HLA-G dimer targets Granzyme B pathway to prolong human renal allograft survival.

Human leukocyte antigen G (HLA-G), a nonclassic HLA class Ib molecule involved in the maintenance of maternal tolerance to semiallogeneic fetal tissues during pregnancy, has emerged as a potential therapeutic target to control allograft rejection. We demonstrate here that the level of soluble HLA-G dimer was higher in a group of 90 patients with a functioning renal allograft compared with 40 patients who rejected (RJ) their transplants. The HLA-G dimer level was not affected by demographic status. One of the potential mechanisms in tissue-organ allograft rejection involves the induction of granzymes and perforin, which are the main effector molecules expressed by CD8+ cytotoxic T lymphocytes and function to destroy allogeneic transplants. Using genomics and molecular and cellular analyses of cells from T-cell-mediated RJ and nonrejected kidney transplant patients, cells from leukocyte Ig-like receptor B1 (LILRB1) transgenic mice, humanized mice, and genetically engineered HLA-G dimer, we demonstrated a novel mechanism by which HLA-G dimer inhibits activation and cytotoxic capabilities of human CD8+ T cells. This mechanism implicated the down-regulation of Granzyme B expression and the essential involvement of LILRB1. Thus, HLA-G dimer has the potential to be a specific and effective therapy for prevention of allograft rejection and prolongation of graft survival.-Ajith, A., Portik-Dobos, V., Nguyen-Lefebvre, A. T., Callaway, C., Horuzsko, D. D., Kapoor, R., Zayas, C., Maenaka, K., Mulloy, L. L., Horuzsko, A. HLA-G dimer targets Granzyme B pathway to prolong human renal allograft survival.

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.

IL-10-producing memory B regulatory cells as a novel target for HLA-G to prolong human kidney allograft survival.

Despite the growing interest in the role of regulatory B cells (Bregs) in autoimmunity, their distinct role and function in kidney transplant outcomes remain elusive. Here, we retrospectively analyzed the proportion of Bregs, transitional Bregs (tBregs) and memory Bregs (mBregs) and their capacity to produce IL-10 in non-rejected (NR) versus rejected (RJ) kidney transplant recipients. In the NR group, we observed a significant increase in the proportion of mBregs (CD19+CD24hiCD27+) but no difference in tBregs (CD19+CD24hiCD38+), as compared to the RJ group. We also observed a significant increase in IL-10-producing mBregs (CD19+CD24hiCD27+IL-10+) in the NR group. As our group and others have previously reported a potential role of the human leukocyte antigen G (HLA-G) in human renal allograft survival, notably through IL-10, we then investigated possible crosstalk between HLA-G and IL-10+ mBregs. Our ex vivo data suggest a role of HLA-G in enhancing IL-10+ mBreg expansion upon stimulation, which further decreased CD3+ T cell proliferation capability. Using RNA-sequencing (RNA-seq), we identified potential key signaling pathways involved in HLA-G-driven IL-10+ mBreg expansion, such as the MAPK, TNF and chemokine signaling pathways. Together, our study highlights a novel HLA-G-mediated IL-10-producing mBreg pathway that may serve as a therapeutic target to improve kidney allograft survival.

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.

HLA-G and humanized mouse models as a novel therapeutic approach in transplantation.

HLA-G is a nonclassical MHC-Class I molecule whose expression, along the feto-maternal barrier contributes towards tolerance of the semiallogeneic fetus during pregnancy. In light of its inhibitory properties, recent research has established HLA-G involvement in mechanisms responsible for directing allogeneic immune responses towards tolerance during allogeneic situations such as organ transplantation. Here, we critically review the data supporting the tolerogenic role of HLA-G in organ transplantation, the various factors influencing its expression, and the introduction of novel humanized mouse models that are one of the best approaches to assess the utility of HLA-G as a therapeutic tool in organ transplantation.

Mentor vs. mentee perceptions of career mentoring partnerships and work outcomes: A multi-institutional study of faculty mentoring programs.

