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 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 (tahun) LAKI-LAKI (kulit hitam) (mg/dL) (kulit putih) WANITA 20-24 1.5 1.3 1.2 1.0 25-29 1.1 30-39 1.4 0.9 40-54 0.8 55-65 >65

Kadar Awal Risk Injury Failure 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 2.25 3.75 - Injury Failure 4.0

Berat badan pasien (kg) 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 UO= <180 cc UO= <210 cc RIFLE - I UO = <240 cc (dalam 12 jam) UO = <300 cc UO = <360 cc UO = <420 cc RIFLE - F UO = < 288 cc (dalam 24 jam) ANURI UO = < 360 cc UO = < 432 cc UO = < 504 cc Roesli R. 2007

Prediksi prognosis dan kematian berdasarkan kriteria RIFLE Kepustakaan Kelompok Pasien Jumlah Pasien (n) Mortalitas % HR (6 bulan) Kebutuhan dialisis Abosaif dkk 15 ICU n = 183 R= 33% I = 31% F= 23% R= 38.3% I = 50.0 % F = 74.5% R= 43.3% I = 53.6 % F = 86.0 % R= 28.3% F = 58.0 % Hoste dkk 16 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 % R =2.5 (2.1-2.9) I = 5,4 (4,6-6,4) F=10,1(8 – 12) HR = hazard ratio; R= risk ; I = Injury ; F = failure

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 HR CO TPC

CC FF% RBF RVC FNAE FEX UREA NITROGEN CREAT UO

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

Early Detection Prognosis Differential Diagnosis 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

a b WITH Early Biomarkers Current Clinical Scenario Kidney Acute SEPSIS Current Clinical Scenario SEPSIS WITH Early Biomarkers CPB CPB Normal Creatinine Elevated Creatinine Early Detection TRAUMA TRAUMA Kidney Insult Acute Kidney Injury Kidney Insult Acute Kidney Injury CONTRAST CONTRAST MORTALITY MORTALITY ARDS Failed Intervention ARDS Opportunity for Early Intervention Early Detection TOXINS TOXINS a b

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

Potential Biomarkers in AKI (Human Data) Early Detection Prognosis Differential Diagnosis Cystatin C ICU (9) (+) ICU (10) (-) IL – 18 CPB (1) DSF (2) ARDS (3) IL – 18 Mortality in ARDS (3) Duration of AKI (1) IL – 18 ATN vs other (13) Cystatin C Need for RRT (16) NGAL CPB (4.5) PCI (6) DSF (7) D+HUS (8) Tubular Enzymes ICU (11) 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 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 Serum NGAL (g/L) 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 Urine NGAL (g/L) 2 4 6 8 12 24 36 48 60 72 84 96 108 120 Time after cardiopulmunary bypass (h) 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

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