Efficacy and Safety of Bleselumab in Preventing the Recurrence of Primary Focal Segmental Glomerulosclerosis in Kidney Transplant Recipients: A Phase 2a, Randomized, Multicenter Study.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease and frequently recurs after kidney transplantation. Recurrent FSGS (rFSGS) is associated with poor allograft and patient outcomes. Bleselumab, a fully human immunoglobulin G4 anti-CD40 antagonistic monoclonal antibody, disrupts CD40-related processes in FSGS, potentially preventing rFSGS. METHODS: A phase 2a, randomized, multicenter, open-label study of adult recipients (aged ≥18 y) of a living or deceased donor kidney transplant with a history of biopsy-proven primary FSGS. The study assessed the efficacy of bleselumab combined with tacrolimus and corticosteroids as maintenance immunosuppression in the prevention of rFSGS >12 mo posttransplantation, versus standard of care (SOC) comprising tacrolimus, mycophenolate mofetil, and corticosteroids. All patients received basiliximab induction. The primary endpoint was rFSGS, defined as proteinuria (protein-creatinine ratio ≥3.0 g/g) with death, graft loss, or loss to follow-up imputed as rFSGS, through 3 mo posttransplant. RESULTS: Sixty-three patients were followed for 12 mo posttransplantation. Relative decrease in rFSGS occurrence through 3 mo with bleselumab versus SOC was 40.7% (95% confidence interval, -89.8 to 26.8; P = 0.37; absolute decrease 12.7% [95% confidence interval, -34.5 to 9.0]). Central-blinded biopsy review found relative (absolute) decreases in rFSGS of 10.9% (3.9%), 17.0% (6.2%), and 20.5% (7.5%) at 3, 6, and 12 mo posttransplant, respectively; these differences were not statistically significant. Adverse events were similar for both treatments. No deaths occurred during the study. CONCLUSIONS: In at-risk kidney transplant recipients, bleselumab numerically reduced proteinuria occurrence versus SOC, but no notable difference in occurrence of biopsy-proven rFSGS was observed.

High-Functioning Deceased Donor Kidney Transplant System Characteristics: The British Columbia Experience With an Opt-In System.

Rationale & Objective: A high level of cooperation between organ procurement organizations and transplant programs may help maximize use of deceased donor kidneys. The practices that are essential for a high functioning organ donation and transplant system remain uncertain. We sought to report metrics of organ donation and transplant performance in British Columbia, Canada, and to assess the association of specific policies and practices that contribute to the system's performance. Study Design: A retrospective observational study. Setting & Participants: Referred deceased organ donors in British Columbia were used in the study from January 1, 2016, to December 31 2019. Exposures: Provincial, organ procurement organization, and center level policies were implemented to improve donor referral and organ utilization. Outcomes: Assessment of donor and kidney utilization along steps of the critical pathway for organ donation. Analytical Approach: Deceased donors were classified according to the critical pathway for organ donation and key donation and transplant metrics were identified. Results: There were 1,948 possible donors referred. Of 1,948, 754 (39%) were potential donors. Of 754 potential donors, 587 (78%) were consented donors. Of 587 consented donors, 480 (82%) were eligible kidney donors. Of 480 eligible kidney donors, 438 (91%) were actual kidney donors. And of 438 actual kidney donors, 432 (99%) were utilized kidney donors. One-year all-cause allograft survival was 95%. Practices implemented to improve the system's performance included hospital donor coordinators, early communication between the organ procurement organization and transplant nephrologists, dedicated organ recovery and implant surgeons, aged-based kidney allocation, and hospital admission of recipients before kidney recovery. Limitations: Assignment of causality between individual policies and practices and organ donation and utilization is limited in this observational study. Conclusions: In British Columbia, consent for donation, utilization of donated kidneys, and transplant survival are exceptionally high, suggesting the importance of an integrated deceased donor and kidney transplant service.

Optimization of all possible opportunities for deceased donor kidney donation and transplantation is essential to meet the need for transplantation. We examined the performance of organ procurement and transplant in a deceased organ donor system in British Columbia, Canada, and reviewed policies and practices that may contribute to the system's performance. We found a high level of donation, transplantation, and survival of donated kidneys and identified policies and practices that likely contribute to the system's performance.

