|Year : 2016 | Volume
| Issue : 3 | Page : 89-96
Interleukin-10 gene polymorphism and graft outcome in live-donor kidney transplantation
Rashad Hassan Rashad1, Khaled Mohamed Mahmoud MD 1, Tarek Medhat Abbas Abdel Hady1, Amgad El-Baz El-Agroudy1, Ahmed Farouk Hamdy1, Amani Mostafa Ismail2, Nagy Abd-El Hady Sayed3, Mohamed Abd El-Kader Sobh1
1 Department of Nephrology, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
2 Department of Immunology, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
3 Department of Internal Medicine Department, Mansoura University, Mansoura, Egypt
|Date of Submission||18-Oct-2016|
|Date of Acceptance||07-Nov-2016|
|Date of Web Publication||2-Jan-2017|
Khaled Mohamed Mahmoud
Department of Nephrology, Urology and Nephrology Center, Mansoura University, Mansoura 35516
Source of Support: None, Conflict of Interest: None
Polymorphism has been described in many immunoregulatory molecules that play a role in the rejection process. It has offered a possible explanation for the individual difference in rejection susceptibility and renal graft survival independent of other risk factors. The aim of this work was to study the impact of the interleukin-10 (IL-10) cytokine gene polymorphism on the clinical course and outcome of a renal transplant.
Materials and methods
This work included 50 transplant recipients treated with a sirolimus-based immunosuppressive regimen for IL-10 cytokine gene polymorphisms. After transplantation, patients were classified into two groups: in group A, patients (12 patients) received sirolimus, tacrolimus, and steroid and in group B, patients (38 patients) received sirolimus, mycophenolate mofetil, and steroid. The results were correlated with rejections (acute and chronic) and patient and graft survival.
In our study, we found no impact of IL-10 on the incidence and degree of acute rejection episodes, incidence of chronic allograft nephropathy, pathological changes in protocol biopsies, graft function, and graft and patient survivals.
On the basis of this work, we concluded that there is no impact of IL-10 cytokine gene polymorphisms on the clinical course and outcome of a renal transplant. Genes other than IL-10 could probably be involved as key molecules in graft function.
Keywords: gene polymorphism, graft outcome, interleukin-10, kidney transplantation, live-donor
|How to cite this article:|
Rashad RH, Mahmoud KM, Hady TA, El-Agroudy AE, Hamdy AF, Ismail AM, Sayed NA, Sobh MA. Interleukin-10 gene polymorphism and graft outcome in live-donor kidney transplantation. J Egypt Soc Nephrol Transplant 2016;16:89-96
|How to cite this URL:|
Rashad RH, Mahmoud KM, Hady TA, El-Agroudy AE, Hamdy AF, Ismail AM, Sayed NA, Sobh MA. Interleukin-10 gene polymorphism and graft outcome in live-donor kidney transplantation. J Egypt Soc Nephrol Transplant [serial online] 2016 [cited 2018 Mar 23];16:89-96. Available from: http://www.jesnt.eg.net/text.asp?2016/16/3/89/197381
| Introduction|| |
The increasing success in preventing acute renal allograft rejection has resulted in rejection rates of less than 20% and 1-year graft survivals of more than 90%. This success has led to a focus on improvement in long-term allograft survival and adjustment of immunosuppression to the individual need. Currently, all patients are treated with broad-spectrum immunosuppression, with their myriad side effects. Yet, we know that some patients may discontinue or considerably lower immunosuppression without developing any adverse effects .
There is an individual variation in the susceptibility to the occurrence of rejection and allograft survival. A possible explanation for this difference has been offered by the polymorphism description of immunoregulatory molecules that play a role in the rejection process. Genetic variabilities that can affect the survival of the renal allograft include major histocompatibility complex molecules and the effect of polymorphisms on chemokines, cytokines, cytokine receptors, adhesion, and costimulatory molecules .
