Acute Kidney Injury (AKI)

Tags:

Preview:

Click to see full reader

DESCRIPTION

Acute Kidney Injury (AKI). Rubin S Gondodiputro. “A NEW CONCEPT THAT STILL MOVES and CHANGES”. OBJECTIVES. DEFINITION and CLASIFICATION of AKI EPIDEMIOLOGY of AKI ETIOLOGY and DIAGNOSIS of AKI PATHOPHYSIOLOGY of AKI BIOMARKER of AKI. DEFINITION and CLASIFICATION AKI. Definitions. - PowerPoint PPT Presentation

Citation preview

Acute Kidney Injury (AKI)

Rubin S Gondodiputro

ldquoA NEW CONCEPT THAT STILL MOVES and CHANGESrdquo

OBJECTIVES

DEFINITION and CLASIFICATION of AKI

EPIDEMIOLOGY of AKI

ETIOLOGY and DIAGNOSIS of AKI

PATHOPHYSIOLOGY of AKI

BIOMARKER of AKI

DEFINITION and CLASIFICATION AKI

Definitions

Acute Renal Failure

Acute Kidney Injury

The need for Defining ARF

bull Acute renal occurs in 5-20 of critically ill patients with a mortality of 28-90

bull Conclusion - We have no idea what ARF is

bull At least 30 definitions of ARF are in use

Penelitian Definisi

de Medonca dkk (2000)4 Tepel dkk (2000) 6

Peningkatan SCr sebesar 05 mgdl dalam waktu 48 jam

Brivet dkk (1996) 10 Kenaikan SCr gt 20 mgdl = (ldquoGGArdquo)Kenaikan SCr gt35 mgdl dan atau kenaikan BUN gt 100 mgdl (ldquoGGA beratrdquo)

Agrawal dan Swartz (2000) 2 Kenaikan SCr gt 05 mgdlhari disertai produksi urin lt 400 cchariDisebut GGA berat (rdquocomplete renal shutdown)

Ricci dkk (2006) 8

( meta-analisis) Kenaikan SCr bervariasi antara 15 ndash 10 mgdlPenurunan produksi urin bervariasi antara 0-900 cchariPenurunan LFG sebesar gt 50 disertai penurunan produksi urin berlangsung beberapa jam sampai beberapa hari

Definisi GGA berdasarkan beberapa penelitian

Keterangan Scr= Serum Creatinin BUN = Blood Urea Nitrogen LFG = Laju Filtrasi glomeruli

AKI A Common Serious Problem

bull AKI is present in 5 of all hospitalized patients and up to 50 of patients in ICUs

bull The incidence is increasing -globallybull Mortality rate 50 - 80 in dialyzed ICU

patientsndash 4 Million die each year of AKIbull AKI requiring dialysis is one of the most

important independent predictors of death in ICU patients

bull 25 of ICU dialysis survivors progress to ESRD within 3 years

Issues in Design of Clinical Trials in ARF

bull Heterogeneity of patient population bull Effect of co-morbidty and illness on outcomebull Large variations in clinical practicebull Lack of a standarddized definition of ARF

Metha et al J Am Soc Nephrol 2002

Diagnosis of AKI isOften Delayed

bull Elevation in serum creatinine is the current gold standard but this is problematic

bull Normal serum creatinine varies widely with age gender diet muscle mass muscle metabolism medications hydration status

bull In AKI serum creatinine can take several days to reach a new steady state

Proposed Diagnostic Criteria for AKI

USIA(tahun)

LAKI-LAKI (kulit hitam)

(mgdL)

LAKI-LAKI (kulit putih)

(mgdL)

WANITA (kulit hitam)

(mgdL)

WANITA (kulit putih)

(mgdL)

20-24 15 13 12 10

25-29 15 12 11 10

30-39 14 12 11 09

40-54 13 11 10 08

55-65 13 11 10 08

gt65 12 10 09 08

Perkiraan kadar kreatinin serum berdasarkan kelompok usia dan ras

Kadar Awal

05 10 15 20 25 30

Risk 075 15 225 30 375 -

Injury 10 20 30 - - -

Failure 15 30 40 40 40 40

Peningkatan kadar serum kreatinin ( mgdl) disesuaikan dengan kriteria RIFLE

Kriteria RIFLE

Berat badan pasien (kg)

40 50 60 70

RIFLE - R UO= lt120 cc(dalam 6 jam)

UO= lt150 cc(dalam 6 jam)

UO= lt180 cc(dalam 6 jam)

UO= lt210 cc(dalam 6 jam)

RIFLE - I UO = lt240 cc(dalam 12 jam)

UO = lt300 cc(dalam 12 jam)

UO = lt360 cc(dalam 12 jam)

UO = lt420 cc(dalam 12 jam)

RIFLE - F UO = lt 288 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 360 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 432 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 504 cc(dalam 24 jam)ANURI(dalam 12 jam)

Kriteria RIFLE berdasarkan urin output (UO) dan berat badan penderita

Roesli R 2007

KepustakaanKelompok

PasienJumlah

Pasien (n)Mortalitas

HR

Mortalitas(6 bulan)

Kebutuhandialisis

Abosaif dkk 15 ICU n = 183R= 33I = 31F= 23

R= 383I = 500 F = 745

R= 433I = 536 F = 860

R= 283I = 500 F = 580

Hoste dkk 16 ICU n = 5383R= 12I = 27F= 28

R= 88I = 114 F = 269

R = 10I = 14 (10-19)F= 27(2 ndash 36)

Kuitunen dkk 18 OperasiJantung

n = 813 R= 80 I = 214 F = 324

R= 11 I = 71 F = 55

Uchino dkk 19 Rumahsakit

n = 20126R= 91 I = 52F= 37

R= 151 I = 292 F= 411

R =25 (21-29)I = 54 (46-64)F=101(8 ndash 12)

Prediksi prognosis dan kematian berdasarkan kriteria RIFLE

HR = hazard ratio R= risk I = Injury F = failure

EPIDEMIOLOGY

Natural History of AKI

ETIOLOGY or COMMON CAUSES OF AKI

AKI Common Causes

bull Ischemia (60) cardiovascular disease cardiac surgery abdominal surgery shock sepsis

bull Nephrotoxins(30) antibiotics contrast chemotherapy anti-rejection NSAIDs

These causes also frequently lead to sub-clinical renal injurya

vastly underestimated problem

Etiology of AKI

COMMON CAUSESETIOLOGY OF AKI

PATHOPHYSIOLOGY

Pathophysiology of AKICurrent Knowledge from Experimental

models

1048710 AKI can result from different triggers 1048710 Kidney response to injury is time dependent and

occurs immediately following injury 1048710 Response can be characterized by measurement

of various markers reflecting activation of different mechanisms and pathways

1048710 Based on the appearance of various markers it is possible to identify the site of injury the nature of the response and describe the stage of the disease

Pathophysiology of AKI

bull Functional alterations lead to injury Failure of autoregulation

bull Injury precedes functional change Direct Nephrotoxicity Ischemia Reperfusion Inflammation

bull Injury and functional change are concurrent Complete vascular occlusion

Etiology of AKI

PATHOPHYSIOLOGY of PRERENAL AKI

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

ldquoA NEW CONCEPT THAT STILL MOVES and CHANGESrdquo

OBJECTIVES

DEFINITION and CLASIFICATION of AKI

EPIDEMIOLOGY of AKI

ETIOLOGY and DIAGNOSIS of AKI

PATHOPHYSIOLOGY of AKI

BIOMARKER of AKI

DEFINITION and CLASIFICATION AKI

Definitions

Acute Renal Failure

Acute Kidney Injury

The need for Defining ARF

bull Acute renal occurs in 5-20 of critically ill patients with a mortality of 28-90

bull Conclusion - We have no idea what ARF is

bull At least 30 definitions of ARF are in use

Penelitian Definisi

de Medonca dkk (2000)4 Tepel dkk (2000) 6

Peningkatan SCr sebesar 05 mgdl dalam waktu 48 jam

Brivet dkk (1996) 10 Kenaikan SCr gt 20 mgdl = (ldquoGGArdquo)Kenaikan SCr gt35 mgdl dan atau kenaikan BUN gt 100 mgdl (ldquoGGA beratrdquo)

Agrawal dan Swartz (2000) 2 Kenaikan SCr gt 05 mgdlhari disertai produksi urin lt 400 cchariDisebut GGA berat (rdquocomplete renal shutdown)

Ricci dkk (2006) 8

( meta-analisis) Kenaikan SCr bervariasi antara 15 ndash 10 mgdlPenurunan produksi urin bervariasi antara 0-900 cchariPenurunan LFG sebesar gt 50 disertai penurunan produksi urin berlangsung beberapa jam sampai beberapa hari

Definisi GGA berdasarkan beberapa penelitian

Keterangan Scr= Serum Creatinin BUN = Blood Urea Nitrogen LFG = Laju Filtrasi glomeruli

AKI A Common Serious Problem

bull AKI is present in 5 of all hospitalized patients and up to 50 of patients in ICUs

bull The incidence is increasing -globallybull Mortality rate 50 - 80 in dialyzed ICU

patientsndash 4 Million die each year of AKIbull AKI requiring dialysis is one of the most

important independent predictors of death in ICU patients

bull 25 of ICU dialysis survivors progress to ESRD within 3 years

Issues in Design of Clinical Trials in ARF

bull Heterogeneity of patient population bull Effect of co-morbidty and illness on outcomebull Large variations in clinical practicebull Lack of a standarddized definition of ARF

Metha et al J Am Soc Nephrol 2002

Diagnosis of AKI isOften Delayed

bull Elevation in serum creatinine is the current gold standard but this is problematic

bull Normal serum creatinine varies widely with age gender diet muscle mass muscle metabolism medications hydration status

bull In AKI serum creatinine can take several days to reach a new steady state

Proposed Diagnostic Criteria for AKI

USIA(tahun)

LAKI-LAKI (kulit hitam)

(mgdL)

LAKI-LAKI (kulit putih)

(mgdL)

WANITA (kulit hitam)

(mgdL)

WANITA (kulit putih)

(mgdL)

20-24 15 13 12 10

25-29 15 12 11 10

30-39 14 12 11 09

40-54 13 11 10 08

55-65 13 11 10 08

gt65 12 10 09 08

Perkiraan kadar kreatinin serum berdasarkan kelompok usia dan ras

Kadar Awal

05 10 15 20 25 30

Risk 075 15 225 30 375 -

Injury 10 20 30 - - -

Failure 15 30 40 40 40 40

Peningkatan kadar serum kreatinin ( mgdl) disesuaikan dengan kriteria RIFLE

Kriteria RIFLE

Berat badan pasien (kg)

40 50 60 70

RIFLE - R UO= lt120 cc(dalam 6 jam)

UO= lt150 cc(dalam 6 jam)

UO= lt180 cc(dalam 6 jam)

UO= lt210 cc(dalam 6 jam)

RIFLE - I UO = lt240 cc(dalam 12 jam)

UO = lt300 cc(dalam 12 jam)

UO = lt360 cc(dalam 12 jam)

UO = lt420 cc(dalam 12 jam)

RIFLE - F UO = lt 288 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 360 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 432 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 504 cc(dalam 24 jam)ANURI(dalam 12 jam)

Kriteria RIFLE berdasarkan urin output (UO) dan berat badan penderita

Roesli R 2007

KepustakaanKelompok

PasienJumlah

Pasien (n)Mortalitas

HR

Mortalitas(6 bulan)