This article was migrated. The article was marked as recommended. Introduction: Formal mentoring programs are a professional development approach to help junior faculty develop an academic medicine career. This study investigated the perceptions of mentors versus mentees in formal career mentoring partnerships across multiple institutions. Methods: The authors implemented departmental mentoring programs for junior faculty at four academic medical centers. They collected post-program data from mentors and mentees in order to examine the predictors of mentoring satisfaction, mentee outcomes, and work-related variables. Results: The pattern of relationships between the variables differed for mentors versus mentees. Mentoring focus, mentor accessibility and mentee initiative predicted partnership satisfaction and mentee progress. Partnerships that used a mentoring agreement reported greater progress and satisfaction. There were some relationships between partnership outcomes and work-related outcomes. While partnership satisfaction predicted job and administrative/leadership satisfaction for mentors, it predicted positive perceptions of the department's mentoring culture and professional development opportunities for mentees. Conclusions: The study identified unique antecedents and consequences of mentoring partnership satisfaction and mentee outcomes. The varying perspectives of mentors versus mentees indicated a need to clearly communicate partnership expectations and desired outcomes. Overall, the positive impact of formal mentoring programs on partnership and work-related outcomes was supported with implications for future programs and research.

Is age associated with the number or types of medications prescribed to renal transplant recipients?

OBJECTIVES: To determine whether age influences the number or types of medications prescribed to younger (aged 18-64) and elderly (aged > or =65) renal transplant recipients 3 years posttransplant. DESIGN: A cross-sectional study involving renal transplant recipients. SETTING: Medical College of Georgia. PARTICIPANTS: A random sample of 100 elderly and 100 younger renal transplant recipients who received posttransplant care at the Medical College of Georgia, were on stable immunosuppressant therapy regimens, and were at least 3 years posttransplant. MEASUREMENTS: Medical and pharmacy data of recipients were evaluated for demographics; presence of a lipid-lowering agent; number of antihypertensives, immunosuppressants, antidiabetic agents, and total medications; number of rejections; dose per kilogram of immunosuppressant(s); infection-related hospitalizations; and measures of blood pressure, blood glucose, serum creatinine, serum tacrolimus/cyclosporine concentrations, total cholesterol, and triglycerides. RESULTS: Elderly recipients were more likely to have diabetes mellitus before the transplant and to develop diabetes mellitus afterwards (P=.04) and were prescribed more total medications (12.40+/-3.72 vs 10.25+/-4.07, P<.001) and antidiabetic agents (0.89+/-0.93 vs 0.42+/-0.77, P<.001) 3 years posttransplant than younger recipients. Elderly recipients also had fewer chronic rejections, more infection-related hospitalizations, lower diastolic blood pressure, and greater fasting blood glucose levels 3 years posttransplant (P<.05) than younger recipients. CONCLUSION: Future investigation should focus on deciphering the implications of the greater numbers of medications prescribed to elderly renal transplant recipients in terms of maximizing desired health outcomes (e.g., graft survival) and minimizing adverse drug-related experiences (e.g., infection).

Fibromuscular dysplasia: an uncommon cause of secondary hypertension.

Fibromuscular dysplasia is a noninflammatory vascular disease that commonly affects the distal two thirds of the renal artery and branch vessels, but occasionally involves other arteries. Progression of stenosis occurs in 16%-38% of renal arteries. Although the etiology is unknown, genetic studies suggest a relationship to the angiotensin-converting enzyme I allele. Thin, young Caucasian women without a family history of hypertension are most commonly affected. An abdominal or flank systolic-diastolic bruit is an important clue for the diagnosis. Most noninvasive screening tests are not sensitive or reproducible to be used to rule out renal artery stenosis, but digital subtraction renal angiography usually confirms the diagnosis. Percutaneous renal artery angioplasty is the treatment of choice, but may not result in normalization of blood pressure if diagnosis is delayed. Since restenosis occurs, continued follow-up is necessary.

Mouse models for studies of HLA-G functions in basic science and pre-clinical research.

