Induction Therapy in Half-Haplotype Low Risk Kidney Transplant Patients: Impact on Acute Rejection, Graft Survival, Infection and Surgical Complications at 3 Years

Maroun M. Abou-Jaoudé^{1, 2,} , Ali H. Moussawi^{1, 3} and Eliane Younes⁴

¹Transplantation Unit, The Middle East Institution of Health, Bsalim, Lebanon

²Lebanese University, Faculty of Medical Sciences, Department of Surgery, Beirut, Lebanon;Nephrology & Transplantation division, Sacré-Coeur Hospital, Brazilia-Baabda, Lebanon

³Lebanese University, Faculty of Medical Sciences, Department of Surgery, Beirut, Lebanon

⁴Nephrology & Transplantation division, Sacré-Coeur Hospital, Brazilia-Baabda, Lebanon

Cite this paper:
Maroun M. Abou-Jaoudé, Ali H. Moussawi and Eliane Younes. Induction Therapy in Half-Haplotype Low Risk Kidney Transplant Patients: Impact on Acute Rejection, Graft Survival, Infection and Surgical Complications at 3 Years. American Journal of Medical Sciences and Medicine. 2019; 7(2):44-53. doi: 10.12691/ajmsm-7-2-5

Abstract

Objective: This retrospective study discusses the need for induction therapy in half haplotype low immunological risk kidney transplant patients. Material and Methods: Records of 70 adult kidney transplant patients were reviewed with 3 years follow up. All patients were half haplotype matched with their living related donors and had PRA < 20% and DSA 0% when available. We divided the patients into 2 groups based on the induction therapy used during kidney transplantation. Hence, we compared 25 patients who were treated by induction therapy (anti-IL2 receptor antibodies or anti-Thymocyte globulin) (Group I) with 45 other patients who did not get any induction therapy (Group II). The primary endpoints comprised the rate and the severity of acute rejection episodes as well as the 3-year graft function and survival. Secondary endpoints contain: the frequency and the type of infections and the surgical complications at 1 year as well as the amount of malignancy and the patient survival at 1, 6, 12 and 36 months after kidney transplantation. Baseline demographic characteristics including: donor age, recipient and donor gender, cause of kidney disease, dialysis duration, donor to recipient CMV matching were similar in the two groups. Whereas, significant differences existed between the 2 groups in relation to: recipient age, pre-transplant hemoglobin blood level, anti-CMV prophylaxis regimen and maintenance immunosuppression. Results: We did not find any significant difference between the 2 groups regarding the length of hospital stay, the rate and severity of acute rejection, the rate of CMV infection, the occurrence of delayed graft function and the rate and type of surgical complications at 1 year. Furthermore, the patient and graft survival as well as the serum creatinine levels upon discharge and at 1, 3, 6, 12 and 36 months were also comparable. Nevertheless, the rate and type of out of Hospital infections and 1-year infection rate as well as the treatment cost were significantly higher in Group I. Conclusion: Induction therapy might not be desirable in low-immunological risk half-haplotype kidney transplant patients.

Keywords:
kidney transplantation induction therapy

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References:

