Prognostic significance of C4-positive vs. negative rejection

January 31, 2018 | Author: Anonymous | Category: Science, Health Science, Immunology
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Prognostic significance of C4-positive vs. negative rejection

Heinz Regele Department of Pathology

Innsbruck Medical University

C4d-negative rejection

Has all clinical and morphological features of antibody mediated rejection but lacks C4d in transplant biopsies

Issues to discuss Clinical relevance (prognosis, diagnostic features) Biology

Mechanisms of Humoral Allograft Rejection

PMN T-cell

NK-cell





C1 MAC

C3b C1 C4d

C3b C4d

MAC

Allograft Endothelial cells

Dual Role of Complement Biology

C3, C5, C5b-9

Diagnostic marker

C4d (C3?)

C4d

Banff classification of renal allograft rejection

ATN

DSA

C4d

Capillaritis

Arterial necrosis

MHC I

+

+ MHC II

anti-C4d

or

or

% Allograft suvival

Capillary C4d deposition and allograft survival

100 90 80 70 60 50 40 30 20 10 0

C4d- (N=42) 90% Total (N=93) 72% C4d (+) (N=8)

63%

C4d+ (N=43)

0

1

2

3

6 4 5 7 Months post TX

57%

8

9

10

11

12

Renal C4d deposits in 93 patients with early allograft dysfunction

Feucht et al, Kidney Int, 43:1333, 1993

C4d staining and FCXM (Flow-Cytometry X-Match) of corresponding sera 113 biopsies of 58 renal allograft recipients

In 2 Patients severe rejection reversible by IA 4 allografts lost

C4d neg/FCXM neg N = 20

C4d pos N = 16

C4d neg/FCXM pos N = 22 1 allograft lost

G.A. Böhmig et al, JASN 2002

Tissue injury and outcome in DSA positive patients

A. Loupy et al., AJT 2011

Microvascular injury and chronic ABMR

….C4d may not be a sufficiently sensitive indicator of activity, MI and DSA being more robust predictors of bad outcome..... A. Loupy et al., AJT 2011

C4d-negative DSA-associated microvascular injury

•Antibody-mediated but complement-independent injury?

•Sampling error?

•Inadequate sensitivity of C4d detection?

•Remnants of previously active ABMR?

Experimental evidence for C4d negative ABMR Recipients without adaptive immune system (RAG1 KO)

MHC incompatible donor

Anti-donor-MHC moAb

Non complement fixing anti donor IgG cause chronic transplant arteriopathy (CTA). CTA even developed in RAG1-/-C3-/- double KO mice upon injection of DSA, strongly suggesting a complement independent mechanism of injury T. Hirohasi, AJT 2010

NK cells are essential for the development of DSA induced CTA in a FcgRIII dependent mechanism (in absence and presence of complement). DSA alone or in conjunction with macrophages only do not generate CTA. T. Hirohasi, AJT 2012

Jindra PT, Transplantation 2006

Current Opinion in Organ Transplantation 2010; 15: 42-48

Expression of endothelial cell associated transcripts (ENDATs) is present in all types of rejection but significantly higher in ABMR.

Only 13/50 (26%) of kidneys with high ENDATs and DSA were C4d positive

Only 38% of kidneys with high ENDATs and DSA that subsequently developed chronic ABMR were C4d positive

Reduced graft survival in C4d-negative ABMR

A: DSA

E: ENDAT

C: C4d B. Sis et al., AJT 2009

C4d negative ABMR – the clinical approach

What is the prevalence of DSA in C4d negative (micro)vascular injury in the general population (of TX-recipients)? What is the clinical course of C4d negative rejection without specific treatment? Which diagnostic features are associated with progression to chronic AMR and/or graft loss?

Prevalence of alloantibodies in C4d-negative microvascular injury

Alloantibodies are present in

38-70% of C4d negative glomerulitis cases Gaston, Transplantation 2010; Loupy AJT 2009

and in

42-100% of C4d negative glomerulopathy cases Issa, Transplantation 2008; Sis, AJT 2007; Shimizu Clin Transpl 2009, Haas AJT 2011

C4d negative ABMR – the clinical approach

Renal TX 12/00 – 2/05 (n=691)

Biopsies for cause (n=481)

C4d neg (n=378)

C4d neg + mv lesions + serum (n=28)

C4d pos (n=75)

Regele et al, manuscript in preparation

DSA in C4d-negative vascular injury

Anti-HLA antibodies P=0.1

Donor specific antibodies

P=0.7

P=0.09

P=0.17

100

100 90

90

80

80

70

70

60

60

50

50

40

40

30

30

20

20

10

10

0

0

Neg Cont

C4d-neg mvi C4d-pos Cont

Neg Cont

C4d-neg mvi C4d-pos Cont

Regele et al, manuscript in preparation

Graft survival in C4d-negative vascular injury

Death censored graft survival

1.0

C4d- (n=378)

0.8

C4d- mvi (n=28) 0.6

C4d+ (n=76)

0.4

0.2

0.0

0

1

2

3

4

5

6

7

8

P
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