HLA-G was described originally as a tolerogenic molecule that allows the semiallogeneic fetus to escape from recognition by the maternal immune response. This review will discuss different steps in the study of HLA-G expression and functions in vivo, starting with analyses of expression of the HLA-G gene and its receptors in transgenic mice, and continuing with applications of HLA-G and its receptors in prevention of allograft rejection, transplantation tolerance, and controlling the development of infection. Humanized mouse models have been discussed for developing in vivo studies of HLA-G in physiological and pathological conditions. Collectively, animal models provide an opportunity to evaluate the importance of the interaction between HLA-G and its receptors in terms of its ability to regulate immune responses during maternal-fetal tolerance, survival of allografts, tumor-escape mechanisms, and development of infections when both HLA-G and its receptors are expressed. In addition, in vivo studies on HLA-G also offer novel approaches to achieve a reproducible transplantation tolerance and to develop personalized medicine to prevent allograft rejection.

Patient factors associated with adherence to immunosuppressant therapy in renal transplant recipients.

PURPOSE: Factors associated with adherence to immunosuppressant therapy (IST) in renal transplant recipients were studied. METHODS: The Immunosuppressant Therapy Adherence Scale (ITAS) was completed by adult renal transplant recipients in Georgia. Those completing the ITAS were classified as adherent to IST if their ITAS score were 12 and nonadherent if their score was less than 12. The relationship between the dichotomized ITAS scores and patient variables that are readily available to clinicians, such as sex, age, kidney donor type, income, marital status, race or ethnicity, and time since transplantation, was assessed. The relationship of ITAS scores to patients' clinical and pharmacy data (e.g., graft rejection, serum IST concentrations, serum creatinine [SCr] concentrations, and pharmacy refill-based adherence rates) was also assessed. RESULTS: One hundred thirty-seven patients completed the ITAS. Eighty-nine patients (65%) were adherent to IST, and the remaining 48 (35%) were nonadherent. Patient sex was unrelated to adherence. Compared with nonadherent patients, adherent patients tended to be younger, to take cyclosporine, to have lower incomes, to have received their transplant more recently, to have targeted immunosuppressant concentrations, to have greater refill-based adherence rates, and to be less likely to exhibit an increase in SCr concentration (p < 0.05). There was no significant difference in the number of rejections between adherent and nonadherent patients. CONCLUSION: Patient age, income, time since transplantation, and the immunosuppressant agent prescribed were associated with IST adherence.

Development and validation of the immunosuppressant therapy adherence instrument (ITAS).

A five-item scale was developed that asked respondents to indicate how often they were non-adherent to immunosuppressant therapy (IST) given a particular circumstance. Two hundred and twenty-two recipients completed the instrument. Validity of the scale was assessed by correlating composite item scores with refill record adherence rates (RRARs), serum immunosuppressant (IS) concentrations, graft rejection, and increased serum creatinine (SCr) levels. One scale item was deleted due to lack of response variability. Cronbach's alpha coefficient for the four-item scale was 0.81, demonstrating that the scale has acceptable reliability. All items loaded on a single principal component, suggesting that the scale measures a single adherence construct, which accounted for 64% of the scale items' variance. The four-item scale, adherence measured by IS RRARs, and "target" IS serum concentrations had positive correlations (p < 0.01). Item scores were shown to be negatively related to rejection occurrence and increased SCr (p < 0.05). The immunosuppressant therapy adherence scale is the first published, valid and reliable instrument that measures recipients IST adherence.

Randomized double-blind study of immunoprophylaxis with basiliximab, a chimeric anti-interleukin-2 receptor monoclonal antibody, in combination with mycophenolate mofetil-containing triple therapy in renal transplantation.

