Early Acute Microvascular Kidney Transplant Rejection in the Absence of Anti-HLA Antibodies Is Associated with Preformed IgG Antibodies against Diverse Glomerular Endothelial Cell Antigens

Abstract

Background Although anti-HLA antibodies (Abs) cause most antibody-mediated rejections of renal allografts, non-anti-HLA Abs have also been postulated to contribute. A better understanding of such Abs in rejection is needed. MethodsWe conducted a nationwide study to identify kidney transplant recipients without anti-HLA donor-specific Abs who experienced acute graft dysfunction within 3 months after transplantation and showed evidence of microvascular injury, called acute microvascular rejection (AMVR). We developed a crossmatch assay to assess serum reactivity to human microvascular endothelial cells, and used a combination of transcriptomic and proteomic approaches to identify non-HLA Abs. ResultsWe identified a highly selected cohort of 38 patients with early acute AMVR. Biopsy specimens revealed intense microvascular inflammation and the presence of vasculitis (in 60.5%), interstitial hemorrhages (31.6%), or thrombotic microangiopathy (15.8%). Serum samples collected at the time of transplant showed that previously proposed anti-endothelial cell Abs-angiotensin type 1 receptor (AT1R), endothelin-1 type A and natural polyreactive Abs-did not increase significantly among patients with AMVR compared with a control group of stable kidney transplant recipients. However, 26% of the tested AMVR samples were positive for AT1R Abs when a threshold of 10 IU/ml was used. The crossmatch assay identified a common IgG response that was specifically directed against constitutively expressed antigens of microvascular glomerular cells in patients with AMVR. Transcriptomic and proteomic analyses identified new targets of non-HLA Abs, with little redundancy among individuals. ConclusionsOur findings indicate that preformed IgG Abs targeting non-HLA antigens expressed on glomerular endothelial cells are associated with early AMVR, and that in vitro cell-based assays are needed to improve risk assessments before transplant.

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“…At 4 months, the transplant biopsy showed mild inflammatory glomerular lesions (g1), no allograft glomerulopathy and only rare and focal sequelae of thrombotic microangiopathy. This case was classified by IDSMB as a rare case of acute humoral rejection without DSA, as recently described . The second patient presented venous graft thrombosis at day 1.…”

Novel insights into non‐HLA alloimmunity in kidney transplantation

“…Overall, these studies revealed a broad variety of antigens associated with rejection and chronic allograft injury. Most recently, Delville et al identified 38 patients with acute microvascular rejection in the absence of anti‐HLA antibodies in a French nationwide cohort of kidney transplant recipients. Microvascular inflammation serves as surrogate for an antibody‐mediated injury in the graft.…”

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“…In recent years, multiple studies have been published showing a relation between the presence of non‐HLA autoantibodies and graft loss and/or rejection episodes . Although none of these studies have proven that autoantibodies actually contribute to the pathogenesis of graft dysfunction, the data indicate that detection of non‐HLA antibodies may be useful in identifying patients at risk for graft loss.…”