腎損傷的生物標(biāo)志物英文版課件

1、腎損傷的標(biāo)志物Biomarkers of Kidney InjuryDamageNormal EpitheliumToxic/ischemic InjuryApoptosisNecrosisCell deathDeathComplicationsNormalIncreasedriskKidneyfailureDamage GFR Kidney Injury Molecule-1 (KIM-1) Neutrophil Gelatinase Associated Lipocalin (NGAL) N-acetyl-D-glucosaminidase (NAG) Cystatin C Interle

2、ukin-18 (L-18), microalbuminuria Serum Creatinine Blood Urea NitrogenPotential biomarkers for early diagnosis of AKIAKIN Scheme, 2006 GFRDelayed biomarkers for kidney injuryFABP, 2 microglobulin, a1-microglobulin n DeathComplicationsNormalIncreasedriskKidneyfailureDamage GFRSeverity ofIllness scores

3、BiomarkersBiomarkersRIFLEAKINDialysisTimeIntervention TrialsSerumCreatinine(mg/dl)A Goal for Biomarker UsePapillaCortexMedullaUreterPelvisProximal TubulesDistal TubulessCollecting DuctLoop of HenleGlomerulusKIM-1L-FABPAlbuminClusterinLipocalin (NGAL)GST2-microglobulina1-microglobulinNAGOsteopontinCy

4、statin CNetrin-1IL-18Retinol binding protHGF, NHE-3Cyr61Exosomal Fetuin-ACreatinineCystatin CProtein, albuminPodocalyxin2-microglobulinWT-1 in exosomesosteopontinCalbindin- D28OsteopontinClusterinLipocalin (NGAL)GST-NAGEGFOsteopontinCystatin CIL-18Calbindin-D28Candidate Biomarkers for Kidney InjuryB

5、onventre et al. Nature Biotech 2010Sensitivity and Specificity of Kim-1, NAG, BUN, SCrHistopathology Grade SubsetSensitivityALL0 to 30 to 20 and 1Kim-1SCrBUNNAG1.00.6ALL0 to 30 to 20 and 1AUC from ROC1.0NAGBUNKim-1SCrVaidya et al. Nature Biotechnology, May, 2010Predictive SafetyTes

6、ting ConsortiumRat Toxicity StudiesFDA and European Medicines Agency Will Consider New Biomarker Test Results When Assessing Kidney Toxicity of Experimental Drugs/recent/2008/061708_e.htmlIn the first use of a framework allowing submission of a single application to the 2 agencies, the U.S. Food and

7、 Drug Administration (FDA) and the European Medicines Agency (EMEA) will allow drug companies to submit the results of 7 new tests that evaluate kidney toxicity,(FDA news release, 6/17/2008).The tests measure levels of 7 key biomarker proteins found in urine that can provide information about drug-i

8、nduced damage to kidney cells (renal toxicity). The new biomarkers are:KIM-1AlbuminClusterinTrefoil factor-3 Cystatin CTotal proteinBeta-2 microglobulinTubular Injury BiomarkersGlomerular changes or impaired tubular reabsorption biomarkersDieterle et al. Nature Biotech 28:455-62, 2010European InnoMe

9、d Predictive Toxicology ConsortiumROC curves for (a) biomarker gene expression and (b) urinary concentrationsHoffmann D et alToxicol. Sci. 2010;116:8-22Urine KIM-1 in Different Strains of Mice Exposed to DB287Harrill et al. Toxicological Sciences 130:416-26, 2012DB283 is the first oral effective dru

10、g for treatment of African trypanosomiasisClinical studystopped becauseof unexpectednephrotoxicitySerum BUN andcreatinine did not increasein any mousestrain.Genome wide association mapping of DB289-induced elevations in KIM-1. The network map of GWA significant genes.Harrill et al. Toxicological Sci

11、encesIn PressTubular DamageKIM-1, L-FABP, a-GST (albumin and NGAL) GFRCreat, Cystatin CKDIGO StageInflammationNGAL, IL-18 GFRCreat, Cystatin CKDIGO Stage+/- Inflammation GFRCreatinine, KDIGO StageInjury MarkerInflammation MarkerGFR Marker? Kidney Injury + +/- + + + + + + + +/- - + - +/- +- (prerenal

