Perspective Chapter: Low Cost Immunosuppressive Strategies in Renal Transplantation

Abstract

Renal transplantation is the treatment modality of choice in end stage renal disease. However, in low economic countries where government or insurance funding is not available, several patients do not opt for this treatment due to financial constraints. However, there could be options of tailored immunosuppression in both initial intensive induction immunosuppression and subsequent maintenance immunosuppression and immunomodulation thereby making this modality of treatment more cost effective. This could include selective use of induction agents, lesser frequency and dosing, use of cheaper induction agents and their combination, monitoring to decide the minimal dosage and frequency required and cost effective maintenance immunosuppressive agents with dose adjustment based on blood levels.

1. Introduction

Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function for more than three months [1]. The prevalence of CKD has been increasing worldwide with presently an estimated global prevalence in the adult population of 9.1percent [2]. Once CKD occurs, there is generally a progressive decline in renal functions to end stage renal disease (ESRD). Almost 0.8% reach ESRD by which time renal replacement therapy in the form of dialysis or renal transplantation becomes necessary to sustain life [3]. Renal transplantation is the ideal form of renal replacement therapy unless there are underlying contraindications. Yet globally only 0.01% undergo renal transplantation and this may be still lower in the lower socioeconomic countries where state funding or insurance facilities are lacking [2]. In developing countries like India, where medical insurance and reimbursement facilities are available to less than 5% of the population, renal transplantation is often out of reach to the majority [4]. The main cost of renal transplantation is for immunosuppressive medication which has to be taken life long to prevent rejection. If the financial burden due to immunosuppressive drugs could be mitigated, it could aid in making renal transplantation a viable option to economically backward patients too. This could involve the use of less costly immunosuppressive drugs with lower dose or frequency but may need added monitoring to prevent rejection.

2. Immunosuppression in renal transplantation

Immunosuppression is necessary in organ transplantation as the transplanted organ may differ in human leucocyte antigens (HLA) and will be recognized as foreign by the recipient immune system causing it to mount a response akin to destroying a invasive microbial organism which could result in rejection of the grafted organ [5]. Immunosuppression of the recipient aims to prevent rejection. As the risk and intensity of rejection is more in the early period following transplantation, a higher degree of immunosuppression may be needed then. This is called initial immunosuppression and may need addition of induction agents which could provide more intense immunosuppression [6]. After around 6 months, the risk of rejection decreases and a lower dose of immunosuppressive drugs (maintenance immunosuppression) may suffice. A higher degree of immunosuppression theoretically reduces the chance of rejection. However, this increases the risk of opportunistic infections, metabolic side effects as well as significantly raises the cost [7, 8, 9].

The following need to be considered when deciding on possible modifications in immunosuppressive strategies with a view to reduce cost, toxicity and at the same time minimizing rejection risks.

1. Is the recipient at increased risk of rejection?

The risk of rejection can be quantified depending on the immunological risk as high or low depending on several factors like recipient age, ethnicity, degree of HLA match, presence of donor specific antibodies (DSA) and delayed graft function [10]. Those without these risk factors could be considered to have low immunologic risk and may not need intense immunosuppression.

1. Can the intensity of initial immunosuppression be reduced without posing an increased risk of graft rejection?

Patients with high immunologic risk may benefit with use of high intensity immunosuppression including use of induction agents with [11]. In the preceding decades, there was a recommendation for using induction agents for all renal transplantations [12]. However it may be possible that this may not be essential in those at a lower risk especially when combined with newer antiproliferative agents like mycophenolic acid (MPA) derivatives and tacrolimus which may confer a lower baseline acute rejection risk [13].

1. What are induction agents used in transplantation?

Induction agents can be classified based on whether they deplete lymphocytes or not. The lymphocyte depleting agents include antithymocyte globulin (ATG), humanized anti-CD52 monoclonal antibodies (mAb) alemtuzumab (Campath-1H) and the murine anti-CD3 mAb Muromonab-CD3 (OKT3) which is no longer in production. The non lymphocyte depleting agents include mAbs directed against the IL-2 receptor (IL2RA) basiliximab and daclizumab, of which the latter was subsequently withdrawn in 2009 [14].

Rituximab is a monoclonal antibody targeting B cells. Rituximab has been successfully tried as induction in highly sensitized patients awaiting renal transplantation [15], as well as in ABO-incompatible renal transplantation [16]. The efficacy of a single dose of rituximab as induction has also been reported [17].

