BOOK02665/07 AKI in Pediatrics Patrick D. Brophy MD Associate Professor University of Iowa- Carver...

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AKI in Pediatrics

Patrick D. Brophy MDAssociate Professor

University of Iowa- Carver College of MedicineDept. of Pediatrics

Division of Nephrology, Hypertension, Dialysis & Transplantation

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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

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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”

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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

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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……?

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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

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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

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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)

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EPIDEMIOLOGY

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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)

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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.

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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

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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

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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

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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

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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


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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%)


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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


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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


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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



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BIOMARKERS

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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

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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

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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

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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

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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


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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


1514131211109876543210

25

50

75

100

125

150

175

200

225

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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)

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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

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RRT OUTCOMERRT OUTCOME

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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

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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

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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

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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

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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)


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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)


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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

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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

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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

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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

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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

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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?

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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?

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ThanksThanks

Stu Goldstein MD-slides

Tim Bunchman MD

ppCRRT members

PICU and Nephrology nursing staff

BOOK02665/07 AKI in Pediatrics Patrick D. Brophy MD Associate Professor University of Iowa- Carver...

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