Mol Biol Rep DOI 10.1007/s11033-014-3427-8
HLA-DRBl and susceptibility to kidney allograft rejection in Southern Iranian patients Behrouz Gharesi-Fard • Leila Rezanezhad • Mohammad Hossein Karimi Bita Geramizadeh • Mohammad Mehdi Salehipour • Seyed Ali Malek Hosseini • Jamshid Roozbeh
•
Received: 6 June 2013 / Accepted: 17 May 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract Kidney transplantation is the best treatment option for the patients with end-stage renal disease. Viral infections and genetic factors such as HLA-II antigens may affect the kidney transplant outcome. The compatibility of HLA-DRB1 molecules in the survival of kidney transplant is important. Also, the correlation between these molecules and viral infections is significant. The current study investigates the allele frequency of HLA-DRB1 in 41 recipient kidney transplant and 203 normal healthy controls by polymerase chain reaction using sequence specific primers. Moreover the relation between HLA-DRB1 allelic groups and hepatitis B, hepatitis C and cytomegalovirus viral infections was also studied. However statistical analysis of the allele frequencies didn’t show any significant association between HLA-DRB1 allelic group distributions or sharing and susceptibility to acute kidney transplant rejection (P [ 0.05). Comparing the allele frequencies between HLA-DRB1*14 and DRB1*04 allelic showed a significant difference in controls and patients (P = 0.03 and P = 0.05 respectively). The results of the present study also showed a
B. Gharesi-Fard Department of Immunology, Shiraz University of Medical Sciences, Shiraz, Iran B. Gharesi-Fard Infertility Research Center, Shiraz University of Medical Sciences, Shiraz, Iran L. Rezanezhad Islamic Azad University, Jahrom Branch, Jahrom, Iran M. H. Karimi (&) B. Geramizadeh M. M. Salehipour S. A. M. Hosseini J. Roozbeh Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran e-mail: [email protected]; [email protected]
significant association between possession of HLADRB1*07 allele in kidney transplant recipients and hepatitis C virus infection (P = 0.009). In conclusion however the results of the present study did not showed relation between HLA-DRB1 allele’s frequencies or sharing and kidney transplantation outcome, the results indicated that HLA-DRB1 alleles may susceptible individuals to renal disease or play a role in susceptibility to viral infection in kidney transplant patients. Keywords Kidney allograft Acute rejection HLA-DRB1 PCR-SSP
Introduction Despite the advance progression in immunosuppressive therapies, acute rejection is still account as an important cause of kidney transplant rejection. One of the most important genetic factors that influence on the kidney transplant outcome is human leukocyte antigen (HLA) [1, 2]. HLA molecules are a risk factor for increased incidence of acute graft rejection and graft dysfunction [3]. However, because of immunosuppressive regimen, matching of HLA molecules indicated no significant impact on graft survival in short term, but in long term HLA matching between donor and recipient significantly affect the kidney transplant survival [4]. Previous studies have been shown that the rate of kidney transplant rejection for patients who transplanted with HLA mismatches tissue was twice as compared with who that received a kidney with zero mismatch for HLA-A, B and DR [5]. It is widely accepted that genotype matching of HLA, especially HLA class II is an important factor for graft survival in renal transplant patients [2].Among HLA class II molecules, HLA-DRB1 is
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the most important molecule that play role in tissue compatibility and susceptibility to viral infection [2]. Previous studies indicated that HLA-DRB1 matching significantly affect the survival of cadaveric kidney transplant while HLA-A or HLA-B matching play less important role [6, 7]. Moreover, one of the most important complications of a renal transplantation is viral infection. Beside their role in tissue compatibility, HLA molecules play an important role in immune responses to the viral infections [8]. The relation between some HLA molecules and susceptibility to viral infections are reported before [8, 9]. HLA-DRB1 molecules have been reported to be associated with susceptibility to viral disease including hepatitis B virus (HBV), hepatitis C virus (HCV) [8, 10]. In this respect association between HCV, HBV and cytomegalovirus (CMV) infections and renal disease have been reported in the previous studies [11–13]. So it seems that HLA molecules not only affect the outcome of a kidney transplant but also may affect the fate of viral infections before and after kidney transplantation. Considering the major role of HLADRB1 matching in the prevention of acute kidney transplant rejection and viral infections response and clearance, the current study was designed. By sequence specific primers (PCR-SSP) method in Iranian renal transplant patients, we investigated the relationship between HLADRB1 compatibility and acute renal rejection, as well as the association of HLA-DRB1 molecules and viral infections before and after transplantation.
Materials and methods Patients and controls A total of 69 kidney transplant (41 unrelated and 28 related) pairs, were included in this study. Patients received renal grafts from live donors between 2007 and 2011 at Transplant Center of Nemazi Hospital affiliated to Shiraz University of Medical Sciences. All patients were investigated for the graft outcome and acute rejection episode(s) for at least 6 months after kidney transplantation. Rejection episodes were identified by an expert nephrology team based on the approved clinical diagnostic criteria and invariably confirmed by needle biopsy as well as elevated serum creatinine and blood urea nitrogen levels [14]. The standard immunosuppressive regimen for all recipients were included 5 mg/kg of cyclosporine initially, and then a maintenance dose of 2–2.5 mg/kg (cyclosporine level was 50–150 ng/mL), prednisolone (120 mg/days initially, tapering to 10 mg/days), and mycophenolate mofetil (1,000 mg twice daily). In this study, the patients were divided into two groups based on the presence (AR group) or absence (non-AR group) of acute rejection episodes. HLA-DRB1 Typing was done on 41 out of 69 pairs
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Table 1 Relation between age, gender, blood group, relative relation and kidney transplant acute rejection in 69 transplant patient HLA-DRB1 typed N = 28 (%)
HLA-DRB1 untyped N = 41 (%)
P value
Related
10 (35.7)
18 (43.9)
NS
Unrelated
18 (64.3)
23 (56.1)
20 (71.4)
26 (63.4)
8 (28.6)
15 (36.6)
Relative relation
Gender Male Female
NS
Infection (HBV, HCV, CMV) Infection
8 (28.6)
7 (17.1)
20 (71.4)
34 (82.9)
A?
