Effect of sirolimus as an immunosuppressive agent on kidney transplantation in patients with diabetes mellitus; a systematic review


 Introduction: Sirolimus is a macrolide and a type of immunosuppressant drug to prevent rejection of transplanted organs. This drug inhibits the activation of T and B lymphocytes and reduces the production of interleukin-2 (IL-2). Objectives: This study aimed to review the effect of sirolimus in kidney transplantation in patients with diabetes mellitus as a systematic review. Materials and Methods: International databases including PubMed, Web of Science and Scopus were considered for search of English articles by 29 June 2019. Twenty-one published articles were finally entered into the study. Keywords were sirolimus, rapamune, rapamycin, diabetes mellitus and kidney transplantation or a combination of them in the title/abstracts. Treatment using a combination of sirolimus and tacrolimus were excluded. Results: There were more than 3244 subjects reviewed in this systematic review including 21 published articles (Total population of 21 articles: 3244 people). Conclusion: According to the results, sirolimus-based immunosuppression for preventing kidney transplantation is effective and has a low-risk in diabetic patients resulting in suitable glucose control.


Introduction
Nowadays, chronic diseases are prevalent such as chronic kidney disease and end-stage renal disease (ESRD), with an average increase of 6% per year (1). ESRD as a form of chronic kidney failure is an irreversible decrease in kidney function that results in death without dialysis or kidney transplantation (2,3). Diabetes, hypertension, polycystic hereditary disease and glomerulonephritis are some important risk factors associated with ESRD (4). Renal replacement therapy (RRT) is a general term used in the treatment of patients with ESRD, including hemodialysis, peritoneal dialysis, and renal allograft transplantation (5). The quality of life of patients receiving kidney transplantation is better than others since the quality of life of hemodialysis patients was significantly lower than other groups (6). Kidney transplantation was encountered with lots of challenges during the development, in which rejection of transplantation is the most important challenging issue. In this regard, some drugs are used to prevent the rejection of the kidney transplantation (7,8). One of the well-tolerated drugs with acceptable results in this field is sirolimus. Sirolimus is a macrolide and a type of immunosuppressant drug to prevent rejection of transplanted organs. This drug inhibits the activation of T and B lymphocytes and reduces the production of interleukin-2 (IL-2) (9-11). There are some systematic reviews about the effect of sirolimus in the past decades e.g. Webster et al suggested that long-term hard-endpoint data from robust randomized trials are still required to make a decision (12). It is worthy to be noted that due to the importance of sirolimus outcome on the transplanted patients, further studies are needed. Thus, this study aimed to review the effect of sirolimus on kidney transplantation in patients with diabetes mellitus as a systematic review.

Search strategy
International databases including PubMed, Web of Science and Scopus were considered for search of English articles by 29 June 2019. Twenty-one published articles were finally entered into the study. Keywords were sirolimus, rapamune, rapamycin, diabetes mellitus and kidney transplantation or a combination of them in the title/abstracts. Treatment using a combination of sirolimus and tacrolimus were excluded. ). After collection of articles of interest, references were imported to Endnote software and removed duplicate titles. Then, after browsing titles, studies with irrelevant purposes were removed, and then the remaining studies assessed by two independent investigators. The selected studies were performed on humans and published in English.

Data extraction
Information dealing with the selected articles (the author's last name, year of publication, study design, sample size and the results of each article) was taken by two independent investigators. The differences observed in this process were corrected by a third investigator who was independent with the two previous investigators.

Results
There were more than 3244 subjects reviewed in this systematic review including 21 published articles consisted of two retrospective studies, two prospective studies and seventeen clinical trial studies (Total population of 21 articles: 3244 people). We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, a checklist of items that should be included in reports of interventional studies for selected articles (13,14). Figure 1 shows the selection process using PRISMA. The summary of the selected articles was shown in Table 1.

Discussion
Kidney transplantation is the best treatment for patients with renal failure after kidney transplantation. Improved kidney function, survival and quality of life using antirejection drugs as suppressive agents had been observed in these patients. Immunosuppressive agents help to prevent graft rejection (36). Similar research done in other countries is largely similar to the results obtained in this review supporting the preventive effect of sirolimus following transplantation (37). A review study by Pascual et al has shown that using sirolimus can reduce the dose of calcineurin inhibitors and the combination results in better outcomes (38). Cooper et al showed sirolimus in combination with low-dose cyclosporine or tacrolimus is more effective in treating and preventing graft rejection, and improves graft transplant function (39). A systematic and meta-analysis performed by Araki et al has yielded similar results in comparison with our review (40). All studies approximately concluded the protective effect of sirolimus after kidney transplantation accompanied with the reduced dose of cyclosporine.

Conclusion
Based on the results, sirolimus-based immunosuppression for preventing kidney transplantation is effective and has a low-risk in diabetic patients resulting in suitable glucose control.

Conflicts of interest
The authors declare that there is no conflict of interest in this study.

Ethical considerations
Ethical subjects such as plagiarism and double publication have observed in this study.  Early steroid-withdrawal in renal transplant recipients with a sirolimus and mycophenolate mofetil-based and calcineurin inhibitor-minimization protocol can effectively reduce many of the steroid-related side effects, decrease risk factors for cardiovascular disease, and is associated with improved recipient survival without compromising graft function.
Johnston et al (24) 124 47±14.6 Crosssectional Sirolimus is independently associated with non-onset diabetes. Given the negative impact of NOD on post-transplantation outcomes, these findings should be confirmed in prospective studies or in meta-analyses of existing trials that involved sirolimus.
Kahan et al (25)  149 18-65 RCT SRL in combination with CsA and steroids not only lowers the incidence of biopsy-proven acute renal allograft rejection episodes, but also may permit CsA sparing, at least among Caucasian patients, without an increased risk of rejection  Podder et al (28) 470 Not reported RCT A concentration-controlled sirolimus-cyclosporine-prednisone regimen (with steroid withdrawal by 3 months) reduced the incidence of acute rejection episodes and increased 6-year graft survivals.

Funding/Support
None.