The combination of a high production of tumor-necrosis factor-α with a low production of interleukin-10 (IL-10 was associated with acute rejection in heart transplant patients, whereas a high production of both tumor-necrosis factor-α and IL-10 was associated with acute rejection in renal transplant patients .
A functional role of polymorphisms has also been implicated in the chronic rejection process . Polymorphisms in both interferon-γ and transforming growth factor-β have been associated with allograft fibrosis in lung transplant recipients.
Two polymorphisms in the intercellular adhesion molecule-1 have been associated with increased chronic renal allograft dysfunction , whereas one of the polymorphisms in intercellular adhesion molecule-1 was found to exert a protective effect with respect to chronic rejection in cardiac transplant recipients.
These data represent just some of the increasing evidence that there is some validity to the hypothesis that polymorphisms in immunoregulatory molecules contribute toward the heterogeneity in outcomes after transplantation .
We aimed to examine the relationship between the recipient cytokine genotype and clinical outcome in patients with a surviving allograft of at least 5 years and to assess its sensitivity and specificity in predicting acute allograft rejection and chronic allograft rejection.
| Materials and methods|| |
This work included 50 recipients of first renal transplants who underwent transplantation at the Mansoura Urology and Nephrology Center. Exclusion criteria included previous transplantation, recipients younger than 18 years of age, pretransplant dyslipidemia with a total cholesterol level higher than 300 mg/dl, and triglycerides higher than 400 mg/dl. Patients with leukopenia (white blood cell count<4000/mm3, thrombocytopenia (platelets<150 000/mm3, and any change in the basal immunosuppressive protocol for any reason were also excluded from the study. The study was approved by the Scientific and Ethical committees at Mansoura Faculty of Medicine. An informed consent was obtained from all participants.
Before kidney transplantation, all patients were subjected to extensive clinical, laboratory, radiological, and immunological evaluations. After transplantation, patients were randomized prospectively into two groups: in group A, patients (12 patients received sirolimus within 24 h after completion of surgery at a dose of 10 mg/day orally for 3 days and then maintained on 5 mg/day. Further doses were concentration controlled to maintain the 24-h whole-blood trough level between 6 and 12 ng/ml. Tacrolimus was added to the immunosuppressive regimen on the third postoperative day. Creatinine clearance must exceed 50 ml/min before the start of tacrolimus. A starting dose of 0.03 mg/kg/day was administered in two divided daily doses. Further doses were subsequently adjusted to maintain a 12-h whole-blood trough level of 3–7 ng/ml .
In group B, patients (38 patients received sirolimus and were maintained on a single oral morning dose of 10 mg/day. Further doses were concentration controlled to maintain 24-h whole-blood trough level between 10 and 15 ng/ml. Mycophenolate mofetil 1 g twice per day was administered on the morning after surgery. Patients were maintained on this dose unless there were any complications or side effects that necessitated dose reduction, for example, leukopenia and gastrointestinal toxicity.
All patients in both groups were administered intravenous basiliximab at a dose of 20 mg on the day of the surgery and on the fourth postoperative day. Two methyl prednisolone doses of 500 mg intravenous were administered to all patients 1 day before surgery and the next day. All patients were maintained on oral steroid (prednisolone, which was started at a dose of 1 mg/kg/day, followed by a gradual reduction of the dose to 0.1 mg/kg by the 10th month after transplantation.
Following kidney transplantation, all recipients were evaluated for graft function, tolerance to drugs, drug monitoring, radiological evaluations, histopathological examination of the graft biopsy, and immunological screening.
In this work, a renal allograft tissue histopathologic examination was carried out in case of renal dysfunction with a 25% or more increase in creatinine (compared with the baseline value unexplained by other factors (prerenal factors or postrenal causes or high tacrolimus trough levels in group A patients, delayed graft function, and nephrotic range proteinuria. In addition, a routine protocol biopsy was carried out in 43 patients in group 1 year after transplantation.
