Racial, Ethnic, and Sex Diversity Trends in Health Professions Programs From Applicants to Graduates.

Importance: Diversity is an essential element of an effective health care system. A key to developing a diverse workforce is establishing a diverse student population in health professions programs. Objective: To examine the diversity of students in Doctor of Medicine (MD), Doctor of Osteopathic Medicine (DO), Doctor of Dental Surgery (DDS), Doctor of Dental Medicine (DMD), and Doctor of Pharmacy (PharmD) programs with emphasis on the trends of underrepresented minoritized groups (American Indian or Alaska Native, Black or African American, Hispanic or Latino, and Native Hawaiian or Other Pacific Islander) and sex relative to the overall age-adjusted US population. Design, Setting, and Participants: This cross-sectional study used deidentified, self-reported data from 2003 to 2019 from the Association of American Medical Colleges, American Association of Colleges of Osteopathic Medicine, American Dental Education Association, American Dental Association, and American Association of Colleges of Pharmacy. Data analysis was performed from 2003 to 2004 and from 2018 to 2019. Exposures: Data on the race, ethnicity, and sex of applicants, matriculants, and degrees conferred by health professions programs were collected and compared with the age-adjusted population in the US Census (aged 20-34 years) over time. Main Outcomes and Measures: The main outcomes were trends in the proportions of underrepresented minoritized groups and sex diversity among applicants, matriculants, and degrees conferred relative to the overall age-adjusted US population. Trends were measured using the representation quotient, which is defined as the ratio of the proportion of each subgroup to the total population of applicants, matriculants, or graduates relative to the proportion for that subgroup within the US Census population of similar age. Regression analysis was used to evaluate the trend over time. Results: A total of 594 352 applicants were analyzed across the examined programs. From 2003 to 2019, the proportions of individuals from underrepresented groups increased for DDS and DMD (applicants, from 1003 of 8176 to 1962 of 11 298 [5.1%]; matriculants, from 510 of 4528 to 966 of 6163 [4.2%]; degrees awarded, from 484 of 4350 to 878 of 6340 [2.7%]), PharmD (applicants, from 9045 of 71 966 to 11 653 of 50 482 [9.0%]; matriculants, from 5979 of 42 627 to 10 129 to 62 504 [6.3%]; degrees awarded, from 922 of 7770 to 2190 of 14 800 [3.0%]), and DO (applicants, from 740 of 6814 to 3478 of 21 090 [5.4%]; degrees awarded, 199 of 2713 to 582 of 6703 [1.4%]) programs, but decreased for MD programs (applicants, from 6066 of 34 791 to 7889 of 52 777 [-2.3%]; matriculants, 2506 of 16 541 to 2952 of 21 622 [-2.4%]; degrees awarded, from 2167 of 15 829 to 2349 of 19 937 [-0.1%]). Compared with age-adjusted US Census data, all programs had more Asian students and fewer male, American Indian or Alaska Native, Black or African American, Hispanic or Latino, and Native Hawaiian or Other Pacific Islander students (representation quotient <1). Conclusions and Relevance: In this cross-sectional study, most of the health professions in the study saw increases in underrepresented minority applicants, matriculants, and degrees conferred from 2003 to 2019; however, all programs were below the age-adjusted US Census data. The increased racial, ethnic, and sex diversity in the programs illustrates progress, but additional strategies are needed to achieve a more representative health care workforce.

Belatacept for the prophylaxis of organ rejection in kidney transplant patients: an evidence-based review of its place in therapy.

BACKGROUND: Belatacept is a novel immunosuppressive therapy designed to improve clinical outcomes associated with kidney transplant recipients while minimizing use of calcineurin inhibitors (CNIs). METHODS: We searched for clinical trials related to administration of belatacept to kidney transplant patients compared to various immunosuppression regimens, as well as for studies that utilized data from belatacept trials to validate new surrogate measures. The purpose of this review is to consolidate the published evidence of belatacept's effectiveness and safety in renal transplant recipients to better elucidate its place in clinical practice. RESULTS: Analysis of the results from the Belatacept Evaluation of Nephroprotection and Effi-cacy as First-Line Immunosuppressive Trial (BENEFIT) study, a de novo trial that compared cyclosporine (CsA)-based therapy to belatacept-based therapy in standard criteria donors, found a significant difference in mean estimated glomerular filtration rate (eGFR) of 13-15 mL/min/1.73 m(2) and 23-27 mL/min/1.73 m(2) at 1 year and 7 years, respectively. The BENEFIT-EXT study was similarly designed with the exception that it included extended criteria donors. Renal function improved significantly for the more intensive belatacept group in all years of the BENEFIT-EXT study; however, it was not significant in the less intensive group until 5 years after transplant. Belatacept regimens resulted in lower blood pressure, cholesterol levels, and incidence of new-onset diabetes after transplant compared to CsA-based regimens. Results from conversion of CNIs to belatacept therapy, dual therapy of belatacept with sirolimus, and belatacept with corticosteroid avoidance therapy are also included in this article. CONCLUSION: The evidence reviewed in this article suggests that belatacept is an effective alternative in kidney transplant recipients. Compared to CNI-based therapy, belatacept-based therapy results in superior renal function and similar rates of allograft survival. In terms of safety, belatacept was shown to have lower incidence of hypertension, hyperlipidemia, and diabetes; however, incidence of posttransplantation lymphoproliferative disorder and the cost of belatacept may hinder use of this medication.

