Angiotensin II Type 1 Receptor Antibodies Research Articles

Effect of angiotensin II type 1 receptor antibodies on graft function and survival in paediatric kidney transplant recipients.

HLA donor specific antibodies (DSA) are implicated in antibody-mediated rejection (AMR), graft dysfunction and failure in kidney transplant (KT) recipients. Non-HLA antibodies including angiotensin II type 1 receptor (AT1R) may also play a role in AMR, impact graft function and survival. Data is limited in paediatric KT cohorts. We aimed to assess the prevalence and effect of pre-transplant AT1R antibodies on rejection, graft function and survival in paediatric KT recipients. This was a retrospective cohort study conducted across two paediatric centres including KT recipients with a pre-transplant AT1R antibody level. Outcomes included rejection, de novo DSA formation, graft function, failure, proteinuria and hypertension. Of 71 individuals, 72% recorded a positive pre-transplant AT1R Ab level (≥17 U/mL). Over a median follow-up of 4.7 years, AT1R Ab positivity demonstrated a trend towards increased risk of rejection however was not statistically significant (HR 3.45, 95% CI 0.97-12.35, p-value 0.06). Sensitivity analysis with AT1R Ab levels of ≥25 U/mL (HR 2.05 95% CI 0.78-5.39, p-value 0.14) and ≥40 U/mL (HR 1.32, CI 95% 0.55-3.17, p-value 0.53) validated this. De novo DSA formation occurred more frequently with AT1R Ab positivity (41% vs. 20%, p-value 0.9). AT1R Ab was not associated with hypertension, proteinuria, graft failure or dysfunction. In conclusion, this cohort study demonstrated a high prevalence of pre-transplant AT1R Ab positivity (72%). AT1R Ab positivity demonstrated a trend towards increased risk of rejection and de novo DSA formation however did not meet statistical significance. There was no association between AT1R Ab and hypertension, proteinuria, graft failure or dysfunction.

Non-HLA Antibodies to G Protein-coupled Receptors in Pediatric Kidney Transplant Recipients: Short- and Long-term Clinical Outcomes.

Angiotensin II type 1 receptor antibodies (AT1R-Abs) and endothelin-type A receptor antibodies (ETAR-Abs) are G protein-coupled receptor activating autoantibodies associated with antibody-mediated rejection, vascular pathology, increased cytokines, allograft dysfunction, and allograft loss in pediatric kidney transplant recipients in the first 2 y posttransplantation. The impact of AT1R-Ab and ETAR-Ab positivity on longer-term 5-y transplant outcomes is unknown. One hundred pediatric kidney transplant recipients were tested for ETAR-Ab and AT1R-Ab on serially collected blood samples in the first 2 y posttransplant. Biopsies were collected per protocol and 6, 12, and 24 mo posttransplant and at any time during the 5-y follow-up period for clinical indication. Clinical outcomes, including renal dysfunction, rejection, HLA donor-specific antibodies, and allograft loss, were assessed through 5 y posttransplantation. AT1R-Ab or ETAR-Ab were positive in 59% of patients. AT1R-Ab or ETAR-Ab positivity was associated with greater declines in estimated glomerular filtration rate, and de novo AT1R-Ab or ETAR-Ab was associated with allograft loss in the first 2 y posttransplant. There was no association between antibody positivity and rejection, antibody-mediated rejection, or allograft loss in the first 5 y posttransplant. In a model controlled for age, sex, immunosuppression, and HLA mismatch, AT1R-Ab or ETAR-Ab positivity was significantly associated with the development of HLA donor-specific antibodies at 5 y posttransplant (odds ratio 2.87, P = 0.034). Our findings suggest temporally distinct clinical complications associated with AT1R-Ab or ETAR-Ab positivity in pediatric patients; these injury patterns are of significant interest for developing effective treatment strategies.

Antibodies against angiotensin II receptor type 1 and endothelin A receptor are increased in COVID-19 patients.

