Why and how of renal allograft rejection and why the different types of rejection need to be treated differently.

Since renal transplants took off in the 1960s the bugbear of allograft rejection hit nephrologists and their patients. It became the problem that had to be dealt with immediately and for the duration of the patient’s life.

The introduction of immunosuppression by means of powerful calcineurin inhibitors in the 1980s and better immunologic matching of recipients with donors changed the character of acute rejection. The overall risk of acute rejection within 1 year after transplantation is now less than 15%. Although the management of acute rejection has been much improved, chronic rejection and survival beyond 5 years remain problems that need attention. That attention is being given to this problem a series of conferences known as the Banff Conference, the 10th one held in Canada which I mention here.

The 10th Banff Conference on Allograft Pathology was held in Banff, Canada from August 9 to 14, 2009. A total of 263 transplant clinicians, pathologists, surgeons, immunologists and researchers discussed several aspects of solid organ transplants with a special focus on antibody mediated graft injury. The willingness of the Banff process to adapt continuously in response to new research and improve potential weaknesses, led to the implementation of six working groups on the following areas: isolated v‐lesion, fibrosis scoring, glomerular lesions, molecular pathology, polyomavirus nephropathy and quality assurance. Banff working groups will conduct multicenter trials to evaluate the clinical relevance, practical feasibility and reproducibility of potential changes to the Banff classification. There were also sessions on quality improvement in biopsy reading and utilization of virtual microscopy for maintaining competence in transplant biopsy interpretation. In addition, compelling molecular research data led to the discussion of incorporation of omics‐technologies and discovery of new tissue markers with the goal of combining histopathology and molecular parameters within the Banff working classification in the near future.

The 2017 Banff Conference was held in Barcelona, Spain. The 2019 Banff Conference was held in Pittsburgh, Pennsylvania, and the 2021 Banff Conference will be in Banff, Alberta, Canada. These are held by the Banff Foundation for Allograft Pathology – BANFF

Rejection can be:

  1. Hyperacute (occurring within minutes),
  2. Acute (occurring within days to weeks),
  3. Late acute (occurring after 3 months),
  4. Chronic (occurring months to years after transplantation).

Rejection can also be classified according to pathophysiological changes:

  1. cellular-interstitial
  2. vascular, antibody-endothelial)
  3. severity (extent of histologic inflammation and injury, as scored and graded by means of the Banff schema)
  4. response to treatment (presence or absence of glucocorticoid resistance)
  5. presence or absence of renal dysfunction (indicating acute or subclinical rejection, respectively)
  6. immunologic mechanisms (adaptive or innate immune system response).

The Innate Immune System.

Who are the culprits?

The T cells. Whenever there is innate injury pathways of inflammation are upregulated, and aggravate the rejection process either directly or indirectly through the activation and recruitment of T lymphocytes. Injured tissues express ligands of the toll-like receptor system — damage-associated molecular-pattern (DAMP) molecules — and other innate danger molecules. Toll-like receptors normally detect pathogens, but they can also sense the presence of foreign-tissue molecules and can produce factors that cause the maturation and activation of dendritic cells. Dendritic cells (DCs), named for their probing, ‘tree-like’ or dendritic shapes, are responsible for the initiation of adaptive immune responses and hence function as the ‘sentinels’ of the immune system and were initially mistaken for cutaneous nerve cells.

The complement system.

Another element of innate immunity, the complement system, produces C3a and C5a, which directly activate intragraft T cells and antigen-presenting cells. Antigenpresenting cells (APCs) are a heterogeneous group of immune cells that mediate the cellular immune response by processing and presenting antigens for recognition by certain lymphocytes such as T cells. Classical APCs include dendritic cells, macrophages, Langerhans cells and B cells.

An increase in major-histocompatibility-complex (MHC) class I peptide–related sequence A (MICA) antigens on endothelial surfaces can activate natural killer cells and CD8 T cells. Moreover, there is an association between poor graft outcomes and sensitization to the highly polymorphic MICA antigens in HLA-matched transplants.

Who are you going to chose as a donor?

Transplants obtained from a spouse, friend, or altruistic donor under optimal physiological conditions and with shorter ischemia times lead to excellent results, even when genetic and HLA differences are greater than from deceased donors, who are of older age, with the presence of hypotension or hypertension, diabetes, renal impairment, donation after cardiac death, and prolonged ischemia of the graft due to a delay in shipping.

Who has preformed antibodies?

