prevalence, risk factors and natural course fda … risk factors and natural course . fda workshop,...

De novo DSA and ABMR: Prevalence, Risk Factors and Natural Course FDA Workshop, Session 1 28 September 2015 Peter Nickerson, MD, FRCPC, FCAHS Flynn Family Chair in Renal Transplantation Professor of Internal Medicine and Immunology

Astellas consultant and core investigator providing central laboratory support for the FKC-014 Canadian clinical trial

AND

My presentation does not include discussion of off-label

or investigational use of drugs

Peter Nickerson, University of Manitoba, Winnipeg, Canada

Relevant Financial Relationship Disclosure Statement

De novo DSA Kidney Allograft Survival Consecutive Adult and Pediatric Kidney Transplants (n=508, 1999 to 2012)

11% Other GN+IFTA (n=20) 4% TCMR+IFTA (n=10) 2% IFTA (n= 8) 1.6% BK Nephro (n= 2) Other (n= 6) Not Bx (n=10)

76% Stable

9% Subclinical DSA

4% Clinical DSA

Years Post-Transplant Wiebe et al., AJT (2015) ePub

Death with Function 9% (n=46)

1% (n= 5)

Ref. 1st Tx

Defn to Rule out Pre-Tx DSA

de novo DSA Induction (Depletional) Race

1st Mo 1st Yr >1st Yr Thymo Campath Cauc AA Hisp Asian

Cooper n.a. FCXM 15.6% 27.0% 0% yr 2 66% 0% 69% 7% 17% n.a.

DeVos 93% >2000 MFI 8.0% 20.0% 5.0%/yr 61% 0% 42% 27% 24% n.a.

Heilman 91% >1000 MFI 8.2% 17.6% n.a. 26% 61% n.a. 5% n.a. n.a.

Everly 100% >1000 MFI 3.0% 11.0% 2.3%/yr 13% 0% n.a. 64% n.a. n.a.

Wiebe 95% >300 MFI 0.0% 2.0% 2.0%/yr 9% 0% 69% 2% 0% 11%

Evolution of de novo DSA Wiebe et al., AJT (2015) ePub DeVos et al., Transplantation (2014) 97:534

Years post-transplant

de novo DSA 2% per year

de novo DSA 5% per year(1-4)

de novo DSA 20% 1st year

STUDY Dominant

de novo DSA HLA

Mismatch Race Young Age of Recip

Donor Type

Imuran vs. MMF

CsA vs. Tac TCMR

I II I+II DR MM DQ MM Worthington et al. X

Hourmant et al. X X X X X

Piazza et al. X X

Lachmann et al. X X

Scornik et al. X

Lachmann et al. X

Hidalgo et al. X

Yabu et al. X

Fotheringham et al. X

Cooper et al. X HLA Mismatch X

Liefeldt et al. X HLA Mismatch X

Willicombe et al. X X X

Ginevri et al. X X

De Kort et al. X

Everly et al. X X none X DD

Wiebe et al. X X X X X

De Vos et al. X HLA Mismatch AA DD

Correlates of de novo DSA

Wiebe et al., Current Opinion Organ Transplant (2013) 18:470

Polymorphic amino acid

Tissue Antigens (2011) 77:525

Functional Epitope (3 radius Eplet)

Structural Epitope (15 radius Epitope)

1 DR MM

1 DQ MM

# of Epitope MM

CONTEXT ( Donor Recipient combination) Single HLA Antigen MM Range of Epitope MM

Wiebe et al., AJT (2013) 13:3114-3122

Early clinical TCMR (

Gibson et al., AJT (2008) 8:819

PTC 2

Patients with de novo DSA have early (0-6 month) TCMR with more intense PTC inflammation

TCMR PTC score

de novo DSA

No DSA

2.0

1.0 p

Non-Adherence is a major risk factor for de novo DSA

Adherent

19% at 12 years

Non-Adherent

72% at 12 years

p

Multivariate Model of de novo DSA Risk Factors

Wiebe et al., AJT (2013) 13:3114-3122

At onset of de novo DSA 76% have ABMR(Banff 2013)

