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BOOK•0266•5/07
AKI in Pediatrics
Patrick D. Brophy MDAssociate Professor
University of Iowa- Carver College of MedicineDept. of Pediatrics
Division of Nephrology, Hypertension, Dialysis & Transplantation
BOOK•0266•5/07
OBJECTIVESOBJECTIVES
The Problematic Definition of ARF New concepts/old habits
The Transition Acute Renal Failure Acute Kidney Injury
Epidemiology- developing and developed countries HUS to ATN
Biomarkers? How are we doing NGAL, IL-18 and creatinine
RRT Treatment Outcomes Update on variables in the PICU
Modalities of choice? PD, HD or CRRT--- What modality, when and why
BOOK•0266•5/07
The Problematic Definition of ARFThe Problematic Definition of ARF
The Conceptual Definition of Acute Renal Failure:
“Sudden loss of renal function resulting in the loss of the kidneys’ ability to regulate electrolyte and fluid homeostasis”
BOOK•0266•5/07
The Problematic Definition of ARFThe Problematic Definition of ARF
Pediatric AKI definition: a moving targetInfants
Cr in the first few weeks of life may reflect maternal values
ChildrenLow baseline Cr makes 0.2-0.3 changes in Cr significantVarying muscle mass
AdolescentsSimilar to adults
BOOK•0266•5/07
The Problematic Definition of ARFThe Problematic Definition of ARF
Over 30 published ARF definitionsAll based on increased serum creatinine levelsDespite extensive adult hospitalized patient study over the
past 50 years
Widely varying spectrum dependent upon study aims and hypothesisSevere (ARF requiring dialysis)Modest (serum creatinine increase of 0.3 mg/dl)
Why is this important……?
BOOK•0266•5/07
The Problematic Definition of ARFThe Problematic Definition of ARF
The lack of a uniform ARF definition has prevented optimal ARF outcome research One study’s ARF is another study’s lab error (or maybe not)
Inherent problems with SCr as ARF marker Does not differentiate
the nature and type of renal insult site of renal insult
Changes in SCr may lag changes in GFR and may be a very late indicator of renal injury
Dialysis removal negates marker effectiveness
BOOK•0266•5/07
The Ideal Disease DefinitionThe Ideal Disease Definition
Wouldascertain disease presenceguide nature and timing of diagnostic and
therapeutic interventionshelp determine prognosis
Should incorporateclinical signs and symptomsalterations in reproducible biological markers
BOOK•0266•5/07
Pediatric Modified RIFLE--definitionPediatric Modified RIFLE--definition
Ackan-Arikan et al: Kid Int 2007
Pediatric Modified RIFLE Criteria
CrCl Urine output
Risk GFR decrease by 25% <0.5ml/kg/hour for 8 hours
Injury GFR decrease by 50% <0.5ml/kg/hour for 16 hours
Failure GFR decrease by 75% or GFR<35ml/min/1.73m2
<0.3 ml/kg/hour for 24 hours or anuric for 12 hours
Loss Persistent ARF > 4 weeks
End stage End Stage Renal Disease (>3 months)
GFR per Schwartz equation: GFR= Ht (cm) X constant / serum creat (mg/dl)
BOOK•0266•5/07
EPIDEMIOLOGY
BOOK•0266•5/07
Epidemiology-The Pediatric Patient with AKIEpidemiology-The Pediatric Patient with AKI
IS NOT a small adult 0 days to 21+ years 2 kg to 200 kg
Primary conditions Congenital heart disease Inborn errors of metabolism Sepsis with multi-organ involvement Bone marrow and solid organ transplantation
Children develop and die of MODS early in ICU course Maximum number of organ failures occurs within 72 hours of ICU
admission (87% of patients) 88.4% of deaths occur within 7 days of MOSF diagnosis
(Proulx et al: Crit Care Med 22:1025, 1994)
BOOK•0266•5/07
Epidemiology-Incidence AKIEpidemiology-Incidence AKI
A retrospective analysis reported an incidence rate of AKI of 2.7% (defined as need for dialysis) in children undergoing cardiopulmonary bypass surgery [Picca NDT 1995].
The prospective study validating the Pediatric Logistic Organ Dysfunction (PELOD) score in pediatric intensive care units (PICU), the incidence of AKI (defined as serum creatinine levels above 55 mol/L to 140 mol/L depending on age of the child) was 129 per 1000 admissions [Leteurtre lancet 2003].
