The new paradigm biomarkers to define aki
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The New Paradigm: Biomarkers to Define AKI. Prasad Devarajan, MD Professor of Pediatrics and Developmental Biology University of Cincinnati College of Medicine Director, Nephrology and Hypertension Director, Nephrology Clinical Laboratory CEO, Dialysis Unit

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The new paradigm biomarkers to define aki

The New Paradigm:Biomarkers to Define AKI

Prasad Devarajan, MD

Professor of Pediatrics and Developmental Biology

University of Cincinnati College of Medicine

Director, Nephrology and Hypertension

Director, Nephrology Clinical Laboratory

CEO, Dialysis Unit

Cincinnati Children’s Hospital Medical Center


Outline
Outline

  • Why do we need better biomarkers of AKI?

  • How are AKI biomarkers discovered, translated, and validated?

  • What are some examples of novel diagnostic and prognostic AKI biomarkers?


Aki versus ami
AKI versus AMI

Early Damage Markers

Multiple Therapies

50% ↓ Mortality


Aki versus ami1
AKI versus AMI

Delayed Functional Marker

Supportive Care

High Mortality

Early Damage Markers

Multiple Therapies

50% ↓ Mortality

Need early damage markers for better treatment of AKI


Interventions that prevent aki in animals
Interventions that prevent AKI in animals

Paradigm Before Injury Soon After Injury

(before SCr rises)

Vasodilators Diuretics, Mannitol, ACE inhibitor, ANP,

Dopamine, Calcium Dopamine, BNP

Channel Blocker, EndothelinAntag

EndothelinAntag

Growth Factors IGF-1, EGF, HGF IGF-1, NGAL

NGAL

Antioxidants/ N-acetylcysteine, ICAM-1 ab, a-MSH

Anti-inflammatory Iron chelators Iron chelators

The paucity of early biomarkers has crippled our ability

to institute timely therapy in humans


Clinical continuum of aki
Clinical Continuum of AKI

Devarajan, Biomarkers Med 4:265-80, 2010


How are aki biomarkers discovered phase 1 listen to the kidney
How Are AKI Biomarkers Discovered?Phase 1: Listen to the Kidney

  • The early adaptive response of the stressed kidney itself is providing us with biomarkers that inform pathophysiology and, serendipitously, the early diagnosis:

  • Neutrophil gelatinase-associated lipocalin (NGAL)

  • Interleukin 18 (IL-18)

  • Kidney injury molecule 1 (KIM-1)

  • Liver type fatty acid binding protein (L-FABP)

Devarajan, NEJM 358(3):312,2008


Kidney Luciferase: kNGAL

LuciferasemCherry

Immunoblot: uNGAL

Phase 1: NGAL Reporter Mouse I/R in vivoTime Course & Organ Specificity

Paragas et al, Nature Medicine 2011;17:216-22


uNGAL is from kNGAL: cross transplants

Paragas et al, Nature Medicine 2011;17:216-22


No kidney ngal in pre renal mice
No Kidney NGAL in Pre-Renal Mice

Paragas et al, Nature Medicine 2011;17:216-22


Phase 1 ngal in aki rigorous biologic plausibility from basic science studies
Phase 1: NGAL in AKI – Rigorous Biologic Plausibility fromBasic Science Studies

  • Most highly upregulated gene and protein in the kidney, very early in the course of intrinsic AKI – major source of urinary NGAL protein

  • Also highly expressed in the lungs, liver, spleen, and other organs that cross-talk with the kidney, early in the course of AKI – these, as well as activation of neutrophils, are the major source of circulating NGAL protein

  • NGAL is nephro-protective

Paragas et al, Nature Medicine 2011;17:216-22


Phase 2 plasma ngal clinical poc kit
Phase 2: Plasma NGAL Clinical POC Kit

* Currently not for sale in US


Phase 2: Urine NGAL Clinical Platform

  • Abbott Diagnostics

  • ARCHITECT: Standardized clinical platform

* Currently not for sale in US


Explosion of phase 2 ngal studies
Explosion of Phase 2 NGAL Studies

  • NGAL for AKI Prediction

    • Cardiac Surgery

    • ICU/ER

    • Kidney Transplant

    • Contrast Nephropathy

    • Sepsis

  • NGAL for AKI Staging

  • NGAL for AKI Differential Diagnosis

  • NGAL for AKI Prognosis




  • Explosion of phase 2 ngal studies1
    Explosion of Phase 2 NGAL Studies

    • NGAL for AKI Prediction

      • Cardiac Surgery

      • ICU/ER

      • Kidney Transplant

      • Contrast Nephropathy

      • Sepsis

  • NGAL for AKI Staging

  • NGAL for AKI Differential Diagnosis

  • NGAL for AKI Prognosis


  • Phase 2 meta analysis early ngal measurements predict subsequent need for dialysis in icu
    Phase 2 Meta-analysis: Early NGAL Measurements Predict Subsequent Need For Dialysis in ICU

