Strategies to optimize kidney transplantation: a systematic review of the evidence

Abstract

The objectives of this thesis are to evaluate the strategies for expanding the donor pool by using expanded criteria donors and for increasing patient and graft survival by optimization of immunosuppression strategies.

It is based on 5 published journal articles: In the first paper: "Pérez-Sáez MJ*, Montero N* et al. Transplantation. 2017 Apr;101(4):727-745." the literature for the use of kidneys from older donors was reviewed and the value of the kidney-donor profile index (KDPI), a preimplantation kidney biopsy, dual kidney transplantation (DKT), machine perfusion, and immunosuppressive protocols was assessed. The main finding was that outcomes (survival and functional outcomes) achieved with ECD, high KDPI, or kidneys from older donors were worse than for kidneys from standard donors. Outcomes in studies that reported on older donors that were brain-dead or cardiac-dead were similar. Preimplantation biopsies and related scores have been useful to predict function; machine-perfusion techniques have decreased delayed graft function. Tailored immunosuppression in older populations may be useful, but no formal trials have been published. The main conclusion was that old donors constitute an enormous source of useful kidneys. The second article is: "Montero N et al. Transpl Int. 2018 Mar 27. doi: 10.1111/tri.13157." Twenty-five studies were included in the meta-analysis. The main results were that one-year serum creatinine was better after dual kidney transplantation (DKT) vs. single kidney transplantation (SKT), with less incidence of acute rejection and delayed graft function and without differences at five years. Mortality at 1 and 3 years was similar after dual or SKT, but mortality at five years was lower after DKT. One-year graft loss was similar between dual and SKT. In conclusion, based on few retrospective reports with a relatively low number of cases, this is a

systematic review updates information about the value (or not) of dual kidney transplants under certain conditions, and in the light of scarcity in organ supply. The third publication is: "Montero N et al. Cochrane Database of Systematic Reviews 2014, Issue 9. Art. No.:CD007669. DOI:10.1002/14651858.CD007669.pub2." is a Cochrane systematic review that compared steroid avoidance or withdrawal versus steroid maintenance in pancreas-kidney transplantation. The main discoveries based on 3 included randomized controlled trials and 13 cohort studies are: no clear evidence of an impact on mortality, risk of kidney or pancreas loss or acute kidney or pancreas rejection. However, results were uncertain and consistent with no difference or important benefit or harm of steroid avoidance/early steroid withdrawal. Based on observational studies, the authors reported that steroid-sparing and withdrawal strategies had benefits in lowering HbAc1 and risk of viral infections and improved blood pressure control without increasing the risk of rejection. In conclusion, there is currently limited evidence for the benefits or harms of steroid withdrawal in pancreas- kidney transplantation. The fourth paper: "Montero N et al. Transplant Reviews (Orlando) 2016;30(3):144- 153." This manuscript reports a systematic review of immunosuppression strategies in elderly renal transplant recipients. Given the different immunosuppressive strategies, none of the studies, including the 4 randomized controlled trials could be pooled. Therefore, it is not clear how the results can be utilized i.e., which immunosuppressive strategy provides the most benefit. Meta-analysis cannot be performed; therefore estimation of an average treatment effect for the older patient attributed to an immunosuppressive strategy cannot be ascertained. The last included publication: "Montero N et al. Mammalian target of rapamycin inhibitors combined with calcineurin inhibitors as initial immunosuppression in renal transplantation: a metaanalysis. Submitted article" is a meta-analysis comparing mTORi and CNI based immunosuppression with standard MMF/AZA/CNI immunosuppression in de novo renal transplantation. 24 studies were included in the meta-analysis. A large number of outcomes are explored and discussed in detail. The main findings are: The incidences of acute-rejection episodes (overall), biopsy-proven acute rejections, and clinical rejections at 1 or >2-years post transplantation were similar across the studies. Patient survival rates, as well as allograft-failure rate, did not

statistically differ across the studies. In contrast to what was expected, kidney-allograft function was better with standard doses of CNIs combined with MPA compared to CNIs plus any dose of mTOR-IS. However, in the sub-analyses, renal function was significantly worse when mTOR-Is were combined with standard doses of CNIs compared to reduced doses of CNIs.