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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.

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Acute kidney injury aki

Acute Kidney Injury (AKI)

Rubin S Gondodiputro


“A NEW CONCEPT THAT STILL

MOVES and CHANGES”


Objectives
OBJECTIVES

DEFINITION and CLASIFICATION of AKI

EPIDEMIOLOGY of AKI

ETIOLOGY and DIAGNOSIS of AKI

PATHOPHYSIOLOGY of AKI

BIOMARKER of AKI



Definitions

Acute Renal Failure

Acute Kidney Injury


The need for defining arf
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

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


Aki a common serious problem
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
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
Diagnosis of AKI isOften 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






Prediksi prognosis dan kematian berdasarkan kriteria penderitaRIFLE

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


Epidemiology

EPIDEMIOLOGY penderita




Aki common causes
AKI: Common Causes penderita

  • 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
Etiology of AKI penderita



Pathophysiology

PATHOPHYSIOLOGY penderita


Pathophysiology of aki current knowledge from experimental models
Pathophysiology of AKI penderitaCurrent 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
Pathophysiology of AKI penderita

  • 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 aki1
Etiology of AKI penderita







PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS) penderita

1. ISCHEMIC-ATN (ISCHEMIC REPERFUSION)

2. AKI RELATED SEPSIS

3. NEPHROTOXIC-ATN


Pathophysiology of AKI penderitaIschemic Injury sets in motion a rapid sequence of events involving various compensatory and reparative mechanisms that are time dependent.


Phases of acute kidney injury
Phases of Acute Kidney Injury penderita

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 penderitaEvaluation 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 penderitaVolume 114 Number 1 July 2004


Pathophysiology of aki1
Pathophysiology of AKI penderita

Abuelo NEJM 2007


The Journal of Clinical Investigation penderitaVolume 114 Number 1 July 2004



AKI Pathophysiology As the injury/repair process progresses several markers are expressed/released and can be identified and measured.


MAP several markers are expressed/released and can be identified and measured.

HR

CO

TPC


CC several markers are expressed/released and can be identified and measured.

FF%

RBF

RVC

FNAE

FEX UREA NITROGEN

CREAT

UO


Crit Care Med 2008 Vol. 36, No. 4 (Suppl.) several markers are expressed/released and can be identified and measured.


Crit Care Med 2008 Vol. 36, No. 4 (Suppl.) several markers are expressed/released and can be identified and measured.


Biomarkers for early prediction of acute kidney injury

Biomarkers for Early Prediction of Acute Kidney Injury several markers are expressed/released and can be identified and measured.


Aki urgent need for early diagnosis
AKI: Urgent Need for several markers are expressed/released and can be identified and measured.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
Biomarkers: several markers are expressed/released and can be identified and measured.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 several markers are expressed/released and can be identified and measured.

Early

Detection

Prognosis

Differential

Diagnosis

  • Difined Timing &

  • Single Insult

  • CPB

  • Contrast

  • DGF

  • Trauma

  • Chemotherapy

Severity of AKI

Need for RRT

Duration of AKI

Response to

Treatment

Length of stay

Mortality

  • Location

  • (proximal vs distal tubule)

  • Etiology

  • (toxin, ischemia, sepsis)

  • ATN vs Pre-renal

  • Acute vs Chronic

  • Underfined Timing &

  • Multiple Insults

  • Sepsis

  • ARDS

  • Critical Illness


WITH several markers are expressed/released and can be identified and measured. Early Biomarkers

Current Clinical Scenario

SEPSIS

SEPSIS

CPB

CPB

Early

Detection

Normal

Creatinine

Elevated

Creatinine

TRAUMA

TRAUMA

Acute

Kidney

Injury

Kidney

Insult

Acute

Kidney

Injury

Kidney

Insult

CONTRAST

CONTRAST

MORTALITY

MORTALITY

ARDS

Failed

Intervention

ARDS

Opportunity

for Early

Intervention

Early

Detection

TOXINS

TOXINS

a

b


Combination of Biomarkers in AKI several markers are expressed/released and can be identified and measured.

350

300

250

200

150

100

50

SCr rise

*

AKI (20)

Urine NGAL pg/mg

*

AKI (20)

*

Urine IL-18 pg/mg

*

*

*

*

*

*

*

Control (35)

*

Hour post CPB


Potential Biomarkers in AKI several markers are expressed/released and can be identified and measured.

(Human Data)

Early

Detection

Prognosis

Differential

Diagnosis

Cystatin C

ICU (9) (+)

ICU (10) (-)

IL – 18

Mortality in ARDS (3)

Duration of AKI (1)

IL – 18

CPB (1)

DSF (2)

ARDS (3)

IL – 18

ATN vs other (13)

Cystatin C

Need for RRT (16)

Tubular

Enzymes

ICU (11)

NGAL

CPB (4.5)

PCI (6)

DSF (7)

D+HUS (8)

KIM – 1

ATN vs other (14)

NGAL

Duration of AKI (1)

KIM - 1

DSF (12)

Na+ / H+

Exchanger

ATN vs other (15)


Translational phase ngal analysis in cpb
Translational Phase: several markers are expressed/released and can be identified and measured.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
Translational Phase: several markers are expressed/released and can be identified and measured.Plasma NGAL Analysis in CPB

Acute renal failure (n=20)

Without acute renal failure (n=51)

Serum creatinine rise

Serum NGAL (g/L)

Time after cardiopulmonary bypas (h)

Mishra et al, Lancet 365:1231-1238, 2005


Translational phase urine ngal analysis in cpb
Translational Phase: several markers are expressed/released and can be identified and measured.Urine NGAL Analysis in CPB

Acute renal failure (n=20)

Without acute renal failure (n=51)

Serum creatinine rise

Urine NGAL (g/L)

0

2

8

12

24

36

48

60

72

84

96

108

120

4

6

Time after cardiopulmunary bypass (h)

Mishra et al, Lancet 365:1231-1238, 2005


An aside the cardiac panel
An Aside: The Cardiac Panel several markers are expressed/released and can be identified and measured.

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 several markers are expressed/released and can be identified and measured.AKI Panel


The emerging plasma aki panel ngal vs cystatin c
The Emerging Plasma several markers are expressed/released and can be identified and measured.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
The Emerging Urine several markers are expressed/released and can be identified and measured.AKI Panel


Take home messages
Take Home Messages several markers are expressed/released and can be identified and measured.

  • 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


Terima Kasih several markers are expressed/released and can be identified and measured.


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