Clinical Trials

The study is designed to assess the impact of in vivo treatment of bortezomib on anti-HLA production by normal antibody secreting cells (ASC) in sensitized renal allograft candidates.  The design involves in vivo treatment with bortezomib for one 4 dose cycle (days 1, 4, 8 and 11).  Using novel assays, anti-HLA production is determined by bone marrow derived ASC at baseline (prior to therapy) and after treatment (at day 14, 3 days after the last bortezomib dose).  Paired data are used with patients serving as their own controls. Finally, the safety of bortezomib is evaluated by monitoring total serum antibody levels and the incidence of side effects (primarily neuropathy) at 1 month, the final follow-up point.

Kidney transplantation is a good treatment option for people with kidney disease. However, there is still much to learn about how to best care for the transplanted kidney and keep it working for a long time. One field of interest is how one's cellular make-up might affect the body's immune response (body's natural defense system to illness and foreign things) to a kidney transplant. Cellular tests, like gene expression, help doctors to study a person's cellular traits. Gene expression is when information found in one's DNA is translated into RNA and eventually proteins. These components are present in each of the body's cells. In this study, researchers are trying to learn if certain changes in the RNA and proteins found in blood, urine, or transplant biopsy tissue can detect rejection before injury can occur or become too severe. The blood and urine tests will look for patterns in one's DNA (called genetic markers). This study will follow subjects for 2 years after transplant. There will be a total of 12 study visits with additional study visits if rejection occurs. The study requires additional samples of blood, urine, and tissue to be collected during routine clinical visits and biopsies (a procedure to remove and examine a small piece of kidney tissue).

The purpose of this study is to see if the study drug bortezomib will prevent transplant glomerulopathy in patients who are at a high risk of developing the condition due to high donor-specific alloantibody in post kidney transplant recipients.

The aim of this risk protocol is to determine the variability of the AlloElispot and Allospecificities assay.

     Our group has developed two novel assays to determine:  1) the number of donor-specific alloantibody (DSA) secreting bone marrow derived plasma cells (AlloELISPOT assay); and 2) the function of DSA-secreting Plasma cells (Allospecificities assay).

     These assays were developed over the past 3 years and already have provided an important means of testing new therapeutic protocols aimed at controlling DSA production.  It is important to note that repeated attempts to isolate PCs from peripheral blood have been unsuccessful (PCs are extremely rare in peripheral blood) and the bone marrow is the only accessible source of PCs.

     It is now clear to that we have reached a point that we must validate these assays (coefficient of variation, etc), in order to appropriately evaluate data derived from these assays.  Inter-assay variability can be assessed by performing two paired assays in the same patient.  This could be done in two ways—paired bone marrow aspirations separated by time or two bone marrow aspirations performed at the same time.  We have decided to pursue the latter approach. We will do both marrows either at the time of transplantation when the subjects are under general anesthesia or in the Clinical Research Unit (CRU) using conscious sedation..  We believe that this is safe and will be well-tolerated and will provide the data that we need to validate the assays.

A strongly positive crossmatch has long been considered an absolute contraindication to kidney transplantation and most patients with anti-HLA antibody never were able to receive a kidney transplant. Over the past decade, significant progress has been made in overcoming early antibody-mediated renal allograft injury. Our group has performed more than 200 such transplants providing the possibility of transplant to previously untransplantable patients. Despite our best efforts, transplantation in these patients is still complicated by a high rate of acute humoral rejection.

     Patients included in this study will be those who have demonstrable anti-HLA antibody specific for their living donor.  It is our hypothesis that blockade of terminal complement activation at the time of transplant in combination with our current protocols will reduce the incidence of AHR in patients with anti-donor HLA antibody.

Kidney transplantation is considered the best therapy for patients with end-stage renal disease. In some instances, the only suitable living kidney donor is ABO blood group incompatible. This usually presents a barrier to successful transplantation because most recipients have circulating serum antibodies that bind to incompatible blood groups that will bind and damage the kidney allograft early after transplantation. Fortunately, over the past decade, we and others have developed protocols involving the pretransplant removal of anti-blood group antibodies using multiple plasmapheresis treatments that allow for the successful transplantation of ABOi LDKTx. Thus, this therapy enables patients to receive a living donor with its advantages rather than having to wait >5 years for a deceased donor kidney.