Increased titers of autoantibodies targeting the G-protein-coupled receptors angiotensin II type 1 receptor (AT1R) and endotelin-1 type A receptor (ETAR) are associated with severe coronavirus disease 2019 (COVID-19) infection. The aim of this study was to determine whether 1) these antibodies are specifically related to COVID-19 disease pathogenesis or increased during any severe respiratory illness, 2) if they are formed during illness, and 3) if they correlate with inflammatory markers or long-term symptoms. Antibodies against AT1R, ETAR, and antinuclear antibodies (ANAs) were measured in n=40 prospectively enrolled COVID-19 patients and n=207 COVID-19 patients included in a biobank. Clinical and laboratory findings were prospectively and retrospectively assessed in both cohorts, and results were combined for analysis. The presence of auto-antibodies against AT1R or ETAR in peripheral blood was compared between hospitalized patients with COVID-19 and controls (n=39). Additionally, AT1R and ETAR titers were compared between patients with an unfavorable disease course, defined as intensive care admission and/or death during hospital admission (n=121), to those with a favorable disease course (n=126). A subset of intubated patients with severe COVID-19 were compared to intubated patients with acute respiratory distress syndrome (ARDS) due to any other cause. Significantly increased AT1R and ETAR antibody titers were found in COVID-19 patients compared to controls, while titers were equal between favorable and unfavorable COVID-19 disease course groups. On ICU, intubated patients with COVID-19 had significantly increased AT1R and ETAR titers compared to patients with ARDS due to any other cause. The titers did not correlate with baseline inflammatory markers during admission or with diffusion capacity, cognitive impairment, or fatigue measured at 3 months follow-up. In patients hospitalized for COVID-19, antibodies against AT1R and ETAR are increased compared to controls and patients with ARDS due to other causes than COVID-19. The baseline antibody titers do not correlate with inflammatory markers or long-term symptoms in this study.

Loss of anti-AT1R reactivity in ELISA post-adsorption - False reactivity or interference in the assay?

Autoantibodies to Angiotensin II type 1 receptor (AT1R) are associated with detrimental outcomes in organ transplants. However, reports showed that adsorption with latex beads reduced positive anti-AT1R antibodies, suggesting possible false reactivity. To investigate this conundrum, we studied 11 samples positive for AT1R antibodies with an ELISA kit before and after adsorption. Adsorption significantly reduced the measurable level of AT1R antibodies (28.3±9.8 vs. 6.3±3.0 U/ml, p<0.001). AT1R antibodies were lower when post-adsorption serum was added back at 1:1 ratio to the neat serum compared to the diluent control (8.6±4.2 vs. 18.1±10.3 U/ml, p=0.02). Sham adsorption with the buffer from Adsorb Out™ kit without beads also suppressed the detection of anti-AT1R antibodies (32.7±9.1 vs. 8.1±3.9 U/ml, p<0.001). Thus, rather than actively removing nonspecific antibodies by the beads, the adsorption process introduces soluble factors that interfere with the detection of anti-AT1R antibodies with the ELISA kit.

Angiotensin II Type 1 Receptor Antibodies Are Higher in Lupus Nephritis and Vasculitis than Other Glomerulonephritis Patients

Angiotensin II type 1 receptor (AT1R) antibodies are considered non-HLA (human leukocyte antigen) antibodies connected with humoral rejection after kidney transplantation. The role of AT1R antibodies in the pathogenesis of glomerular diseases and systemic vasculitis is unknown. We assessed the level of AT1R antibodies in 136 patients with different types of glomerulonephritis and systemic vasculitis and we observed kidney function and proteinuria, serum albumin and total protein levels for 2 years. The mean levels of AT1R antibodies were the following: 6.00 ± 1.31 U/ml in patients with membranous nephropathy (n = 18), 5.67 ± 1.31 U/ml with focal and segmental glomerulosclerosis (n = 25), 6.26 ± 2.25 U/ml with lupus nephropathy (n = 17), 10.60 ± 6.72 U/ml with IgA nephropathy (n = 14), 6.69 ± 2.52 U/ml with mesangial proliferative (non IgA) glomerulonephritis (n = 6), 6.63 ± 1.38 U/ml with systemic vasculitis (n = 56), including c-ANCA (anti-neutrophil cytoplasmic antibodies) vasculitis: 11.22 ± 10.78 U/ml (n = 40) and p-ANCA vasculitis: 12.65 ± 14.59 U/ml (n = 16). The mean AT1R antibodies level was higher in patients with lupus nephropathy and systemic vasculitis compared to glomerulonephritis groups. An inverse statistically significant correlation between AT1R antibodies and serum albumin (r = − 0.51) in membranous nephropathy group was also found. Prospective analysis of creatinine levels indicated an increase of creatinine levels during time among patients with higher AT1R antibodies levels in p-ANCA vasculitis. Lupus nephropathy and systemic vasculitis patients may have high levels of AT1R antibodies. AT1R antibodies may be associated with the severity of membranous nephropathy and the course of p-ANCA vasculitis, although influence of concomitant factors is difficult to exclude.