Inhibitory interactions between BK and JC virus among kidney transplant recipients.

BK and JC polyomaviruses can reactivate after transplantation, causing renal dysfunction and graft loss. The incidence of JC reactivation after renal transplant is not well understood. Here, we characterized JC reactivation using samples collected during the first year after transplantation from 200 kidney recipients. We detected BK and JC viruses in the urine of 35 and 16% of transplant recipients, respectively. The median viral load in the urine was 400 times higher for BK virus than JC virus. The presence of BK viruria made concurrent JC viruria less likely: JC viruria was detected in 22% of non-BK viruric recipients compared with 4% of BK viruric recipients (P=0.001). The co-detection rate was 1.5%, which is less than the expected 5.6% if reactivation of each virus was independent (P=0.001). We did not observe JC viremia, JC nephropathy, or progressive multifocal leukoencephalopathy. The onset of JC viruria was associated with donor, but not recipient, JC-specific antibody in a titer-dependent fashion and inversely associated with donor and recipient BK-specific antibody. Donor and recipient JC seropositivity did not predict BK viruria or viremia. In conclusion, among renal transplant recipients, infection with one polyomavirus inversely associates with infection with the other.

The influence of bortezomib on donor specific antibody reduction in patients with antibody mediated rejection.

Renal allograft biopsy is the gold standard for monitoring and diagnosing antibody mediated rejection (AMR), yet a biopsy is invasive, expensive, and may result in complications. Monitoring antibodies may aid in diagnosing and monitoring AMR, although many questions remain unanswered regarding the clinical utility of antibody monitoring. The purpose of this review is to examine the influence of bortezomib on reduction of donor specific antibody after AMR in renal transplant recipients. A retrospective review of patients was performed. Patients who received bortezomib after suffering AMR refractory to intravenous immunoglobulin and plasmapheresis from 2009 to 2011 were selected. Seven patients were identified. Three patients had antibodies tested after IVIG treatment with a mean antibody lowering of 29 percent from baseline. Five of the seven patients had antibodies tested after bortezomib treatment and the mean antibody reduction was 47 percent from baseline. Four patients were biopsied after treatment and all were C4d negative. The other three patients were not biopsied. Renal function improved in most patients. One patient returned to dialysis 16 months after transplant and treatment and another patient died with a functioning graft, due to pneumonia five months after transplant and treatment. In these seven cases, the use of intravenous immune globulin, plasmapheresis, and bortezomib appear to decrease antibodies, improve renal function, and reverse histological markers for rejection. Long-term, prospective follow-up is warranted to determine the influence of bortezomib on donor antibody removal, histological changes, and graft survival.

Bortezomib as rescue therapy for antibody mediated rejection: a single-center experience.

Case series have reported the use of bortezomib for treatment of primary and refractory treatment of cell-mediated acute rejection. The purpose of this article is to review a single-center experience with bortezomib used to treat humoral rejection in four transplant recipients. All patients received bortezomib after suffering antibody-mediated rejection refractory to intravenous immunoglobulin and plasmapheresis. Each patient had improved renal function after bortezomib treatment, biopsies became c4d negative in three of the four patients and the level of donor specific antibody reduction was mixed. Adverse drug events were not encountered, although two patients suffered infections, H1N1 pneumonia and cytomegalovirus colitis. In conclusion, these four cases demonstrate the promising use of bortezomib as rescue therapy for antibody mediated rejection. Future research is needed to explore the impact of bortezomib on HLA removal, histological reversal of rejection, and long-term graft function after transplantation.

Bortezomib for acute humoral rejection in two repeat transplant recipients.

