Transcript Pathophysiology of AKI

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
Acute Renal Failure
Acute Kidney Injury
The need for Defining ARF
• Acute renal occurs in 5-20% of critically ill
patients with a mortality of 28-90%
• Conclusion :
- We have no idea what ARF is!
• At least 30 definitions of ARF are in use
Definisi GGA berdasarkan beberapa penelitian
Penelitian
Definisi
de Medonca dkk (2000)4 ,
Tepel dkk (2000) 6
Peningkatan SCr sebesar 0,5 mg/dl dalam waktu 48 jam
Brivet dkk (1996) 10
Kenaikan SCr > 2.0 mg/dl = (“GGA”)
Kenaikan SCr >3.5 mg/dl dan /atau kenaikan BUN > 100 mg/dl
(“GGA berat”)
Agrawal dan Swartz (2000) 2 Kenaikan SCr > 0,5 mg/dl/hari disertai produksi urin < 400 cc/hari
Disebut GGA berat (”complete renal shutdown)
Ricci dkk (2006) 8
( meta-analisis)
Kenaikan SCr bervariasi antara 1,5 – 10 mg/dl
Penurunan produksi urin bervariasi antara 0-900 cc/hari
Penurunan LFG sebesar > 50 % disertai penurunan
produksi urin berlangsung beberapa jam sampai beberapa hari
Keterangan : Scr= Serum Creatinin. BUN = Blood Urea Nitrogen. LFG = Laju Filtrasi glomeruli
AKI: A Common, Serious Problem
• AKI is present in 5% of all hospitalized patients,
and up to 50% of patients in ICUs
• The incidence is increasing -globally
• Mortality rate 50 - 80% in dialyzed ICU patients–
4 Million die each year of AKI
• AKI requiring dialysis is one of the most
important independent predictors of death in
ICU patients
• 25% of ICU dialysis survivors progress to ESRD
within 3 years
Issues in Design of Clinical Trials in
ARF
•
•
•
•
Heterogeneity of patient population
Effect of co-morbidty and illness on outcome
Large variations in clinical practice
Lack of a standarddized definition of ARF
Metha et al, J Am Soc Nephrol 2002
Diagnosis of AKI is
Often Delayed
• Elevation in serum creatinine is the current gold
standard, but this is problematic
• Normal serum creatinine varies widely with age,
gender, diet, muscle mass, muscle metabolism,
medications, hydration status
• In AKI, serum creatinine can take several days
to reach a new steady state
Proposed Diagnostic Criteria for AKI
Perkiraan kadar kreatinin serum berdasarkan
kelompok usia dan ras
USIA
(tahun)
LAKI-LAKI
(kulit hitam)
(mg/dL)
LAKI-LAKI
(kulit putih)
(mg/dL)
WANITA
(kulit hitam)
(mg/dL)
WANITA
(kulit putih)
(mg/dL)
20-24
1.5
1.3
1.2
1.0
25-29
1.5
1.2
1.1
1.0
30-39
1.4
1.2
1.1
0.9
40-54
1.3
1.1
1.0
0.8
55-65
1.3
1.1
1.0
0.8
>65
1.2
1.0
0.9
0.8
Peningkatan kadar serum kreatinin ( mg/dl)
disesuaikan dengan kriteria RIFLE
Kadar
Awal
0.5
1.0
1.5
2.0
2.5
3.0
Risk
0.75
1.5
2.25
3.0
3.75
-
Injury
1.0
2.0
3.0
-
-
-
Failure
1.5
3.0
4.0
4.0
4.0
