc Pulm Surg Other

#SCR per days treated

0

10

20

30

40

50

Peds H-Onc Pulm Surg Other

%AKI

Zappitelli and Goldstein, submitted

Pediatric AKI Risk Factors:The Critically Ill Patient

Highest risk for AKI developmentAKI now results from other systemic illness

or its treatment and not from primary kidney disease

Most pediatric AKI studies focus on patients who receive RRT

More recent studies compare patients with AKI versus without AKI

Single-center, prospective observational study over one year (2000-2001)

Pediatric ICU population3 days to 18 years of age

AKI defined as doubling SCrDoubling of upper limit of normalDoubling of PICU admission SCrTrue “baseline” pre-PICU SCr not assessedCKD patients: AKI defined as 25% increase in

SCr

1047 admissionsExclusions for patient

age, prematurity, decision to withhold care, pregnancy

4.5% AKI rate

Risk factorsThrombocytopeniaOlder ageHypoxemiaHypotensionCoagulopathy

Increased PRISM and PELOD scores also AKI risk factors

Is All AKI Created Equal?

Recent adult patient data demonstrateSmall SCr rises associated with mortalityAKI associated with mortality and length of

hospitalizationAKI is now recognized as risk factor for poor

outcome, independent of severity of illness

AKI Severity and Outcome

Chertow GM et al: J Am Soc Nephrol, 2005

All AKI is NOT Equal

Multidimensional classification system is needed toGrade AKI severityFollow changes in kidney functionStandardize AKI as a hard outcome measure

AKI RIFLE Criteria: ADQI II

Prospective single center observational studyPICU patients receiving mechanical ventilation

and vasoactive medicationsAKI defined by a pediatric modified RIFLE criteria

(pRIFLE)pRIFLEmax defined as highest pRIFLE stratum

achieved at 14 days of PICU admission or patient discharge, whichever came first

eCCl determined by Schwartz formula

Baseline eCCl from three months before PICU100 ml/min/1.73m2 if no

data availablepRIFLE differs from

RIFLE inOliguria durationRIFLE-F limit eCCl

AKI occurred early in PICU admission

• 82% of AKI patients attained their initial RIFLE stratum in the first 7 days.

Initial RIFLE R N=76

Initial RIFLE I N=31

3/76 (4%) RIFLEmax F

12/31 (39%) pRIFLEmax F

“Persistent” AKI on admission

BiomarkersA biologic characteristic that is measured and evaluated objectively as an indicator of normal biologic processes, pathogenic processes, or pharmacologic response to therapeutic intervention. Hewitt et al, JASN, 2004

imaging test (renal ultrasound for kidney size)

gene expression profiles for specific health or disease states

proteinuria

lipid profile

metabolomic profiles

Why do we need biomarkers of AKI?

Independent RF for mortality and longer LOS in critically ill children.Ackan-Arikan et al, KI, 2007; Plotz et al, Intens Care Med, 2008

Independent RF for LOS in children having cardiac surgery.Bernier et al, ASN, 2008

Independent RF for longer LOS in children treated with aminoglycosides.Zappitelli et al, CJASN, 2008; Zappitelli et al, ASN, 2007

May be a RF for long-term abnormal renal function problems.Askenazi et al, KI, 2006

Because AKI is important.

Why do we need biomarkers of AKI? No treatment.

Diagnosis based on SCr rise: 1 to 3 days after injury – failed past clinical trials.

Several issues with SCr as a marker of GFR.

Utilities of biomarkers in AKIEarly diagnosis

Define severity of injury, monitor AKI course

Define AKI subtypes & etiology (pre-renal, septic, nephrotoxic)

Monitor response to AKI interventions

Risk stratify for poor outcomes (dialysis need, CKD, mortality)

Identify location of renal tubular injury

Devarajan & Williams, Seminars in Nephrol, 2007

What is an ideal biomarker? Qualities

Accurate, reliable Relatively

non-invasive/acceptable to patients

Rapidly measurable, standardized assay

Sensitive/specific with reproducible cutoff values

Requires case definition: AKIN, pRIFLE

Nguyen & Devarajan, Ped Nephrol, 2008

Phases of biomarker discovery: bench to bedside

Phases of biomarker development

Phase Terminology Action Steps Phase 1 Preclinical Discovery • Discover biomarkers in tissues or body fluids • Confirm and prioritize promising candidates

