The evaluation of the relationship between anti angiotensin type I antibodies in hypertensive patients undergoing kidney transplantation

Introduction

Kidney transplantation has been the most up-to-date treatment method in patients with end stage renal failure [1]. One of the important problems detected in patients, who have received a kidney transplant, is the rejection of the transplanted organ by the recipient. Immunosuppressive treatment is administered to prevent the rejection of the transplanted kidney [2]. Recently, increasing efficiency due to the increasing diversity of immunosuppressive drugs used in treatments and therefore effective immunosuppression, Human Leukocyte Antigen (HLA) typing in recipients and donors, and developing anti-HLA antibody detection techniques have significantly improved the results of kidney transplantation and reduced rejection rates, graft survival. It has been reported that the retention rate has increased [3]. Long-term survival of the graft after kidney transplantation is affected by immunological and non-immunological factors. Antibody-mediated rejection (AMR) prevents long-term graft survival by contributing to both acute and chronic allograft rejection [4]. Protocol biopsy results are important in terms of revealing post-transplant alloimmune responses, drug toxicities, acute and chronic organ rejections and viral enfections.

Some centers conduct routine follow-up protocols, however, most centers do not perform these protocols [5], 6]. Although donor specific HLA antibodies (DSA) are known to cause damage in the transplanted kidney through complement-associated and antibody-mediated cellular cytotoxicity, the importance of the effects of non-HLA antibodies after kidney transplantation in the early and late period has not been fully clarified [7]. Researchers reported that the development of antibodies against non-HLA auto-antigens after transplantation was associated with rejection and graft survival [8]. Non-HLA antibodies are classified into two groups: antibodies against polymorphic antigens that indicate differences between patient and donor, and autoantibodies that recognize self-antigens. Because the vasculature is located at the interface of the transplanted organ, a significant portion of the non-HLA antibodies reported to mediate renal rejection also recognize autoantigens expressed by endothelial cells [9], 10]. Anti-endothelial antibodies, gene A and B antigens (MIC-A and MIC-B), major histocompatibility complex class I chain, vimentin, cardiolipin, glomerular basal membrane protein agrin, glutathione S-transferase T1 and angiotensin II type I receptor (AT1R) are among the non-HLAs that have been studied [11], 12]. AT1R antibodies are non-HLA antibodies that have recently been studied in graft injury, and rejection. First, they were identified in adult kidney transplants. Some studies associated the AT1R antibodies with unfavourable outcomes in other solid organ transplants such as heart, lung and liver transplants [13], 14]. Among non-HLA antibodies, AT1R antibodies are a component of the Renin-Angiotensin Aldosterone System (RAS). Antibodies against AT1R were first demonstrated in the studies on preeclampsia. These antibodies were shown to have caused maternal and fetal mortality and morbidity [15]. Recent studies have emphasized the importance of RAS in transplantation immunology and immune regulation [16], 17]. Some studies reported that RAS is also involved in endothelial changes occurring in organ injury after kidney transplantation and leads to vascular endothelial activation with antibody-mediated mechanisms [16], 17]. In the study, it was reported for the first time that AT1R antibody levels increased in recipients with severe steroid-resistant vascular rejection and malignant hypertension in the absence of HLA-DSA after kidney transplantation [16]. Studies have reported severe vascular rejection independent of donor-specific antibodies in kidney transplant patients who were found to have AT1R-antibody [18]. AT1R is the receptor for Ang II in the glomeruli and has a role in regulating arterial blood pressure and salt balance. Additionally, AT1R is expressed in the brush border of the proximal tubule, basolateral membrane, and vessels. AT1R is a member of the family of seven transmembrane G protein receptors (GPCR). The extracellular glycolysated region is attached to the seven-transmembrane alpha helix. AT1R antibodies (AT1R-Antibody=AT1R-AA) bind to the second extracellular portion of AT1R [17], 19]. The main mechanism among the antibody-mediated mechanisms of organ injury after kidney transplantation is suggested to be the changes occurring in the endothelium as a result of vascular endothelial activation. Endothelial cells were reported to have expressed the AT1R and these receptors’ AT1R antibodies might be allosteric activators like AT1R’s natural ligands [20]. The binding of AT1R-antibody to AT1R is suggested as a critical step in kidney injury after transplantation.

In this study, we aimed to examine the serum AT1R antibody levels in kidney transplant patients who had primary and secondary hypertension and post-transplant renal dysfunction, and to associate these levels with the clinical condition. The primary outcome is to compare AT1R antibody levels, taking into account post-transplant PRA developments, pathologically confirmed humoral or vascular rejection reactions, and late complications. Secondary outcome is to clarify whether there is a factor accompanying PRA positivity if there are patients among the patient groups showing de novo PRA positivity.

Materials and methods

Results

The mean age of the patients included in the study was found as 46.88 ± 12.23 years. The mean age was found as 46.88 ± 12.01 years in men and 46.89 ± 12.46 years in women. Twenty nine (59.2 %) men and 20 women (40.8 %) participated in the study. The mean duration of chronic renal failure was found as 34.45 ± 49.94 months (range= 0–216 months) and the mean duration of dialysis was found as 15.61 ± 37.04 months (range=0–144 months) among the patients (Table 1). Demographic and clinical information is shown in Table 1.

