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