The early impact of preformed angiotensin II type 1 receptor antibodies on graft function in a low immunological risk cohort of kidney transplant recipients

Intruduction and aim: Angiotensin II type 1 receptor antibodies (AT1R-Ab) are associated with graft rejection and poor graft outcomes in kidney transplantation (KT). We aimed to assess the frequency of preformed AT1R-Ab and their impact on graft function and survival at 1 year after KT in a low immunological risk cohort. Methods: We performed a prospective, observational cohort study in 67 adult KT recipients, transplanted between 2018 and 2019. A cut-off value >10 U/ml was used for AT1R-Ab detection. Results: The frequency of preformed AT1R-Ab was 10.4% and the median value of their level was 8.4 U/ml (IQR: 6.8–10.4). Donor-specific anti-human leukocyte antigen antibodies (HLA-DSA) were absent, no case of biopsy-proven rejection was reported and the incidence of graft failure was 7.5%. Estimated glomerular filtration rate (eGFR) was significantly reduced in the AT1R-Ab group [35 (29.8–55.2) vs 56.1 (41.3–66.5) ml/min, p = 0.02] at 1 year after KT. After multivariate linear regression analysis, preformed AT1R-Ab were found as an independent determinant of eGFR at 1 year after KT (β: -15.395; 95% CI: −30.49 - -0.30; p = 0.04). By Cox multivariate regression analysis, preformed AT1R-Ab were not associated with graft failure (HR: 1.36; 95% CI:0.10–14.09; p = 0.80). Conclusion: Preformed AT1R-Ab are an independent determinant of graft function but do not impact graft survival at 12 months after transplantation in a prospective low immunological risk cohort of KT recipients.

POS-732 A STUDY OF ANGIOTENSIN ii TYPE II RECEPTOR ANTIBODY IN RENAL ALLOGRAFT REJECTION

Preformed antibodies influence the graft outcome. The detrimental impact of anti HLA antibodies on kidney transplantation has been extensively studied. However, the impact of antibodies against non-HLA antigens is less well understood. Recent studies suggest Angiotensin II type 1 receptor antibodies(AT1RAbs) have been an independent risk factor of graft failure and Acute rejection. This study was done to determine the incidence, type of rejections and graft outcome in renal allograft recipients with high AT1R Abs level.

AT1R-Ab: A New Player in Pediatric Heart Transplant AMR?

<h3>Purpose</h3> Angiotensin II type 1 receptor antibodies (AT1R-Ab) are associated with non-human leukocyte antigen (HLA) mediated antibody mediated rejection (AMR) and graft failure in adult renal transplantation. They can be stimulated by ventricular assist device (VAD) support, but data regarding AT1R-Ab in pediatric heart transplantation (HT) are scarce. The purpose of this study is to describe the incidence of non-HLA mediated AMR and identification of AT1R-Ab in a pediatric HT cohort. <h3>Methods</h3> We performed a single-center retrospective review of children who underwent primary HT from July 2016 to July 2020. AMR was defined by the presence of complement deposition (+C4d) on heart biopsy. Non-HLA mediated AMR was defined by the absence of donor-specific HLA antibodies (HLA-DSA). AT1R-Ab testing was defined as < 10 negative, 10-17 borderline, and > 17 positive (ELISA). <h3>Results</h3> There were 100 patients who underwent primary HT during the study period (median age 4.5 years). There were 19 episodes of AMR in 17 patients. HLA-DSA were present in 12 episodes (63%) and absent in 7 (37%) episodes. Non-HLA mediated AMR occurred earlier post-HT compared to AMR with HLA-DSA (median 7 days vs 244 days, p = 0.04). Four patients with AMR in the absence of HLA-DSA were tested for AT1R-Ab; 3 were positive and 1 was borderline. Of the 3 patients with positive AT1R-Ab, 2 were previously supported on VAD, 2 had symptomatic AMR, 2 subsequently received losartan, and none have had recurrence of AMR (Table). <h3>Conclusion</h3> Non-HLA mediated AMR accounted for 37% of AMR episodes and occurred earlier post-HT compared to AMR with HLA-DSA in a single-center cohort. AT1R-Ab were present in 3 of 4 patients with non-HLA mediated AMR in whom AT1R-Ab testing was performed. In light of the recent data regarding AT1R-Ab in renal transplantation, investigation of the prevalence and clinical significance of AT1R-Ab in pediatric HT, particularly in early non-HLA mediated AMR and in those bridged to HT with VAD, is warranted.

