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
de Medonca dkk (2000)
4
Tepel dkk (2000)
6
,
Definisi
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 25-29 30-39 40-54 55-65 >65 1.5
1.5
1.4
1.3
1.3
1.2
1.3
1.2
1.2
1.1
1.1
1.0
1.2
1.1
1.1
1.0
1.0
0.9
1.0
1.0
0.9
0.8
0.8
0.8
Peningkatan kadar serum kreatinin ( mg/dl) disesuaikan dengan kriteria RIFLE Kadar Awal Risk Injury Failure
0.5
0.75
1.0
1.5
1.0
1.5
2.0
3.0
1.5
2.25
3.0
4.0
2.0
3.0
4.0
2.5
3.75
4.0
3.0
4.0
Kriteria RIFLE berdasarkan urin output (UO) dan berat badan penderita Kriteria RIFLE RIFLE - R RIFLE - I RIFLE - F 40 UO= <120 cc
(dalam 6 jam)
UO = <240 cc
(dalam 12 jam)
UO = < 288 cc
(dalam 24 jam)
ANURI
(dalam 12 jam)
Berat badan pasien (kg) 50 60 UO= <150 cc
(dalam 6 jam)
UO= <180 cc
(dalam 6 jam)
UO = <300 cc
(dalam 12 jam)
UO = < 360 cc
(dalam 24 jam)
ANURI
(dalam 12 jam)
UO = <360 cc
(dalam 12 jam)
UO = < 432 cc
(dalam 24 jam)
ANURI
(dalam 12 jam)
70 UO= <210 cc
(dalam 6 jam)
UO = <420 cc
(dalam 12 jam)
UO = < 504 cc
(dalam 24 jam)
ANURI
(dalam 12 jam) Roesli R. 2007
Prediksi prognosis dan kematian berdasarkan kriteria
RIFLE
Kepustakaan
Abosaif dkk 15
Kelompok Pasien
ICU
Jumlah Pasien (n)
n = 183 R= 33% I = 31% F= 23%
Mortalitas %
R= 38.3% I = 50.0 % F = 74.5%
HR Mortalitas (6 bulan)
R= 43.3% I = 53.6 % F = 86.0 %
Kebutuhan dialisis
R= 28.3% I = 50.0 % F = 58.0 % Hoste dkk 16 ICU n = 5383 R= 12% I = 27% F= 28% R= 8.8% I = 11.4 % F = 26.9 % R = 1,0 I = 1.4 (1,0-1.9) F= 2.7(2 – 3,6) Kuitunen dkk 18 Operasi Jantung n = 813 R= 8.0 % I = 21,4 % F = 32,4 % R= 1.1 % I = 7.1 % F = 55 % Uchino dkk 19 Rumah sakit n = 20.126
R= 9,1 % I = 5,2% F= 3,7 % R= 15,1 % I = 29,2% F= 41.1 % HR = hazard ratio; R= risk ; I = Injury ; F = failure R =2.5 (2.1-2.9) I = 5,4 (4,6-6,4) F=10,1(8 – 12)
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
Injury
Figure 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 CC UO FF% F NA E
F EX 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
Differential Diagnosis
• Location (proximal vs distal tubule) • Etiology (toxin, ischemia, sepsis) • ATN vs Pre-renal • Acute vs Chronic
Prognosis
Severity of AKI Need for RRT Duration of AKI Response to Treatment Length of stay Mortality
SEPSIS CPB TRAUMA CONTRAST ARDS a TOXINS Current Clinical Scenario Normal Creatinine Elevated Creatinine Kidney Insult Acute Kidney Injury MORTALITY Failed Intervention SEPSIS CPB TRAUMA CONTRAST ARDS b TOXINS WITH Early Biomarkers Early Detection Kidney Insult Acute Kidney Injury MORTALITY Early Detection Opportunity for Early Intervention
350 300 250 200 150 100 50 0 0 Combination of Biomarkers in AKI
*
2 AKI (20)
* * * *
4 6
* *
AKI (20)
*
Control (35)
*
SCr rise
*
350 300 250 200 150 100 50 12 Hour post CPB 24
*
48
IL – 18 CPB (1) DSF (2) ARDS (3) Early Detection Cystatin C ICU (9) (+) ICU (10) (-) NGAL CPB (4.5) PCI (6) DSF (7) D+HUS (8) Tubular Enzymes ICU (11) KIM - 1 DSF (12) Potential Biomarkers in AKI
(Human Data)
Differential Diagnosis IL – 18 ATN vs other (13) KIM – 1 ATN vs other (14) Na + / H + Exchanger ATN vs other (15) Prognosis IL – 18 Mortality in ARDS (3) Duration of AKI (1) Cystatin C Need for RRT (16) NGAL Duration of AKI (1)
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
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
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
Time after cardiopulmunary bypass (h)
84 96 108 120
Mishra et al, Lancet 365:1231-1238, 2005
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