Abstract and Introduction
Abstract
Unlike antibody-mediated rejection (AMR) with clinical features, it remains unclear whether subclinical AMR should be treated, as its effect on allograft loss is unknown. It is also uncertain if AMR's effect is homogeneous across donor (deceased/live) and (HLA/ABO) antibody types. We compared 219 patients with AMR (77 subclinical, 142 clinical) to controls matched on HLA/ABO-compatibility, donor type, prior transplant, panel reactive antibody (PRA), age and year. One and 5-year graft survival in subclinical AMR was 95.9% and 75.7%, compared to 96.8% and 88.4% in matched controls (p = 0.0097). Subclinical AMR was independently associated with a 2.15-fold increased risk of graft loss (95% CI: 1.19–3.91; p = 0.012) compared to matched controls, but not different from clinical AMR (p = 0.13). Fifty three point two percent of subclinical AMR patients were treated with plasmapheresis within 3 days of their AMR-defining biopsy. Treated subclinical AMR patients had no difference in graft loss compared to matched controls (HR 1.73; 95% CI: 0.73–4.05; p = 0.21), but untreated subclinical AMR patients did (HR 3.34; 95% CI: 1.37–8.11; p = 0.008). AMR's effect on graft loss was heterogeneous when stratified by compatible deceased donor (HR = 4.73; 95% CI: 1.57–14.26; p = 0.006), HLA-incompatible deceased donor (HR = 2.39; 95% CI: 1.10–5.19; p = 0.028), compatible live donor (no AMR patients experienced graft loss), ABO-incompatible live donor (HR = 6.13; 95% CI: 0.55–67.70; p = 0.14) and HLA-incompatible live donor (HR = 6.29; 95% CI: 3.81–10.39; p < 0.001) transplant. Subclinical AMR substantially increases graft loss, and treatment seems warranted.
Introduction
Over 30% of the kidney transplant waitlist is comprised of sensitized patients (PRA ≥ 20%). In an effort to transplant these vulnerable patients, advances in desensitization protocols and kidney paired donation have promoted the widespread adoption of incompatible kidney transplantation at centers across the United States. While antibody-mediated rejection (AMR) occurs in approximately 5% of compatible kidney transplants, the incidence seems to be significantly higher in incompatible kidney transplant recipients, as high as 40% in some reports. As incompatible kidney transplantation and retransplantation become more common, the incidence of AMR can only be expected to increase.
AMR has long been known to threaten graft survival. However, severity of presentation varies from subclinical rejection that is found only on protocol biopsies to severe, imminently graft-threatening rejection. While the implications of developing AMR in the latter group on graft loss are clear, the effect of subclinical AMR on graft loss is less well defined. Studies to date have suggested that patients with a subclinical presentation of AMR have poorer graft function and worse pathological findings on subsequent allograft biopsies, though an association between subclinical AMR and increased graft loss has not been directly established. Furthermore, while the magnitude of AMR's effect on graft loss is estimated to range from 1.53 (95% CI: 1.21–1.91) to 4.58 (95% CI: 1.75–12.00), it remains unknown, both epidemiologically and mechanistically, if AMR differentially affects graft outcomes depending upon donor compatibility and donor type (deceased vs. live donor). Indeed, the 2013 Banff Conference on Allograft Pathology reported that, for the first time, there would be a Banff Working Group formed to evaluate possible differences between nonsensitized patients who develop AMR and patients requiring desensitization who develop AMR.
The objective of this study was to understand the risk of allograft loss associated with AMR using a well-defined set of clinicopathologic criteria. Specifically, we sought to quantify the risk of graft loss associated with a clinical versus subclinical presentation of AMR and the risk of graft loss by the type of transplant (e.g. compatible deceased donor, HLA-incompatible deceased donor, compatible live donor, HLA-incompatible live donor and ABO-incompatible live donor).