Angiotensin II Type 1 Receptor Antibodies: Risk for rejection and impaired graft function
Angeliki Vittoraki1, Vasilis Ch. Filiopoulos2, Kalliopi Vallianou2, Petros Kalogeropoulos2, Pavlina V. Markaki1, Maria Gkouna1, George Ch. Liapis3, Aliki G. Iniotaki2, John N. Boletis2.
1Immunology Department and National Tissue Typing Center, General Hospital of Athens, ‘G.Gennimatas’, Athens, Greece; 2Department of Nephrology and Kidney Transplantation, Medical School, National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greece; 31st Department of Pathology, Medical School, National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greece
Introduction: Several studies have identified that antibodies against the Angiotensin II type 1 receptor (AT1R-ab) are risk factors for transplant rejection and graft failure. In this study pre and de novo developed post-transplantation (Tx) AT1R-ab were validated for graft outcome in Greek renal transplant recipients (RTR).
Materials and Methods: Pre and post-Tx sera from 88 RTR were tested for AT1R-ab and donor specific HLA antibodies (DSA) using a quantitative solid-phase assay and a Luminex assay, (EIA-AT1R and Single Antigen Bead Assay, One Lambda Inc),respectively. The RTR had been transplanted between 2011-17 with negative CDC and T/B Flow crossmatch.
Forty four (n=44) RTR developed biopsy proven acute rejection episodes, 31 T cell mediated rejection (TCMR) and 13 antibody mediated rejection (AMR) and formed the study group (SG) while 44 RTR without rejection were included as control group (CG).
The RTR had available pre- and post-Tx sera stored at -70oC. Serum at the time of biopsy was also stored from all SG RTR.Serum samples were tested retrospectively for AT1R-Abs and were classified as positive (≥10U/mL) or negative (<10U/mL). For HLA-DSA an MFI>1000 was considered positive.
Results and Discussion: Preformed anti-AT1R-ab were found in 16 RTR with rejection (36.4%) as compared to 4 RTR w/o rejection (9.1%) p=0.002. The mean AT1R-ab level before Tx was significantly higher in RTR who experienced rejection as compared to RTR w/o rejection (mean±SD,20,77±42,57U/mL vs 7,583±1,845U/mL) with p<0,0001. Preformed anti-AT1R-abs were found in 35.5%(11/31) of RTR diagnosed with TCMR and 38.5%(5/13) with AMR (p=NS). No correlation of pre-AT1R-abs and development of rejection at the first year post-Tx was observed (p=NS).
At the time of biopsy 12(27.3%) RTR were positive for anti-AT1R-abs, 8 with preformed and 4 with de novo AT1R-abs. De novo post-Tx DSA were detected in 9 (20.5%) cases. In 7 (15.9%) RTR, 4 cases with AMR and 3 with TCMR, AT1R-ab and de novo DSA were detected at the same time.
During the follow up 8 RTR from the SG (4 with TCMR and 4 with AMR) lost the graft vs 0 from the CG, p=0.0094. No difference was observed in graft survival between positive and negative AT1R-ab RTR (Log-rank, p=0.48). The parallel detection of anti-AT1R-ab and DSA was not correlated with graft loss.
In patients with functioning graft, the renal function was better, but not significantly, in RTR w/o AT1R-ab with creatinine 2±1,56mg/dl and eGFR (CKD-EPI) 47,95±25,36 ml/min/1.73m2 comparatively to positive RTR for AT1R-abs with creatinine 3,042±2,446mg/dl and eGFR 37,29±20,54ml/min/1.73m2.
Conclusion: This study confirms previous observations that preformed before Tx and de novo post- Tx AT1R-abs characterize patients with high risk of TCMR or AMR. These antibodies may co-exist with de novo DSA and are associated with impaired graft function. Screening for these antibodies may identify patients with high immunological risk and help clinicians to fine tune immunosuppression.
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