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ARTICLE
Relationship Between Angiotensin II Type 1 Receptor Antibody Positivity and Cytokine Gene Polymorphism in Renal Transplant Patients When Organ Rejection Occurs

Objectives: Kidney transplant remains the gold standard for the treatment of end-stage renal disease. Relationships between the presence of non-HLA antibodies, antibodies to AT1R, and cytokine gene polymorphisms with rejection have recently been shown. We sought to determine whether the presence of antibodies to AT1R and cytokine gene polymorphisms affected the development of rejection in pediatric and adult patients, whether a relationship is present between cytokine polymorphism and level of antibodies to AT1R, and whether their presence can be a biomarker pretransplant.
Materials and Methods: Our study included 100 pediatric and adult kidney transplant patients plus 50 healthy controls. Levels of AT1R antibodies (by enzyme-linked immunosorbent assay) and gene polymorphisms of the cytokines transforming growth factor β, tumor necrosis factor α, interleukins 6 and 10, and interferon gamma cytokines (by sequence-specific primer-polymerase chain reaction) were studied retrospectively and evaluated with the SPSS statistical program.
Results: We found no statistically significant relationship between levels of antibodies to AT1R and gene polymorphisms among the studied cytokines in patients with rejection compared with the healthy controls and patients with uneventful courses posttransplant. However, higher levels of antibodies to AT1R were observed in pediatric compared with adult transplant recipients (P < .001). A statistically significant relationship was also observed between transforming growth factor β1 C/C G/C low-release and interleukin 6 G/C high-release gene polymorphism and levels of antibodies to AT1R (P < .001).
Conclusions: Because we observed that some gene polymorphisms among the studied cytokines may affect AT1R antibody levels, future studies are needed to understand the mechanism of the relationship. In addition, studies with larger groups are required to sufficiently confirm that higher antibody levels are present in pediatric versus adult patients.


Key words : AT1R antibody, Interleukin 6, Non-HLA antibody, Rejection, Transforming growth factor β

Introduction

Today, kidney transplant is a widely accepted and exclusive treatment for patients with end-stage renal disease. The most significant reason for failure in organ transplant is rejection of the transplanted graft by the recipient’s immune system. Both natural and acquired immune system responses, as well as cellular and humoral mechanisms, are involved in the rejection process. Although it is known that donor-specific HLA antibodies (DSA) cause damage with complement-related and antibody-dependent cellular cytotoxicity in the transplanted kidney, the importance of early and late effects of non-HLA antibodies in kidney transplant remains uncertain.1 The most studied non-HLA targets include antiendothelial cell antibodies, gene A and B antigens (MIC-A and MIC-B) related to the major histo-compatibility complex class I chain, vimentin, cardiac myosin, cardiolipin, collagen V, k-alpha-1 tubulin, glomerular basement membrane protein agrin, LG3 fragment of Perlecan, glutathione S-transferase T1, and angiotensin II type I receptor (AT1R).2-5 Antibodies developed against AT1R (AT1R-Ab), a component of the renin-angiotensin-aldosterone system (RAS), are the most widely studied biomarker and the most attendant biomarker in kidney transplant.6 In recent years, the implementation of non-HLA antibody screening as a routine step in organ transplant preparations has come to the fore. Studies on the availability of plasmapheresis and AT1R blockade treatment options for patients with known presence of AT1R-Ab in the future are still ongoing.7

Determinations of the HLA tissue group, ABO compatibility, panel reactive antibody, and lymphocyte crossmatch within the scope of immunologic evaluations before transplant are all tests performed in routine practice today.7,8 However, the observation of rejection, even in fully compatible twins, among all of these tests supports the idea that there may be different mechanisms other than HLA at work. In the Collaborative Transplant Study performed in 2005 that encompassed 245 centers, 4048 HLA fully compatible donors were studied and the importance of non-HLA immunity in rejection was mentioned.9 In the determination of risk groups, the following factors were reported as parameters to be addressed: donor and recipient age, ethnic group, previous transplant and transfusion, living or deceased donor transplant, previous pregnancy, percent panel reactive antibodies, HLA DSA presence, AT1R-Ab presence, T-cell ELISPOT assessment, soluble CD30 assessment, HLA compatibility, cytomegalovirus and Epstein-Barr virus infections, cold ischemia time, and delayed graft function.10 Recent studies have shown that examination of the cytokine gene polymorphism may also provide information about possible rejection.