BACKGROUND: Acute rejection remains a major problem in renal transplantation. Immunoprophylaxis with basiliximab (Simulect) has achieved significant reductions in acute rejection episodes in renal allograft recipients receiving dual immunosuppression. This study explored the tolerability and cumulative benefit of combining basiliximab with triple-drug therapy-cyclosporine (USP Modified, Neoral), mycophenolate mofetil, and steroids. METHODS: In a randomized, double-blind, placebo-controlled, multicenter study, 123 kidney transplant recipients received either basiliximab at 20 mg before transplantation (day 0) and 20 mg on day 4 (n=59), or placebo (n=64). All received triple-drug immunosuppression and were followed for 6 months. RESULTS: Tolerability of basiliximab was equivalent to placebo, with no increase in serious adverse events, infection, malignancy, or posttransplant lymphoproliferative disorder. At 6 months, there were trends in favor of basiliximab over placebo in the incidences of first biopsy-confirmed acute rejection (15.3% vs. 26.6%, P=NS) and of acute rejection treated with antibody (5.1% vs. 15.6%, P=NS). Kaplan-Meier estimates at 4 weeks and 6 months were significantly in favor of basiliximab treatment for first acute rejection, biopsy-confirmed rejection, rejection episodes treated with antibody therapy, and treatment failure. Renal function improved more rapidly in the basiliximab group, with mean creatinine clearance at week 2 being 54.7 mL/min versus 43.2 mL/min for placebo (P=0.034). At 12 months, patient survival was 100% in both groups; graft survival was 94.9% with basiliximab and 92.2% with placebo. CONCLUSIONS: Basiliximab immunoprophylaxis is safe, well tolerated, and shows a trend toward reduction in number of acute rejection episodes in renal transplant patients receiving cyclosporine, mycophenolate mofetil, and steroids.

Scleroderma renal crisis.

Abrupt onset of severe uncontrolled hypertension and rapidly progressive oliguric renal failure characterizes scleroderma renal crisis. The etiology is unclear, but very high renin levels are present. While scleroderma is more common in women and whites, there is no difference in the prevalence of scleroderma renal crisis by gender. However, there appears to be a higher prevalence of scleroderma renal crisis among African Americans than whites. Survival was dismal prior to the introduction of the vigorous treatment of hypertension and use of converting-enzyme inhibitors. However, most data on the benefit of these medications are derived from uncontrolled and unblinded studies. Prospective, randomized controlled trials are needed to assess the role of angiotensin receptor blockers. Prevention trials could define the role of various drugs in decreasing the rate of scleroderma renal crisis.

Effect of clinical pharmacy services on the blood pressure of African-American renal transplant patients.

OBJECTIVE: The objective of this study was to determine if African-American renal transplant patients who received direct patient care from a clinical pharmacist had better blood pressure control compared to African-American renal transplant patients who did not have clinical pharmacy services. METHODS: Renal transplant patients were prospectively randomized into an intervention group or a control group. Patients in the intervention group received clinical pharmacy services that included a clinical pharmacist performing patient medication reviews, with emphasis on preventing or resolving medication-related problems and providing medication recommendations. Patients in the control group received routine clinic services, but had no clinical pharmacist interaction. Analysis was performed to detect differences between the intervention and control groups in baseline and quarterly systolic blood pressure (SBP) and diastolic blood pressure (DBP) for one year post-study enrollment. RESULTS: There were no differences between the intervention (N = 13) and control (N = 10) groups in baseline blood pressures or in the percentage of hypertensive patients. Significant differences in the change in SBP and DBP from baseline between the intervention and control groups were observed at the second, third, and fourth quarters of the study, favoring the intervention group (P < .01). Mean SBP was significantly lower in the intervention group at the second (137.8 +/- 15.0 vs 168.9 +/- 15.3), third (135.9 +/- 11.7 vs 164.6 +/- 20.1), and fourth (145.3 +/- 16.8 vs 175.8 +/- 33.9) quarters of the study (P < .05). Mean DBP was significantly lower in the intervention group at the second (76.0 +/- 11.8 vs 84.9 +/- 6.1) and fourth (77.0 +/- 10.2 vs 91.8 +/- 12.0) quarters (P < .05). CONCLUSION: Direct patient care services provided by a clinical pharmacist, in addition to routine clinical services, have a positive effect on the blood pressure of African-American renal transplant patients. A multidisciplinary team that includes a clinical pharmacist is beneficial to patient care.

HLA-G dimers in the prolongation of kidney allograft survival.