Phase 2 Assay Development • Develop and optimize clinically useful assay • Test on existing samples of established disease

Phase 3 Retrospective Study • Test biomarker in completed clinical trial • Test if biomarker detects the disease early • Evaluate sensitivity, specificity, ROC

Phase 4 Prospective Screening • Use biomarker to screen population • Identify extent and characteristics of disease • Identify false referral rate

Phase 5 Disease Control • Determine impact of screening on reducing

disease burden

Devarajan & Williams, Seminars Nephrol, 2007; Coca & Parikh, CJASN, 2008

Dis

covery

Tra

nsl

ati

onal

Valid

ati

on

Biomarker discovery in AKI: bench to bedside

NGAL: Expressed in proximal and distal nephron Binds and transports iron-carrying molecules Role in injury and repair Rises very early (hours) after injury in animals, confirmed in children

having CPB

IL-18: Role in inflammation, activating macrophages and mediates ischemic

renal injury IL-18 antiserum to animals protects against ischemic AKI Studied in several human models

KIM-1: Epithelial transmembrane protein, ?cell-cell interaction. Appears to have strong relationship with severity of renal injury

Biomarker studies in different populationsCardiac surgery

Critically ill patients

Sepsis

Nephrotoxin-treated patients

Renal transplant

General hospital population

Cardiac surgery: Known timing of AKI

NGAL: Children led the way! Mishra et al, Lancet, 2005

SCr rise48-72 hrs

Wagener et al, Anesthesiology, 2006Adults

Not quite as good

Cardiac surgery

Parikh et al,KI, 2006

Children

Critical Illness: unknown timing of AKI

IL-18SCr rise

Parikh et al, JASN, 2005Critically ill adults: retrospective. Landmark study.

Critical illness population

0.0

00

.25

0.5

00

.75

1.0

0S

en

sitiv

ity

0.00 0.25 0.50 0.75 1.001 - Specificity

Area under ROC curve = 0.7692

NGAL KIM-1

The day of SCr rise: Can biomarkers tell us WHO has “true AKI” versus who has volume depletion?

Predict lack of SCr return to normal within 48 hrs when taken at time of SCr rise

Texas Children’s AKI Biomarker Study

Previous published pediatric AKI biomarker reports from homogeneous patients populations, many with primary renal disease

Prospective study of 150 patients admitted to TCH PICU who received mechanical ventilation and/or vasoactive medications

Outcome MeasurespRIFLEmax at 14 days of ICU admissionPersistent AKI (AKI that did not resolve in 48 hoursPredict AKI prior to pRIFLE

Texas Children’s AKI Biomarker Study150 patients (enrolled in pRIFLE study)

10 patients excluded from biomarker study for anuria or no indwelling Foley

Urine obtained at 2 PM for up to four days after study enrollmentNGAL (Devarajan)IL-18 (Edelstein)KIM-1 (Bonventre)

pRIFLE creatinine calculated from Day 1 to Day 14 of ICU admission

140 patients’ urine samples availableMean age 6.3 years (1 year to 21 years)Mean ICU day of admission = 3 + 1.5

dayspRIFLE

No AKI: 24.3%R: 33.7%I: 22.1%F: 17.9%

02

46

uN

GA

L (n

g/m

g c

reati

nin

e)

-3 -2 -1 0 1 2

Days from Day of first pRIFLE (Day 0)

AKI higher than controls from Day -2 to Day 2, p<0.05

● ● ● ● ● ●

Increase in NGAL to predict AKI: AUC=0.78

Increase in NGAL to predict persAKI: AUC=0.80

01

00

20

03

00

40

0M

ean a

nd P

eak u

IL1

8 (

pg

/ml)

Control R I F

Mean uIL18 Peak uIL18

All Patients Non-septic

01

00

20

03

00

40

0F

irst u

IL-1

8 (p

g/m

l)

Survivors Non-survivorsexcludes outside values

P<0.05

Pediatric AKI and Biomarkers: Conclusions

Pediatric AKI is seen as a complication of other systemic illness

Earlier recognition and treatment of AKI sequelae may improve outcome

Active investigation/validation of urinary biomarkers may lead to therapies to prevent or mitigate the effects of AKI