8 (28.6)
15 (36.6)
B?
3 (10.7)
8 (19.5)
AB
1 (3.6)
3 (7.3)
O? O-
14 (50.0) 2 (7.1)
14 (34.2) 1 (2.4)
10–20
3 (10.7)
5 (12.2)
21–30
8 (28.6)
9 (21.9)
31–40
5 (17.9)
10 (24.4)
12 (42.8)
17 (41.5)
Non infection
NS
Blood Group NS
Age
[41
NS
NS non significant
(Donor & Recipient) of patients and compared with 203 healthy controls. Blood groups, sex and age were also identified and compared between rejection group and non-rejection groups. Moreover infections with three important and common viral infections in kidney transplant recipients including HBV, HCV and CMV were also determined using molecular method. This study was approved by the Ethics Committee of Shiraz University of Medical Sciences. Genomic DNA extraction After collecting buffy coat or whole blood samples in Ethylene Diamine Tetra Acetic acid (EDTA), DNA was extracted using a column based DNA extraction kit according to the kit instruction (Genet Bio kit, Korea). HLA typing and statistical analysis For HLA-DRB1 typing PCR-SSP method was performed using the BAG HLA-SSP low/intermediate resolution kits (BAG, Germany). Twenty-four PCR reactions for each sample were performed according to the kit instruction. PCR products were analyzed by electrophoresis on a 2 % agarose gel and the results were interpreted using BAG
Mol Biol Rep Table 2 Association between HLA-DRB1 frequencies and rejection
HLA
Non rejection frequency N = 22 (%)
Rejection frequency N = 19 (%)
P value
OR
95 % CI
0.09–2.73
HLA-DRB1*01:01
3 (6.8)
5 (13.1)
0.47
0.47
HLA-DRB1*03:01
4 (9.1)
5 (13.1)
0.72
0.66
0.13–3.15
HLA-DRB1*04:01
10 (22.7)
3 (7.9)
0.06
3.43
0.77–17.36
HLA-DRB1*07:01
2 (4.5)
6 (15.8)
0.13
0.25
0.03–1.54
HLA-DRB1*08:01
1 (2.3)
0 (0)
1.00
00000
0000
HLA-DRB1*09:01
1 (2.3)
1 (2.6)
1.00
0.86
0.02–32.84
HLA-DRB1*10:01 HLA-DRB1*11:01/02/03
2 (4.5) 9 (20.5)
0 (0) 9 (23.7)
0.49 0.83
00000 0.82
0000 0.26–2.66
HLA-DRB1*12:01
0 (0)
1 (2.6)
0.46
000000
0.00–15.21
HLA-DRB1*13:01/02/03
5 (11.4)
2 (5.3)
0.44
2.31
0.36–18.47
HLA-DRB1*14:01
0 (0)
0 (0)
Undefined
Undefined
000
Each p value is the result of comparing corresponding row with the sum of other rows
HLA-DRB1*15:01/02
5 (11.4)
2 (5.3)
0.32
00000
00000
HLA-DRB1*16:01
2 (4.5)
4 (10.5)
0.4
0.40
0.05–2.81
Table 3 HLA-DRB1 allele frequencies in 41 patients in comparison with 203 normal Controls
HLA
Patient N = 41 (%)
Each p value is the result of comparing corresponding row with the sum of other rows
P value
OR
95 % CI
HLA-DRB1*01:01
8 (9.8)
35 (8.6)
0.74
1.15
0.47–2.71
HLA-DRB1*03:01
9 (11)
42 (10.3)
0.86
1.07
0.46–2.40
HLA-DRB1*04:01
13 (15.9)
36 (8.9)
0.05*
1.94
0.92–4.02
HLA-DRB1*07:01
8 (9.8)
33 (8.1)
0.62
1.22
0.50–2.90
HLA-DRB1*08:01
1 (1.2)
6 (1.5)
1
0.82
HLA-DRB1*09:01
2 (2.4)
4 (1)
0.26
2.51
0.31–16.26
HLA-DRB1*10:01
2 (2.4)
12 (3)
1
0.82
0.12–3.97 0.55–1.86
HLA-DRB1*11:01/02/03 * Considered significant with p value threshold of 0.05
Normal control N = 203 (%)
18 (22)
88 (21.7)
0.95
1.02
1
0.99
18 (4.4)
0.16
2.01
0.73–5.33
20 (4.9) 48 (11.8)
0.03* 0.39
0.00 0.7
0.00–1.20 0.28–1.68
59 (14.5)
0.07
0.46
0.17–1.17
HLA-DRB1*12
1 (1.2)
5 (1.2)
HLA-DRB1*13:01/02/03
7 (8.5)
HLA-DRB1*14:01 HLA-DRB1*15:01/02
0 (0) 7 (8.5)
HLA-DRB1*16
6 (7.3)
typing software (BAG, Germany) and re-checked manually by typing worksheet. For analysis of the effect of HLADRB1 sharing on kidney transplant outcome, transplant pairs with at least one match allele considered as shared. Chi square test and SPSS or Epi Info software’s were used for statistical analysis.