Human leukocyte antigen-G (HLA-G) contributes to acceptance of allografts in solid organ/tissue transplantation. Most studies have determined that soluble HLA-G isoforms are systematically detected in serum/plasma of transplanted patients with significantly fewer episodes of acute and/or chronic rejection of allogeneic tissue/organ. Current models of the interactions of HLA-G and its specific receptors explain it as functioning in a monomeric form. However, in recent years, new data has revealed the ability of HLA-G to form disulfide-linked dimeric complexes with high preferential binding and functional activities. Limited data are available on the role of soluble HLA-G dimers in clinical pathological conditions. We describe here the presence of soluble HLA-G dimers in kidney transplant patients. Our study showed that a high level of HLA-G dimers in plasma and increased expression of the membrane-bound form of HLA-G on monocytes are associated with prolongation of kidney allograft survival. We also determined that the presence of soluble HLA-G dimers links to the lower levels of proinflammatory cytokines, suggesting a potential role of HLA-G dimers in controlling the accompanying inflammatory state.

Isoforms of human leukocyte antigen-G and their inhibitory receptors in human kidney allograft acceptance.

Novel therapeutic strategies such as the modulation of dendritic cell and T-cell function have exhibited great potential in clinical transplantation. Human leukocyte antigen (HLA)-G is a molecule that plays a significant role in establishing complex mechanisms to protect semiallogeneic fetuses from rejection by the maternal immune system. The unique characteristics of both cell-surface and soluble isoforms of HLA-G, the formation of disulfide-bonded dimers with the potential to augment inhibitory receptor signaling, and the function of HLA-G as a preferential ligand for the immunoglobulin-like transcript receptors make HLA-G very important in fundamental approaches for the modulation of immune responses to improve allogeneic graft survival in clinical transplantation. Experimental data from several groups as well as our data from experiments involving HLA-G-mediated human tolerogenic dendritic cells in vitro and receptor transgenic mice in vivo indicate that different isoforms of HLA-G have various immunomodulatory effects through the inhibitory receptors. This knowledge is crucial in understanding mechanisms of prolongation of allograft survival. The analyses of HLA-G isoforms and inhibitory receptors in patients with kidney allograft and the relationship among different isoforms of HLA-G, inhibitory receptors, their mediated immunoregulation, and graft acceptance or failure will be discussed here.

Impact of clinical pharmacy services on renal transplant recipients' adherence and outcomes.

The purpose of this article is to provide a description of a clinical pharmacy services program implemented in a renal transplant clinic to improve medication access and adherence as well as health and economic outcomes among renal transplant recipients (RTRs). Following a team-based planning process and an informal survey of RTRs, a clinical pharmacy service intervention was implemented in the Medical College of Georgia renal transplant clinic. As part of the intervention, a clinical pharmacist reviewed and optimized medication therapy, provided instructions on how to take medication, and assisted with enrollment into medication assistance programs. Significant differences were found between RTRs who did and did not receive clinical pharmacy services on measures of adherence, health, economics, and quality of life. Clinical pharmacy services, as described in this article, have a positive impact on renal transplant recipients' medication adherence, health and economic outcomes, and health-related quality of life. The findings described here suggest that clinical pharmacy services are a viable and effective option for improving care for RTRs in an outpatient clinic setting.

Nonmodifiable characteristics associated with nonadherence to immunosuppressant therapy in renal transplant recipients.

PURPOSE: Relationships between adherence to immunosuppressant therapy and adult renal transplant recipients' age, time posttransplant, race, and sex were evaluated to identify factors that predict nonadherence. METHODS: Pharmacy refill data were used to measure adherence. In a primary analysis, stepwise regression was used to assess the relationship between independent variables (age, sex, time posttransplant, and race) and adherence. In a secondary analysis to provide categorical summaries, stepwise regression was used to assess the relationship between independent variables (age quartiles, sex, time posttransplant quartiles, and race) and adherence. RESULTS: In the primary analysis, age and time posttransplant were significant predictors of adherence rate (p < 0.05), with adherence rate decreasing as age and time posttransplant increased. In the secondary analysis, age quartile 4 (>or=60 years) and time posttransplant quartile 1 (