In this study, we reviewed the graft survival of 654 patients who underwent kidney transplantation at Jiangsu Province People’s Hospital within 30 years after surgery, and established two models based on preoperative and postoperative factors by statistical methods to provide a possible prediction for graft prognosis. The overall graft survival rate of our center is 20.9%. A multivariate Cox proportional-hazards model was constructed to screen out the potential prognosis-related factors. We focused on the immunosuppressive regimens and further subgroup analysis was performed on the factors that were significantly associated with the prognosis according to the model. The combination of rapamycin to traditional protocol was found to effectively improve the graft prognosis.

For nearly a century, patients with end-stage renal disease have had a relatively good long-term survival due to kidney transplantation. However, this outcome does not appear to have a further progress over the past 10 years from worldwide view [20]. In addition, thanks to the influence of modern medicine and globalization, the difference of survival rate of kidney grafts after kidney transplantation has decreased among different regions and races in the world [13,14,15,16], including the difference between China and the Western world. Most existing studies mainly focus on postoperative immune rejection [26], while the age of donors and patients, recurrence of glomerular disease, duration of dialysis, pre-existing cardiovascular burden, drug side effects, and traditional risk factors such as hypertension, albuminuria, anemia, dyslipidemia, diabetes, and bone mineral disorders may ultimately lead to severe endothelial cell disorders as well as graft loss and death [17, 18]. These traditional risk factors common in these patients are generally considered minor in comparison to allogenic immunity and immunosuppression problems. Carminatti M’s team indicated in a review that they found relatively fewer studies have considered the clinical impact of multidisciplinary interventions on traditional CKD-related risk factors for CKD progression in kidney recipients, which is clearly an attractive field waiting more research [19]. Although all possible aspects can be useful for assessing the pathophysiology of CKD, not all risk factors are ultimately treatable. Therefore, individualized treatment is critical, as no single treatment recommendation is appropriate for all patients.

On this basis, more factors, especially those were more amenable to individualized intervention, were urgent to be found to influence the outcome of kidney transplant recipients, including surgical conditions, immunosuppressive drugs, and post-op compliactions [20, 21]. Therefore, in this study, both donor and recipient factors as well as preoperative and postoperative factors were included in the analysis. In addition, another shortcoming of existing studies is that they mainly consider hard endpoints such as patient survival and graft failure, however, these are late events. To predict early prognosis, our study selected eGFR as an alternative endpoint that could be evaluated at an early stage, and determined end events by CKD staging, which allowed us to retain data of patients who died early after surgery or were lost to follow-up at a later stage, thus maximizing data utilization. Thus, we constructed a reliable Cox model and screen out some factors which are more novel than previous studies, having the potential to provide constructive references for the personalized clinical monitoring after kidney transplantation and the quality control and optimization of organ transplantation programs.

Among the factors we screened, some conventional factors such as BMI, blood glucose levels, plasma globulin, were found in the model. In recent years, many studies have set a threshold for BMI, believing that patients with BMI higher than this threshold would bear more risks of poor prognosis of kidney transplantation. Shoko Ishikawa’s team found in a single-center study that pretransplant BMI should be less than 25 in Japanese kidney transplant recipients and The mechanism behind this has been suggested in the literature that it may be related to the decline of renal function related to obesity [22]. However, in this study, we found that a higher BMI value in the non-obese range is more conducive to the prognosis of kidney transplantation, which may be related to the effect of nutrition on postoperative recovery after transplantation [23, 24]. Hyperglycemia caused by various causes has been recognized as the cause of diabetes, and is directly related to the decline of renal function [25], which is confirmed by our study here. However, whether blood glucose affects the prognosis of kidney transplantation through other ways such as immune rejection remains to be further studied.

More importantly, with the continuous development of immunosuppressant, the prognosis of kidney transplantation has made significant progress in this century, and the selection of postoperative immunosuppressant regimen has become one of the factors affecting the prognosis of kidney transplantation, because drug interaction and drug side effects vary from person to person. In recent years, there has been no consensus on the selection of cyclosporin and tacrolimus for KTx [26], but our study have confirmed that the addition of rapamycin can improve the long-term prognosis of kidney transplantation, which is also consistent with the short-term outcome of many other studies [27, 28]. Since rapamycin was approved by the FDA in 1994 for the prevention of organ rejection in liver transplant patients [29], many effects of rapamycin in the field of transplantation have been discovered [30]. Many studies have demonstrated its effectiveness in reducing the use of calcineurin inhibitors, slowing the progression of heart graft vasculopathy, and reducing cytomegalovirus infection in the heart transplant maintenance population [31]. The cohort study by Dr. Guang and colleagues demonstrated that rapamycin prevented HCC recurrence in some patients after liver transplantation, but it also caused metabolic disorders, but overall rational use of rapamycin was beneficial to liver transplant recipients [32]. At the same time, our long-term follow-up confirmed that the addition of rapamycin reduced the incidence of rejections and improved graft outcomes, which are exciting results and should inform the development of new immunosuppressive regimens. We further compared the indication biopsy and banff score between the two groups, and the results showed that the addition of rapamycin after transplantation could reduce vascular inflammation and interstitial fibrosis around the renal allograft. More and more studies have focused on myeloid-derived suppressor cells (MDSC). Chao Wei and colleagues found that Exosomal miR-181d-5p Derived from Rapamycin-Conditioned MDSC Alleviated Allograft Rejection by Targeting KLF6 [33]. RAPA nano-micelle ophthalmic solution could improve the immunosuppressive activity of MDSCs through elevated expression of Arg-1 and iNOS [34]. However, the specific types of rejection affected by rapamycin have not been elucidated by enough studies. The clinical utility of rapamycin has changed over the past more than 15 years, including rapamycin with or without CNIs, and switching from CNI-based regimens to rapamycin. Our study also provides a new idea for the formulation of immunosuppression regimens after solid organ transplantation.

Notwithstanding it is important to acknowledge the limitations of this study. Firstly, the inclusion of risk factors is still incomplete as detailed information regarding donors, intraoperative conditions, and postoperative rejection and complications was not thoroughly examined. To address this, future studies should focus on enhancing surgical data recording and conducting more comprehensive follow-up investigations. Collaborating with multiple centers to obtain a larger patient dataset and applying the model to predict graft outcomes would yield more robust and convincing results. As for subsequent studies, new alternative endpoints for renal transplantation survival have been proposed, such as the eGFR slope on renal disease progression which was not adopted in this study. Exploring the potential changes in the model and its predictive ability by adopting eGFR slope as an endpoint is an avenue for further research. Furthermore, the mechanism behind how rapamycin affects the long-term prognosis of KTx is still not complete in existing research, so further experimental research for the molecular level mechanism behind them is urgent.