PICU prospective trial reported an incidence rate of AKI of 44.7/1000 admissions [Bailey reanimation 2005].
In the face of the lack of common defining terms of pediatric AKI, clear incidence and prevalence data is difficult to establish based on the literature.
BOOK•0266•5/07
Pediatric AKI - Incidence of cases requiring Pediatric AKI - Incidence of cases requiring RRTRRT
227 cases in the years 84-91. Yorkshire UK
Incidence: 0.8/yr/100.000 total populationneonate-infant: 19.7/yr/100.000 age related population1-4 years: 5.9/yr/100.000 age related population5-15 years: 1.5/yr/100.000 age related populationchildren: 3.9/yr/100.000 age related population
1/5 of the adult incidence
BOOK•0266•5/07
Pediatric AKI Literature: EpidemiologyPediatric AKI Literature: EpidemiologyWhat’s Out There?What’s Out There?
Most original data all single center
Predate current ICU technology and practice
Predate recent disease therapies Bone marrow transplantation Cardiac transplantation Congenital heart surgery
Cite Hemolytic-Uremic Syndrome and other primary renal disease as most common causes
Most articles after 1995 are literature review
BOOK•0266•5/07
Epidemiology/EtiologyEpidemiology/Etiology
11%-25(20.3%)Sepsis
37(30%)Infections (malaria)
19(7.7%)--Genetics diseases
11(4.4%)--Hepatic/intestinal transplantation
33(13.3%)-17(13.4%)renal Burkitt lymphoma
Hematology /oncology
43(17.3%)11(13.4%)-Post cardiac surgery
Renal ischemia or nephrotoxic drugs in the context of:
20(8.0%)7(8.7%)7(5.7%)Urology
19(23.8%)Acute tubular necrosis
9(3.6%)18(22.5%)10(8, 1%)AGN
3(1.2%)25(31%)2(1.6%)HUS
Causes
25480123Number of patients (%)
United StatesIndiaKenyaLocation
Hui-Stickle et al[ajkd 2005]Arora et al [ped neph 1997]Oluwu et al[KI 2004]Study
BOOK•0266•5/07
Pediatric AKI: Recent EpidemiologyPediatric AKI: Recent Epidemiology
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 AKI as GFR by Schwartz < 75 ml/min/1.73m2 (n=254)
Stickle SH et al: Am J Kid Dis 45:96-101, 2005
BOOK•0266•5/07
Pediatric AKI: Recent EpidemiologyPediatric AKI: Recent Epidemiology
Data Reviewed
Retrospective chart review for the following data: Patient age (years) and size (kg) Disease/condition leading to ARF Pediatric Renal Service consult obtained (yes/no) Corrected GFR (ml/min/1.73m2) by Schwartz formula
nadir during ARF course GFR at time of Pediatric Renal Service consult
Renal replacement therapy required (yes/no) ICU care required (yes/no)
pressors required (yes/no) ICU length of stay (days)
Survival defined as discharge from hospital
Stickle SH et al: Am J Kid Dis 45:96-101, 2005
BOOK•0266•5/07
Pediatric AKI: Recent EpidemiologyPediatric AKI: Recent Epidemiology
Most Common ARF Causes ATN-Dehydration (21%) Nephrotoxic drugs (16%) Sepsis (11%) Unknown (14%)
Patient Survival 176/254 patients (70%) 110/185 patients with ICU care (60%) 43/77 patients receiving renal replacement therapy (56%)
Stickle SH et al: Am J Kid Dis 45:96-101, 2005
BOOK•0266•5/07
Pediatric AKI: Recent EpidemiologyPediatric AKI: Recent Epidemiology
Pediatric ARF: Age Distribution
22%
15%
13%
34%
16%0 to 30 d1 to 12 mo1 to 5 yr6 to 14 yr15 to 20 yr
Stickle SH et al: Am J Kid Dis 45:96-101, 2005
BOOK•0266•5/07
Pediatric AKI: Recent EpidemiologyPediatric AKI: Recent Epidemiology
Age (n) GFR Survival n (%)
ICU Stay n (%), LOSa
RRTb
n (%) Commonest ARF Cause
