ISSN: 2581-3870
Archives of Clinical Nephrology
Review Article       Open Access      Peer-Reviewed

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, Sheffield Teaching Hospitals, Sheffield, UK
*Corresponding author: Nalaka Gunawansa, Consultant Vascular and Transplant Surgeon, National Institute of Nephrology Dialysis and Transplant,National Hospital of Sri Lanka, Sri Lanka, Email: vascular@drnalakagunawansa.com
Published: 18 August, 2017 | Accepted: 27 September, 2017 | Received: 03 October, 2017
Keywords: Induction; Low risk transplant; Immunosuppression; Basiliximab

Cite this as

Gunawansa N, Sharma A, Halawa A (2017) Tailor-Made Induction Therapy in ‘Low Risk’ Renal Transplants; A South Asian Perspective. Arch Clin Nephrol 3(1): 032-038. DOI: 10.17352/acn.000024

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 ‘low-risk’ 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.

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 non-existent, 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 modifications, 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 significant 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.

Induction Therapy in Modern-Day Transplantation

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 benefit 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].

Numerous biological agents have been introduced and are used as induction agents in RT. The choice of which induction agent to use depends on different factors including degree of immunological risk, local availability, cost and clinician familiarity. Over the last two decades, there has been a steady increase in use of induction agents for RT across the world. Andreoni et al (2007) reported that over 74% of centers in United States used induction therapy for transplantation by 2004 [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 benefit of induction therapy is seen among patients with higher risk of acute rejection [5]. ‘High risk’ is defined 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) [12–15] (Table 1).

Induction agents in current practice have demonstrated a significant definitive 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 benefits 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 identification of induction agent to be used in each individual patient need to be defined using a careful risk-benefit assessment.

The commonly used induction agents include monoclonal antibodies; mAb (muromonab-CD3, daclizumab, basiliximab, alemtuzumab) and polyclonal antibodies; pAb (ATG [equine / rabbit]) [22,23]. These are further classified based on their effect on the host T cells; T cell depleting agents (alemtuzumab, ATG, and muromonab-CD3) and T cell non-depleting agents (basiliximab and daclizumab) (Table 2).

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 significant 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 findings of a landmark study by Brennan et al (1999), rATG remains the preferred agent over eATG [29,30]. Results of the study showed significantly 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 significantly higher incidence of leukopenia (56%) compared to eATG (4%), (p < 0.0001). Nevertheless, the overall incidence of infections was not significantly 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 significant 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 significant advantage of rATG in all composite end points including overall event-free survival [32].

Despite the proven efficacy in reducing BPAR, the sustained and profound immunosuppression caused by T cell depletion have had significant drawbacks in terms of long-term safety. In a study looking at over 73,000 transplants in the United States between 1988 and 1997, ATG was associated with increased post-transplant mortality both in early and late follow up. The early deaths were attributable to infection and cardiovascular morbidity while the late post-transplant deaths were mainly due to malignancy [33].

In other studies, ATG use has shown significantly 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 profile 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]. The resultant reaction causes immune cell lysis with effects often lasting up to one year. Profound and sustained immunosuppression with alemtuzumab is often used to minimize other maintenance immunosuppression, thereby contributing to lower overall cardio-vascular morbidity [38]. The commonest adverse effects include bone marrow suppression (40-70%) affecting all three cell lines along with constitutional symptoms such as vomiting, diarrhea and headache [39]. These effects can be quite profound requiring mandatory premedication with antihistamines, steroids and acetaminophen [40,41].

There has been an increasing trend for the use of alemtuzumab for transplants especially where early steroid withdrawal (ESW) or CNI minimization have been planned. Hannaway et al (2011) compared alemtuzumab induction with rATG and basiliximab across different risk categories, and found lower incidence of BPAR with alemtuzumab compared to basiliximab in ‘low risk’ transplants, without any observed advantage in graft or patient survival [42]. In the ‘high risk’ patients, alemtuzumab showed no significant advantage over rATG.

In another review comparing ATG with alemtuzumab for transplants where ESW was carried out, alemtuzumab showed lower incidence of BPAR at I-year compared to ATG. Among 6 studies that compared these two modalities, the above finding was seen in 4 studies while the other two studies showed equivocal results [35].

