1. Chronic vascular injury of the kidney allograft: The contribution of rejection Heinz Regele Heinz Regele Department of Pathology Innsbruck Medical University Heinz Regele Heinz Regele Department of Pathology Innsbruck Medical University

3. Origin of chronic vascular lesions CNI-toxicity Hypertension Donor derived Rejection Diabetes mellitus Glomerulonephritis Recurrence of disease

4. CNI-toxicity Diabetes mellitus Donor derived Hypertension Rejection Thrombotic microangiopathy Rejection Hypertension Donor derived

6. Elastic stain CD3

7. Banff definition of chronic T-cell mediated rejection K. Solez et al., AJT 2008

8. C4d Capillaropathy Intimal Fibrosis Glomerulopathy + or + DSA MHC I anti-C4d MHC II Banff definition of chronic antibody-mediated rejection

9. Mechanisms of chronic transplant arteriopathy Acute and Chronic Vascular Rejection in Nonhuman Primate Kidney Transplantation G1: Adequate immunosuppression ➔ No rejection G2: Insufficient immunosuppression ➔ Acute rejection with graft loss G3: Suboptimal immunosuppression ➔ Smoldering (chronic) rejection G Wieczorek et al., AJT 2006 G2 G3 G2 G3 G2 G3

10. Mechanisms of chronic transplant arteriopathy CD8 lymphocytes are sufficient for the development of chronic rejection Wild-type CD8 lymphocytes were transferred to nude mice followed by heterotopic heart transplantation. Unprimed CD8 lymphocytes in the absence of CD4 lymphocytes can cause intimal lesions of CAV. Schinckel et al., Transplantation 2004 Chronic Antibody Mediated Rejection of Renal Allografts: Pathological, Serological and Immunologic Features in Nonhuman Primates Chronic transplant arteriopathy (CTA) was found in 8 out of 9 antibody and C4d positive animals and none of eight animals without antibodies or C4d deposits. The intima showed proliferation of spindle-shaped cells with a variable mononuclear cell infiltration, similar to that observed in human renal allografts. RN Smith et al., AJT 2006

11. JASN 22:975-983 2011

12. G.S. Hill et al. JASN 22:975-983 2011 Progression of arteriosclerosis at 1 year post transplant Banff cv grade Donor age

13. Diagnostic criteria for antibody-induced CTA Hypercellular intimal fibrosisHypercellular intimal fibrosis Lack of elastic fibersLack of elastic fibers Associated features of antibody-mediated rejectionAssociated features of antibody-mediated rejection

14. Regele, JASN 2002; Sis, AJT 2007; Issa, Transplantation 2008; Haas AJT 2011 No C4d in33-76% Transplant glomerulopathy cases Donor-specific antibodies are associated with (micro)vascular injury Regele, NDT 2001; Magil, Kid Int 2005; Fahim AJT 2007; Gaston, Transplantation 2010; Loupy, AJT 2011 No C4d in40-52% Transplant glomerulitis casesBUT

15. 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

16. Recipients without adaptive immune system (RAG1 KO) MHC incompatible donorAnti-donor-MHC moAb Experimental evidence for complement independent vascular injury Non complement fixing anti donor IgG cause chronic transplant arteriopathy (CTA). CTA even developed in RAG1 and 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 Fc  RIII dependent mechanism (in absence and presence of complement). DSA alone or in conjunction with macrophages only do not generate CTA. T. Hirohasi, AJT 2011 EA Farkash, RB Colvin, Nat Rev Nephrol 2012

17. Intimal arteritis is a manifestation of T-cell mediated rejection K. Solez et al., AJT 2008

18. Antibody mediated vascular rejection 302/2079 patients (15%) had acute biopsy-proven rejection with four distinct patterns of kidney allograft rejection: T cell-mediated vascular rejection (26 patients [9%]), Antibody-mediated vascular rejection (64 [21%]) T cell-mediated rejection without vasculitis (139 [46%]) Antibody- mediated rejection without vasculitis (73 [24%]) C. Lefaucheur et al. Lancet 2013; 381: 313–19

19. Antibody mediated vascular rejection V. Nickeleit et al., JASN 2002

20. Summary Chronic transplant arteriopathy is multifactorial Pathogenesis based classification of chronic arterial lesions in allograft biopsies is therefore challenging and can only be achieved if morphological lesions are judged in the context of clinical and serological findings Different contributing pathogenic mechanisms are not mutually exclusive, but rather might synergistically aggravate tissue injury