chronic vascular injury of the kidney allograft: the contribution of rejection
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
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Chronic vascular injury of the kidney allograft: The contribution of rejection
Heinz RegeleDepartment of Pathology
Innsbruck Medical University
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Origin of chronic vascular lesions
• CNI-toxicity
• Hypertension
• Donor derived
• Rejection
• Diabetes mellitus
• Glomerulonephritis
• Recurrence of disease
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CNI-toxicityDiabetes mellitus
Donor derived
Hypertension
RejectionThrombotic microangiopathy Rejection
RejectionHypertensionDonor derived
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Elastic stain
Elastic stain
CD3
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Banff definition of chronic T-cell mediated rejection
K. Solez et al., AJT 2008
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C4d Capillaropathy Intimal FibrosisGlomerulopathy
+ or or+
DSA
MHC I
anti-C4d
MHC II
Banff definition of chronic antibody-mediated rejection
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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
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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
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JASN 22:975-983 2011
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G.S. Hill et al. JASN 22:975-983 2011
Progression of arteriosclerosis at 1 year post transplant
Ban
ff cv
gra
de
Donor age
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Diagnostic criteria for antibody-induced CTA
• Hypercellular intimal fibrosis
• Lack of elastic fibers
• Associated features of antibody-mediated rejection
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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 cases
BUT
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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
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Recipients without adaptive immune system (RAG1 KO)
MHC incompatible donor Anti-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 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
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Intimal arteritis is a manifestation of T-cell mediated rejection
K. Solez et al., AJT 2008
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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
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Antibody mediated vascular rejection
V. Nickeleit et al., JASN 2002
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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