There are differing dosing schedules of alemtuzumab from a single dose to two doses. The single-dose regime involves an intra-operative dose of 30 mg given subcutaneously as opposed to the two-dose regimen where a second dose may be given on day-01 or day-04. The single-dose subcutaneous administration as opposed to the intravenous route is considered a compromise between desired immunosuppressive effect and adverse reactions [43].

Muromonab-CD3 (OKT3)

Muromonab-CD3 was the first biological agent used in transplantation. It was initially developed for treatment of BPAR and was later used as an induction agent. It is an anti-CD-3 antibody and binds to the CD-3 receptor on the surface of T cells. Despite encouraging early results, its clinical use soon waned due to the potential life-threatening adverse effects and costs, resulting in its discontinuation.

T-Cell Non-Depleting Agents

Basiliximab: Basiliximab is a mAb and an interleukin 2 receptor antagonist (IL-2RA). Its binding to the CD-25 molecule of the IL-2 receptor causes inhibition of T cell activation and subsequent proliferation without actual T cell lysis [44]. The resulting IL-2 binding saturates the relevant receptors thereby inactivating the T cells for up to 8 weeks [16]. Basiliximab is a genetically modified mAb where majority of the original murine amino acids have been replaced with human amino acids, being referred to as a chimeric antibody with 70:30 human and murine components. The presence of human protein confers lower immunogenicity resulting in reduced allergenic reactions.

Basiliximab is given as a two-dose regime; first dose given approximately 2 hours before implantation and the second dose given on day-04. The absence of actual T cell lysis avoids the cytokine mediated ‘serum sickness type’ adverse effects seen with ATG. Furthermore, the T cell non-depleting nature prevents any appreciable increase in post-transplant infection or malignancy, making it one of the safest induction agents in use [16]. While no major adverse effects have been reported over placebo drugs in clinical trials, the only significant adverse effect reported is hypersensitivity reactions (<1%) [45].

The actual drug to drug cost of basiliximab is higher compared to ATG. However, when considering the greater number of doses required with ATG and the overall costs to avoid and manage adverse reactions, basiliximab has been more economical than ATG. In a study conducted in the United States by Lilliu et al (2004), the average cost saving per patient 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].

Daclizumab: Daclizumab was the first IL-2RA used in induction. Its function, efficacy and adverse effect profile was similar to basiliximab with no significant difference in BPAR or overall outcomes [48]. However, daclizumab was associated with significantly 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 significant 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 significant 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 profiles 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 cost-effective 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.

The ‘Low-Risk’ Recipient and Induction

Although the advantage of induction therapy in all transplants have been shown in the Western literature including the UNOS registry, its role in the ‘low risk’, live donor, primary transplant recipient has not been quite conclusively proven. Furthermore, most of the recommendations for routine induction therapy in all forms of RT have been based on relatively obsolete data from studies which did not use the current best triple regimen maintenance immunosuppression [55]. With this current tacrolimus based triple drug maintenance therapy, the addition of induction may contribute to reduction of BPAR by only 1-4% and with no appreciable advantage in graft or patient survival. A retrospective study based on Organ Procurement and Transplant Network (OPTN) data studying the place of induction in ‘low risk’ live donor transplants, failed to show any significant reduction in BPAR or graft loss at 5 years [56]. Another retrospective analysis by Tanriover and colleagues (2015) from the same registry data of more than 35000 live donor transplants with tacrolimus based triple immunosuppression, failed to show any advantage of IL-2RA in terms of BPAR or graft survival [57]. Lim and colleagues (2009) have also reported similar observations in Australasia. 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].

The South Asian Perspective

There remains a relative scarcity of data for induction therapy concerning RT in South Asia. A few smaller studies from India and Sri Lanka have looked at the effect of induction therapy on live donor transplants using tacrolimus based triple therapy maintenance immunosuppression. They observed no significant advantage of IL-2RA induction in terms of BPAR or graft/ patient survival in ‘low risk’ live donor transplants [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]. The review described that to avoid one episode of BPAR it would require induction of 33 such patients, with no clear benefit of long-term outcome. Therefore, the place of expensive induction therapy in the ‘low-risk’ live donor transplant candidate remains inconclusive especially in the context of limited-resource transplant centers in South Asia.