Kebutuhandialisis

Abosaif dkk 15 ICU n = 183R= 33I = 31F= 23

R= 383I = 500 F = 745

R= 433I = 536 F = 860

R= 283I = 500 F = 580

Hoste dkk 16 ICU n = 5383R= 12I = 27F= 28

R= 88I = 114 F = 269

R = 10I = 14 (10-19)F= 27(2 ndash 36)

Kuitunen dkk 18 OperasiJantung

n = 813 R= 80 I = 214 F = 324

R= 11 I = 71 F = 55

Uchino dkk 19 Rumahsakit

n = 20126R= 91 I = 52F= 37

R= 151 I = 292 F= 411

R =25 (21-29)I = 54 (46-64)F=101(8 ndash 12)

Prediksi prognosis dan kematian berdasarkan kriteria RIFLE

HR = hazard ratio R= risk I = Injury F = failure

EPIDEMIOLOGY

Natural History of AKI

ETIOLOGY or COMMON CAUSES OF AKI

AKI Common Causes

bull Ischemia (60) cardiovascular disease cardiac surgery abdominal surgery shock sepsis

bull Nephrotoxins(30) antibiotics contrast chemotherapy anti-rejection NSAIDs

These causes also frequently lead to sub-clinical renal injurya

vastly underestimated problem

Etiology of AKI

COMMON CAUSESETIOLOGY OF AKI

PATHOPHYSIOLOGY

Pathophysiology of AKICurrent Knowledge from Experimental

models

1048710 AKI can result from different triggers 1048710 Kidney response to injury is time dependent and

occurs immediately following injury 1048710 Response can be characterized by measurement

of various markers reflecting activation of different mechanisms and pathways

1048710 Based on the appearance of various markers it is possible to identify the site of injury the nature of the response and describe the stage of the disease

Pathophysiology of AKI

bull Functional alterations lead to injury Failure of autoregulation

bull Injury precedes functional change Direct Nephrotoxicity Ischemia Reperfusion Inflammation

bull Injury and functional change are concurrent Complete vascular occlusion

Etiology of AKI

PATHOPHYSIOLOGY of PRERENAL AKI

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

OBJECTIVES

DEFINITION and CLASIFICATION of AKI

EPIDEMIOLOGY of AKI

ETIOLOGY and DIAGNOSIS of AKI

PATHOPHYSIOLOGY of AKI

BIOMARKER of AKI

DEFINITION and CLASIFICATION AKI

Definitions

Acute Renal Failure

Acute Kidney Injury

The need for Defining ARF

bull Acute renal occurs in 5-20 of critically ill patients with a mortality of 28-90

bull Conclusion - We have no idea what ARF is

bull At least 30 definitions of ARF are in use

Penelitian Definisi

de Medonca dkk (2000)4 Tepel dkk (2000) 6

Peningkatan SCr sebesar 05 mgdl dalam waktu 48 jam

Brivet dkk (1996) 10 Kenaikan SCr gt 20 mgdl = (ldquoGGArdquo)Kenaikan SCr gt35 mgdl dan atau kenaikan BUN gt 100 mgdl (ldquoGGA beratrdquo)

Agrawal dan Swartz (2000) 2 Kenaikan SCr gt 05 mgdlhari disertai produksi urin lt 400 cchariDisebut GGA berat (rdquocomplete renal shutdown)

Ricci dkk (2006) 8

( meta-analisis) Kenaikan SCr bervariasi antara 15 ndash 10 mgdlPenurunan produksi urin bervariasi antara 0-900 cchariPenurunan LFG sebesar gt 50 disertai penurunan produksi urin berlangsung beberapa jam sampai beberapa hari

Definisi GGA berdasarkan beberapa penelitian

Keterangan Scr= Serum Creatinin BUN = Blood Urea Nitrogen LFG = Laju Filtrasi glomeruli

AKI A Common Serious Problem

bull AKI is present in 5 of all hospitalized patients and up to 50 of patients in ICUs

bull The incidence is increasing -globallybull Mortality rate 50 - 80 in dialyzed ICU

patientsndash 4 Million die each year of AKIbull AKI requiring dialysis is one of the most

important independent predictors of death in ICU patients

bull 25 of ICU dialysis survivors progress to ESRD within 3 years

Issues in Design of Clinical Trials in ARF

bull Heterogeneity of patient population bull Effect of co-morbidty and illness on outcomebull Large variations in clinical practicebull Lack of a standarddized definition of ARF

Metha et al J Am Soc Nephrol 2002

Diagnosis of AKI isOften Delayed

bull Elevation in serum creatinine is the current gold standard but this is problematic

bull Normal serum creatinine varies widely with age gender diet muscle mass muscle metabolism medications hydration status

bull In AKI serum creatinine can take several days to reach a new steady state

Proposed Diagnostic Criteria for AKI

USIA(tahun)

LAKI-LAKI (kulit hitam)

(mgdL)

LAKI-LAKI (kulit putih)

(mgdL)

WANITA (kulit hitam)

(mgdL)

WANITA (kulit putih)

(mgdL)

20-24 15 13 12 10

25-29 15 12 11 10

30-39 14 12 11 09

40-54 13 11 10 08

55-65 13 11 10 08

gt65 12 10 09 08

Perkiraan kadar kreatinin serum berdasarkan kelompok usia dan ras

Kadar Awal

05 10 15 20 25 30

Risk 075 15 225 30 375 -

Injury 10 20 30 - - -

Failure 15 30 40 40 40 40

Peningkatan kadar serum kreatinin ( mgdl) disesuaikan dengan kriteria RIFLE

Kriteria RIFLE

Berat badan pasien (kg)

40 50 60 70

RIFLE - R UO= lt120 cc(dalam 6 jam)

UO= lt150 cc(dalam 6 jam)

UO= lt180 cc(dalam 6 jam)

UO= lt210 cc(dalam 6 jam)

RIFLE - I UO = lt240 cc(dalam 12 jam)

UO = lt300 cc(dalam 12 jam)

UO = lt360 cc(dalam 12 jam)

UO = lt420 cc(dalam 12 jam)

RIFLE - F UO = lt 288 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 360 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 432 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 504 cc(dalam 24 jam)ANURI(dalam 12 jam)

Kriteria RIFLE berdasarkan urin output (UO) dan berat badan penderita

Roesli R 2007

KepustakaanKelompok

PasienJumlah

Pasien (n)Mortalitas

HR

Mortalitas(6 bulan)

Kebutuhandialisis

Abosaif dkk 15 ICU n = 183R= 33I = 31F= 23

R= 383I = 500 F = 745

R= 433I = 536 F = 860

R= 283I = 500 F = 580

Hoste dkk 16 ICU n = 5383R= 12I = 27F= 28

R= 88I = 114 F = 269

R = 10I = 14 (10-19)F= 27(2 ndash 36)

Kuitunen dkk 18 OperasiJantung

n = 813 R= 80 I = 214 F = 324

R= 11 I = 71 F = 55

Uchino dkk 19 Rumahsakit

n = 20126R= 91 I = 52F= 37

R= 151 I = 292 F= 411

R =25 (21-29)I = 54 (46-64)F=101(8 ndash 12)

Prediksi prognosis dan kematian berdasarkan kriteria RIFLE

HR = hazard ratio R= risk I = Injury F = failure

EPIDEMIOLOGY

Natural History of AKI

ETIOLOGY or COMMON CAUSES OF AKI

AKI Common Causes

bull Ischemia (60) cardiovascular disease cardiac surgery abdominal surgery shock sepsis

bull Nephrotoxins(30) antibiotics contrast chemotherapy anti-rejection NSAIDs

These causes also frequently lead to sub-clinical renal injurya

vastly underestimated problem

Etiology of AKI

COMMON CAUSESETIOLOGY OF AKI

PATHOPHYSIOLOGY

Pathophysiology of AKICurrent Knowledge from Experimental

models

1048710 AKI can result from different triggers 1048710 Kidney response to injury is time dependent and

occurs immediately following injury 1048710 Response can be characterized by measurement

of various markers reflecting activation of different mechanisms and pathways

1048710 Based on the appearance of various markers it is possible to identify the site of injury the nature of the response and describe the stage of the disease

Pathophysiology of AKI

bull Functional alterations lead to injury Failure of autoregulation

bull Injury precedes functional change Direct Nephrotoxicity Ischemia Reperfusion Inflammation

bull Injury and functional change are concurrent Complete vascular occlusion

Etiology of AKI

PATHOPHYSIOLOGY of PRERENAL AKI

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

DEFINITION and CLASIFICATION AKI

Definitions

Acute Renal Failure

Acute Kidney Injury

The need for Defining ARF

bull Acute renal occurs in 5-20 of critically ill patients with a mortality of 28-90

bull Conclusion - We have no idea what ARF is

bull At least 30 definitions of ARF are in use

Penelitian Definisi

de Medonca dkk (2000)4 Tepel dkk (2000) 6

Peningkatan SCr sebesar 05 mgdl dalam waktu 48 jam

Brivet dkk (1996) 10 Kenaikan SCr gt 20 mgdl = (ldquoGGArdquo)Kenaikan SCr gt35 mgdl dan atau kenaikan BUN gt 100 mgdl (ldquoGGA beratrdquo)

Agrawal dan Swartz (2000) 2 Kenaikan SCr gt 05 mgdlhari disertai produksi urin lt 400 cchariDisebut GGA berat (rdquocomplete renal shutdown)

Ricci dkk (2006) 8

( meta-analisis) Kenaikan SCr bervariasi antara 15 ndash 10 mgdlPenurunan produksi urin bervariasi antara 0-900 cchariPenurunan LFG sebesar gt 50 disertai penurunan produksi urin berlangsung beberapa jam sampai beberapa hari

Definisi GGA berdasarkan beberapa penelitian

Keterangan Scr= Serum Creatinin BUN = Blood Urea Nitrogen LFG = Laju Filtrasi glomeruli

AKI A Common Serious Problem

bull AKI is present in 5 of all hospitalized patients and up to 50 of patients in ICUs

bull The incidence is increasing -globallybull Mortality rate 50 - 80 in dialyzed ICU

patientsndash 4 Million die each year of AKIbull AKI requiring dialysis is one of the most

important independent predictors of death in ICU patients

bull 25 of ICU dialysis survivors progress to ESRD within 3 years

Issues in Design of Clinical Trials in ARF

bull Heterogeneity of patient population bull Effect of co-morbidty and illness on outcomebull Large variations in clinical practicebull Lack of a standarddized definition of ARF

Metha et al J Am Soc Nephrol 2002

Diagnosis of AKI isOften Delayed

bull Elevation in serum creatinine is the current gold standard but this is problematic

bull Normal serum creatinine varies widely with age gender diet muscle mass muscle metabolism medications hydration status

bull In AKI serum creatinine can take several days to reach a new steady state

Proposed Diagnostic Criteria for AKI

USIA(tahun)

LAKI-LAKI (kulit hitam)

(mgdL)

LAKI-LAKI (kulit putih)

(mgdL)

WANITA (kulit hitam)

(mgdL)

WANITA (kulit putih)

(mgdL)

20-24 15 13 12 10

25-29 15 12 11 10

30-39 14 12 11 09

40-54 13 11 10 08

55-65 13 11 10 08

gt65 12 10 09 08

Perkiraan kadar kreatinin serum berdasarkan kelompok usia dan ras

Kadar Awal

05 10 15 20 25 30

Risk 075 15 225 30 375 -

Injury 10 20 30 - - -

Failure 15 30 40 40 40 40

Peningkatan kadar serum kreatinin ( mgdl) disesuaikan dengan kriteria RIFLE

Kriteria RIFLE

Berat badan pasien (kg)