Case series have reported the use of bortezomib to remove antibodies in live-donor transplant recipients with HLA alloantibodies and to treat antibody and cell-mediated acute rejection. The purpose of this article is to review a single-center experience with bortezomib used to treat humoral rejection in two sensitized, repeat transplant recipients. Both patients received bortezomib after suffering antibody-mediated rejection refractory to intravenous immunoglobulin and plasmapheresis. Short-term follow-up of the case reports presented here demonstrated that renal function has improved after bortezomib treatment while the immunological outcomes were mixed. In the first case the donor specific antibodies initially decreased, but then rebounded and in the second case the DR antibodies decreased while the DQ antibodies increased slightly. In conclusion, these two cases demonstrate the promising use of bortezomib in antibody mediated rejection. Future research is needed to explore the impact of bortezomib on HLA removal, histological reversal of rejection, and long-term graft function after transplantation.

A prospective, randomized, double-blinded comparison of thymoglobulin versus Atgam for induction immunosuppressive therapy: 10-year results.

BACKGROUND: Use of induction for renal transplantation is controversial because of the concerns about long-term safety and efficacy. METHODS: We compared the safety and efficacy at 10 years among patients randomized to thymoglobulin or Atgam induction in a single center, randomized, double-blinded trial. Quality-adjusted life years (QALYs) were calculated using utility weights. RESULTS: The primary composite endpoint of freedom from death, graft loss, or rejection, "event-free survival," was higher with thymoglobulin compared with Atgam (48% vs. 29%; P=0.011). At 10 years, patient survival (75% vs. 67%) and graft survival (48% vs. 50%) were similar, whereas acute rejection remained lower (11% vs. 42%, P=0.004) in the thymoglobulin group. The incidence of all types of cancer was numerically lower with thymoglobulin compared with Atgam (8% vs. 21%, P=NS). There were no posttransplant lymphoproliferative disorder in the thymoglobulin group and there were two cases in the Atgam group. There were no new cases of cytomegalovirus disease in either group. Mean serum creatinine levels were higher (1.7+/-0.5 mg/dL vs. 1.2+/-0.3 mg/dL; P=0.003) and estimated glomerular filtration rates tended to be lower (49+/-22 mL/min vs. 65+/-19 mL/min; P=0.065) in the thymoglobulin group. There were 0.53 QALYs gained (3.68 thymoglobulin vs. 3.15 Atgam; 16.7% improvement) from thymoglobulin compared with Atgam. CONCLUSIONS: This long-term follow-up showed that thymoglobulin was associated with higher event-free survival and improved QALYs, without increased posttransplant lymphoproliferative disorder or cytomegalovirus disease, compared with Atgam at 10 years.

Health insurance considerations for adolescent transplant recipients as they transition to adulthood.

The advent of improved immunosuppression and enhanced allograft outcomes has resulted in a growing number of patients taking expensive immunosuppression medications for the rest of their lives. Healthcare costs for the majority of transplantation procedures in the USA currently are covered by Medicare, but coverage ends for outpatient immunosuppression medications 36-44 months after transplantation. Two or three immunosuppressive agents typically are included in post-transplant regimens with a total annual cost that can exceed 13,000 dollars. This represents a significant financial burden for families no matter if they have adequate health insurance coverage because of co-payment obligations. Evidence suggests that some patients have reduced immunosuppression doses because of an inability to afford their medication, increasing the risk of graft failure. The purpose of this article was to review these and other issues pertaining to medical insurance coverage and transplantation, particularly for adolescent recipients as they transition to adulthood.

Thymoglobulin induction is safe and effective in live-donor renal transplantation: a single center experience.

BACKGROUND: The relative benefit versus safety of induction therapy in live-donor renal transplant recipients is controversial. This paper presents observational data of live-donor recipients who received Thymoglobulin induction and standard maintenance immunosuppressive therapy. METHODS: Review and analysis of clinic records and electronic databases of live-donor renal transplants that received Thymoglobulin induction from May 1996 through 2003. RESULTS: Data analysis included 214 live-donor recipients (146 related, 68 unrelated) with a mean follow-up of 3.0+/-1.9 years. The average age of recipients was 44+/-13 years, with a majority being Caucasian (86%) and male (64%). Nineteen (9%) received previous transplants. No patients experienced delayed graft function and 10 (5%) developed acute rejection. Overall, predicted five-year patient survival was 96% and graft survival was 82%. The rates of CMV infection (5%), malignancy (3%), and lymphoproliferative disorder (0.5%) were low. When compared to live-donor kidney transplant recipients nationwide, the center cohort demonstrated improved five year patient (96% center versus 90% national, P=0.0326) and graft survival (82% center versus 79% national, P=0.0901), and a lower one-year acute rejection rate (2% center versus 21 % national, P<0.001). CONCLUSIONS: In this analysis, the use of Thymoglobulin in live-donor renal transplantation was associated with an absence of delayed graft function, low acute rejection rates, and high patient and graft survival without increasing the risk of infection or lymphoproliferative disorder.

