The Pathology of Transplant Rejection

In this GlomCon Nephropathology Essentials session, Dr. Ibrahim Batal discussed the pathology of transplant rejection. Our Moderator’s Notes are based on his live presentation, which you can watch here: https://glomcon.org/transplant/the-pathology-of-transplant-rejection/

Moderator’s Note
Author: Dr. Kate Robson
Editors: Dr. Pravir Baxi, Dr. Ali Poyan Mehr

Dr Batal reviewed the pathology of T-cell-mediated rejection (TCMR) and antibody-mediated rejection (AMR), emphasising that these are not two purely distinct entities: while one usually dominates the clinical picture, cell-mediated and antibody-mediated responses often coexist.

T-cell-mediated rejection (TCMR)

  • Recipient immune cells recognise donor MHC molecules either by direct presentation (donor-derived antigen-presenting cells (APCs) present alloantigens to recipient T cells) or indirect presentation (recipient APCs capture alloantigen and present them to T cells).

  • CD4+ helper T cells cause interstitial inflammation in the graft, and CD8+ cytotoxic T cells cause tubulitis and vasculitis.

  • Morphologic features of acute TCMR include interstitial inflammation, tubulitis, and intimal arteritis.

  • Evolution of induction and maintenance therapies has seen a decline in fulminant acute TCMR. TCMR remains important, however: it is associated with graft dysfunction and can be a predictor for subsequent de novo DSA formation.

  • Chronic-active TCMR now poses particular ongoing diagnostic and therapeutic challenges.

  • Inflammation in scarred areas of interstitial fibrosis and tubular atrophy (i-IFTA) is now recognised as a diagnostic feature of chronic-active TCMR in the 2017 (Revised) Banff Criteria, provided other causes of i-IFTA have been excluded (e.g. BK-virus nephropathy, pyelonephritis).

Antibody-mediated rejection (AMR)

  • Rejection resulting from antibodies against donor antigens

  • Stages of AMR (per Colvin J Am Soc Nephrol 2007)
    I. Donor-specific antibody (DSA) in circulation
    II. C4d staining in graft
    III. Morphological injury in graft
    IV. Graft dysfunction

  • Diagnosis depends on serologic, immunologic and morphologic evidence, the sensitivity and specificity of which can be influenced by several factors.

  • Serologic
    DSA detection (usually by Luminex)
    Complicating issues include:
    • DSA absorption by the graft (‘sponge’ effect) ⇒ sensitivity
    • Non-HLA antibodies (e.g. AT-1)
    • IgG subclasses, mean fluorescence index (MFI) values, complement-activating vs. not, and pre-formed vs. de novo: all influence the course of AMR

  • Immunologic
    C4d linear staining along peritubular +/- glomerular capillaries on kidney biopsy via immunofluorescence (IF) or immunohistochemistry (IHC) (C4d covalently binds to tissue, so is a more useful indicator of activation of the classical pathway of complement than e.g. C1 which has a very short half life)
    Complicating issues include:
    • C4d may be negative in the presence of DSA which do not activate complement
    • C4d may be negative when severe injury causes endothelial sloughing
    • C4d staining can be positive in the absence of AMR (e.g. with accommodation of anti-ABO Abs)

  • Morphologic
    Acute tubular injury (ATI), peritubular capillaritis (ptc), glomerulitis (g), fibrinoid necrosis and thrombotic microangiopathy (TMA) are all morphologic features of AMR.
    Complicating issues include:
    • Inter-observer variability
    • Features may be absent early in the course of AMR
    • Features are non-specific, and can be observed in other diseases, possibly leading to overdiagnosis of AMR

  • The diagnostic use of endothelial-associated gene expression profiles (microarray on frozen kidney biopsy samples) in AMR has been a recent research focus. While currently used in some centres, it remains to be validated for wider use.

  • 2017 (Revised) Banff Criteria for AMR
    Morphologic evidence: 1 or more of: g>0 (in the absence of GN), ptc>0, v>0, acute TMA (in the absence of any known cause), ATI (in the absence of any known cause).
    Antibody interaction with endothelium: 1 or more of: C4d staining, g+ptc≥2, expression of genetic transcripts (endothelial injury & NK cell-associated, if thoroughly validated).
    Serologic evidence: DSA (HLA or other antigens). C4d staining or validated transcript expression may substitute for DSA.

  • Treatment of AMR can involve steroid therapy, plasmapheresis and/or intravenous immunoglobulin (IVIG). These are often insufficiently effective, resulting in chronic transplant glomerulopathy.

Selected References