Results Statistical analysis indicated that there is no any relation between age, gender, blood group or infection with HCV, HBV or CMV and kidney transplant acute rejection (Table 1). The results of HLA-DRB1 typing in rejection and non rejection patients are shown in Table 2. As
indicated in Table 2, statistical analysis didn’t show any significant association between HLA-DRB1 allelic group distributions and susceptibility to acute kidney transplant rejection (P [ 0.05). Comparing the HLA-DRB1 allele frequencies between patients and controls showed that in patients the HLA-DRB1*04 allelic group was more frequent, while in control group, HLA-DRB1*14 allelic group was more frequent (P = 0.03 and P = 0.05 respectively, Table 3). Moreover HLA-DRB1*11 was found to be more frequent allele among patients and control group (Table 3). Regarding the relation between infections and kidney transplant acute rejection, as shown in Table 4, while the relation between all infections together and kidney transplant rejection was studied, results indicated that there were no significant association between HLA-DRB1 allelic
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Mol Biol Rep Table 4 Association of HLADRB1 alleles frequencies and infections with HBV, HCV and CMV
Each p value is the result of comparing corresponding row with the sum of other rows
HLA
Non viral infection N = 33 (%)
Viral infection N = 8 (%)
P value
HLA-DRB1*01:01
8 (12.1)
0 (0)
0.34
HLA-DRB1*03:01
6 (9.1)
3 (18.8)
0.36
HLA-DRB1*04:01
13 (19.7)
0 (0)
0.06
HLA-DRB1*07:01
5 (7.6)
3 (18.8)
0.18
0.36
0.08–2.54
HLA-DRB1*08:01
0 (0)
1 (6.2)
0.18
0.43
0.06–2.18
HLA-DRB1*09:01
2 (3)
0 (0)
1.00
HLA-DRB1*10:01
2 (3)
0 (0)
1.00
HLA-DRB1*11:01/02/03
14 (21.2)
4 (25)
0.74
0.81
0.20–3.52
HLA-DRB1*12:01
1 (1.5)
0 (0)
1.00
HLA-DRB1*13:01/02/03
4 (6.1)
3 (18.8)
0.13
0.28
0.04–1.82
HLA-DRB1*14:01 HLA-DRB1*15:01/02
0 (0) 6 (9.1)
0 (0) 1 (6.2)
Undefined 0.71
Undefined 1.50
Undefined 0.15–35.59
HLA-DRB1*16
5 (7.6)
1 (6.2)
1.00
1.23
0.12–29.93
group frequencies and infection. However the results indicated that HLA-DRB1*04 could be a protective allele against infection in renal transplant recipients (P = 0.06, Table 4). Analysis of the relationship between each studied infection and kidney acute transplant rejection is presented in Table 5. As indicated in Table 5, statistical analysis indicated that HLA-DRB1*07 alleles may be associated with hepatitis C virus infection (P \ 0.009, Table 5). In addition as indicated in Table 6 the result of statistical analysis regarding the relation between HLA-DRB1 allele sharing and kidney transplant acute rejection showed that HLA-DRB1 allele sharing did not significantly affect the kidney transplant outcome (Table 6).
Discussion HLA molecules have wide distribution and are expressed on almost all nucleated cells. HLA molecules play a major role in recognition of foreign antigens by T lymphocytes in immune system. Several studies have emphasized on the role of HLA molecules in tissue compatibility. Previous studies indicated that two major factors including HLA similarities between recipients and donors and also viral infections affect the kidney allograft survival [15, 16]. Progress in surgery techniques along with new specific immune suppressive drugs, remarkably increased the kidney transplant survival rate [17]. Despite the use of effective immunosuppressive drugs, most studies indicated that HLA compatibility between recipients and donors remarkably will increase the allograft long term survival [18–20]. Among HLA molecules, HLA-DRB1 matching has been reported to be more important in prevention of acute kidney rejection as compare with HLA-A or HLA-B matching [21, 22]. Previous reports have indicated that
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OR
95 % CI
0.43
0.08–2.54
even a single incompatibility in HLA-DR molecules eliminates the HLA-A and HLA-B matching effect for kidney transplantation rejection [21]. Indeed HLA-DR antigens matching decreases the number of early acute rejection episodes, whereas matching for HLA-A, HLA-B antigens is especially associated with improved long-term graft survival [23]. Considering the major role of HLA-class II, especially HLA-DRB1, molecules in immune responses, in the present study, the effect of HLA-DRB1 alleles and sharing on graft survival was investigated using PCR-SSP method. However our results indicated that HLA-DRB1 allele frequencies or sharing are not different between reject as compared with non-reject groups, but because of a trend to significant level, HLA-DRB1*04 may protect (P = 0.12) while, HLA-DRB1*07 (P = 0.13) may susceptible the graft to acute rejection. In line with our results several published papers have been shown that HLA matching is not related to transplant survival [24–27]. Indeed it seems that HLA matching is not the only effective factor that play role in the kidney transplant outcome and other factors such as immune suppressive drugs are other players in this scenario [5, 18, 28]. In contrast several studies have been demonstrated the prognostic value of HLA matching, especially HLA-DRB1 matching in kidney graft survival [7, 29, 30]. Reisaeter and et al. [31] demonstrated that the number of HLA-DRB1 mismatches significantly affect on the kidney acute rejection episodes. One of the reasons for these discrepancies is the method which is used for typing. Several studies have been indicated that good HLA-DRB1 matching by using molecular method significantly may reduce the chance for acute rejection [7, 19, 32, 33]. Other possible factors may include racial differences, immunosuppressive drugs regimes and sample size of the studies. Moreover all patients in this study received a kidney
Mol Biol Rep Table 5 HLA-DRB1 allele frequencies and viral infections in kidney transplant recipients HLA
HBV N=3 (%)
No HBV infection N = 38 (%)
P value
HCV N=2 (%)
