Talk on Kidney Transplant Fibrosis by Maarten Naesens

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Information about Talk on Kidney Transplant Fibrosis by Maarten Naesens
Health & Medicine

Published on February 27, 2014

Author: mnaesens

Source: slideshare.net

Kidney Transplant Fibrosis Prof. Dr. Maarten Naesens Leuven, 27-02-2014

Kidney Transplantation in Eurotransplant Worldwide: 69.400 KTX/year (WHO data) Eurotransplant Annual Report 2012

Kidney Transplantation in UZ Leuven

Kidney Transplantation in UZ Leuven

Kidney transplantation evolution Treatment Treatment Treatment?? Creatinine Diagnostic threshold Acute dysfunction Subclinical acute rejection Chronic dysfunction Time BX BX for cause BX BX

Tubular atrophy and interstitial fibrosis • Chronisch

Why do kidney allografts fail? Creatinine Diagnostic threshold Acute dysfunction Subclinical acute rejection Chronic dysfunction Time BX BX for cause BX

Clinical vs. subclinical pathology Creatinine Treatment Diagnostic threshold Acute dysfunction Subclinical acute rejection Chronic dysfunction Acute pathology BX BX BX for cause Time

Clinical vs. subclinical pathology Treatment Creatinine Diagnostic threshold Acute dysfunction Subclinical acute rejection Chronic dysfunction BX Chronic pathology Chronic pathology BX for cause Time Protocol BX BX BX BX BX

IF/TA grade 2-3 Arteriolar hyalinosis Vascular intimal thickening >25% Glomerulosclerosis > 25% 80 60 40 20 0 Cumulative prevalence (%) Cumulative prevalence (%) Histology in protocol biopsies 80 IF/TA 60 cv 40 0 3 12 24 36 Time after transplantation (months) Number of patients at risk IF/TA grade 2-3 Arteriolar hyalinosis Vascular intimal thickening Glomerusclerosis Nankivell et al. NEJM 2003 247 247 247 247 168 131 155 169 101 56 84 105 39 16 30 47 Number of patients at risk IF/TA grade 2-3 Arteriolar hyalinosis Vascular intimal thickening Glomerusclerosis 20 11 3 10 0 16 0 247 247 247 247 3 12 24 36 Time after transplantation (months) 168 131 155 169 101 56 84 105 39 11 16 Naesens et al. JASN3 2009 30 10 47 16 IF/T Art Vas Glo

Clinical vs. subclinical pathology Treatment Creatinine Diagnostic threshold Acute dysfunction Subclinical acute rejection Chronic dysfunction BX Chronic pathology Chronic pathology Time Protocol BX BX BX BX BX

Clinical vs. subclinical pathology Treatment Creatinine Diagnostic threshold Acute dysfunction Subclinical acute rejection BX Chronic dysfunction Chronic pathology Chronic pathology Time Protocol BX BX BX BX BX

Early IF/TA and graft loss N=1197; indication biopsies within the FIRST YEAR posttransplant Death-censored graft survival IFTA = 0 Max IFTA grade in 1st year IFTA = 1 IFTA = 0 IFTA = 2-3 IFTA = 1 IFTA = 2-3 80 100 60 80 Percent survival Percent survival 100 (all patients) Death-censored graft atrophy Max interstitial fibrosis/tubularsurvival IFTA grade in 1st year (all patients) 70% 40 60 20 40 30% 0 20 5 15 P<0.0001 10 0 Time postTX (years) 5 10 15 Time postTX (years) Naesens et al Am J Transplant 2013 20 20

Specific diseases and graft loss? N=1197 kidney transplant recipients, transplanted between 1991-2001; mean 14.8±2.8 years follow-up, 918 indication biopsies within first year Progressive disease Percent survival 100 80 60 40 No progressive disease Progressive disease 20 0 N° at risk p<0.0001 1 5 10 15 20 Time after transplantation (years) No progressive disease 832 Progressive disease 245 737 199 569 148 197 65 *progressive disease = ABMR or de novo/recurrent glomerular disease Naesens et al Am J Transplant 2013

IF/TA as cause of graft loss? N=1197 kidney transplant recipients, transplanted between 1991-2001; mean 14.8±2.8 years follow-up, 914 indication biopsies within first year Progressive disease and K-means clustering on chronic damage Percent survival 100 No progressive disease no chronic damage Progressive disease no chronic damage 80 60 No progressive disease chronic damage 40 Progressive disease chronic damage 20 0 N° at risk p=0.0005 1 5 10 15 20 Time after transplantation (years) No progr. dis - cluster 1 187 169 121 49 Progressive disease - cluster 1 176 153 118 55 No progr. dis - cluster 2 59 44 34 11 *progressive disease = ABMR or de novo/recurrent glomerular disease Progressive disease - cluster 2 69 47 31 11 Naesens et al Am J Transplant 2013

