Stuart L. Goldstein, MD Professor of Pediatrics
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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
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