“Translational Research in AcuteKidney Injury”
Patrick Murray, MD, FASN, FRCPIProfessor, University College Dublin,
Mater Misericordiae University Hospital,Dublin, Ireland
CRCClinical
ResearchCentre
Dublin Academic Medical Centre
www.ucd.ie/crc/
Kidneys are important……
Divorce man 'wants kidney back'
GARDEN CITY, N.Y. - A U.S. MANDIVORCING HIS WIFE IS DEMANDINGTHAT SHE RETURN THE KIDNEY HE
DONATED TO HER OR PAY HIM $1.5M(£1M) IN COMPENSATION.
DR RICHARD BATISTA TOLD REPORTERSTHAT HE DECIDED TO GO PUBLIC BECAUSEHE WAS FRUSTRATED AT THE SLOW PACE
OF DIVORCE NEGOTIATIONS WITH HISESTRANGED WIFE.
HE SAID HE HAD NOT ONLY GIVEN HISHEART TO HIS WIFE, DAWNELL, BUT
DONATED HIS KIDNEY TO SAVE HER LIFE.
………..Everywhere
Nephrology
Marketos SG, et al: J R Soc Med1993; 86(5): 290–293
Early Diagnosis of Kidney Disease
www.worldkidneyday.org
Incidence of End-Stage Renal Disease (ESRD)
United States Renal Database System. 2007 Annual Report
Stages in Progression of Chronic KidneyDisease (CKD) and Therapeutic Strategies
NormalNormal IncreasedIncreasedriskrisk
DamageDamage GFR GFR KidneyKidneyfailurefailure
CKDCKDdeathdeath
ComplicationsComplications
Screening for CKDScreening for CKDrisk factorsrisk factors
CKD risk reductionCKD risk reduction
Screening for CKDScreening for CKDDiagnosis &Diagnosis &treatmenttreatment
Treat Treat comorbidcomorbidconditionsconditions
Slow progressionSlow progression
EstimateEstimateprogressionprogression
Treat complicationsTreat complications
Prepare forPrepare forreplacementreplacement
Replacement byReplacement bydialysis & transplantdialysis & transplant
DIAGNOSIS: Albuminuria Increased Serum CreatinineProteinuria Decreased Glomerular FiltrationKidney Biopsy Rate (GFR)
Increasing Frequency of Acute Kidney DiseaseHospitalisations
Morb Mortal Wkly Rep, 57: 309-12, 2008.
100% -
80% –
60% –
40% –
20% –
0% –
100% -
80% –
60% –
40% –
20% –
0% –0 1 2 3 4
No. of other failed organsSimple ANP ICU
ARF trial setting
RA Star, Kidney Int, 1998
Mortality Mortality
Distant organ injury caused by AKI
Scheel PJ et al.Kidney Int 2008;74:849-851
Serum Creatinine• Creatinine (from the Greek
kreas, flesh) is a break-downproduct of creatinephosphate in muscle, and isusually produced at a fairlyconstant rate by the body(depending on musclemass). Chemically,creatinine is a spontaneouslyformed cyclic derivative ofcreatine.
Moran SM, Myers BD: Kidney International1985;27:928-37
GFR(ml/min)
SerumCreatinine(mg%)
Relationship between GFR loss and Serum Creatinineduring evolution of AKI
Sutton TA et al. Kidney Int 2002
Relationship between GFR loss and cellularinjury during evolution of AKI
Molitoris BA et al. Improving outcomes of acute kidney injury: report of an initiative.Nat Clin Pract Nephrol 2007 3:439–442
AKIN classification/staging system for acute kidneyinjury, based on modification of RIFLE criteria
Proposed classification / staging system for AKI,based on modification of RIFLE criteria
Urine output criteria
Stage Serum creatinine criteria
1 Increase of ≥ 26.4 μmol/L (0.3 mg/d) OR to150%-200% of baseline (1.5- to 2-fold)
< 0.5 mL/kg/h for > 6h
2 Increase to > 200-300% of baseline (> 2- to 3-fold)
< 0.5 mL/kg/h for > 12h
3a Increase > 300% (> 3-fold; or serumcreatinine ≥ 354 μmol/L [4.0 mg/dL] with anacute rise of at least 44 μmol/L [0.5 mg/d])
< 0.3 mL/kg/h for 24 hOR anuria for 12h
Murray PT et al. Clin J Am Soc Nephrol 2008;3:864-868Copyright © 2008 American Society of Nephrology
Conceptual model of acute kidney injury (AKI)
Definition of “Biomarker” (Biological Marker)