Induction Therapy in Sri Lnaka

Alemtuzumab is not freely available in Sri Lanka and has been used only sporadically. Although both rATG and basiliximab are available, the head to head costing of the agents compares quite favourably with basiliximab, making it the induction agent of choice among transplant centers in the country. Basiliximab is also the only induction agent provided by the Ministry of Health, under the free state-run health care system. The safety profile of basiliximab in term of post-transplant infections is an added advantage in the local set up considering the excess cost implications of managing such infections. Nevertheless, further limitations do exist.

Basiliximab made available in the state health sector is often inadequate to meet the demand of all transplants that take place, resulting in a significant disparity between demand and supply. Often, transplant centers have had to make their own individual protocols to suit the local immunological risks and stay within the allocated institutional budgets. One such individualized protocol involves the use of a single dose of basiliximab instead of the usual two doses in the ‘low risk’ patients. Cunningham and colleagues (2016) have published their own experience with a single dose basiliximab protocol and reported no demonstrable difference in the rate of BPAR, graft survival or patient survival in over 760 patients [61].

1. The National Institute of Nephrology and Transplant, Colombo is the only dedicated transplant hospital in Sri Lanka, performing approximately 30% of all state sector transplants in the country. Pre-transplant donor specific antibody screening is not available in the state-run transplant system. Our current protocol of induction is as follows.rATG for all re-transplants and ‘high-risk’ transplants (live or deceased donor) with HLA 6/6 mismatch

2. Basiliximab two doses (day 0 and 4) for all other deceased donor transplants

3. Basiliximab two doses (day 0 and 4) for all other live donor transplants considered ‘moderate risk’ (HLA mismatch 3-5/6)

4. Basiliximab single dose (day 0) or no induction for ‘low risk’ (live donor, HLA mismatch 0-2/6, recipient >30 years and donor <60 years)

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 benefit 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 confirm its advantage in terms of long-term graft and patient survival as well as its benefit 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 stratification 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 benefit 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 justifiable.

