Tailor-Made Induction Therapy in ‘Low Risk’ Renal Transplants; A South Asian Perspective

Induction therapy has established itself as an integral component of modern-day renal transplantation. Carefully selected induction therapy helps not only to avoid early rejection of grafts but also allows grafts with delayed function to recover prior to introduction of potentially nephrotoxic immunosuppressants. While the place of induction therapy and reduction in early acute rejection is well established, its overall impact on long-term graft and patient survival is still unclear, especially in the ‘lowrisk’ transplant recipient. Considering the substantial initial costs of induction therapy and their potential adverse reactions, transplant clinicians in developing countries have had to weigh the true advantages in induction against affordability and sustainability in the ‘free’ state health care systems. This review looks at the place of induction therapy in the current clinical setting with special emphasis on the ‘low-risk’ transplant candidates in limited resource settings. Review Article Tailor-Made Induction Therapy in ‘Low Risk’ Renal Transplants; A South Asian Perspective Gunawansa Nalaka1,2*, Ajay Sharma2,3 and Ahmed Halawa2,4 1National Institute of Nephrology Dialysis and Transplant, National Hospital of Sri Lanka, Sri Lanka. 2Faculty of Health and Science, Institute of Learning and Teaching, University of Liverpool, UK. 3Renal Transplant Unit, Royal Liverpool University Hospitals, Liverpool, UK. 4Renal Transplant Unit, Sheffi eld Teaching Hospitals, Sheffi eld, UK. Dates: Received: 18 August, 2017; Accepted: 27 September, 2017; Published: 03 October, 2017 *Corresponding author: Nalaka Gunawansa, Consultant Vascular and Transplant Surgeon, National Institute of Nephrology Dialysis and Transplant,National Hospital of Sri Lanka, Sri Lanka, E-mail:


Introduction
The global incidence and prevalence of Chronic Kidney Disease (CKD) and End Stage Kidney Disease (ESKD) have reached epidemic proportions. Although a global problem, its burden on health economy has had far more devastating implications in developing countries such as Sri Lanka. While boasting of far superior regional health indices in areas such as neonatal mortality and maternal mortality, the magnitude of CKD, ESKD and associated mortality in Sri Lanka remains relatively high [1,2].
Although nationwide renal registries in Sri Lanka are nonexistent, the crude calculated incidence of ESKD in the different provinces is reported between 37-82 per one Million population [3]. It has also been reported that CKD and genito-urinary related hospital admissions in the country have almost doubled over the past two decades. Concurrently, the in-hospital mortality from CKD has increased to 9.1 from 2.6 per 100,000 population [4]. Some of the reasons for these disappointing results include; lack of adequate state sponsored renal replacement therapy, poor patient acceptance of peritoneal dialysis, relatively low rate of deceased donor organ donation and prohibitive costs of transplant immunosuppression.
Renal Transplantation (RT) remains the optimum treatment modality for ESKD. While surgical technique has shown only minor modifi cations, the dramatic improvement in overall outcomes of RT all over the world has been attributed to improvements in the transplant pharmacotherapy. Advances in transplant pharmacotherapy have aimed at achieving better graft and patient survival, minimization of graft rejection and avoidance of signifi cant adverse effects. In this regard, numerous new pharmacological agents have been introduced to maximize the graft and patient outcomes. Nevertheless, in the developing world, transplant clinicians face a constant battle in their attempt to maintain comparable outcomes amidst numerous socio-economic restrictions. Foremost among these restrictions come the relatively poor health care infrastructure beyond the tertiary hospitals and the limited public health funding. Transplant  pharmacotherapy  consists  of  three  chief components; induction therapy, maintenance immunosuppression and treatment of established rejection. Induction therapy is now recommended for all transplants with potential benefi t over no induction in terms of reducing biopsy proven acute rejection (BPAR) [5,6]. The United Network for Organ sharing (UNOS) registry data also showed that induction with any of the commonly used agents contributed to better short-term and long-term allograft and patient outcomes [7]. The aim of induction therapy is to achieve an intense and selective suppression of the immune system at the time of graft implantation and immediate post-transplant period to minimize the incidence of early acute rejection [8].  [9]. UNOS Registry data showed that the different agents used for induction were; rabbit anti-thymocyte globulin (rATG) 39%, interleukin-2 receptor antagonists (IL-2RA) 28%, alemtuzumab 9% and equine anti-thymocyte globulin (eATG) <2% [10]. However, outside the United States, this trend is different with IL-2RA being the commonest induction agent among most transplant centers [11].