40 50 60 70

RIFLE - R UO= lt120 cc(dalam 6 jam)

UO= lt150 cc(dalam 6 jam)

UO= lt180 cc(dalam 6 jam)

UO= lt210 cc(dalam 6 jam)

RIFLE - I UO = lt240 cc(dalam 12 jam)

UO = lt300 cc(dalam 12 jam)

UO = lt360 cc(dalam 12 jam)

UO = lt420 cc(dalam 12 jam)

RIFLE - F UO = lt 288 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 360 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 432 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 504 cc(dalam 24 jam)ANURI(dalam 12 jam)

Kriteria RIFLE berdasarkan urin output (UO) dan berat badan penderita

Roesli R 2007

KepustakaanKelompok

PasienJumlah

Pasien (n)Mortalitas

HR

Mortalitas(6 bulan)

Kebutuhandialisis

Abosaif dkk 15 ICU n = 183R= 33I = 31F= 23

R= 383I = 500 F = 745

R= 433I = 536 F = 860

R= 283I = 500 F = 580

Hoste dkk 16 ICU n = 5383R= 12I = 27F= 28

R= 88I = 114 F = 269

R = 10I = 14 (10-19)F= 27(2 ndash 36)

Kuitunen dkk 18 OperasiJantung

n = 813 R= 80 I = 214 F = 324

R= 11 I = 71 F = 55

Uchino dkk 19 Rumahsakit

n = 20126R= 91 I = 52F= 37

R= 151 I = 292 F= 411

R =25 (21-29)I = 54 (46-64)F=101(8 ndash 12)

Prediksi prognosis dan kematian berdasarkan kriteria RIFLE

HR = hazard ratio R= risk I = Injury F = failure

EPIDEMIOLOGY

Natural History of AKI

ETIOLOGY or COMMON CAUSES OF AKI

AKI Common Causes

bull Ischemia (60) cardiovascular disease cardiac surgery abdominal surgery shock sepsis

bull Nephrotoxins(30) antibiotics contrast chemotherapy anti-rejection NSAIDs

These causes also frequently lead to sub-clinical renal injurya

vastly underestimated problem

Etiology of AKI

COMMON CAUSESETIOLOGY OF AKI

PATHOPHYSIOLOGY

Pathophysiology of AKICurrent Knowledge from Experimental

models

1048710 AKI can result from different triggers 1048710 Kidney response to injury is time dependent and

occurs immediately following injury 1048710 Response can be characterized by measurement

of various markers reflecting activation of different mechanisms and pathways

1048710 Based on the appearance of various markers it is possible to identify the site of injury the nature of the response and describe the stage of the disease

Pathophysiology of AKI

bull Functional alterations lead to injury Failure of autoregulation

bull Injury precedes functional change Direct Nephrotoxicity Ischemia Reperfusion Inflammation

bull Injury and functional change are concurrent Complete vascular occlusion

Etiology of AKI

PATHOPHYSIOLOGY of PRERENAL AKI

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Definitions

Acute Renal Failure

Acute Kidney Injury

The need for Defining ARF

bull Acute renal occurs in 5-20 of critically ill patients with a mortality of 28-90

bull Conclusion - We have no idea what ARF is

bull At least 30 definitions of ARF are in use

Penelitian Definisi

de Medonca dkk (2000)4 Tepel dkk (2000) 6

Peningkatan SCr sebesar 05 mgdl dalam waktu 48 jam

Brivet dkk (1996) 10 Kenaikan SCr gt 20 mgdl = (ldquoGGArdquo)Kenaikan SCr gt35 mgdl dan atau kenaikan BUN gt 100 mgdl (ldquoGGA beratrdquo)

Agrawal dan Swartz (2000) 2 Kenaikan SCr gt 05 mgdlhari disertai produksi urin lt 400 cchariDisebut GGA berat (rdquocomplete renal shutdown)

Ricci dkk (2006) 8

( meta-analisis) Kenaikan SCr bervariasi antara 15 ndash 10 mgdlPenurunan produksi urin bervariasi antara 0-900 cchariPenurunan LFG sebesar gt 50 disertai penurunan produksi urin berlangsung beberapa jam sampai beberapa hari

Definisi GGA berdasarkan beberapa penelitian

Keterangan Scr= Serum Creatinin BUN = Blood Urea Nitrogen LFG = Laju Filtrasi glomeruli

AKI A Common Serious Problem

bull AKI is present in 5 of all hospitalized patients and up to 50 of patients in ICUs

bull The incidence is increasing -globallybull Mortality rate 50 - 80 in dialyzed ICU

patientsndash 4 Million die each year of AKIbull AKI requiring dialysis is one of the most

important independent predictors of death in ICU patients

bull 25 of ICU dialysis survivors progress to ESRD within 3 years

Issues in Design of Clinical Trials in ARF

bull Heterogeneity of patient population bull Effect of co-morbidty and illness on outcomebull Large variations in clinical practicebull Lack of a standarddized definition of ARF

Metha et al J Am Soc Nephrol 2002

Diagnosis of AKI isOften Delayed

bull Elevation in serum creatinine is the current gold standard but this is problematic

bull Normal serum creatinine varies widely with age gender diet muscle mass muscle metabolism medications hydration status

bull In AKI serum creatinine can take several days to reach a new steady state

Proposed Diagnostic Criteria for AKI

USIA(tahun)

LAKI-LAKI (kulit hitam)

(mgdL)

LAKI-LAKI (kulit putih)

(mgdL)

WANITA (kulit hitam)

(mgdL)

WANITA (kulit putih)

(mgdL)

20-24 15 13 12 10

25-29 15 12 11 10

30-39 14 12 11 09

40-54 13 11 10 08

55-65 13 11 10 08

gt65 12 10 09 08

Perkiraan kadar kreatinin serum berdasarkan kelompok usia dan ras

Kadar Awal

05 10 15 20 25 30

Risk 075 15 225 30 375 -

Injury 10 20 30 - - -

Failure 15 30 40 40 40 40

Peningkatan kadar serum kreatinin ( mgdl) disesuaikan dengan kriteria RIFLE

Kriteria RIFLE

Berat badan pasien (kg)

40 50 60 70

RIFLE - R UO= lt120 cc(dalam 6 jam)

UO= lt150 cc(dalam 6 jam)

UO= lt180 cc(dalam 6 jam)

UO= lt210 cc(dalam 6 jam)

RIFLE - I UO = lt240 cc(dalam 12 jam)

UO = lt300 cc(dalam 12 jam)

UO = lt360 cc(dalam 12 jam)

UO = lt420 cc(dalam 12 jam)

RIFLE - F UO = lt 288 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 360 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 432 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 504 cc(dalam 24 jam)ANURI(dalam 12 jam)

Kriteria RIFLE berdasarkan urin output (UO) dan berat badan penderita

Roesli R 2007

KepustakaanKelompok

PasienJumlah

Pasien (n)Mortalitas

HR

Mortalitas(6 bulan)

Kebutuhandialisis

Abosaif dkk 15 ICU n = 183R= 33I = 31F= 23

R= 383I = 500 F = 745

R= 433I = 536 F = 860

R= 283I = 500 F = 580

Hoste dkk 16 ICU n = 5383R= 12I = 27F= 28

R= 88I = 114 F = 269

R = 10I = 14 (10-19)F= 27(2 ndash 36)

Kuitunen dkk 18 OperasiJantung

n = 813 R= 80 I = 214 F = 324

R= 11 I = 71 F = 55

Uchino dkk 19 Rumahsakit

n = 20126R= 91 I = 52F= 37

R= 151 I = 292 F= 411

R =25 (21-29)I = 54 (46-64)F=101(8 ndash 12)

Prediksi prognosis dan kematian berdasarkan kriteria RIFLE

HR = hazard ratio R= risk I = Injury F = failure

EPIDEMIOLOGY

Natural History of AKI

ETIOLOGY or COMMON CAUSES OF AKI

AKI Common Causes

bull Ischemia (60) cardiovascular disease cardiac surgery abdominal surgery shock sepsis

bull Nephrotoxins(30) antibiotics contrast chemotherapy anti-rejection NSAIDs

These causes also frequently lead to sub-clinical renal injurya

vastly underestimated problem

Etiology of AKI

COMMON CAUSESETIOLOGY OF AKI

PATHOPHYSIOLOGY

Pathophysiology of AKICurrent Knowledge from Experimental

models

1048710 AKI can result from different triggers 1048710 Kidney response to injury is time dependent and

occurs immediately following injury 1048710 Response can be characterized by measurement

of various markers reflecting activation of different mechanisms and pathways

1048710 Based on the appearance of various markers it is possible to identify the site of injury the nature of the response and describe the stage of the disease

Pathophysiology of AKI

bull Functional alterations lead to injury Failure of autoregulation

bull Injury precedes functional change Direct Nephrotoxicity Ischemia Reperfusion Inflammation

bull Injury and functional change are concurrent Complete vascular occlusion

Etiology of AKI

PATHOPHYSIOLOGY of PRERENAL AKI

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

The need for Defining ARF

bull Acute renal occurs in 5-20 of critically ill patients with a mortality of 28-90

bull Conclusion - We have no idea what ARF is

bull At least 30 definitions of ARF are in use

Penelitian Definisi

de Medonca dkk (2000)4 Tepel dkk (2000) 6

Peningkatan SCr sebesar 05 mgdl dalam waktu 48 jam

Brivet dkk (1996) 10 Kenaikan SCr gt 20 mgdl = (ldquoGGArdquo)Kenaikan SCr gt35 mgdl dan atau kenaikan BUN gt 100 mgdl (ldquoGGA beratrdquo)

Agrawal dan Swartz (2000) 2 Kenaikan SCr gt 05 mgdlhari disertai produksi urin lt 400 cchariDisebut GGA berat (rdquocomplete renal shutdown)

Ricci dkk (2006) 8

( meta-analisis) Kenaikan SCr bervariasi antara 15 ndash 10 mgdlPenurunan produksi urin bervariasi antara 0-900 cchariPenurunan LFG sebesar gt 50 disertai penurunan produksi urin berlangsung beberapa jam sampai beberapa hari

Definisi GGA berdasarkan beberapa penelitian

Keterangan Scr= Serum Creatinin BUN = Blood Urea Nitrogen LFG = Laju Filtrasi glomeruli

AKI A Common Serious Problem

bull AKI is present in 5 of all hospitalized patients and up to 50 of patients in ICUs

bull The incidence is increasing -globallybull Mortality rate 50 - 80 in dialyzed ICU

patientsndash 4 Million die each year of AKIbull AKI requiring dialysis is one of the most

important independent predictors of death in ICU patients

bull 25 of ICU dialysis survivors progress to ESRD within 3 years

Issues in Design of Clinical Trials in ARF

bull Heterogeneity of patient population bull Effect of co-morbidty and illness on outcomebull Large variations in clinical practicebull Lack of a standarddized definition of ARF

Metha et al J Am Soc Nephrol 2002

Diagnosis of AKI isOften Delayed

bull Elevation in serum creatinine is the current gold standard but this is problematic

bull Normal serum creatinine varies widely with age gender diet muscle mass muscle metabolism medications hydration status

bull In AKI serum creatinine can take several days to reach a new steady state

Proposed Diagnostic Criteria for AKI

USIA(tahun)

LAKI-LAKI (kulit hitam)

(mgdL)

LAKI-LAKI (kulit putih)

(mgdL)

WANITA (kulit hitam)

(mgdL)

WANITA (kulit putih)

(mgdL)

