PURPOSE OF REVIEW: In this review, we discuss achievements in immunosuppression in kidney transplant recipients published at last 18 months. RECENT FINDINGS: Results of recent trials with everolimus in low-risk primary kidney transplant recipients suggest that lowTAC/EVR combination is noninferior and CMV and BKV viral infections are less frequent to standTAC/MPA. Iscalimab monoclonal antibody, which prevents CD40 to CD154 binding, has just recently entered phase II clinical studies in kidney transplantation. Eculizumab, anti-C5 monoclonal antobody was recently shown to improve outcomes in DSA+ living-donor kidney transplant recipients requiring pretransplant desensitization because of crossmatch positivity. Proximal complement C1 inhibition in patients with antibody-mediated rejection was studied in several phase I trials. SUMMARY: Recent knowledge creates a path towards future immunosuppression success in sensitized recipients and in those in high risk of viral infections or CNI nephrotoxicity.

Department of Nephrology Transplant Center

Transplant Laboratory Institute for Clinical and Experimental Medicine Prague Czech Republic

See more in PubMed

Sommerer C, Suwelack B, Dragun D, et al. An open-label, randomized trial indicates that everolimus with tacrolimus or cyclosporine is comparable to standard immunosuppression in de novo kidney transplant patients. Kidney Int 2019; 96:231–244.

Pascual J, Berger SP, Witzke O, et al. TRANSFORM Investigators. Everolimus with reduced calcineurin inhibitor exposure in renal transplantation. J Am Soc Nephrol 2018; 29:1979–1991.

Qazi Y, Shaffer D, Kaplan B, et al. Efficacy and safety of everolimus plus low-dose tacrolimus versus mycophenolate mofetil plus standard-dose tacrolimus in de novo renal transplant recipients: 12-month data. Am J Transplant 2017; 17:1358–1369.

Tedesco-Silva H, Pascual J, Viklicky O, et al. TRANSFORM Investigators. Safety of everolimus with reduced calcineurin inhibitor exposure in de novo kidney transplants: an analysis from the randomized TRANSFORM Study. Transplantation 2019; 103:1953–1963.

Berger SP, Sommerer C, Witzke O, et al. TRANSFORM investigators. Two-year outcomes in de novo renal transplant recipients receiving everolimus-facilitated calcineurin inhibitor reduction regimen from the TRANSFORM study. Am J Transplant 2019; 19:3018–3034.

Ferreira AN, Felipe CR, Cristelli M, et al. Prospective randomized study comparing everolimus and mycophenolate sodium in de novo kidney transplant recipients from expanded criteria deceased donor. Transpl Int 2019; 32:1127–1143.

Chadban S, Tedesco-Silva H. ATHENA: wisdom and warfare in defining the role of de novo mTOR inhibition in kidney transplantation. Kidney Int 2019; 96:27–30.

Archdeacon P, Dixon C, Belen O, et al. Summary of the US FDA approval of belatacept. Am J Transplant 2012; 12:554–562.

Vincenti F, Rostaing L, Grinyo J, et al. Belatacept and long-term outcomes in kidney transplantation. N Engl J Med 2016; 374:333–343.

Woodle ES, Kaufman DB, Shields AR, et al. BEST Study Group. Belatacept-based immunosuppression with simultaneous calcineurin inhibitor avoidance and early corticosteroid withdrawal: a prospective, randomized multicenter trial. Am J Transplant 2020; 20:1039–1055.

Burghuber CK, Manook M, Ezekian B, et al. Dual targeting: combining costimulation blockade and bortezomib to permit kidney transplantation in sensitized recipients. Am J Transplant 2019; 19:724–736.

Parsons RF, Zahid A, Bumb S, et al. The impact of belatacept on third-party HLA alloantibodies in highly sensitized kidney transplant recipients. Am J Transplant 2020; 20:573–581.

Kumar D, Raynaud M, Chang J, et al. Impact of belatacept conversion on renal function, histology and gene expression in kidney transplant patients with chronic active antibody-mediated rejection. Transplantation 2020; [Epub ahead of print].

Kim SC, Wakwe W, Higginbotham LB, et al. Fc-silent anti-CD154 domain antibody effectively prevents nonhuman primate renal allograft rejection. Am J Transplant 2017; 17:1182–1192.

Espie P, He Y, Koo P, et al. First-in-human clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody. Am J Transplant 2020; 20:463–473.

Cernoch M, Viklicky O. Complement in kidney transplantation. Front Med (Lausanne) 2017; 4:66.

Legendre CM, Licht C, Muus P, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 2013; 368:2169–2181.

Glotz D, Russ G, Rostaing L, et al. C10-002 Study Group. Safety and efficacy of eculizumab for the prevention of antibody-mediated rejection after deceased-donor kidney transplantation in patients with preformed donor-specific antibodies. Am J Transplant 2019; 19:2865–2875.

Marks WH, Mamode N, Montgomery RA, et al. C10-001 Study Group. Safety and efficacy of eculizumab in the prevention of antibody-mediated rejection in living-donor kidney transplant recipients requiring desensitization therapy: a randomized trial. Am J Transplant 2019; 19:2876–2888.

Tan EK, Bentall A, Dean PG, et al. Use of eculizumab for active antibody-mediated rejection that occurs early postkidney transplantation: a consecutive series of 15 cases. Transplantation 2019; 103:2397–2404.

