Rejection of kidney transplantation
- Dragun, D. N. Müller, and R. Dechend et al described AT1R-Ab as a risk factor for a rejection after kidney transplantations for the first time in 2005 (1). In a translational approach, they identified the role of anti-AT1R aab as drivers for non-HLA-dependent transplant rejections.
- L. Reinsmoen et al. showed for the first time a correlation between anti-AT1R-aab levels and antibody-mediated rejection (AMR) in patients without antibodies against human leukocyte antigen (HLA) or major histocompatibility class I chain-related gene A (MICA) (2). Sera from 63 recipients were determined to have no HLA- donor-specific HLA antibodies (DSA) and no donor-specific MICA antibodies pre-transplant and at the time of acute rejection AR 16 of these recipients were diagnosed with AR including seven with AMR and nine with cellular AR (cell-mediated rejection). High-binding AT1R antibodies were identified in six of seven in the AMR+ group, but in none of nine patients with the cell-mediated rejection (P=0.0009).
Anti-AT1R aab are an independent risk factor for the loss of function of kidneys after a Transplantation. P. I. Terasaki et al. tested anti-AT1R aab and DSA in pre and post-transplant sera from 351 consecutive kidney recipients (3). 134 patients have biopsy-proven rejection and/or lesions and 217 remain free of rejections (control group patients). The rate with rejection or lesions of anti-AT1R was significantly higher compared to the control group (18% vs. 6%, p < 0.001). Moreover, 79% of patients with rejection or lesions with anti-AT1R aab lost their grafts (vs. 0% in the control group). Anti-AT1R aab levels increased post-transplant in 58% of the patients with graft failure. Patients with both anti-AT1R aab and DSA had lower graft survival than those with DSA alone (log-rank p = 0.007). Multivariate analysis showed that anti-AT1R aab levels above the cut-off were an independent predictor of graft failure in the abnormal biopsy group (ABG), alone (HR: 6.6.) and in the entire population (HR: 5.4.).
In addition, J.P. Soulillou et al. showed that the presence of pre-transplant anti-AT1R aab are an independent risk factor for long-term graft loss in association with a higher risk of early acute rejection (AR) episodes (4). The study included 599 kidney recipients between 1998 and 2007 from Nantes, France. Patients with anti-AT1R aab levels >10 U had a 2.6.-fold higher risk of graft failure from 3 years post-transplantation onwards (p = 0.0005) and a 1.9.-fold higher risk of experiencing an AR episode within the first 4 months of transplantation (p = 0.0393).
In the following years a higher risk of a rejection after kidney transplantation related to the presence of anti-AT1R aab was confirmed by more groups (5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19). Furthermore anti-AT1R aab are a marker for the deterioration of organ function after transplantation independent of or together with donor-specific antibodies (20, 21, 22, 23, 24, 25, 26). Moreover, recurrence of focal segmental glomerulosclerosis (FSGS) in the kidneys post transplantation is a major problem. The detection of anti-AT1R aab levels before transplantation appears to be a helpful biomarker in identifying patients at high risk of post-transplant FSGS recurrence (23, 27, 28).
Due to the overwhelming evidence NL Reinsmoen, Cedar Sinai Los Angeles, stated in a review (29) the absolute necessity to stratify the immunological risk of patients before kidney transplantation (and probably heart transplantation) by examining HLA as well as non-HLA antibodies. Hence, she voted for the implementation of tests determining anti-AT1R aab in the profile of routine clinical antibody analyses Profile (30). In addition, the XIII Banff meeting, associated with the Canadian Society of Transplantation in Vancouver, reviewed the clinical impact of the relationship of donor-specific antibody tests (anti-HLA and non-HLA) with transplant histopathology for the first time (31). It was highlighted that anti-AT1R aab can produce allograft injury alone or together with anti-HLA DSAs. Because rising healthcare costs dictate judicious use of laboratory testing, the department of Medicine, Johns Hopkins University School of Medicine, Baltimore sought to define characteristics of kidney transplant recipients who may benefit from screening for anti-AT1R aab (28). Philogene MC, Montgomery RA, Leffell MS, Zachary AA et al. investigated Kidney recipients transplanted between 2011 and 2016 at Johns Hopkins, for anti-AT1R aab. Pre-transplant antibody levels were compared to clinical and biopsy indications of graft dysfunction. Biopsies were graded using the Banff’ 2009-2013 criteria. Patients with focal segmental glomerulosclerosis (FSGS) showed higher titers of anti-AT1R aab at time of transplantation (p=0.04). In addition, recipients who were positive for anti-AT1R aab prior to transplantation had increases in serum creatinine within 3 months post-transplantation (p<0.0001) and developed abnormal biopsies earlier than did anti-AT1R aab negative patients (126 days versus 368 days respectively; p=0.02).
