"Continue FK, MMF, pred."
Most nephrologists learn early in their training that the most common immunosuppressant regimen for patients with a kidney transplant consists of a calcineurin inhibitor (CNI), mycophenolic acid (usually mycophenolate mofetil [MMF]), with or without some corticosteroid. Let’s take a quick look at two emerging outside-the-box immunosuppression tools.
The new kid on the block
CNIs have long been a thorn in kidney transplantation’s side—with a laundry list of adverse effects ranging from tremors to electrolyte disturbances to paradoxical nephrotoxicity (1). One newer drug that has provided a CNI-free option in some patients is belatacept (approved by the US Food and Drug Administration [FDA] in 2011 for use in kidney transplantation), a fusion protein of the Fc fragment of human immunoglobulin G1 (IgG1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that interrupts the co-stimulatory step or “signal 2” of T cell activation. An analysis of efficacy and safety outcomes of the open-label Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT) study at 7 years (2), although not perfect, found higher patient and graft survival and mean estimated glomerular filtration rate (eGFR) in the belatacept group when compared to cyclosporine (despite higher rates of acute rejection in the belatacept groups). Belatacept is given as monthly infusions and provides a potential CNI alternative in patients with evidence of CNI toxicity or who experience challenges with adherence. Belatacept has been used for both induction and maintenance immunosuppression in kidney transplantation, with practices varying by transplant center (3−6).
Pesky plasma cells
Long-lived plasma cells (LLPCs) are terminally differentiated B cells arising from germinal centers that produce antibodies. LLPCs play a key role in antibody-mediated rejection (AMR) of the kidney transplant. Unfortunately, mainstays of AMR treatment, including intravenous Ig, plasmapheresis, and rituximab, are unable to target the majority of mature plasma cells (PCs) that do not express CD20 (8). Bortezomib, a first-generation proteasome inhibitor with a long track record in myeloma therapy, has been shown to reduce antibody levels before or after transplantation by inducing PC apoptosis (9). Carfilzomib, a second-generation proteasome inhibitor with minimal neurotoxicity (as opposed to bortezomib), has demonstrated efficacy in LLPC elimination and reduced antibody levels, although antibody rebound was also observed (10). The use of proteasome inhibitors to target LLPCs represents a needed advance in the treatment of AMR, as the persistence of LLPCs presents an ongoing challenge in improving long-term allograft survival. An improved understanding of PC biology, including its generation and survival, has allowed for development of and trials of newer therapies, including chemokine and cytokine antagonism (10).
Advances in immunosuppression that result from our better understanding of immune biology have the potential to improve allograft outcomes by either providing less toxic immunosuppressant options or allowing options to treat rejection more effectively.
References
- 1.↑
Farouk SS , Rein JL . The many faces of calcineurin inhibitor toxicity—What the FK? Adv Chronic Kidney Dis 2020; 27:56–66. doi: 10.1053/j.ackd.2019.08.006
- 2.↑
Vincenti F , et al. Belatacept and long-term outcomes in kidney transplantation. N Engl J Med 2016; 374:333–343. doi: 10.1056/NEJMoa1506027. Erratum in: N Engl J Med 2016; 374:698. doi: 10.1056/NEJMx160003
- 3.
Adams AB , et al. Belatacept combined with transient calcineurin inhibitor therapy prevents rejection and promotes improved long-term renal allograft function. Am J Transplant 2017; 17:2922–2936. doi: 10.1111/ajt.14353
- 4.
Cicora F , et al. Belatacept-based, ATG-Fresenius-induction regimen for kidney transplant recipients: A proof-of-concept study. Transpl Immunol 2015; 32:35–39. doi: 10.1016/j.trim.2014.10.002
- 5.
Kumar D , et al. Belatacept as an alternative to calcineurin inhibitors in patients with solid organ transplants. Front Med (Lausanne) 2017; 4:60. doi: 10.3389/fmed.2017.00060
- 6.
Ferguson R , et al. Immunosuppression with belatacept-based, corticosteroid-avoiding regimens in de novo kidney transplant recipients. Am J Transplant 2011; 11:66–76. doi: 10.1111/j.1600-6143.2010.03338.x
- 7.
Radbruch A , et al. Competence and competition: The challenge of becoming a long-lived plasma cell. Nat Rev Immunol 2006; 6:741–750. doi: 10.1038/nri1886
- 8.↑
Ajaz B , et al. Plasma cell CD20 expression: Primary aberrant expression or receptor up-regulation. Leuk Lymphoma 2014; 55:444−446. doi: 10.3109/10428194.2013.802782
- 9.↑
Lee J , et al. The effect of bortezomib on antibody-mediated rejection after kidney transplantation. Yonsei Med J 2015; 56:1638–1642. doi: 10.3349/ymj.2015.56.6.1638
- 10.↑
Woodle ES , et al. Plasma cell targeting to prevent antibody-mediated rejection. Am J Transplant 2020; 20:33–41. doi: 10.1111/ajt.15889