All the patients were investigated for gene polymorphism in IL-10 (at position −1082 as follows:
RNA isolation was performed using the automated MagNA pure lightcycler (LC system and the MagNA pure LC RNA isolation kit (Roche Applied Science, Mannheim, Germany. Isolated RNAs were reverse transcribed and amplified using the LC RNA master hybridization probes kit (Roche Applied Science and the PCR master SYBR green kit (GeneCraft, Köln, Germany)according to the manufacturer’s instructions.
Detection of cytokine polymorphisms of IL10 (at position −1082)
The LC RNA master hybridization probes kit (Roche Molecular Biochemicals, Mannheim, Germany was used to determine the level of IL-10. A real-time PCR reaction using 20 μl was performed with 7.0 μl RNA and 7.5 μl enzyme mix in addition to 0.5 μmol/l of each primer and 0.25 μmol/l of each probe. The forward primer was 5′-AGCTGAGAACCAAGACCCAGA-3′ and the reverse primer was 5′-GGGCTGGGTCAGCTATCC-3′. Two hybridization probes (Metabion, Munich, Germany were designed for identification of the adjacent internal sequences within the amplified fragment. One was labeled at the 5′ end with LC Red 640 and phosphorylated at the 3′ end to prevent probe elongation by the Taq DNA polymerase. The other was labeled at the 3′ end with fluorescein (Flu. The sequences of the two probes were 5′-CGGCGCTGTCATCGATTTCTTCCCT-3′ Flu and LC Red 640 5′-TGAAAACAAGAGCAAGGCCGTGGAGC-3′. After 25 min of incubation at 60°C for reverse transcription, a first denaturation step of 1 min at 95°C was started. Next, amplification was carried out for 45 cycles of denaturation at 95°C for 10 s, annealing at 58°C for 15 s, and extension at 72°C for 20 s. Continuous fluorescence was monitored at the annealing step for each sample . Results were interpreted as follows: AA (low producer, GA (intermediate producer, and GG (high producer ,,.
Qualitative data were presented as cross tabulations. Quantitative data were described as mean±SD. For the evaluation of contrasts, bivariate techniques were initially used. To compare the frequencies of qualitative variables, we used χ2-test and Fisher’s exact test. The Mann–Whitney test and the unpaired t-test were used for comparisons of quantitative variables. A P-value less than 0.05 was considered significant. All analyses were carried out using the SPSS for Windows, Version 16.0. Chicago, SPSS Inc.
| Results|| |
This work included 38 male and 12 female patients with a mean age of 33.86±9.79 years. These patients received their allografts from relatively young donors (mean=34.38±10.42 years) who were related in 82% of cases. The duration of pretransplant hemodialysis ranged from 0 to 48 months; during this period, the patients received a mean of 3.11±2.89 blood units. The mean duration of post-transplant follow-up was 72.48±6.28 months (range=62–85 months ([Table 1]).
|Table 1 Demographic and clinical characteristics of the 50 renal allograft recipients at commencement of the study|
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Our data showed that there was no statistically significant difference between HLA and DR matching and the sum of HLA and DR in relation to the incidence of acute rejection (P=0.613, 0.317, and 0.783, respectively or chronic allograft nephropathy (P=0.565, 0.268, and 0.129, respectively.
Data analysis in relation to interleukin-10 production
The 50 patients included in this study were divided into three groups on the basis of their IL-10 production levels [low (n=22, intermediate (n=15, and high (n=13].