IF/TA as cause of graft loss? N=1197 kidney transplant recipients, transplanted between 1991-2001; mean 14.8±2.8 years follow-up, last indication biopsies Naesens et al Submitted

Causes of fibrosis (and tubular damage) Tubular damage Nankivell et al Transplantation 2006 Interstitial fibrosis

Causes of fibrosis (and tubular damage) Tubular damage Interstitial fibrosis “The prognosis of an injured kidney is dependent on the extent of the damage rather than the underlying disease” Tampe and Zeisberg Nat Rev Nephrol 2014 Nankivell et al Transplantation 2006

Studying IF/TA KIDNEY TRANSPLANTATION x years Stable kidney recipient Allo-immune damage (“rejection”) x years Normal histology Non-immune chronic damage (e.g. CNIT)

Prediction of IF/TA KIDNEY TRANSPLANTATION x years Stable kidney recipient Allo-immune damage (“rejection”) x years Normal histology Targeted, individualized therapy? Non-immune chronic damage (e.g. CNIT) Biomarkers? Pathogenesis (-> therapeutic target discovery)?

Prediction of IF/TA N= 120 protocol biopsies, 0-6-24 months, Affymetrix HG U133 Plus 2.0 KIDNEY TRANSPLANTATION Stable kidney recipient x years Allo-immune damage x years Targeted, individualized therapy? Biomarkers? Pathogenesis? Naesens, Butte, Sarwal et al Kidney Int 2011 Normal histology Non-immune chronic damage

Prediction of IF/TA N= 120 protocol biopsies, 0-6-24 months, Affymetrix HG U133 Plus 2.0 KIDNEY TRANSPLANTATION Project 1 Allo-immune damage Gene expression and CADI score Stable kidney recipient x years x years Discovery set Normal histology Targeted, (N=24 post-TX protocol biopsies) individualized therapy? Project 2-3 Gene expression dynamics and CADI score over time after transplantation 0 months (N=24 protocol biopsies) Non-immune chronic damage Low CADI score (N=12 biopsies) Biomarkers? High CADI score (N=12 biopsies) 6 mo – low CADI score (N=24 biopsies) Pathogenesis? Validation set (N=24 protocol biopsies at 24 mo) Low CADI score (N=12 biopsies) High CADI score (N=12 biopsies) 24 mo – low CADI score (N=12 biopsies) “Non-progressors” 24 mo – high CADI score (N=12 biopsies) “Progressors” 601/54k probesets differently expressed over time 92/54k probesets differently expressed Project at 6 months 4 Immune geneset scores as a quantitative marker for inflammation Naesens, Butte, Sarwal et al Kidney Int 2011 N=72 post-TX biopsies from 72 patients

Prediction of IF/TA N= 120 protocol biopsies, 0-6-24 months, Affymetrix HG U133 Plus 2.0 KIDNEY TRANSPLANTATION Project 1 Allo-immune damage Gene expression and CADI score Stable kidney recipient x years x years Project 2-3 Gene expression dynamics and CADI score over time after transplantation Discovery set Normal histology 0 months (N=24 protocol biopsies) Targeted, (N=24 post-TX protocol biopsies) individualized therapy? Non-immune chronic damage Low CADI score (N=12 biopsies) Biomarkers? High CADI score (N=12 biopsies) 6 mo – low CADI score (N=24 biopsies) Pathogenesis? Validation set (N=24 protocol biopsies at 24 mo) Low CADI score (N=12 biopsies) High CADI score (N=12 biopsies) 24 mo – low CADI score (N=12 biopsies) “Non-progressors” 24 mo – high CADI score (N=12 biopsies) “Progressors” 601/54k probesets differently expressed over time 92/54k probesets differently expressed Project at 6 months 4 Pathway analysis geneset scores as a quantitative Immune Naesens, Butte, Sarwal et al Kidney Int 2011 marker for inflammation N=72 post-TX biopsies from 72 patients