Non-HLA AT1R antibodies are highly prevalent after pediatric intestinal transplantation.

The role of angiotensin II type-1 receptor (AT1R) antibodies in intestinal transplantation (ITx) is unclear. The aims were 1) to identify the prevalence of AT1R antibodies in pediatric ITx, compared to pediatric intestinal failure (IF), and 2) to determine whether AT1R antibodies were associated with graft dysfunction. 46 serum samples from 25 ITx patients (3 isolated ITx, 22 liver-inclusive ITx) were collected during routine visits >6months apart and during episodes of graft dysfunction as a result of infectious enteritis or rejection. For comparison, samples were collected from 7 IF control patients. AT1R antibodies were considered positive for levels >17 U/mL. The median (range) AT1R antibody level for ITx patients was 40.0 U/mL (7.2-40.0), compared to 7.0 U/mL (5.7-40.0) for IF patients (p=.02). There was a trend toward higher prevalence of AT1R antibodies in ITx compared with IF patients (68% versus 29%, p=.09). Among ITx patients, the prevalence of AT1R antibodies was not different between periods of active graft dysfunction and normal health (83% versus 67%, p=.31). For 16 patients with >2 samples, AT1R antibodies remained positive in 67% cases, developed in 14% cases, disappeared in 10% cases, and remained negative in 10% cases. The changes in AT1R antibodies did not correlate with de/sensitizing events. This is the first study of AT1R antibodies in pediatric ITx. AT1R antibodies are highly prevalent after ITx and may be triggered by immune activation associated with the transplant. However, their pathogenicity and clinical utility remain in question.

Presentation and Outcomes of Antibody-Mediated Rejection Associated With Angiotensin II Receptor 1 Antibodies Among Kidney Transplant Recipients

BackgroundIt remains challenging to manage antibody-mediated rejection (ABMR) associated with angiotensin II type 1 receptor antibodies (AT1R-Abs) in kidney transplant recipients and the outcomes are not well defined. We describe the presentation, clinical course, and outcomes of this condition. MethodsThis retrospective study included kidney transplant recipients with AT1R-Ab levels ≥10 units/mL and biopsy-proven ABMR in the absence of significant HLA-donor-specific antibodies at the time of rejection. ResultsWe identified 13 recipients. Median creatinine (Cr) at rejection was significantly higher (2.05 mg/dL) compared with baseline (1.2 mg/dL), P = .006. After ABMR management, the difference in median Cr was not significant (1.5 mg/dL), P = .152. Median AT1R-Ab level was higher in the pretransplant sample (34.5 units/mL) compared with the level at rejection (19 units/mL) and after rejection treatment (13 units/mL); however, these differences were not significant, P = .129. Eight of the 13 recipients received antibody reduction therapy with plasmapheresis and intravenous immunoglobulin, and 5 of the 13 recipients had other therapies. After rejection management, 6 of the 13 recipients had improvement in Cr to baseline and 7 of the 13 recipients had > 50% reduction in proteinuria. ConclusionsAT1R-Ab–associated ABMR management and outcomes depend on the clinical presentation and may include antibody-reducing therapies among other therapies. Further prospective cohorts will improve recognizing and managing this condition.

Elevated Donor-Derived Cell-Free DNA (dd-cfDNA) Attributed to Angiotensin II Type 1 Receptor Antibodies (AT1R-Ab) in Renal Re-Transplantation

Elevated Donor-Derived Cell-Free DNA (dd-cfDNA) Attributed to Angiotensin II Type 1 Receptor Antibodies (AT1R-Ab) in Renal Re-Transplantation

Angiotensin II Type-1 Receptor Antibodies Are Associated With Active Allograft Dysfunction Following Pediatric Liver Transplantation.