The three groups of renal allograft recipients were comparable with respect to donor age, donor sex, recipient age, recipient sex, original kidney disease, donor relation, and duration of hemodialysis ([Table 2]).
|Table 2 Demographic and clinical characteristics of the 50 renal allograft recipients in relation to IL-10 production|
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In our study, there was no statistically significant difference among the three groups in the number of acute rejection episodes, degree of the first attack of acute rejection, and incidence of chronic allograft nephropathy. Only one recipient from the first group (low producers had a second attack of acute cellular rejection ([Table 3]).
|Table 3 Relation between number, degree, management & response to therapy in acute rejection episodes; incidence of chronic allograft nephropathy and IL-10 production|
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The results of the first biopsy showed no statistically significant differences among the three groups and according to the Banff classification, all first biopsies showed border line rejection [these rejecters were all from the first group (low producers]. The results of the second biopsy and the Banff classification of these biopsies showed that there was no statistically significant difference between the three groups. Only two recipients were subjected to a third graft biopsy [one from the first group (low producers, with a normal result, and the second from the third group (high producers, who had chronic rejection]. Forty-three recipients were subjected to protocol biopsy 1 year after transplantation, with no statistically significant difference among the three groups in the results of these protocol biopsies ([Table 4]).
|Table 4 Relation between results, Banff classification of the graft biopsies; results of protocol biopsies and IL-10 production|
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Analysis of the MMF group (n=38 in relation to IL-10 production showed no statistically significant difference among the three groups in the number of acute rejection episodes, incidence of chronic allograft nephropathy, incidence, degree, and onset of proteinuria, and the results of protocol biopsies ([Table 5]).
Analysis of the FK group (n=12 in relation to IL-2 production also showed no statistically significant difference among the three groups in the number of acute rejection episodes, incidence of chronic allograft nephropathy, incidence of proteinuria, and the results of protocol biopsies ([Table 6]).
All rejection episodes were managed and a complete response was observed to pulse steroid therapy.
Finally, the three groups were comparable in the graft survival (P=0.496 and the 50 patients who were included in this study were alive with functioning grafts at the last follow-up.
| Discussion|| |
Genetic variations with single nucleotide polymorphisms, dinucleotide repeats, and microsatellites have been found in a number of genes encoding adhesion molecules, cytokines, chemokines, and their receptors. Many polymorphisms are present in the promoter region of the gene. They affect transcription, translation, and the level of the protein product expression. Various disease states extending from infection susceptibility, autoimmunity to hypertension have been found to be associated with known sequence variations .
Interleukin-10 gene polymorphism and acute rejection
It was found that IL-10 exerts an inhibitory effect on antigen-dependent T-cell proliferation in vitro. In addition, it exerts suppressive effects on the responses in the primary mixed lymphocyte reaction  and a paradoxical impact on organ transplantation. Elevated IL-10 gene expression was associated with reduced rejection episodes in heart and liver transplantation ,. However, in kidney transplantation, it was associated with increased incidence of acute rejections ,.
The relation of IL-10 polymorphisms to rejection is controversial; some studies have reported that IL-10 polymorphisms affect the risk of rejection , and others have found no influence of IL-10 polymorphisms ,.
In our study, we did not find associations between the IL-10 gene polymorphism and the incidence or the degree of acute graft rejection. In contrast to our findings, many reports found an association between the IL-10 gene polymorphism and the risk of rejection, although some of these reports yielded conflicting results on the association between the level of IL-10 production and the risk of rejection.
The first group found that high producers of IL-10 have a higher incidence of rejection. Sankaran and colleagues studied 115 renal allograft recipients. All patients with primary function were maintained on cyclosporine A monotherapy. Those with delayed graft function were maintained on a triple-therapy regimen of prednisolone, cyclosporine A, and azathioprine. Analysis of all patients independent of HLA-DR matching found no association between cytokine gene polymorphism and rejection episodes. However, a separate analysis of HLA-DR mismatched allograft recipients with a high IL-10 production genotype showed a higher incidence of rejection episodes .
This can be explained on the basis of potentiation of antibody responses to the graft by IL-10 as reported by Merville et al. . Low IL-10 responses are a predictor of a low risk of acute rejection . Other studies reported that IL-10 is a potent stimulator that can induce B-cell differentiation and proliferation. This will drive the patient immune response toward the humoral pathway .
Also, Yang and Liu found higher levels of IL-10 in patients with acute rejection (compared with rejection-free recipients. The investigators did an analysis of renal allograft recipients with HLA-DR mismatch in the first three months after kidney transplantation. They found a higher incidence of acute rejections among patients with IL-10 GG genotype (high producers) .
