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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


Acute kidney injury aki

“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


Acute kidney injury aki

DEFINITION and CLASIFICATION AKI


Acute kidney injury 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


Acute kidney injury aki

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


Proposed diagnostic criteria for aki

Proposed Diagnostic Criteria for AKI


Acute kidney injury aki

Perkiraan kadar kreatinin serum berdasarkan kelompok usia dan ras


Acute kidney injury aki

Peningkatan kadar serum kreatinin ( mg/dl) disesuaikan dengankriteria RIFLE


Acute kidney injury aki

Kriteria RIFLE berdasarkan urin output (UO) dan berat badan penderita

Roesli R. 2007


Acute kidney injury aki

Prediksi prognosis dan kematian berdasarkan kriteria RIFLE

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


Epidemiology

EPIDEMIOLOGY


Natural history of aki

Natural History of AKI


Acute kidney injury aki

ETIOLOGY or COMMON CAUSES OF AKI


Aki common causes

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

Etiology of AKI


Common causes etiology of aki

COMMON CAUSES/ETIOLOGY OF AKI


Pathophysiology

PATHOPHYSIOLOGY


Pathophysiology of aki current knowledge from experimental models

Pathophysiology of AKICurrent 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

  • 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


Acute kidney injury aki

PATHOPHYSIOLOGY of PRERENAL AKI


Pathophysilogy aki

PATHOPHYSILOGY AKI


Intrarenal mechanisms for autoregulation of gfr

Intrarenal mechanisms for autoregulation of GFR


Acute kidney injury aki

Intrarenal mechanisms for autoregulation of GFR


Intrarenal mechanisms for autoregulation of gfr1

Intrarenal mechanisms for autoregulation of GFR


Acute kidney injury aki

PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS)

1. ISCHEMIC-ATN (ISCHEMIC REPERFUSION)

2. AKI RELATED SEPSIS

3. NEPHROTOXIC-ATN


Acute kidney injury aki

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

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


Acute kidney injury aki

AKI PathophysiologyEvaluation of sequential changes in blood, urine and tissue samples following an injury permit the labeling of the stage of the disease.


Acute kidney injury aki

The Journal of Clinical Investigation Volume 114 Number 1 July 2004


Pathophysiology of aki1

Pathophysiology of AKI

Abuelo NEJM 2007


Acute kidney injury aki

The Journal of Clinical Investigation Volume 114 Number 1 July 2004


Acute kidney injury aki

PATHOPHYSIOLOGY of AKI RELATED SEPSIS


Acute kidney injury aki

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


Acute kidney injury aki

MAP

HR

CO

TPC


Acute kidney injury aki

CC

FF%

RBF

RVC

FNAE

FEX UREA NITROGEN

CREAT

UO


Acute kidney injury aki

Crit Care Med 2008 Vol. 36, No. 4 (Suppl.)


Acute kidney injury aki

Crit Care Med 2008 Vol. 36, No. 4 (Suppl.)


Biomarkers for early prediction of acute kidney injury

Biomarkers for Early Prediction of Acute Kidney Injury


Aki urgent need for early diagnosis

AKI: Urgent Need forEarly 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: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


Acute kidney injury aki

Potential Roles of Biomarkers in AKI

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


Acute kidney injury aki

WITH 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


Acute kidney injury aki

Combination of Biomarkers in AKI

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


Acute kidney injury aki

Potential Biomarkers in AKI

(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: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: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: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

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 PlasmaAKI Panel


The emerging plasma aki panel ngal vs cystatin c

The Emerging PlasmaAKI 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 UrineAKI Panel


Take home messages

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


Acute kidney injury aki

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