A new preoperative drug therapy may reduce antibodies in kidney patients better than using traditional methods, according to a three-year clinical trial led by University of Cincinnati transplant researchers. The novel approach may increase patients' candidacy for kidney transplantation and decrease the chances of rejection.
The study, entitled "Prospective Iterative Trial of Proteasome Inhibitor-Based Desensitization" and published in the January 2015 issue of American Journal of Transplantation, shows promise.
The researchers performed a prospective iterative trial of proteasome inhibitor (PI)-based therapy for reducing HLA antibody (Ab) levels. The investigators conducted the trial in five phases that differed in bortezomib-dosing density and plasmapheresis timing.
Each phase included one or two bortezomib cycles (1.3 mg/m(2) × 6-8 doses), one rituximab dose and plasmapheresis. The researchers used solid-phase and flow cytometry (FCM) assays to measure HLA Abs and defined immunodominant Ab (iAb) as highest HLA Ab level.
In all, 44 patients received 52 desensitization courses, with seven participants enrolled in multiple phases. Researchers recorded iAb reductions in 33 of 44 subjects, with reductions persisting for up to 10 months. In Phase 1, the investigators noted a 51.5 percent iAb reduction at 28 days with bortezomib alone.
Immunodominant Ab reductions increased with higher bortezomib dosing densities. The reductions included class I, II and public antigens (HLA DRβ3, HLA DRβ4 and HLA DRβ5). Researchers noted that the FCM medial channel shifts decreased by a mean of 103 ± 54 mean channel shifts (log scale). Out of the 44 participants, 19 showed low acute-rejection rates of only 18.8 percent and de novo DSA formation of 12.5 percent after transplantation.
The research shows that PI-based desensitization therapy durably and consistently reduces HLA Ab levels, potentially providing an alternative to the traditional approach of intravenous immune globulin-based desensitization. This innovative approach could bring a new desensitization strategy to immunized wait-listed patients.
The study's principal investigator, E. Steve Woodle, M.D., UC Health transplant surgeon and director of the division of transplantation at the UC College of Medicine, says that the study is important because it could potentially change the way practitioners approach kidney transplantation.
Woodle says the novel approach may also "benefit 10 to 20 percent of heart and pancreas transplant candidates who often have such high levels of antibodies that transplantation is nearly impossible."
"The rejection rates were low and the chances of the patient developing a new antibody against their kidney were very low. In addition, in some patients, antibodies remained suppressed for several months — something that has not previously been described with other approaches,'' Woodle said.
The University of Cincinnati research team has worked toward developing therapies to target plasma cells since 2008. Many of these novel therapies use bortezomib, a proteasome inhibitor that has already won approval from the FDA for the treatment of multiple myeloma. Traditional methods use intravenous immune globulin (IVIG).
The UC Transplant Clinical Research team expects to evaluate four new regimens in 2015, described by Woodle as "second-generation plasma cell-targeted therapies."