No HCV infection N = 39 (%)
P value
CMV N=3 (%)
No CMV infection N = 38 (%)
P value
HLA-DRB1*01:01
0
8 (10.5)
1.00
0
8 (10.3)
1.00
0
8 (10.5)
0.40
HLA-DRB1*03:01
1 (16.6)
8 (10.5)
0.51
0
9 (11.5)
1.00
2 (33)
7 (9.2)
0.12
HLA-DRB1*04:01 HLA-DRB1*07:01
0 0
13 (17.1) 8 (10.5)
0.26 0.40
0 2 (50)
13 (16.7) 6 (7.7)
0.37 0.04
0 1 (16.6)
13 (17.1) 7 (9.2)
0.26 0.47
HLA-DRB1*08:01
1 (16.6)
0
0.07
0
1 (1.3)
0.81
0
1 (1.3)
1.00
HLA-DRB1*09:01
0
2 (2.6)
1.00
0
2 (2.6)
0.74
0
2 (2.6)
1.00 1.00
HLA-DRB1*10:01
0
2 (2.6)
1.00
0
2 (2.6)
0.74
0
2 (2.6)
HLA-DRB1*11:01/02/03
3 (50)
15 (19.7)
0.11
0
18 (23.1)
0.57
1 (16.6)
17 (22.4)
1.00
HLA-DRB1*12:01
0
1 (1.3)
1.00
0
1 (1.3)
0.81
0
1 (1.3)
1.00
HLA-DRB1*13:01/02/03
1 (16.6)
6 (7.9)
0.42
1 (25)
6 (7.7)
0.30
1 (16.6)
6 (7.9)
0.42
HLA-DRB1*14:01
0
0
0
0
0
0
HLA-DRB1*15:01/02
0
7 (9.2)
1.00
0
7 (9)
0.53
1 (16.6)
6 (7.9)
0.42
HLA-DRB1*16:01
0
6 (7.9)
1.00
1 (25)
5 (6.4)
0.26
0
6 (7.9)
1.00
Table 6 Effect of allele sharing on kidney transplant rejection HLA-DRB1 sharing
a
Outcome
Positive number (%)
Negative number (%)
P value
Rejection
15 (78.9)
4 (21.1)
NS
Non-rejection
15 (68.2)
7 (31.8)
NS
NS non significant a
HLA-DRB1 sharing was defined as at least one allele sharing
transplant from a living donor that this issue could affect the transplant outcome. Moreover, the influence of relative relation, gender, blood group, age on kidney transplant rejection has been investigated in this study and the results indicated that there is no any relation between these factors and kidney transplant rejection as reported by others [34, 35]. Frequencies analysis of HLA-DRB1 alleles indicated that the HLA-DRB1*11 allelic groups was the most common allelic group among both normal and patient groups as reported before by Amirzargar et al. [36] in Iranian population. Our study also showed that HLA-DRB1*14 may has a protective effect on the susceptibility to renal disease (P \ 0.03) while HLA-DRB1*04 play an opposite role, it means that posses of this allele significantly susceptible individuals to renal disease. Viral infection is one of the important reasons for renal transplant loss. Considering the important role of HLADRB1 alleles in immune response to viral infection possession of some alleles may susceptible or protect kidney transplant recipients to graft rejection. The most important finding of the present study regarding the relation between viral infection, HLA-DRB1 molecules and kidney
transplant acute rejection, was the susceptible effect of HLA-DRB1*07 in infection with hepatitis C virus. In line with this finding the relation between HLA-DRB1*07 allele and HCV infection is reported in several studies [8, 37, 38]. Finally our results showed that HLA-DRB1*04 allele may protect the kidney transplant recipients from infection with HBV, HCV and CMV infections however the calculated P value was 0.06. In conclusion however the results of the present study did not showed relation between HLA-DRB1 alleles and kidney transplant rejection, Considering the significant role and relation of HLADRB1 molecules in tissue compatibility and susceptibility to renal diseases or viral infections, HLA-DRB1 typing for both recipients and donors is highly recommended. Acknowledgments The authors also thanks from Transplant Research Center for financial supports.
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37.
38.
serologically HLA-DR-matched renal transplant combinations. Transplantation 64:612–616 Ghods AJ, Ossareh S, Savaj S (2000) Results of renal transplantation of the Hashemi-Nejad Hospital-Tehran. Clin Transpl 14:203–210 Thorogood J, Persijn GG, Schreuder GM, D’Amaro J, Zantvoort FA, van Houwelingen JC, van Rood JJ (1990) The effect of HLA matching on kidney graft survival in separate post transplantation intervals. Transplantation 50:146–150 Terasaki PI, Cecka JM, Gjertson DW, Takemoto S (1995) High survival rates of kidney transplants from spousal and living unrelated donors. N Engl J Med 333(6):333–336 Jones JW Jr, Gillingham KJ, Sutherland DE, Payne WD, Dunn DL, Gores PF, Gruessner RW, Najarian JS, Matas AJ (1994) Successful long-term outcome with 0-haplotype-matched livingrelated kidney donors. Transplantation 57(4):512–515 Nojima M, Ihara H, Kyo M, Hashimoto M, Ito K, Kunikata S, Nakatani T, Hayashi R, Ueda H, Ichikawa Y, Ikoma F (1996) The significant effect of HLA-DRB1 matching on acute rejection in kidney transplants. Transpl Int 9:s11–s15 Coupel S, Giral-Classe M, Karam G, Morcet JF, Dantal J, Cantarovich D, Blancho G, Bignon JD, Daguin P, Soulillou JP, Hourmant M (2003) Ten-year survival of second kidney transplants: impact of immunologic factors and renal function at 12 months. Kidney Int 64:674–680 Heinold A, Opelz G, Do¨hler B, Unterrainer C, Scherer S, Ruhenstroth A, Hien Tran T (2013) Deleterious impact of HLADRB1 allele mismatch in sensitized recipients of kidney retransplants. Transplantation 95(1):137–141 Reisaeter AV, Leivestad T, Vartdal F, Spurkland A, Fauchald P, Brekke IB, Thorsby E (1998) A strong impact of matching for a limited number of HLA-DR antigens on graft survival and rejection episodes: a single-center study of first cadaveric kidneys to nonsensitized recipients. Transplantation 66(4):523–528 Adib M, Yaran M, Rezaie A (2004) HLA-DR typing by polymerase chain reaction with sequence-specific primers compared to serological typing. J Res Med Sci 6:255–259 Beckingham IJ, Dennis MJ, Bishop MC, Blamey RW, Smith SJ, Nicholson ML (1994) Effect of human leucocyte antigen matching on the incidence of acute rejection in renal transplantation. Br J Surg 81(4):574–577 Almasi Hashiani A, Hassanzadeh J, Rajaeefard AR, Salahi H (2011) The relationship between graft survival rate of renal transplantation and donor source in transplanted patients at the transplantation center of Namazi Hospital of Shiraz. Arak Med Univ J 14:10–17 Tuncer M, Gurkan A, Erdogan O, Yucetin L, Demirbas A (2005) Lack of impact of human leukocyte antigen matching in living donor kidney transplantation: experience at Akdeniz University. Transplant Proc 37:2969–2972 Amirzargar A, Mytilineos J, Farjadian S, Doroudchi M, Scherer S, Opelz G, Ghaderi A (2001) Human leukocyte antigen class II allele frequencies and haplotype association in Iranian normal population. Hum Immunol 62:1234–1238 Kallinowski B, Scherer S, Mehrabi A, Theilmann L, Stremmel W (1999) Clinical impact of HLA DRB1 genotypes in chronic Hepatitis C virus infection. Transplant Proc 31:3346–3349 Shaheen NM, Soliman AR, El-Khashab SO, Hanna MO (2013) HLA DRB1 alleles and hepatitis C virus infection in chronic kidney disease patients. Ren Fail 35(3):386–390. doi:10.3109/ 0886022X.2012.761038