Anti-AT1R aab are strongly associated with antibodies against the endothelin receptor type-A (ETAR) and the ab levels correlate with each other (32). In heart transplant recipients, cardiac allograft vasculopathy (CAV) is a major factor of morbidity and mortality in the long-term graft outcome. R. Hetzer et al. discovered an association between elevated levels of anti-AT1R and anti-ETAR aab with early onset of microvasculopathy as well as with antibody mediated rejection (AMR) and with cellular-mediated rejection (CMR) (33). In a study of 30 cardiac transplant recipients, patients with high pre-transplant levels of anti-AT1R and anti-ETAR aab presented CMR, AMR, and microvasculopathy more often than patients without these antibodies at one year post-transplant (p=0.041, p=0.0002, and p=0.048, respectively).
- Kobashigawa established that the presence of both DSA and non-HLA specific antibodies appeared to increase the risk of heart allograft rejection (34). In 200 heart recipients, freedom from AMR and/ or CMR was significantly decreased at two years’ post-transplant when both de novo DSA and increased AT1R antibodies levels were identified; the hazard ratio was 7.1 for patients with de novo DSA (P=<0.0002), 2.0 for patients with anti-AT1R aab levels >12 U (P=0.2), and 10.5 when both de novo DSA and AT1R antibody levels >12 were considered (P=<0.0001).
These two studies (33, 34) in heart transplantation indicate that antibodies to the non- HLA antigens AT1R and ETAR have a negative impact on heart allograft outcome. Therefore anti-AT1R and anti-ETAR aab were described in the Banff 2015 Heart Meeting Report (35). In detail, P. Bruneval et al. indicate that newly ELISAs allow a reliable detection of anti-AT1R and anti-ETAR aab (CellTrend GmbH, Luckenwalde, Germany). These reagents together with the availability of proficiency testing programs have allowed their implementation in testing for clinical Transplantation.
A few weeks ago N. Reinsmoen et al. published the development of anti-AT1R aab after mechanical circulatory support device implantation (36). The implantation of mechanical circulatory support devices significantly increases anti-AT1R aab levels. The saturated level of anti-AT1R-aab is associated with lower patient survival post implantation
O’Leary et al. identified the role of anti-AT1R and anti-ETAR aab and the interaction between HLA DSA and non-HLA autoantibodies also in liver transplant patients (37). They analyzed 1269 recipients of primary liver transplantation from January of 2000 to April of 2009 with known HLA DSA status for anti-AT1R and anti- ETAR aab pre and one year post liver Transplantation. The combination of anti-AT1R or anti-ETAR aab and HLA DSA was associated with an increased mortality risk. Isolated de novo anti-AT1R and anti-ETAR aab were associated with an increased risk of rejection and progression of fibrosis. Ohe et al. investigated 81 pediatric patients who stopped immunosuppression (IS) after living-donor liver transplants at Kyoto University Hospital in a cross-sectional study (38). After withdrawal of immunosuppression high incidence of long-term progressive graft fibrosis is a major challenge for these patients. In this study, the authors showed that all patients with a high-level of both HLA DSA and anti-AT1R aab were found to have advanced fibrosis (p<0.001).
Reinsmoen et al. determined the impact of anti- AT1R and of anti-ETAR aab on graft outcomes in lung transplantation (39). Pre-transplant and post-transplant sera from 162 lung recipients transplanted between 2011 and 2013 at Cedars-Sinai Medical Center, Los Angeles, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, and University of Texas Health Science Center, San Antonio, were tested for the anti-AT1R and anti-ETAR aab levels using the enzyme-linked immunosorbent assay (CellTrend GmbH). There was a negative impact on antibody mediated rejection (AMR)-free survival for those recipients with increased pre-transplant levels of anti-AT1R (p = 0.014) and anti-ETAR aab (p = 0.005). These findings suggest the importance to stratify the patient’s immunologic risk by assessing both the HLA and non-HLA-specific antibodies.
Stem cell transplantation
Riemekasten et al. reported the association between anti-AT1R and anti-ETAR aab and an autoimmune disorder with clinical fibrotic symptoms developed by patients with systemic sclerosis (32). The chronic graft-versus-host disease (cGVHD) after hematopoietic stem cell transplantation may have similar clinical fibrotic features and its pathogenesis could be similar to systemic sclerosis.
Based on these findings, Chiron et al investigated the association of anti-AT1R aab and cGVHD in patients after stem cell transplantation (40). Sera from 87 patients including 45 hematopoietic stem cell transplantation patients with extensive cGVHD and 42 without cGVHD were retrospectively analyzed for the presence of anti-AT1R aab using an enzymatic immunoassay (CellTrend GmbH). In the cGVHD group, anti-AT1R aab levels were significantly higher compared to the non-cGvHD group (p=0.04, 24.4% vs 7.1%).
By analyzing sera from 205 patients, Taniguchi et al. showed that patients with increasing levels of anti-AT1R aab during engraftment had significantly higher chance of developing acute GVHD (p=0.03) as those lacking this complication (41).
Banasik et al. investigated the presence of anti-AT1R and anti-ETAR aab in five patients with hand transplantations (42). Both anti-AT1R and anti- ETAR aab were found strongly positive in one patient who repeatedly developed acute rejection episodes. Therefore, further investigations are necessary to confirm a possible association between the rejection and high levels of anti-AT1R and anti-ETAR aab.
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