Discussion

In our study, we aimed to evaluate the occurrence frequency of AT1R antibody in patients who had rejection after kidney transplantation and the role of these antibodies in terms of clinical outcomes such as rejection and late complications, and to demonstrate the frequency of AT1R antibody in hypertensive patients. In addition, we also investigated the role of AT1R antibodies in post-transplant anti-HLA antibodies and whether the AT1R antibody could be a factor accompanying anti-HLA antibody positivity in patients showing de novo anti-HLA positivity. We aimed to obtain data about the issue if AT1R antibody occurred de novo or was present before transplantation. The role of AT1R antibodies has recently been frequently emphasized In a study conducted by Lee et al. [22] it was aimed to evaluate the frequency and role of occurrence of AT1R antibody in patients who had renal allograft rejection. In this study, the positivity of AT1R antibody was found as 9.4 % in 53 transplant patients. They found HLA class-I DSAs with a higher rate in AT1R antibody positive patients compared to AT1R antibody negative patients. However, they found no association between HLA class-II DSA and AT1R antibody positivity. They observed more severe cases of Banff IIA/IIB or antibody-mediated rejection (AMR) in four of five AT1R antibody positive patients. On the other hand, AMR was observed in 24 of 48 AT1R antibody negative patients and no statistical significance was found. In addition, they reported that both AT1R antibody and DSA were detected with a higher rate in AMR compared to T cell-mediated rejection (TCMR) and this was statistically significant [22]. In another study conducted with 351 patients, thegraft survival rates were found lower in patients who had both AT1R antibody and DSA compared to the patients who had DSA alone [23]. In a prospective cohort study conducted by Lefaucheur et al. which included 1,845 kidney transplant patients, it was shown that presence of non-HLA agonistic AT1R antibodies in the circulation was associated with an increase in antibody-mediated allograft rejection one year after transplantation and with a decrease in long term allograft survival [24]. In our study, we found AT1R antibody positivity in 11 of 49 kidney transplant patients. AT1R antibody positivity was found in a total of 14 samples including eight samples before transplantation and six samples after transplantation. In our study, AT1R antibody positivity was found with a higher rate in the presence of anti-HLA antibody compared to the absence of anti-HLA antibody after transplantation. In a study conducted by Reinsmoen et al. a higher level of pre-transplant AT1R antibody positivity was reported in the AMR patients who had no major tissue compatibility class-I chain related gene A (MICA) and DSA [25]. In our study, no significant difference could be found in terms of AT1R antibody levels in pre-transplant sera between the patients who had and did not have vascular and humoral rejection. The same investigators reported that the AT1R antibody level was higher in AMR patients at the time of rejection in the study conducted by Reinsmoen et al. In addition, the AT1R antibody levels were found lower at the time of rejection compared to pre-transplant AT1R antibody levels in the study of Reinsmoen et al., although no comparison was performed between pre-transplant and post-transplant AT1R antibody levels [25]. In this study, a statistically significant difference was found between pre-transplant and post-transplant AT1R antibody levels. Pre-transplant levels were found to be higher compared to post-transplant levels. It is suggested that the binding of AT1R antibodies, which is one of the non-HLA antibodies, to AT1R besides classical HLA antibodies is a critical step in terms of kidney injury after kidney transplantation. Recent studies have attempted to elucidate its association with rejection. Some studies state that the positivity of AT1R antibodies is associated with rejection in kidney transplantation. In a preliminary study conducted by Giral et al. with a group of 599 patients, they found that the presence of AT1R antibodies before transplantation was associated with acute rejection and showed that it was an independent risk factor for graft loss in the long term [26]. The same findings were obtained in two different studies published in 2014. In a study conducted by Banasik et al. from Poland, which included 117 patients, and a study conducted by Hernández-Méndez et al. from Mexico, which included 174 patients, it was reported that the rejection rate was higher and graft survival was lower in the group who had AT1R antibodies positivity before transplantation in the first post-transplant year compared to the group who had no AT1R antibody positivity [27], 28].

Conclusions

Many scientific studies are carried out on non-HLA antibody screening in addition to detecting HLA antibodies. This study showed a statistically significant difference in our primary composite outcome based on pre- and post-transplant AT1R antibody levels. Besides selecting a compatible donor before transplantation, knowing the reason of post-transplant organ rejection in the early period and rapid and accurate treatment are highly important for long term organ survival and function. Studies on the use of other treatment options such as plasmapheresis and AT1R antibody blockage later on for patients who are known to have AT1R antibody positivity have been pursued. Further studies should be conducted to confirm the immunological risk of AT1R in kidney transplantation. The limitation of our study was that the frequency of AT1R antibody positivity was low in post-transplant groups and the numbers of rejection was lower in our study group. The reading values of the kit that detects AT1R antibody levels may vary among populations. The lower limits of the kit are already low and these values may give even lower results in the patient group that has not had rejection. Higher values are expected in the patient group that has had rejection. In our study, the number of patients with rejection is also lower. The distribution of AT1R antibody values in the results of the patients is low. We predict that further studies with larger groups will give more illuminating results.