Antibodies that can mediate rejection include those against HLA molecules, endothelial-cell antigens, and ABO blood-group antigens on endothelial cells and red cells. Most recipients do not have antibodies against HLA molecules before transplantation unless they were sensitized by exposure to alloantigens through pregnancy, blood transfusion, or previous transplantation.

Antibodies against ABO antigens. Will you use a kidney donor who is ABO incompatible?

Kidneys selected for transplantation are routinely assigned to recipients with a compatible blood group; however, ABO-incompatible kidneys have been successfully transplanted with the use of an experimental protocol that entails perioperative removal of antibodies from the recipient by means of plasmapheresis or immunoadsorption. After they have been removed, anti–blood-group antibodies can rise to pretreatment levels after transplantation, adhere to the microvasculature, and activate complement, yet they generally do not injure the endothelium. This anomaly has been attributed to “accommodation” within the kidney, but the mechanism responsible for this benign response is unknown. In contrast, injury to the graft by anti-HLA antibodies is frequently insidious, and accommodation is uncommon.

Hyper acute rejection/ activation of complement cascade in the graft.

Rejection of the renal graft that occurs almost immediately after release of the vascular cross-clamps is classified as hyperacute. Instead of “pinking up” as a result of normal reperfusion, the kidney appears flaccid and mottled, reflecting the deposition of antibodies against HLA antigens expressed on the endothelium of the glomeruli and microvasculature. Activation of the classic complement cascade within the graft is followed by endothelial necrosis, platelet deposition, and local coagulation. In these cases, the initial transplant ends with removal of the kidney.

Acute Antibody-Mediated Rejection.

Can this be delayed for weeks? Why is it necessary to recognize that it is antibody mediated?

Antibody-mediated rejection often begins within days after transplantation (or within weeks, if antilymphocyte antibody therapy was given). The main feature is rapid graft dysfunction due to inflammation. An anamnestic response engendered by previous exposure to the relevant antigen rapidly generates high titers of complement-fixing antibodies. The main targets of these “recall” antibodies are MHC antigens displayed by the endothelium of the donor peritubular and glomerular capillaries.

Is the rejection likely to be steroid resistant?

 Agonistic angiotensin II type 1 (AT1)–receptor antibodies have been associated with corticosteroid-resistant vascular rejection accompanied by malignant hypertension, but their pathogenic role remains unclear. Microthrombi, with hemorrhage and arterial-wall necrosis and infarction, occur in severe cases. Detection of potentially harmful antibodies before transplantation should prompt a search for an alternative donor or an aggressive approach to post-transplantation management.

Early diagnosis and treatment are essential for salvaging grafts undergoing acute antibody-mediated rejection. Treatments include removal of antibodies by plasmapheresis or immunoadsorption, high-dose pulses of glucocorticoids, intravenous immune globulin, and antiproliferative agents. Supplementary therapies include rituximab or antilymphocyte antibody, if there is concurrent T-cell–mediated rejection. These treatments can be useful when given as prophylaxis to highly sensitized or ABO-mismatched recipients.  Eculizumab (a monoclonal antibody that inhibits the cleavage of C5) and bortezomib (a proteasome inhibitor that can inhibit plasma cells) are new, investigational agents that have shown promise in preliminary studies of antibody-mediated acute rejection, but the results require confirmation.

T cell mediated acute rejection.

This is the most common form of acute allograft rejection. It is initiated when donor alloantigens are presented to the T lymphocytes of the recipient by antigen-presenting cells (APCs). Immature dendritic cells within the graft carry donor antigens from the transplanted organ to the recipient’s draining lymph nodes and spleen; during their journey, these antigens mature into APCs. The recipient’s antigen-presenting dendritic cells also participate and circulate through the graft. The APCs then home to lymphoid organs, where they activate the recipient’s T cells. These T cells differentiate into various subgroups and return to the graft, where they take part in destroying the transplanted organ.

Endogenous antigens are digested into peptides by proteosomes and are loaded into class I MHC. Exogenous antigens are degraded in or within endosomes and are loaded into class II MHC. Assembly of the MHC within the cell’s endoplasmic reticulum precedes its transport through the Golgi apparatus and its ultimate expression on the cell surface along with peptide, where the MHC–peptide complex interacts with CD8+ or CD4+ T lymphocytes. β2m denotes β2-microglobulin, CLIP class II-associated invariant-chain peptide, and TAP transporter associated with antigen processing.

Role of the T cells in recognizing antigens.

