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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.

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Presentation on theme: "The New Paradigm: Biomarkers to Define AKI Prasad Devarajan, MD Professor of Pediatrics and Developmental Biology University of Cincinnati College of Medicine."— Presentation transcript:

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 The Center for Acute Care Nephrology 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 The Center for Acute Care Nephrology AKI versus AMI PeriodAcute Myocardial InfarctionAcute Kidney Injury 1960sLDH 1970sCPK, myoglobin 1980sCK-MB 1990sTroponin T 2000sTroponin I Early Damage Markers Multiple Therapies 50% ↓ Mortality

4 The Center for Acute Care Nephrology AKI versus AMI PeriodAcute Myocardial InfarctionAcute Kidney Injury 1960sLDH Serum creatinine 1970sCPK, myoglobin Serum creatinine 1980sCK-MB Serum creatinine 1990sTroponin T Serum creatinine 2000sTroponin I Serum creatinine Delayed Functional Marker Supportive Care High Mortality Need early damage markers for better treatment of AKI Early Damage Markers Multiple Therapies 50% ↓ Mortality

5 The Center for Acute Care Nephrology Interventions that prevent AKI in animals Paradigm Before Injury Soon After Injury (before SCr rises) VasodilatorsDiuretics, Mannitol, ACE inhibitor, ANP, Dopamine, Calcium Dopamine, BNP Channel Blocker, Endothelin Antag Endothelin Antag Growth FactorsIGF-1, EGF, HGF IGF-1, NGAL NGAL Antioxidants/N-acetylcysteine, ICAM-1 ab,  -MSH Anti-inflammatoryIron chelators Iron chelators The paucity of early biomarkers has crippled our ability to institute timely therapy in humans

6 The Center for Acute Care Nephrology Clinical Continuum of AKI Devarajan, Biomarkers Med 4:265-80, 2010

7 The Center for Acute Care Nephrology 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 The Center for Acute Care Nephrology Kidney Luciferase: kNGAL Immunoblot: uNGAL Luciferase mCherry Phase 1: NGAL Reporter Mouse I/R in vivo Time Course & Organ Specificity Paragas et al, Nature Medicine 2011;17:216-22

9 The Center for Acute Care Nephrology Paragas et al, Nature Medicine 2011;17:216-22 uNGAL is from kNGAL: cross transplants

10 The Center for Acute Care Nephrology No Kidney NGAL in Pre-Renal Mice Paragas et al, Nature Medicine 2011;17:216-22

11 The Center for Acute Care Nephrology Paragas et al, Nature Medicine 2011;17:216-22 Phase 1: NGAL in AKI – Rigorous Biologic Plausibility from Basic 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

12 The Center for Acute Care Nephrology Phase 2: Plasma NGAL Clinical POC Kit * Currently not for sale in US

13 The Center for Acute Care Nephrology Phase 2: Urine NGAL Clinical Platform Abbott Diagnostics ARCHITECT: Standardized clinical platform * Currently not for sale in US

14 The Center for Acute Care Nephrology 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 The Center for Acute Care Nephrology NGAL For AKI Prediction After Cardiac Surgery AuthorPublicationPatientsAKI EventsPlasma/UrineAUCSensSpec Avg Peak Cut- offComments MishraLancet 20057120Urine0.991009817850AKI = RIFLE R or greater WagenerAnesthesiol 20068116Urine0.873785994213AKI = RIFLE R or greater BennettCJASN 200819699Urine0.9582901113100AKI = RIFLE R or greater KoynerKI 20087234Urine0.7167581136300AKI = RIFLE R or greater WagenerAJKD 200842685Urine0.613978178665AKI = RIFLE R or greater TuladharJ Cardio Pharm 2009509Urine0.9690782924433>0.5 mg/dl Creat increase HanCJASN 20099036 Urine0.6571394579456>0.3 mg/dl Creat increase LiangosBiomark 200910313Urine0.56711400166AKI = RIFLE R or greater CheNephron 20103015Urine0.85848025050AKI = RIFLE R or greater KoynerCJASN 201012346Urine0.88461AKIN Criteria HeiseEJCTS 20115038Urine0.778278146AKIN Criteria ParikhJASN Adult 2011121960Urine0.674681350102Doubling of Creat ParikhJASN Ped 201131153Urine0.71428534872Doubling of Creat KrawczeskiJ Peds 2011374112Urine0.92858622050AKI = RIFLE R or greater KrawczeskiJACC 201122060Urine0.98883990AKI = RIFLE R or greater MishraLancet 20057120Plasma0.9501006250AKI = RIFLE R or greater DentCrit Care 200712045Plasma0.968494233150AKI = RIFLE R or greater Haase-FielitzCCM 200910023Plasma0.87978162150AKI = RIFLE R or greater TuladharJ Cardio Pharm 2009509Plasma0.89078476433>0.5 mg/dl Creat increase HaaseATS 200910046Plasma0.777374205150AKIN Criteria PrabhuAnn Vasc Surg 2010308Plasma0.9810091353229AKI = RIFLE R or greater PerryAnesthesiol 210187975Plasma0.643982269354AKI = RIFLE R or greater ParikhJASN Adult 2011121960Plasma0.75082290293Doubling of Creat ParikhJASN Ped 201131153Plasma0.562781210261Doubling of Creat KrawczeskiJ Peds 2011374112Plasma0.94908818050AKI = RIFLE R or greater NGAL Totals25667011470.87178933190

