Humanized Mouse Model as a Novel Approach in the Assessment of Human Allogeneic Responses in Organ Transplantation.

The outcome of organ transplantation is largely dictated by selection of a well-matched donor, which results in less chance of graft rejection. An allogeneic immune response is the main immunological barrier for successful organ transplantation. Donor and recipient human leukocyte antigen (HLA) mismatching diminishes outcomes after solid organ transplantation. The current evaluation of HLA incompatibility does not provide information on the immunogenicity of individual HLA mismatches and impact of non-HLA-related alloantigens, especially in vivo. Here we demonstrate a new method for analysis of alloimmune responsiveness between donor and recipient in vivo by introducing a humanized mouse model. Using molecular, cellular, and genomic analyses, we demonstrated that a recipient's personalized humanized mouse provided the most sensitive assessment of allogeneic responsiveness to potential donors. In our study, HLA typing provided a better recipient-donor match for one donor among two related donors. In contrast, assessment of an allogeneic response by mixed lymphocyte reaction (MLR) was indistinguishable between these donors. We determined that, in the recipient's humanized mouse model, the donor selected by HLA typing induced the strongest allogeneic response with markedly increased allograft rejection markers, including activated cytotoxic Granzyme B-expressing CD8+ T cells. Moreover, the same donor induced stronger upregulation of genes involved in the allograft rejection pathway as determined by transcriptome analysis of isolated human CD45+cells. Thus, the humanized mouse model determined the lowest degree of recipient-donor alloimmune response, allowing for better selection of donor and minimized immunological risk of allograft rejection in organ transplantation. In addition, this approach could be used to evaluate the level of alloresponse in allogeneic cell-based therapies that include cell products derived from pluripotent embryonic stem cells or adult stem cells, both undifferentiated and differentiated, all of which will produce allogeneic immune responses.

A Randomized Trial to Reduce Disparities in Referral for Transplant Evaluation.

Georgia has the lowest kidney transplant rates in the United States and substantial racial disparities in transplantation. We determined the effectiveness of a multicomponent intervention to increase referral of patients on dialysis for transplant evaluation in the Reducing Disparities in Access to kidNey Transplantation Community Study (RaDIANT), a randomized, dialysis facility-based, controlled trial involving >9000 patients receiving dialysis from 134 dialysis facilities in Georgia. In December of 2013, we selected dialysis facilities with either low transplant referral or racial disparity in referral. The intervention consisted of transplant education and engagement activities targeting dialysis facility leadership, staff, and patients conducted from January to December of 2014. We examined the proportion of patients with prevalent ESRD in each facility referred for transplant within 1 year as the primary outcome, and disparity in the referral of black and white patients as a secondary outcome. Compared with control facilities, intervention facilities referred a higher proportion of patients for transplant at 12 months (adjusted mean difference [aMD], 7.3%; 95% confidence interval [95% CI], 5.5% to 9.2%; odds ratio, 1.75; 95% CI, 1.36 to 2.26). The difference between intervention and control facilities in the proportion of patients referred for transplant was higher among black patients (aMD, 6.4%; 95% CI, 4.3% to 8.6%) than white patients (aMD, 3.7%; 95% CI, 1.6% to 5.9%; P<0.05). In conclusion, this intervention increased referral and improved equity in kidney transplant referral for patients on dialysis in Georgia; long-term follow-up is needed to determine whether these effects led to more transplants.

The RaDIANT community study protocol: community-based participatory research for reducing disparities in access to kidney transplantation.

BACKGROUND: The Southeastern United States has the lowest kidney transplant rates in the nation, and racial disparities in kidney transplant access are concentrated in this region. The Southeastern Kidney Transplant Coalition (SEKTC) of Georgia, North Carolina, and South Carolina is an academic and community partnership that was formed with the mission to improve access to kidney transplantation and reduce disparities among African American (AA) end stage renal disease (ESRD) patients in the Southeastern United States. METHODS/DESIGN: We describe the community-based participatory research (CBPR) process utilized in planning the Reducing Disparities In Access to kidNey Transplantation (RaDIANT) Community Study, a trial developed by the SEKTC to reduce health disparities in access to kidney transplantation among AA ESRD patients in Georgia, the state with the lowest kidney transplant rates in the nation. The SEKTC Coalition conducted a needs assessment of the ESRD population in the Southeast and used results to develop a multicomponent, dialysis facility-randomized, quality improvement intervention to improve transplant access among dialysis facilities in GA. A total of 134 dialysis facilities are randomized to receive either: (1) standard of care or "usual" transplant education, or (2) the multicomponent intervention consisting of transplant education and engagement activities targeting dialysis facility leadership, staff, and patients within dialysis facilities. The primary outcome is change in facility-level referral for kidney transplantation from baseline to 12 months; the secondary outcome is reduction in racial disparity in transplant referral. DISCUSSION: The RaDIANT Community Study aims to improve equity in access to kidney transplantation for ESRD patients in the Southeast. TRIAL REGISTRATION: Clinicaltrials.gov number NCT02092727.