  1. Wanigasuriya KP, Peiris-John RJ, Wickremasinghe R (2011) Chronic kidney disease of unknown aetiology in Sri Lanka: is cadmium a likely cause? BMC Nephrol 12:32. Link: https://goo.gl/Bwc9mv
  2. Jayasekara KB, Dissanayake DM, Sivakanesan R, Ranasinghe A, Karunarathna RH, et al. (2015) Epidemiology of chronic kidney disease, with special emphasis on chronic kidney disease of uncertain etiology, in the north central region of Sri Lanka. J Epidemiol  25:275–280. Link: https://goo.gl/oFQx9K
  3. Gunathilake SK, Samarathunga SS RR (2014) Chronic Kidney Disease ( CKD ) in Sri Lanka - Current Research Evidence Justification : A Review. Sabaragamuwa Univ J 13:31–58. Link: https://goo.gl/WWRHHP
  4. Gooneratne IK, Ranaweera AKP, Liyanarachchi NP, Gunawardane N, Lanerolle RD (2008) Epidemiology of chronic kidney disease in a Sri Lankan population. Int J Diabetes Dev Ctries 28: 60–64. Link: https://goo.gl/4njc4o
  5. Group KW (2009) KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 9:151-155. Link: https://goo.gl/nBc6mG
  6. Chouhan K, Zhang R (2012) Antibody induction therapy in adult kidney transplantation: A controversy continues. World J Transpl 2: 19–26. Link: https://goo.gl/qeoFef
  7. Cai J, Terasaki PI (2010) Induction Immunosuppression Improves Long-Term Graft and Patient Outcome in Organ Transplantation: An Analysis of United Network for Organ Sharing Registry Data. Transplantation 90: 1511–1515. Link: https://goo.gl/iF5kCX
  8. Halloran PF (2004) Immunosuppressive Drugs for Kidney Transplantation. N Engl J Med 351: 2715–2729. Link: https://goo.gl/eN82z7
  9. Andreoni KA, Brayman KL, Guidinger MK, Sommers CM, Sung RS (2007) Kidney and Pancreas Transplantation in the United States, 1996?2005. Am J Transplant 7: 1359–1375. Link: https://goo.gl/3QYCfH
  10. (2012)The Scientific Registry of Transplant Recipients and Organ Procurement and Transplantation Network. OPTN & SRTR Annual Data Report 2012. annual Data Report.
  11. Opelz G, D?hler B (2009) Collaborative Transplant Study. Influence of Immunosuppressive Regimens on Graft Survival and Secondary Outcomes After Kidney Transplantation. Transplantation 87: 795–802. Link: https://goo.gl/tmrnA7
  12. Pratschke J, Dragun D, Hauser IA, Horn S, Mueller TF, et al. (2016) Immunological risk assessment : The key to individualized immunosuppression after kidney transplantation. Transplant Rev 30: 77–84. Link: https://goo.gl/8K9Dik
  13. Saidi RF, Elias N, Kawai T, Hertl M, Farrell ML, et al. (2007) Outcome of Kidney Transplantation Using Expanded Criteria Donors and Donation After Cardiac Death Kidneys: Realities and Costs. Am J Transplant 7: 2769–2774. Link: https://goo.gl/ZjWW6s
  14. Diet C, Audard V, Roudot-Thoraval F, Matignon M, Lang P, et al. (2010) Immunological risk in recipients of kidney transplants from extended criteria donors. Nephrol Dial Transplant 25: 2745–2753. Link: https://goo.gl/w4AdZb
  15. Dunn TB, Noreen H, Gillingham K, Maurer D, Ozturk OG, et al. (2011) Revisiting traditional risk factors for rejection and graft loss after kidney transplantation. Am J Transplant 11: 2132–2143. Link: https://goo.gl/DvXaz1
  16. Ramirez CB, Marino IR (2007) The role of basiliximab induction therapy in organ transplantation. Expert Opin Biol Ther 7: 137–148. Link: https://goo.gl/8dR8ek
  17. Beiras FA, Thein E, Hammer C (2003) Induction of immunosuppression with polyclonal antithymocyte globulins: an overview. Exp Clin Transpl 1: 79–84. Link: https://goo.gl/dHcqBc
  18. Ekberg H, Tedesco SH, Halloran PF, Demirbas A, Vítko S, et al. (2007) Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 357: 2562–2575. Link: https://goo.gl/1HL3Sb
  19. Nashan B (2005) Antibody induction therapy in renal transplant patients receiving calcineurin-inhibitor immunosuppressive regimens: a comparative review. BioDrugs 19: 39–46. Link: https://goo.gl/7iY5FZ
  20. Gabardi S, Martin ST, Roberts KL, Grafals M (2011) Induction immunosuppressive therapies in renal transplantation. Am J Heal Pharm 68: 211–218. Link: https://goo.gl/sHDjBS
  21. Khurana A, Brennan DC (2011) Pathology of Solid Organ Transplantation [Internet]. Liapis H, Wang HL, editors. Springer. Link: https://goo.gl/urTvS6