Erythrocytosis and thrombotic events in kidney transplant recipients prescribed a sodium glucose cotransport-2 inhibitor.

INTRODUCTION: The safety and efficacy of sodium glucose cotransport-2 inhibitors (SGLT2i) in kidney transplant recipients remains uncertain. Transplant recipients may be at risk of thrombosis because of post-transplant erythrocytosis and SGLT2i are associated with an increase in hematocrit. METHODS: We determined SGLT2i use, the change in hematocrit and incidence of thrombotic events in kidney transplant recipients in 1700 prevalent patients in our center. RESULTS: Among the 42 patients treated with SGLT2i, the mean pre-transplant hematocrit was 31%, and none of the patients had a hematocrit ≥50%. The mean percent change in hematocrit measured at an average of 53 days after initiation of an SGLT2i was 11% and four patients (10%) had a hematocrit ≥ 50%. The mean hematocrit measured 3 months after treatment was 42% and two patients (5%) had a hematocrit ≥50%. One patient had a cerebellar stroke 14 months post-SGLT2i initiation when the hemoglobin was 173 grams/liter, and the hematocrit was 52%. CONCLUSIONS: All patients had a sustained increase in hematocrit 3 months after SGLT2i treatment. Hematocrit ≥50% occurred in 10%, and one patient had a thrombotic event that may or may not have been related to an increase in hematocrit. Clinicians may consider monitoring for erythrocytosis after starting and SGLT2i in kidney transplant recipients.

Differences in medication adherence by sex and organ type among adolescent and young adult solid organ transplant recipients.

BACKGROUND: Identification of differences in medication adherence by sex or organ type may help in planning interventions to optimize outcomes. We compared immunosuppressive medication adherence between males and females, and between kidney, liver and heart transplant recipients. METHODS: This multicenter study of prevalent kidney, liver and heart transplant recipients 14-25 years assessed adherence 3 times (0, 3, 6 months post-enrollment) with the BAASIS self-report tool. At each visit, participants were classified as adherent if they missed no doses in the prior 4 weeks and non-adherent otherwise. Adherence was also assessed using the coefficient of variation (CV) of tacrolimus trough levels; CV < 30% was classified as adherent. We used multivariable mixed effects logistic regression models adjusted for potential confounders to compare adherence by sex and by organ. RESULTS: Across all visits, males (n = 150, median age 20.4 years, IQR 17.2-23.3) had lower odds of self-reported adherence than females (n = 120, median age 19.8 years, IQR 17.1-22.7) (OR 0.41, 95% CI 0.21-0.80) but higher odds of adherence by tacrolimus CV (OR 2.50, 95% CI 1.30-4.82). No significant differences in adherence (by self-report or tacrolimus CV) were noted between the 184 kidney, 58 liver, and 28 heart recipients. CONCLUSION: Females show better self-reported adherence than males but greater variability in tacrolimus levels. Social desirability bias, more common in females than males, may contribute to better self-reported adherence among females. Higher tacrolimus variability among females may reflect biologic differences in tacrolimus metabolism between males and females rather than sex differences in adherence. There were no significant differences in adherence by organ type.

Immunosuppressant Medication Use in Patients with Kidney Allograft Failure: A Prospective Multicenter Canadian Cohort Study.

BACKGROUND: Patients with kidney transplant failure have a high risk of hospitalization and death due to infection. The optimal use of immunosuppressants after transplant failure remains uncertain and clinical practice varies widely. METHODS: This prospective cohort study enrolled patients within 21 days of starting dialysis after transplant failure in 16 Canadian centers. Immunosuppressant medication use, death, hospitalized infection, rejection of the failed allograft, and anti-HLA panel reactive antibodies were determined at 1, 3, 6, and 12 months and and then twice yearly until death, repeat transplantation, or loss to follow-up. RESULTS: The 269 study patients were followed for a median of 558 days. There were 33 deaths, 143 patients hospitalized for infection, and 21 rejections. Most patients (65%) continued immunosuppressants, 20% continued prednisone only, and 15% discontinued all immunosuppressants. In multivariable models, patients who continued immunosuppressants had a lower risk of death (hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.17 to 0.93) and were not at increased risk of hospitalized infection (HR, 1.81; 95% CI, 0.82 to 4.0) compared with patients who discontinued all immunosuppressants or continued prednisone only. The mean class I and class II panel reactive antibodies increased from 11% to 27% and from 25% to 47%, respectively, but did not differ by immunosuppressant use. Continuation of immunosuppressants was not protective of rejection of the failed allograft (HR, 0.81; 95% CI, 0.22 to 2.94). CONCLUSIONS: Prolonged use of immunosuppressants >1 year after transplant failure was not associated with a higher risk of death or hospitalized infection but was insufficient to prevent higher anti-HLA antibodies or rejection of the failed allograft.