16 The Center for Acute Care Nephrology NGAL For AKI Prediction In ER/ICU Setting AuthorPublicationPatientsAKI EventsPlasma/UrineAUCSensSpec Avg Peak Cut- offComments ZappitelliCrit Care 2007140106Urine0.785497103AKI by RIFLE VaidyaClin Transl Sci 2008204102Urine0.898096566283AKI by RIFLE NickolasAnn Int Med 200863530Urine0.9590100416130AKI by RIFLE SiewJASN 2009451150Urine0.717870190AKIN Criteria MakrisCCLM 20093111Urine0.98919515625AKI by RIFLE MartenssonInt Care Med 20104418Urine0.867110031968AKI by RIFLE de GeusAJRCCM 2011632171Urine0.8889702013247AKI by RIFLE EndreKI 2011529147Urine0.66408041AKI by RIFLE DuPed Nephrol 201125218Urine0.8185AKI by RIFLE SingerKI 201114575Urine0.87104AKI by RIFLE NickolasJACC 2012163596Urine0.816881335104AKI by RIFLE WheelerCCM 200814322Plasma0.688639355140Creat > 2 mg/dl ConstantinJ Crit Care 20098842Plasma0.928297342155AKI by RIFLE NiemannLiver Transpl 20094524Plasma0.796882156139AKI by RIFLE CruzInt Care Med 2010307133Plasma0.787381225150AKI by RIFLE ShapiroAnn Emer Med 201066124Plasma0.829651456150Creat rise >0.5 mg/dl MartenssonInt Care Med 20104418Plasma0.858386216120AKI by RIFLE de GeusAJRCCM 2011632171Plasma0.868270680245AKI by RIFLE SotoWCN 2011616130Plasma0.88591173150AKI by RIFLE NGAL Totals19723414880.837782705128

17 The Center for Acute Care Nephrology 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 The Center for Acute Care Nephrology Phase 2 Meta-analysis: Early NGAL Measurements Predict Subsequent Need For Dialysis in ICU Haase et al, AJKD 54(6):1012-24, 2009

19 The Center for Acute Care Nephrology Phase 3 Transition: “Added Value”: Outcome of NGAL(+) Creat(-) “Subclinical AKI” in ICU Subjects

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

21 The Center for Acute Care Nephrology Phase 3 Transition: “Added Value” of NGAL Over Clinical Models

22 The Center for Acute Care Nephrology Biomarkers for AKI Prediction in Clinical Settings NGALL-FABPIL-18KIM-1 Post-CPB++++ Contrast++++ Nephrotoxins++++ DGF+?+? Sepsis++??

23 The Center for Acute Care Nephrology Biomarkers for Differential Diagnosis of AKI

24 The Center for Acute Care Nephrology Biomarkers to Refine AKI Definition and Staging Functional CriteriaBiomarker Criteria Subclinical AKI+ RIFLE-R or AKIN-1++ RIFLE-I or AKIN-2+++ RIFLE-F or AKIN-3+++++

25 The Center for Acute Care Nephrology Biomarkers to Refine AKI Classification Decreased FunctionIncreased BiomarkerClassification -- Normal +- Transient Azotemia -+ Subclinical AKI ++ Intrinsic AKI

26 The Center for Acute Care Nephrology 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 The Center for Acute Care Nephrology Biomarkers for Timing of AKI 2 hr12 hr

28 The Center for Acute Care Nephrology Fold Increase in Concentration Time post-CPB NGAL (0.95) Marker (AUC) Biomarkers for Timing of AKI

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

30 The Center for Acute Care Nephrology Fold Increase in Concentration Time post-CPB NGAL (0.95) L-FABP (0.8) IL-18 (0.75) KIM-1 (0.83) Marker (AUC) CREAT Biomarkers for Timing of AKI

31 The Center for Acute Care Nephrology Initiation: vasoconstriction, ATP depletion, oxidant and labile iron generation Extension: apoptosis and necrosis, inflammatory response Maintenance: ongoing injury, dedifferentiation, regeneration, repair Vasodilators, ATP donors, Anti-oxidants, Fe Chelator Anti-inflammatory, Anti- apoptotic, Stem cells Growth factors, Stem cells, RRT, renal devices Pathophys Therapy Sequential Biomarkers to Guide AKI Therapy

32 The Center for Acute Care Nephrology Summary 1.Injury biomarkers of AKI such as NGAL, KIM-1, L-FABP and IL-18 are now becoming available 2.Early measurements of injury biomarkers predict development of AKI and its adverse outcomes 3.Biomarker combinations may be desirable but challenging to develop and commercialize 4.Biomarkers should be used in the context of the clinical setting, and should improve upon clinical scores 5.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 The Center for Acute Care Nephrology 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) Rinaldo Bellomo (Austin Hosp)David Askenazi (UAB) Zoltan Endre (U Otago)Michael Haase (Charité Hosp) David Humes (U Mich)Christoph Westenfelder (U Utah) Adeera Levin (U Br Columbia)Uptal Patel (Duke U) Amit Garg (U London) Tim Bunchman (VCU) Sean Bagshaw (U Alberta)Kiyoshi Mori (Kyoto U) Mike Zappittelli (McGill U)Abbott Diagnostics Neesh Pannu (U Alberta)Biosite/Alere Funding: Thank You for your Attention!

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