[1]	Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. American Journal of Transplantation 2009; 9(Suppl 3): S1-S157.
[2]	Marcen R. Immunosuppression and renal transplant rejection: review of current and emerging therapies. Clin Invest 2011 1(6), 859-877.
[3]	Hardinger KL, Brennan DC, Klein CL. Selection of induction therapy in kidney transplantation. Transpl Int 2013; 26: 662-672.
[4]	Butler T, Hayde N. Impact of induction therapy on Delayed Graft Function Following Kidney transplantation in Mated Kidneys. Transplant Proc. 2017 Oct;49(8):1739-1742.
[5]	Ekberg H, Tedesco-Silva H, Demirbas A et al. for the ELITE–Symphony Study. Reduced Exposure to Calcineurin Inhibitors in Renal Transplantation. N Engl J Med 2007; December 20; 357: 2562-2575.
[6]	Dharnidharka VR, Naik AS, Axelrod et al. Center practice drives variation in choice of US kidney transplant induction therapy: a retrospective analysis of contemporary practice. Transpl Int. 2018 Feb; 31(2): 198-211.
[7]	Grenda R. Biologics in renal transplantation. Pediatr Nephrol 2015; 30: 1087-1098.
[8]	Ramirez C.B., Marino I.R. The role of basiliximab induction therapy in organ transplantation. Expert Opin. Biol. Ther. 2007; 7: 137-148.
[9]	Novartis Pharmaceutical Corporation Simulect® (basiliximab): Summary of product characteristics. [(accessed on 11 November 2013)]. Available online: www.pharma.us.novartis.com.
[10]	Mottershead M., Neuberger J. Daclizumab. Expert Opin. Biol. Ther. 2007; 7: 1583-1596.
[11]	Deeks E.D., Keating G.M. Rabbit antithymocyte globulin (thymoglobulin): A review of its use in the prevention and treatment of acute renal allograft rejection. Drugs. 2009; 69: 1483-1512.
[12]	Wagner SJ and Brennan DC. Induction therapy in renal transplant recipients: How convincing is the current evidence? Drugs 2012; 72(5), pp. 671-683.
[13]	Kaisike B.L., Kukla A, Thomas D et al. Lymphoprolifertaive disorders after adult kidney transplant: epidemiology and comparison of registry report with claims-based diagnoses. Am J Kidney Dis, 58 (2011), pp 971-980.
[14]	Razonable RR. Strategies for managing cytomegalovirus in transplant recipients. Expert Opin Pharmacother. 2010; 11: 1983-1997.
[15]	F. Luan FL. Six-month low-dose valganciclovir prophylaxis in cytomegalovirus D+/R- kidney transplant patients receiving thymoglobulin induction. Transplant Proc. 2013; 45: 175-177.
[16]	Requião-Moura LR, Ferraz E, Matos AC et al. Comparison of long-term effect of thymoglobulin treatment in patients with a high risk of delayed graft function. Transplant Proc. 2012; 44: 2428-2433.
[17]	Shanfield, I. (1972). New experimental methods for implantation of ureter in bladder and conduit. Transplant. Proc. 4, 637.
[18]	Padiyar A, Akoum FH, Hricik DE. Management of the kidney transplant recipient. Prim Care 2008; 35: 433-506.
[19]	Maki DG, Weise CE, Sarafin HW. A semi-quantitative culture method for identifying intravenous-catheter-related infection. N Engl J Med 1977; 296: 1305-9.
[20]	Solez K et al. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant. 2008 Apr; 8(4): 753-60.
[21]	Chapal M, Foucher Y, Marguerite M et al. PREventing Delayed Graft Function by Driving Immunosuppressive InduCtion Treatment (PREDICT-DGF): study protocol for a randomized controlled trial. Trials. 2015; 16: 282.
[22]	Padiyar A, Augustine JJ, Hricik DE. Induction antibody therapy in kidney transplantation. Am J Kidney Dis 2009; 54: 935-944.
[23]	Mohty M. Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia 2007; 21: 1387-1394.
[24]	Mohty M, Bacigalupo A, Saliba F et al. New directions for rabbit antithymocyte globulin (Thymoglobulin®) in solid organ transplants, stem cell transplants and autoimmunity. Drugs 2014; 74: 1605-1634.
[25]	Bumgardner GL, Hardie I, Johnson RW et al. Phase III Daclizumab Study Group. Results of 3-year phase III clinical trials with daclizumab prophylaxis for prevention of acute rejection after renal transplantation. Transplantation. 2001; 72: 839-845.