n (%) 0 – 30 d (62) 11.5 ± 9.8 34 (56%) 59 (97%), 46 34 (58%) Ischemic
16 (26%) 1 – 12 mos (37) 18.4 ± 14.3 22 (59%) 32 (86%), 26 10 (32%) Ischemic
13 (35%) 1 – 6 yrs (43) 32.9 ± 20.1 36 (84%) 30 (70%), 21 8 (27%) Ischemic
10 (23%) 5 – 16 yrs (83) 29.3 ± 20.4 61 (73%) 49 (59%), 18 28 (57%) Nephrotoxins
22 (26%) 16 – 21 yrs (29) 35.5 ± 17 23 (79%) 15(52%), 23 8 (53%) Nephrotoxins
6 (21%) TOTAL (254) 35.2 ± 39.2 176 (70%) 185 (73%), 26 80 (43%) Ischemic
45 (22%)
a. Average Length of ICU stay, daysb. RRT – Renal Replacement Therapy
Stickle SH et al: Am J Kid Dis 45:96-101, 2005
BOOK•0266•5/07
Renal Function at Hospital Discharge 116/176 (66%) survivors completely
recovered 50/176 (29%) had improved renal function
or chronic renal insufficiency 11/176 (5%) required renal replacement
therapy
Stickle SH et al: Am J Kid Dis 45:96-101, 2005
Pediatric AKI: Recent EpidemiologyPediatric AKI: Recent Epidemiology
BOOK•0266•5/07
BIOMARKERS
BOOK•0266•5/07
Biomarkers for Acute Kidney InjuryBiomarkers for Acute Kidney Injury
Ideally AKI would have a biomarkers like myocardial infarction (i.e. troponin-1)
Currently no Troponin-I like marker to identify the site or severity of injury, although various markers are being evaluatedKidney Injury Molecule (KIM-1)Neutrophil gelatinase-associated lipocalcin (NGAL) IL-18Cystatin C
BOOK•0266•5/07
Nguyen- ped neph 2007Nguyen- ped neph 2007
Three hypothetical receiver-operating characteristic (ROC) curves are shown. The blue (straight) line represents a biomarker with an area under the curve (AUC) of 0.5, which indicates a result that is no better than expected by random chance. The red (middle) curve yields an AUC of about 0.75, which is generally considered a good biomarker. The green (top) curve gives an AUC of approximately 0.9, which would represent an excellent biomarker
BOOK•0266•5/07
Nguyen- ped neph 2007Nguyen- ped neph 2007
Current status of promising acute kidney injury (AKI) biomarkers in various clinical situations
NoneNot TestedNot testedNot testedIntermediateUrineKIM-1
NoneIntermediateIntermediateAbsentIntermediateUrineIL-18
Abbotta EarlyEarlyEarlyEarlyUrineNGAL
Dade-BehringIntermediateIntermediateIntermediateIntermediatePlasmaCystatin C
Biositea EarlyEarlyEarlyEarlyPlasmaNGAL
Commercial Test?
Kidney Transplant
Sepsis or ICUContrast Nephropathy
Cardiac Surgery
Sample Source
Biomarker Name
NGAL neutrophil gelatinase-associated lipocalin, IL-18 interleukin 18, KIM-1 kidney injury molecule 1 aIn development
BOOK•0266•5/07
MethodsMethods
Infants had urinary NGAL assessed at frequent intervals after undergoing cardiac bypass for congenital heart surgery
The primary outcome variable was the development of ARF, defined as a 50% or greater increase in serum creatinine
Other data collected included age, gender, bypass time, previous surgery, urine output, urine creatinine, urine NGAL, length of ICU stay, complications, and death
Mishra J et al: Lancet 2005
BOOK•0266•5/07
1 20
5
10
15
20
25
30
35
40
45
50
55
1 2 30
2
4
6
8
10
Num
ber
of
Pati
ents
Pati
ents
wit
h A
RF
No ARF(n=51)
ARF(n=20)
24 48 72
Post CPB Time (hours)
Incidence and Timing of AKIIncidence and Timing of AKI
Using serum creatinine, the diagnosis of ARF can be made only after 24-72 hours post CPB
Mishra J et al: Lancet 2005
BOOK•0266•5/07
2 4 6 8 12 24 36 48 60 72 84 96 108 120
Post CPB Time (hours)
