Studies have investigated the potential pathogenic effects of non-HLA antibodies (Ab), with a few reporting that Ab against the angiotensin II type 1 receptor (AT₁R) are a risk factor for rejection and graft loss. This study sought to validate the risk of AT₁R Ab for acute rejection and to explore the role of other non-HLA Ab in this regard.

Pre- and post-transplant sera from a selected cohort of 102 patients (n=455 samples) were tested for AT₁R Ab and other non-HLA Abs. Serum from healthy living donors (n=10) was used as a non-transplant control. AT₁R Ab was tested using a commercially available ELISA kit, with readout assigning a negative, at risk, or positive value. Antibodies against other non-HLA targets including the endothelin-A receptor (EDNRA) were detected using the Luminex platform. Based on EDNRA Ab MFI levels found in living donors (MFI 787±741), we assigned risk categories, with 93 samples at risk (1528<MFI<3010), and 18 samples were positive (MFI>3010).

Contingency analyses were performed based on AT₁R Ab status at the time of transplant. Patients “at risk” or “positive” for AT₁R Ab at time of transplant were more likely to experience an acute rejection within the first 12 months post-transplant (51% vs, 16%, p=0.0181). Further, patients “at risk” or “positive” for AT₁R Ab had higher rates of dnDSA (n=43/53) compared to patients without dnDSA (n=33/49, p=0.0458). Mean time to dnDSA development was 59.1 ± 38.9 months. Pre-transplant levels of EDNRA Ab were significantly higher in patients with acute rejection in the first 12 months post-transplant (MFI 1301±1010 vs 985±970, p=0.0406). When we examined pre-transplant sera, all patients that were positive for EDNRA Ab were also positive or at risk for AT₁R Ab (p=0.0089).

As AT₁R and EDNRA are G-coupled protein receptors expressed on endothelium, it suggests that patients become sensitized pre-transplant due to prior endothelial injury. The linkage to subsequent acute rejection suggests that these antibodies may be inducing endothelial injury in the graft, creating an environment favouring allorecognition. Moreover, these antibodies could be considered a risk factor for early acute rejection.

CITATION INFORMATION: Gareau A, Wiebe C, Pochinco D, Gibson I, Rush D, Nickerson P. Preformed Antibodies Against AT₁R and EDNRA Correlate with Rejection Post-Transplant. Am J Transplant. 2016;16 (suppl 3).

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