The RAS has been shown to provide important functions in the regulation of blood pressure and maintenance of fluid and electrolyte balance, with studies on inflammation, immune regulation, and its importance in organ transplant immunology recently conducted.6 Dragun first reported development of vascular rejection and malignant hypertension in a female transplant recipient and in 16 of 33 kidney transplant recipients despite the absence of anti-HLA antibodies; the activation of immunoglobulin G-type antibodies against AT1R in the patient sera proved its existence. A possible mechanism for the role of AT1R-Ab in the development of vascular damage in the kidney after transplant was also suggested Dragun.2 This process was thought to be caused by ischemia-reperfusion injury and posttransplant alloantigen-induced immune stimuli, oxidative stress, and inflammatory responses.11 Moreover, AT1R-Ab could lead to endothelial dysfunction, causing vasoconstrictive arterial response, effector cell transmigration, or a procoagulatory state, which play a role in the pathogenesis of hypertension and vascular damage.

On the other hand, AT1R-Ab can increase local inflammation by affecting tubular epithelium and renal interstitial cells. As a result, antigen presentation by the local antigen-presenting cell increases and/or the production of Th1 cytokines and inflammatory chemokines increases, resulting in cellular rejection.11,12 Transfusion, pregnancy, or previous transplant can lead to HLA-specific antibody formation and may also lead to AT1R-Ab formation.12 Endothelial cells express AT1R and the AT1R-Ab of these receptors can be allosteric activators, like the natural ligands of AT1R. Binding AT1R-Ab to AT1R may be a critical step in kidney damage after transplant and contributes to rejection by stimulating inflammatory responses.12

In inflammatory events and immune responses, cytokines are vital mediators in renal endothelial damage. Secreted proinflammatory and anti-inflammatory cytokines play a role as representatives of the complex mechanism of rejection. In addition, the effects of RAS are also regulated by cytokines.

Cytokine gene polymorphisms affect the produc-tion level of cytokines, their affinity to receptors, and their activities. Investigations on the relationship between cytokine gene polymorphism effect and rejection in kidney transplant have shown conflicting results. In addition, there are conflicting results on the importance of the gene polymorphism effect.14

In this study, we investigated the effects of AT1R-Ab positivity and cytokine gene polymorphism distribution on the development of rejection and whether results of these effects can be used as pretransplant biomarkers.

Materials and Methods

This retrospective study included 100 patients with rejection (73 adult and 27 pediatric patients) who underwent kidney transplant between 2010 and 2016 at the Ba?kent University Dr Turgut Noyan Practice and Research Hospital in Turkey. For comparison, 50 healthy controls were included, with consent obtained before study inclusion.

As shown in medical records, blood samples were drawn from patients with a stable condition for routine examinations, twice before and after transplant, and during any episode of clinically and/or pathologically proven rejection. Serum samples (1 mL) and venous blood samples (0.5 mL with potassium-EDTA) from both the patients and healthy volunteers were analyzed.

Measurements of AT1R-Ab levels were made with the enzyme-linked immunosorbent assay (ELISA) method, and the ELISA immunoassay kit (One Lambda) was used for quantitative determination of commercially available AT1R-Abs. Tests were carried out according to the manufacturer’s instructions, with results >17 U/mL considered positive, results from 10 to 17 U/mL considered suspicious, and results <10 U/mL considered negative.

Cytokine gene polymorphisms were determined by the sequence-specific primer method. DNA was isolated from blood samples using an automated system. DNA samples purified to an absorbance ratio of 260/280 between 1.65 and 1.80 with a final concentration of 200 ng/μL were reproduced with the polymerase chain reaction-sequence-specific primer method, and polymorphic regions for cytokines were determined using a commercial cytokine gene polymorphism kit (Cytokine Genotyping Tray; One Lambda) to help determine polymorphism regions compatible with low, medium, and high release of cytokines according to manufacturer’s instructions. Cytokines were transforming growth factor β1 (TGF-β1), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), interleukin 10 (IL-10), and interferon γ (IFN-γ). Polymorphic regions that were studied included -308 G/A for TNF-α; C/T codon 10 and C/G codon 25 for TGF-β1; -1082 G/A, -819 T/C, and -592 A/C for IL-10; -174 G/C for IL-6; and +874 A/T for IFN-γ. We did not study cytokine levels.