Uri
ne N
GA
L (n
g/m
l)
No ARF(n=51)
ARF(n=20)
Serum Creatinine Rise
Detection of Urinary NGAL by ELISADetection of Urinary NGAL by ELISA
Urine NGAL is upregulated 15-fold within 2 hours after CPB in patients who later develop ARF
Mishra J et al: Lancet 2005
1514131211109876543210
25
50
75
100
125
150
175
200
225
BOOK•0266•5/07
Biomarkers in Pediatric AKIBiomarkers in Pediatric AKI
140 children evaluated for AKI (heterogeneous population)
In those with AKI
6 x greater of uNGAL on day 0 of pRIFLE as compared to no AKI
IL 18 elevation was noted on day 0 of pRIFLE as compared to no AKI
Washburn KK, et al Nephrol Dial Transpln 2007 (epub) Zappitelli M et al Crit Care 2007 (epub)
BOOK•0266•5/07
SummarySummary
A consistent AKI classification system may allow for more reliable assessment of the effect of AKI on patient outcomepRIFLE
Waiting for classic signs of kidney failure may lead to unnecessary morbidity and mortality, early biomarkers are critical to assess for AKI riskCombinations of biomarkers early NGAL, prognostic and
differential intermediate markersHelp with guidance towards early initiation and which
type of therapy
BOOK•0266•5/07
RRT OUTCOMERRT OUTCOME
BOOK•0266•5/07
Renal Replacement Therapy in the PICU:Renal Replacement Therapy in the PICU:Pediatric Outcome LiteraturePediatric Outcome Literature
Few pediatric studies (all single center) use severity of illness measure to evaluate outcomes in pediatric RRT:Lane noted that mortality was greater after bone marrow
transplant who had > 10% fluid overload at the time of HD initiation
Smoyer2 found higher mortality in patients on pressorsFaragson3 found PRISM to be a poor outcome predictor in
patients treated with HDZobel4 demonstrated that children who received CRRT with
worse illness severity by PRISM score had increased mortality Did not stratify by modality
1. Bone Marrow Transplant 13:613-7, 19942. JASN 6:1401-9, 19953. Pediatr Nephrol 7:703-7, 19944. Child Nephrol Urol 10:14-7, 1990
BOOK•0266•5/07
CRRT and Outcome in ChildrenCRRT and Outcome in Children
Retrospective review of all patients who received CVVH(D) in the Texas Children’s Hospital PICU from February 1996 through September 1998 (32 months)
Pre-CVVH initiation data: Age Primary disease leading to need for CVVH Co-morbid diseases Reason for CVVH Fluid intake (Fluid In) from PICU admission to CVVH initiation Fluid output (Fluid Out) from PICU admission to CVVH initiation GFR (Schwartz formula) at CVVH initiation
Goldstein SL et al: Pediatrics 2001 Jun;107(6):1309-12
BOOK•0266•5/07
Percent Fluid Overload CalculationPercent Fluid Overload Calculation
% FO at CVVH initiation =[ Fluid In - Fluid OutICU Admit Weight ] * 100%
Goldstein SL et al: Pediatrics 2001 Jun;107(6):1309-12
BOOK•0266•5/07
CRRT and Outcome in ChildrenCRRT and Outcome in Children
PRISM scores at PICU admission and CVVH initiation calculated by same nurse
PICU Course Data: Maximum number of pressors used Pressors completely weaned (y/n) Mean Airway Pressure (Paw) at CVVH initiation and termination ICU length of stay (days) CVVH complications Outcome (death or survival)
Goldstein SL et al: Pediatrics 2001 107:1309-12
BOOK•0266•5/07
CRRT and Outcome in ChildrenCRRT and Outcome in Children
22 pt (12 male/10 female) received 23 courses (3028 hrs) of CVVH (n=10) or CVVHD (n=12) over study period.
