1. AKI in Pediatrics Patrick D. Brophy MD Associate Professor
University of Iowa- Carver College of Medicine
Dept. of Pediatrics
Division of Nephrology, Hypertension, Dialysis & Transplantation

2. OBJECTIVES The Problematic Definition of ARF The Transition
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

3. The 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”

4. The Problematic Definition of ARF
Pediatric AKI definition: a moving target
Infants
Cr in the first few weeks of life may reflect maternal values
Children
Low baseline Cr makes changes in Cr significant
Varying muscle mass
Adolescents
Similar to adults

5. The Problematic Definition of ARF
Over 30 published ARF definitions
All based on increased serum creatinine levels
Despite extensive adult hospitalized patient study over the past 50 years
Widely varying spectrum dependent upon study aims and hypothesis
Severe (ARF requiring dialysis)
Modest (serum creatinine increase of 0.3 mg/dl)
Why is this important……?

6. The 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

7. The Ideal Disease Definition
Would
ascertain disease presence
guide nature and timing of diagnostic and therapeutic interventions
help determine prognosis
Should incorporate
clinical signs and symptoms
alterations in reproducible biological markers

8. Pediatric Modified RIFLE--definition
GFR per Schwartz equation: GFR= Ht (cm) X constant / serum creat (mg/dl)
Pediatric Modified RIFLE Criteria
CrCl
Urine output
Risk
GFR decrease by 25%
<0.5ml/kg/hour for
8 hours
Injury
GFR decrease by 50%
16 hours
Failure
GFR decrease by 75% or
GFR<35ml/min/1.73m 2
<0.3 ml/kg/hour for
24 hours or
anuric fo
r 12 hours
Loss
Persistent ARF > 4 weeks
End
stage
End Stage Renal Disease (>3 months)
Ackan-Arikan et al: Kid Int 2007

9. EPIDEMIOLOGY

10. Epidemiology-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)

11. Epidemiology-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.

12. Pediatric AKI - Incidence of cases requiring RRT
227 cases in the years Yorkshire UK
Incidence: 0.8/yr/ total population
neonate-infant: /yr/ age related population
years: 5.9/yr/ age related population
5-15 years: 1.5/yr/ age related population
children: /yr/ age related population
1/5 of the adult incidence

13. Pediatric AKI Literature: Epidemiology 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

14. Epidemiology/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
254 80
123
Number of patients (%)
United States
India
Kenya
Location
Hui-Stickle et al[ajkd 2005]
Arora et al [ped neph 1997]
Oluwu et al[KI 2004]
Study

15. Pediatric 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

16. Pediatric 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

17. Pediatric 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

18. Pediatric AKI: Recent Epidemiology
Stickle SH et al: Am J Kid Dis 45:96-101, 2005

19. Pediatric AKI: Recent Epidemiology
Average Length of ICU stay, days
RRT – Renal Replacement Therapy
Stickle SH et al: Am J Kid Dis 45:96-101, 2005

20. Pediatric AKI: Recent Epidemiology
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

21. BIOMARKERS

22. Biomarkers 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 evaluated
Kidney Injury Molecule (KIM-1)
Neutrophil gelatinase-associated lipocalcin (NGAL)
IL-18
Cystatin C

23. Nguyen- 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

24. Nguyen- ped neph 2007
 Current status of promising acute kidney injury (AKI) biomarkers in various clinical situations
None
Not Tested
Not tested
Intermediate
Urine
KIM-1
Absent
IL-18
Abbotta
Early
NGAL
Dade-Behring
Plasma
Cystatin C
Biositea
Commercial Test?
Kidney Transplant
Sepsis or ICU
Contrast Nephropathy
Cardiac Surgery
Sample Source
Biomarker Name
NGAL neutrophil gelatinase-associated lipocalin, IL-18 interleukin 18, KIM-1 kidney injury molecule 1
aIn development

25. Methods
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

26. Incidence and Timing of AKI
Number of Patients
Patients with ARF
No ARF
(n=51)
ARF
(n=20) 24 48 72
Post CPB Time (hours)
Using serum creatinine, the diagnosis of ARF can be made only after
24-72 hours post CPB
Mishra J et al: Lancet 2005

27. Detection of Urinary NGAL by ELISA15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 25 50 75
100
125
150
175
200
225
Serum Creatinine Rise
Urine NGAL (ng/ml)
ARF
(n=20)
No ARF
(n=51)
Post CPB Time (hours)
Urine NGAL is upregulated 15-fold within 2 hours after CPB in patients who later develop ARF
Mishra J et al: Lancet 2005

28. Biomarkers 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)

29. Summary
A consistent AKI classification system may allow for more reliable assessment of the effect of AKI on patient outcome
pRIFLE
Waiting for classic signs of kidney failure may lead to unnecessary morbidity and mortality, early biomarkers are critical to assess for AKI risk
Combinations of biomarkers early NGAL, prognostic and differential intermediate markers
Help with guidance towards early initiation and which type of therapy

30. RRT OUTCOME

31. Renal Replacement Therapy in the PICU: Pediatric 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 pressors
Faragson3 found PRISM to be a poor outcome predictor in patients treated with HD
Zobel4 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, 1994
2. JASN 6:1401-9, 1995
3. Pediatr Nephrol 7:703-7, 1994
4. Child Nephrol Urol 10:14-7, 1990

32. CRRT 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):

33. Percent Fluid Overload Calculation[ ]
Fluid In - Fluid Out
ICU Admit Weight
% FO at CVVH initiation =
* 100%
Goldstein SL et al: Pediatrics 2001 Jun;107(6):

34. CRRT 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 :

35. CRRT 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 /- 5.7 and /- 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 :

36. CRRT and Outcome in Children
Lesser % FO at CVVH (D) initiation was associated with improved outcome (p=0.03)
Lesser % FO at CVVH (D) initiation was also associated with improved outcome when sample was adjusted for severity of illness (p=0.03; multiple regression analysis)
Goldstein SL et al: Pediatrics :

37. Fluid Overload as a Risk Factor
N=113
*p=0.02; **p=0.01
Foland et al, CCM 2004; 32:

38. Fluid Overload as a Risk Factor
Kaplan-Meier survival estimates, by percentage fluid overload category
Gillespie et al, Pediatr Nephrol (2004) 19:

39. The Prospective Pediatric CRRT (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

40. ppCRRT 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

41. ppCRRT MODS Data: Clinical Variables
Goldstein SL et al: Kidney International 2005

42. ppCRRT 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: (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

43. OUTCOMES
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?

44. FUTURE
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?

45. Thanks Stu Goldstein MD -slides Tim Bunchman MD ppCRRT members
PICU and Nephrology nursing staff