Preemptive Rituximab to Prevent Recurrent Focal Segmental Glomerulosclerosis Post-Transplant
Abstract
Relevance to Topic Area: This proposal specifically targets the Topic Area of Focal Segmental Glomerulosclerosis (FSGS). This proposal also targets the FSGS Area of Encouragement “Development of a curative therapy or treatments to delay or halt the progression of FSGS and/or prevent post-transplant recurrence.” Rationale: FSGS is a progressive chronic kidney disease that accounts for 4% of adults and 12% of children with end-stage kidney disease in the US. Unfortunately, FSGS recurs in the kidney transplant in 30%-50% of patients, leading to poor kidney survival. There are currently no methods to predict who will develop recurrent FSGS or pre-emptive treatments to prevent recurrent FSGS. Recurrent FSGS has been treated with plasmapheresis, a method of removing plasma proteins from the body, or rituximab, a medication that targets certain immune cells known as B-cells, in some patients with mixed results. Our central hypothesis is that recurrent FSGS can be prevented by combination treatment with plasmapheresis and rituximab prior to kidney transplantation. Additionally, we hypothesize that there are clinical and genetic factors that can predict recurrence of FSGS following kidney transplantation. Identification of such factors will lead to personalized immunosuppression pre- and post-transplant. The long-term goal of this work is to improve kidney transplant outcomes in patients with FSGS and to identify risk factors that can predict recurrence. Completion of the specific aims described below has the potential to change clinical practice by confirming the effectiveness of a currently available therapy to prevent recurrent FSGS and to shed light on clinical and genetic risk factors for FSGS recurrence. Specific Aim 1: Conduct a Phase III multicenter, randomized, open label clinical trial to test the hypothesis that rituximab in addition to plasmapheresis prior to kidney transplant in children and adults with FSGS can prevent recurrent disease in the first year. Study Design: We will prospectively enroll adults and children with a primary diagnosis of FSGS who receive a kidney transplant at 20 US transplant centers. All participants will receive one plasmapheresis session prior to kidney transplant. In addition, participants will be randomized 1:1 to receive either rituximab 375mg/m2 following plasmapheresis or no additional therapy. The primary outcome of the trial will be the number of patients with recurrent FSGS at 1 year post-transplant. Specific Aim 2: Determine clinical and genetic risk factors for recurrent FSGS. Study Design: We will collect a DNA sample from 700 patients with a primary diagnosis of FSGS who have received a kidney transplant from 20 North American transplant centers. We will collect clinical information about them and perform genetic analysis to determine whether there are variations in the genome that predict the risk of recurrent disease. Impact: Completion of Aim 1 will determine whether preemptive plasmapheresis combined with rituximab can prevent recurrent FSGS post-transplant. Prevention of recurrent FSGS will lead to longer graft survival in these patients and eliminate or delay the need to return to dialysis. Prolonging graft survival in one patient can save over $72,000/year in dialysis costs alone. Rituximab is commercially available, thus this preemptive therapy could be applied to patients immediately. The long-term goal of this work is to improve kidney transplant outcomes in patients with FSGS. In addition to the individual benefits of prolonged graft survival, prolonging graft survival in the wider FSGS population will reduce the need for future kidney transplants, allowing for scarce donor kidneys to be more widely distributed in the population. Identification of one or more genotypic markers that can predict FSGS recurrence will likely characterize specific biological mechanisms responsible for this devastating complication as well as potential
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810577
Entities
People
- Michelle Rheault
Organizations
- United States Army
- University of Minnesota