Solid organ transplantation has become an established therapy for the treatment of organ failure. Early allograft survival has improved dramatically over the last 3 decades with improvements in surgical and laboratory techniques as well as improvements in immunosuppressive regimes such as the use of the calcineurin inhibitors (CNI) Cyclosporin A and later Tacrolimus and the introduction of Sirolimus. Late graft loss however remains fairly static with 10 year graft survival at around 50% for kidneys and even lower for other organs.
Various techniques exist for monitoring graft function post transplant for signs non function and rejection, some of which do not typically involve the H&I laboratory. In the case of kidney transplantation, these include monitoring of serum creatinine levels for signs of a rise. This may be accompanied by monitoring of other signs of kidney dysfunction such as haematuria and proteinuria levels. The results of these may indicate a need for a biopsy. Biopsy signs of rejection include amongst other things, interstitial lymphocytic infiltration, interstitial fibrosis, tubulitis, tubular atrophy, vascular occlusion, thickening of glomerular capillaries, expansion and duplication of the glomerular basement membrane and C4d deposition. Other assays undertaken to assess renal function post transplant include monitoring levels of cytotoxic T lymphocyte transcripts such as granzyme B and perforin.
The role of the H&I laboratory in post kidney transplant monitoring mainly involves testing for HLA antibodies post transplant but may also include testing for other antibodies such as anti-MICA or anti-endothelial cell antibodies. HLA antibodies have been implicated in all stages of allograft rejection from the hyperacute and accelerated stage, to the acute and chronic phases. Hyperacute rejection occurs within minutes of transplant and is usually due to the presence of pre-formed donor specific antibodies. Accelerated rejection occurs within days, acute rejection occurs within days to weeks, while chronic antibody mediated rejection occurs months to years post transplant. Recent data from the 14th international histocompatibility workshop demonstrated that four year deceased donor kidney allograft survival was 20% less in patients with donor specific antibodies compared to donors with no antibodies. Care is however needed as the time between detection of circulating donor specific antibodies and allograft failure does vary considerable in different studies, with some grafts functioning normally many years post the detection of DSA. Patients with non donor specific HLA antibodies also had a significant reduction in graft survival compared to non sensitised patients. In other studies, patients with HLA and MICA antibodies alone were shown to have significantly reduced allograft survival compared antibody negative patients. Patients with MICA antibodies alone also had reduced allograft survival though the effect was less than in patients with HLA antibodies alone.
The BSHI/BTS 2010 guidelines recommend that post-transplant antibody monitoring should be performed at agreed regular intervals, at the time of biopsy and in cases of suspected rejection. Antibody testing should also be undertaken at times of declining graft function when there is no other clinical cause. The guidelines do not however recommend a testing frequency.
The testing frequency is agreed between the H&I laboratory and the transplant centre. One example is to test at 1 week post transplant, then again at 1, 3, 6 and 12 months post transplant, then annually. Some labs collect samples at three monthly intervals as in the pre-transplant setting but store these rather than routinely test them unless the patient experiences declining renal function. This strategy allows a retrospective review of the patients post transplant antibody history should rejection be suspected without the costs of routine and regular screening of all post transplant samples. For patients who undergo HLA antibody incompatible transplantation, the BTS/BSHI guidelines recommend a post transplant testing frequency that matches the risk of adverse immunological events, especially for those patients who have antibody removal prior to transplant. The testing frequency for antibody incompatible transplantation with antibody removal in some protocols is daily for the first week, followed by weekly for the first month and monthly thereafter.
Post transplant antibody testing in the UK is mainly carried out by Luminex solid phase assays. Any of the three types of Luminex assays may be used depending on the clinical scenario. Routine screening in suspected cases of rejection may use the mixed bead screen method or the phenotype panel system, with specificity confirmed by single antigen bead assays as required. Desensitisation programs will likely use single antigen bead methods. The Luminex solid phase assays have the advantage of also giving results for anti MIC antibodies.
Circulating donor specific antibodies together with C4d+ staining in biopsy in the presence of declining graft function indicate antibody mediated rejection. Early diagnosis is required if the graft is to be salvaged. Treatment options include removal of antibody by plasmapheresis, use of IvIg, use of anti-proliferative agents and Rituximab.
The H&I laboratory may also be involved in testing for antibodies to organ specific markers in other solid organ transplantation. Antibodies directed against the endothelial cell antigen vimentin for instance have been shown to be associated with the development of transplant associated vasculopathy in cardiac transplantation.
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