HLA-DRBl and susceptibility to kidney allograft rejection in Southern Iranian patients Behrouz Gharesi-Fard • Leila Rezanezhad • Mohammad Hossein Karimi Bita Geramizadeh • Mohammad Mehdi Salehipour • Seyed Ali Malek Hosseini • Jamshid Roozbeh
•
Received: 6 June 2013 / Accepted: 17 May 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract Kidney transplantation is the best treatment option for the patients with end-stage renal disease. Viral infections and genetic factors such as HLA-II antigens may affect the kidney transplant outcome. The compatibility of HLA-DRB1 molecules in the survival of kidney transplant is important. Also, the correlation between these molecules and viral infections is significant. The current study investigates the allele frequency of HLA-DRB1 in 41 recipient kidney transplant and 203 normal healthy controls by polymerase chain reaction using sequence specific primers. Moreover the relation between HLA-DRB1 allelic groups and hepatitis B, hepatitis C and cytomegalovirus viral infections was also studied. However statistical analysis of the allele frequencies didn’t show any significant association between HLA-DRB1 allelic group distributions or sharing and susceptibility to acute kidney transplant rejection (P [ 0.05). Comparing the allele frequencies between HLA-DRB1*14 and DRB1*04 allelic showed a significant difference in controls and patients (P = 0.03 and P = 0.05 respectively). The results of the present study also showed a
B. Gharesi-Fard Department of Immunology, Shiraz University of Medical Sciences, Shiraz, Iran B. Gharesi-Fard Infertility Research Center, Shiraz University of Medical Sciences, Shiraz, Iran L. Rezanezhad Islamic Azad University, Jahrom Branch, Jahrom, Iran M. H. Karimi (&) B. Geramizadeh M. M. Salehipour S. A. M. Hosseini J. Roozbeh Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran e-mail: [email protected]; [email protected]
significant association between possession of HLADRB1*07 allele in kidney transplant recipients and hepatitis C virus infection (P = 0.009). In conclusion however the results of the present study did not showed relation between HLA-DRB1 allele’s frequencies or sharing and kidney transplantation outcome, the results indicated that HLA-DRB1 alleles may susceptible individuals to renal disease or play a role in susceptibility to viral infection in kidney transplant patients. Keywords Kidney allograft Acute rejection HLA-DRB1 PCR-SSP
Introduction Despite the advance progression in immunosuppressive therapies, acute rejection is still account as an important cause of kidney transplant rejection. One of the most important genetic factors that influence on the kidney transplant outcome is human leukocyte antigen (HLA) [1, 2]. HLA molecules are a risk factor for increased incidence of acute graft rejection and graft dysfunction [3]. However, because of immunosuppressive regimen, matching of HLA molecules indicated no significant impact on graft survival in short term, but in long term HLA matching between donor and recipient significantly affect the kidney transplant survival [4]. Previous studies have been shown that the rate of kidney transplant rejection for patients who transplanted with HLA mismatches tissue was twice as compared with who that received a kidney with zero mismatch for HLA-A, B and DR [5]. It is widely accepted that genotype matching of HLA, especially HLA class II is an important factor for graft survival in renal transplant patients [2].Among HLA class II molecules, HLA-DRB1 is
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the most important molecule that play role in tissue compatibility and susceptibility to viral infection [2]. Previous studies indicated that HLA-DRB1 matching significantly affect the survival of cadaveric kidney transplant while HLA-A or HLA-B matching play less important role [6, 7]. Moreover, one of the most important complications of a renal transplantation is viral infection. Beside their role in tissue compatibility, HLA molecules play an important role in immune responses to the viral infections [8]. The relation between some HLA molecules and susceptibility to viral infections are reported before [8, 9]. HLA-DRB1 molecules have been reported to be associated with susceptibility to viral disease including hepatitis B virus (HBV), hepatitis C virus (HCV) [8, 10]. In this respect association between HCV, HBV and cytomegalovirus (CMV) infections and renal disease have been reported in the previous studies [11–13]. So it seems that HLA molecules not only affect the outcome of a kidney transplant but also may affect the fate of viral infections before and after kidney transplantation. Considering the major role of HLADRB1 matching in the prevention of acute kidney transplant rejection and viral infections response and clearance, the current study was designed. By sequence specific primers (PCR-SSP) method in Iranian renal transplant patients, we investigated the relationship between HLADRB1 compatibility and acute renal rejection, as well as the association of HLA-DRB1 molecules and viral infections before and after transplantation.
