Discovery & Validation of Kidney Injury Biomarkers

Transcription

1 Dublin Academic Medical Centre Discovery & Validation of Kidney Injury Biomarkers Patrick Murray, MD, FASN, FRCPI, FJFICMI Professor, University College Dublin, Mater Misericordiae University Hospital, Dublin, Ireland HRB/IMDA Symposium, October 27th, 2010

2 Definition of Biomarker (Biological Marker) A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Biomarkers Definitions Working Group Bethesda, MD: Clinical Pharmacology & Therapeutics 2001;69:89-95

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4 Kidneys are important

5 Increasing Frequency of AKI Hospitalisations Morb Mortal Wkly Rep, 57: , 2008.

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7 A Call to Action ;Volume 374 (9699): Pages COMMENT NCEPOD Report on Acute Kidney Injury- We Must Do Better Alison MacLeod

8 Sutton, et al: Kidney Int 2002

9 Evolution in Renal Diagnostics AMI WBC count LDH CPK CK -MB Troponin -T Troponin - I Time 1950 s 1960 s 1970 s 1980 s 1990 s 2000 AKI Change in serum creatinine Change in serum creatinine The renal testing arena is in need of the introduction of novel, early and more sensitive and specific biomarkers Conger JD, Am J Kidney Dis 26: , Star RA, Kidney Int 54: , 1998.

10 Effect of an acute GFR decline on generation, filtration, excretion, balance, and serum level of endogenous filtration markers Stevens, L. A. et al. J Am Soc Nephrol 2009;20:

11 Conceptual model of acute kidney injury (AKI) Murray, P. T. et al. Clin J Am Soc Nephrol 2008;3: Copyright 2008 American Society of Nephrology

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13 Urine NGAL (µg/l) Serum NGAL (µg/l) Analysis of Urine and Serum NGAL After Cardiopulmonary Bypass Urine NGAL Serum NGAL Serum Creatinine Rise Serum Creatinine Rise Time after cardiopulmonary bypass (h) Time after cardiopulmonary bypass (h) N = 71 Acute renal failure (n=20) Without acute renal failure (n51) NGAL increased 2 hours after cardiopulmonary bypass 13 Adapted from Mishra J, et al. Lancet. 2005;365:

14 Box plots of urinary neutrophil gelatinase-associated lipocalin (NGAL) and serum creatinine levels, by diagnostic group Nickolas, T. L. et. al. Ann Intern Med 2008;148:

15 Kidney injury biomarkers versus clinical outcome Nickolas, T. L. et. al. Ann Intern Med 2008;148:

16 Acute Kidney Injury N-gal Evaluation of Symptomatic heart failure Study UCSD KUMC St. Vincent, Univ. H UHB, Switzerland Stanford Henry Ford Health Mater Misericordiae UMC Groningen VAMC, CA NY Methodist Lariboisiere Hospital Charite, Germany ALERE Medical VCU Abbott Diagnostic San Filippo Neri Sponsors Enrolling Center Data Analysis Center Core Lab Center

17 Site-specific AKI Biomarkers Goodsaid F, et al: Clin Pharm & Therap 2009

18 Immunohistochemical Localisation in Human Kidney GST in Proximal Tubules GST in Distal Tubules Collagen IV in Glom HCD (green) in Collecting Duct

19 AKI Prognosis at Time of Dx: Urine CyC and NGAL median (25-75% IQR) Biomarker performance at the time of Clinical Serum Creatinine increase Stage 1 or 2 N=37 Stage 3 N=9 AUC (95%CI) P value Chi squared ROC comparison CyC (mg/l) CyC / Creat mg/g NGAL (pg/ml) ( ) ( ) 98.3 ( ) NGAL/Cr 79.7 (14.6 eat 37.63) ng/mg ( ) ( ) 461 ( ) ( ) 0.74 ( ) ( ) 0.01 NS 0.78 ( ) ( ) 0.01 NS Koyner J, et al: Clin J Am Soc Nephrol 2010