• “A characteristic that is objectively measured andevaluated as an indicator of normal biologicalprocesses, pathogenic processes, or pharmacologicresponses to a therapeutic intervention”.– Biomarkers Definitions Working Group Bethesda, MD:
Clinical Pharmacology & Therapeutics 2001;69:89-95
Wu, A. H., Journal of Clinical Immunoassay 17, 45-48 (1994)
Normal Range
Multiples
of Upper
Reference
Limit
5
0
Days After Onset of AMI
10
15
50
1 2 3 4 5 6 107
Myoglobin
CK-MB
Troponin T
LD1
Serum Markers for AMI: Kinetic Release
Development of new renal biomarkers over time
Timeline of the development of biomarkers
Acute kidney• Serum creatinine 1926
Chronic kidney disease
Biomarker isolated
Biomarker used in human studies
• KIM-1 1961• Cystatin C 1968• IL-18 1985• NGAL 1993
• • Urine KIM-1 2002• Serum Cystatin C 1985• Urine IL-18 2004• Urinary NGAL 2005
• Serum creatinine 1926
• Creatinine clearance by 24 hrurine collection 1933
• Cockcrof: Gault equation 1976
• Serum Cystatin C 1985
• MDRD equation to estimate GFR 1999
Wu I et al. Clin J Am Soc Nephrol 2008;3:1895-1901 Copyright © 2008 American Society of Nephrology
Emerging biomarkers of AKI and CKD
Wu I et al. Clin J Am Soc Nephrol 2008;3:1895-1901 Copyright © 2008 American Society of Nephrology
Phases of Biomarker Development
DISCOVERY PHASE
TRANSLATIONAL PHASES
VALIDATION PHASES
Pepe MS, et al:J NCI 2001;93(14):1054-61
AKI biomarker discovery & validation needs• Early diagnosis of evolving AKI could result in earlier
changes in management:– to stop harmful interventions– to make early therapeutic interventions
• More accurate differential diagnosis of AKI coulddirect appropriate therapy of AKI
• More accurate staging of AKI could help prognosticstratification and therapy of AKI– serial staging of phases of AKI– assessment of current and future severity of injury
Schmidt-Ott KM et al. J Am Soc Nephrol 2007;18:407-413Copyright © 2007 American Society of Nephrology
Ischemic kidneys synthesize NGALfor at least 50h after reperfusion,manifest by an approximately1000-fold increase in NGAL message(measured by real-time RT-PCR)
After renal injury, NGAL mRNA isexpressed predominantly in the loopof Henle and collecting ducts asdetermined by in situ hybridization
NGAL expression in AKI
Urine from patients with mild (lanes 1 and4) and severe (lanes 2, 3, and 5) renalepithelial injury contains NGAL (immunoblotfor NGAL protein- standards on left)
Urine NGAL and AKI post-CPBUrine NGAL
(ug/L)
Urine NGAL(ng/g creatinine)
Urine NGAL (ug/L)2 h after surgery
Time after cardiopulmonary bypass (h)
Without acute renal failure (n=51)Mishra J et al.Lancet 2005;365:1231-38 Acute renal failure (n=20)
Urinary AKI markers post-CPB
Koyner et al. Kidney Int 2008 Oct;74(8):1059-69
Urine CyC/ Creatinine(mg/g)
Urine NGAL/ Creatinine(ng/g)
Identification of ATN requiring RRT
Herget-Rosenthal S, et al: Clin Chem 2004;552-558
Plasma AKI markers post-CPB
Koyner et al. Kidney Int 2008 Oct;74(8):1059-69
AKI biomarkers post-CPB
Koyner, et al: Kidney Int. 2008 Oct;74(8):1059-69
Serum AKI markers post-CPB
Haase-Fielitz A, et al:Crit Care Med 2009;37:553-60
Roles of AKI biomarkers
Lameire N et al. Lancet2008 Nov 29;372(9653):1863-5
New Biomarkers for Early Detection of AKI
Variable48hr pre-AKI8hr post-contrast
12hr post-CPB
PlasmaCystatin C
Not tested48hr pre-AKI2hr post-contrast
2hr post-CPBPlasmaNGAL
Not testedNot testedNot tested12-24hr post-CPB
UrineKIM-1
12-24hr post-tx
48hr pre-AKINot tested4-6hr post-CPB
UrineIL-18
12-24hrpost-tx
48hr pre-AKI
4hr post-contrast
2hr post-CPB
UrineNGAL
RenalTxplant
Sepsis/ICUCINCPBSampleBiomarker
Adapted from: Parikh CR, Devarajan P: Crit Care Med 2008;36[Suppl.]:S159-S165
Rivers E et al.NEJM 2001;345:1368-77
AKI Biomarkers?