[26]	Saran R, Li Y, Robinson B et al. US Renal Data System 2014 Annual Data Report: Epidemiology of Kidney Disease in the United States. Am J Kidney Dis 2015; 65(6 Suppl 1): A7.
[27]	Brennan DC, Daller JA, Lake KD et al. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med 2006; 355: 1967-1977.
[28]	Noel C, Abramowicz D, Durand D et al. Daclizumab versus antithymocyte globulin in high-immunological-risk renal transplant recipients. J Am Soc Nephrol 2009; 20: 1385-1392.
[29]	Wagner SJ, Brennan DC. Induction therapy in renal transplant recipients: how convincing is the current evidence? Drugs 2012; 72: 671-683.
[30]	Heemann U, Abramowicz D, Spasovski G et al. Endorsement of the Kidney Disease Improving Global Outcomes (KDIGO) guidelines on kidney transplantation: a European Renal Best Practice (ERBP) position statement. Nephrol Dial Transplant 2011; 26: 2099-2106.
[31]	Kidney Disease: Improving Global Outcomes Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9(Suppl 3): S1-S155.
[32]	Webster AC, Ruster LP, Mc Gee R et al. Interleukin 2 receptor antagonists for kidney transplant recipients. Cochrane Database Syst Rev 2010; CD003897.
[33]	OPTN/SRTR Annual Report 2012. http://srtr.transplant.hrsa.gov/annual_reports/2012/pdf/2012_SRTR_ADR.pdf.
[34]	Ekberg H, Tedesco-Siva H, Demirbas A et al. ELITE-Symphony Study. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007; 357: 2562-2575.
[35]	Meier-Kriesche HU, Schold JD, Srinivas TR et al. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant 2004; 4: 378-383.
[36]	Gralla J, Wiseman AC. The impact of IL2-RA induction therapy in kidney transplantation using tacrolimus and mycophenolate based immunsuppression. Transplantation 2010; 90: 639-644.
[37]	Willoughby LM, Schnitzler MA, Brennan DC et al. early outcomes of thymoglobulin and basiliximab induction in kidney trasnplantation: Application of statistical approaches to reduce bias in observational comparisons. Transplantation 2009; 87: 1520-1529.
[38]	Tanriover B, Zhang S, MacConmara M et al. Induction therapies in live donor kidney transplantation on tacrolimus and mycophenolate with or without steroid maintenance. Clin J Am Soc Nephol 2015; 10:1041-1049.
[39]	Lim WH, Chadban SJ, Campbell S et al. Interleukin-2 receptor antibody does not reduce rejection risk in low immunological risk or tacrolimus-treated intermediate immunological risk renal transplant recipients. Nephrology 2010; 15: 368-376.
[40]	Opelz G, Unterrainer C, Susal C et al. Efficacy and safety of antibody induction therapy in the current era of kidney transplantation. Nephrol Dial Transplant. 2016; 31(10): 1730-1738.
[41]	Albano L, Banas B, Klempnauer JL et al. Optimizing immunosuppression after kidney transplantation with ADVAGRAF study group. OSAKA trial: A randomized, controlled trial comparing tacolimus OD and BD in kidney transplantation. Transplantation 2013; 96: 897-903.
[42]	Bunnapradist S, Hong A, Lee B et al. Multivariate analysis of the effectiveness of using antibody induction therapy according to the degree of HLA mismatches. Transplant Proc. 2005; 37(2): 886-888.
[43]	Hardinger KL, Schnitzler MA, Koch MJ et al. Thymoglobulin induction is safe and effective in live-donor renal transplantation: a single center experience. Transplantation 2006; 81: 1285.
[44]	Miller JT, Collins CD, Stuckey LJ et al. Clinical and economic outcomes of rabbit antithymocyte globulin induction in adults who received kidney transplants from living unrelated donors and received cyclosporine-based immunosuppression. Pharmacotherapy 2009; 29: 1166.
[45]	Schenker P, Ozturk A, Vonend O et al. Single-dose thymoglobulin induction in living-donor renal transplantation. Ann Transplant 2011; 16: 50.