Wiebe et al., AJT (2015) ePub

Banff Grade 0 1 2 3

TCMR(Banff 2007) common (91% with ABMR) 32% Borderline 29% Grade 1

Transplant glomerulopathy uncommon

IFTA common

At DSA onset 18% have no TCMR or ABMR

Time to Graft Loss from de novo DSA Onset Consecutive Adult and Pediatric Kidney Transplants (n=508, 1999 to 2012)

Mean time to graft failure from 1st detection of de novo DSA

~ 3.3 to 8.3 years


De Novo DSA and Graft Dysfunction Estimated eGFR Rate of Decline (ml/min/1.73m2/year)

Pre dnDSA Post dnDSA

Rowe et al. J. Genontology (1976)

Healthy Men (n=293)

Age eGFR decline (Years) (ml/min/1.73m2/year) 17-84 -0.90 3.08 ________________________________________________________________

25-34 -1.09 3.13 35-44 -0.11 2.88 45-54 -0.73 2.92

Stable


For each 1.0 ml/min/1.73m2 decrease in eGFR at 3 years post-subclinical dnDSA onset, the risk of graft loss increased (HR 1.06 [1.03-1.09], p

Clinical Predictors for Graft Loss at DSA onset Consecutive Adult and Pediatric Kidney Transplants (n=508, 1999 to 2012)

DGF

MNA

DSA Titer


Univariate Multivariate

76% ABMR(Banff 2013) at biopsy for de novo DSA

Biopsy Predictors for Graft Loss at DSA onset Consecutive Adult and Pediatric Kidney Transplants (n=508, 1999 to 2012)

Tubulitis

CG


Independent Predictors of Banff Chronic Scores

Banff cg score increases 1 grade per 3 years of post de novo DSA follow-up (R2 = 0.36, p=0.0018)


Working Model of Kidney Allograft Loss

Under Immunosupression Non-adherence Physician guided

HLA MM

DGF

TCMR Clinical Subclinical

ABMR Clinical Subclinical

dnDSA CG

IFTA

Graft Loss

Class II Epitope MM

(Immunodominant)

IRI

CNI Toxicity Brain Death

eGFR

Stable Graft

Subclinical DSA (mixed rejection)

Clinical DSA (mixed rejection)

Time Post-Transplant

Proteinuria: Rate of 0.004 0.09 0.21 0.48 (p=0.003) (g/day/year)


Acknowledgements

Transplant Manitoba Adult & Pediatric Kidney Programs

David Rush Chris Wiebe

Julie Ho Martin Karpinski

Leroy Storsley Patricia Birk

Aviva Goldberg

Transplant Immunology Laboratory (DSM)

Denise Pochinco

Manitoba Centre for Proteomics & Systems Biology

John Wilkins

Department of Pathology Ian Gibson

Department of Immunology Kent HayGlass

Universitt Basel Stefan Schaub

Patricia Hirt-Minkowski Gideon Hnger

CTOT Consortia Peter Heeger

Don Hricik Robert Fairchild Richard Formica Emilio Poggio Nancy Bridges

David Ilke

DeKAF Consortia Arthur Matas Robert Gaston

Sita Gourishankar Joseph Grande

Lawrence Hunsicker Bert Kasiske

Michael Cecka Roslyn Mannon Fernando Cosio

Slide Number 1Slide Number 2Slide Number 3Evolution of de novo DSA Correlates of de novo DSASlide Number 6Slide Number 7Slide Number 8Slide Number 9Slide Number 10Slide Number 11Slide Number 12Slide Number 13Slide Number 14Slide Number 15Slide Number 16Slide Number 17Slide Number 18Working Model of Kidney Allograft LossSlide Number 20

prevalence, risk factors and natural course fda … risk factors and natural course . fda workshop,...

Documents