Care processes and structures associated with higher medication adherence in adolescent and young adult transplant recipients.

BACKGROUND: We aimed to identify care processes and structures that were independently associated with higher medication adherence among young transplant recipients. METHODS: We conducted a prospective, observational cohort study of 270 prevalent kidney, liver, and heart transplant recipients 14-25 years old. Patients were ≥3 months post-transplant, ≥2 months post-discharge, and followed in one of 14 pediatric or 14 adult transplant programs in Canada. Patients were enrolled between June 2015 and March 2018 and followed for 6 months. Adherence was assessed at baseline, 3, and 6 months using the BAASIS© self-report tool. Patients were classified as adherent if no doses were missed in the prior 4 weeks. Transplant program directors and nurses completed questionnaires regarding care organization and processes. RESULTS: Of the 270 participants, 99 were followed in pediatric programs and 171 in adult programs. Median age was 20.3 years, and median time since transplant was 5 years. At baseline, 71.5% were adherent. Multivariable mixed effects logistic regression models with program as a random effect identified two program-level factors as independently associated with better adherence: minimum number of prescribed blood draws per year for those >3 years post-transplant (per 1 additional) (OR 1.12 [95% CI 1.00, 1.26]; p = .047), and average time nurses spend with patients in clinic (per 5 additional minutes) (OR 1.15 [1.03, 1.29]; p = .017). CONCLUSION: Program-level factors including protocols with a greater frequency of routine blood testing and more nurse time with patients were associated with better medication adherence. This suggests that interventions at the program level may support better adherence.

Exercise for Solid Organ Transplant Candidates and Recipients: A Joint Position Statement of the Canadian Society of Transplantation and CAN-RESTORE.

BACKGROUND: The objectives of this position statement were to provide evidence-based and expert-informed recommendations for exercise training in adult and children solid organ transplant (SOT) candidates and recipients and on the outcomes relevant to exercise training and physical function that should be evaluated in SOT. METHODS: We identified randomized controlled trials (RCTs) and systematic reviews of exercise interventions in adult and pediatric SOT candidates and recipients. When RCTs were not available, studies of any design were reviewed. The key recommendations were based on scientific evidence and expert-informed opinion. RESULTS: We recommended that exercise training should be offered in the pre- and posttransplant phase for both adults and children. In adults, exercise training pretransplant was safe, but there was insufficient evidence to provide specific guidelines on the training characteristics. RCTs in adult SOT recipients demonstrated that exercise training improved exercise capacity, lower extremity muscle strength, and health-related quality of life. To obtain benefits, exercise training should be of moderate to vigorous-intensity level, 3-5 times a week for a minimum of 8 weeks. In pediatrics, there is an urgent need for high-quality multicenter clinical trials in the pre- and posttransplant phases. Due to limited evidence, specific recommendations regarding training characteristics could not be provided for pediatrics. CONCLUSIONS: The clinical relevance of this position statement is that it provides a key step toward raising awareness of the importance of exercise training in SOT patients among transplant professionals. It also identifies key areas for further research.

Posttransplant Lymphoproliferative Disorder in Adults Receiving Kidney Transplantation in British Columbia: A Retrospective Cohort Analysis.

BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) is a major complication following kidney transplantation. OBJECTIVE: We undertook this study to characterize PTLD in kidney transplant patients in British Columbia with regard to incidence, patient and graft survival, histological subtypes, treatment modalities, and management of immunosuppression. DESIGN: Retrospective cohort analysis. SETTING: British Columbia. PATIENTS: All adult patients who underwent kidney transplantation in British Columbia between January 1, 1996, and December 31, 2012, were included. Patients less than 18 years of age at the time of first transplant and multiple organ transplant recipients were excluded from analysis. MEASUREMENTS: Patients with lymphoproliferative disorders that occurred subsequent to kidney transplantation were considered to have developed PTLD. METHODS: Cases of PTLD were identified by cross-referencing data abstracted from the provincial transplant agency's clinical database with the provincial cancer agency's lymphoma registry. Patients were followed up for the development of PTLD until December 31, 2012, and for outcomes of death and graft failure until December 31, 2014. Data collection was completed via an electronic chart review. RESULTS: Of 2217 kidney transplant recipients, 37 (1.7%) developed PTLD. Nine cases were early-onset PTLD, occurring within 1 year of transplant; of these cases, 6 were known/presumed Epstein-Barr virus mismatch, compared with only 2 of 28 late-onset cases. Patient survival for early-onset PTLD was 100% at 2 years post diagnosis. Late-onset PTLD had survival rates of 71.4% and 67.9% at 1 and 2 years, respectively. PTLD was associated with significantly decreased patient survival (P = .031) and graft survival (uncensored for death, P = .017), with median graft survival of PTLD and non-PTLD patients being 9.5 and 16 years, respectively. Immunosuppressant therapy was reduced in the majority of patients; additional therapies included rituximab monotherapy, CHOP-R, radiation, and surgery. LIMITATIONS: Limitations to this study include its retrospective nature and the unknown adherence of patients to prescribed immunosuppressant regimens. In addition, cumulative doses of immunosuppression received and the degree of immunosuppression reduction for PTLD management were not effectively captured. CONCLUSIONS: The incidence of PTLD in British Columbia following kidney transplantation was low and consistent with rates reported in the literature. The incidence of late-onset PTLD and its association with reduced patient and graft survival warrant further analysis of patients' long-term immunosuppression.

CONTEXTE: Le syndrome lymphoprolifératif post-greffe (SLPG) est une complication grave survenant à la suite d'une transplantation rénale. OBJECTIF DE L'ÉTUDE: Nous avons mené cette étude afin de caractériser le SLPG chez les receveurs d'une greffe rénale en Colombie-Britannique en ce qui a trait à son incidence, à la survie du patient et du greffon, aux sous-types histologiques, aux modalités de traitement et à la gestion de l'immunosuppression. CADRE ET TYPE D'ÉTUDE: Il s'agit d'une étude de cohorte rétrospective effectuée en Colombie-Britannique. SUJETS: Ont été inclus dans l'étude tous les patients adultes ayant subi une transplantation rénale entre le 1er janvier 1996 et le 31 décembre 2012 en Colombie-Britannique. Les patients âgés de moins de 18 ans au moment de l'intervention et les patients receveurs de greffe de multiples organes ont été exclus. MESURES: Tout cas de SL apparu après une greffe rénale étaient considérés comme un SLPG. MÉTHODOLOGIE: Les cas de SLPG ont été répertoriés en recoupant les données extraites de la base de données cliniques de l'agence provinciale de transplantation avec les données du registre des lymphomes tenu par l'agence provinciale de lutte contre le cancer. Les participants ont été suivis jusqu'au 31 décembre 2012 pour l'apparition du SLPG et jusqu'au 31 décembre 2014 pour les issues défavorables telles que la mort du patient ou le rejet du greffon. L'examen du dossier électronique des patients a complété la collecte des données. RÉSULTATS: Des 2 217 receveurs d'une greffe rénale répertoriés, seuls 37 (1,7 %) ont développé un SLPG. L'apparition du SLPG s'est faite de façon précoce, soit dans la première année post-greffe, pour neuf de ces patients, dont six représentaient un cas connu ou présumé de non-concordance pour le virus d'Epstein Barr (EBV). En comparaison, seuls deux des 28 patients ayant expérimenté un développement tardif du SLPG étaient présumés non-concordants pour l'EBV. Deux ans après le diagnostic, 100 % des patients ayant eu une apparition précoce du SLPG avaient survécu. Dans les cas de développement tardif de la maladie, le taux de survie passait à 71,4 % après un an et à 67,9 % après deux ans pour les patients. Le développement du SLPG a été associé avec une réduction significative de la chance de survie du patient (p = 0,031) et du greffon (p = 0,017, cas de décès non censurés). La survie médiane du greffon était de 9,5 ans pour les patients ayant développé un SLPG alors qu'elle était de 16 ans pour les autres. L'intensité du traitement immunosuppresseur a pu être réduite pour la majorité des patients. Les traitements additionnels incluaient la monothérapie au rituximab, le R-CHOP, la radiation et la chirurgie. LIMITES DE L'ÉTUDE: La nature rétrospective de l'étude est un facteur limitant la portée de nos résultats, de même que l'absence de données sur l'adhérence des patients au traitement immunosuppressif. De plus, nous n'avons pu mesurer précisément les doses cumulatives d'immunosuppresseurs reçues, ni le degré de réduction de ces derniers dans la prise en charge du SLPG. CONCLUSION: En Colombie-Britannique, l'incidence du SL post-greffe rénale s'est avérée faible et cohérente avec les taux rapportés dans la littérature. L'incidence de l'apparition tardive du SLPG et son association à un taux et une durée de survie amoindris (à la fois pour le patient et pour le greffon) justifient une analyse plus poussée de l'immunosuppression à long terme dans la population en question.