However, the second group found that patients with a low production of IL-10 have a higher incidence of rejection. George and colleagues compared patients with acute rejections (34 patients with those with no rejections (71 patients. They found that low IL-10 production associated with the IL-10 (−1082 AA genotype was more frequent in the first group (patients with acute rejections even when HLA-DR-matched transplant recipients were included (P=0.01 . These results were consistent with the data found in some experimental studies that concluded that IL-10 exerts an inhibitory effect on inflammatory cytokines ,.
In 2007, Amirzargar and colleagues studied 100 kidney transplant recipients; all patients received immunosuppressive medications in the form of cyclosporine or tacrolimus, azathioprine or Mycophenolate Mofetil (MMF), and methylprednisolone. All patients were followed up for a period of 1 year after transplantation. It was found that the IL-10 low-producer genotype was more frequent in patients who had acute rejection episodes .
In a renal transplant study, 22 polymorphisms were found in 11 cytokine and cytokine receptor genes (including IL-10. No association was found between polymorphism and acute rejections in terms of the incidence or severity . This was in agreement with our results.
Finally, Chen et al. , in their study in 2014, which included 325 renal transplant recipients, found no association between the IL-10 genotype and the incidence of rejection or graft survival.
Interleukin-10 gene polymorphism and chronic rejection
A functional role of polymorphisms has also been implicated in the chronic rejection process .
Our results showed no statistically significant difference between IL-10 production and the incidence of chronic rejection.
Similar results were published by Canossi and colleagues in 2007 when they studied 86 renal transplant recipients. All patients received immunosuppressive medications including cyclosporine, prednisolone, and azathioprine or mycophenolate mofetil. The average follow-up period was 78 months for all patients after transplantation. Chronic rejection was diagnosed in nine patients. There was no significant relationship between the IL-10 gene polymorphism and the incidence of chronic rejection .
In contrast, Uboldi de Capei and colleagues, who studied 416 first cadaveric renal allograft recipients 10 years after transplantation, found that after 10 years of follow-up, the renal allograft was still functioning in 171 patients (41%. In all, 102 of 171 patients were also typed for cytokine polymorphisms by PCR-SSP. They found that patients with high IL-10 production and HLA class I mismatched (but class II matched were protected against chronic rejection (P=0.0008 . A possible explanation for these results could be that interferon-γ induces the expression of MHC class II molecules, but is not suppressed by IL-10 .
Other researchers evaluated the association between IL-10 (−1082 SNP genotypes and chronic rejection after kidney transplantation. They found an association between the high IL-10 producer genotype (GG and better graft function 5 years after transplant, although this did not achieve statistical significance. Patient survival estimated 1 and 5 years after transplantation was not associated with any IL-10 genotype .
Interleukin-10 gene polymorphism and graft and patient survival
Analysis of our data showed that there was no impact of IL-10 production on patient and graft survival. A possible explanation for this could be the comparable results in all groups in terms of the incidence of acute and chronic rejections.
Mytilineos and colleagues studied 4199 renal transplant recipients (of whom 2298 were first transplants and 1901 had undergone retransplantation. Records were obtained from 73 transplant centers that participated in this study (Collaborative Transplant Study. White patients who underwent transplantation in the period between 1987 and 2000 were included in this report. Similar to our results, there was no effect of IL-10 gene polymorphisms on kidney graft survival .
Other investigators reported that in patients with long-term (more than 10 years renal allograft survival, there was an association between patient and graft survival and the high IL-10 producer genotype .
| Conclusion|| |
From this study, we conclude that the IL-10 gene polymorphism does not play a role in the incidence of acute rejection, chronic rejection, and patient and graft survival. Further studies evaluating all other cytokine genes involved in immune reaction are needed to explore the role of the cytokine gene polymorphism in the outcome of renal transplantation.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]