YSPSL (rPSGL-Ig) for improvement of early renal allograft function: a double-blind, placebo-controlled, multi-center Phase IIa study.

INTRODUCTION: Recombinant P-selectin glycoprotein ligand IgG fusion protein, rPSGL-Ig (YSPSL), a fusion protein of human P-selectin ligand and IgG1-Fc, blocks leukocyte adhesion and protects against ischemia reperfusion injury (IRI) in animal models. PATIENTS AND METHODS: This randomized 15-center, double-blind, 59-patient Ph2a study assessed YSPSL's safety in recipients of deceased-donor kidney allografts and its potential efficacy in improving early graft function. Two doses and two dosing modalities were evaluated. RESULTS: No drug-specific toxicities or increased adverse event rates were noted. Two YSPSL-treated patients died of causes determined as unrelated to study drug. YSPSL did not reduce the incidence of dialysis within the first week post-transplant (41% in treated vs. 20% in placebo patients). Renal function endpoints scored at post-operative days 1 & 2 were also not impacted by YSPSL. However, at day 5, the fraction of patients with serum creatinine above 6 mg/dL was lower in the YSPSL vs. placebo group (26% vs. 55%, p = 0.043). Large variations in the dialysis-delayed graft function (DGF) rates were observed between centers, independently of treatment assignment, indicating subjectivity of this endpoint. CONCLUSION: In this first Ph2a study in kidney transplantation, YSPSL was safe but did not impact the dialysis-DGF rate. Further studies with more objective efficacy endpoints are required to define the impact of YSPSL on early renal allograft function.

Assessing professionalism in health profession degree programs: A scoping review.

BACKGROUND: To identify and classify methods for assessing professionalism across health profession degree programs and identify gaps in the literature regarding types of assessments. METHODS: The authors conducted a scoping review of articles published from database inception through 24 January 2020. Included articles described an assessment approach for professionalism in health profession degree programs available in full-text in the English language. Articles were classified based on profession, timing of assessment, feedback type, assessment type, professionalism dimension, and Barr's modified Kirkpatrick hierarchy. RESULTS: Authors classified 277 articles meeting inclusion criteria. Most articles were from medical education (62.5%) conducted during didactic (62.1%) or experiential/clinical curriculum (49.8%). Few articles (15.5%) described longitudinal assessment. Feedback type was formative (32.2%) or summative (35%), with only 8.3% using both. Assessment types frequently reported included self-administered rating scales (30%), reflections (18.8%), observed clinical encounters (17.3%), and knowledge-based tests (13.4%). Ethical practice principles (65%) and effective interactions with patients (48.4%) were the most frequently assessed dimensions of professionalism. Authors observed balanced distribution among Barr's modified Kirkpatrick model at levels of reaction (38.3%), modification of perceptions and attitudes (33.6%), acquisition of knowledge and skills (39%), and behavioral change (36.1%). IMPLICATIONS: The classification scheme identified in current literature on professionalism assessment does not align with International Ottawa Conference Working Group on the Assessment of Professionalism recommendations. Gaps identified were limited description of professionalism assessment during admissions, infrequent longitudinal assessment, limited use of methods for both formative and summative assessment, and limited reports of assessments applicable to interprofessional education settings.

Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study.

BACKGROUND: : The efficacy of the combination of voriconazole and caspofungin when used as primary therapy for invasive aspergillosis in organ transplant recipients has not been defined. METHODS: : Transplant recipients who received voriconazole and caspofungin (n=40) as primary therapy for invasive aspergillosis (proven or probable) in a prospective multicenter study between 2003 and 2005 were compared to a control group comprising a cohort of consecutive transplant recipients between 1999 and 2002 who had received a lipid formulation of AmB as primary therapy (n=47). In vitro antifungal testing of Aspergillus isolates to combination therapy was correlated with clinical outcome. RESULTS: : Survival at 90 days was 67.5% (27/40) in the cases, and 51% (24/47) in the control group (HR 0.58, 95% CI, 0.30-1.14, P=0.117). However, in transplant recipients with renal failure (adjusted HR 0.32, 95% CI: 0.12-0.85, P=0.022), and in those with A. fumigatus infection (adjusted HR 0.37, 95% CI: 0.16-0.84, P=0.019), combination therapy was independently associated with an improved 90-day survival in multivariate analysis. No correlation was found between in vitro antifungal interactions of the Aspergillus isolates to the combination of voriconazole and caspofungin and clinical outcome. CONCLUSIONS: : Combination of voriconazole and caspofungin might be considered preferable therapy for subsets of organ transplant recipients with invasive aspergillosis, such as those with renal failure or A. fumigatus infection.

