Kidney transplantation is the most promising therapeutic approach for patients with end-stage renal disease (ESRD), which prolongs survival and improves the quality of life compared to long-term dialysis (Abramyan and Hanlon, 2025; Dash et al., 2023; Kostro et al., 2016; Molnar et al., 2016). During the post-transplantation period, anti-rejection therapy plays an important role in determining the graft and patients’ survival (Khan et al., 2025; Shokeir et al., 2021). Calcineurin inhibitors (CNIs), represented by tacrolimus and cyclosporine, are commonly used in preventing acute rejection post transplantation (Kajdas et al., 2025; Mok et al., 2025). Despite their efficacy, it should not neglected that the CNIs might induce the serious side effects, such as the nephrotoxicity, which would finally cause the graft loss and other adverse events including the hypertension, hyperlipidemia, and post-transplant malignancies (Hansen et al., 2025; Oliveras et al., 2024). Therefore, it is urgent to explore the alternative immunosuppressive drugs with fewer adverse events in these patients.

Rapamycin (sirolimus, SRL) is an mTOR inhibitor, which shows the reduced nephrotoxicity and anti-proliferative properties; therefore, it is considered to be a promising alternative to CNIs (Chen et al., 2013; Préterre et al., 2021). In recent studies, SRL combined with CNIs might help to reduce the dosage of CNIs, which subsequently reduces the incidence of post-transplant adverse events and improves graft survival. For instance, it is shown that converting to an SRL-containing regimen might elevate the renal function in patients after kidney transplantation (Pankewycz et al., 2011). Apart from that, the anti-BK virus of sirolimus should also be noticed (Liacini et al., 2010). In recent studies, it indicates that the SRL might reduce the BK virus to 4.3%, which is lower than the 17.9% of tacrolimus in kidney transplant recipients (Tohme et al., 2015). However, the evidence about applying the SRL-containing regimen in post-kidney-transplant patients is still inadequate, which largely affects its clinical application.

Hence, the current study aimed to evaluate the efficacy and safety of an SRL-containing regimen in patients who received kidney transplants.

In this study, we compared two immunosuppressive regimens, CNI + MPA + SRL + glucocorticoid and CNI + MPA + glucocorticoid, to evaluate their effects on renal function, acute rejection, BK virus infection rates, and overall safety in kidney transplant recipients. Our results demonstrated that the addition of SRL to the immunosuppressive regimen offered several advantages, particularly in terms of renal function and BK virus infection rates.

In this study, the CNI + MPA + SRL + glucocorticoid group achieved higher eGFR and lower serum creatinine levels compared to the CNI + MPA + glucocorticoid group, which was consistent with previous studies (Cucchiari et al., 2020; Rodrigues et al., 2023; Tomita et al., 2023). This finding might be explained as follows: (1) As an mTOR inhibitor, the SRL would modulate immune responses and reducing the production of pro-fibrotic cytokines, therefore act as an nephroprotector (Song et al., 2021; White et al., 2025). (2) SRL could inactivate T-cells and the subsequent inflammatory response, thereby preventing tissue injury and fibrosis in the renal graft via inhibiting the mTOR pathway. Hence, the involvement of SRL to CNI contained regimen might be an optimal method to improve the kidney function in renal transplantation patients. It should be noticed that the creatinine significantly decreases on M6 and M12 in CNI + MPA + SRL + glucocorticoid groups, while eGFR significantly increases only on M12 but not on M6. The potential reason might be that: eGFR was an estimated parameter derived from serum creatinine, age, sex, etc. and minor or short-term decreased in creatinine may not immediately result in detectable changes in eGFR. Therefore, there was no difference in eGFR between groups at M6.

Besides, we also found that the incidence of acute rejection was numerically lower in the CNI + MPA + SRL + glucocorticoid group compared with the CNI + MPA + glucocorticoid group (3.6% vs. 9.1%), although there is no statistical significance. This finding could be explained as follows: (1) The small sample size limited the statistical significance leading to the statistical insignificance. (2) The duration of follow-up was too short to explicate the impact of SRL on long-term rejection outcomes. (3) Hypothesized from the previous study that SRL can reduce acute rejection by enhancing graft function and modulating immune responses (Ehx et al., 2021; Tanrısev et al., 2021; Kishimoto et al., 2023; Li et al., 2025); therefore the reduction in T-cell activation may contribute to decreased rejection episodes; however, this hypothesis needed larger studies to validate.