20-24 15 13 12 10

25-29 15 12 11 10

30-39 14 12 11 09

40-54 13 11 10 08

55-65 13 11 10 08

gt65 12 10 09 08

Perkiraan kadar kreatinin serum berdasarkan kelompok usia dan ras

Kadar Awal

05 10 15 20 25 30

Risk 075 15 225 30 375 -

Injury 10 20 30 - - -

Failure 15 30 40 40 40 40

Peningkatan kadar serum kreatinin ( mgdl) disesuaikan dengan kriteria RIFLE

Kriteria RIFLE

Berat badan pasien (kg)

40 50 60 70

RIFLE - R UO= lt120 cc(dalam 6 jam)

UO= lt150 cc(dalam 6 jam)

UO= lt180 cc(dalam 6 jam)

UO= lt210 cc(dalam 6 jam)

RIFLE - I UO = lt240 cc(dalam 12 jam)

UO = lt300 cc(dalam 12 jam)

UO = lt360 cc(dalam 12 jam)

UO = lt420 cc(dalam 12 jam)

RIFLE - F UO = lt 288 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 360 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 432 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 504 cc(dalam 24 jam)ANURI(dalam 12 jam)

Kriteria RIFLE berdasarkan urin output (UO) dan berat badan penderita

Roesli R 2007

KepustakaanKelompok

PasienJumlah

Pasien (n)Mortalitas

HR

Mortalitas(6 bulan)

Kebutuhandialisis

Abosaif dkk 15 ICU n = 183R= 33I = 31F= 23

R= 383I = 500 F = 745

R= 433I = 536 F = 860

R= 283I = 500 F = 580

Hoste dkk 16 ICU n = 5383R= 12I = 27F= 28

R= 88I = 114 F = 269

R = 10I = 14 (10-19)F= 27(2 ndash 36)

Kuitunen dkk 18 OperasiJantung

n = 813 R= 80 I = 214 F = 324

R= 11 I = 71 F = 55

Uchino dkk 19 Rumahsakit

n = 20126R= 91 I = 52F= 37

R= 151 I = 292 F= 411

R =25 (21-29)I = 54 (46-64)F=101(8 ndash 12)

Prediksi prognosis dan kematian berdasarkan kriteria RIFLE

HR = hazard ratio R= risk I = Injury F = failure

EPIDEMIOLOGY

Natural History of AKI

ETIOLOGY or COMMON CAUSES OF AKI

AKI Common Causes

bull Ischemia (60) cardiovascular disease cardiac surgery abdominal surgery shock sepsis

bull Nephrotoxins(30) antibiotics contrast chemotherapy anti-rejection NSAIDs

These causes also frequently lead to sub-clinical renal injurya

vastly underestimated problem

Etiology of AKI

COMMON CAUSESETIOLOGY OF AKI

PATHOPHYSIOLOGY

Pathophysiology of AKICurrent Knowledge from Experimental

models

1048710 AKI can result from different triggers 1048710 Kidney response to injury is time dependent and

occurs immediately following injury 1048710 Response can be characterized by measurement

of various markers reflecting activation of different mechanisms and pathways

1048710 Based on the appearance of various markers it is possible to identify the site of injury the nature of the response and describe the stage of the disease

Pathophysiology of AKI

bull Functional alterations lead to injury Failure of autoregulation

bull Injury precedes functional change Direct Nephrotoxicity Ischemia Reperfusion Inflammation

bull Injury and functional change are concurrent Complete vascular occlusion

Etiology of AKI

PATHOPHYSIOLOGY of PRERENAL AKI

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Penelitian Definisi

de Medonca dkk (2000)4 Tepel dkk (2000) 6

Peningkatan SCr sebesar 05 mgdl dalam waktu 48 jam

Brivet dkk (1996) 10 Kenaikan SCr gt 20 mgdl = (ldquoGGArdquo)Kenaikan SCr gt35 mgdl dan atau kenaikan BUN gt 100 mgdl (ldquoGGA beratrdquo)

Agrawal dan Swartz (2000) 2 Kenaikan SCr gt 05 mgdlhari disertai produksi urin lt 400 cchariDisebut GGA berat (rdquocomplete renal shutdown)

Ricci dkk (2006) 8

( meta-analisis) Kenaikan SCr bervariasi antara 15 ndash 10 mgdlPenurunan produksi urin bervariasi antara 0-900 cchariPenurunan LFG sebesar gt 50 disertai penurunan produksi urin berlangsung beberapa jam sampai beberapa hari

Definisi GGA berdasarkan beberapa penelitian

Keterangan Scr= Serum Creatinin BUN = Blood Urea Nitrogen LFG = Laju Filtrasi glomeruli

AKI A Common Serious Problem

bull AKI is present in 5 of all hospitalized patients and up to 50 of patients in ICUs

bull The incidence is increasing -globallybull Mortality rate 50 - 80 in dialyzed ICU

patientsndash 4 Million die each year of AKIbull AKI requiring dialysis is one of the most

important independent predictors of death in ICU patients

bull 25 of ICU dialysis survivors progress to ESRD within 3 years

Issues in Design of Clinical Trials in ARF

bull Heterogeneity of patient population bull Effect of co-morbidty and illness on outcomebull Large variations in clinical practicebull Lack of a standarddized definition of ARF

Metha et al J Am Soc Nephrol 2002

Diagnosis of AKI isOften Delayed

bull Elevation in serum creatinine is the current gold standard but this is problematic

bull Normal serum creatinine varies widely with age gender diet muscle mass muscle metabolism medications hydration status

bull In AKI serum creatinine can take several days to reach a new steady state

Proposed Diagnostic Criteria for AKI

USIA(tahun)

LAKI-LAKI (kulit hitam)

(mgdL)

LAKI-LAKI (kulit putih)

(mgdL)

WANITA (kulit hitam)

(mgdL)

WANITA (kulit putih)

(mgdL)

20-24 15 13 12 10

25-29 15 12 11 10

30-39 14 12 11 09

40-54 13 11 10 08

55-65 13 11 10 08

gt65 12 10 09 08

Perkiraan kadar kreatinin serum berdasarkan kelompok usia dan ras

Kadar Awal

05 10 15 20 25 30

Risk 075 15 225 30 375 -

Injury 10 20 30 - - -

Failure 15 30 40 40 40 40

Peningkatan kadar serum kreatinin ( mgdl) disesuaikan dengan kriteria RIFLE

Kriteria RIFLE

Berat badan pasien (kg)

40 50 60 70

RIFLE - R UO= lt120 cc(dalam 6 jam)

UO= lt150 cc(dalam 6 jam)

UO= lt180 cc(dalam 6 jam)

UO= lt210 cc(dalam 6 jam)

RIFLE - I UO = lt240 cc(dalam 12 jam)

UO = lt300 cc(dalam 12 jam)

UO = lt360 cc(dalam 12 jam)

UO = lt420 cc(dalam 12 jam)

RIFLE - F UO = lt 288 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 360 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 432 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 504 cc(dalam 24 jam)ANURI(dalam 12 jam)

Kriteria RIFLE berdasarkan urin output (UO) dan berat badan penderita

Roesli R 2007

KepustakaanKelompok

PasienJumlah

Pasien (n)Mortalitas

HR

Mortalitas(6 bulan)

Kebutuhandialisis

Abosaif dkk 15 ICU n = 183R= 33I = 31F= 23

R= 383I = 500 F = 745

R= 433I = 536 F = 860

R= 283I = 500 F = 580

Hoste dkk 16 ICU n = 5383R= 12I = 27F= 28

R= 88I = 114 F = 269

R = 10I = 14 (10-19)F= 27(2 ndash 36)

Kuitunen dkk 18 OperasiJantung

n = 813 R= 80 I = 214 F = 324

R= 11 I = 71 F = 55

Uchino dkk 19 Rumahsakit

n = 20126R= 91 I = 52F= 37

R= 151 I = 292 F= 411

R =25 (21-29)I = 54 (46-64)F=101(8 ndash 12)

Prediksi prognosis dan kematian berdasarkan kriteria RIFLE

HR = hazard ratio R= risk I = Injury F = failure

EPIDEMIOLOGY

Natural History of AKI

ETIOLOGY or COMMON CAUSES OF AKI

AKI Common Causes

bull Ischemia (60) cardiovascular disease cardiac surgery abdominal surgery shock sepsis

bull Nephrotoxins(30) antibiotics contrast chemotherapy anti-rejection NSAIDs

These causes also frequently lead to sub-clinical renal injurya

vastly underestimated problem

Etiology of AKI

COMMON CAUSESETIOLOGY OF AKI

PATHOPHYSIOLOGY

Pathophysiology of AKICurrent Knowledge from Experimental

models

1048710 AKI can result from different triggers 1048710 Kidney response to injury is time dependent and

occurs immediately following injury 1048710 Response can be characterized by measurement

of various markers reflecting activation of different mechanisms and pathways

1048710 Based on the appearance of various markers it is possible to identify the site of injury the nature of the response and describe the stage of the disease

Pathophysiology of AKI

bull Functional alterations lead to injury Failure of autoregulation

bull Injury precedes functional change Direct Nephrotoxicity Ischemia Reperfusion Inflammation

bull Injury and functional change are concurrent Complete vascular occlusion

Etiology of AKI

PATHOPHYSIOLOGY of PRERENAL AKI

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

AKI A Common Serious Problem

bull AKI is present in 5 of all hospitalized patients and up to 50 of patients in ICUs

bull The incidence is increasing -globallybull Mortality rate 50 - 80 in dialyzed ICU

patientsndash 4 Million die each year of AKIbull AKI requiring dialysis is one of the most

important independent predictors of death in ICU patients

bull 25 of ICU dialysis survivors progress to ESRD within 3 years

Issues in Design of Clinical Trials in ARF

bull Heterogeneity of patient population bull Effect of co-morbidty and illness on outcomebull Large variations in clinical practicebull Lack of a standarddized definition of ARF

Metha et al J Am Soc Nephrol 2002

Diagnosis of AKI isOften Delayed

bull Elevation in serum creatinine is the current gold standard but this is problematic

bull Normal serum creatinine varies widely with age gender diet muscle mass muscle metabolism medications hydration status

bull In AKI serum creatinine can take several days to reach a new steady state

Proposed Diagnostic Criteria for AKI

USIA(tahun)

LAKI-LAKI (kulit hitam)

(mgdL)

LAKI-LAKI (kulit putih)

(mgdL)

WANITA (kulit hitam)

(mgdL)

WANITA (kulit putih)

(mgdL)

20-24 15 13 12 10

25-29 15 12 11 10

30-39 14 12 11 09

40-54 13 11 10 08

55-65 13 11 10 08

gt65 12 10 09 08

Perkiraan kadar kreatinin serum berdasarkan kelompok usia dan ras

Kadar Awal

05 10 15 20 25 30

Risk 075 15 225 30 375 -

Injury 10 20 30 - - -

Failure 15 30 40 40 40 40

Peningkatan kadar serum kreatinin ( mgdl) disesuaikan dengan kriteria RIFLE

Kriteria RIFLE

Berat badan pasien (kg)

40 50 60 70

RIFLE - R UO= lt120 cc(dalam 6 jam)

UO= lt150 cc(dalam 6 jam)

UO= lt180 cc(dalam 6 jam)

UO= lt210 cc(dalam 6 jam)

RIFLE - I UO = lt240 cc(dalam 12 jam)

UO = lt300 cc(dalam 12 jam)

UO = lt360 cc(dalam 12 jam)

UO = lt420 cc(dalam 12 jam)

RIFLE - F UO = lt 288 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 360 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 432 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 504 cc(dalam 24 jam)ANURI(dalam 12 jam)

