Acute Kidney Injury (AKI)Rubin S Gondodiputro

AKI: A Common, Serious ProblemAKI is present in 5% of all hospitalized patients, and up to 50% of patients in ICUs The incidence is increasing -globallyMortality rate 50 - 80% in dialyzed ICU patients 4 Million die each year of AKIAKI requiring dialysis is one of the most important independent predictors of death in ICU patients25% of ICU dialysis survivors progress to ESRD within 3 years

The need for Defining ARFAcute 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

Issues in Design of Clinical Trials in ARFHeterogeneity of patient population Effect of co-morbidty and illness on outcomeLarge variations in clinical practiceLack of a standarddized definition of ARFMetha et al, J Am Soc Nephrol 2002

AKI: Common CausesIschemia (60%): cardiovascular disease, cardiac surgery, abdominal surgery, shock, sepsis Nephrotoxins(30%): antibiotics, contrast, chemotherapy, anti-rejection, NSAIDsThese causes also frequently lead to sub-clinical renal injury,a vastly underestimated problem

Diagnosis of AKI isOften DelayedElevation 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 statusIn AKI, serum creatinine can take several days to reach a new steady state

Definisi GGA berdasarkan beberapa penelitianKeterangan : Scr= Serum Creatinin. BUN = Blood Urea Nitrogen. LFG = Laju Filtrasi glomeruli

PenelitianDefiniside Medonca dkk (2000)4 , Tepel dkk (2000) 6 Peningkatan SCr sebesar 0,5 mg/dl dalam waktu 48 jamBrivet dkk (1996) 10Kenaikan 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) 2Kenaikan SCr > 0,5 mg/dl/hari disertai produksi urin < 400 cc/hariDisebut GGA berat (complete renal shutdown)Ricci dkk (2006) 8 ( meta-analisis) Kenaikan SCr bervariasi antara 1,5 10 mg/dlPenurunan produksi urin bervariasi antara 0-900 cc/hariPenurunan LFG sebesar > 50 % disertai penurunan produksi urin berlangsung beberapa jam sampai beberapa hari

Lamaire et al, The Lancet 2005, 365: 417-430

Kriteria RIFLE untuk Gangguan Ginjal Akut

KriteriaKenaikan kreatinin serum & penurunan LFGPenurunan produksi urin (Urin Output=UO)

RiskKenaikan kreatinin 1.5 kali atau penurunan LFG > 25%UO < 0.5 ml/kg/jam selama 6 jamSensitivitasTinggi

InjuryKenaikan kreatinin 2 kali atau penurunan LFG > 50%UO < 0.5 ml/kg/jamselama 12 jam

FailureKenaikan kreatinin 3 kali atau penurunan LFG > 75% / kreatinin 4 mg/dl (peningkatan akut 0.5 mg/dl) UO < 0.3 ml/kg/jam selama 24 jam atau anuria selama 12 jam

LossGGA menetap = penurunan fungsi ginjal lebih dari 4 mingguSpesifitastinggi

ESRDGagal ginjal terminal (> 3 bulan)= ESRD

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)20-241.51.31.21.025-291.51.21.11.030-391.41.21.10.940-541.31.11.00.855-651.31.11.00.8>651.21.00.90.8

Peningkatan kadar serum kreatinin ( mg/dl) disesuaikan dengan kriteria RIFLE

Kadar Awal0.51.01.52.02.53.0Risk0.751.52.253.03.75-Injury1.02.03.0---Failure1.53.04.04.04.04.0

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

Kriteria RIFLEBerat badan pasien (kg)40506070RIFLE - RUO=

Prediksi prognosis dan kematian berdasarkan kriteria RIFLEHR = hazard ratio; R= risk ; I = Injury ; F = failure

KepustakaanKelompokPasienJumlahPasien (n)Mortalitas%HRMortalitas(6 bulan)KebutuhandialisisAbosaif dkk 15ICUn = 183R= 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 16ICUn = 5383R= 12%I = 27%F= 28%R= 8.8%I = 11.4 %F = 26.9 %R = 1,0I = 1.4 (1,0-1.9)F= 2.7(2 3,6)Kuitunen dkk 18OperasiJantungn = 813R= 8.0 %I = 21,4 %F = 32,4 %R= 1.1 %I = 7.1 %F = 55 %Uchino dkk 19Rumahsakitn = 20.126R= 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)