Early goal-directed therapy of AKI?
Fenoldopam and dialysis-free survival inearly ICU ARF
Tumlin JA, et al: Am J Kidney Dis 2005;46:26-34
Urinary NGAL & response to AKI prevention
Haase M et al. Crit Care Med 2009;37:39–47
AKI biomarker discovery & validationneeds
• Early diagnosis of evolving AKI could result in earlierchanges in management:– to stop harmful interventions– to make early therapeutic interventions
• More accurate differential diagnosis of AKI could directappropriate therapy of AKI
• More accurate staging of AKI could help prognosticstratification and therapy of AKI– serial staging of phases of AKI– assessment of current and future severity of injury
Thadhani R et al. NEJM 1996; 334:1448-60
Differential diagnosis of AKI
Current AKI biomarkers
Lameire N et al. Lancet 2005;365:417-430
Prerenal RenalUrinanalysis Hyaline casts AbnormalSpecific gravity 1.020 1.010Osmolality (mmol/kg) > 500 > 300Sodium (mmol/L) < 20 > 40Fractional excretion of sodium (%) < 1 > 2Fractional excretion of urea (%) < 35 > 35Fractional excretion of uric acid (%) < 7 > 15Fractional excretion of lithium (%) < 7 > 20Low-molecular-weight proteins Low HighBrush-border enzymes Low High
Human urinary biomarkers in AKI vs. controls
Vaidya V et al. Clin Transl Sci 2008 December;1(3): 200–208
Emergency room AKI biomarker study flow diagram
Nickolas TL 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
Urinary NGAL(µg/g)
Presenting SerumCreatinine(mg/dL)
Nickolas TL et al. Ann Intern Med 2008;148:810-819
Kidney injury biomarkers vs. clinical outcome
Proportionof Patients
Nickolas TL et al. Ann Intern Med 2008;148:810-819
Multivariate analysis of AKI biomarker levels derived from receiver-operating characteristic curve analysis
Nickolas TL et al. Ann Intern Med 2008;148:810-819
AKI biomarker discovery & validationneeds
• Early diagnosis of evolving AKI could result in earlierchanges in management:– to stop harmful interventions– to make early therapeutic interventions
• More accurate differential diagnosis of AKI could directappropriate therapy of AKI
• More accurate staging of AKI could help prognosticstratification and therapy of AKI– serial staging of phases of AKI– assessment of current and future severity of injury
AKI Outcomes Renal Outcomes
(Horizontal Continuum)
• Renal Function endpoints– AKI Stage– RRT requirement– RRT duration– Recovery of renal function– CKD: sustained eGFR loss
post-AKI– ? GFR measurements– ? Fluid balance
Non-Renal Outcomes
• Survival duration• Morbidity– Non-renal Organ dysfunction– MOF
• Length of stay– ICU, hospital
• Functional status• Economic analysis
Composite endpoints
Dialysis-free survival
Cerda J et al. Clin J Am Soc Nephrol 2008;3:881-886Copyright © 2008 American Society of Nephrology
Natural history of AKI
Patient-oriented AKI research roadmap
Renal Perfusion & Function Monitoring
Acute Kidney Injury “Staging” Biomarkers
ProphylaxisTrials
EarlyInterventionTrials
ATN Recovery and RRT Trials
Risk Factor Identification
First Biomarker ?
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
Ongoing AKI Biomarker Projects• Multicenter study of the utility of urinary NGAL to diagnose
and risk stratify AKI in patients admitted with acutedecompensated heart failure
• International, five-centre randomised, controlled trial ofsodium bicarbonate to prevent AKI following cardiac surgery
• International multicenter study of AKI epidemiology (AKI-EPI) in critically-ill patients
• Three-centre study of AKI biomarkers (genomic and urinary)for prediction and early diagnosis of AKI in patients receivingcisplatin for cancer chemotherapy
AKIN Web Portal: http://www.akinet.org
“If Urine then you’re in…….”
Summary: AKI 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 oftargeted early AKI therapies in clinical trials
• Ideal AKI biomarkers will be detected early in AKI causedby a variety of insults, predict AKI severity, and measureresponse to therapy
• Some AKI biomarkers will have utility for the diagnosis andmonitoring of CKD