Angiotensin II type-1 receptor (AT1R) antibodies have been associated with rejection and allograft loss in solid organ transplantation and may act synergistically with HLA donor-specific antibodies (DSA). Our aims were to assess the prevalence of AT1R antibodies and determine if they were associated with allograft dysfunction in pediatric liver transplant recipients. We performed a retrospective, cross-sectional study of HLA DSA and AT1R antibodies in 2 cohorts of pediatric liver transplant recipients: a stable control cohort with normal allograft function (n = 70) who consented to have serum samples collected for research purposes during a routine clinic visit and a cohort with active allograft dysfunction (n = 9) whose serum samples were collected as part of clinical care. AT1R antibodies >17 U/mL were detected in 29% of stable control patients and 89% of patients with active allograft dysfunction (P = 0.001). In stable control patients, AT1R antibodies were associated with younger age at transplant (P = 0.010), younger age at time of sample collection (P < 0.001), shorter interval since transplant (P = 0.090), and presence of HLA DSA (P = 0.003). AT1R antibodies in stable control patients were not associated with rejection or allograft loss. However, AT1R antibodies combined with HLA DSA in patients with active allograft dysfunction were associated with rejection and allograft loss. Our results suggest that AT1R antibodies are more common in patients with active allograft dysfunction and may be a risk factor for worse outcomes. Further research is needed to longitudinally assess the clinical impact of HLA DSA and AT1R antibodies.

Angiotensin II type 1 receptor antibodies in kidney transplantation

Angiotensin II type 1 receptor (AT1R) antibodies directly injure endothelial and vascular smooth muscle cells by activating transcription factors associated with proinflammatory responses. Previous studies have shown that AT1R antibodies are associated with allograft rejection and decreased graft survival in kidney transplantation. Development of enzyme-linked immunosorbent assay has facilitated semiquantitative detection of AT1R antibodies. Assessing AT1R antibodies along with donor specific human leukocyte antigen antibodies may have potential to identify patients with possible risk for allograft injury and improve overall outcomes. In this review, we summarize recent clinical studies about AT1R antibodies in kidney transplantation and provide perspectives for future research area.

Effect of Bortezomib Desensitization Therapy on Levels of AT1R Antibody

Purpose Increased levels of angiotensin II type 1 receptor (AT1R) antibody have been shown to be associated with antibody mediated rejection (AMR), cell mediated rejection (CMR), and early onset of microvasculopathy at one year post heart transplant. MCS patients with the saturated levels of AT1R antibody also trend lower survival. The presence of AT1R antibody pretransplant increases risk of development of de novo donor specific antibodies posttransplant in lung transplantation. Bortezomib, a protease inhibitor, has been used for desensitization or for treatment of AMR. This study aims to determine if Bortezomib treatment can decrease the level of AT1R antibody. Methods 25 heart transplant candidates who were highly sensitized were desensitized with the Bortezomib therapy. Levels of AT1R antibody were evaluated pre-therapy, 1 month and 6 months post-therapy. Results Out of 25 patients who were treated with Bortezomib, 22 patients who were tested for AT1R antibody at all three-time points were evaluated. 8 patients had AT1R levels 17 U). Of these 14 patients, the levels of AT1R antibody decreased below 17 U in 5 patients 1 month post Bortezomib treatment. Of note, 2 patients who had the saturated levels of AT1R antibody (>40 U) remained negative ( Conclusion The Bortezomib therapy can reduce the level of AT1R antibody in some heart transplant patients. Of interest, 2 patients who were still negative for AT1R antibodies 6 month post therapy were implanted with LVAD.

Association of angiotensin II type 1 receptor antibodies with graft histology, function and survival in paediatric renal transplant recipients

