Role of Bortezomib in Kidney Transplantation

1. Role of Bortezomib in Kidney Transplantation Reference: Raghavan R, Jeroudi A, Achkar K, et al. Bortezomib in kidney transplantation. J Transplant. 2010;1–6.

2. In most stage five chronic kidney disease patients, transplantation has been observed to be the common treatment of choice. In sensitized patients with any panel reactive antibody (PRA) level, it is difficult to carry out transplantation, and thus these patients have to wait longer prior to transplantation. The process of removing or reducing preformed antibodies in such candidates is known as desensitization. The two desensitization protocols backed by proven clinical efficacy include highdose intravenous immunoglobulin (IVIG) or low-dose IVIG with either plasmapheresis (PP) or immunoadsorption.

3. Although existing therapies for treatment of antibodymediated rejection (AMR) and pretransplant desensitization have recorded some success, they do not particularly reduce plasma cells producing antihuman leukocyte antigen antibodies (see Fig. 1). The role of plasma cells in mediating humoral rejection has not been effectively addressed. Bortezomib, a proteasome inhibitor, which has been approved for the treatment of multiple myeloma, could be considered as an alternative option to deplete plasma cells through proteasome inhibition.

5. The Biological Effect of Bortezomib Bortezomib, which was first synthesized in 1995, is an FDA approved drug for the treatment of multiple myeloma, a plasma cell dyscrasia. Since 2005, Bortezomib has been used off label in the transplantation setting to lower donorspecific antibodies (DSAs) in highly sensitized patients and in AMR as an adjunct therapy. Bortezomib (C19H25BN4O4) has a central boron atom that unites the catalytic site of the 26S proteasome with high specificity and affinity.

6. Bortezomib’s interference with nuclear factor kappa B (NFkB) (regulatory protein) and IkB (transcription factor) leads to the accretion and aggregation of unfolded proteins and ultimate apoptosis of plasma cell. Bortezomib indirectly affects the circulating B cells and TH cells. The drug may lead to T-cell cycling blockade, thereby causing apoptosis of TH cells and lowering of bone marrow interleukin-6 that may decrease the B-cell numbers.

7. Bortezomib Pharmacokinetics,Pharmacodynamics, and Side-Effects Bortezomib has a rapid and broad distribution, hepatic cytochrome P-450 (CYP) isoenzyme metabolism and an extended elimination half life. Following a fast distribution half life of about 10 min, peak plasma bortezomib concentrations vary from 60 to 120 ng/mL after repeated doses of 1–1.3 mg/m2. Total body clearance reduces from 102 to 112 L/h after the initial dose and from 15 to 32 L/h following repeated doses. Subsequent elimination half-life ranges from 40 to 190 h.

8. Following intravenous bortezomib administration, the highest percentage of 20S proteasome inhibition is observed after 5 min, reaching a mean of 70−84% inhibition. Bortezomib-related adverse effects reported in phase II and phase III studies include neurotoxicity, thrombocytopenia, and other common side-effects like nausea, diarrhea, fatigue, and mild gastrointestinal disturbances. The Bortezomib dosing is similar irrespective of the route of administration. The drug does not require hepatic or renal dosing alterations, and the drug is not detectable within 30 min of injection.

9. Bortezomib Use in Kidney Transplantation There are numerous published case reports and series detailing bortezomib’s use in kidney transplantation. Studies suggest that bortezomib can be employed to reduce donor specific antibodies (DSA) levels with minimal toxicity. The drug may also have a role in reducing complement fixation. However, owing to bortezomib’s mild effect on PRA for pretransplant desensitization, it may indicate the need for adjunct modalities that target antibodies such as PP and IVIG, and further investigation of bortezomib in transplant desensitization.

10. Studies also back the use of bortezomib in rejection protocols. It has been observed that bortezomib therapy aids in prompt rejection reversal (within days to weeks) and improved renal function and reduction in DSA levels. Bortezomib has also shown efficacy in lowering bone marrow plasma cells, antibody production (including DSA), and number of plasma cell allospecificities in the bone marrow aspirates. Bortezomib-based regimens could be an advantageous adjunct therapy option in the acute AMR setting, as compared to common modalities like PP.

11. Conclusion The ability of bortezomib in targeting the antibody-producing plasma cell has evoked the use of it in pretransplant desensitization and in an AMR setting. Bortezomib offers potential insight into kidney transplantation management in highly sensitized patients who are on the kidney transplant waiting list. Novel therapeutic modalities targeting the DSA reduction and management of AMR could offer opportunities for these patients. However, limited use of bortezomib in such settings may be an issue of concern. In addition, the use of bortezomib along with other accepted desensitization modalities like PP, IVIG, and rituximab may make it difficult to tease out bortezomib’s role in transplant desensitization and treatment of AMR. As more and more clinical data and well-designed clinical trials become available bortezomib’s role in transplant desensitization will be elucidated better.