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Acute Kidney Injury (AKI) Rubin S Gondodiputro. “A NEW CONCEPT THAT STILL MOVES and CHANGES”

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Presentasi berjudul: "Acute Kidney Injury (AKI) Rubin S Gondodiputro. “A NEW CONCEPT THAT STILL MOVES and CHANGES”"— Transcript presentasi:

1 Acute Kidney Injury (AKI) Rubin S Gondodiputro

2 “A NEW CONCEPT THAT STILL MOVES and CHANGES”

3 OBJECTIVES DEFINITION and CLASIFICATION of AKI EPIDEMIOLOGY of AKI ETIOLOGY and DIAGNOSIS of AKI PATHOPHYSIOLOGY of AKI BIOMARKER of AKI

4 DEFINITION and CLASIFICATION AKI

5 Definitions Acute Renal Failure Acute Kidney Injury

6 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

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8 PenelitianDefinisi 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 cc/hari Penurunan LFG sebesar > 50 % disertai penurunan produksi urin berlangsung beberapa jam sampai beberapa hari Definisi GGA berdasarkan beberapa penelitian Keterangan : Scr= Serum Creatinin. BUN = Blood Urea Nitrogen. LFG = Laju Filtrasi glomeruli

9 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 % 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

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11 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

12 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

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15 Proposed Diagnostic Criteria for AKI

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17 USIA (tahun) LAKI-LAKI (kulit hitam) (mg/dL) LAKI-LAKI (kulit putih) (mg/dL) WANITA (kulit hitam) (mg/dL) WANITA (kulit putih) (mg/dL) > Perkiraan kadar kreatinin serum berdasarkan kelompok usia dan ras

18 Kadar Awal Risk Injury Failure Peningkatan kadar serum kreatinin ( mg/dl) disesuaikan dengan kriteria RIFLE

19 Kriteria RIFLE Berat badan pasien (kg) RIFLE - RUO= <120 cc (dalam 6 jam) UO= <150 cc (dalam 6 jam) UO= <180 cc (dalam 6 jam) UO= <210 cc (dalam 6 jam) RIFLE - IUO = <240 cc (dalam 12 jam) UO = <300 cc (dalam 12 jam) UO = <360 cc (dalam 12 jam) UO = <420 cc (dalam 12 jam) RIFLE - FUO = < 288 cc (dalam 24 jam) ANURI (dalam 12 jam) UO = < 360 cc (dalam 24 jam) ANURI (dalam 12 jam) UO = < 432 cc (dalam 24 jam) ANURI (dalam 12 jam) UO = < 504 cc (dalam 24 jam) ANURI (dalam 12 jam) Kriteria RIFLE berdasarkan urin output (UO) dan berat badan penderita Roesli R. 2007

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24 Kepustakaan Kelompok Pasien Jumlah Pasien (n) Mortalitas % HR Mortalitas (6 bulan) Kebutuhan dialisis Abosaif dkk 15 ICUn = 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% I = 50.0 % F = 58.0 % Hoste dkk 16 ICUn = 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 = 813R= 8.0 % I = 21,4 % F = 32,4 % R= 1.1 % I = 7.1 % F = 55 % Uchino dkk 19 Rumah sakit n = R= 9,1 % I = 5,2% F= 3,7 % R= 15,1 % I = 29,2% F= 41.1 % R =2.5 ( ) I = 5,4 (4,6-6,4) F=10,1(8 – 12) Prediksi prognosis dan kematian berdasarkan kriteria RIFLE HR = hazard ratio; R= risk ; I = Injury ; F = failure

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28 EPIDEMIOLOGY

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34 Natural History of AKI

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36 ETIOLOGY or COMMON CAUSES OF AKI

37 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

38 Etiology of AKI

39 COMMON CAUSES/ETIOLOGY OF AKI

40 PATHOPHYSIOLOGY

41 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.

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44 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

45 Etiology of AKI

46 PATHOPHYSIOLOGY of PRERENAL AKI

47 PATHOPHYSILOGY AKI

48 Intrarenal mechanisms for autoregulation of GFR

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51 PATHOPHYSIOLOGY OF INTRINSIC AKI (ACUTE TUBULER NECROSIS) 1. ISCHEMIC-ATN (ISCHEMIC REPERFUSION) 2. AKI RELATED SEPSIS 3. NEPHROTOXIC-ATN

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

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54 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: , 2003

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

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57 The Journal of Clinical Investigation Volume 114 Number 1 July 2004

58 Pathophysiology of AKI Abuelo NEJM 2007

59 The Journal of Clinical Investigation Volume 114 Number 1 July 2004

60 PATHOPHYSIOLOGY of AKI RELATED SEPSIS

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

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71 MAPHR COTPC

72 RBF CREAT RVC UO CC F NA E FF% F EX UREA NITROGEN

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

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75 Biomarkers for Early Prediction of Acute Kidney Injury

76 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

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78 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

79 Potential Roles of Biomarkers in AKI Early Detection Differential Diagnosis Prognosis Difined Timing & Single Insult CPB Contrast DGF Trauma Chemotherapy Location (proximal vs distal tubule) Etiology (toxin, ischemia, sepsis) ATN vs Pre-renal Acute vs Chronic Severity of AKI Need for RRT Duration of AKI Response to Treatment Length of stay Mortality Underfined Timing & Multiple Insults Sepsis ARDS Critical Illness

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

81 Urine IL-18 pg/mg Urine NGAL pg/mg SCr rise Combination of Biomarkers in AKI AKI (20) Control (35) AKI (20) Hour post CPB * * * * * * * * * * *

82 Potential Biomarkers in AKI (Human Data) Early Detection Differential Diagnosis Prognosis IL – 18 ATN vs other (13) IL – 18 Mortality in ARDS (3) Duration of AKI (1) Cystatin C Need for RRT (16) NGAL Duration of AKI (1) KIM – 1 ATN vs other (14) Na + / H + Exchanger ATN vs other (15) Cystatin C ICU (9) (+) ICU (10) (-) IL – 18 CPB (1) DSF (2) ARDS (3) NGAL CPB (4.5) PCI (6) DSF (7) D+HUS (8) Tubular Enzymes ICU (11) KIM - 1 DSF (12)

83 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 hr later

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85 Translational Phase: Plasma NGAL Analysis in CPB Mishra et al, Lancet 365: , 2005 Acute renal failure (n=20) Without acute renal failure (n=51) Serum creatinine rise Serum NGAL (  g/L) Time after cardiopulmonary bypas (h)

86 Translational Phase: Urine NGAL Analysis in CPB Mishra et al, Lancet 365: , 2005 Time after cardiopulmunary bypass (h) Urine NGAL (  g/L) Acute renal failure (n=20) Without acute renal failure (n=51) Serum creatinine rise

87 An Aside: The Cardiac Panel A similar panel for AKI will dramatically improve our ability to diagnose, predict, prevent, and treat acute renal failure

88 The Emerging Plasma AKI Panel

89 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

90 The Emerging Urine AKI Panel

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96 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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