BK virus reactivation would vastly impact on the graft function in kidney transplant patients, which also concerns the nephrologist (Kant et al., 2022; Nakamura et al., 2024). Another finding should not be neglected that BK virus infection was lower in the CNI + MPA + SRL + glucocorticoid group compared to the CNI + MPA + glucocorticoid group. This finding would be explained as follows: SRL shows the immunosuppressive properties, and it could inhibited the viral replication by modulating T-cell responses (Liacini et al., 2010). The inclusion of SRL in the immunosuppressive regimen appeared to provide additional protection against BK virus, making it a valuable component in managing viral complications in transplant patients. This effect may be due to SRL’s ability to suppress the immune response in a way that reduces viral replication while still preventing rejection (Liacini et al., 2010). However, while the data was promising, further investigation was needed to fully understand the mechanism by which SRL affects BK virus reactivation and to confirm its role in reducing viral infections in transplant recipients. Furthermore, recent study also mentions that the medicine and food homology, which propose the possibility of adding the traditional Chinese medicine to the treatment might further improve the efficacy of SRL based regimen for anti-rejection (Law and Au, 2025). However, there is still long way to go to achieve this goal.

Finally, in terms of overall safety, our study found no significant differences between the two regimens in terms of adverse events or complications, except the BK virus infection. This suggested that the addition of SRL to the immunosuppressive regimen did not increase the risk of adverse effects when compared to the CNI + MPA + glucocorticoid regimen. This finding was consistent with previous reports on the safety of SRL in kidney transplant recipients, which have demonstrated that SRL does not lead to significant increases in the incidence of adverse events (Toniato de Rezende Freschi et al., 2024). The favorable safety profile of SRL made it an attractive option for inclusion in kidney transplant immunosuppressive protocols.

The selection of follow-up time points in this study was based on both clinical practice the pharmacological features of the study durgs. (1) The chosen of W2 was because: during the early post-transplant phase, the risk of acute rejection is high and the blood concentration would achieve a steady state; therefore, the W2 was chosen. The chosen of subsequent M3, M6, M9, and M12 was because: the graft function would be relative stable, even though there is risk of acute rejection but low, and the safety concerns as well as the blood concentration of SRL and CNI also needed periodic monitoring; therefore, the M3, M6, M9, and M12 were chosen.

Despite these promising findings, several limitations of this study need to be acknowledged. First, the relatively small sample size limited the statistical power of some of our analyses, particularly in detecting significant differences in acute rejection rates. Future studies with larger sample sizes are needed to better assess the impact of SRL on rejection outcomes. Second, the follow-up period was relatively short, which may have limited our ability to detect long-term outcomes such as chronic graft dysfunction or late-onset BK virus reactivation. Longer follow-up studies are necessary to evaluate the sustained effects of SRL on renal function and transplant outcomes. Third, this study did not assess the long-term safety profile of SRL, which remained a critical consideration when incorporating new immunosuppressive agents into clinical practice. As such, future research should explore the long-term safety and efficacy of SRL in larger cohorts of kidney transplant patients. Forth, patients were grouped according to the actual protocol they received, rather than randomly assigned, which might leading to the selection bias.

In conclusion, our study suggested that the CNI + MPA + SRL + glucocorticoid regimen may offer superior renal function preservation and a reduction in BK virus infection rates compared to the CNI + MPA + glucocorticoid regimen. While the addition of SRL did not significantly reduce acute rejection rates in this study, the promising trends observed warranted further investigation. Additionally, the overall safety profile of SRL was favorable, supporting its potential use in kidney transplant immunosuppressive regimens. However, larger, longer-term studies are needed to confirm these findings and better understand the role of SRL in improving long-term transplant outcomes.