Kriteria RIFLE berdasarkan urin output (UO) dan berat badan penderita

Roesli R 2007

KepustakaanKelompok

PasienJumlah

Pasien (n)Mortalitas

HR

Mortalitas(6 bulan)

Kebutuhandialisis

Abosaif dkk 15 ICU n = 183R= 33I = 31F= 23

R= 383I = 500 F = 745

R= 433I = 536 F = 860

R= 283I = 500 F = 580

Hoste dkk 16 ICU n = 5383R= 12I = 27F= 28

R= 88I = 114 F = 269

R = 10I = 14 (10-19)F= 27(2 ndash 36)

Kuitunen dkk 18 OperasiJantung

n = 813 R= 80 I = 214 F = 324

R= 11 I = 71 F = 55

Uchino dkk 19 Rumahsakit

n = 20126R= 91 I = 52F= 37

R= 151 I = 292 F= 411

R =25 (21-29)I = 54 (46-64)F=101(8 ndash 12)

Prediksi prognosis dan kematian berdasarkan kriteria RIFLE

HR = hazard ratio R= risk I = Injury F = failure

EPIDEMIOLOGY

Natural History of AKI

ETIOLOGY or COMMON CAUSES OF AKI

AKI Common Causes

bull Ischemia (60) cardiovascular disease cardiac surgery abdominal surgery shock sepsis

bull Nephrotoxins(30) antibiotics contrast chemotherapy anti-rejection NSAIDs

These causes also frequently lead to sub-clinical renal injurya

vastly underestimated problem

Etiology of AKI

COMMON CAUSESETIOLOGY OF AKI

PATHOPHYSIOLOGY

Pathophysiology of AKICurrent Knowledge from Experimental

models

1048710 AKI can result from different triggers 1048710 Kidney response to injury is time dependent and

occurs immediately following injury 1048710 Response can be characterized by measurement

of various markers reflecting activation of different mechanisms and pathways

1048710 Based on the appearance of various markers it is possible to identify the site of injury the nature of the response and describe the stage of the disease

Pathophysiology of AKI

bull Functional alterations lead to injury Failure of autoregulation

bull Injury precedes functional change Direct Nephrotoxicity Ischemia Reperfusion Inflammation

bull Injury and functional change are concurrent Complete vascular occlusion

Etiology of AKI

PATHOPHYSIOLOGY of PRERENAL AKI

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Issues in Design of Clinical Trials in ARF

bull Heterogeneity of patient population bull Effect of co-morbidty and illness on outcomebull Large variations in clinical practicebull Lack of a standarddized definition of ARF

Metha et al J Am Soc Nephrol 2002

Diagnosis of AKI isOften Delayed

bull Elevation in serum creatinine is the current gold standard but this is problematic

bull Normal serum creatinine varies widely with age gender diet muscle mass muscle metabolism medications hydration status

bull In AKI serum creatinine can take several days to reach a new steady state

Proposed Diagnostic Criteria for AKI

USIA(tahun)

LAKI-LAKI (kulit hitam)

(mgdL)

LAKI-LAKI (kulit putih)

(mgdL)

WANITA (kulit hitam)

(mgdL)

WANITA (kulit putih)

(mgdL)

20-24 15 13 12 10

25-29 15 12 11 10

30-39 14 12 11 09

40-54 13 11 10 08

55-65 13 11 10 08

gt65 12 10 09 08

Perkiraan kadar kreatinin serum berdasarkan kelompok usia dan ras

Kadar Awal

05 10 15 20 25 30

Risk 075 15 225 30 375 -

Injury 10 20 30 - - -

Failure 15 30 40 40 40 40

Peningkatan kadar serum kreatinin ( mgdl) disesuaikan dengan kriteria RIFLE

Kriteria RIFLE

Berat badan pasien (kg)

40 50 60 70

RIFLE - R UO= lt120 cc(dalam 6 jam)

UO= lt150 cc(dalam 6 jam)

UO= lt180 cc(dalam 6 jam)

UO= lt210 cc(dalam 6 jam)

RIFLE - I UO = lt240 cc(dalam 12 jam)

UO = lt300 cc(dalam 12 jam)

UO = lt360 cc(dalam 12 jam)

UO = lt420 cc(dalam 12 jam)

RIFLE - F UO = lt 288 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 360 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 432 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 504 cc(dalam 24 jam)ANURI(dalam 12 jam)

Kriteria RIFLE berdasarkan urin output (UO) dan berat badan penderita

Roesli R 2007

KepustakaanKelompok

PasienJumlah

Pasien (n)Mortalitas

HR

Mortalitas(6 bulan)

Kebutuhandialisis

Abosaif dkk 15 ICU n = 183R= 33I = 31F= 23

R= 383I = 500 F = 745

R= 433I = 536 F = 860

R= 283I = 500 F = 580

Hoste dkk 16 ICU n = 5383R= 12I = 27F= 28

R= 88I = 114 F = 269

R = 10I = 14 (10-19)F= 27(2 ndash 36)

Kuitunen dkk 18 OperasiJantung

n = 813 R= 80 I = 214 F = 324

R= 11 I = 71 F = 55

Uchino dkk 19 Rumahsakit

n = 20126R= 91 I = 52F= 37

R= 151 I = 292 F= 411

R =25 (21-29)I = 54 (46-64)F=101(8 ndash 12)

Prediksi prognosis dan kematian berdasarkan kriteria RIFLE

HR = hazard ratio R= risk I = Injury F = failure

EPIDEMIOLOGY

Natural History of AKI

ETIOLOGY or COMMON CAUSES OF AKI

AKI Common Causes

bull Ischemia (60) cardiovascular disease cardiac surgery abdominal surgery shock sepsis

bull Nephrotoxins(30) antibiotics contrast chemotherapy anti-rejection NSAIDs

These causes also frequently lead to sub-clinical renal injurya

vastly underestimated problem

Etiology of AKI

COMMON CAUSESETIOLOGY OF AKI

PATHOPHYSIOLOGY

Pathophysiology of AKICurrent Knowledge from Experimental

models

1048710 AKI can result from different triggers 1048710 Kidney response to injury is time dependent and

occurs immediately following injury 1048710 Response can be characterized by measurement

of various markers reflecting activation of different mechanisms and pathways

1048710 Based on the appearance of various markers it is possible to identify the site of injury the nature of the response and describe the stage of the disease

Pathophysiology of AKI

bull Functional alterations lead to injury Failure of autoregulation

bull Injury precedes functional change Direct Nephrotoxicity Ischemia Reperfusion Inflammation

bull Injury and functional change are concurrent Complete vascular occlusion

Etiology of AKI

PATHOPHYSIOLOGY of PRERENAL AKI

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Diagnosis of AKI isOften Delayed

bull Elevation in serum creatinine is the current gold standard but this is problematic

bull Normal serum creatinine varies widely with age gender diet muscle mass muscle metabolism medications hydration status

bull In AKI serum creatinine can take several days to reach a new steady state

Proposed Diagnostic Criteria for AKI

USIA(tahun)

LAKI-LAKI (kulit hitam)

(mgdL)

LAKI-LAKI (kulit putih)

(mgdL)

WANITA (kulit hitam)

(mgdL)

WANITA (kulit putih)

(mgdL)

20-24 15 13 12 10

25-29 15 12 11 10

30-39 14 12 11 09

40-54 13 11 10 08

55-65 13 11 10 08

gt65 12 10 09 08

Perkiraan kadar kreatinin serum berdasarkan kelompok usia dan ras

Kadar Awal

05 10 15 20 25 30

Risk 075 15 225 30 375 -

Injury 10 20 30 - - -

Failure 15 30 40 40 40 40

Peningkatan kadar serum kreatinin ( mgdl) disesuaikan dengan kriteria RIFLE

Kriteria RIFLE

Berat badan pasien (kg)

40 50 60 70

RIFLE - R UO= lt120 cc(dalam 6 jam)

UO= lt150 cc(dalam 6 jam)

UO= lt180 cc(dalam 6 jam)

UO= lt210 cc(dalam 6 jam)

RIFLE - I UO = lt240 cc(dalam 12 jam)

UO = lt300 cc(dalam 12 jam)

UO = lt360 cc(dalam 12 jam)

UO = lt420 cc(dalam 12 jam)

RIFLE - F UO = lt 288 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 360 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 432 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 504 cc(dalam 24 jam)ANURI(dalam 12 jam)

Kriteria RIFLE berdasarkan urin output (UO) dan berat badan penderita

Roesli R 2007

KepustakaanKelompok

PasienJumlah

Pasien (n)Mortalitas

HR

Mortalitas(6 bulan)

Kebutuhandialisis

Abosaif dkk 15 ICU n = 183R= 33I = 31F= 23

R= 383I = 500 F = 745

R= 433I = 536 F = 860

R= 283I = 500 F = 580

Hoste dkk 16 ICU n = 5383R= 12I = 27F= 28

R= 88I = 114 F = 269

R = 10I = 14 (10-19)F= 27(2 ndash 36)

Kuitunen dkk 18 OperasiJantung

n = 813 R= 80 I = 214 F = 324

R= 11 I = 71 F = 55

Uchino dkk 19 Rumahsakit

n = 20126R= 91 I = 52F= 37

R= 151 I = 292 F= 411

R =25 (21-29)I = 54 (46-64)F=101(8 ndash 12)

Prediksi prognosis dan kematian berdasarkan kriteria RIFLE

HR = hazard ratio R= risk I = Injury F = failure

EPIDEMIOLOGY

Natural History of AKI

ETIOLOGY or COMMON CAUSES OF AKI

AKI Common Causes

bull Ischemia (60) cardiovascular disease cardiac surgery abdominal surgery shock sepsis

bull Nephrotoxins(30) antibiotics contrast chemotherapy anti-rejection NSAIDs

These causes also frequently lead to sub-clinical renal injurya

vastly underestimated problem

Etiology of AKI

COMMON CAUSESETIOLOGY OF AKI

PATHOPHYSIOLOGY

Pathophysiology of AKICurrent Knowledge from Experimental

models

1048710 AKI can result from different triggers 1048710 Kidney response to injury is time dependent and

occurs immediately following injury 1048710 Response can be characterized by measurement

of various markers reflecting activation of different mechanisms and pathways

1048710 Based on the appearance of various markers it is possible to identify the site of injury the nature of the response and describe the stage of the disease

Pathophysiology of AKI

bull Functional alterations lead to injury Failure of autoregulation

bull Injury precedes functional change Direct Nephrotoxicity Ischemia Reperfusion Inflammation

bull Injury and functional change are concurrent Complete vascular occlusion

Etiology of AKI

PATHOPHYSIOLOGY of PRERENAL AKI

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Proposed Diagnostic Criteria for AKI

USIA(tahun)

LAKI-LAKI (kulit hitam)

(mgdL)

LAKI-LAKI (kulit putih)

(mgdL)

WANITA (kulit hitam)

(mgdL)

WANITA (kulit putih)

(mgdL)

20-24 15 13 12 10

25-29 15 12 11 10

30-39 14 12 11 09

40-54 13 11 10 08

55-65 13 11 10 08

gt65 12 10 09 08

Perkiraan kadar kreatinin serum berdasarkan kelompok usia dan ras

Kadar Awal

05 10 15 20 25 30

Risk 075 15 225 30 375 -

Injury 10 20 30 - - -

Failure 15 30 40 40 40 40

Peningkatan kadar serum kreatinin ( mgdl) disesuaikan dengan kriteria RIFLE

Kriteria RIFLE

Berat badan pasien (kg)