Effects of a medication assistance program with medication therapy management on the health of renal transplant recipients.

PURPOSE: The effects of a medication assistance program with medication therapy management (MTM) on the clinical outcomes and health-related quality of life (HQOL) of renal transplant recipients were studied. METHODS: All renal transplant recipients who were enrolled in the Medication Access Program at the Medical College of Georgia for at least one year were included in the study. Patients' demographics, number of graft rejections (for one year pre-enrollment and one year post-enrollment), and diagnoses of hypertension, diabetes, and dyslipidemia were recorded and confirmed by medical and pharmacy records. The use of antihypertensive, antidiabetic, antilipemic, and immunosuppressant agents and laboratory values for fasting blood glucose, glycosylated hemoglobin (HbA(1c)), blood pressure, low-density-lipoprotein (LDL) cholesterol, total cholesterol, triglycerides, and serum immunosuppressant concentrations were identified for one year pre-enrollment and one year post-enrollment. HQOL was measured at the time of enrollment and one year post-enrollment. RESULTS: Thirty-six adult renal transplant recipients were included in the study. All patients had hypertension, 72% had dyslipidemia, and 42% had diabetes. Patients received significantly more antihypertensive agents post-enrollment versus pre-enrollment (p < 0.001) and significantly more antidiabetic agents (p = 0.004) and antilipemics (p = 0.001). Measures of fasting blood glucose, glycosylated hemoglobin, LDL cholesterol, total cholesterol, triglycerides, blood pressure, and number of graft rejections decreased from pre-enrollment levels (p < 0.01). A significantly greater number of patients reached target serum cyclosporine levels post-enrollment versus pre-enrollment (p = 0.008). HQOL was significantly increased one year post-enrollment (p < 0.01). CONCLUSION: A medication assistance program that included MTM services improved medication access, clinical outcomes, and HQOL in renal transplant recipients.

Comparing renal transplant patients' adherence to free cyclosporine and free tacrolimus immunosuppressant therapy.

BACKGROUND: The purpose of this study is to determine if there is a difference in renal transplant patients' (RTPs) adherence to cyclosporine compared to tacrolimus when medications are supplied free to the RTPs. METHODS: Adult primary RTPs were included in the study if they received a renal transplant at the Medical College of Georgia (MCG) from June 1998 through August 2001 and received their first post-transplant year of follow-up care at MCG and free cyclosporine or free tacrolimus from the MCG outpatient pharmacy. Adherence was estimated by comparing each RTPs' tacrolimus or cyclosporine pharmacy refill records to the prescribed regimen for 12 months after transplant. Patients' cyclosporine and tacrolimus serum concentrations were used to validate adherence. Kaplan-Meier analysis was used to estimate the fraction of RTPs remaining adherent and to compare the mean time RTPs were adherent in each group (cyclosporine vs. tacrolimus). RESULTS: Thirty-three RTPs were included in the study, 25 (76%) received cyclosporine and eight received tacrolimus. The mean time to the first non-adherent month was 8 months post-transplant. At 12-months post-transplant, approximately 42% of the patients remained adherent. A greater percentage of the patients who received tacrolimus remained adherent compared with those who were taking cyclosporine (63% vs. 33%, p < 0.05). Approximately 75% of non-adherent patients were found to have subtarget drug concentrations, and only 24% of adherent patients had subtarget levels (p < 0.01). CONCLUSIONS: When provided free, patients are more adherent to tacrolimus than cyclosporine. Regardless of treatment, intensive efforts to increase adherence should be implemented.