Materials and methods Patients and controls A total of 69 kidney transplant (41 unrelated and 28 related) pairs, were included in this study. Patients received renal grafts from live donors between 2007 and 2011 at Transplant Center of Nemazi Hospital affiliated to Shiraz University of Medical Sciences. All patients were investigated for the graft outcome and acute rejection episode(s) for at least 6 months after kidney transplantation. Rejection episodes were identified by an expert nephrology team based on the approved clinical diagnostic criteria and invariably confirmed by needle biopsy as well as elevated serum creatinine and blood urea nitrogen levels [14]. The standard immunosuppressive regimen for all recipients were included 5 mg/kg of cyclosporine initially, and then a maintenance dose of 2–2.5 mg/kg (cyclosporine level was 50–150 ng/mL), prednisolone (120 mg/days initially, tapering to 10 mg/days), and mycophenolate mofetil (1,000 mg twice daily). In this study, the patients were divided into two groups based on the presence (AR group) or absence (non-AR group) of acute rejection episodes. HLA-DRB1 Typing was done on 41 out of 69 pairs
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Table 1 Relation between age, gender, blood group, relative relation and kidney transplant acute rejection in 69 transplant patient HLA-DRB1 typed N = 28 (%)
HLA-DRB1 untyped N = 41 (%)
P value
Related
10 (35.7)
18 (43.9)
NS
Unrelated
18 (64.3)
23 (56.1)
20 (71.4)
26 (63.4)
8 (28.6)
15 (36.6)
Relative relation
Gender Male Female
NS
Infection (HBV, HCV, CMV) Infection
8 (28.6)
7 (17.1)
20 (71.4)
34 (82.9)
A?
8 (28.6)
15 (36.6)
B?
3 (10.7)
8 (19.5)
AB
1 (3.6)
3 (7.3)
O? O-
14 (50.0) 2 (7.1)
14 (34.2) 1 (2.4)
10–20
3 (10.7)
5 (12.2)
21–30
8 (28.6)
9 (21.9)
31–40
5 (17.9)
10 (24.4)
12 (42.8)
17 (41.5)
Non infection
NS
Blood Group NS
Age
[41
NS
NS non significant
(Donor & Recipient) of patients and compared with 203 healthy controls. Blood groups, sex and age were also identified and compared between rejection group and non-rejection groups. Moreover infections with three important and common viral infections in kidney transplant recipients including HBV, HCV and CMV were also determined using molecular method. This study was approved by the Ethics Committee of Shiraz University of Medical Sciences. Genomic DNA extraction After collecting buffy coat or whole blood samples in Ethylene Diamine Tetra Acetic acid (EDTA), DNA was extracted using a column based DNA extraction kit according to the kit instruction (Genet Bio kit, Korea). HLA typing and statistical analysis For HLA-DRB1 typing PCR-SSP method was performed using the BAG HLA-SSP low/intermediate resolution kits (BAG, Germany). Twenty-four PCR reactions for each sample were performed according to the kit instruction. PCR products were analyzed by electrophoresis on a 2 % agarose gel and the results were interpreted using BAG
Mol Biol Rep Table 2 Association between HLA-DRB1 frequencies and rejection
HLA
Non rejection frequency N = 22 (%)
Rejection frequency N = 19 (%)
P value
OR
95 % CI
0.09–2.73
HLA-DRB1*01:01
3 (6.8)
5 (13.1)
0.47
0.47
HLA-DRB1*03:01
4 (9.1)
5 (13.1)
0.72
0.66
0.13–3.15
HLA-DRB1*04:01
10 (22.7)
3 (7.9)
0.06
3.43
0.77–17.36
HLA-DRB1*07:01
2 (4.5)
6 (15.8)
0.13
0.25
0.03–1.54
HLA-DRB1*08:01
1 (2.3)
0 (0)
1.00
00000
0000
HLA-DRB1*09:01
1 (2.3)
1 (2.6)
1.00
0.86
0.02–32.84
HLA-DRB1*10:01 HLA-DRB1*11:01/02/03
2 (4.5) 9 (20.5)
0 (0) 9 (23.7)
0.49 0.83
00000 0.82
0000 0.26–2.66
HLA-DRB1*12:01
0 (0)
1 (2.6)
0.46
000000
0.00–15.21
HLA-DRB1*13:01/02/03
5 (11.4)
2 (5.3)
0.44
2.31
0.36–18.47
HLA-DRB1*14:01
0 (0)
0 (0)
Undefined
Undefined
000
Each p value is the result of comparing corresponding row with the sum of other rows
HLA-DRB1*15:01/02
5 (11.4)
2 (5.3)
0.32
00000
00000
HLA-DRB1*16:01
2 (4.5)
4 (10.5)
0.4
0.40
0.05–2.81
Table 3 HLA-DRB1 allele frequencies in 41 patients in comparison with 203 normal Controls
HLA
Patient N = 41 (%)
Each p value is the result of comparing corresponding row with the sum of other rows
P value
OR
95 % CI
HLA-DRB1*01:01
8 (9.8)
35 (8.6)
0.74
1.15
0.47–2.71
HLA-DRB1*03:01
9 (11)
42 (10.3)
0.86
1.07
0.46–2.40
HLA-DRB1*04:01
13 (15.9)
36 (8.9)
0.05*
1.94
0.92–4.02
HLA-DRB1*07:01
8 (9.8)
33 (8.1)
0.62
1.22
0.50–2.90
HLA-DRB1*08:01
1 (1.2)
6 (1.5)
1
0.82
HLA-DRB1*09:01
2 (2.4)
4 (1)
0.26
2.51
0.31–16.26
HLA-DRB1*10:01
2 (2.4)
12 (3)
1
0.82
0.12–3.97 0.55–1.86
HLA-DRB1*11:01/02/03 * Considered significant with p value threshold of 0.05
Normal control N = 203 (%)
18 (22)
88 (21.7)
0.95
1.02
1
0.99
18 (4.4)
0.16
2.01
0.73–5.33
20 (4.9) 48 (11.8)
0.03* 0.39
0.00 0.7
0.00–1.20 0.28–1.68
59 (14.5)
0.07
0.46
0.17–1.17
HLA-DRB1*12
1 (1.2)
5 (1.2)
HLA-DRB1*13:01/02/03
7 (8.5)
HLA-DRB1*14:01 HLA-DRB1*15:01/02
0 (0) 7 (8.5)
HLA-DRB1*16
6 (7.3)
typing software (BAG, Germany) and re-checked manually by typing worksheet. For analysis of the effect of HLADRB1 sharing on kidney transplant outcome, transplant pairs with at least one match allele considered as shared. Chi square test and SPSS or Epi Info software’s were used for statistical analysis.