40 50 60 70

RIFLE - R UO= lt120 cc(dalam 6 jam)

UO= lt150 cc(dalam 6 jam)

UO= lt180 cc(dalam 6 jam)

UO= lt210 cc(dalam 6 jam)

RIFLE - I UO = lt240 cc(dalam 12 jam)

UO = lt300 cc(dalam 12 jam)

UO = lt360 cc(dalam 12 jam)

UO = lt420 cc(dalam 12 jam)

RIFLE - F UO = lt 288 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 360 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 432 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 504 cc(dalam 24 jam)ANURI(dalam 12 jam)

Kriteria RIFLE berdasarkan urin output (UO) dan berat badan penderita

Roesli R 2007

KepustakaanKelompok

PasienJumlah

Pasien (n)Mortalitas

HR

Mortalitas(6 bulan)

Kebutuhandialisis

Abosaif dkk 15 ICU n = 183R= 33I = 31F= 23

R= 383I = 500 F = 745

R= 433I = 536 F = 860

R= 283I = 500 F = 580

Hoste dkk 16 ICU n = 5383R= 12I = 27F= 28

R= 88I = 114 F = 269

R = 10I = 14 (10-19)F= 27(2 ndash 36)

Kuitunen dkk 18 OperasiJantung

n = 813 R= 80 I = 214 F = 324

R= 11 I = 71 F = 55

Uchino dkk 19 Rumahsakit

n = 20126R= 91 I = 52F= 37

R= 151 I = 292 F= 411

R =25 (21-29)I = 54 (46-64)F=101(8 ndash 12)

Prediksi prognosis dan kematian berdasarkan kriteria RIFLE

HR = hazard ratio R= risk I = Injury F = failure

EPIDEMIOLOGY

Natural History of AKI

ETIOLOGY or COMMON CAUSES OF AKI

AKI Common Causes

bull Ischemia (60) cardiovascular disease cardiac surgery abdominal surgery shock sepsis

bull Nephrotoxins(30) antibiotics contrast chemotherapy anti-rejection NSAIDs

These causes also frequently lead to sub-clinical renal injurya

vastly underestimated problem

Etiology of AKI

COMMON CAUSESETIOLOGY OF AKI

PATHOPHYSIOLOGY

Pathophysiology of AKICurrent Knowledge from Experimental

models

1048710 AKI can result from different triggers 1048710 Kidney response to injury is time dependent and

occurs immediately following injury 1048710 Response can be characterized by measurement

of various markers reflecting activation of different mechanisms and pathways

1048710 Based on the appearance of various markers it is possible to identify the site of injury the nature of the response and describe the stage of the disease

Pathophysiology of AKI

bull Functional alterations lead to injury Failure of autoregulation

bull Injury precedes functional change Direct Nephrotoxicity Ischemia Reperfusion Inflammation

bull Injury and functional change are concurrent Complete vascular occlusion

Etiology of AKI

PATHOPHYSIOLOGY of PRERENAL AKI

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

USIA(tahun)

LAKI-LAKI (kulit hitam)

(mgdL)

LAKI-LAKI (kulit putih)

(mgdL)

WANITA (kulit hitam)

(mgdL)

WANITA (kulit putih)

(mgdL)

20-24 15 13 12 10

25-29 15 12 11 10

30-39 14 12 11 09

40-54 13 11 10 08

55-65 13 11 10 08

gt65 12 10 09 08

Perkiraan kadar kreatinin serum berdasarkan kelompok usia dan ras

Kadar Awal

05 10 15 20 25 30

Risk 075 15 225 30 375 -

Injury 10 20 30 - - -

Failure 15 30 40 40 40 40

Peningkatan kadar serum kreatinin ( mgdl) disesuaikan dengan kriteria RIFLE

Kriteria RIFLE

Berat badan pasien (kg)

40 50 60 70

RIFLE - R UO= lt120 cc(dalam 6 jam)

UO= lt150 cc(dalam 6 jam)

UO= lt180 cc(dalam 6 jam)

UO= lt210 cc(dalam 6 jam)

RIFLE - I UO = lt240 cc(dalam 12 jam)

UO = lt300 cc(dalam 12 jam)

UO = lt360 cc(dalam 12 jam)

UO = lt420 cc(dalam 12 jam)

RIFLE - F UO = lt 288 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 360 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 432 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 504 cc(dalam 24 jam)ANURI(dalam 12 jam)

Kriteria RIFLE berdasarkan urin output (UO) dan berat badan penderita

Roesli R 2007

KepustakaanKelompok

PasienJumlah

Pasien (n)Mortalitas

HR

Mortalitas(6 bulan)

Kebutuhandialisis

Abosaif dkk 15 ICU n = 183R= 33I = 31F= 23

R= 383I = 500 F = 745

R= 433I = 536 F = 860

R= 283I = 500 F = 580

Hoste dkk 16 ICU n = 5383R= 12I = 27F= 28

R= 88I = 114 F = 269

R = 10I = 14 (10-19)F= 27(2 ndash 36)

Kuitunen dkk 18 OperasiJantung

n = 813 R= 80 I = 214 F = 324

R= 11 I = 71 F = 55

Uchino dkk 19 Rumahsakit

n = 20126R= 91 I = 52F= 37

R= 151 I = 292 F= 411

R =25 (21-29)I = 54 (46-64)F=101(8 ndash 12)

Prediksi prognosis dan kematian berdasarkan kriteria RIFLE

HR = hazard ratio R= risk I = Injury F = failure

EPIDEMIOLOGY

Natural History of AKI

ETIOLOGY or COMMON CAUSES OF AKI

AKI Common Causes

bull Ischemia (60) cardiovascular disease cardiac surgery abdominal surgery shock sepsis

bull Nephrotoxins(30) antibiotics contrast chemotherapy anti-rejection NSAIDs

These causes also frequently lead to sub-clinical renal injurya

vastly underestimated problem

Etiology of AKI

COMMON CAUSESETIOLOGY OF AKI

PATHOPHYSIOLOGY

Pathophysiology of AKICurrent Knowledge from Experimental

models

1048710 AKI can result from different triggers 1048710 Kidney response to injury is time dependent and

occurs immediately following injury 1048710 Response can be characterized by measurement

of various markers reflecting activation of different mechanisms and pathways

1048710 Based on the appearance of various markers it is possible to identify the site of injury the nature of the response and describe the stage of the disease

Pathophysiology of AKI

bull Functional alterations lead to injury Failure of autoregulation

bull Injury precedes functional change Direct Nephrotoxicity Ischemia Reperfusion Inflammation

bull Injury and functional change are concurrent Complete vascular occlusion

Etiology of AKI

PATHOPHYSIOLOGY of PRERENAL AKI

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Kadar Awal

05 10 15 20 25 30

Risk 075 15 225 30 375 -

Injury 10 20 30 - - -

Failure 15 30 40 40 40 40

Peningkatan kadar serum kreatinin ( mgdl) disesuaikan dengan kriteria RIFLE

Kriteria RIFLE

Berat badan pasien (kg)

40 50 60 70

RIFLE - R UO= lt120 cc(dalam 6 jam)

UO= lt150 cc(dalam 6 jam)

UO= lt180 cc(dalam 6 jam)

UO= lt210 cc(dalam 6 jam)

RIFLE - I UO = lt240 cc(dalam 12 jam)

UO = lt300 cc(dalam 12 jam)

UO = lt360 cc(dalam 12 jam)

UO = lt420 cc(dalam 12 jam)

RIFLE - F UO = lt 288 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 360 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 432 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 504 cc(dalam 24 jam)ANURI(dalam 12 jam)

Kriteria RIFLE berdasarkan urin output (UO) dan berat badan penderita

Roesli R 2007

KepustakaanKelompok

PasienJumlah

Pasien (n)Mortalitas

HR

Mortalitas(6 bulan)

Kebutuhandialisis

Abosaif dkk 15 ICU n = 183R= 33I = 31F= 23

R= 383I = 500 F = 745

R= 433I = 536 F = 860

R= 283I = 500 F = 580

Hoste dkk 16 ICU n = 5383R= 12I = 27F= 28

R= 88I = 114 F = 269

R = 10I = 14 (10-19)F= 27(2 ndash 36)

Kuitunen dkk 18 OperasiJantung

n = 813 R= 80 I = 214 F = 324

R= 11 I = 71 F = 55

Uchino dkk 19 Rumahsakit

n = 20126R= 91 I = 52F= 37

R= 151 I = 292 F= 411

R =25 (21-29)I = 54 (46-64)F=101(8 ndash 12)

Prediksi prognosis dan kematian berdasarkan kriteria RIFLE

HR = hazard ratio R= risk I = Injury F = failure

EPIDEMIOLOGY

Natural History of AKI

ETIOLOGY or COMMON CAUSES OF AKI

AKI Common Causes

bull Ischemia (60) cardiovascular disease cardiac surgery abdominal surgery shock sepsis

bull Nephrotoxins(30) antibiotics contrast chemotherapy anti-rejection NSAIDs

These causes also frequently lead to sub-clinical renal injurya

vastly underestimated problem

Etiology of AKI

COMMON CAUSESETIOLOGY OF AKI

PATHOPHYSIOLOGY

Pathophysiology of AKICurrent Knowledge from Experimental

models

1048710 AKI can result from different triggers 1048710 Kidney response to injury is time dependent and

occurs immediately following injury 1048710 Response can be characterized by measurement

of various markers reflecting activation of different mechanisms and pathways

1048710 Based on the appearance of various markers it is possible to identify the site of injury the nature of the response and describe the stage of the disease

Pathophysiology of AKI

bull Functional alterations lead to injury Failure of autoregulation

bull Injury precedes functional change Direct Nephrotoxicity Ischemia Reperfusion Inflammation

bull Injury and functional change are concurrent Complete vascular occlusion

Etiology of AKI

PATHOPHYSIOLOGY of PRERENAL AKI

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Kriteria RIFLE

Berat badan pasien (kg)

40 50 60 70

RIFLE - R UO= lt120 cc(dalam 6 jam)

UO= lt150 cc(dalam 6 jam)

UO= lt180 cc(dalam 6 jam)

UO= lt210 cc(dalam 6 jam)

RIFLE - I UO = lt240 cc(dalam 12 jam)

UO = lt300 cc(dalam 12 jam)

UO = lt360 cc(dalam 12 jam)

UO = lt420 cc(dalam 12 jam)

RIFLE - F UO = lt 288 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 360 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 432 cc(dalam 24 jam)ANURI(dalam 12 jam)

UO = lt 504 cc(dalam 24 jam)ANURI(dalam 12 jam)

Kriteria RIFLE berdasarkan urin output (UO) dan berat badan penderita

Roesli R 2007

KepustakaanKelompok

PasienJumlah

Pasien (n)Mortalitas

HR

Mortalitas(6 bulan)

Kebutuhandialisis

Abosaif dkk 15 ICU n = 183R= 33I = 31F= 23

R= 383I = 500 F = 745

R= 433I = 536 F = 860

R= 283I = 500 F = 580

Hoste dkk 16 ICU n = 5383R= 12I = 27F= 28

R= 88I = 114 F = 269

R = 10I = 14 (10-19)F= 27(2 ndash 36)

Kuitunen dkk 18 OperasiJantung

n = 813 R= 80 I = 214 F = 324

R= 11 I = 71 F = 55

Uchino dkk 19 Rumahsakit

n = 20126R= 91 I = 52F= 37

R= 151 I = 292 F= 411

R =25 (21-29)I = 54 (46-64)F=101(8 ndash 12)

