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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

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The New Paradigm: Biomarkers to Define AKI

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  1. 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

  2. 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?

  3. AKI versus AMI Early Damage Markers Multiple Therapies 50% ↓ Mortality

  4. 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

  5. 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

  6. Clinical Continuum of AKI Devarajan, Biomarkers Med 4:265-80, 2010

  7. 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

  8. 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

  9. uNGAL is from kNGAL: cross transplants Paragas et al, Nature Medicine 2011;17:216-22

  10. No Kidney NGAL in Pre-Renal Mice Paragas et al, Nature Medicine 2011;17:216-22

  11. 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

  12. Phase 2: Plasma NGAL Clinical POC Kit * Currently not for sale in US

  13. Phase 2: Urine NGAL Clinical Platform • Abbott Diagnostics • ARCHITECT: Standardized clinical platform * Currently not for sale in US

  14. 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

  15. NGAL For AKI Prediction After Cardiac Surgery

  16. NGAL For AKI Prediction In ER/ICU Setting

  17. 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

  18. Phase 2 Meta-analysis: Early NGAL Measurements Predict Subsequent Need For Dialysis in ICU Haase et al, AJKD 54(6):1012-24, 2009

  19. Phase 3 Transition: “Added Value”: Outcome of NGAL(+) Creat(-) “Subclinical AKI” in ICU Subjects

  20. Phase 3 Transition: “Added Value”: Outcome of NGAL(+) Creat(-) “Subclinical AKI” in ICU Subjects Haase, Devarajan et al, JACC 57:1752-61, 2011

  21. Phase 3 Transition: “Added Value” of NGAL Over Clinical Models

  22. Biomarkers for AKI Prediction in Clinical Settings

  23. Biomarkers for Differential Diagnosis of AKI

  24. Biomarkers to Refine AKI Definition and Staging

  25. Biomarkers to Refine AKI Classification

  26. Biomarkers in Early AKI – Cut-offs Approach • 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

  27. Biomarkers for Timing of AKI 2 hr 12 hr

  28. Biomarkers for Timing of AKI Fold Increase in Concentration NGAL (0.95) Marker (AUC) Time post-CPB

  29. Biomarkers for Timing of AKI IL-18 (0.75) Fold Increase in Concentration L-FABP (0.8) NGAL (0.95) Marker (AUC) Time post-CPB

  30. Biomarkers for Timing of AKI 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

  31. Sequential Biomarkers to Guide AKI Therapy 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

  32. Summary • 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

  33. Acknowledgement of NGAL Collaborators 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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