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

Heinz RegeleDepartment of Pathology

Innsbruck Medical University

Origin of chronic vascular lesions

• CNI-toxicity

• Hypertension

• Donor derived

• Rejection

• Diabetes mellitus

• Glomerulonephritis

• Recurrence of disease

CNI-toxicity

Diabetes mellitus

Donor derived

Hypertension

RejectionThrombotic microangiopathy Rejection

Rejection

Hypertension

Donor derived

Elastic stain

Elastic stain

CD3

Banff definition of chronic T-cell mediated rejection

K. Solez et al., AJT 2008

C4d Capillaropathy Intimal FibrosisGlomerulopathy

+ or or+

DSA

MHC I

anti-C4d

MHC II

Banff definition of chronic antibody-mediated rejection

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

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

JASN 22:975-983 2011

G.S. Hill et al. JASN 22:975-983 2011

Progression of arteriosclerosis at 1 year post transplant

Ban

ff c

v g

rad

e

Donor age

Diagnostic criteria for antibody-induced CTA

• Hypercellular intimal fibrosis

• Lack of elastic fibers

• Associated features of antibody-mediated rejection

Regele, JASN 2002; Sis, AJT 2007; Issa, Transplantation 2008; Haas AJT 2011

No C4d in

33-76%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 in

40-52%Transplant glomerulitis cases

BUT

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

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

Intimal arteritis is a manifestation of T-cell mediated rejection

K. Solez et al., AJT 2008

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

Antibody mediated vascular rejection

V. Nickeleit et al., JASN 2002

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