Prediksi prognosis dan kematian berdasarkan kriteria RIFLE

HR = hazard ratio R= risk I = Injury F = failure

EPIDEMIOLOGY

Natural History of AKI

ETIOLOGY or COMMON CAUSES OF AKI

AKI Common Causes

bull Ischemia (60) cardiovascular disease cardiac surgery abdominal surgery shock sepsis

bull Nephrotoxins(30) antibiotics contrast chemotherapy anti-rejection NSAIDs

These causes also frequently lead to sub-clinical renal injurya

vastly underestimated problem

Etiology of AKI

COMMON CAUSESETIOLOGY OF AKI

PATHOPHYSIOLOGY

Pathophysiology of AKICurrent Knowledge from Experimental

models

1048710 AKI can result from different triggers 1048710 Kidney response to injury is time dependent and

occurs immediately following injury 1048710 Response can be characterized by measurement

of various markers reflecting activation of different mechanisms and pathways

1048710 Based on the appearance of various markers it is possible to identify the site of injury the nature of the response and describe the stage of the disease

Pathophysiology of AKI

bull Functional alterations lead to injury Failure of autoregulation

bull Injury precedes functional change Direct Nephrotoxicity Ischemia Reperfusion Inflammation

bull Injury and functional change are concurrent Complete vascular occlusion

Etiology of AKI

PATHOPHYSIOLOGY of PRERENAL AKI

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

KepustakaanKelompok

PasienJumlah

Pasien (n)Mortalitas

HR

Mortalitas(6 bulan)

Kebutuhandialisis

Abosaif dkk 15 ICU n = 183R= 33I = 31F= 23

R= 383I = 500 F = 745

R= 433I = 536 F = 860

R= 283I = 500 F = 580

Hoste dkk 16 ICU n = 5383R= 12I = 27F= 28

R= 88I = 114 F = 269

R = 10I = 14 (10-19)F= 27(2 ndash 36)

Kuitunen dkk 18 OperasiJantung

n = 813 R= 80 I = 214 F = 324

R= 11 I = 71 F = 55

Uchino dkk 19 Rumahsakit

n = 20126R= 91 I = 52F= 37

R= 151 I = 292 F= 411

R =25 (21-29)I = 54 (46-64)F=101(8 ndash 12)

Prediksi prognosis dan kematian berdasarkan kriteria RIFLE

HR = hazard ratio R= risk I = Injury F = failure

EPIDEMIOLOGY

Natural History of AKI

ETIOLOGY or COMMON CAUSES OF AKI

AKI Common Causes

bull Ischemia (60) cardiovascular disease cardiac surgery abdominal surgery shock sepsis

bull Nephrotoxins(30) antibiotics contrast chemotherapy anti-rejection NSAIDs

These causes also frequently lead to sub-clinical renal injurya

vastly underestimated problem

Etiology of AKI

COMMON CAUSESETIOLOGY OF AKI

PATHOPHYSIOLOGY

Pathophysiology of AKICurrent Knowledge from Experimental

models

1048710 AKI can result from different triggers 1048710 Kidney response to injury is time dependent and

occurs immediately following injury 1048710 Response can be characterized by measurement

of various markers reflecting activation of different mechanisms and pathways

1048710 Based on the appearance of various markers it is possible to identify the site of injury the nature of the response and describe the stage of the disease

Pathophysiology of AKI

bull Functional alterations lead to injury Failure of autoregulation

bull Injury precedes functional change Direct Nephrotoxicity Ischemia Reperfusion Inflammation

bull Injury and functional change are concurrent Complete vascular occlusion

Etiology of AKI

PATHOPHYSIOLOGY of PRERENAL AKI

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

EPIDEMIOLOGY

Natural History of AKI

ETIOLOGY or COMMON CAUSES OF AKI

AKI Common Causes

bull Ischemia (60) cardiovascular disease cardiac surgery abdominal surgery shock sepsis

bull Nephrotoxins(30) antibiotics contrast chemotherapy anti-rejection NSAIDs

These causes also frequently lead to sub-clinical renal injurya

vastly underestimated problem

Etiology of AKI

COMMON CAUSESETIOLOGY OF AKI

PATHOPHYSIOLOGY

Pathophysiology of AKICurrent Knowledge from Experimental

models

1048710 AKI can result from different triggers 1048710 Kidney response to injury is time dependent and

occurs immediately following injury 1048710 Response can be characterized by measurement

of various markers reflecting activation of different mechanisms and pathways

1048710 Based on the appearance of various markers it is possible to identify the site of injury the nature of the response and describe the stage of the disease

Pathophysiology of AKI

bull Functional alterations lead to injury Failure of autoregulation

bull Injury precedes functional change Direct Nephrotoxicity Ischemia Reperfusion Inflammation

bull Injury and functional change are concurrent Complete vascular occlusion

Etiology of AKI

PATHOPHYSIOLOGY of PRERENAL AKI

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Natural History of AKI

ETIOLOGY or COMMON CAUSES OF AKI

AKI Common Causes

bull Ischemia (60) cardiovascular disease cardiac surgery abdominal surgery shock sepsis

bull Nephrotoxins(30) antibiotics contrast chemotherapy anti-rejection NSAIDs

These causes also frequently lead to sub-clinical renal injurya

vastly underestimated problem

Etiology of AKI

COMMON CAUSESETIOLOGY OF AKI

PATHOPHYSIOLOGY

Pathophysiology of AKICurrent Knowledge from Experimental

models

1048710 AKI can result from different triggers 1048710 Kidney response to injury is time dependent and

occurs immediately following injury 1048710 Response can be characterized by measurement

of various markers reflecting activation of different mechanisms and pathways

1048710 Based on the appearance of various markers it is possible to identify the site of injury the nature of the response and describe the stage of the disease

Pathophysiology of AKI

bull Functional alterations lead to injury Failure of autoregulation

bull Injury precedes functional change Direct Nephrotoxicity Ischemia Reperfusion Inflammation

bull Injury and functional change are concurrent Complete vascular occlusion

Etiology of AKI

PATHOPHYSIOLOGY of PRERENAL AKI

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

ETIOLOGY or COMMON CAUSES OF AKI

AKI Common Causes

bull Ischemia (60) cardiovascular disease cardiac surgery abdominal surgery shock sepsis

bull Nephrotoxins(30) antibiotics contrast chemotherapy anti-rejection NSAIDs

These causes also frequently lead to sub-clinical renal injurya

vastly underestimated problem

Etiology of AKI

COMMON CAUSESETIOLOGY OF AKI

PATHOPHYSIOLOGY

Pathophysiology of AKICurrent Knowledge from Experimental

models

1048710 AKI can result from different triggers 1048710 Kidney response to injury is time dependent and

occurs immediately following injury 1048710 Response can be characterized by measurement

of various markers reflecting activation of different mechanisms and pathways

1048710 Based on the appearance of various markers it is possible to identify the site of injury the nature of the response and describe the stage of the disease

Pathophysiology of AKI

bull Functional alterations lead to injury Failure of autoregulation

bull Injury precedes functional change Direct Nephrotoxicity Ischemia Reperfusion Inflammation

bull Injury and functional change are concurrent Complete vascular occlusion

Etiology of AKI

PATHOPHYSIOLOGY of PRERENAL AKI

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

AKI Common Causes

bull Ischemia (60) cardiovascular disease cardiac surgery abdominal surgery shock sepsis

bull Nephrotoxins(30) antibiotics contrast chemotherapy anti-rejection NSAIDs

These causes also frequently lead to sub-clinical renal injurya

vastly underestimated problem

Etiology of AKI

COMMON CAUSESETIOLOGY OF AKI

PATHOPHYSIOLOGY

Pathophysiology of AKICurrent Knowledge from Experimental

models

1048710 AKI can result from different triggers 1048710 Kidney response to injury is time dependent and

occurs immediately following injury 1048710 Response can be characterized by measurement

of various markers reflecting activation of different mechanisms and pathways

1048710 Based on the appearance of various markers it is possible to identify the site of injury the nature of the response and describe the stage of the disease

Pathophysiology of AKI

bull Functional alterations lead to injury Failure of autoregulation

bull Injury precedes functional change Direct Nephrotoxicity Ischemia Reperfusion Inflammation

bull Injury and functional change are concurrent Complete vascular occlusion

Etiology of AKI

PATHOPHYSIOLOGY of PRERENAL AKI

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Etiology of AKI

COMMON CAUSESETIOLOGY OF AKI

PATHOPHYSIOLOGY

Pathophysiology of AKICurrent Knowledge from Experimental

models

1048710 AKI can result from different triggers 1048710 Kidney response to injury is time dependent and

occurs immediately following injury 1048710 Response can be characterized by measurement

of various markers reflecting activation of different mechanisms and pathways

1048710 Based on the appearance of various markers it is possible to identify the site of injury the nature of the response and describe the stage of the disease

Pathophysiology of AKI

bull Functional alterations lead to injury Failure of autoregulation

bull Injury precedes functional change Direct Nephrotoxicity Ischemia Reperfusion Inflammation

bull Injury and functional change are concurrent Complete vascular occlusion

Etiology of AKI

PATHOPHYSIOLOGY of PRERENAL AKI

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

COMMON CAUSESETIOLOGY OF AKI

PATHOPHYSIOLOGY

Pathophysiology of AKICurrent Knowledge from Experimental

models

1048710 AKI can result from different triggers 1048710 Kidney response to injury is time dependent and

occurs immediately following injury 1048710 Response can be characterized by measurement

of various markers reflecting activation of different mechanisms and pathways

1048710 Based on the appearance of various markers it is possible to identify the site of injury the nature of the response and describe the stage of the disease

Pathophysiology of AKI

bull Functional alterations lead to injury Failure of autoregulation

bull Injury precedes functional change Direct Nephrotoxicity Ischemia Reperfusion Inflammation

bull Injury and functional change are concurrent Complete vascular occlusion

Etiology of AKI

PATHOPHYSIOLOGY of PRERENAL AKI

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

PATHOPHYSIOLOGY

Pathophysiology of AKICurrent Knowledge from Experimental

models

1048710 AKI can result from different triggers 1048710 Kidney response to injury is time dependent and

occurs immediately following injury 1048710 Response can be characterized by measurement

of various markers reflecting activation of different mechanisms and pathways

1048710 Based on the appearance of various markers it is possible to identify the site of injury the nature of the response and describe the stage of the disease

Pathophysiology of AKI

bull Functional alterations lead to injury Failure of autoregulation

bull Injury precedes functional change Direct Nephrotoxicity Ischemia Reperfusion Inflammation

bull Injury and functional change are concurrent Complete vascular occlusion

Etiology of AKI

PATHOPHYSIOLOGY of PRERENAL AKI

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Pathophysiology of AKICurrent Knowledge from Experimental

models

1048710 AKI can result from different triggers 1048710 Kidney response to injury is time dependent and

occurs immediately following injury 1048710 Response can be characterized by measurement

of various markers reflecting activation of different mechanisms and pathways

1048710 Based on the appearance of various markers it is possible to identify the site of injury the nature of the response and describe the stage of the disease

Pathophysiology of AKI

bull Functional alterations lead to injury Failure of autoregulation

bull Injury precedes functional change Direct Nephrotoxicity Ischemia Reperfusion Inflammation

bull Injury and functional change are concurrent Complete vascular occlusion

Etiology of AKI

PATHOPHYSIOLOGY of PRERENAL AKI

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Pathophysiology of AKI

bull Functional alterations lead to injury Failure of autoregulation

bull Injury precedes functional change Direct Nephrotoxicity Ischemia Reperfusion Inflammation

bull Injury and functional change are concurrent Complete vascular occlusion

Etiology of AKI

PATHOPHYSIOLOGY of PRERENAL AKI

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Etiology of AKI

PATHOPHYSIOLOGY of PRERENAL AKI

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

PATHOPHYSIOLOGY of PRERENAL AKI

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

PATHOPHYSILOGY AKI

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Intrarenal mechanisms for autoregulation of GFR