We analysed in a carefully phenotyped cohort of paediatric patients the association of serum angiotensin II type 1 receptor antibodies (AT1R-Ab) with specific histological lesions and with graft function and survival in conjunction with overall and complement-binding donor-specific human leucocyte antigen donor-specific antibodies (HLA-DSA). Sera of 62 patients at the time of renal graft biopsy for clinical indication >1 year post-transplant were assessed for AT1R-Ab by enzyme-linked immunosorbent assay (ELISA) and for DSA and C1q-fixing DSA by single-antigen bead technology. Serum AT1R-Ab concentration was significantly higher in antibody-mediated rejection (ABMR) than in T-cell-mediated rejection or control. By receiver operating characteristic (ROC) curve analysis, the optimal AT1R-Ab cut-off value discriminating between patients with features of ABMR and those without was 9.5 U/mL. A total of 6 of 28 patients (21.4%) with ABMR were only positive for AT1R-Ab. Patients with AT1R-Ab and HLA-DSA double positivity had a significantly higher vascular micro-inflammation score than DSA-negative patients. The 5-year graft survival was only 59% in the AT1R-Ab-positive group compared with 87% in the AT1R-Ab-negative group. Patients with AT1R-Ab and HLA-DSA double positivity tended to have a more rapid decline of estimated glomerular filtration rate (eGFR) than patients who were only positive for AT1R-Ab or HLA-DSA. In a multivariate Cox regression model of non-invasive factors, C1q-positive HLA-DSA, eGFR and AT1R-Ab positivity were significantly associated with accelerated graft function decline. Serum AT1R-Ab positivity in the context of an indication biopsy >1 year post-transplant is associated with the histopathology of ABMR and is an independent non-invasive risk factor for adverse graft outcome.

Pre-transplant Screening for Non-HLA Antibodies: Who should be Tested?

Retrospective studies of angiotensin II type 1 receptor antibodies (AT1R-Ab) and anti-endothelial cell antibodies (AECA) have linked these antibodies to allograft injury. Because rising healthcare costs dictate judicious use of laboratory testing, we sought to define characteristics of kidney transplant recipients who may benefit from screening for non-HLA antibodies. Kidney recipients transplanted between 2011 and 2016 at Johns Hopkins, were evaluated for AT1R-Ab and AECA. Pre-transplant antibody levels were compared to clinical and biopsy indications of graft dysfunction. Biopsies were graded using the Banff' 2009–2013 criteria. AT1R-Ab and AECA were detected using ELISA and endothelial cell crossmatches, respectively. AT1R-Ab levels were higher in patients who were positive for AECAs. Re-transplanted patients (p < 0.0001), males (p = 0.008) and those with FSGS (p = 0.04) and younger (p = 0.04) at time of transplantation were more likely to be positive for AT1R-Ab prior to transplantation. Recipients who were positive for AT1R-Ab prior to transplantation had increases in serum creatinine within 3 months post-transplantation (p < 0.0001) and developed abnormal biopsies earlier than did AT1R-Ab negative patients (126 days versus 368 days respectively; p = 0.02). Defining a clinical protocol to identify and preemptively treat patients at risk for acute rejection with detectable non-HLA antibodies is an important objective for the transplant community.

Successful Treatment of Anti–angiotensin II Type 1 Receptor Antibody–Associated Rejection in Kidney Transplantation: A Case Report

Angiotensin II type 1 receptor (AT1R) antibody, a non-HLA antibody, has been found to have a detrimental effect on kidney allografts. Similarly to HLA antibodies, recipients who have AT1R antibodies are at risk for allograft rejection and poor long-term graft outcome. Besides mediating allograft rejections via direct effects on endothelial and vascular smooth muscle without complement activation, AT1R antibodies may lead to accelerated hypertension via the renin-angiotensin pathway. There has been no definite level of AT1R antibody that predicts allograft rejection. Because of a low incidence of AT1R antibody–associated rejection, there are few reports on specific treatment. The results of conventional treatment, which aims to remove these pathologic antibodies similarly to the treatment of HLA antibody–associated rejection, have been unsatisfactory. Some studies recommend using angiotensin receptor blocker to attenuate the adverse effects of AT1R antibody on kidney allograft. Herein we present a kidney transplant recipient with AT1R antibody–associated refractory allograft rejection who was successfully treated with the use of steroid, plasmapheresis, intravenous immunoglobulin, and rituximab.

