Kidney allografts with biopsy features of chronic mixed rejection reflect

poorer survival than those with pure chronic antibody-mediated rejection

D. Dobi, Zs. Bodó, É. Kemény, K. Bodaa, P. Szenohradszkyb, E. Szederkényib, B. Iványi

Departments of Pathology, Medical Physics and Informaticsa and Surgeryb

University of Szeged, Szeged, Hungary

Introduction

In late dysfunctional kidney allograft biopsies

three rejection phenotypes can be observed:

• chronic antibody-mediated rejection (AMR)

• acute T-cell-mediated rejection (TMR)

• chronic active TMR

ptcmlcg

Chronic AMR: transplant glomerulopathy and/or transplant capillaropathy

Acute TMR: interstitial infiltrates and tubulitis (interstitial rejection, ISR) with or without intimal arteritis

Chronic active TMR: mononuclears in intimal fibrosis (cvmo)

• Frequency: chronic AMR > acute TMR; chronic active TMR is exceptional

• Chronic AMR and TMR may concur, termed chronic mixed rejection (CMR)

Objectives

To analyze

• the histological patterns of chronic mixed rejection (CMR)

• the clinicopathological relevance of the different patterns of CMR

Material and methods

• From 2001 to 2011, 61 biopsies displayed the histological features of chronic AMR (cg and/or ptcml ± C4d-positivity)

• Luminex data were not avaible

• Re-evaluation according to the Banff scheme (v, g, i, t, ptc, cg, ci,ct, ah) plus

• Scoring of chronic arterial changes: mononuclears in

intimal fibrosis (cvmo), intimal fibrosis (cvIF), intimal

fibroelastosis (cvIFE); and tubular HLA-DR and ptcml

• Staining of chronic active arteritis (cvmo) cases

with CD3 and CD68 in adjacent sections

• Two groups for clinicopathological analysis:

purely CAMR vs CMR

• Statistics: Spearman’s correlation, hierarchical

cluster analysis, Kaplan-Meier estimator, Cox

regression

Results: main clinical data

 All

patients (n=61)

Purely CAMR (n=35)

CMR (n=26) p

Posttransplant time (months) 66±49 70±49 60±49 ns

eGFR (ml/min/1.73 m2) 26±12 28±12 23±13 ns

Postbiopsy follow-up (months) 23±22 26±22 19±20 ns

Chronic active TMR Chronic active TMR and acute ISR

Acute ISR

Purely CAMR CMR

35

12

4

10

Histological patterns

Features of chronic active arteritis

Severe luminal narrowing (median score 3),

mononuclears scattered throughout the fibrotic intima,

T-cell predominance

PAS

CD3

CD68

Significant (p<0.05) and positive Spearman correlation coefficients between Banff scores and chronic arterial changes

t HLA-DR cvmo ptc C4d g cg ptcml cvIF ci ct ah cvIFE

i 0.769 0.606 0.347 0.301 0.264t 0.654 0.2750.354

HLA-DR 0.363cvmo

ptc 0.3280.331C4d 0.303

g 0.338cg 0.258

ptcml 0.414 0.269 0.263cvIF

ci 0.806 0.299ct

ahcvIFE

Hierarchical cluster analysis

cvIF

cvIFE

cvmo

-36 -30 -24 -18 -12 -6 -1 +1 +6+12

15

20

25

30

35

40

45

50

purely CAMR

CMR

Time before (-) and after (+) biopsy (Bx) (months)

Mea

n eG

FR v

alue

(ml/m

in/1

.73

m2)

Mean eGFR values in purely CAMR and CMR

Postbiopsy therapy

Therapy

Purely CAMR CMR

CAMR (n=35)

Chronic active TMR (n=12)

Chronic active TMR and acute ISR

(n=4)

Acute ISR (n=10)

Steroid pulse 5 5 4 10

Intensification of maintenance

immunosuppression8 6 1 0

Anti-thymocyte globulin 0 0 2 0

Plasmapheresis 0 0 2 0

Left untreated 22 2 0 0

Mean graft survival in purely CAMR and CMR groups

Purely CAMR

CMR

p=0.011

50 vs 22 months

Multivariable Cox regression of morphological variables

g

ptc

ci ah

cvmo

ct

i

cg ptcml

HLA-DR

C4d

t

cvIF

cvIFECNI-tox.

Discussion

I. CMR was frequent in our series (43%)II. Chronic active arteritis appeared to be T-

cell-relateda. T-cell predominance in 14/16 casesb. Clustered with TMR lesions

C. Lefaucheur et al. Antibody-mediated vascular rejection of kidney allografts: a population-based study. Lancet 2013; 381: 313-319.

III. CMR was characterized by poorer allograft survival and more reduced allograft function than purely chronic AMR if chronic active arteritis was part of the TMR component

IV. The immunohistochemical profiling of chronic active arteritis is recommended