dublin academic medical centre - irish medtech …€¢ideal aki biomarkers will be detected early...

“Discovery & Validation of Kidney Injury

Biomarkers”

Patrick Murray, MD, FASN, FRCPI, FJFICMI

Professor, University College Dublin,

Mater Misericordiae University Hospital,

Dublin, Ireland

[email protected]

Dublin Academic Medical Centre

HRB/IMDA Symposium, October 27th, 2010

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

Kidneys are important……

Increasing Frequency of AKI Hospitalisations

Morb Mortal Wkly Rep, 57: 309-12, 2008.

www.ncepod.org.uk

http://www.ncepod.org.uk/

A Call to Action.......

2009;Volume 374 (9699): Pages 1405-1406

COMMENT

“NCEPOD Report

on Acute Kidney

Injury- We Must

Do Better”

Alison MacLeod

Sutton, et al: Kidney Int 2002

Evolution in Renal Diagnostics

1950 ’s

1960 ’s

1970 ’s

1980 ’s

1990 ’s

2000

The renal testing arena is in need of the introduction

of novel, early and more sensitive and specific biomarkers

AMI

WBC count

LDH

CPK

CK -MB

Troponin -T

Troponin - I

AKI

Change in serum creatinine

Change in serum creatinine

Time

Conger JD, Am J Kidney Dis 26:565-576, 1995.

Star RA, Kidney Int 54:1817-1831, 1998.

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;20:2305-2313

Copyright ©2008 American Society of Nephrology

Murray, P. T. et al. Clin J Am Soc Nephrol 2008;3:864-868

Conceptual model of acute kidney injury (AKI)

13

Analysis of Urine and Serum NGAL

After Cardiopulmonary Bypass

Adapted from Mishra J, et al. Lancet. 2005;365:1231-1238.

Urine NGAL Serum NGAL

NGAL increased 2 hours after cardiopulmonary bypass

N = 71

Time after cardiopulmonary bypass (h)

225

200

175

150

125

100

75

50

25

0

Urin

e N

GA

L (

µg/L

)

0 2 4 6 8 12 24 36 48 60 72 84 96 108 120

Serum

Creatinine Rise


225

200

175

150

125

100

75

50

25

0

Urin

e N

GA

L (

µg/L

)

0 2 4 6 8 12 24 36 48 60 72 84 96 108 1200 2 4 6 8 12 24 3612 24 36 48 60 7248 60 72 84 96 10884 96 108 120

Serum

Creatinine Rise

Acute renal failure (n=20) Without acute renal failure (n51)


225

200

175

150

125

100

75

50

25

0

Se

rum

NG

AL

(µ

g/L

)

0 2 4 6 8 12 24 36 48 60 72 84 96 108 120

Serum

Creatinine Rise


225

200

175

150

125

100

75

50

25

0

Se

rum

NG

AL

(µ

g/L

)

0 2 4 6 8 12 24 36 48 60 72 84 96 108 1200 2 4 6 8 12 24 3612 24 36 48 60 7248 60 72 84 96 10884 96 108 120

Serum

Creatinine Rise

Nickolas, T. L. et. al. Ann Intern Med 2008;148:810-819

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;148:810-819

Kidney injury biomarkers versus clinical outcome

UCSD

VAMC, CA

Stanford

UHB , Switzerland

Charite’, Germany

UMC Groningen

Lariboisiere HospitalNY Methodist

Henry Ford Health

KUMC St. Vincent, Univ. H

VCU

Data Analysis CenterEnrolling Center Core Lab Center

ALERE Medical Abbott Diagnostic

Sponsors

San Filippo Neri

Mater Misericordiae

Acute Kidney Injury N-gal Evaluation of Symptomatic heart failure Study

Site-specific AKI Biomarkers

Goodsaid F, et al: Clin Pharm & Therap 2009

Immunohistochemical Localisation in Human Kidney

GST in Proximal Tubules GST in Distal Tubules

Collagen IV in Glom HCD (green) in Collecting Ductwww.argutusmed.com18

AKI Prognosis at Time of Dx: Urine CyC and NGALBiomarker performance at the time of Clinical Serum Creatinine increase

median

(25-75%

IQR)