[46]	Hardinger KL, Schnitzler MA, Koch MJ et al. Thymoglobulin induction is safe and effective in live-donor renal transplantation: a single center experience. Transplantation 2006; 81: 1285].
[47]	Miller JT, Collins CD, Stuckey LJ et al. Clinical and economic outcomes of rabbit antithymocyte globulin induction in adults who received kidney transplants from living unrelated donors and received cyclosporine-based immunosuppression. Pharmacotherapy 2009; 29: 1166].
[48]	Lim WH, Chang SH, Chadban SJ et al. Interleukin-2 receptor antibody reduces rejection rates and graft loss in live-donor kidney transplant recipients. Transplantation 2009; 88: 1208].
[49]	Molnar MZ, Czira M, Ambrus C et al. Anemia is associated with mortality in kidney transplanted patients: A prospective cohort study. Am J Transplant 2007; 7: 818-824.
[50]	Hellemans R, Bosmans JL and Abramowicz D. Induction therapy for kidney transplant recipients: Do we still need Anti-IL2 receptor monoclonal antibodies?. Am J Transplant 2016; 10: 1-6.
[51]	Rostaing L, Charpentier B, Glyda M et al. Alefacept combined with tacrolimus, mycophenolate mofetil and steroids in de novo kidney transplantation: A randomized controlled trial. Am J Transplant 2013; 13: 1724-1733.
[52]	Webster AC, Ruster LP, McGee R et al. Interleukin 2 receptor antagonists for kidney transplant recipients. Cochrane Database Syst Rev 2010; CD003897.
[53]	Mourad G, Garrigue V, Squifflet JP et al. Induction versus noninduction in renal transplant recipients with tacrolimus‐based immunosuppression. Transplantation 2001; 72: 1050-1055.
[54]	Charpentier B, Rostaing L, Berthoux F et al. A three‐arm study comparing immediate tacrolimus therapy with antithymocyte globulin induction therapy followed by tacrolimus or cyclosporine A in adult renal transplant recipients. Transplantation 2003; 75: 844-851.
[55]	Owers DS, Webster AC, Strippoli GF et al. Pre‐emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst Rev2013; 2: CD005133.
[56]	Opelz G, Naujokat C, Daniel V et al. Disassociation between risk of graft loss and risk of non‐Hodgkin lymphoma with induction agents in renal transplant recipients. Transplantation 2006; 81: 1227-1233.
[57]	Kirk AD, Cherikh WS, Ring M et al. Dissociation of depletional induction and posttransplant lymphoproliferative disease in kidney recipients treated with alemtuzumab. Am J Transplant 2007; 7: 2619-2625.
[58]	Hertig A, Zuckermann A. Rabbit antithymocyte globulin induction and risk of post‐transplant lymphoproliferative disease in adult and pediatric solid organ transplantation: An update. Transpl Immunol2015; 32: 179-187.
[59]	Caillard S, Lamy FX, Quelen C et al. French Transplant Centers. Epidemiology of posttransplant lymphoproliferative disorders in adult kidney and kidney pancreas recipients: Report of the French registry and analysis of subgroups of lymphomas. Am J Transplant 2012; 12: 682-693.
[60]	Hall EC, Engels EA, Pfeiffer RM et al. Association of antibody induction immunosuppression with cancer after kidney transplantation. Transplantation 2015; 99: 1051-1057.
[61]	Marks WH, Ilsley JN, Dharnidharka VR. Posttransplantation lymphoproliferative disorder in kidney and heart transplant recipients receiving Thymoglobulin: A systematic review. Transplant Proc 2011; 43: 1395-1404.
[62]	Bustami RT, Ojo AO, Wolfe RA et al. Immunosuppression and the risk of post‐transplant malignancy among cadaveric first kidney transplant recipients. Am J Transplant 2004; 4: 87-93.
[63]	Erickson KF, Winkelmayer WC, Busque S et al. A Cost Analysis of Tolerance Induction for Two-Haplotype Match Kidney Transplant Recipients. American Journal of Transplantation 2016; 16: 371-373.
[64]	Heemann U, Abramowicz D, Spasovski G et al. Endorsement of the Kidney Disease Improving Global Outcomes (KDIGO) guidelines on kidney transplantation: a European Renal Best Practice (ERBP) position statement. Nephrol Dial Transplant 2011; 26: 2099-2106.