    Haase et al, AJKD 54(6):1012-24, 2009


    Phase 3 transition added value outcome of ngal creat subclinical aki in icu subjects
    Phase 3 Transition: “Added Value”: Outcome of NGAL(+) Creat(-) “Subclinical AKI” in ICU Subjects


    Phase 3 transition added value outcome of ngal creat subclinical aki in icu subjects1
    Phase 3 Transition: “Added Value”: Outcome of NGAL(+) Creat(-) “Subclinical AKI” in ICU Subjects

    Haase, Devarajan et al, JACC 57:1752-61, 2011







    Biomarkers in early aki cut offs approach
    Biomarkers in Early AKI – Cut-offs Approach Models

    • Measure only if AKI is clinically suspected

    • Low levels (NGAL < 50 ng/ml)

      • Low risk of AKI, repeat measures if clinical suspicion persists

  • Grey Zone (NGAL 50-150 ng/ml)

    • Indeterminate, repeat measures if clinical suspicion persists

  • Moderately high levels (NGAL 150-300 ng/ml)

    • High Sensitivity for AKI, monitor fluids and kidney function, avoid nephrotoxins, consider early interventions if clinical risk factors present

  • Very high levels (NGAL >300 ng/ml)

    • High Specificity for AKI, implement early interventions

  • Cut-offs depend on assay used


    Biomarkers for timing of aki
    Biomarkers for Timing of AKI Models

    2 hr

    12 hr


    Biomarkers for Timing of AKI Models

    Fold Increase in Concentration

    NGAL (0.95)

    Marker (AUC)

    Time post-CPB


    Biomarkers for timing of aki1
    Biomarkers for Timing of AKI Models

    IL-18 (0.75)

    Fold Increase in Concentration

    L-FABP (0.8)

    NGAL (0.95)

    Marker (AUC)

    Time post-CPB


    Biomarkers for timing of aki2
    Biomarkers for Timing of AKI Models

    Marker (AUC)

    KIM-1 (0.83)

    IL-18 (0.75)

    Fold Increase in Concentration

    L-FABP (0.8)

    NGAL (0.95)

    CREAT

    Time post-CPB


    Sequential biomarkers to guide aki therapy
    Sequential Biomarkers to Guide AKI Therapy Models

    Initiation: vasoconstriction,

    ATP depletion, oxidant and

    labile iron generation

    Extension: apoptosis and

    necrosis, inflammatory

    response

    Maintenance: ongoing injury,

    dedifferentiation, regeneration,

    repair

    Pathophys

    Growth factors, Stem cells,

    RRT, renal devices

    Anti-inflammatory,Anti-

    apoptotic, Stem cells

    Vasodilators, ATP donors,

    Anti-oxidants, Fe Chelator

    Therapy


    Summary
    Summary Models

    • Injury biomarkers of AKI such as NGAL, KIM-1, L-FABP and IL-18 are now becoming available

    • Early measurements of injury biomarkers predict development of AKI and its adverse outcomes

    • Biomarker combinations may be desirable but challenging to develop and commercialize

    • Biomarkers should be used in the context of the clinical setting, and should improve upon clinical scores

    • Future studies should evaluate the utility of injury and functional biomarkers both independently and together, and should consider injury biomarkers as entry criteria for AKI therapeutic trials in the appropriate clinical context


    Acknowledgement of ngal collaborators
    Acknowledgement of NGAL Collaborators Models

    Chirag Parikh (Yale U) Jon Barasch (Columbia U)

    Charles Edelstein (U Colorado) Tom Nickolas (Columbia U)

    Stuart Goldstein (CCHMC) Joseph Bonventre (Harvard)

    Didier Portilla (U Arkansas) Karina Soto (U Lisbon)

    Pat Murray (U Dublin) Sarah Faubel (U Colorado)

    Jay Koyner (U Chicago) Catherine Krawczeski (CCHMC)

    RinaldoBellomo (Austin Hosp) David Askenazi (UAB)

    ZoltanEndre (U Otago) Michael Haase (CharitéHosp)

    David Humes (U Mich) ChristophWestenfelder (U Utah)

    Adeera Levin (U Br Columbia) Uptal Patel (Duke U)

    AmitGarg (U London) Tim Bunchman (VCU)

    Sean Bagshaw (U Alberta) Kiyoshi Mori (Kyoto U)

    Mike Zappittelli (McGill U) Abbott Diagnostics

    NeeshPannu (U Alberta) Biosite/Alere

    Funding:

    Thank You for your Attention!


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