Department of Surgery
Transplant Surgery Research
Division of Transplant Surgery Research
Transplant Research Faculty
Currently, there are over 17,000 people on the waiting list for a liver transplant. Unfortunately, slightly over 5,000 livers are available yearly to satisfy this need, leading to hundreds of needless deaths each year. Worsening this problem, nearly one third of donor livers cannot be used due to high levels of fat (steatosis) within the organ. When transplanted, livers with high amounts of steatosis undergo a phenomenon called primary non-function (PNF), which is liver graft failure for reasons other than surgical error or rejection. There is massive hepatocyte necrosis, and ultimately, there is not enough remaining liver mass to sustain life. The current practice is to discard donor livers with high amounts of fat. However, studies have also demonstrated that if these livers are supported well early after surgery, they will have excellent long-term function.
MUSC transplant laboratories, under the direction of Kenneth D. Chavin, have identified two molecules which they believe are ultimately responsible for PNF in steatotic livers. The first, uncoupling protein-2 (UCP2), is upregulated in the mitochondria in situations of substrate excess, as in steatosis, and short-circuits the electron transport chain to deal with the excess reducing potential. However, during periods of stress, such as during liver transplantation, UCP2 prevents cells from being able to produce appropriate amounts of ATP and the cells die of necrosis because of energy deficit. The other molecule, toll-like receptor-4 (TLR4), is the main receptor for LPS. We have shown that removal of LPS with an antibody prior to steatotic liver ischemia/reperfusion dramatically improves the survival rate in steatotic animals. Therefore, we are investigating the surface receptor, TLR4, as a potential therapeutic target to improve the performance of steatotic livers after transplantation. We believe that pharmacological targeting of these two molecules will allow us to use steatotic livers in the future, thereby dramatically improving the liver donor pool. Our current research focuses on using several promising medications targeting TLR4 and UCP2. There are projects underway to re-engineer livers through these two molecules. An additional area of focus is the engineering of liposomes to deliver ATP to cells. This avenue of research will involve perfusion of marginal livers or donor tissue for breast reconstruction with these liposome delivery systems to improve viability of cells, tissue and whole organs and prevent ischemia reperfusion injury.
In addition to basic research, MUSC transplant division, under the direction of Dr. Prabhakar Baliga, conducts many clinical trials. Currently, pre-transplant patients can enroll in various trials including ones to improve graft function in kidney transplant and prevent vasculopathy in cardiac transplant. Post kidney transplant patients can enroll in a study to determine genetic variants and biomarkers predictive of posttransplant adverse effects. At the 2013 American Transplant Congress they had 14 oral and poster presentations. MUSC transplant division continues to be a leader in basic and translational research.
Research in Disparity on Organ Donation. There exists a great disparity between the number of African-Americans on the transplant waiting list and those who undergo living donation. Of the more than 600 patients waiting for kidney donation in South Carolina, 80 percent are African-Americans. After applying the national average to South Carolina, only 15 percent of live organs are donated by African-Americans. It is estimated that more than a quarter of the waiting patients will never receive their much-needed organs. Living organ donation has several important advantages over cadaver donation. Through live donation, the transplant can be scheduled ahead of time, live donated kidneys begin to function immediately after transplantation, and there is improved long term survival.
Under the direction of Dr.’s Prabhakar Baliga and Kenneth Chavin, transplant research at MUSC has been devoted to determining the reason why the disparity between African-Americans needing kidneys and those donating kidneys exists in addition to developing strategies to reduce this discrepancy. This research has been funded for over a decade by the NIH grant “A Program to Increase Living Donations in African Americans”. The current goal of this grant is to test the hypothesis that live kidney donation in African Americans will increase with (1) the utilization of educators who are professionally trained to work with African Americans, (2) early identification and education of African American donors in potentially “high yield” settings, and (3) improved navigation of the African American donors by these educators. Increasing the number of living donors in the AA community will result in more transplants in this racial group which will ultimately improve graft and patient survival and lower waiting times. A past postdoctoral fellow was most recently involved in this work.
Quality Outcome in kidney transplantation. A multidisciplinary quality improvement initiative was developed at MUSC that targeted eliminating these issues. The team developed key initiatives including improved medication reconciliation, development of a diabetes management service, and improved discharge medication dispensing, delivery, education, and scrutiny. Follow-up analysis demonstrated reduced medication discrepancies by >2 per patient and obtaining 100% adherence with reconciliation. Pharmacists reviewed discharge medications, reaching 100% by study end, leading to a 40% reduction in medication safety issues. LOS remained short, and delayed discharges were reduced by 14%; 7-day readmission rates decreased by 50%. Acute rejection and infection rates also significantly decreased. In conclusion, a multidisciplinary quality improvement initiative has improved medication safety in kidney transplant patients, which lead to improved clinical outcomes. The faculty has published 11 papers on transplant quality outcome under the direction of Dr.David J. Taber so far in 2013 alone. These papers include, but are not limited to, how diabetes, Factor VIIa, antithymocyte globulin, pharmacist instructions, medications errors, and team communication effect quality and clinical outcomes post-transplantation. MUSC transplant division will continue its commitment to improve outcomes by improving quality.
Transplant Immunity. The laboratory of Dr. Chenthamarakshan Vasu’s, director of Translational and Transplantation Immunology, is dedicated to understanding the immune tolerance mechanism and developing novel strategies to treat autoimmunity and transplant rejection. There are three projects: 1) Co-stimulation and co-repression in immune tolerance. The primary focus of this project is on understanding the role of signaling through CD28, CTLA-4, PD-1 and BTLA in maintaining peripheral tolerance. These studies can lead to development of effective targeted immunotherapy approaches for autoimmunity and transplant rejection. 2) Innate immune receptors on mucosal immune tolerance: Immune cells in the intestinal mucosa provide first line of defense against microbial invasion. However, these cells are continuously exposed to microbial and food components, and if the immune response is not held in check, then the development of an exaggerated immune response could lead to chronic inflammatory disorders. the project focuses the role of innate immune receptors such as TLR2 and dectin 1 in promoting tolerogenic immune response and/or preventing inflammation. The ultimate goal of this study is to appropriately and safely manipulate the immune response of intestinal mucosa using dietary approaches for treating autoimmunity. 3) Approaches to treat autoimmunity and transplant rejection: Traditional therapeutic approaches for autoimmune diseases and transplant rejection have relied upon administration of immunosuppressive agents which results in global, non-specific attenuation of the immune response with side effects and variable therapeutic outcomes. This project is focused on developing and testing novel antigen specific targeted immune tolerance strategies. The approach is to engineer dendritic cells to manipulate signaling at the immune synapse during antigen presentation.