12、) + + - + - + - +/- - - - -Tubular DamagePotential Context of Interpretation of AKI MarkersDiagnostic performance of the first postoperative value of urine IL-18, urine NGAL, and plasma NGAL for the detection of AKI Parikh C R et al. JASN 2011;22:1748-17572011 by American Society of NephrologyUrine

13、IL-18 AUC 0.74Urine NGAL AUC 0.67Plasma NGAL AUC 0.70402060801001-Specificity020806010040SensitivityBiomarkers at 4 hr to predict AKI (AKIN) in childrenZheng et al. PedCardiol. 2013Plasma NGAL as a Predictor of AKI and Clinical OutcomesCruzRonco Intensive Care Med.36:444-451, 2010 301 ICU patients;

14、133 (44%) developed AKI during ICU stay0246810121416C1D1C1D1POSTC1D2C1D3C1D4C1D5C2D1C2D1POSTC2D2C2D3C2D4C2D5C3D1C3D1POSTC3D2C3D3C3D4C3D5C4D1C4D1POSTC4D2C4D3C4D4C4D5Cycle and DayNormalized biomarker valueKIM-1/creatNAG/creatMean Urinary KIM-1 and NAG Levels During Cisplatin TreatmentsIn Patients with

15、 Testicular CancerSCr did not changeUrinary KIM-1 Levels in Chinese Factory Workers Exposed to TrichloroethyleneVermeulen et al. Carcinogenesis 33: 1538-41, 2012OSHA:100 ppm/ 8 hr100000100001000100101KIM-1 (pg/mL)CCENCutoff for AKI vs. non-AKIPatients with or at risk of Endemic (Balkan) Nephropathyc

16、aused by Aristolochic Acid Three weekly subcut doses of a PCSK9 antisense (to lower LDL-cholesterol)oligonucleotide in 56 yr old otherwise healthy female volunteer. Recommendation“ We conclude that measurement of KIM-1 suits many purposes and is therefore an appropriate choice. It allows for early d

17、etection of proximal tubule injury, differentiation between glomerular and tubular damage and assessment of reversibility and regeneration provided this occurs. KIM-1 can be used to detect sub-chronic and chronic kidney injury.”Van Meer et al. Brit J Clin Pharm 77:947-57, 2014Example of use of KIM-1

18、 and RecommendationKIM-1Plasma KIM-1pg/mlPlasma Creatininemg/dLAbsolute Urinary KIM-1Normalized Urinary KIM-1ng/ mg uCrng/mlPlasma KIM-1 is elevated in I/R mice* P0.001Ischemia, 37 CT= 3-144 hBiomarker measurementT=30 minReperfusionBALB/C, malePlasma KIM-1Plasma CreatinineNormalized Urinary KIM-1mg/

19、dLpg/mlng/ mg uCrTime(hr)Time(hr)Time(hr)* P0.001(daBiomarker measurementSprague Dawley ratGentamicin ( 50 & 200 mg/kgdaily for 10 days)day 11(*p0.001, #p0.05)Necrosis scoremg/dLPlasma Creatininepg/mlPlasma KIM-1ng/mg uCrUrinary KIM-1050200050200Plasma KIM-1 is elevated in gentamicin induced kidney

20、injury in ratsGentamicin(mg/kg)050200Tubular necrosis*Plasma and urinary KIM-1 is not elevated in mice treated with CCl4 LiverKidneyBiomarker measurementBALB/C, male10 % CCl4 (0.5 ml/kg)T=48 hPlasma CreatinineUrine KIM-1Plasma KIM-1mg/dlpg/mg uCrpg/mlElevation of Plasma KIM-1 in patients who develop

21、ed AKI after CPBPlasma Creatininemg/dLPlasma KIM-1pg/ml*#*#*#Normalized urinary KIM-1ng/mg uCr*#*#*#Albuminuriamg/g uCr*# p0.05, significant difference from baseline* p0.05, significant difference between AKI and non-AKI group (N=9) Plasma KIM-1 is elevated in patients who had developed AKI(*p0.001,

22、 #p 2 ng/mg Ucr as gold standard)AUC-ROC = 0.55Very good biomarkerSerum CreatinineEffect of Specificity of Gold Standard on Apparent Performance of “Perfect” BiomarkerAdmission-to-discharge percentage change in GFR grouped by presence or absence of hemoconcentration. Testani J M et al. Circulation 2010;122:265-272Copyright American Heart AssociationSurvival curves gr