4.0
Kriteria RIFLE berdasarkan urin output (UO) dan
berat badan penderita
Kriteria
RIFLE
Berat badan pasien (kg)
40
50
60
70
RIFLE - R
UO= <120 cc
(dalam 6 jam)
UO= <150 cc
(dalam 6 jam)
UO= <180 cc
(dalam 6 jam)
UO= <210 cc
(dalam 6 jam)
RIFLE - I
UO = <240 cc
(dalam 12 jam)
UO = <300 cc
(dalam 12 jam)
UO = <360 cc
(dalam 12 jam)
UO = <420 cc
(dalam 12 jam)
RIFLE - F
UO = < 288 cc
(dalam 24 jam)
ANURI
(dalam 12 jam)
UO = < 360 cc
(dalam 24 jam)
ANURI
(dalam 12 jam)
UO = < 432 cc
(dalam 24 jam)
ANURI
(dalam 12 jam)
UO = < 504 cc
(dalam 24 jam)
ANURI
(dalam 12 jam)
Roesli R. 2007
Prediksi prognosis dan kematian berdasarkan
kriteria RIFLE
Kelompok
Pasien
Jumlah
Pasien (n)
Mortalitas
%
Abosaif dkk 15
ICU
n = 183
R= 33%
I = 31%
F= 23%
R= 38.3%
I = 50.0 %
F = 74.5%
Hoste dkk 16
ICU
n = 5383
R= 12%
I = 27%
F= 28%
R= 8.8%
R = 1,0
I = 11.4 % I = 1.4 (1,0-1.9)
F = 26.9 % F= 2.7(2 – 3,6)
Kuitunen dkk 18
Operasi
Jantung
n = 813
R= 8.0 %
I = 21,4 %
F = 32,4 %
Uchino dkk 19
Rumah
sakit
n = 20.126
R= 9,1 %
I = 5,2%
F= 3,7 %
Kepustakaan
HR
R= 15,1 % R =2.5 (2.1-2.9)
I = 29,2% I = 5,4 (4,6-6,4)
F= 41.1 % F=10,1(8 – 12)
HR = hazard ratio; R= risk ; I = Injury ; F = failure
Mortalitas
(6 bulan)
R= 43.3%
I = 53.6 %
F = 86.0 %
Kebutuhan
dialisis
R= 28.3%
I = 50.0 %
F = 58.0 %
R= 1.1 %
I = 7.1 %
F = 55 %
EPIDEMIOLOGY
Natural History of AKI
ETIOLOGY or COMMON
CAUSES OF AKI
AKI: Common Causes
• Ischemia (60%): cardiovascular disease, cardiac
surgery, abdominal surgery, shock, sepsis
• Nephrotoxins(30%): antibiotics, contrast,
chemotherapy, anti-rejection, NSAIDs
These causes also frequently lead to
sub-clinical renal injury,a vastly
underestimated problem
Etiology of AKI
COMMON CAUSES/ETIOLOGY OF AKI
PATHOPHYSIOLOGY
Pathophysiology of AKI
Current Knowledge from Experimental models
􀂆 AKI can result from different triggers
􀂆 Kidney response to injury is time dependent and occurs
immediately following injury.
􀂆 Response can be characterized by measurement of
various markers reflecting activation of different
mechanisms and pathways
􀂆 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
• Functional alterations lead to injury
 Failure of autoregulation
• Injury precedes functional change
 Direct Nephrotoxicity
 Ischemia Reperfusion
 Inflammation
• 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 SEPSIS
3. NEPHROTOXIC-ATN
Pathophysiology of AKI
Ischemic 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 14:265-267, 2003
AKI Pathophysiology
Evaluation 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 injury/repair process
progresses several markers are expressed/released and can
be identified and measured.