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Intrarenal mechanisms for autoregulation of GFR

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1 ISCHEMIC-ATN (ISCHEMIC REPERFUSION)2 AKI RELATED SEPSIS3 NEPHROTOXIC-ATN

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Pathophysiology of AKIIschemic Injury sets in motion a rapid sequence of events

involving various compensatory and reparative mechanisms that are time dependent

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Phases of Acute Kidney Injury

InjuryFigure 1 Phases of ischemic acute renal failure A B and C refer to therapies aimed at preventing (A) limiting the extension phase (B) and treating established ARF (C) Reprinted with permission from Molitoris BA J Am Soc Nephrol 14265-267 2003

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

AKI PathophysiologyEvaluation of sequential changes in blood urine and tissue

samples following an injury permit the labeling of the stage of the disease

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Pathophysiology of AKI

Abuelo NEJM 2007

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

The Journal of Clinical Investigation Volume 114 Number 1 July 2004

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

PATHOPHYSIOLOGY of AKI RELATED SEPSIS

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased

and can be identified and measured

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

MAP HR

CO TPC

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

RBF

CREAT

RVC

UO

CC

FNAE

FF

FEX UREA NITROGEN

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Crit Care Med 2008 Vol 36 No 4 (Suppl)

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Biomarkers for Early Prediction of Acute Kidney

Injury

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

AKI Urgent Need forEarly Diagnosis

bull Early forms of AKI are often reversiblebull Early diagnosis may enable timely therapybull Animal and human studies have revealed

a narrow window of opportunitybull The paucity of early biomarkers has

impaired our ability to institute timely therapy in humans

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

BiomarkersFrom Bench To Bedside

bull Discovery phasebull Identification of candidate biomarkers using

basic science technologiesbull Translational phase

bull Development of robust assays for the candidate

biomarkers and testing in limited clinical studies

bull Validation phasebull Testing the assays in large clinical trials

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Potential Roles of Biomarkers in AKI

EarlyDetection

DifferentialDiagnosis

Prognosis

Difined Timing amp Single Insultbull CPBbull Contrastbull DGFbull Traumabull Chemotherapy

bull Location (proximal vs distal tubule)

bull Etiology (toxin ischemia sepsis)

bull ATN vs Pre-renal

bull Acute vs Chronic

Severity of AKI

Need for RRT

Duration of AKI

Response toTreatment

Length of stay

MortalityUnderfined Timing ampMultiple Insultsbull Sepsisbull ARDSbull Critical Illness

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

Current Clinical Scenario

KidneyInsult

AcuteKidneyInjury MORTALITY

FailedIntervention

NormalCreatinine

ElevatedCreatinine

SEPSIS

CPB

TRAUMA

CONTRAST

ARDS

TOXINS

WITH Early Biomarkers

KidneyInsult

AcuteKidneyInjury

MORTALITY

Opportunityfor Early

Intervention

EarlyDetection

EarlyDetection

a b

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

350

300

250

200

150

100

50

0

50

100

150

200

250

300

350

0 2 4 6 12 24 48

Urin

e IL

-18

pgm

g

Urin

e N

GA

L pg

mg

SCr rise

Combination of Biomarkers in AKI

AKI (20)

Control (35)

AKI (20)

Hour post CPB

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Potential Biomarkers in AKI(Human Data)

EarlyDetection

DifferentialDiagnosis

Prognosis

IL ndash 18ATN vs other (13)

IL ndash 18Mortality in ARDS (3)Duration of AKI (1)

Cystatin CNeed for RRT (16)

NGALDuration of AKI (1)

KIM ndash 1ATN vs other (14)

Na+ H+

ExchangerATN vs other (15)

Cystatin CICU (9) (+)ICU (10) (-)

IL ndash 18CPB (1)DSF (2)ARDS (3)

NGALCPB (45)PCI (6)DSF (7)D+HUS (8)

TubularEnzymes

ICU (11)

KIM - 1DSF (12)

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Translational PhaseNGAL Analysis in CPB

bull Hypothesis NGAL levels can predict human AKIbull Model of AKI cardiopulmonary bypass (CPB)bull Study design Prospective enrollment of

patients undergoing CPB at a single pediatric center

bull Sampling Plasma and urine at baseline and at frequent intervals for 5 days post-CPB

bull Analysis NGAL by ELISAbull Primary outcome AKI (50 increase in serum

creatinine) ndashusually occurs 24-72 hr later

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Translational PhasePlasma NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Ser

um

NG

AL

(g

L)

Time after cardiopulmonary bypas (h)

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Translational PhaseUrine NGAL Analysis in CPB

Mishra et al Lancet 3651231-1238 2005

Time after cardiopulmunary bypass (h)

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

Urin

e N

GA

L (

gL)

Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

An Aside The Cardiac Panel

A similar panel for AKI will dramatically improve our ability todiagnose predict prevent and treat acute renal failure

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

The Emerging PlasmaAKI Panel

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

The Emerging PlasmaAKI Panel NGAL vs Cystatin C

NGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al JASN 17404A 2006

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

The Emerging UrineAKI Panel

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Take Home Messages

bull AKI is a common and serious problembull The diagnosis of AKI is frequently delayedbull Preventive and therapeutic measures are

often delayed due to lack of early biomarkersbull Novel technologies are providing emerging

biomarkers to identify nephrotoxic and ischemic AKI early to potentially improve the drug development process and to minimize drug attrition due to safety concerns

  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97
  • Acute Kidney Injury (AKI)
  • Slide 2
  • OBJECTIVES
  • Slide 4
  • Slide 5
  • The need for Defining ARF
  • Slide 7
  • Slide 8
  • AKI A Common Serious Problem
  • Slide 10
  • Issues in Design of Clinical Trials in ARF
  • Diagnosis of AKI is Often Delayed
  • Slide 13
  • Slide 14
  • Proposed Diagnostic Criteria for AKI
  • Slide 16
  • Slide 17
  • Slide 18
  • Slide 19
  • Slide 20
  • Slide 21
  • Slide 22
  • Slide 23
  • Slide 24
  • Slide 25
  • Slide 26
  • Slide 27
  • EPIDEMIOLOGY
  • Slide 29
  • Slide 30
  • Slide 31
  • Slide 32
  • Slide 33
  • Natural History of AKI
  • Slide 35
  • Slide 36
  • AKI Common Causes
  • Etiology of AKI
  • COMMON CAUSESETIOLOGY OF AKI
  • PATHOPHYSIOLOGY
  • Pathophysiology of AKI Current Knowledge from Experimental models
  • Slide 42
  • Slide 43
  • Pathophysiology of AKI
  • Slide 45
  • Slide 46
  • PATHOPHYSILOGY AKI
  • Intrarenal mechanisms for autoregulation of GFR
  • Slide 49
  • Slide 50
  • Slide 51
  • Pathophysiology of AKI Ischemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent
  • Slide 53
  • Phases of Acute Kidney Injury
  • AKI Pathophysiology Evaluation of sequential changes in blood urine and tissue samples following an injury permit the labeling of the stage of the disease
  • Slide 56
  • Slide 57
  • Pathophysiology of AKI
  • Slide 59
  • Slide 60
  • AKI Pathophysiology As the injuryrepair process progresses several markers are expressedreleased and can be identified and measured
  • Slide 62
  • Slide 63
  • Slide 64
  • Slide 65
  • Slide 66
  • Slide 67
  • Slide 68
  • Slide 69
  • Slide 70
  • Slide 71
  • Slide 72
  • Slide 73
  • Slide 74
  • Biomarkers for Early Prediction of Acute Kidney Injury
  • AKI Urgent Need for Early Diagnosis
  • Slide 77
  • Biomarkers From Bench To Bedside
  • Slide 79
  • Slide 80
  • Slide 81
  • Slide 82
  • Translational Phase NGAL Analysis in CPB
  • Slide 84
  • Translational Phase Plasma NGAL Analysis in CPB
  • Translational Phase Urine NGAL Analysis in CPB
  • An Aside The Cardiac Panel
  • The Emerging Plasma AKI Panel
  • The Emerging Plasma AKI Panel NGAL vs Cystatin C
  • The Emerging Urine AKI Panel
  • Slide 91
  • Slide 92
  • Slide 93
  • Slide 94
  • Slide 95
  • Take Home Messages
  • Slide 97

Recommended

ACUTE KIDNEY INJURY · Acute kidney injury (AKI) Can resolve in 6 weeks if the kidneys are going to recover Acute Kidney Injury (AKI) NCEPOD NCEPOD (National Confidential Enquiry
Documents
Acute Renal Failure aka Acute Kidney Injury. Definition of Acute Kidney Injury (AKI) based on “Acute Kidney Injury Network” StageIncrease in Serum Creatinine
Documents
Acute Kidney Injury - WordPress.com · differenal diagnosis of Acute Kidney Injury (AKI). • Discuss signs and symptoms of AKI, including pre‐renal, intrinsic and post‐renal
Documents
QI initiative: Acute Kidney Injury (AKI) Care in Acute Oncology
Healthcare
AKI-6 Epidemiology of Acute Kidney Injury · AKI-6 Epidemiology of Transient Acute Kidney Injury 2. Introduction Acute Kidney Injury (AKI) is a common condition in critical ill patients
Documents
An Introduction to Acute Kidney Injury (AKI) - Home - · PDF file · 2015-10-07An Introduction to Acute Kidney Injury (AKI) ... •An AKI case study •Monitoring and assessing AKI
Documents
National Acute Kidney Injury (AKI) Programme. National AKI Programme - Richard Fluck.pdf · National Acute Kidney Injury (AKI) Programme . 01/07/2014 2 ... Don’t press the start
Documents
Acute Kidney Injury (AKI) Clinical Audit Tools 2011
Health & Medicine
Acute kidney injury (aki)
Health & Medicine
ACUTE KIDNEY INJURY AKI laboratory investigation
Health & Medicine
Acute Kidney Injury 6-8-13 - Mahidol University€¦ · Acute Kidney Injury AKI Acute Renal Failure ARF. Conceptual model of AKI. Outlines • Diagnosis of AKI • GFR measurement
Documents
Pharmacotherapy II Second Semester 2014 Acute Kidney Injury (AKI)
Documents
Acute Kidney Injury(AKI) and Hypotension in Total Elective
Documents
Acute Renal Failure Acute Kidney Injury (AKI)
Documents
Acute Kidney Injury (AKI) › drugsatfda_docs › ... · 5.2 Acute Kidney Injury (AKI) In patients with chronically reduced renal function, acute kidney injury requiring dialysis
Documents
Acute Kidney Injury (AKI) Biomarker - inaactamedica.orginaactamedica.org/archives/2012/22983082.pdf · Acute Kidney Injury (AKI) Biomarker Sri S ... disorder or signs of renal damage
Documents
Acute Kidney Injury (AKI) (a.k.a. Acute Renal Failure)
Documents
Acute Kidney Injury (AKI) - congresshome.com · 2018-06-15 · Acute kidney injury (AKI) represents a significant challenge in clinical practice. AKI is avoidable but when it develops,
Documents
Acute kidney Injury(AKI)
Documents
Acute Kidney Injury (AKI) Alerts for Primary Care
Documents