1. Is high cost induction immunosuppression mandatory in all cases?

As acute rejection episodes are thought to have a bearing on successful outcome in renal transplantation, induction agents like IL2RA in mild immunologic risk and ATG in those with high immunologic risk were recommended as they were presumed to decrease acute rejection [11, 18]. However, most induction agents in conventional doses and frequency substantially add to the cost. The cost of two doses of IL2-RA is approximately INR 1, 00,000/−(US$ 1333) and ATG costs INR 33524 for a single dose of 50 mg (US$ 447). Conventional dosage of lymphocyte depleting agents often needs Cytomegalo virus (CMV) prophylaxis with drugs like Valganciclovir [19]. Cost of 450 mg of Valganciclovir if used for prophylaxis for 100 days is around INR 25,000-(US$ 333). Moreover the benefit of induction therapy with IL2RA has not been shown to be superior to no induction when tacrolimus was used instead of cyclosporine along with MPA thereby conferring a lower risk of acute rejection. ATG use with steroids was associated with 22% and in the setting of steroid withdrawal 27% reductions in the risk of acute rejection compared with IL-2RA, with no effect on graft survival [20]. It was observed that in standard-risk recipients on tacrolimus and MPA-based triple maintenance therapy, the addition of induction therapy with IL2RA or ATG achieved an absolute risk reduction for acute rejection of 1–4% but with no improvement in graft or patient survival. Others have also reported no benefit from use of IL-2RA induction with respect to acute rejection or graft survival [13].

1. Can induction agents be combined?

It may be possible to combine induction agents acting at different sites. ATG targets T cells and as Rituximab targets B cells, there may be a role in combining both [9, 21, 22]. Though a combination of ATG and IL2Ra has not been recommended [12], there are reports of combining ATG or IL2RA with rituximab in selected patients [9, 21, 22].

1. Is there a rationale in combining induction agents?

T cell depleting agents could decrease the risk of acute rejections [11, 18]. However, this benefit is mainly for early graft loss whereas long term graft survival has not improved [23]. Similarly the benefit of IL2RA is mainly with respect to decreasing acute cellular rejection (ACR) with even reports of increasing prevalence of antibody mediated rejection (AMR) with their usage [24]. This could be due to their less effective targeting of B cells. Rituximab targets the CD20 B cells and has been used in treating AMR [25], as well as in preventing AMR [26]. This action has been extrapolated to its use prior to ABO incompatible renal transplantation [16]. As anti donor antibodies are the main barrier to long term graft loss, it is possible that ATG alone which primarily target T cells may not have the desired effect in preventing occurrence of DSAs [27]. As Rituximab targets B cells and has been used in the management of antibody mediated rejections, there could be a role of combining it with a T cell depleting agent or IL2RA. There are reports on its use as an induction agent in combination with ATG or IL2RA albeit with differing doses and frequency [9, 21, 28].

1. Can a reduced dose and frequency of induction immunosuppression be considered?

As renal transplantation offers the best form of treatment to patients with end stage renal disease, cost cutting measures are often used in resource stretched countries with induction agents being avoided in patients with low immunologic risk. Dose of ATG as induction has traditionally been 1.5 mg/kg per day for 7 days [11]. Reducing the cumulative dose to 3–4.5 mg/kg has also been used [29]. A single dose of 50–75 mg of ATG has been used successfully in 98 Indian patients with ACR occurring in seven, combined ACR and AMR in one and hyperacute rejection in one. One patient needed a second dose of ATG due to steroid resistant ACR [4]. This suggests efficacy of even a single dose of ATG with suppression of CD3 and CD4 lymphocyte count with 1 mg/kg of ATG for upto 4–7 days. Others have also reported similar results with a lesser occurrence of AMR and lymphocyte counts being supressed in the majority by day 3 with even for 5 days in some [9]. This could suggest that daily doses of ATG for upto 7 days may not be essential if there is adequate lymphocyte suppression. Monitoring of daily peripheral lymphocyte counts, and if needed CD3 and CD4 counts and deciding need for further doses based on that may help to avoid further doses with reduction in infection episodes and cost benefit.

