Immunologically mediated allograft damage or rejection may be hyperacute, acute or chronic. Acute rejection is classified as acute cellular/T cell-mediated rejection or acute antibody-mediated/ humoral rejection, according to which arm of the immune system is principally involved in mediating allograft damage.
Hyperacute rejection occurs immediately post-transplant (within minutes to hours) in recipients who have pre-formed, complement-fixing donor-specific antibodies (DSA, typically ABO or HLA). On perfusion of the transplant with the recipient’s blood, these antibodies bind to endothelial cells activating complement and phagocytes. This results in endothelial damage, platelet aggregation and rapid arterial and venous thrombosis with subsequent allograft infarction. Once initiated, the process is essentially untreatable, and inevitably leads to allograft loss. Historically, the first attempts at transplantation were performed across blood groups, leading to hyperacute rejection and rapid graft loss. In the current era, hyperacute rejection is very rare, and usually only occurs if there is a mistake in performing the cross-match or transcribing a blood group.
Acute cellular rejection
The most common type of rejection is acute cellular rejection (also known as T cell-mediated rejection [TMR]), occurring in 20–25% of transplants, usuallywithinthefirst 6 monthspost-transplant. Patients present with unexplained deterioration in transplant function should undergo an ultrasound scan to exclude obstruction, a urine dipstick and culture to exclude infection, and should have their CNI levels assessed to exclude toxicity. If no alternative cause for decline in graft function is identified, a transplant biopsy is performed.
TMR occurs when there is presentation of donor antigen to recipient CD4 T cells by antigen-presenting cells (APCs), which may be donor-or recipient-derived (direct antigen presentation = donor MHCI/II/APC; indirect antigen presentation = recipient MHC Class II/APC; see Chapter 9). Following antigen presentation, and the provision of co-stimulation through the interaction of surface pairs of co-stimulatory molecules, activated CD4 T cells provide help to CD8 (cytotoxic) T cells, phagocytes and B cells, leading to their infiltration into the graft. Cytotoxic T cells damage anddestroytargetcells viatheproductionofperforinandgranzyme, and through the induction of Fas/Fas ligand-mediated apoptosis.
Renal allograft pathology is categorised according to the Banff classification. This is a set of guidelines devised by an international consortium of transplant histopathologists who originally met in the Canadian city of Banff. They are regularly updated to incorporate advances in techniques and in the understanding of pathophysiology.
TMR can affect the tubules and interstitium, causing an inter-stitial lymphocytic infiltrate and tubulitis (Banff 1 TMR) and, in more severe cases, an arteritis (Banff 2 TMR).
The treatment for TMR is high-dose steroid (e.g. 0.5–1 g boluses of methyl prednisolone on three successive days). Baseline maintenance immunosuppression is also increased to prevent recurrent rejection. Most (80–90%) episodes of acute cellular are amenable to treatment with corticosteroids. If the patient’s creatinine does not fall in response to corticosteroids (steroid-resistant TMR) then further treatment with a lymphocyte-depleting agent such as anti-thymocyte globulin (ATG) is undertaken. ATG causes profound lymphopaenia, therefore maintenance doses of anti-proliferative agents (azathioprine or mycophenolate) should be omitted during the 10–14 days of ATG administration.
Acute antibody-mediated rejection
Acute antibody-mediated rejection (AMR) occurs in around 2–4% of transplants. The diagnosis requires:
· a decline in allograft function
· the presence of donor-specific HLA antibodies
· the presence of C4d in peritubular capillaries (PTC) on biopsy
· the presence of acute tissue injury (e.g. capillaritis) on biopsy. Recent studies suggest that non-HLA antibodies, including those recognising major histocompatibility complex class I-related chain A and B antigens (MICA and MICB) and angiotensin II type I receptor may also have an adverse impact on allograft outcomes.
DSA are produced by terminally differentiated B cells, either short-lived plasmablasts or long-lived bone marrow plasma cells. These antibodies bind to endothelium and activate complement via the classical pathway. Deposited antibody will also activate phagocytes with Fc receptors, including neutrophils.
C4d (a degradation product of C4) can be identified on peritubular capillaries and may be focal (<50% of PTCs) or diffuse (>50% of PTCs). Peritubulary capillaries may also contain inflammatory cells (capillaritis) or there may be a more severe arteritis.
There is an increasing, but unresolved, debate about whether peritubular C4d staining in the absence of graft dysfunction has prognostic significance and warrants treatment.
AMR is treated by removing DSA via plasma exchange or immu- noadsorption, and preventing antibody-associated inflammation with corticosteroids and lymphocyte depletion with ATG. The treatment strategy should also aim to prevent the synthesis of further antibody; however, this is difficult to achieve with current therapies. In de novo AMR in a previously non-sensitised patient, some DSA may be produced by short-lived splenic plasmablasts. These may be reduced by treatment with the CD20 antibody rituximab, as some of these plasmablasts continue to express CD20, and their B cell precursors will also be depleted. In sensitised patients, long-lived bone marrow plasma cells may be the source of antibody, replenished by memory B cells. These are not amenable to rituximab treatment but DSA-producing plasma cells may be sensitive to proteosome inhibition with bortezomib.
An alternative to antibody elimination is to block antibody-mediated graft injury. Eculizumab, an antibody against the C5 complement component, is effective in preventing complement-mediated red cell lysis in patients with paroxysmal nocturnal haemoglobinuria. Recent data suggest that eculizumab may also be effective in preventing DSA-mediated complement activation in the allograft. Even with treatment, AMR may result in chronic allograft damage and is a much more serious condition than TMR.