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Pediatric Acute Kidney Injury and Biomarkers

Pediatric Acute Kidney Injury and Biomarkers. Stuart L. Goldstein, MD Professor of Pediatrics Baylor College of Medicine. Acknowledgements. Baylor College of Medicine/Texas Children’s AKI Study Group Laura Loftis, MD Annabelle Chua, MD Ayse Arikan, MD Michael Zappitelli, MD

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Pediatric Acute Kidney Injury and Biomarkers

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  1. Pediatric Acute Kidney Injury and Biomarkers Stuart L. Goldstein, MD Professor of Pediatrics Baylor College of Medicine 6th PCRRT Conference, Rome 2010

  2. Acknowledgements Baylor College of Medicine/Texas Children’s AKI Study Group Laura Loftis, MD Annabelle Chua, MD Ayse Arikan, MD Michael Zappitelli, MD Alyssa Riley-Kothari, MD Yue Du, PhD Leticia Castillo, MD Jack Price, MD David Nelson, MD John Lynn Jeffries, MD Joshua Blinder, MD Jeffrey Towbin, MD Anjan Shah, MD Brady Moffett, RPh

  3. Outline • AKI Epidemiology – Old Definitions • Risk Factor Assessment • New AKI Definitions • Treatment • Prognosis • New Advancements - Biomarkers

  4. AKI Definitions to 2002 • Over 30 definitions in published literature • Nearly all based on absolute or change in serum creatinine concentration • Pediatric AKI definitions – All AKI is created equal • 100% rise in SCr • eCCL < 75 ml/min/1.73m2 • SCr twice normal for patient age • Few prospective pediatric studies • Retrospective studies assess AKI causes • Control group without AKI not assessed to determine risk factors for AKI

  5. Pediatric AKI Epidemiology until 2002: What was 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/primary renal disease as most common causes • Most articles after 1995 are literature review

  6. 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)

  7. 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%)

  8. Pediatric AKI Epidemiology

  9. 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)

  10. AKI Risk Factors – Assessment Issues • Retrospective aminoglycoside study • AKI defined as 50% decrease • Heme/Onc and Pulm with highest AKI • Surgery with lowest AKI • Heme/Onc and Pulm assessed SCr significantly more often than Surgery Zappitelli and Goldstein, submitted

  11. Pediatric AKI Risk Factors:The Critically Ill Patient • Highest risk for AKI development • AKI 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

  12. Single-center, prospective observational study over one year (2000-2001) • Pediatric ICU population • 3 days to 18 years of age • AKI defined as doubling SCr • Doubling of upper limit of normal • Doubling of PICU admission SCr • True “baseline” pre-PICU SCr not assessed • CKD patients: AKI defined as 25% increase in SCr

  13. 1047 admissions • Exclusions for patient age, prematurity, decision to withhold care, pregnancy • 4.5% AKI rate

  14. Risk factors • Thrombocytopenia • Older age • Hypoxemia • Hypotension • Coagulopathy • Increased PRISM and PELOD scores also AKI risk factors

  15. Is All AKI Created Equal? • Recent adult patient data demonstrate • Small SCr rises associated with mortality • AKI associated with mortality and length of hospitalization • AKI is now recognized as risk factor for poor outcome, independent of severity of illness

  16. AKI Severity and Outcome Chertow GM et al: J Am Soc Nephrol, 2005

  17. All AKI is NOT Equal • Multidimensional classification system is needed to • Grade AKI severity • Follow changes in kidney function • Standardize AKI as a hard outcome measure

  18. AKI RIFLE Criteria: ADQI II

  19. Prospective single center observational study • PICU patients receiving mechanical ventilation and vasoactive medications • AKI 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

  20. eCCl determined by Schwartz formula • Baseline eCCl from three months before PICU • 100 ml/min/1.73m2 if no data available • pRIFLE differs from RIFLE in • Oliguria duration • RIFLE-F limit eCCl

  21. 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 3/76 (4%) RIFLEmax F 12/31 (39%) pRIFLEmax F Initial RIFLE I N=31

  22. “Persistent” AKI on admission

  23. Biomarkers • A 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

  24. Why do we need biomarkers of AKI? • Because AKI is important. • 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

  25. 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.

  26. Utilities of biomarkers in AKI • Early 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

  27. What is an ideal biomarker? Nguyen & Devarajan, Ped Nephrol, 2008 • Qualities • Accurate, reliable • Relatively non-invasive/acceptable to patients • Rapidly measurable, standardized assay • Sensitive/specific with reproducible cutoff values • Requires case definition: AKIN, pRIFLE

  28. 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 Discovery Translational Validation

  29. 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

  30. Biomarker studies in different populations • Cardiac surgery • Critically ill patients • Sepsis • Nephrotoxin-treated patients • Renal transplant • General hospital population

  31. Cardiac surgery: Known timing of AKI NGAL: Children led the way! Mishra et al, Lancet, 2005 SCr rise 48-72 hrs Not quite as good Wagener et al, Anesthesiology, 2006 Adults

  32. Cardiac surgery Children Parikh et al,KI, 2006

  33. Critical Illness: unknown timing of AKI Critically ill adults: retrospective. Landmark study. Parikh et al, JASN, 2005 IL-18 SCr rise

  34. Critical illness population 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 NGAL KIM-1

  35. 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 Measures • pRIFLEmax at 14 days of ICU admission • Persistent AKI (AKI that did not resolve in 48 hours • Predict AKI prior to pRIFLE

  36. Texas Children’s AKI Biomarker Study • 150 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 enrollment • NGAL (Devarajan) • IL-18 (Edelstein) • KIM-1 (Bonventre) • pRIFLE creatinine calculated from Day 1 to Day 14 of ICU admission

  37. 140 patients’ urine samples available • Mean age 6.3 years (1 year to 21 years) • Mean ICU day of admission = 3 + 1.5 days • pRIFLE • No AKI: 24.3% • R: 33.7% • I: 22.1% • F: 17.9%

  38. 6 4 uNGAL (ng/mg creatinine) 2 ● ● ● ● ● ● 0 -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

  39. Increase in NGAL to predict AKI: AUC=0.78

  40. Increase in NGAL to predict persAKI: AUC=0.80

  41. 400 300 Mean and Peak uIL18 (pg/ml) 200 100 0 Control R I F Mean uIL18 Peak uIL18

  42. All Patients Non-septic

  43. P<0.05

  44. 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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