Overall survival was 41% (9/22).Survival in septic patients was 45% (5/11).PRISM scores at ICU admission and CVVH initiation were 13.5
+/- 5.7 and 15.7 +/- 9.0, respectively (p=NS).Conditions leading to CVVH (D)
Sepsis (11) Cardiogenic shock (4) Hypovolemic ATN (2) End Stage Heart Disease (2) Hepatic necrosis, viral pneumonia, bowel obstruction and End-Stage
Lung Disease (1 each)
Goldstein SL et al: Pediatrics 2001 107:1309-12
BOOK•0266•5/07
CRRT and Outcome in ChildrenCRRT and Outcome in Children
Lesser % FO at CVVH (D) Lesser % FO at CVVH (D) initiation was associated with initiation was associated with improved outcome (p=0.03)improved outcome (p=0.03)
Lesser % FO at CVVH (D) Lesser % FO at CVVH (D) initiation was also associated with initiation was also associated with improved outcome when sample improved outcome when sample was adjusted for severity of illness was adjusted for severity of illness (p=0.03; multiple regression (p=0.03; multiple regression analysis)analysis)
Goldstein SL et al: Pediatrics 2001 107:1309-12
BOOK•0266•5/07
Fluid Overload as a Risk FactorFluid Overload as a Risk Factor
Foland et al, CCM 2004; 32:1771-1776
N=113 *p=0.02; **p=0.01
BOOK•0266•5/07 Gillespie et al, Pediatr Nephrol (2004) 19:1394-1999
Kaplan-Meier survival estimates, by
percentage fluid overload category
Fluid Overload as a Risk FactorFluid Overload as a Risk Factor
BOOK•0266•5/07
The Prospective Pediatric CRRT The Prospective Pediatric CRRT (ppCRRT) Registry(ppCRRT) Registry
No single pediatric center cares for enough CRRT patients annually to analyze the effect of more than a few variables on patient outcome
BOOK•0266•5/07
ppCRRT ExperienceppCRRT Experience
First patient enrolled on 1/1/01~400 patients entered into database Currently 13 active pediatric centers
–Texas Children’s–Boston Children’s–Seattle Children’s–UAB–University of Michigan–Mercy Children’s, KC–Egleston Children’s, Atlanta
–All Children’s, St. Petersburg–DC Children’s–Columbus Children’s–Packard Children’s, Palo Alto–DeVos Children’s, Grand Rapids–Cleveland Clinic
BOOK•0266•5/07
ppCRRT MODS Data: Clinical VariablesppCRRT MODS Data: Clinical Variables
Variable (values mean +/- SD) Survivors Non-Survivors
p-value (t-test)
Age (years) 8.5+6.7 8.5+7.2 NS
Weight (kg) 34.2+25.4 31.7+25.8 NS
PRISM at ICU Admit 14.3 + 8.2 16.2 + 9.7 NS
PRISM at CRRT Initiation 13.9 + 8.2 18.6 + 7.2 <0.001
CVP at CRRT Initiation 16.5 + 21.2 21.2+6.6 <0.003
GFR at CRRT Initiation 36.3 + 32.2 41.4 + 32.2 NS
% FO at CRRT Initiation 14.2 + 15.9 25.4 + 32.9 <0.005
No. of Pressors 1.4 + 1.0 1.7 + 1.1 NS
Goldstein SL et al: Kidney International 2005
BOOK•0266•5/07
ppCRRT MODS Data: Other AnalysesppCRRT MODS Data: Other Analyses
77% of non-survivors die within 3 weeks of ICU admission Survival rates similar by CRRT modality (H 57%), (DF 53%), (HD 50%) Survival rates similar for patients on: 0-1 (53%), 2 (54%) or 3+ (39%) pressors Survival rates better for patients with: <20% FO (59%) versus >20% FO (35%) at CRRT initiation (p<0.001)
Goldstein SL et al: Kidney International 2005
BOOK•0266•5/07
OUTCOMESOUTCOMES
Impacting on AKI demands that we overcome barriers perceived or real in order to optimize therapies
Technology can be adapted, we wouldn’t hold ventilation if the patient’s clinical and biochemical measures deemed it necessary---so why does this happen in the case of AKI?
Access? Fear? Failure to appreciate the consequences of with-holding therapy? Knowing when to start? (the great debate) Knowing what modality to use (availability?) Available data?
BOOK•0266•5/07
FUTUREFUTURE
WHEN HAS SYMPTOMATIC THERAPY FAILED: TIMING OF RRT INITIATION IN PEDIATRIC AKI
CAN WE INTERVENE BEFORE USING BIOMARKERS AS A GUIDE?
WHAT THERAPY TO USE? WHAT VARIABLES TO ASSESS ALONG THE WAY?
BOOK•0266•5/07
ThanksThanks
Stu Goldstein MD-slides
Tim Bunchman MD
ppCRRT members
PICU and Nephrology nursing staff