A randomized, prospective, pharmacoeconomic trial of tacrolimus versus cyclosporine in combination with thymoglobulin in renal transplant recipients.

BACKGROUND: To date, the clinical trials of tacrolimus (TAC) versus cyclosporine modified (CsA), have not defined which agent is more cost-effective for immunosuppression in renal transplant recipients especially in a quadruple immunosuppressive regimen. METHODS: The objective of this randomized, prospective study was to compare the clinical and economic outcomes of TAC versus CsA, in a regimen that consisted of Thymoglobulin induction, an antimetabolite, and prednisone. Between December 2000 and October 2002, 200 patients were enrolled and randomized in a 2:1 fashion (TAC n=134, CsA n=66). RESULTS: At 1 year, acute rejection (4% TAC vs. 6% CsA), patient survival (TAC 99% vs. CsA 100%), and graft survival (95% TAC versus 100% CsA, P=0.059) were similar. Serum creatinine levels were lower in the TAC group compared with the CsA group (1.3+/-0.3 vs. 1.6+/-0.7 mg/dL, P=0.03). The incidence of CMV infection was similar between the groups and two patients, both in the TAC arm, developed malignancy. Anti-hypertensive requirement (32% TAC vs. 32% CsA) and the incidence of posttransplant diabetes mellitus (4% TAC vs. 2% CsA) were similar. Pretransplant, fewer TAC patients received dyslipidemia treatment (40% TAC vs. 67% CsA, P=0.0005), while more CsA patients were able to discontinue these medications posttransplant (absolute change 25% TAC vs. 47% CsA). Total 12-month medication costs were similar (17,723 +/- 11,647 dollars TAC vs. 16,515 +/- 10,189 dollars CsA). CONCLUSIONS: When combined with Thymoglobulin induction, an antimetabolite, and corticosteroids, TAC and CsA are comparable in safety, efficacy, and cost in renal transplantation.

Incidence of BK with tacrolimus versus cyclosporine and impact of preemptive immunosuppression reduction.

Our purposes were to determine the incidence of BK viruria, viremia or nephropathy with tacrolimus (FK506) versus cyclosporine (CyA) and whether intensive monitoring and discontinuation of mycophenolate (MMF) or azathioprine (AZA), upon detection of BK viremia, could prevent BK nephropathy. We randomized 200 adult renal transplant recipients to FK506 (n = 134) or CyA (n = 66). Urine and blood were collected weekly for 16 weeks and at months 5, 6, 9 and 12 and analyzed for BK by polymerase chain reaction (PCR). By 1 year, 70 patients (35%) developed viruria and 23 (11.5%) viremia; neither were affected independently by FK506, CyA, MMF or AZA. Viruria was highest with FK506-MMF (46%) and lowest with CyA-MMF (13%), p = 0.005. Viruria >/= 9.5 log(10) copies/mL was associated with a 3-fold increased risk of viremia and a 13-fold increased risk of sustained viremia. After reduction of immunosuppression, viremia resolved in 95%, without increased acute rejection, allograft dysfunction or graft loss. No BK nephropathy was observed. Choice of calcineurin inhibitor or adjuvant immunosuppression, independently, did not affect BK viruria or viremia. Viruria was highest with FK506-MMF and lowest with CyA-MMF. Monitoring and preemptive withdrawal of immunosuppression were associated with resolution of viremia and absence of BK nephropathy without acute rejection or graft loss.

Five-year follow up of thymoglobulin versus ATGAM induction in adult renal transplantation.

BACKGROUND: One-year results of a randomized, double-blinded trial of Thymoglobulin versus Atgam for induction therapy in renal transplantation revealed that Thymoglobulin was associated with higher event-free survival (94% vs. 63%), less acute rejection (4% vs. 25%), and better graft survival. This article compares the safety and efficacy of Thymoglobulin versus Atgam induction through 5 years. METHODS: Review and analysis of clinic records and electronic databases. RESULTS: At 5 years, event-free survival (73% vs. 33%, P<0.001), graft survival (77% vs. 55%, P=0.047), and freedom from rejection (92% vs. 66%, P=0.007) were higher with Thymoglobulin versus Atgam. No additional cytomegalovirus (CMV) disease occurred after the first year with Thymoglobulin or Atgam (13% vs. 33%, P=0.056). There were two cases of posttransplant lymphoproliferative disorder (PTLD) with the Atgam arm and none with Thymoglobulin. Thymoglobulin was associated with profound lymphopenia at 2 years after transplantation. CONCLUSIONS: Thymoglobulin was associated with higher event-free survival, graft survival, and freedom from rejection without increased PTLD or CMV disease at 5 years compared with Atgam. The prolonged and profound lymphopenia may contribute to the long-term results associated with Thymoglobulin.

