Investigational immunosuppressive drugs and approaches in clinical kidney transplantation
- John Vella, MD, FACP, FRCP, FASN
John Vella, MD, FACP, FRCP, FASN
- Associate Professor of Medicine
- Tufts University School of Medicine
The introduction of cyclosporine in the early 1980s improved renal allograft survival by approximately 15 percent at one year posttransplant . However, cyclosporine failed to enhance long-term graft survival because of the inability to suppress the chronic and progressive loss of functioning renal tissue arising from antigen-dependent and -independent immunologic factors [2-4]. (See "Chronic renal allograft nephropathy".)
The administration of cyclosporine or tacrolimus may also exacerbate this process because of direct nephrotoxicity [5,6]. In addition, renal transplant recipients are at risk for significant side effects due to immunosuppression, including infection, cardiovascular disease, hypertension, and malignancy. (See "Cyclosporine and tacrolimus nephrotoxicity".)
These limitations constitute the rationale for the continued development of new immunosuppressive agents [7-11]. This topic will review the status of some of the new drugs that are currently under evaluation for use in renal transplantation.
This section will review those drugs and/or approaches undergoing current investigation.
Eculizimab — Eculizimab is a complement-inhibitory monoclonal antibody that inhibits assembly of the membrane attack complex via C5. The drug is licensed for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. It has been used "off label" to treat refractory antibody-mediated rejection in a very limited number of patients, although with impressive efficacy. Additional study is required before even preliminary recommendations can be made about its administration to transplant recipients. Cost is a major limitation to the use of this agent as it is extraordinarily expensive.
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- UNDER DEVELOPMENT
- Voclosporine (ISA247)
- Sotrastaurin (AEB071)
- Tofacitinib (formerly Tasocitinib [CP690550]) Jak 3 inhibitor
- No maintenance immunosuppression
- STALLED DEVELOPMENT
- Humanized OKT3
- T10B9.1A monoclonal antibody
- Anti-ICAM-1 antibodies
- Anti-LFA-1 antibodies
- Fingolimod (FTY720)
- FK778, metabolite of leflunomide
- SUMMARY AND RECOMMENDATIONS