Treating tobacco use and dependence in kidney transplant recipients: development and implementation of a program.

Tobacco use adversely affects transplant outcomes such as graft survival, patient survival, and other conditions that alter transplant patient longevity. Especially concerning is tobacco's relationship to cardiovascular disease, the number 1 cause of death in kidney transplant recipients. Many authors conclude that tobacco interventions ought to be provided to patients and sometimes lament that there are no tobacco dependence interventions designed for kidney transplant recipients. European Best Practice Guidelines for Renal Transplantation also support tobacco dependence interventions. The purpose of this article is to describe one institution's experience in implementing the clinical practice guideline for treating tobacco use and dependence within a kidney and pancreas transplant program.

A Novel Application of a Biopsychosocial Theory in the Understanding of Disturbed Sleep before and after Kidney Transplantation.

STUDY OBJECTIVES: Sleep and fatigue difficulties appear to be highly prevalent among individuals with end-stage renal disease and individuals who have received a kidney transplant. While there is some evidence of biopsychosocial factors predicting sleep disturbance in these populations, previous studies have relied on single time point retrospective measurements. METHODS: The study utilized a 2-week prospective measurement approach, including one night of polysomnographic measurement, nightly sleep diaries, and self-report measures of health, sleep, and mood. RESULTS: The current study demonstrates that a number of psychological and behavioral factors, including negative mood, quality of life, napping, and caffeine consumption, are related to sleep disturbance among pre- and post-kidney transplant patients. This study also found that many of these factors have different relationships with sleep disturbance when comparing pre- and post-kidney transplant patients. CONCLUSIONS: These results suggest that such factors may be worthwhile areas for intervention in treating the symptoms of insomnia among pre- and post-transplant recipients. A nuanced approach to understanding sleep problems is likely warranted when conceptualizing insomnia and developing a treatment plan.

The changing causes of graft loss and death after kidney transplantation.

BACKGROUND: The results of kidney transplantation have improved markedly over the last three decades. Despite this, patients still lose grafts and die. We sought to determine whether the causes of graft loss and death have changed over the last 30 years. METHODS: We reviewed patients who underwent transplantation or who died between January 1, 1970 and December 31, 1999. We compared the causes of graft loss or death for three decades: 1970 to 1979, 1980 to 1989, and 1990 to 1999. RESULTS: From January 1, 1970 to December 31, 1999, we performed 2501 kidney transplantations in 2225 patients. For the three periods, 210, 588, and 383 patients lost their grafts, respectively. Graft survival increased substantially. Graft loss occurred later after transplantation, with 36.0% losing grafts in the first year during 1970 to 1970, 22.8% during 1980 to 1989, and 11.4% during 1990 to 1999. Death with a functioning graft increased from 23.8% for 1970 to 1979 to 37.5% for 1990 to 1999. Concomitantly, rejection as a cause of graft loss fell from 65.7% for 1970 to 1979 to 44.6% for 1990 to 1999. Approximately two thirds of the patients who died after transplantation died with a functioning graft and one third died after returning to dialysis. Cardiac disease as a cause of death increased from 9.6% for 1970 to 1979 to 30.3% for 1990 to 1999. Deaths from cancer and stroke also increased significantly over the three decades from 1.2% and 2.4%, respectively, for 1970 to 1979, to 13.2% and 8.0%, respectively, for 1990 to 1999. CONCLUSIONS: The causes of graft loss and death have changed over the last three decades. By better addressing the main causes of death, cardiac disease, and stroke with better prevention, graft loss due to death with a functioning graft will be reduced.

