Kidney transplantation in Malaysia has evolved significantly over the past few decades and remains an important option for patients diagnosed with end stage kidney disease [1]. The number of patients on dialysis has increased exponentially while kidney transplants are limited due to lack of donors [2]. In the 13th report of the Malaysian National Transplant Registry, the number of new kidney transplant performed was 113 in 2007, however this has decreased to 82 transplant cases performed in 2016 [2]. In Malaysia, most kidney transplants are performed in two major government hospitals, with some private hospitals offering transplant services too.

Following kidney transplantation, kidney transplant recipients (KTRs) will be given a combination of immunosuppressants. Among these, the most common maintenance treatment is a combination of a calcineurin inhibitor (CNI), that is tacrolimus or cyclosporin, an antiproliferative agent namely mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS) and a corticosteroid [3]. Tacrolimus is the preferred first-line CNI for long-term maintenance immunosuppression following kidney transplantation [3]. This preference stems from its demonstrably superior efficacy in reducing the incidence and severity of biopsy-proven acute rejection (BPAR) episodes, a critical complication known to significantly compromise graft function and potentially lead to graft loss [4]. Furthermore, tacrolimus exhibits several pharmacological advantages where preclinical and clinical data suggest a potentially lower risk of nephrotoxicity, a major long-term concern in KTRs with pre-existing compromised kidney function [4]. Additionally, tacrolimus boasts a more predictable pharmacokinetic profile, allowing for more precise individualization of dosing regimens [4]. This characteristic enables clinicians to optimize immunosuppressive efficacy while minimizing the risk of adverse effects through therapeutic drug monitoring, supporting its use as the gold standard CNI for maintenance immunosuppression in KTRs.

Despite demonstrably improved short-term outcomes following kidney transplantation, long-term graft function and survival rates remain stagnant beyond the first year [5]. This plateauing effect is likely attributable to the development of chronic adverse drug reactions (ADRs) associated with long-term CNI use [5]. CNIs, while effective in preventing rejection, carry a significant burden of nephrotoxicity, directly damaging the transplanted kidney and potentially leading to graft dysfunction [6]. Furthermore, CNIs are implicated in other long-term ADRs that significantly impact patient morbidity and mortality. These include post-transplant diabetes mellitus (PTDM), characterized by impaired insulin sensitivity and contributing to cardiovascular complications [6]. Additionally, CNIs’ immunosuppressive nature increases the risk of various malignancies, particularly skin cancers, necessitating vigilant monitoring as well as compromising the immune system’s ability to combat viral infections, potentially leading to serious complications like cytomegalovirus (CMV) reactivation [6]. The cumulative burden of these chronic ADRs necessitates exploring alternative immunosuppressive strategies or minimizing CNI use as early as 3 months post-transplant in some patients [7]. This ongoing challenge underscores the need for novel immunosuppressive approaches that balance efficacy with a minimized risk of long-term complications to optimize long-term graft function and patient outcomes.

In the quest to mitigate the long-term complications, such as adverse effects and toxicities associated with tacrolimus-based immunosuppression regimens in kidney transplantation, switching to the mammalian target of rapamycin (mTOR) inhibitors like everolimus have emerged as a promising strategy. Studies have demonstrated improved overall graft function following a switch to everolimus combined with reduced-dose tacrolimus, without compromising the rates of BPAR or viral infections [8, 9]. However, this approach is not without drawbacks. mTOR inhibitors themselves carry a risk of ADRs including metabolic complications and even acute rejection episodes [8]. Additionally, the higher cost of these agents and the need for frequent laboratory monitoring in the initial period following regimen switch present significant economic and logistical considerations [10]. Therefore, the optimal balance between minimizing tacrolimus-related toxicities and mitigating the potential ADRs of mTOR inhibitors remains an ongoing area of research in optimizing long-term outcomes for KTRs.

This study aims to identify factors predictive of switching from the tacrolimus-MPA immunosuppressive regimen to alternative combinations in KTRs. Early identification of patients at high risk for regimen switches would enable healthcare professionals to implement closer monitoring and potentially optimize CNI-based immunosuppression according to individual patient’s needs, thereby minimizing complications associated with chronic ADRs. To date, no prior research, be it local, regional or international, has explored the factors influencing the initial switch from tacrolimus-MPA therapy within an unselected kidney transplant population. This investigation aims to address this knowledge gap and contribute valuable insights for personalized immunosuppressive management following kidney transplantation.

In Malaysia, KTRs universally receive initial and maintenance immunosuppression with a tacrolimus-MPA-prednisolone triple therapy regimen, as endorsed by the Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Workgroup (2009). This approach is well-supported by its established efficacy in reducing acute rejection episodes and promoting graft function [4]. Our current study reflects this success, demonstrating a high overall graft survival rate of 97.7% and 96.1% at one and 2 years, respectively, which aligns with previous findings [16]. However, despite the initial effectiveness of the tacrolimus regimen, a significant proportion of patients required a switch to alternative immunosuppressants, with the average switch occurring around 17 weeks, typically within the first 10–16 weeks post-transplant. The majority of kidney transplant recipients transitioned from the initial tacrolimus–MPA–prednisolone regimen to a combination of everolimus and low-dose tacrolimus, reflecting similar findings by Taber et al., who reported a comparable switch timeframe [7]. Therefore, elucidating the associated factors that prompt this early regimen switch to mostly everolimus combined with low-dose tacrolimus, holds significant value for nephrologists, pharmacists and other healthcare professionals, allowing them to optimize post-transplant management strategies for KTRs.