The T cells in graft rejection seem to be more experienced in recognizing allograft antigen (up to 10% will recognize antigens versus 1% in normal people). They pick up the antigen displayed by the APCs from the donor (direct pathway) and the recipient (indirect pathway). They have a low threshold for reacting to MHC antigens. The recipient’s APCs can also take up membrane fragments of other cells; these fragments contain MHC molecules bearing “predigested” peptides derived from the donor’s MHC glycoproteins (the semidirect pathway). APCs can present such MHC–peptide complexes to CD4 T cells, which in turn activate CD8 T cells.

This picture may help you understand the differentiated T cells and their products.

After presentation of antigen by the antigen-presenting cell (APC), naive T lymphocytes become activated, proliferate, and differentiate into subtypes with characteristic cytokine profiles. Type 1 helper T (Th1) cells drive the cellular immune response, and type 2 helper T (Th2) cells produce the humoral immune response. Regulatory T (Treg) cells can limit the rejection response, and type 17 helper T (Th17) cells can mediate glucocorticoid-resistant rejection. APC denotes antigen-presenting cell, DC donor cell, IFN-γ interferon-γ, MHC major histocompatibility complex, TCR T-cell receptor, and TGF-β transforming growth factor β.

T-cell activation requires signals other than those engendered by the MHC–peptide complex, termed costimulatory signals. T cells become anergic when presented with an antigen in the absence of these signals, and agents that block these signals are under development. Early clinical trials of agents that block costimulation were disappointing; Belatacept, a fusion protein containing CTLA-4 and the Fc fragment of IgG1, blocks T-cell stimulation engendered by the CD80–CD28 and CD86–CD28 pathways. Clinical trials are assessing this more potent inhibitor as a potential replacement for nephrotoxic calcineurin inhibitors.

How do CD8 cells physically damage the graft itself?

 Invading CD8 T lymphocytes, which have immunologic specificity for the allograft, cross the basement membrane of the tubule, where they proliferate and induce apoptosis of tubular cells. Sublethally injured tubular cells can also transform from their native epithelial phenotype into primitive mesenchymal myofibroblasts, promoting interstitial fibrosis. Necrosis of tubular epithelial cells and basement-membrane rupture cause urinary leakage, graft dysfunction, and progressive tubular atrophy.

Acute vascular rejection.

Vascular rejection is a severe condition that does not respond to glucocorticoid therapy and instead requires potent antilymphocyte-antibody therapy (muromonab-CD3 [Orthoclone OKT3, Ortho Biotech] or antithymocyte globulin).

Late acute allograft rejection

Late acute allograft rejection is often severe and difficult to reverse, with a high risk of subsequent graft loss. Its main features are active immune inflammation and chronic tubulointerstitial damage, which frequently involves graft-directed antibody. It can develop in graft recipients with high-grade immunity against the transplant or in those who receive reduced amounts of immunosuppressive therapy because of cancer, prior severe infection, or noncompliance.

Chronic allograft rejection — ongoing immune injury to the graft — is due to a failure to maintain sufficient immunosuppression to control residual antigraft lymphocytes or antibodies. Its features include a progressive decline in renal function, invasion of the renal parenchyma by T cells, and persistent infiltration of the interstitium by T cells and macrophages. Occasionally, one also sees smooth-muscle proliferation and hyperplasia in vessels, forming a neointima; focal destruction of internal elastic lamina; and finally, vascular occlusion.

What does the future hold?

Despite technical advances and improvements in management, the alloimmune response remains the primary obstacle to successful kidney transplantation. Rejection of the graft entails much more than T-cell responses. Other elements include the innate immune system of natural killer cells, macrophages, and complement; the adaptive immune system of antigen-specific T lymphocytes and B cells; and cells intrinsic to the graft, such as endothelium. Antibody-mediated rejection is increasingly recognized as a contributor to late graft injury.

Current therapies are focused on the initial stages of T-cell activation, and this strategy has minimized early acute rejection. However, we need to improve our understanding of the mechanisms underlying chronic graft dysfunction and develop better treatments to prevent loss of the graft. Protocols that are designed to induce immunologic tolerance and the transplantation of organs in highly sensitized patients (those previously exposed to alloantigens) are also likely to alter the nature and presentation of rejection.

REVIEW ARTICLEMECHANISMS OF DISEASE. REJECTION OF KIDNEY ALLOGRAFT.

  1. Brian J. Nankivell, M.D., Ph.D., 
  2. and Stephen I. Alexander, M.B., B.S., M.P.H.

October 7, 2010
N Engl J Med 2010; 363:1451-1462
DOI: 10.1056/NEJMra0902927

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shaheenmoin

I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

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