Upload
grace
View
60
Download
2
Tags:
Embed Size (px)
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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