Obesity does not portend a bad outcome for kidney transplant recipients.

BACKGROUND: Kidney transplant programs may avoid transplantation in obese patients because of reports indicating that obese patients have poorer outcomes than do nonobese patients. We recently reviewed our experience. METHODS: Patients receiving a kidney transplant between January 1, 1990 and December 31, 1999 were divided according to body mass index (BMI): group 1, BMI<25 (n=457); group 2, BMI> or =25 and <30 (n=278); and group 3, BMI> or =35 (n=98). RESULTS: Cadaveric graft survival rates at 2 years were 85% for group 1, 88% for group 2, and 85% for group 3 (P>0.10). Cadaveric patient survival rates at 2 years were 92% for group 1, 91% for group 2, and 94% for group 3 (P>0.10). There were no differences in technical losses or in posttransplantation wound complications. Group 3 patients, however, did have a higher incidence of steroid-induced posttransplantation diabetes mellitus than the other two groups (P<0.01). CONCLUSION: Obese transplant recipients have similar outcomes to nonobese patients.

Barriers to evaluation and wait listing for kidney transplantation.

BACKGROUND AND OBJECTIVES: Many factors have been shown to be associated with ESRD patient placement on the waiting list and receipt of kidney transplantation. Our study aim was to evaluate factors and assess the interplay of patient characteristics associated with progression to transplantation in a large cohort of referred patients from a single institution. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We examined 3029 consecutive adult patients referred for transplantation from 2003 to 2008. Uni- and multivariable logistic models were used to assess factors associated with progress to transplantation including receipt of evaluations, waiting list placement, and receipt of a transplant. RESULTS: A total of 56%, 27%, and 17% of referred patients were evaluated, were placed on the waiting list, and received a transplant over the study period, respectively. Older age, lower median income, and noncommercial insurance were associated with decreased likelihood to ascend steps to receive a transplant. There was no difference in the proportion of evaluations between African Americans (57%) and Caucasians (56%). Age-adjusted differences in waiting list placement by race were attenuated with further adjustment for income and insurance. There was no difference in the likelihood of waiting list placement between African Americans and Caucasians with commercial insurance. CONCLUSIONS: Race/ethnicity, age, insurance status, and income are predominant factors associated with patient progress to transplantation. Disparities by race/ethnicity may be largely explained by insurance status and income, potentially suggesting that variable insurance coverage exacerbates disparities in access to transplantation in the ESRD population, despite Medicare entitlement.

Malignant melanoma in solid transplant recipients: collection of database cases and comparison with surveillance, epidemiology, and end results data for outcome analysis.

OBJECTIVE: To determine malignant melanoma cause-specific and overall survival among patients with melanoma diagnosed after organ transplantation compared with a national sample with malignant melanoma. DESIGN: Retrospective review. SETTING: Mayo Clinic sites. PATIENTS: Immunosuppressed organ transplant recipients with malignant melanoma identified from surgical and medical databases at Mayo Clinic (1978-2007), the Organ Procurement and Transplantation Network/United Network for Organ Sharing database (1999-2006), and the Israel Penn International Transplant Tumor Registry (1967-2007). MAIN OUTCOME MEASURES: Prognostic analyses by Breslow thickness and Clark level of overall and melanoma cause-specific survival. Expected survival rates were estimated by applying the age-, sex-, and calendar year-specific survival rates of patients with malignant melanoma cases reported in the Surveillance, Epidemiology, and End Results Program to the study cohort. RESULTS: Malignant melanoma was diagnosed in 638 patients (724 cases) after transplantation. Breslow thickness was available for 123 patients; Clark level, for 175. Three-year overall survival rates for patients stratified by Breslow thickness (≤ 0.75, 0.76-1.50, 1.51-3.00, and >3.00 mm) were 88.2%, 80.8%, 51.2%, and 55.3%, respectively, and 3-year cause-specific survival rates (95% confidence intervals) were 97.8% (93.7%-100%), 89.4% (76.5%-100%), 73.2% (53.2%-100%), and 73.9% (56.4%-96.6%), respectively. Three-year cause-specific survival rates (95% confidence intervals) for patients stratified by Clark level (I-IV) were 100%, 97.4% (92.4%-100%), 82.8% (65.3%-100%), and 65.8% (51.8%-83.7%), respectively. For patients with Breslow thickness of 1.51 to 3.00 mm and Clark level III or IV, the cause-specific survival rate in the study sample was significantly different from the expected estimates for patients with the same Breslow thickness or Clark level. CONCLUSIONS: Compared with the expected survival rates derived from malignant melanoma cases reported in the Surveillance, Epidemiology, and End Results Program, immunosuppressed organ transplant recipients with thicker melanomas (ie, with a Clark level of III or IV or a Breslow thickness of 1.51 to 3.00 mm) had a significantly poorer malignant melanoma cause-specific survival rate. The overall survival rate was worse among patients with a prior history of transplantation, regardless of Breslow thickness or Clark level.