The dose of Rituximab in nephrology practice has often been extrapolated from the higher dose and frequency used to treat lymphoproliferative disorders [30]. A single and lower dose of 100 and 200 mg was successfully used in ABO incompatible transplants [16]. A single dose of 375 mg/m2 was effective in reducing the incidence of AMR in immunologically high-risk patients [31]. It has been shown that doses as low as 100 mg in renal transplantation while on other immunosupressants can produce prolonged CD19B cell suppression for even a year justifying avoiding the weekly doses used in lymphoproliferative disorders [22]. The cost of 100 mg Rituximab is INR3000 (US$40) making it one of the potentially cheapest induction agent. Monitoring CD 19 counts every 1–2 months subsequently and giving boosters if needed could limit the frequency of rituximab and cost.

It has also been reported that the number of CMV infections increase when the total ATG dose exceeds 7 mg/kg with the incidence of CMV being as high as 82% [32]. It is possible that valganciclovir prophylaxis may not be essential if low dose ATG is used especially if the recipient is has pre-existing CMV antibodies. Valganciclovir in a reduced dose of 450 mg on alternate days for 6 weeks has been with low dose ATG with cost benefits [4]. This could not only lessen the overall cost but more importantly decrease morbidity and mortality.

When rituximab was combined with ATG for patients with panel reactive antibody levels >50%, no rejections were seen compared to 30% cellular rejection and 26% humoral rejection when rATG was used alone [28]. This suggests a role for combining low dose rituximab with low dose ATG in those with moderate immunologic risk. In the Covid pandemic, it has been suggested that avoidance of over immunosuppression should be considered [33]. It has also been suggested that antiproliferative agents and Tcell depleting agents should be used with caution [34]. As Rituximab affects the B cells its effect on covid may not be significant. However as it can affect antibody production, it may be theoretically better to vaccinate them against Covid infection and give rituximab once protective antibodies develop. Future studies may throw light on these.

Using rituximab alone as an induction agent along with tacrolimus and mycophenolate mofetil may suffice in those with mild immunologic risk as rejection rates particularly as ACR has declined decreasing the impact of conventional induction therapy [20, 35], while AMR has increased [24] where rituximab may have a preventable role [28]. The majority of ACR in the tacrolimus era respond to 3 pulses of methyl prednisolone and only minority who do not respond need ATG [36]. As AMR responds less to therapy compared to ACR, preventing AMR may be more important suggesting a role for rituximab [37].

1. Can the dose of maintenance immunosuppressive drugs be reduced without significantly increasing the risk of rejection?

Maintenance immunosuppression protocol in most centers includes use of prednisolone, antiproliferative agent like MPA derivatives and calcineurin inhibitors (CNI) like tacrolimus or cyclosporine (CsA) [38]. The first calcineurin inhibitor used was CsA and was introduced in the early 1980sand made a significant improvement in long term graft survival [39]. However the initially suggested dose was 17 mg/kg and was associated with a risk of renal failure and other evidence of cyclosporine toxicity [40]. Subsequently dose was adjusted based on improved glomerular filtration rate (GFR) and blood pressure measurements using a target of fifty percent of the standard area-under-the-curve (AUC) dose [41]. This resulted in a significant reduction in the CsA dose. Current trials suggest better graft survival with tacrolimus compared to CsA [38]. Adjusting the CNI levels to the lower threshold recommended can be tried in patients without history of acute rejections in the first six months, stable renal functions and low immunologic risk with cost benefits, reduction of CNI toxicity including nephrotoxicity with lesser risk of infections.

Since CNIs are metabolized by the cytochrome P450 enzyme, combining it with drugs that inhibit the cytochrome P-450 system like ketoconazole, erythromycin or calcium-channel blockers could lead to higher blood levels of CNI. This strategy has been employed with significant cost benefits [42].

1. Is there a role for cost saving maintenance immunosuppression?

The main cost of maintenance immunosuppression is due to antiproliferative agents like MPA derivatives like mycophenolate mofetil (MMF) and mycophenolate sodium and CNIs. Azathioprine (Aza) was the initial antiproliferative agent [43] until MMF became commercially available in 1995 [44]. Initial reports suggesed lesser rejection episodes with MMF compared to Aza [45], with a 30–50% reduced 6-month cumulative rates of acute kidney graft rejection [46]. However, this has not been replicated in other studies where in deceased donor kidney transplant recipients on low-dose CsA and no steroids, MMF had no significant benefits over Aza [47].

The cost of Aza is approx. INR 6–18 for a day while the daily expenditure for MMF is almost ten times higher (INR 60–180; US$ 1–2.25). Using Aza could thus significantly reduce the cost as been observed by others without significantly altering rejection rates [48]. Even if some reports of lesser rejection episodes with MMF compared to Aza are considered, given that the risk of rejection episodes are less after 6 months, there could be a cost advantage if MMF is substituted with Aza after 1 year in patients with stable graft functions and without preceding acute rejections.

