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Chronic vascular injury of the kidney allograft: The contribution of rejection

Chronic vascular injury of the kidney allograft: The contribution of rejection. Heinz Regele Department of Pathology Innsbruck Medical University. Origin of chronic vascular lesions. Donor derived. Hypertension. Diabetes mellitus. CNI-toxicity. Rejection. Glomerulonephritis.

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Chronic vascular injury of the kidney allograft: The contribution of rejection

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

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

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

  4. Elastic stain CD3 Elastic stain

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

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

  7. 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 G3 G2 G3 G2 G3 G2 G Wieczorek et al., AJT 2006

  8. 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.Schinckelet 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

  9. JASN 22:975-983 2011

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

  11. Diagnostic criteria for antibody-induced CTA • Hypercellularintimalfibrosis • Lack ofelasticfibers • Associated featuresofantibody-mediatedrejection

  12. Donor-specificantibodiesareassociatedwith (micro)vascularinjury BUT No C4d in 33-76% Transplant glomerulopathycases No C4d in 40-52% Transplant glomerulitiscases Regele, JASN 2002; Sis, AJT 2007; Issa, Transplantation 2008; Haas AJT 2011 Regele, NDT 2001; Magil, Kid Int 2005; Fahim AJT 2007; Gaston, Transplantation 2010; Loupy, AJT 2011

  13. 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

  14. Experimental evidence for complement independent vascular injury 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 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 FcgRIII 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

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

  16. 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

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

  18. Summary Chronic transplant arteriopathy is multifactorial Different contributing pathogenic mechanisms are not mutually exclusive, but rather might synergistically aggravate tissue injury 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

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