Dendritic cell deficiency associated with development of BK viremia and nephropathy in renal transplant recipients.

BACKGROUND: BK virus nephropathy (BKVN) is a significant cause of renal allograft loss. Although overall intensity of immunosuppression is the greatest risk factor, recipient immune factors likely also play a role in the pathogenesis. Dendritic cells (DC) are potent antigen-presenting cells important for the induction of anti-viral cytotoxic T-cell responses. In a previous univariate analysis, we demonstrated a peripheral blood DC (PBDC) deficiency in patients with biopsy-proven BKVN, raising the possibility that reduction in DC predisposed to BK reactivation. METHODS: In this study, we refined our previous analysis by comparing random posttransplant PBDC levels between an expanded group of patients with BKVN and controls without viremia using a multivariate analysis that accounted for factors known to influence PBDC levels. Next, we compared pretransplant PBDC levels between patients stratified by the presence or absence of posttransplant viremia. Finally, we assessed the predictive value of pretransplant PBDC levels for the development of posttransplant viremia. RESULTS: Analyses revealed a PBDC level deficiency not only posttransplant in patients with BKVN but also pretransplant in patients who subsequently developed posttransplant BK viremia. Furthermore, we identified a pretransplant PBDC level that is a reasonable predictor for the development of posttransplant viremia. CONCLUSIONS: Our results identify PBDC deficiency as a previously unrecognized risk factor for BKV reactivation after renal transplantation. Pretransplant PBDC monitoring may prove to be a useful clinical tool in the assessment of patient vulnerability to BKVN posttransplant, which may allow more focused screening.

Late-onset invasive aspergillosis in organ transplant recipients in the current era.

We assessed predictive factors and characteristics of patients with late-onset invasive aspergillosis in the current era of novel immunosuppressive agents. Forty transplant recipients with invasive aspergillosis were included in this prospective, observational study initiated in 2003 at our institutions. In 50% (20/40) of these patients, the infections were late-occurring. Receipt of sirolimus in conjunction with tacrolimus for refractory rejection or cardiac allograft vasculopathy (P=0.047) was significantly associated with late-onset infection. The use of depleting or non-depleting T or B-cell antibodies, either as induction or as antirejection therapy did not correlate with time to onset of invasive aspergillosis. Mortality at 90 days was 20% (4/20) for the patients with early-onset infection and 45% (9/20) for those with late-onset infection (P=0.17). Thus, nearly one-half of the Aspergillus infections in transplant recipients in the current era are late-occurring. These data have implications relevant for prophylactic strategies and guiding clinical management of transplant recipients presenting with pulmonary infiltrates.

The effects of renal transplantation on peripheral blood dendritic cells.