MAP
CO
HR
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 for
Early Diagnosis
• Early forms of AKI are often reversible
• Early diagnosis may enable timely therapy
• Animal and human studies have revealed a
narrow window of opportunity
• The paucity of early biomarkers has impaired
our ability to institute timely therapy in humans
Biomarkers:
From Bench To Bedside
• Discovery phase
• Identification of candidate biomarkers using basic
science technologies
• Translational phase
• Development of robust assays for the candidate
biomarkers, and testing in limited clinical studies
• Validation phase
• Testing the assays in large clinical trials
Potential Roles of Biomarkers in AKI
Early
Detection
Difined Timing &
Single Insult
• CPB
• Contrast
• DGF
• Trauma
• Chemotherapy
Underfined Timing &
Multiple Insults
• Sepsis
• ARDS
• Critical Illness
Prognosis
Differential
Diagnosis
Severity of AKI
• Location
(proximal vs distal tubule)
Need for RRT
• Etiology
(toxin, ischemia, sepsis)
Response to
Treatment
• ATN vs Pre-renal
Length of stay
• Acute vs Chronic
Mortality
Duration of AKI
SEPSIS
Current Clinical Scenario
SEPSIS
CPB
CPB
Normal
Creatinine
Early
Detection
Elevated
Creatinine
TRAUMA
TRAUMA
CONTRAST
WITH Early Biomarkers
Kidney
Insult
Acute
Kidney
Injury
MORTALITY
CONTRAST
Kidney
Insult
Acute
Kidney
Injury
MORTALITY
ARDS
TOXINS
a
Failed
Intervention
ARDS
TOXINS
b
Early
Detection
Opportunity
for Early
Intervention
Combination of Biomarkers in AKI
350
SCr rise
*
250
250
AKI (20)
200
AKI (20)
150
*
100
*
*
50
4
150
100
*
*
Control (35) *
0
2
*
*
*
0
200
6
12
Hour post CPB
24
50
*
48
Urine NGAL pg/mg
300
300
Urine IL-18 pg/mg
350
Potential Biomarkers in AKI
(Human Data)
Early
Detection
IL – 18
Cystatin C
CPB (1)
DSF (2)
ARDS (3)
ICU (9) (+)
ICU (10) (-)
NGAL
Tubular
Enzymes
CPB (4.5)
PCI (6)
DSF (7)
D+HUS (8)
Prognosis
Differential
Diagnosis
IL – 18
ICU (11)
ATN vs other (13)
DSF (12)
Mortality in ARDS (3)
Duration of AKI (1)
Cystatin C
Need for RRT (16)
KIM – 1
ATN vs other (14)
KIM - 1
IL – 18
NGAL
Duration of AKI (1)
Na+ / H+
Exchanger
ATN vs other (15)
Translational Phase:
NGAL Analysis in CPB
• Hypothesis: NGAL levels can predict human AKI
• Model of AKI: cardiopulmonary bypass (CPB)
• Study design: Prospective enrollment of patients
undergoing CPB at a single pediatric center
• Sampling: Plasma and urine at baseline and at
frequent intervals for 5 days post-CPB
• Analysis: NGAL by ELISA
• Primary outcome: AKI (50% increase in serum
creatinine) –usually occurs 24-72 hr later
Translational Phase:
Plasma NGAL Analysis in CPB
Serum NGAL (g/L)
Acute renal failure (n=20)
Without acute renal failure (n=51)
Serum creatinine rise
Time after cardiopulmonary bypas (h)
Mishra et al, Lancet 365:1231-1238, 2005
Translational Phase:
Urine NGAL Analysis in CPB
Urine NGAL (g/L)
Acute renal failure (n=20)
Without acute renal failure (n=51)
Serum creatinine rise
0
2
4
6
8
12
24
36
48
60
72
84
Time after cardiopulmunary bypass (h)
Mishra et al, Lancet 365:1231-1238, 2005
96
108 120
An Aside: The Cardiac Panel
A similar panel for AKI will dramatically improve our ability to
diagnose, predict, prevent, and treat acute renal failure
The Emerging Plasma
AKI Panel
The Emerging Plasma
AKI Panel: NGAL vs Cystatin C
NGAL outperforms Cystatin C as a biomarker of AKI in CPB
Devarajan et al, JASN 17:404A, 2006
The Emerging Urine
AKI Panel
Take Home Messages
• AKI is a common and serious problem
• The diagnosis of AKI is frequently delayed
• Preventive and therapeutic measures are often
delayed due to lack of early biomarkers
• 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