Serial measurements of bone density at the lumbar spine do not predict fracture risk after liver transplantation.

Bone disease has emerged as a serious and complex complication after liver transplantation. The purpose of this study is to determine risk factors for fracture and bone loss after liver transplantation. Dual-energy x-ray absorptiometry (DEXA) of the lumbar spine was performed routinely pretransplantation, 6 months posttransplantation, and at yearly intervals thereafter at our center. We followed up patients who underwent transplantation in the past 10 years and compared bone mineral density (BMD) and fracture rate with known risk factors for bone loss in primary transplant recipients who met the inclusion criteria of a pretransplantation DEXA and at least one follow-up DEXA scan postoperatively (n = 153). We observed a 15% (n = 23) prevalence of symptomatic fractures at a mean of 2.2 +/- 1.8 years after transplantation. Change in BMD was greatest from pretransplantation to 6 months posttransplantation (-4.2%; P =.006), then increased at a rate of 1.4% per year. Logistic regression analysis showed an association of fracture risk with several factors, including number of acute rejection episodes (P =.045), smoking (P =.02), and female sex (P =.02). Stepwise logistic regression analysis reported female sex (P =.004) as the only factor associated with fracture after transplantation. Age, time listed for transplantation, race, menopause, chronic renal insufficiency, loss of height, family history of osteoporosis, BMD, and T score did not predict fracture or bone loss after transplantation. In conclusion, serial measurements of BMD at the lumbar spine do not appear to predict fracture risk; however, data suggest that female sex is the strongest predictor of fracture after liver transplantation.

Prospective, pilot, open-label, short-term study of conversion to leflunomide reverses chronic renal allograft dysfunction.

Leflunomide (LEF) is a synthetic isoxazole derivative with anti-inflammatory and antiviral properties, which has been reported to prevent acute rejection and delay progression of chronic allograft nephropathy (CAN) in animal models. We performed a pilot, crossover trial in 22 renal transplant recipients who were converted from azathioprine (AZA) or mycophenolate mofetil (MMF) to LEF in an effort to slow progression of renal dysfunction [deteriorating renal function (n = 5), cyclosporine (CyA) nephrotoxicity (n = 4) or biopsy-proven CAN (n = 13)]. Baseline maintenance immunosuppression consisted of CyA, AZA or MMF and prednisone. Six-month postconversion patient and graft survival was 100% and 91%, respectively. Mean serum creatinine 6months preconversion was 2.2 +/- 0.6mg/dL, at initiation was 3.0 +/- 1.1 mg/dL, and 6 months postconversion was 2.8 +/- 1.3 mg/dL. The rate of change in serum creatinine was 35 +/- 39%/6 months preconversion and -5 +/- 21%/6 months postconversion to LEF (p = 0.003). Two patients discontinued LEF for diarrhea and myalgia. No readmissions, increase in liver function tests, infections or acute rejection episodes occurred. Mean CyA levels did not change, 146 +/- 72 ng/ mL pre-LEF vs. 132 +/- 51 ng/mL post-LEF, p = NS. Conversion to LEF reversed progression of chronic renal allograft dysfunction with minimal toxicity.

Sirolimus-induced leukocytoclastic vasculitis.

A 41-year-old white woman with cystic fibrosis underwent lung transplantion that was complicated by cyclosporine-induced nephrotoxicity, which required kidney transplantation. Three years after the renal transplant, sirolimus was substituted for mycophenolate mofetil in a maintenance immunosuppressive regimen that consisted of cyclosporine and prednisone, with the hope of lowering cyclosporine concentrations and avoiding the nephrotoxic effects. Three weeks after the initiation of sirolimus, the patient developed palpable purpura on the bilateral lower extremities that resolved after discontinuation of sirolimus and reappeared with rechallenge. Punch biopsy of the initial eruption revealed leukocytoclastic vasculitis with focal fibrinoid necrosis. Sirolimus should be considered as a causative agent of cutaneous leukocytoclastic vasculitis.