ArticlesAntibody-mediated vascular rejection of kidney allografts: a population-based study
Introduction
Kidney transplantation is the treatment of choice for patients with end-stage renal disease, improving survival and quality of life and lowering costs compared with dialysis.1, 2, 3 The alloimmune response induced by transplantation from a donor who differs genetically from the kidney recipient has always been the major obstacle to graft success. When not controlled, this response will destroy the graft,4 leading to increased morbidity, mortality, and costs.
In the past decade, the view of acute allograft rejection has changed greatly. Although rejection was initially thought to be a T cell-mediated process, humoral mechanisms have progressively been recognised and are now acknowledged to lead to high rates of graft loss in HLA-incompatible kidney transplants.5, 6 International classification presently includes two acute rejection phenotypes: T cell-mediated rejection and antibody-mediated acute rejection.7, 8 However, rejection phenotypes and outcomes are more complex in clinical practice than in theory. Phenotypes might be difficult to identify or missed entirely, with direct negative effects on therapeutic management.
Vascular rejection of kidney allografts—defined by endarteritis, which is infiltration of immune cells beneath the endothelium—has been thought to be a T cell-mediated process.4 Since the late 1990s, vascular rejection has been reported as a severe clinical disorder that does not respond to usual treatments directed at T cells.4 More recently, clinical findings have suggested its association with alloantibodies,9, 10, 11, 12 challenging the notion of a unique T cell-mediated rejection process in vascular rejection. Importantly, these findings have been extended to transplantation of hearts,13 composite tissues,14 and small bowels,15 and are reinforced by murine models showing that alloantibodies interact with vessels,16, 17 pointing towards a general idea of vascular damage and immune-mediated arteriosclerosis.18
We thus aimed to redefine rejection patterns by addressing their distinct clinical, histological, and immunological phenotypes, and their prognoses. In view of new immunosuppressive drugs available, such information would be particularly useful for adaptation of treatment strategies to rejection type, which might improve long-term prognoses of kidney allografts. We postulated that vascular rejection could be associated with anti-HLA antibodies, which might have important clinical implications for graft survival.
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Participants
Patients who underwent kidney transplantation in Necker Hospital and Saint-Louis Hospital (Paris, France) between Jan 1, 1998, and Dec 31, 2008, were included in our population-based study. Patients were followed up until March 31, 2010. We used an additional independent validation sample of patients who underwent kidney transplantation in Foch Hospital (Suresnes, France) between Jan 1, 2004, and Jan 31, 2010 (appendix).
All transplants were ABO compatible (ie, donors and recipients had the same
Results
2079 patients received a kidney allograft in Necker Hospital or Saint-Louis Hospital, of whom 302 (15%) had acute biopsy-proven rejection. Table 1 shows the characteristics of recipients at time of renal transplantation who subsequently did and did not have acute allograft rejection. Acute biopsy-proven rejection occurred at a median of 3·1 months post-transplant (IQR 1·0–11·3). 790 patients provided 952 indication biopsy samples. 147 samples (15%) showed acute tubular necrosis, 64 (7%)
Discussion
We have defined four relevant clinical phenotypes of rejection after kidney transplantation. With contemporary immunological and histopathological techniques, we have shown that the previously unrecognised phenotype of antibody-mediated vascular rejection is characterised by endarteritis, associated with circulating donor-specific anti-HLA antibodies, and has the poorest graft survival. Our data suggest that antibody-depleting strategies could be beneficial in the long term in patients with
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These authors contributed equally