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. Boda a, P. Szenohradszky b, E. Szederkényi b, B. Iványi Departments of Pathology, Medical Physics and Informatics a and Surgery b 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 (cv mo )

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 (cv mo ), intimal fibrosis (cv IF ), intimal fibroelastosis (cv IFE ); and tubular HLA-DR and ptcml

Staining of chronic active arteritis (cv mo ) 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±4970±4960±49ns eGFR (ml/min/1.73 m 2 ) 26±1228±1223±13ns Postbiopsy follow-up (months) 23±2226±2219±20ns

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 tHLA-DRcv mo ptcC4d gcgptcmlcv IF cictahcv IFE i t HLA-DR0.363 cv mo ptc C4d0.303 g0.338 cg0.258 ptcml cv IF ci ct ah cv IFE

Hierarchical cluster analysis cv IF cv IFE cv mo

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 pulse55410 Intensification of maintenance immunosuppression 8610 Anti-thymocyte globulin 0020 Plasmapheresis0020 Left untreated22200

Mean graft survival in purely CAMR and CMR groups Purely CAMR CMR p= vs 22 months

Multivariable Cox regression of morphological variables g ptc ciah cv mo ct i cgptcml HLA-DR C4d t cv IF cv IFE CNI-tox.

Discussion I.CMR was frequent in our series (43%) II.Chronic active arteritis appeared to be T- cell-related a.T-cell predominance in 14/16 cases b.Clustered with TMR lesions C. Lefaucheur et al. Antibody-mediated vascular rejection of kidney allografts: a population-based study. Lancet 2013; 381:

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