on 24 2 4 24 m mo m on 2on nt 4 th th hs s ms 0 6 6m6 m o m6 on onm nt th tho hs s sn p = NS Time after=6NS 0 24 p transplantation Time after(months) transplantation 0 6 24 0 6 24 0 m 0m0 mo m o on on n nt t h th hs s s 0.50 0.50 Prediction of IF/TA Timeline set (months) Time after transplantation Time after transplantation (months) (months) Timeline set T cell proliferation T cell proliferation cell proliferation BB cell proliferation BBcell geneset score cell geneset score Timeline set Timeline set BBcell geneset score cell pproliferation cell proliferation BB cellgeneset score < < 0.01 p 0.01 Score Score Score Geneset score Geneset score Geneset score Score Geneset score 1.00 0.75 0.75 24 on on on tth th hs s s p = NS on 24 24 th24 m ms m s m Timeline set (months) activation NK cell B cell proliferation B cell geneset score Timeline set NK Timeline set NK cell<activation cell activation 0.05 cell pproliferation proliferation BBcell geneset score cell geneset score BB cellp < 0.01 p = NS 24 p < 0.05 p < 0.01 p = NS p = NS p< 0.05 p = NS p = NS 1.25 p = NS Mast cell activation p = NS p< 0.05 p = NS p< 0.05 1.25 1.25 Progressive CADI score (N=12) 1.00 p = NS Progressive CADI score (N=12) 1.00 Progressive CADI score p< 0.05 1.00 CADI score (N=12) p = NS Progressive (N=12) 1.25 Non-progressive CADI score 0.75 Geneset score Score Geneset score Geneset score Score Score p= 1.00 p = NS 1.00 NS 1.00 1.0 24 Mast cell activation (months) Mast cell=activation Mast cell activation p NS Geneset score Score 1.00 1.00 p = NS p < 0.01 p < 0.01 p= p = NS 0 p = NS p < 0.01 NS 6 p = NS p = NS p = NS p = NS 0 6 24 Time after transplantation 0 6 24 (months) 0 6 24 Time after transplantation Time after transplantation (months) (months) Time after transplantation Time 6 (months) 24 Time after transplantation after transplantation (months) (months) after transplantation p = NSp set p = NSp < 0.05 p < 0.05 1.5 1.25 1.25 NKTimeline < 0.01 p = NS cellpactivation= NS p = NS p = NS p < 0.01p = NS p = NS NS p = NS B p= 1.5 1.25 B cell proliferationNS p= 1.25 cell geneset score 1.5 1.25 Progressive CADI score (N=12) (N=12) Progressive CADI score (N=12) Non-progressive CADI score Non-progressive CADI score 0.75 0.75 Non-progressive CADI score (N=12) (N=12)0.50 Progressive CADI score (N=12) 1.00 (N=12) Non-progressive CADI score Non-progressive CADI score p < 0.05 (N=12)0.50 (N=12)0.50 p = NS p = NS Progressive CADI score (N=12) 0.75 0.75 1.0 1.0 0.75 0.75 0.75 0.25 24 24 24 m mo m on on nt th th hs s s 6 6m6 mo m on on nt th th hs s s (months) Time 0.05 transplantation (months) p < after Time after transplantation (months) Naesens,NSp < 0.01 p etNSKidney Int 2011 Butte, Sarwal = al (months) p= (months) Dendritic cell migration p = NS 0 0m0 mo m on on nt th th hs s s 24 24 24 m mo m on on nt th th hs s s 6 6m6 mo m on on nt th th hs s s p < 0.05 p = NSp < 0.01 p = NS p < 0.05 0.25 p < 0.05 Non-progressive CADI score p < 0.05 p = NS p = NS p < 0.05 p = NS 0.75 p = NS 24 p = NSp < 0.01 p = NS p = NS 0 p = NS 6 p < 0.01 p = NS 24 (N=12) 0 p = NS 6 0.25 0.25 p = NS p = NS NS 0 p = after transplantation 6 p = NS 24 24 Time after transplantation 0 6 24 Time 0 6 0 6 24 0 6 24 Non-progressive CADI score (months) 0 6 24 Time after transplantation24 (N=12)0.50 after transplantation transplantation (months) 0 Time after transplantation Time after 6 Time after transplantation Time 0 0m0 mo m on on nt th th hs s s 0.50 0.50 0.5 0.50 0.50 0.50 0.5 0.5 0.5 0.5 0.5 Time after transplantation 0 6 24 0 6 24 6 Time 6 6m6 mo m on on nt th th hs s s p = NS 0 0 0m0 mo m on on nt th th hs s s s m on th p = NS p = NS p = NS p = NS p = NS p = NS p = NS = NS p =6NS p Progressive Progressive CADI scoreCADI score (N=12) Progressive CADI score (N=12) (N=12) Non-progressive CADI score (N=12) Non-progressive CADI score CADI score Non-progressive CADI score Non-progressive (N=12) (N=12) (N=12) Non-progressive CADI score (N=12) Non-progressive CADI score Non-progressive CADI score Non-progressive CADI score (N=12) 0.5 (N=12) p < 0.01 (N=12) p = NS 0.50 Score Geneset score Score Score Geneset score Geneset score Score Score Score Progressive CADI score (N=12) 1.0 Progressive CADI score(N=12) (N=12) Progressive CADI score (N=12) Progressive CADI score 1.0 1.0 1.0 0.75 0 1.5 1.5 Progressive CADI score (N=12) 1.0 1.00 1.00 0.50 0.50 NS p = NSp < 0.01 p = p = NS p = NS < 0.01 p p = NS p = NS p = NS p = NS 1.5 1.5 p = NS p = NS p = NS p = NS 1.25 1.25 m on th Score Geneset score Score Score Geneset score Geneset score T cell proliferation pT cell p < 0.05 < 0.05proliferation p = NSp <= NSp = NS p 0.05 p < 0.05 1.25 p = NS p < 0.05 (months) (months) p = NS p = NS Granulocyte migration Progressive CADI score (N=12) Progressive CADICADI score Progressive CADI score (N=12) Non-progressive score (N=12) (N=12) Non-progressive CADI score Non-progressive CADI score (N=12) (N=12) Progressive CADI score (N=12) Non-progressive CADI score (N=12)