PATHOPHYSIOLOGY

MAPHRCOTPC

RBFCREATRVCUOCCFNAEFF%FEX UREA NITROGEN

EPIDEMIOLOGY

Biomarkers for Early Prediction of Acute Kidney Injury

Take Home MessagesAKI is a common and serious problemThe diagnosis of AKI is frequently delayedPreventive and therapeutic measures are delayed due to lack of early biomarkersNovel technologies are providing emerging biomarkers for the early prediction of AKI

AKI: Urgent Need forEarly DiagnosisEarly forms of AKI are often reversibleEarly diagnosis may enable timely therapyAnimal and human studies have revealed a narrow window of opportunityThe paucity of early biomarkers has impaired our ability to institute timely therapy in humans

Biomarkers:From Bench To BedsideDiscovery phase Identification of candidate biomarkers using basic science technologiesTranslational phase Development of robust assays for the candidate biomarkers, and testing in limited clinical studiesValidation phase Testing the assays in large clinical trials

Discovery Phase:Identification of NGALNeutrophil Gelatinase-Associated LipocalinFirst identified in neutrophilsFound in low quantities in the normal kidneyMost up-regulated gene in the kidney after AKIProtein product is dramatically upregulated in the kidney, and easily detected in plasma and urine in animal models of AKISupavekin et al, Kidney Int 63:1714-24, 2003Mishra et al, JASN 14:2534-43, 2003Mishra et al, AJN 24:307-15, 2004

Translational Phase:Assay for NGALSandwich monoclonal ELISA for human NGALInter-and intra-assay coefficient variations 5%Linear relationship in the 1-1000 ng/ml rangeExcellent correlation with results obtained from Western blots

Translational Phase:NGAL Analysis in CPBHypothesis: NGAL levels can predict human AKIModel of AKI: cardiopulmonary bypass (CPB)Study design: Prospective enrollment of patients undergoing CPB at a single pediatric centerSampling: Plasma and urine at baseline and at frequent intervals for 5 days post-CPBAnalysis: NGAL by ELISAPrimary outcome: AKI (50% increase in serum creatinine) usually occurs 24-72 hr later

Translational Phase:Plasma NGAL Analysis in CPBMishra et al, Lancet 365:1231-1238, 2005Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine riseSerum NGAL (g/L)Time after cardiopulmonary bypas (h)

Translational Phase:Plasma NGAL Analysis in CPBMishraet al, Lancet 365:1231-1238, 2005 AUC = 0.91Serum NGAL at 2 h after cardiopulmonary bypass Sensitivity1-specificity

Translational Phase:Urine NGAL Analysis in CPBMishra et al, Lancet 365:1231-1238, 2005Time after cardiopulmunary bypass (h)024681224364860728496108120Urine NGAL (g/L)Acute renal failure (n=20)Without acute renal failure (n=51)Serum creatinine rise

Translational Phase:NGAL Analysis in CPBWagener et al: Anesthesiology 105: 485-491, 2006Han et al: ASN 2006Murray et al: ASN 2006, WCN 2007

Other studies demonstrating NGAL as a predictive biomarker of AKI in CPB:

An Aside: The Cardiac PanelA similar panel for AKI will dramatically improve our ability todiagnose, predict, prevent, and treat acute renal failure

The Emerging PlasmaAKI Panel: NGAL vs Cystatin CNGAL outperforms Cystatin C as a biomarker of AKI in CPBDevarajan et al, JASN 17:404A, 2006

The Emerging PlasmaAKI Panel

The Emerging UrineAKI Panel

Emerging AKI Biomarkers:Current Status * In Development

Interventions that preventAKI in animal models

Take Home MessagesAKI is a common and serious problemThe diagnosis of AKI is frequently delayedPreventive and therapeutic measures are often delayed due to lack of early biomarkersNovel 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

Response to an Early BiomarkerMonitor intensivelyMonitor fluid balance, urine outputMonitor BP, cardiac functionMonitor electrolytes, kidney function

Be Warned, Be Watchful

Response to an Early BiomarkerAvoid and treat hypotensionAvoid and treat hypovolemiaAvoid and treat oliguriaAvoid contrast agentsAvoid nephrotoxic medications

Do No Harm

Response to an Early BiomarkerReverse vasoconstriction:vasodilatorsLimit tubule cell damage: anti-oxidantsEnhance regeneration:growth factorsLimit inflammation:anti-inflammatory agents

Specific Therapies