Results Statistical analysis indicated that there is no any relation between age, gender, blood group or infection with HCV, HBV or CMV and kidney transplant acute rejection (Table 1). The results of HLA-DRB1 typing in rejection and non rejection patients are shown in Table 2. As
indicated in Table 2, statistical analysis didn’t show any significant association between HLA-DRB1 allelic group distributions and susceptibility to acute kidney transplant rejection (P [ 0.05). Comparing the HLA-DRB1 allele frequencies between patients and controls showed that in patients the HLA-DRB1*04 allelic group was more frequent, while in control group, HLA-DRB1*14 allelic group was more frequent (P = 0.03 and P = 0.05 respectively, Table 3). Moreover HLA-DRB1*11 was found to be more frequent allele among patients and control group (Table 3). Regarding the relation between infections and kidney transplant acute rejection, as shown in Table 4, while the relation between all infections together and kidney transplant rejection was studied, results indicated that there were no significant association between HLA-DRB1 allelic
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Mol Biol Rep Table 4 Association of HLADRB1 alleles frequencies and infections with HBV, HCV and CMV
Each p value is the result of comparing corresponding row with the sum of other rows
HLA
Non viral infection N = 33 (%)
Viral infection N = 8 (%)
P value
HLA-DRB1*01:01
8 (12.1)
0 (0)
0.34
HLA-DRB1*03:01
6 (9.1)
3 (18.8)
0.36
HLA-DRB1*04:01
13 (19.7)
0 (0)
0.06
HLA-DRB1*07:01
5 (7.6)
3 (18.8)
0.18
0.36
0.08–2.54
HLA-DRB1*08:01
0 (0)
1 (6.2)
0.18
0.43
0.06–2.18
HLA-DRB1*09:01
2 (3)
0 (0)
1.00
HLA-DRB1*10:01
2 (3)
0 (0)
1.00
HLA-DRB1*11:01/02/03
14 (21.2)
4 (25)
0.74
0.81
0.20–3.52
HLA-DRB1*12:01
1 (1.5)
0 (0)
1.00
HLA-DRB1*13:01/02/03
4 (6.1)
3 (18.8)
0.13
0.28
0.04–1.82
HLA-DRB1*14:01 HLA-DRB1*15:01/02
0 (0) 6 (9.1)
0 (0) 1 (6.2)
Undefined 0.71
Undefined 1.50
Undefined 0.15–35.59
HLA-DRB1*16
5 (7.6)
1 (6.2)
1.00
1.23
0.12–29.93
group frequencies and infection. However the results indicated that HLA-DRB1*04 could be a protective allele against infection in renal transplant recipients (P = 0.06, Table 4). Analysis of the relationship between each studied infection and kidney acute transplant rejection is presented in Table 5. As indicated in Table 5, statistical analysis indicated that HLA-DRB1*07 alleles may be associated with hepatitis C virus infection (P \ 0.009, Table 5). In addition as indicated in Table 6 the result of statistical analysis regarding the relation between HLA-DRB1 allele sharing and kidney transplant acute rejection showed that HLA-DRB1 allele sharing did not significantly affect the kidney transplant outcome (Table 6).
