An Update on Alloantibody and Post-Transplant Failure

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There have been a number of studies reported in the past month which broaden our understanding of the complexity of alloantibodies post kidney transplant. It is well recognized that the presence of donor specific anti-HLA antibodies (DSA) infers a worse allograft prognosis, both in terms of early antibody mediated rejection (AMR) and graft survival. It is also becoming clear, from groups such as the DeKAF study investigators, that most causes of late graft failure are due to chronic AMR. Treatment options for this entity are unfortunately dismal at present. Our current understanding of immunological risk is somewhat simple and DSA alone do not fully explain a patients’ risk of AMR events. AMR can occur without DSA, presumably due to non-HLA antibodies (see NEJM MICA antibodies paper). Moreover, the presence of DSA alone does not necessarily associate with immunological injury. Recent studies help with our understanding of these important points.
Non-HLA antibodies
Two reports in the current edition of American Journal of Transplantation identify antibodies against Angiotensin II type-1 receptor (Anti-AT1R), with AMR and allograft failure. Anti-AT1R have previously been associated with AMR and polymorphisms in AT1R have been associated with steroid resistant acute rejection. In the first AJT study, 351 consecutive kidney recipients had sera tested for anti-AT1R. In patients with abnormal biopsies/acute rejection, the rate of anti-AT1R was significantly higher than the control group (18% vs. 6%, p < 0.001). What is novel however is the survival data; with 79% of abnormal biopsy patients with anti-AT1R losing their grafts (vs. 0% in control group). Patients with both anti-AT1R and DSA had lower graft survival than those with DSA alone. In a multi-factorial model, de novo anti-AT1R was an independent predictor of graft failure.
second report included 599 kidney recipients and determined a cut-off of anti-AT1R >10 U, with individuals above this level having 2.6-fold higher risk of graft failure from 3 years onwards (p = 0.0005) and a 1.9-fold higher risk of experiencing an acute rejection episode in the first 4 months (p = 0.0393). Notably, AMR only accounted for one third of all acute rejection cases.
       Complement-binding DSA
What makes some DSA pathogenic and others not? Does the complement-binding capacity of anti-HLA antibodies play a role in their capacity to cause immunological injury? This question was partially addressed in this French NEJM study of 1016 kidney transplant recipients. Complement-fixing DSA (tested for the presence of C1q-binding by single-antigen bead assays) were associated with more C4 deposition, more AMR and worse allograft survival (54% V 93% 5 year survival). Interestingly, patients with no DSA and those with non-complement binding DSA had similar 5 year survivals.
Overall, these studies certainly add to our understanding of post-transplant allo-antibody but additional work needs to be done before they become clinically useful and exact indications for the tests remain unclear. Certainly in the case of Anti-AT1R, the increased risk of allograft failure needs to be clarified. Is it truly independent from Anti-HLA antibodies? Regarding Anti-HLA antibodies, it is likely that the pathogenicity of DSA is more nuanced than just their ability to fix complement. However, these studies are beginning to explain some of our unanswered questions regarding sensitization, alloantibody and post-transplant risk.

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