Deciding on the Induction Therapy
Assessment of pre-transplant immunological risk of a given recipient helps in the decision regarding induction therapy. The highest benefi t of induction therapy is seen among patients with higher risk of acute rejection [5]. 'High risk' is defi ned by the presence of characteristics such as young recipient age, older donor age, presence of preformed antibodies, re-transplantation, poor human leucocyte antigen (HLA) match, prolonged cold ischaemia (>24 hours), donation after cardiac death, extended criteria donors and recipients of certain races known to have increased immunogenicity (eg. African-Americans) [12][13][14][15] (Table 1).
Induction agents in current practice have demonstrated a signifi cant defi nitive reduction in incidence of acute rejection and early graft loss [16,17]. An additional advantage of certain induction therapies is the ability to delay the introduction of potentially nephrotoxic calcineurin inhibitors (CNI) as maintenance therapy. This is especially useful in deceased donor RT with delayed graft function, where CNI therapy can be delayed until some recovery of the graft is obtained [18,19]. While the overall benefi ts of induction therapy are well documented, they also have inherent adverse reactions including infection and malignancy secondary to the potent inhibition of host immune responses [20,21]. Hence, clear identifi cation of induction agent to be used in each individual patient need to be defi ned using a careful risk-benefi t assessment.

T-Cell Depleting Agents
These induction agents act by depleting the circulating host T lymphocytes. Extensive T cell destruction may result in the release of cytokines that mediate a 'serum sickness type' reaction with signifi cant adverse effects to the drug. The resulting T cell depletion is long standing and may even be permanent in elderly patients, results in a chronic increased susceptibility to infections and malignancy [24,25]. The commonly used T cell depleting agents include anti-thymocyte globulin (ATG), muromonab-CD3 and alemtuzumab.

Antithymocyte Globulin (ATG)
ATG is acquired by injecting either horses or rabbits with human lymphoid tissue and harvesting the resulting antibodies to make equine (eATG) or rabbit (rATG) respectively. ATG induction therapy causes host T cell depletion by a combination of cell lysis and clearance by the reticulo-endothelial system. The overall result is a profound suppression of host cellular and humoral immunity [26].
Immediate adverse effects related to ATG are caused by the cytokine release phenomenon. This involves a combination of constitutional symptoms including fever, chills, headache, nausea, diarrhea, malaise and dizziness that is often poorly tolerated by the patient. The intensity of these adverse reactions can be suppressed by antihistamine and acetaminophen premedication. Furthermore, it is recommended to be administered via a central line, to minimize thrombotic complications of the access route [27]. Serious bone marrow suppression with leukopenia and thrombocytopenia has also been reported in up to 30% of recipients [28].
ATG treatment is initiated at or just before the time of graft implantation and may consist of 5-7 divided doses. Based on the fi ndings of a landmark study by Brennan et al (1999), rATG remains the preferred agent over eATG [29,30]. Results of the study showed signifi cantly lower incidence of BPAR  with rATG compared to eATG (4% vs 25%). The overall 1-year graft survival was 98% with rATG compared to 83% with eATG (p = 0.02). However, rATG was associated with a signifi cantly higher incidence of leukopenia (56%) compared to eATG (4%), (p < 0.0001). Nevertheless, the overall incidence of infections was not signifi cantly increased with rATG. Interestingly, the incidence of post-transplant cytomegalovirus infection was in fact lower with rATG (12.5%) compared to eATG (33%), (p = 0.025). There was no signifi cant difference between the two with regard to incidence of long-term post-treatment malignancy [31]. A 10-year follow up study between the two preparations also showed signifi cant advantage of rATG in all composite end points including overall event-free survival [32].
Despite the proven effi cacy in reducing BPAR, the sustained In other studies, ATG use has shown signifi cantly lower rates of BPAR compared to no induction across all transplants albeit with no difference in graft or patient survival [34,35].
This advantage was also seen among highly sensitized and 'high risk' recipients, making ATG the induction therapy of choice in such patients [36,37]. Therefore, considering the adverse effect profi le of ATG, it is mostly reserved for transplants categorized as 'high risk' of early rejection [5].

Alemtuzumab
Alemtuzumab is a mAb originally produced for treatment of chronic lymphocytic leukaemia. It is an anti CD-52 antibody which acts against the CD-52 molecules present on a variety of immune modulatory cells including B cells, T cells, macrophages and natural killer cells [38].