  22. Opelz G, Unterrainer C, Süsal C, Döhler B (2016) Efficacy and safety of antibody induction therapy in the current era of kidney transplantation. Nephrol Dial Transplant 31: 1730–1738. Link: https://goo.gl/LbgyoT
  23. Hill P, Cross NB, Barnett ANR, Palmer SC, Webster AC (2017) Polyclonal and monoclonal antibodies for induction therapy in kidney transplant recipients. Hill P, editor. Vol. 2017, Cochrane Database of Systematic Reviews. John Wiley & Sons. Link: https://goo.gl/e7qrtB
  24. Gabardi S, Tichy EM (2012) Overview of immunosuppressive therapies in renal transplantation. In: Core Concepts in Renal Transplantation 97–127. Link: https://goo.gl/k3HxT6
  25. Ciancio G, Burke GW, Miller J (2007) Induction therapy in renal transplantation : an overview of current developments. Drugs 67: 2667–2680. Link: https://goo.gl/4Ndt3S
  26. Deeks ED, Keating GM (2009) Rabbit Antithymocyte Globulin (Thymoglobulin®): A review of its use in the prevention and treatment of acute renal allograft rejection. Drugs 69: 1483–1512. Link: https://goo.gl/x2pkZZ
  27. Somerville KT (2003) Antibody Agents in Solid Organ Transplantation. J Pharm Pract 16: 388–400. Link: https://goo.gl/oXomcy
  28. Thiyagarajan UM, Ponnuswamy A, Bagul A (2013) Thymoglobulin and its use in renal transplantation: A review. Am J Nephrol. 37: 586–601. Link: https://goo.gl/9aQx7E
  29. Brennan DC, Flavin K, Lowell JA, Howard TK, Shenoy S, et al. (1999) A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients. Transplantation 67: 1011–1018. Link: https://goo.gl/C4tkmU
  30. Hardinger KL, Brennan DC, Klein CL (2013) Selection of induction therapy in kidney transplantation. Transpl Int 26: 662–672. Link: https://goo.gl/j9qLhC
  31. Hardinger KL, Schnitzler MA, Miller B, Lowell JA, Shenoy S, et al. (2004) Five-year follow up of thymoglobulin versus ATGAM induction in adult renal transplantation. Transplantation 78: 136–141. Link: https://goo.gl/4Nj2Bd
  32. Hardinger KL, Rhee S, Buchanan P, Koch M, Miller B, et al. A prospective, randomized, double-blinded comparison of thymoglobulin versus Atgam for induction immunosuppressive therapy: 10-year results. Transplantation 86: 947–952. Link: https://goo.gl/sUuW36
  33. Meier-Kriesche HU, Arndorfer JA, Kaplan B (2002) Association of antibody induction with short- and long-term cause-specific mortality in renal transplant recipients. J Am Soc Nephrol 13: 769–772. Link: https://goo.gl/7dawQe
  34. Brennan DC, Daller JA, Lake KD, Cibrik D, Del Castillo D, et al. (2006) Rabbit Antithymocyte Globulin versus Basiliximab in Renal Transplantation. N Engl J Med 355: 1967–1977. Link: https://goo.gl/RK74LX
  35. Penny H, B CN, R BAN, C PS, C WA (2017) Polyclonal and monoclonal antibodies for induction therapy in kidney transplant recipients. Cochrane Database Syst Rev. Link: https://goo.gl/138SMt
  36. Noel C, Abramowicz D, Durand D, Mourad G, Lang P, et al. (2009) Daclizumab versus antithymocyte globulin in high-immunological-risk renal transplant recipients. J Am Soc Nephrol 20: 1385–1392. Link: https://goo.gl/hpuZ15
  37. Thibaudin D, Alamartine E, De Filippis JP, Diab N, Laurent B, et al. (1998) Advantage of antithymocyte globulin induction in sensitized kidney recipients: A randomized prospective study comparing induction with and without antithymocyte globulin. Nephrol Dial Transplant 13: 711–715. Link: https://goo.gl/7ApCcW
  38. Masson P, Henderson L, Craig Jc, Webster Ac (2014) Belatacept for kidney transplant recipients ( Review ). Cochrane Database Syst Rev. Link: https://goo.gl/g8W1fp
  39. Morris PJ, Russell NK. Alemtuzumab (Campath-1H): A Systematic Review in Organ Transplantation. Transplantation 81: 1361–1367. Link: https://goo.gl/9ztpWx
  40. Ciancio G, Burke GW (2008) Alemtuzumab (Campath-1H) in kidney transplantation. Am J Transplant 8: 15–20. Link: https://goo.gl/6xmyXa
  41. Friend PJ (2013) Alemtuzumab induction therapy in solid organ transplantation. Transplant Res. Link: https://goo.gl/daEPhr
  42. Hanaway MJ, Woodle ES, Mulgaonkar S, Peddi VR, Kaufman DB, et al. (2011) Alemtuzumab induction in renal transplantation. N Engl J Med 364: 1909–1919. Link: https://goo.gl/e28Zgu
  43. Vo AA, Wechsler EA, Wang J, Peng A, Toyoda M, et al. (2008) Analysis of subcutaneous (SQ) Alemtuzumab induction therapy in highly sensitized patients desensitized with IVIG and rituximab. Am J Transplant 8: 144–149. Link: https://goo.gl/VWJHvZ