Schinstock CA, Bentall AJ, Smith BH, et al. Long-term outcomes of eculizumab-treated positive crossmatch recipients: allograft survival, histologic findings, and natural history of the donor-specific antibodies. Am J Transplant 2019; 19:1671–1683.

Cornell LD, Schinstock CA, Gandhi MJ, et al. Positive crossmatch kidney transplant recipients treated with eculizumab: outcomes beyond 1 year. Am J Transplant 2015; 15:1293–1302.

Viglietti D, Gosset C, Loupy A, et al. C1 inhibitor in acute antibody-mediated rejection nonresponsive to conventional therapy in kidney transplant recipients: a pilot study. Am J Transplant 2016; 16:1596–1603.

Montgomery RA, Orandi BJ, Racusen L, et al. Plasma-derived C1 esterase inhibitor for acute antibody-mediated rejection following kidney transplantation: results of a randomized double-blind placebo-controlled pilot study. Am J Transplant 2016; 16:3468–3478.

Muhlbacher J, Jilma B, Wahrmann M, et al. Blockade of HLA antibody-triggered classical complement activation in sera from subjects dosed with the anti-C1 s monoclonal antibody TNT009-results from a randomized first-in-human phase 1 trial. Transplantation 2017; 101:2410–2418.

Eskandary F, Jilma B, Muhlbacher J, et al. Anti-C1 s monoclonal antibody BIVV009 in late antibody-mediated kidney allograft rejection-results from a first-in-patient phase 1 trial. Am J Transplant 2018; 18:916–926.

Winstedt L, Jarnum S, Nordahl EA, et al. Complete removal of extracellular IgG antibodies in a randomized dose-escalation phase i study with the bacterial enzyme IdeS--a novel therapeutic opportunity. PLoS One 2015; 10:e0132011.

Jordan SC, Lorant T, Choi J, et al. IgG endopeptidase in highly sensitized patients undergoing transplantation. N Engl J Med 2017; 377:442–453.

Lonze BE, Tatapudi VS, Weldon EP, et al. IdeS (imlifidase): a novel agent that cleaves human IgG and permits successful kidney transplantation across high-strength donor-specific antibody. Ann Surg 2018; 268:488–496.

Aletaha D, Smolen JS. Diagnosis and management of rheumatoid arthritis: a review. JAMA 2018; 320:1360–1372.

Jordan SC, Choi J, Kim I, et al. Interleukin-6, a cytokine critical to mediation of inflammation, autoimmunity and allograft rejection: therapeutic implications of IL-6 receptor blockade. Transplantation 2017; 101:32–44.

Choi J, Aubert O, Vo A, et al. Assessment of tocilizumab (anti-interleukin-6 receptor monoclonal) as a potential treatment for chronic antibody-mediated rejection and transplant glomerulopathy in HLA-sensitized renal allograft recipients. Am J Transplant 2017; 17:2381–2389.

Shin BH, Everly MJ, Zhang H, et al. Impact of tocilizumab (anti-IL-6R) treatment on immunoglobulins and anti-HLA antibodies in kidney transplant patients with chronic antibody-mediated rejection. Transplantation 2020; 104:856–863.

Lavacca A, Presta R, Gai C, et al. Early effects of first-line treatment with antiinterleukin-6 receptor antibody tocilizumab for chronic active antibody-mediated rejection in kidney transplantation. Clin Transplant 2020; 34:e13908.

Perez-Saez MJ, Blasco M, Redondo-Pachon D, et al. Spanish Society of Nephrology COVID-19 Group. Use of tocilizumab in kidney transplant recipients with COVID-19. Am J Transplant 2020; 10:

Weinblatt ME, Mease P, Mysler E, et al. The efficacy and safety of subcutaneous clazakizumab in patients with moderate-to-severe rheumatoid arthritis and an inadequate response to methotrexate: results from a multinational, phase IIb, randomized, double-blind, placebo/active-controlled, dose-ranging study. Arthritis Rheumatol 2015; 67:2591–2600.

Mease PJ, Gottlieb AB, Berman A, et al. The efficacy and safety of clazakizumab, an anti-interleukin-6 monoclonal antibody, in a phase IIb study of adults with active psoriatic arthritis. Arthritis Rheumatol 2016; 68:2163–2173.

Eskandary F, Durr M, Budde K, et al. Clazakizumab in late antibody-mediated rejection: study protocol of a randomized controlled pilot trial. Trials 2019; 20:37.

Navarra SV, Guzman RM, Gallacher AE, et al. BLISS-52 Study Group. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 2011; 377:721–731.

Banham GD, Flint SM, Torpey N, et al. Belimumab in kidney transplantation: an experimental medicine, randomised, placebo-controlled phase 2 trial. Lancet 2018; 391:2619–2630.

Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med 2016; 375:754–766.

van de Donk N, Richardson PG. Malavasi F: CD38 antibodies in multiple myeloma: back to the future. Blood 2018; 131:13–29.

Doberer K, Klager J, Gualdoni GA, et al. CD38 antibody daratumumab for the treatment of chronic active antibody-mediated kidney allograft rejection. Transplantation 2020; [Epub ahead of print].

Kwun J, Matignon M, Manook M, et al. Daratumumab in sensitized kidney transplantation: potentials and limitations of experimental and clinical use. J Am Soc Nephrol 2019; 30:1206–1219.

Bohmig GA, Eskandary F, Doberer K, et al. The therapeutic challenge of late antibody-mediated kidney allograft rejection. Transpl Int 2019; 32:775–788.

See more in PubMed

ClinicalTrials.gov
NCT03221842