Stage 1 or 2

N=37

Stage 3

N=9AUC (95%CI) P value

Chi

squared

ROC

comparison

CyC

(mg/L)

0.114

(0.027-0.23)

0.272

(0.22 – 0.72)0.74 (0.53 – 0.96) 0.02

CyC /

Creat

mg/g

0.101

(0.040 – 0.32)

0.725

(0.51 – 1.17)0.77 (0.55- 0.98) 0.01 NS

NGAL

(pg/ml)

98.3

(17.0 – 324)

461

(231 – 2047)0.78 (0.61 – 0.96) 0.02

NGAL/Cr

eat

ng/mg

79.7 (14.6 –

37.63)

571.4 (332 –

6273)0.78 (0.59 – 0.98) 0.01 NS

Koyner J, et al: Clin J Am Soc Nephrol 2010

AKI Prognosis at Time of Dx: Urinary GSTs

Biomarker performance at the time of Clinical Serum Creatinine increase

median

(25-75%

IQR)

Stage 1 or 2

N=37

Stage 3

N=9AUC (95%CI) P value

Chi

squared

ROC

comparison

α-GST

(μg/L)

1.29

(0.79 – 2.82)

2.18

(0.38 – 20.9)0.54 (0.25 – 0.84) NS

α-GST /

Creat

(ng/mg)

1.45

(0.89 – 4.41)

2.93

(0.33 – 88.5)0.54 (0.26 -0.82) NS NS

π - GST

(μg/L)

3.4

(3.4 – 10.9)

46.5

(13.5 – 286.3)0.84 (0.69 – 0.99) 0.003

π -GST

/Creat

(ng/mg)

3.69

(2.35 – 11.5)

54.8

(17.0 – 1175.2)0.86 (0.74- 0.99) 0.002 NS

Koyner J, et al: Clin J Am Soc Nephrol 2010

Declining Success Rate of Drug Development

Woosley RL, et al: Clin Pharmacol & Therapeutics 2007;81:129-133

Innovative Strategies for Improving Drug Development

Wagner JA: Clin Pharmacol & Therapeutics 2008;83:199-202

IMI SAFE-T ConsortiumSafer 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

2323

Phases of Biomarker Development

DISCOVERY PHASE

TRANSLATIONAL PHASES

VALIDATION PHASES

Pepe MS, et al:

J NCI 2001;93(14):1054-61

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

OR ICU OPD

Spot Urine Sample

Point of Care Laboratory ELISA

Kidney Injury Biomarker Applications

Patient-oriented AKI research roadmap

Renal Perfusion & Function Monitoring

Acute Kidney Injury “Staging” Biomarkers

Prophylaxis

Trials

Early

Intervention

Trials

ATN Recovery and RRT Trials

Risk Factor Identification

Stages in Progression of Chronic Kidney

Disease (CKD) and Therapeutic Strategies

Normal Increased risk

Damage GFR Kidney failure

CKD death

Complications

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)

0

10

20

30

40

50

60

70

Controls Normo Alb Micro Alb Macro Alb

% o

f P

ati

en

ts w

ith

Bio

ma

rker

lev

els

ab

ov

e th

ose

in th

e C

on

tro

l G

rou

p

Collagen IV

0

10

20

30

40


% o

f P

ati

en

ts w

ith

Bio

ma

rker

lev

els

ab

ov

e th

ose

in th

e C

on

tro

l G

rou

p

PiGST

0

10

20

30

40


% o

f P

ati

en

ts w

ith

Bio

ma

rker

lev

els

ab

ov

e th

ose

in th

e C

on

tro

l G

rou

p

AlphaGSTC

A B

* **

Site-Specific Kidney Injury Biomarkers in CKD:

Diabetic Nephropathy

Cawood TJ, et al: Am J Nephrol

2010;32(3):219-25

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

Further Information

• www.ncepod.org.uk

• www.renal.org/Clinical/GuidelinesSecti

on/AcuteKidneyInjury.aspx

• www.KDIGO.org

• www.akin.org

• www.adqi.net

http://www.ncepod.org.uk/

dublin academic medical centre - irish medtech …€¢ideal aki biomarkers will be detected early...

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