Cytokine Polymorphisms Do Not Influence Acute Rejection in Renal Transplantation Under Tacrolimus-Based Immunosuppression M. Loucaidou, J. Stitchbury, J. Lee, R. Borrows, S.E. Marshall, A.G. McLean, T. Cairns, M. Griffith, N. Hakim, A. Palmer, V. Papalois, K. Welsh, and D. Taube ABSTRACT Introduction. Acute rejection remains an important cause of graft loss after renal transplantation. It has been suggested that cytokine genotyping may play a predictive role in identifying individuals who are at higher risk of acute rejection with a view to individualizing their immunosuppression. The aim of this study was to investigate any possible associations between acute rejection and certain cytokine polymorphisms. Methods. We genotyped 91 cadaveric renal transplant recipients on tacrolimus-based immunosuppression and 84 of their donors. The cytokine polymorphisms studied were the following: tumor necrosis factor (TNF)-␣-1032 T/C, TNF-␣-865 C/A, TNF-␣-859 G/A, interleukin (IL)1-R1-970 C/T, IL-10 haplotype [⫺1082, ⫺819, ⫺592], and IL-6-174 C/G. Results. We found no association between any polymorphism and the incidence of acute rejection. This was true for both the recipient and donor population. Conclusion. Cytokine polymorphisms did not influence acute rejection in our study. We conclude that in the modern era of immunosuppression cytokine genotyping is not a significant predictor of acute rejection in renal transplantation.
ESPITE DEATH WITH functioning graft becoming the leading cause of graft loss in recent years, acute rejection remains ahead after censoring for death.1,2 Several studies have suggested that intimal arteritis3,4 is the main pathomorphological feature associated with subsequent graft failure. Newer, improved immunosuppressive regimens contribute significantly not only to reduced acute rejection rates but also to death with functioning graft, for example from sepsis, malignancy, and cardiovascular disease. Tailoring immunosuppression to the individual need in order to achieve a balance between the risks and benefits of immunosuppression is therefore highly appealing to the transplant community. Identification of increasing number of gene polymorphisms has been possible in the recent years, and as the study of interindividual differences of gene profiles has linked these to the susceptibility and clinical severity of disease, there has been renewed hope for investigating the relative risk of rejection for a given individual. Cytokine and cytokine receptor polymorphisms have been the focus of a large number of studies of the complications of transplantation, particularly acute rejection. Polymorphisms in the interleukin (IL)-105–10 and IL-6
genes9 –11 have been among the most extensively analyzed. While many studies have reported associations, no clear positive association between any specific recipient or donor gene variant and transplant endpoint has been reproducibly identified. The aim of this study was to correlate the incidence of acute rejection to a cytokine genotype of the recipients and donors in a single center. MATERIALS AND METHODS A total of 91 caucasoid cadaveric renal transplant recipients and their respective donors took part in this study. These patients were selected on the basis of their homogeneous tacrolimus-based immunosuppressive regimens and were transplanted at St Mary’s Hospital between 1995 and 2002. Material was unsuitable for analysis from seven donors; thus the final study group consisted of 91 recipients and 84 donors. This study was approved by the St Mary’s Hospital Local and Research Ethics Committee. Acute rejection was diagnosed on the basis of a creatinine rise or delayed From the Renal and Transplant Unit, St Mary’s Hospital, London, United Kingdom. Address reprint requests to M. Loucaidou, Renal Unit, St Mary’s Hospital, Praed Street, London, UK. E-mail: [email protected]
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.03.151
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Transplantation Proceedings, 37, 1760 –1761 (2005)
CYTOKINE POLYMORPHISMS AND ACUTE REJECTION graft function and confirmed in all cases histologically (Banff 97 classification). All recipients and their donors were genotyped for the following polymorphisms: tumor necrosis factor (TNF)-␣-1032 T/C, TNF-␣-865 C/A, TNF-␣-859 G/A, IL1-R1-970 C/T, IL-10 haplotype [⫺1082, ⫺819, ⫺592], and IL-6-174 C/G. Cytokine genotyping was performed using a unified polymerase chain reaction with sequence-specific primers system. Phenotype, genotype, and allele frequencies were measured for all polymorphisms. Associations were assessed using 2 ⫻ n contingency table analysis and the chi-square test, with Yates correction or Fisher exact tests where appropriate.