Discussion HLA molecules have wide distribution and are expressed on almost all nucleated cells. HLA molecules play a major role in recognition of foreign antigens by T lymphocytes in immune system. Several studies have emphasized on the role of HLA molecules in tissue compatibility. Previous studies indicated that two major factors including HLA similarities between recipients and donors and also viral infections affect the kidney allograft survival [15, 16]. Progress in surgery techniques along with new specific immune suppressive drugs, remarkably increased the kidney transplant survival rate [17]. Despite the use of effective immunosuppressive drugs, most studies indicated that HLA compatibility between recipients and donors remarkably will increase the allograft long term survival [18–20]. Among HLA molecules, HLA-DRB1 matching has been reported to be more important in prevention of acute kidney rejection as compare with HLA-A or HLA-B matching [21, 22]. Previous reports have indicated that
123
OR
95 % CI
0.43
0.08–2.54
even a single incompatibility in HLA-DR molecules eliminates the HLA-A and HLA-B matching effect for kidney transplantation rejection [21]. Indeed HLA-DR antigens matching decreases the number of early acute rejection episodes, whereas matching for HLA-A, HLA-B antigens is especially associated with improved long-term graft survival [23]. Considering the major role of HLA-class II, especially HLA-DRB1, molecules in immune responses, in the present study, the effect of HLA-DRB1 alleles and sharing on graft survival was investigated using PCR-SSP method. However our results indicated that HLA-DRB1 allele frequencies or sharing are not different between reject as compared with non-reject groups, but because of a trend to significant level, HLA-DRB1*04 may protect (P = 0.12) while, HLA-DRB1*07 (P = 0.13) may susceptible the graft to acute rejection. In line with our results several published papers have been shown that HLA matching is not related to transplant survival [24–27]. Indeed it seems that HLA matching is not the only effective factor that play role in the kidney transplant outcome and other factors such as immune suppressive drugs are other players in this scenario [5, 18, 28]. In contrast several studies have been demonstrated the prognostic value of HLA matching, especially HLA-DRB1 matching in kidney graft survival [7, 29, 30]. Reisaeter and et al. [31] demonstrated that the number of HLA-DRB1 mismatches significantly affect on the kidney acute rejection episodes. One of the reasons for these discrepancies is the method which is used for typing. Several studies have been indicated that good HLA-DRB1 matching by using molecular method significantly may reduce the chance for acute rejection [7, 19, 32, 33]. Other possible factors may include racial differences, immunosuppressive drugs regimes and sample size of the studies. Moreover all patients in this study received a kidney
Mol Biol Rep Table 5 HLA-DRB1 allele frequencies and viral infections in kidney transplant recipients HLA
HBV N=3 (%)
No HBV infection N = 38 (%)
P value
HCV N=2 (%)
No HCV infection N = 39 (%)
P value
CMV N=3 (%)
No CMV infection N = 38 (%)
P value
HLA-DRB1*01:01
0
8 (10.5)
1.00
0
8 (10.3)
1.00
0
8 (10.5)
0.40
HLA-DRB1*03:01
1 (16.6)
8 (10.5)
0.51
0
9 (11.5)
1.00
2 (33)
7 (9.2)
0.12
HLA-DRB1*04:01 HLA-DRB1*07:01
0 0
13 (17.1) 8 (10.5)
0.26 0.40
0 2 (50)
13 (16.7) 6 (7.7)
0.37 0.04
0 1 (16.6)
13 (17.1) 7 (9.2)
0.26 0.47
HLA-DRB1*08:01
1 (16.6)
0
0.07
0
1 (1.3)
0.81
0
1 (1.3)
1.00
HLA-DRB1*09:01
0
2 (2.6)
1.00
0
2 (2.6)
0.74
0
2 (2.6)
1.00 1.00
HLA-DRB1*10:01
0
2 (2.6)
1.00
0
2 (2.6)
0.74
0
2 (2.6)
HLA-DRB1*11:01/02/03
3 (50)
15 (19.7)
0.11
0
18 (23.1)
0.57
1 (16.6)
17 (22.4)
1.00
HLA-DRB1*12:01
0
1 (1.3)
1.00
0
1 (1.3)
0.81
0
1 (1.3)
1.00
HLA-DRB1*13:01/02/03
1 (16.6)
6 (7.9)
0.42
1 (25)
6 (7.7)
0.30
1 (16.6)
6 (7.9)
0.42
HLA-DRB1*14:01
0
0
0
0
0
0
HLA-DRB1*15:01/02
0
7 (9.2)
1.00
0
7 (9)
0.53
1 (16.6)
6 (7.9)
0.42
HLA-DRB1*16:01
0
6 (7.9)
1.00
1 (25)
5 (6.4)
0.26
0
6 (7.9)
1.00
Table 6 Effect of allele sharing on kidney transplant rejection HLA-DRB1 sharing
a
Outcome
Positive number (%)
Negative number (%)
P value
Rejection
15 (78.9)
4 (21.1)
NS
Non-rejection
15 (68.2)
7 (31.8)
NS
NS non significant a
HLA-DRB1 sharing was defined as at least one allele sharing
transplant from a living donor that this issue could affect the transplant outcome. Moreover, the influence of relative relation, gender, blood group, age on kidney transplant rejection has been investigated in this study and the results indicated that there is no any relation between these factors and kidney transplant rejection as reported by others [34, 35]. Frequencies analysis of HLA-DRB1 alleles indicated that the HLA-DRB1*11 allelic groups was the most common allelic group among both normal and patient groups as reported before by Amirzargar et al. [36] in Iranian population. Our study also showed that HLA-DRB1*14 may has a protective effect on the susceptibility to renal disease (P \ 0.03) while HLA-DRB1*04 play an opposite role, it means that posses of this allele significantly susceptible individuals to renal disease. Viral infection is one of the important reasons for renal transplant loss. Considering the important role of HLADRB1 alleles in immune response to viral infection possession of some alleles may susceptible or protect kidney transplant recipients to graft rejection. The most important finding of the present study regarding the relation between viral infection, HLA-DRB1 molecules and kidney
transplant acute rejection, was the susceptible effect of HLA-DRB1*07 in infection with hepatitis C virus. In line with this finding the relation between HLA-DRB1*07 allele and HCV infection is reported in several studies [8, 37, 38]. Finally our results showed that HLA-DRB1*04 allele may protect the kidney transplant recipients from infection with HBV, HCV and CMV infections however the calculated P value was 0.06. In conclusion however the results of the present study did not showed relation between HLA-DRB1 alleles and kidney transplant rejection, Considering the significant role and relation of HLADRB1 molecules in tissue compatibility and susceptibility to renal diseases or viral infections, HLA-DRB1 typing for both recipients and donors is highly recommended. Acknowledgments The authors also thanks from Transplant Research Center for financial supports.
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