We used SPSS for Windows, version 23.0, for data analyses. The mean and standard deviation in descriptive statistics of continuous variables was used, and categorical variables were expressed as numbers and percentages. We evaluated the distribution of variables by a skewness coefficient, kurtosis coefficient, and the Kolmogorov-Smirnov test. We used parametric tests to analyze normally distributed data and nonparametric tests to analyze nonnormally distributed data. We used the Mann-Whitney U test for analysis of nonnormally distributed data and the t test for data that showed normal distribution in paired group comparisons. We evaluated the significance of differences between the means of more than 2 groups with Kruskal-Wallis in nonnormally distributed data and with one-way analysis of variance in normally distributed data. Differences between groups of categorical variables were evaluated with the chi-square test and the linear association test. All calculations were done as 2 tailed, and P < .05 was considered statistically significant.

This study was approved by the Ba?kent University Medical and Health Sciences Research Board and Ethics Committee (project no: KA14/329).

Results

The characteristics and distribution of the study groups are shown in Table 1. Mean age of the pediatric group was 13.0 ± 4.7 years (range, 3-18 years), and mean age of the adult group was 38.3 ± 11.5 years (range, 19-68 years). Sex, donor type, donor relation, donor sex, rejection status, AT1R-Ab positivity, and cytokine gene polymorphism positivity or negativity parameters were all evaluated.

Rejection was found to be more common in the adult group than in the pediatric group (P = .009) (Table 2). Donor type and relationship were not related to rejection. Although sex of donor was not associated with rejection in female recipients (P = .527), rejection was more frequent in male recipients who had female donors (P = .032). AT1R-Ab positivity rate was more frequent in the pediatric group than in the adult group (P < .001). Levels of AT1R-Ab were not correlated with donor type, donor sex, or donor relationship. Tests of AT1R-Ab positivity were found to be negative in all patients with rejection after transplant and also during rejection. We found that AT1R-Ab positivity before or after transplant was not associated with rejection status (Table 3).

We studied 24 different polymorphisms for 5 cytokines (TNF-α, TGF-β1, IL-10, IL-6, and IFN-γ), and we detected 19 polymorphisms in the study group. The determined cytokine gene polymorphisms did not correlate with rejection. No statistically significant difference was observed in the distribution of cytokine gene polymorphism in terms of sex and prognosis (Table 4). When the release levels were evaluated collectively (low, medium, and high release), no significant difference was found in terms of prognosis.

When we analyzed the relationship between cytokine gene polymorphism and AT1R-Ab level, we found an association between presence of TGF-β1 and IL-6 gene polymorphisms and AT1R-Ab levels (Table 5). Although there was a higher rate of AT1R-Ab negativity in patients without TGF-β1 C/C G/C (low release) polymorphism, suspected positivity and an increase in positivity were found in patients where it was present (P = .002). A significantly suspected positivity and positivity was found in the AT1R-Ab levels in patients without IL-6 G/C (high release) polymorphism, and a statistically significant correlation was found in terms of negativity in patients with IL-6 G/C (high release) polymorphism (P = .044). In addition, IL-10 GCC/ACC (intermediate release) polymorphism was found in more adults than in pediatric patients (P = .016).

Discussion

In addition to classic HLA antibodies, the importance of non-HLA antibodies is increasing in kidney transplant, with AT1R-Ab in particular being the most prominent non-HLA antibody to be present in patients with rejection. Although an association between AT1R-Ab positivity in kidney transplant recipients and rejection in kidney transplant has been previously shown,15-22 there have also been reports that found no association between AT1R-Ab positivity and rejection, especially in recent studies with higher patient numbers. Dragun and colleagues reviewed 16 published studies that investigated the effects of AT1R-Ab in kidney transplant, which included 1883 patients.5 It has also been noted that the presence of AT1R-Ab can be used as a biomarker, which could show those patients with high risk for rejection during routine screening in some centers.21

In a meta-analysis from Zhang and associates, 154 studies related to AT1R-Ab and rejection in adult patients were evaluated. Although the investigators reported a relationship between the elevation of AT1R-Ab and acute insufficiency/kidney graft failure, pretransplant AT1R-Ab levels could not be used as a biomarker.23 Pinelli and associates found a relationship between graft failure and DSA in their study, whereas AT1R-Ab and antiendothelial cell antibodies were not shown to be related.24 Kimball and associates reported that high AT1R-Ab levels before transplant may be a stimulant for tissue damage but levels could not be used as a biomarker for antibody-mediated rejection, suggesting possible poor prognosis.25 Deltombe and associates reported no relationship between AT1R-Ab and rejection in their multicenter DIVOT study,26 which they reconducted with a larger patient group with the same team, in contrast to an earlier report that showed a relationship between AT1R-Ab and rejection.17 Similar to these reports, we observed that AT1R-Ab level was not related to rejection and that AT1R-Ab level may not be a good indicator for predicting graft failure.