0.50 0.50 Low CADI High CADI Low CADI High CADI Prediction of IF/TA Histology at 24 months B Histology at 24 months T cell proliferation B cell proliferation 100 80 80 60 40 AUC = 0.82 p = 0.008 20 Sensitivity (%) Sensitivity (%) 100 0 60 40 AUC = 0.88 p = 0.002 20 0 0 20 40 60 80 100 0 20 100% - Specificity% NK cell activation 60 80 100 Early immune gene transcripts = markers for progressive renal fibrosis Dendritic cell migration 100 80 80 60 40 AUC = 0.83 p = 0.006 20 0 Sensitivity (%) 100 Sensitivity (%) 40 100% - Specificity% 60 40 AUC = 0.92 p = 0.0005 20 0 0 20 40 60 80 100% - Specificity% Naesens, Butte, Sarwal et al Kidney Int 2011 100 0 20 40 60 100% - Specificity% 80 100

Evolution of IF/TA Naesens et al Kidney Int 2011; Fehr et al Kidney Int 2011; Drachenberg et al Kidney Int 2012

Pathophysiology of fibrosis Wynn et al Nat Med 2012

Pathophysiology of renal fibrosis Cytokine milieu Zeisberg and Neilson JASN 2010

Prediction of fibrosis: CTGF uCTGF at 3 months for prediction of fibrosis at 24 months post-transplant Metalidis, …, Naesens, …, Kuypers. Transplantation 2013

Pathogenesis of fibrosis: CNI toxicity Patient-specific proximal tubular cell lines (ciPTC) CTGF PAI-1 TGFβ SMAD-6 Knops, Kuypers et al. unpublished data

Wynn et al Nat Med 2012

Antifibrosis pipeline in kidney disease Tampe and Zeisberg Nat Rev Nephrol feb 2014

UZL Biobank Kidney Transplantation Time post-TX 0m 3m Histology Biopsy RNA Plasma Serum Blood RNA Urine Clinicaltrials.gov NCT01331668 6m 1y 2y 5y

UZL Biobank Kidney Transplantation Time post-TX 0m 3m Histology Biopsy RNA Plasma Serum Blood RNA Urine Clinicaltrials.gov NCT01331668 6m 1y 2y 5y

UZL Biobank Kidney Transplantation Time post-TX 0m 3m Time post-TX Ind 6m Ind 1y 0m 2y Histology Plasma Serum Blood RNA Blood RNA Urine 1y 5y Biopsy RNA Plasma Serum Ind 6m Ind Histology Biopsy RNA 3m Urine N=830 N=906 N=914 N=772 N=560 Total now in biobank: 4464 biopsies and concomitant samples Clinicaltrials.gov NCT01331668 N=236

Prediction/pathogenesis of IF/TA KIDNEY TRANSPLANTATION x years Stable kidney recipient Allo-immune damage (“rejection”) x years Normal histology Targeted, individualized therapy? Non-immune chronic damage (e.g. CNIT) Biomarkers? Pathogenesis (-> therapeutic target discovery)?

Conclusion • Fibrosis occurs in the first few years after transplantation • Fibrosis is very important predictor of kidney transplant outcome • Fibrosis is the common end result of many different inciting events • Post-transplant renal fibrosis follows the current paradigms of fibrogenesis, irrespective of its underlying trigger • Only few therapeutic targets are being tested in kidney diseases, none has made it to the clinic (yet) • The UZ Leuven Biobank Renal Transplantation allows for prospective evaluation of ongoing and future fibrosis, and could yield targets for prevention of fibrosis

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