Innovative immunosuppression in kidney transplantation: A challenge for unmet needs

Abstract

Due to the optimal results obtained in kidney transplantation and to the lack of interest of the industries, new innovative drugs in kidney transplantation are difficult to be encountered. The best strategy to find the new drugs recently developed or under development is to search in the sections of kidney transplantation still not completely covered by the drugs on the market. These unmet needs are the prevention of delayed graft function (DGF), the protection of the graft over the long time and the desensitization of preformed anti human leukocyte antigen antibodies and the treatment of the acute antibody-mediated rejection. These needs are particularly relevant due to the expansion of some kind of kidney transplantation as transplantation from non-heart beating donor and in the case of antibody-incompatible grafts. The first are particularly exposed to DGF, the latter need a safe desensitization and a safe treatments of the antibody mediated rejections that often occur. Particular caution is needed in treating these drugs. First, they are described in very recent studies and the follow-up of their effect is of course rather short. Second, some of these drugs are still in an early phase of study, even if in well-conducted randomized controlled trials. Particular caution and a careful check need to be used in trials launched 2 or 3 years ago. Indeed, is always necessary to verify whether the study is still going on or whether and why the study itself was abandoned.

Keywords: Anti-human leukocyte antigen antibodies; Delayed graft function; Kidney inflammation; Long-term outcomes; New drugs; Unmet needs in kidney transplantation.

Figure 1

Block of co-stimulation with Belatacept. APC: Antigen presenting cell; T eff: T effector; T reg: Regulatory T cells; PDL1: Programmed cell death receptor ligand 1; CTLA4: Cytotoxic T-lymphocyte-associated antigen 4.

Figure 2

Block of co-stimulation with anti CD28. APC: Antigen presenting cell; T eff: T effector; T reg: Regulatory T cells; PDL1: Programmed cell death receptor ligand 1; CTLA4: Cytotoxic T-lymphocyte-associated antigen 4.

Figure 3

CTOT24 trial.

Figure 4

Drugs acting at different levels to control the antibody formation. BLyS: B Lymphocyte stimulating factor; mAb: Monoclonal antibody; C1-INH: C1 inhibitors; NK: Natural killer; Cp: Complement; FcyR: FcyReceptor; MAC: Membrane attacking complex; MHC: Major histocompatibility complex; IL: Interleukin.

Figure 5

Principal drugs affecting complement. C1-INH: C1 inhibitor; MAC: Membrane attacking complex.

Figure 6

Cleaving intact immunoglobulin G by imlifidase. CDC: Complement dependent cytotoxicity; ADCC: Antibody dependent cell cytotoxicity; F(ab): Fragment ab; Fc: Fragment c; Ides: Imlifidase; IgG: Immunoglobulin G.