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Non-HLA endothelial antibodies such as agonistic antibodies that target angiotensin II receptor type 1 (AT1R) and endothelin 1 receptor type A (ETAR) have been implicated in the pathogenesis of antibody-mediated rejection (ABMR).
Objetive: To evaluate the presence of non-HLA endothelial antibodies, associated or not with the presence of donor-specific antiHLA antibodie(HLA Ab) , their clinical behavior and results one year and 2 years after the clinical event in patients with a diagnosis of ABMR.
Collaborative prospective study of two institutions : Barros Luco Trudeau Hospital(HBLT) and Santa Maria Clinic(CSM). 21 patients (19 kidney and 2 kidney pancreas) were recruited between June 1, 2019 to November 1 of 2021 ,with ABMR diagnosed by renal biopsy. Donor donor specific HLA Ab and Anti Non-HLA Antibodies (Non-HLAAb) were measured at the time of rejection. The samples were stored at -80 ºC with the objective of making the determination of non-HLA antibodies: agonistic antibodies that target the angiotensin II type 1 (ATR1) and endothelin receptor type A (ETAR2) retrospectively. HLA Ab levels >500 by luminex and >10 u/l for ATR1 and >2 pg/ml for ETAR by ELISA (one lamba LA USA: ATR1 and ETAR) are considered positive. The diagnosis of rejection was histological under Banff criteria 2013-2017 by a renal pathologist. Immunosuppressive management was according to the institutional protocol of CSM and HBLT.
21 patients with ABMR were analyzed. Age 37.9 years, 57% men, 9 living donors, 11 cadaveric donors. Nine patients (43%) presented early ABMR (<3 months) and late 12 (57%) Table 1. Of the total patients, 15 (72.4%) presented some type of antibody: 33% (7/21) specific donor HLA Ab (5 of them exclusively HLA Ab and 2 HLA Ab + non-HLA Ab); 8/21 (38%) presented only Non-HLA Ab (3 only ETAR, 2 only ATR1 and 3 ETAR+ATR). Two patients presented all three antibodies. 28.5% (6/21) did not present antibodies Figure 1. Rejections with the presence of Non-HLA Ab occurred in a median of 23 days (2 days -11 years) and with HLA Ab they occurred in a median of 5.4 years (0.3-8 years) Figure 2. In the 9 patients with early ABMR, 54% presented Non-HLA Ab and 11% HLA Ab. In 12 patients with late rejection, 50% had HLA Ab and only 25% Non-HLA Ab(p=003 Chi2 adjusted) Figure 3 . One year after diagnosis of ABMR, patients with Non-HLA Ab had a GFR of 46.5ml/min and 46.6ml/min at two years. Patients with HLA Ab had a mean GFR of 30.5ml/min at 1 year and 24/min at 2 years. There was no difference in the presence of C4d(+) or Thrombotic microangiopathy (MAT) between the groups. One patient died of sepsis and two patients have lost a graft; 1 patient lost graft due to immediate thrombosis postoperative.
In our study, ABMR in renal transplant patients is not only associated with HLA Ab but also with Non-HLA Ab (ATR1-Ab and ETAR-Ab) either alone (38%) or together with HLA Ab (48%).
Patients with Non- HLA Ab were associated with early ABMR phenotype.
In this study, renal function at 2 years was higher in the group with non-HLA Ab.
In the presence of especially early ABMR and in the absence of anti-HLA ab, it is advisable to consider identifying the presence of a Non- HLA Ab .Further studies will be required to confirm these findings.