Although there are many studies on AT1R-Ab, there are few that have evaluated pediatric transplant recipients. In 2016, Bjerre and colleagues included 30 children and 28 adults who had had kidney transplants, as well as a healthy control group, in their study to measure AT1R-Ab levels. The group reported that the median total AT1R-Ab levels in the pediatric group were significantly higher than in adult transplant group.27 Although it was not found to be associated with rejection in our study, AT1R-Ab levels in the pediatric transplant recipient group were found to be higher than in the adult transplant recipient group, similar to the study of Bjerre and associates (P < .001). Similar to our study, Hesemann and colleagues evaluated AT1R-Ab levels in 29 pediatric transplant recipients and found no positive AT1R-Ab levels in the pretransplant period, whereas they found AT1R-Ab positivity in 40% of the patients after transplant, although relation to graft function was not shown.28 In 2 other studies involving only pediatric patients, Fichtner and colleagues and Pearl and colleagues reported that AT1R-Ab positivity may be associated with graft loss.29,30

The detection of AT1R-Ab in serum using the sandwich ELISA method, developed after Dragun and associates reported the presence of AT1R-Ab, has come to the fore. Different threshold values have so far been accepted as AT1R-Ab positivity: >9 U/mL,31 >9.05 U/mL,20 >9.1 U/mL,22 >9.5 U/mL,29 >10 U/mL,16-18,21,22,32 >15 U/mL,18 and >17 U/mL.15,30 In 1 pediatric study, neither a cut-off value was given nor defined for positivity.28

Many studies have reported on the relationship between cytokine gene polymorphism effect and rejection in kidney transplant. Among the cytokines, TNF-α, TGF-β1, IFN-γ, lymphotoxin, IL-1, IL-4, IL-6, and IL-10 are polymorphisms that have been examined.33,34 For IFN-γ, +874 A/T and UTR5644 polymorphisms; for IL-10, -1082 G/A, -819 C/T, -592, and 571 C/A polymorphisms; for IL-2, -330 T/G polymorphism; for IL-4, -590 T/C polymorphism; for IL-6, -174 G/C polymorphism; for TGF-β, +869 C/T, +29 Leu10Pro, c10, +915 G/C, Arg25Pro, +74, and c25 polymorphisms; and for TNF-α -308 G/A and TNF 1/2 polymorphisms have been reported to be associated with kidney transplant.14 In our study, results obtained were consistent with a previous study.35

Studies on gene polymorphism should continue and should be evaluated separately for each community; in Turkey, cytokine gene polymorphism studies in transplant recipients are still quite limited. In our study, TNF-α G/G (low related) polymorphism was the most common type and found to be high in both study groups. There was no statistically significant relationship between rejection and any of the TNF-α, IL-10, IL-6, TGF-β1, and IFN-γ gene polymorphisms studied. In our study, similar to one performed by Seyhun and colleagues, in Turkish patients, no relationship was found between TNF-α, IL-10, IL-6, and IFN-γ cytokine gene polymorphisms and rejection. Unlike our study, Seyhun and colleagues reported that, although no relationship could be shown between rejection and genotype with high cytokine release for TGF-1, the genotype providing low cytokine release was observed at a higher rate in the group without rejection.35

As far as we know, there are no published studies that have evaluated the relationship between AT1R-Ab and cytokine gene polymorphisms. When we assessed the relationship between TNF-α, IL-10, and IFN-γ gene polymorphisms and AT1R-Ab levels, we found no statistically significant difference, but the presence of IL-6 and TGF-β1 gene polymorphisms were related to differences in AT1R-Ab levels.