P216 Case of suspected hyperacute rental transplant rejection due to angiotensin II type 1 receptor antibodies

Though the majority of antibody-mediated renal transplant rejections are thought to be due to HLA antibodies, there is increasing evidence that non-HLA antibodies also can mediate rejection. For example, antibodies directed against the Angiotensin II type 1 receptor (AT1R) have been implicated in humoral renal transplant rejection episodes and impaired graft survival. While many cases of acute rejection potentially due to AT1R antibodies have been reported, there is little published evidence relating to AT1R antibodies causing hyperacute rejection. We report the case of a patient with pre-existing AT1R antibodies and no donor-specific HLA antibodies who experienced an episode of hyperacute rejection. The patient is a 47 year old female with a longstanding history of type 1 diabetes and end stage renal disease secondary to diabetic nephropathy. She had received 2 previous renal transplants approximately 21 and 22 years ago. Pre-transplant she was highly sensitized with a T-cell flow PRA of 99% and B-cell flow PRA of 100%, but did not demonstrate any donor- specific HLA antibody. The T- and B-cell flow and T-cell CDC crossmatches performed between the patient and donor were negative. She had a pre-transplant AT1R antibody level of 18.5 Units/ml measured 8 days before transplant. During the surgical procedure the patient experienced a hyperacute rejection episode. Biopsy of the organ demonstrated possible antibody-mediated rejection. The patient was treated with plasmapheresis and IVIG and her renal function stabilized over the following 6 weeks. The patient has also been maintained on Losartan, an AT1R inhibitor. The patient has now continued to demonstrate stable renal function for the previous 2 years. Our case highlights the importance of appreciating the possible peri-transplant risks of AT1R antibody particularly as treatment with the AT1R inhibitor, Losartan, has been shown by others to provide therapeutic benefits.

Non-human leukocyte antigen-specific antibodies in thoracic transplantation.

Development of donor human leukocyte antigen (HLA)-specific antibodies is associated with graft loss, yet the role of non-HLA antibodies in solid organ transplant needs to be further defined. It is suggested that HLA antibodies and non-HLA antibodies collaborate together to impact graft outcome. This review focuses on the latest findings on antibodies against these non-HLA antigens in thoracic organ transplant. These non-HLA antigens include signaling proteins expressed on the cell surface, such as angiotensin II type 1 receptor (AT1R), endothelin type A receptor, and structure proteins, such as myosin, vimentin, and Kα1 tubulin, and extracellular matrix protein collagen. Antibodies against these antigens may impact the allograft in different ways. Although these non-HLA antibodies can damage the allograft through complement-mediated or cell-mediated cytotoxicity, antibodies against AT1R and endothelin type A receptor can also alter the endothelial cell function by activating intracellular signals. The presence of these non-HLA antibodies may predispose the patient to develop HLA-specific antibodies. Recently, it has been shown patients with AT1R antibodies pretransplant have a higher chance to develop de-novo donor-specific HLA antibodies. The findings suggest it is important to stratify the patient's immunologic risk by assessing both the HLA and non-HLA-specific antibodies.

LBP37: The incidence of AT1R antibody in solid organ transplant and correlation with pre-transplant factors

Aim Antibodies to Angiotensin II type 1 receptor (AT1R) have been reported to be a risk factor for graft rejection and loss (Dragun). It is proposed that autoreactive and alloreactive antibodies to AT1R arise through multiple mechanisms, including transfusion, prior transplant and after tapering of immunosuppression (Reinsmoen, 2012). Thus, we hypothesized that AT1R antibodies (AT1R-Ab) would occur at a higher incidence in candidates for retransplantion. If true, this could factor into an effective algorithm screening algorithm. The purpose of this study was to determine the incidence of AT1R-Abs in the solid organ transplant candidates at our institution, comparing first transplant to retransplant candidates. Methods Pre-transplant sera from 101 solid organ transplant candidates, evaluated for transplant between January 2011 and June 2014 were retrospectively tested for AT1R-Ab. The presence of AT1R-Abs was determined using AT1R-Ab EIA test (One Lambda; Division of ThermoFisher, Inc., Canoga Park, CA) according to manufacturer instructions. The manufacturer suggested cut offs were used to categorize Results 17 U/mL as positive. Transplant candidates were sorted into groups based on organ(s) to be transplanted and whether it represented the candidate’s first or subsequent transplant. The percent of candidates with results positive for AT1R-Abs was calculated. Results Overall, 34% of all candidates were positive for AT1R antibodies prior to transplant. Another 14% of patients were classified as ‘At Risk’ with 10–17 U/mL AT1R Ab. The table below shows the breakdown of these results by organ type and transplant number. Conclusion AT1R antibodies were observed in a significant portion of solid organ transplant candidates. However, contrary to our hypothesis, we observed a significantly lower incidence of AT1R antibodies in retransplant candidates (26%), compared to previously untransplanted candidates (43%).