  44. Marcen R. Immunosuppression and renal transplant rejection : review of current and emerging therapies. Clin Investig (Lond) 1: 859–877. Link: https://goo.gl/8pQXcP
  45. Chapman TM, Keating GM (2003) Basiliximab: A Review of its Use as Induction Therapy in Renal Transplantation. Drugs 63: 2803–2835. Link: https://goo.gl/mQvULB
  46. Lilliu H, Brun SC, Le PC, Büchler M, Al Najjar A, et al. Cost-minimization study comparing Simulect® vs. Thymoglobulin® in renal transplant induction. Clin Transplant 18: 247–253. Link: https://goo.gl/796hUY
  47. Morton RL, Howard K, Webster AC, Wong G, Craig JC (2009) The cost-effectiveness of induction immunosuppression in kidney transplantation. Nephrol Dial Transplant 24: 2258–2269. Link: https://goo.gl/R1hUFK
  48. Arnol M, Omahen K, Oblak M, Vidan-jeras B, Kmetec A, et al. (2010) Basiliximab Versus Daclizumab Combined With Triple Immunosuppression in Deceased Donor Renal Transplantation : A Prospective , Randomized Study. Transplantation 89: 1022–1027. Link: https://goo.gl/P6wHcs
  49. Webster AC, Playford EG, Higgins G, Chapman JR, Craig JC (2004) Interleukin 2 receptor antagonists for renal transplant recipients: a meta-analysis of randomized trials. Transplantation 77: 166–176. Link: https://goo.gl/STPLpx
  50. Lim WH, Chang SH, Chadban SJ, Campbell SB, Dent H, Russ GR, et al. (2009) Interleukin-2 receptor antibody reduces rejection rates and graft loss in live-donor kidney transplant recipients. Transplantation 88: 1208–1213. Link: https://goo.gl/QQNGzz
  51. Jones HT, Snowsill T, Haasova M, Coelho H, Crathorne L, et al. (2016) Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model. Health Technol Assess 20: 591–594. Link: https://goo.gl/cmgVJf
  52. Jones HT, Snowsill T, Haasova M, Coelho H, Crathorne L, et al. (2016) Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model. Health Technol Assess 20: 591–594. Link: https://goo.gl/Vx7tgL
  53. Polsky D, Weinfurt KP, Kaplan B, Kim J, Fastenau J, et al. (2001) An Economic and Quality‐of‐Life Assessment of Basiliximab Vs Antithymocyte Globulin Immunoprophylaxis in Renal Transplantation. Nephrol Dial Transplant 16: 1028–1033. Link: https://goo.gl/9jwVRi
  54. Keown Pa, Balshaw R, Krueger H, Baladi JF (2001) Economic analysis of basiliximab in renal transplantation. Transplantation 71: 1573–1579. Link: https://goo.gl/sQKLHD
  55. Hellemans R, Bosmans JL, Abramowicz D (2017) Induction Therapy for Kidney Transplant Recipients: Do We Still Need Anti‐IL2 Receptor Monoclonal Antibodies? Am J Transplant 17: 22–27. Link: https://goo.gl/nircaF
  56. Emami S, Huang E, Kuo HT, Kamgar M, Bunnapradist S (2012) Multivariate analysis of antibody induction therapy and their associated outcomes in live donor kidney transplantation in the recent era. Clin Transplant 26: 351–358. Link: https://goo.gl/MeVgdV
  57. Tanriover B, Zhang S, MacConmara M, Gao A, Sandikci B, et al. (2015) Induction therapies in live donor kidney transplantation on tacrolimus and mycophenolate with or without steroid maintenance. Clin J Am Soc Nephrol 10: 1041–1049. Link: https://goo.gl/zfcmvy
  58. Gundlapalli S, Rathi M, Kohli HS, Jha V, Sharma A, et al. (2013) Efficacy of basiliximab induction in poorly matched living donor renal transplantation. Indian J Nephrol 23: 409–412. Link: https://goo.gl/wegdXv
  59. Rodrigo C, Sheriff R, Rajapakse S, Lanerolle RD, Sheriff R (2011) A two-year retrospective analysis of renal transplant patients in Sri Lanka. Saudi J Kidney Dis Transpl 22: 174–178. Link: https://goo.gl/P9TNYG
  60. Wiseman AC (2015) Induction therapy in renal transplantation: Why? What agent? What dose? We may never know. Clin J Am Soc Nephrol10: 923–925. Link: https://goo.gl/ifkAib
  61. Cunningham KC, Hager DR, Fischer J, D’Alessandro AM, Leverson GE, et al. (2016) Single-Dose Basiliximab Induction in Low-Risk Renal Transplant Recipients. Pharmacother J Hum Pharmacol Drug Ther 36: 823–829. Link: https://goo.gl/cwNV2s
© 2017 Nalaka G, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
 

Order for reprints


Print Friendly and PDF

Article Alerts

Subscribe to our articles alerts and stay tuned.


Creative Commons License This work is licensed under a Creative Commons Attribution 4.0 International License.