In our study, suspected positivity and positivity were found in AT1R-Ab levels in transplant recipients without IL-6 G/C (high release) polymorphism, and a statistically significant correlation was found in terms of negativity in those who did not have this polymorphism (P = .044). When the effects of IL-6 on RAS were examined, an interaction between IL-6 and AT1R-Ab was shown to be crucial in the pathogenesis of hypertension19 and hypertension response occurred due to IL-6 elevation because of AT1R-Ab and an increase of renin activity along with decreased renal functions.36 Inhibition of IL-6 with tocilizumab can change the effects of AT1R-Ab and can be used in treatment.19 Although TGF-β, IL-6, and IL-8 have been reported as cytokines that may be associated with AT1R-Ab activation, some studies have reported that AT1R-Ab levels are associated with TNF-α, IL-1β, and IL-8 and are unrelated to IFN-γ, IL-17, and IL-6 levels.30

We also observed a significant relationship bet-ween TGF-β1 C/C G/C (low release) polymorphism and AT1R-Ab levels (P = .002). In patients without TGF-1 C/C G/C (low release) polymorphism, more AT1R-Ab negativity was seen; in patients with TGF-1 C/C G/C (low release) polymorphism, increased suspected positivity and positivity rates were found. Transforming growth factor β1 is an immune-regu-latory cytokine that inhibits T-cell activation. It is a potent anti-inflammatory cytokine involved in the differentiation of many cell types, apoptosis, and proliferation regulation and is vital in chronic rejection because of its role in profibrotic process activation.37

Different molecules regulate a variety of local RAS functions with immunologic functions such as TGF-β1 and platelet growth factor. Angiotensin II has been reported to be a potent stimulator of TGF-β1 synthesis, leading to critical biological effects such as extracellular matrix accumulation, cell proliferation, and hypertrophy.6 In addition, RAS-induced fibro-genesis has been shown to occur mainly through TGF-1; experimental investigations showed that this activity is partially mediated by AT1R and angiotensin II has a strong relationship with TGF-β1, contributing to increased extracellular matrix protein production.38 Transforming growth factor β1 has been identified as a key cytokine in the pathogenesis of chronic allograft nephropathy, which is the major cause of graft loss during the first year posttransplant.

As with other cytokines, the place of IL-6 in the AT1R-Ab mechanism has not been clarified yet. In our study, we observed that TGF-β1 C/C G/C (low related) gene polymorphism and IL-6 G/C (high related) gene polymorphism affected AT1R-Ab levels. As far as we know, these effects on AT1R-Ab levels have not been previously reported. The presence of TGF-β1 low-release polymorphism, that is, with lower level of TGF release, may cause fewer anti-inflammatory effects and thus effects in the environment to shift toward inflammation. If AT1R-Ab positivity causes inflammation, the low TGF-β1 level in the environment supports increased AT1R-Ab. Although TGF-β1 is an anti-inflammatory cytokine, IL-6 is both a proinflammatory and anti-inflammatory cytokine. A statistically significant relationship was found in terms of suspected positivity and positivity in AT1R-Ab levels in patients without IL-6 high-level polymorphism and negativity in those with polymorphism.

Although AT1R-Abs have been reported to play an important role in kidney transplant, the threshold values for positivity are yet to be established. It should be taken into consideration that ethnic differences and the necessity to consider different immune-genetic backgrounds may lead to differing threshold values. This difference has also been observed in studies from Asia.16,20,22 Because, as far as we know, no study related to AT1R-Ab levels has been reported from Turkey, it has not been possible to comment by comparing threshold values for our country with our study. In our study, according to the manufacturer’s instructions, >17 U/mL was accepted as positive for AT1R-Ab and a relationship between positivity and rejection was not detected. The conflicting results in the relationship between AT1R-Ab levels and rejection may be due to threshold values that have not yet been fully established. In addition, in accordance with other studies, more studies with higher numbers of patients are required to understand the reason for the higher antibody levels in pediatric patients that we found in our study.


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DOI : 10.6002/ect.2022.0043


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From the 1Department of Immunology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir; the 2Department of Immunology, Faculty of Medicine, Başkent University, Ankara; the 3Department of Immunology, Faculty of Medicine, Gazi University, Ankara; the 4Department of General Surgery, Division of Transplantation, Faculty of Medicine, Ba?kent University, Adana; the 5Department of Nephrology, Faculty of Medicine, Başkent University, Adana; the 6Department of Pediatrics, Division of Pediatric Nephrology, Faculty of Medicine, Başkent University, Ankara; the 7Immunology Tissue Typing Laboratory, Faculty of Medicine, Başkent University, Adana, Turkey
Acknowledgements: This study was supported by Başkent University Research Fund. The authors have no declarations of potential conflicts of interest. The authors would like to thanks Fatih Buyukcam,MD, for statistical analysis.
Corresponding author: Emel Yantir, Eskisehir Osmangazi University, Faculty of Medicine, Department of Immunology, 26040, Odunpazarı/Eskisehir, Turkey
Phone: +90 222 2392979 (ext. 3853)
E-mail: dremelyntr@gmail.com