Muromonab-CD3 (OKT3)
Muromonab-CD3 was the fi rst biological agent used in  when using basiliximab instead of ATG was 1459 U.S dollars [46]. Furthermore, the use of basiliximab over placebo has also proved cost effective considering the advantages of reduced incidence of BPAR and its management [47].

T-Cell Non-Depleting Agents
Daclizumab: Daclizumab was the fi rst IL-2RA used in induction. Its function, effi cacy and adverse effect profi le was similar to basiliximab with no signifi cant difference in BPAR or overall outcomes [48]. However, daclizumab was associated with signifi cantly higher production costs and technical demands compared to basiliximab. In the absence of any advantage over the cheaper and simpler alternative of basiliximab, daclizumab fell out of favour among clinicians and eventually was withdrawn from the market in 2009. IL-2RA have shown a signifi cant reduction in BPAR as well as improved graft outcomes compared to placebo in a comprehensive Cochrane review looking at over 30 randomized controlled trials [49]. The same review also showed no increase in the incidence of malignancy although it did not show any advantage of IL-2RA in all-cause mortality. A similar review of results from Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) also showed a 26% reduction of BPAR with basiliximab over placebo in patients given cyclosporine maintenance, although this advantage was not seen in 'low risk' patients given tacrolimus based maintenance [50] (Table  3).

Discussion
Induction therapy is an integral part in the current management of peri-transplant immunosuppression. Induction therapy has resulted in a signifi cant reduction in BPAR and an overall improvement in short term and possibly long-term graft survival, especially in 'high-risk' recipients [7]. The different induction agents available in current practice have differing immunosuppressive potencies, adverse effect profi les and cost implications. Therefore, the choice of induction agent and its dosing schedule is often individualized according to the recipient immunological risk, clinician familiarity and affordability in the local set up. These factors become even more important in the developing world where the transplant teams face a constant battle to achieve comparable results amidst limited funding and resources.

Cost Implications of Induction
Outside the United States, basiliximab remains the commonest induction agent used in modern day practice. When comparing basiliximab, rATG and no induction, with standard maintenance therapy, basiliximab was the only regimen found to be cost-effective at £ 20,000 and £ 30,000 of quality adjusted life years in the United Kingdom [51,52]. The same study also found that rATG was not cost-effective at the above determined economic parameters. Basiliximab was found to be more costeffective owing to lower medicinal costs as well as the reduced cost of ancillary treatment required as infection prophylaxis and management compared to rATG. Although the reduced incidence of BPAR with rATG made the cost comparison closer, the overall costs were still higher compared to basiliximab [52].
Similar cost-effective outcomes of basiliximab over rATG were found in other studies across United States, Canada and France [46,53,54]. Although a similar cost and economic evaluation of immunosuppressive therapy is not available in the South Asian region, the overall trend is likely to be quite similar. Data from ANZDATA registry for 'low risk' transplants (primary transplants with <2/6 HLA mismatches) with tacrolimus based maintenance therapy, showed no advantage of IL-2RA in reducing BPAR [50].  [58,59]. A review and cost analysis by Wiseman (2015) concluded that with a modern-day acute rejection risk of <10% in 'low risk' live donor transplants, the sample of patients needed to be treated with induction therapy to show a statistical and clinical advantage was too large and too expensive [60].

Induction Therapy in Sri Lnaka
Alemtuzumab  All patients are given standard triple therapy of steroids, mycophenolate and tacrolimus for maintenance immunosuppression. The small geographical extent of the country has allowed closer surveillance of such patients who are transplanted without induction and allowed in the achievement of satisfactory and comparable outcomes.

Conclusion
The use of biological agents as induction therapy has steadily increased all over the transplant world in recent years. Induction therapy has shown a clear benefi t over no induction in reducing BPAR after RT, paving the way for their introduction in to most transplant protocols. However, there remains considerable skepticism and a lack of robust data to confi rm its advantage in terms of long-term graft and patient survival as well as its benefi t in recipients at low immunological risk. In addition, the associated costs and potential adverse effects have prevented induction therapy from being incorporated routinely in all categories of renal transplants in the developing world. This has led to a new paradigm of immunological risk stratifi cation among transplant recipients and making individualized protocols based on potential advantage over risk and affordability in the health care economy. In the absence of level-1 multicenter randomized clinical trial evidence of clear benefi t in the patients with low immunological risk, the selective use of induction therapy in 'moderate' to 'high risk' patients and induction sparing in 'low risk' patients appear justifi able.