Recent advances allow accurate quantification of peripheral blood (PB) myeloid and plasmacytoid dendritic cell (DC) populations (mDC and pDC, respectively), although the response to renal transplantation (RT) remains unknown. Using flow cytometry, PBDC levels were quantified in patients with end stage renal disease (ESRD) undergoing RT. PBDC levels were significantly reduced in ESRD patients pre-RT compared to healthy controls, with further reduction noted immediately following a hemodialysis session. RT resulted in a dramatic decrease in both subsets, with a greater reduction of pDC levels. Both subset levels were significantly lower than in control patients undergoing abdominal surgery without RT. Subgroup analysis revealed significantly greater mDC reduction in RT recipients receiving anti-lymphocyte therapy, with preferential binding of antibody preparation to this subset. Samples from later time points revealed a gradual return of PBDC levels back to pre-transplant values concurrent with overall reduction of immunosuppression (IS). Finally, PBDC levels were significantly reduced in patients with BK virus nephropathy compared to recipients with stable graft function, despite lower overall IS. Our findings suggest that PBDC levels reflect the degree of IS in renal allograft recipients. Furthermore, PBDC monitoring may represent a novel strategy to predict important outcomes such as acute rejection, long-term graft loss and infectious complications.

Long-term outcomes of kidney transplantation in recipients 60 years of age and older at the University of Florida.

As the population ages, the transplant community will continue to see "elderly" patients with end-stage kidney disease who are seeking transplantation. In this report we describe long-term outcomes of 315 primary kidney transplants performed at the University of Florida in recipients aged > or = 60 years and compare them to results from 3 younger recipient cohorts. Among recipients > or = 60 years, patient survival was significantly worse than for younger recipients but no differences in graft or death-censored graft survival were seen. We suspect that although patient survival was worst in the oldest group, there were likely other causes of graft loss within the younger groups that balanced the effects of death on graft survival in the oldest group. Among recipients aged > or = 60 years, patient survival at 10 years was 55% for living-donor kidney recipients and 46% for deceased-donor kidney recipients. African-American recipients had a higher risk of mortality and graft loss in all age groups after deceased donor kidney transplantation but not after living donor transplantation. Delayed graft function negatively impacted outcomes among all recipients and the adverse effects were greater after deceased donor than living donor transplantation. These effects were also seen within the oldest recipient age group. Increased donor age was a significant risk factor for death and graft loss among all age groups after deceased donor kidney transplantation but not among living-donor kidney recipients. More specifically, recipients aged > or = 60 years who received kidneys from donors > or = 60 years demonstrated significantly worse outcomes when compared to those receiving donor kidneys < 60 years. The presence of diabetes mellitus in recipients > or = 60 years was not a significant risk factor for mortality or graft loss after transplantation. Acceptable results can be obtained after kidney transplantation in recipients aged > or = 60 years. Future investigations should focus on improving recipient selection in the elderly population, identifying strategies to minimize DGF in deceased donor kidneys, understanding all variables involved in the risk associated with recipient race, and increasing living donor transplantation across all age groups.

Effect of sirolimus withdrawal in patients with deteriorating renal function.

Sirolimus has been an important addition to immunosuppressive regimens utilized in kidney transplantation. However, sirolimus can potentiate calcineurin inhibitor (CNI) nephrotoxicity by some still uncertain mechanisms. Studies have demonstrated that withdrawal of a CNI under sirolimus immunosuppression can improve renal function. However, it has yet to be demonstrated that withdrawal of sirolimus from such a regimen can also improve renal function and reverse progressive functional deterioration. We studied 17 patients who developed deterioration of renal function while on a CNI and sirolimus. Once an established deterioration in renal function was noted, sirolimus was withdrawn from the regimen and replaced with mycophenolate mofetil. Out of 17 patients with a negative slope in 1/cr, 15 demonstrated a positive treatment effect (change to a positive slope). On aggregate, renal function improved by 18% (creatinine 2.75-2.24 mg/dL), LDL cholesterol improved, as did hematocrit values after withdrawal. The majority of patients on a CNI and sirolimus regimen who experience deterioration in renal function demonstrate improvement in renal function after withdrawal of sirolimus. This strategy may be particularly useful in those patients where CNI withdrawal is considered to be of high immunologic or metabolic risk.