The recipient mean age was 43.3 years, which was comparable to the donor mean age of 40.2 years. Ninety one recipients and 84 donors were genotyped for eight polymorphisms including IL-6-174 C/G and IL-10 haplotype [⫺1082, ⫺819, ⫺592]. Acute rejection rate in this group was 33%. Extensive statistical analysis did not reveal an association between acute rejection and recipient or donor polymorphisms. The effect of the above polymorphisms on vascular rejection, delayed graft function, and graft loss was also analyzed. No associations were observed in this cohort of recipients and donors. DISCUSSION
We have found no evidence to suggest that either recipient or cytokine cytokine polymorphisms determine the incidence of acute rejection after cadaveric renal transplantation in the modern era of immunosuppression. The scope of analysis required to understand the complex interactions between cytokine polymorphisms and solid organ transplant outcome is much greater than it initially appeared. This study and indeed others have yet to identify any strong and unequivocal links with specific cytokine genotypes that would allow us to predict low- or high-risk patients and ultimately tailor appropriate immunosuppression. The identification of true associations and their clinical applications will require multicenter studies, necessitating consensus of treatment protocols and endpoint definition. One advantage of the considerable work that has gone into this area is that many important lessons have been learned, and it has set the scene for the application of non-HLA genetic risk factors to transplantation in general. Perhaps the most
likely area of clinical application is pharmacogenetics, or the genetic basis of interindividual differences in drug response. Genetic variation has been estimated to account for 20% to 95% of variability in drug handling and side effects,12 and this is a growing area of research in transplantation. With the expansion of immunosuppressant regimens available, it is likely that pharmacogenetic profiling will become an important aspect of tailoring immunosuppressive therapy to individual patients’ needs in the next era of transplantation. REFERENCES 1. Howard RJ, Patton PR, Reed AI, et al: The changing causes of graft loss and death after kidney transplantation. Transplantation 73:1923, 2002 2. Matas AJ, Gillingham KJ, Sutherlan DE: Half-life and risk factors for kidney transplant outcome-importance of death with function. Transplantation 55:757, 1993 3. Mueller A, Schnuelle P, Waldherr R, et al: Impact of the Banff ’97 classification for histological diagnosis of rejection on clinical outcome and renal function parameters after kidney transplantation. Transplantation 69:1123, 2000 4. van Saase JL, van der Woude FJ, Thorogood J, et al: The relation between acute vascular and interstitial renal allograft rejection and subsequent chronic rejection. Transplantation 59: 1280, 1995 5. Asderakis A, Sankaran D, Dyer P, et al: Association of polymorphisms in the human interferon-␥ and interleukin-10 gene with acute and chronic kidney transplant outcome. Transplantation 71:674, 2001 6. Sankaran D, Asderakis A, Ashraf S, et al: Cytokine gene polymorphisms predict acute graft rejection following renal transplantation. Kidney Int 56:281, 1999 7. Pelletier R, Pravica V, Perrey C, et al: Evidence for a genetic predisposition towards acute rejection after kidney and simultaneous kidney-pancreas transplantation. Transplantation 70:674, 2000 8. Poole KL, Gibbs PJ, Evans PR, et al: Influence of patient and donor cytokine genotypes on renal allograft rejection: evidence from a single centre study. Transpl Immunol 8:259, 2001 9. Marshall SE, McLaren AJ, Haldar NA, et al: The impact of recipient cytokine genotype on acute rejection after renal transplantation. Transplantation 70:1485, 2000 10. Marshall SE, McLaren AJ, McKinney EF, et al: Donor cytokine genotype influences the development of acute rejection after renal transplantation. Transplantation 71:469, 2001 11. Poli F, Boschiero L, Giannoni F, et al: Tumour necrosis factor-alpha gene polymorphism: implications in kidney transplantation. Cytokine 12:1778, 2000 12. Evans WE, McLeod HL: Pharmacogenomics— drug disposition, drug targets and side effects. N Engl J Med 348:538, 2003