20 median (25-75% IQR) α-gst (μg/l) α-gst / Creat (ng/mg) π - GST (μg/l) π -GST /Creat (ng/mg) AKI Prognosis at Time of Dx: Urinary GSTs Biomarker performance at the time of Clinical Serum Creatinine increase Stage 1 or 2 N= ( ) 1.45 ( ) 3.4 ( ) 3.69 ( ) Stage 3 N= ( ) 2.93 ( ) 46.5 ( ) 54.8 ( ) AUC (95%CI) 0.54 ( ) NS P value 0.54 ( ) NS NS 0.84 ( ) ( ) NS Koyner J, et al: Clin J Am Soc Nephrol 2010 Chi squared ROC comparison

21 Declining Success Rate of Drug Development Woosley RL, et al: Clin Pharmacol & Therapeutics 2007;81:

22 Innovative Strategies for Improving Drug Development Wagner JA: Clin Pharmacol & Therapeutics 2008;83:

23 IMI SAFE-T Consortium Safer and Faster Evidence-based Translation Three organs that need better clinical monitoring of drug-induced injuries: Kidney (DIKI) Liver (DILI) Vascular System (DIVI) Consortium goals: To evaluate utility of safety BMs for monitoring DIKI, DILI and DIVI in humans. To develop assays and devices for clinical application of safety BMs To compile enough evidence to qualify safety BMs for regulatory decision making in clinical drug development and in a translational context To gain evidence for how safety BMs may also be used in the diagnosis of diseases and in clinical practice 23 23

24 Phases of Biomarker Development DISCOVERY PHASE Pepe MS, et al: J NCI 2001;93(14): TRANSLATIONAL PHASES VALIDATION PHASES

25 Other Ongoing UCD AKI Biomarker Projects Cardiac Surgery International, four-centre randomised, controlled trial of sodium bicarbonate to prevent AKI following cardiac surgery MMUH study of statin effects on perioperative end-organ injury Intensive Care Unit 2-centre (with UChicago) study of AKI biomarkers and epidemiology in critically-ill patients Cancer Chemotherapy Two-centre study (with UChicago) of AKI biomarkers (genomic and urinary) for prediction and early diagnosis of AKI in patients receiving cisplatin for cancer chemotherapy

26 OR ICU OPD Spot Urine Sample Point of Care Laboratory ELISA

27 Kidney Injury Biomarker Applications

28 Prophylaxis Trials Patient-oriented AKI research roadmap Risk Factor Identification Renal Perfusion & Function Monitoring Acute Kidney Injury Staging Biomarkers Early Intervention Trials ATN Recovery and RRT Trials

29 Kidney Injury Biomarkers in Acute and Chronic Kidney Disease Wu, I. et al. Clin J Am Soc Nephrol 2008;3: Copyright 2008 American Society of Nephrology

30 Stages in Progression of Chronic Kidney Disease (CKD) and Therapeutic Strategies Complications Normal Increased risk Damage GFR Kidney failure CKD death Screening for CKD risk factors CKD risk reduction Screening for CKD Diagnosis & treatment Treat comorbid conditions Slow progression Estimate progression Treat complications Prepare for replacement Replacement by dialysis & transplant DIAGNOSIS: Albuminuria Increased Serum Creatinine Proteinuria Decreased Glomerular Filtration Kidney Biopsy Rate (GFR)

31 % of Patients with Biomarker levels above those in the Control Group % of Patients with Biomarker levels above those in the Control Group % of Patients with Biomarker levels above those in the Control Group Site-Specific Kidney Injury Biomarkers in CKD: Diabetic Nephropathy A PiGST B Collagen IV * 70 ** Controls Normo Alb Micro Alb Macro Alb 0 Controls Normo Alb Micro Alb Macro Alb C AlphaGST Cawood TJ, et al: Am J Nephrol 2010;32(3): Controls Normo Alb Micro Alb Macro Alb

32 Summary: Kidney Injury Biomarkers Validation of the diagnostic and prognostic utility of several AKI biomarkers is underway AKI biomarkers are useful to diagnose AKI in a variety of clinical settings Clinical availability of AKI biomarkers will facilitate timely discontinuation of harmful therapies, as well as testing of targeted early AKI therapies in clinical trials Ideal AKI biomarkers will be detected early in AKI caused by a variety of insults, predict AKI severity, and measure response to therapy Some AKI biomarkers will have utility for the diagnosis and monitoring of CKD

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