The occurrence of transaminitis and infections were the primary reasons for switching immunosuppressants, with BKV as a significant factor in influencing the switch of immunosuppressants. Everolimus combined with low-dose tacrolimus emerged as the preferred alternative. Studies by Saliba et al. support this approach, demonstrating no significant difference in liver enzymes after a year compared to traditional regimens [17]. Additionally, Pascual et al. reported a lower incidence of abnormal liver function tests with everolimus compared to MPA, further justifying the switch [18]. The observed link between immunosuppression and viral infections, including CMV and BKV, aligns with findings from Vanichanan et al. who reported a higher prevalence in Asia [19]. This association is likely due to the combined effect of potent immunosuppression and high-risk transplants (e.g., blood group incompatibility) requiring aggressive preconditioning to minimize rejection [20]. These complications observed stem from the inherent nature of tacrolimus-based immunosuppression independent of drug concentration, where the immunosuppressive effect compromises the immune system’s ability to control viral replication [8]. This was further confirmed by our results which showed no significant association between tacrolimus trough levels and ISA switch. In contrast, everolimus exerts less T-cell suppression compared to tacrolimus besides having shown to have some anti-viral properties against CMV and BKV [20]. Therefore, simply reducing immunosuppression may not be suitable. Instead, as suggested by Tan et al., switching to mTOR inhibitors, specifically everolimus with low-dose tacrolimus, offers a safer alternative, potentially balancing immunological risk minimization with mitigation of ADR associated with traditional regimens like MPA [22], offering a dual benefit in managing KTRs.

Despite this, it is important to understand that switching to everolimus with low-dose tacrolimus or other combination immunosuppression may lead to undesired outcomes such as increased rejection risk or unresolved viral load, which was not investigated in the present study. A balanced approach in modifying immunosuppressive therapy is therefore advocated. While reduced immunosuppression may help in managing BKV and CMV infections, it may compromise graft survival due to heightened immune activation [23]. These conflicting outcomes mandate the need for individualized patient management especially among patients with high immunological risk, where switching of ISA should be accompanied by close monitoring of viral load, immune risk profiling and careful timing of intervention when needed.

This study also identified ethnicity as a significant factor influencing immunosuppressant switches among KTRs, with Malays demonstrating a higher propensity for regimen changes compared to other ethnicities. While prior research suggests immunological differences potentially contribute to racial variations in graft survival, existing literature largely focuses on Caucasian populations in Western countries [24]. Limited data exists regarding the specific susceptibility of Malays to early switches from the tacrolimus-MPA-prednisolone regimen. However, one study by Mastuki reported a higher prevalence of CMV infection in Malays, possibly prompting adjustments in immunosuppression [25]. On the other hand, the impact of ethnicity on response variation in immunosuppressive therapy may be attributable to genetic variations [26]. Variations in the pharmacokinetic profile of immunosuppressants are attributed to inter-individual variations in the functional activity of metabolizing enzymes and drug transporters, which are governed by the differences in their pharmacogenetic properties depending on ethnic groups [26]. One’s ethnicity may influence one’s health or disease condition, for example the Asian Americans were reported to have significantly higher risk of cardiovascular diseases [27]. Since there is currently little data on the prediction of ADRs or efficacy of immunosuppressants due to genetic variation in association with different ethnic backgrounds, more research is needed with the understanding that ethnic considerations might provide us with valuable information for optimizing individualized immunosuppressive therapy following kidney transplantation. Given that Malays comprise the largest ethnic group in Malaysia, further investigation into the factors governing their response to everolimus, a potentially cost-prohibitive therapy [10], is warranted. While the observed association between Malay ethnicity and initial regimen switches requires further exploration, it holds promise as a potential marker for identifying patients at higher risk for early switches, thereby facilitating closer monitoring and potentially optimizing post-transplant management strategies.

Factors beyond traditional ADRs influenced the decision to switch immunosuppressive regimens in the current KTRs. Notably, the absence of post-transplant hypertension emerged as a significant predictor for switching away from the tacrolimus-MPA-prednisolone regimen. This finding is intriguing as some studies suggest a potential link between everolimus, a common alternative therapy, and an increased prevalence of hypertension [28]. While the exact mechanisms remain unclear, one study reported a rise in arterial hypertension from 49% to 65.9% following conversion to everolimus [28]. However, it’s important to note that other studies haven’t observed a significant impact on mean blood pressure [29]. These contrasting findings highlight the need for further research into the relationship between everolimus and blood pressure. Regardless, our study underscores the importance of vigilant blood pressure monitoring, particularly for patients transitioning to everolimus-based regimens, to minimize the potential for cardiovascular complications [29]. This unexpected association between hypertension and immunosuppressive switch warrants further investigation to optimize post-transplant management strategies for KTRs.

In conclusion, this study sheds light on factors beyond traditional ADR that influence the decision to switch immunosuppressive regimens in KTRs. Our findings suggest that Malay ethnicity, the absence of post-transplant hypertension, and BKV infection are significant predictors for switching from the initial tacrolimus-MPA regimen. By identifying these factors healthcare professionals can implement closer monitoring and potentially explore alternative therapies like everolimus with greater discernment. While existing data indicate that such switches typically occur within the first 10–16 weeks post-transplant following viremia, clear guidelines on optimal timing and its impact on graft outcomes remain limited. Ultimately, this study underscores the importance of a nuanced approach to immunosuppression in kidney transplantation. This shift away from a one-size-fits-all model and towards personalized regimens that balance efficacy with patient-specific considerations has the potential to improve long-term patient outcomes. By incorporating these findings into treatment plans, healthcare professionals can create individualized immunosuppressive strategies that minimize the risk of complications while ensuring adequate graft function. This tailored approach holds promise for not only improving patient survival rates but also enhancing their overall cost and quality of life following transplantation.