1. Are there laboratory parameters which could suggest reduction in dosage and frequency of immunosuppressive drugs?

It is possible to titrate the dose of several of immunosuppressive agents depending on their therapeutic blood levels, effects on cell counts and other parameters

1. Antithymocyte globulin

It has been suggested that the traditionally recommended dose of ATG could be reduced by targeting CD3 counts could prevent unnecessary higher doses [49]. Others have also reported this method as useful, reliable, and cost effective [50]. As ATG reduces the lymphocyte counts, it is possible to decide on need and timing of the subsequent dose of ATG following an initial dose based on lymphocyte counts. If they are suppressed following the initial dose, subsequent doses of ATG could be deferred till the counts normalize. Titrating further doses of ATG based on lymphocyte count alone in the absence of monitoring facilities for CD lymphocyte counts with further doses of ATG given only if absolute lymphocyte count exceeded 750/μL has also been reported [9]. This may result in a lesser number of ATG doses and a lesser cumulative dose of ATG needed [51].

1. CNIs

Titrating the area under the curve (AUC) for cyclosporine or the trough (C0) and and peak levels have been used to decide on the dose which would provide adequate immunosuppression, This could help in reducing the dose to a trough 50–100 ng/mL with the same effect as standard trough of 150–300 ng/mL [38]. Assessing the genotype of cytochrome 450 enzyme system could aid in deciding the adequate dose needed to achieve adequate blood levels with CYP3A5 expressers having a ~ 40–50% higher dose requirement compared to non-expressers. This could avoid unnecessary higher dose of CNIs like tacrolimus in some patients [52].

1. Mycophenolate mofetil

Measuring MMF levels are not as commonly used as CNI levels in renal transplantation though there are reports of adjusting the dose of MMF based on blood levels. This could result in a lesser dose of MMF without compromising on the efficacy. An AUC of 30-60 mg/hour/l at 0–12 hours is recommended to prevent renal allograft rejection [53]. This method of titrating the dose of MMF based on these levels can help to maintaining effective immunosuppression while avoiding overdosing [54].

1. Rituximab

As Rituximab is a monoclonal antibody targeting B cells, its efficacy is reflected by measuring CD19 B cells which costs approx. INR 3000 (US$ 37.5). Monitoring CD19 counts suggests a lower initial dose may suffice and targeting subsequent doses depending on B cell repopulation can result in lesser boosters and at time intervals ranging from 6 to 12 months [22]. Targeting initial dose and deciding on need for further doses depending on the CD 19 count has been found to be effective with limiting state of immunosuppression [55]. This could have significant cost advantages [22, 56].

When considering the option of lowering maintenance immunosuppression in renal transplantation, the trade-off of an increased risk of rejection should be anticipated and methods to prevent it as well as timely detection for early treatment should be ensured. Recipients with a low risk of rejection based on their immunologic risk profile, absence of previous rejection episodes and those with stable renal functions could be considered for lower immunosuppression strategies. Screening for donor specific antibodies (DSA) and protocol biopsies could provide additional information on the risk of development of future rejections and subsequent graft loss. Absence of DSA and protocol biopsies showing no evidence of active rejection could justify use of lower immunosuppression. Such patients should be advised the need for periodic check-up of renal parameters, stressed the need for drug compliance and to report promptly if any symptoms or laboratory evidence of renal dysfunction occur as response to antirejection therapies are most effective if detected early. Lowering immunosuppression has multiple advantages like lesser chances for infection, decreased risk of metabolic abnormalities and malignancies and could have advantages in the covid pandemic [9]. Multi centre trials randomizing selected patients to lower and conventional immunosuppressive protocols may shed more light on the clinical utility of lower immunosuppression strategies.

3. Conclusion

Reducing the cost of immunosuppression can help to make renal transplantation financially viable to low cost economies without state funded insurance schemes. As this could lead to increased risk of graft rejection, these strategies may need to be restricted to those committed for regular follow up and drug compliance with low immunological risk.

Acknowledgments

The assistance of residents and staff in the department of Nephrology, Government Medical College, Thiruvananthapuram in preparing this manuscript is gratefully acknowledged.

Conflict of interest statement

The author reports no conflict of interest in this manuscript.

Funding Statement

This study has not received any funding from any source.