Urinary biomarkers of chronic allograft nephropathy.

PURPOSE: Chronic allograft nephropathy (CAN) is widely accepted as the leading cause of renal allograft loss after the first year post transplantation. This study aimed to identify urinary biomarkers that could predict CAN in transplant patients. EXPERIMENTAL DESIGN: The study included 34 renal transplant patients with histologically proven CAN and 36 renal transplant patients with normal renal function. OrbiTrap MS was utilized to analysis a urinary fraction in order to identify other members of a previously identified biomarker tree . This novel biomarker pattern offers the potential to distinguish between transplant recipients with CAN and those with normal renal function. RESULTS: The primary node of the biomarker pattern was reconfirmed as ß2 microglobulin. Three other members of this biomarker pattern were identified: neutrophil gelatinase-associated lipocalin, clusterin, and kidney injury biomarker 1. Significantly higher urinary concentrations of these proteins were found in patients with CAN compared to those with normal kidney function. CONCLUSIONS AND CLINICAL RELEVANCE: While further validation in a larger more-diverse patient population is required to determine if this biomarker pattern provides a potential means of diagnosing CAN by noninvasive methods in a clinical setting, this study clearly demonstrates the biomarkers' ability to stratify patients based on transplant function.

Levofloxacin for BK virus prophylaxis following kidney transplantation: a randomized clinical trial.

IMPORTANCE: BK virus infection is a significant complication of modern immunosuppression used in kidney transplantation. Viral reactivation occurs first in the urine (BK viruria) and is associated with a high risk of transplant failure. There are currently no therapies to prevent or treat BK virus infection. Quinolone antibiotics have antiviral properties against BK virus but efficacy at preventing this infection has not been shown in prospective controlled studies. OBJECTIVE: To determine if levofloxacin can prevent BK viruria in kidney transplant recipients. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, placebo-controlled randomized trial involving 154 patients who received a living or deceased donor kidney-only transplant in 7 Canadian transplant centers between December 2011 and June 2013. INTERVENTIONS: Participants were randomly assigned to receive a 3-month course of levofloxacin (500 mg/d; n = 76) or placebo (n = 78) starting within 5 days after transplantation. MAIN OUTCOMES AND MEASURES: The primary outcome was time to occurrence of BK viruria (detected using quantitative real-time polymerase chain reaction) within the first year after transplantation. Secondary outcomes included BK viremia, peak viral load, rejection, and patient and allograft survival. RESULTS: The mean follow-up time was 46.5 weeks in the levofloxacin group and 46.3 weeks in the placebo group (27 patients had follow-up terminated before the end of the planned follow-up period or development of viruria because the trial was stopped early owing to lack of funding). BK viruria occurred in 22 patients (29%) in the levofloxacin group and in 26 patients (33.3%) in the placebo group (hazard ratio, 0.91; 95% CI, 0.51-1.63; P = .58). There was no significant difference between the 2 groups in regard to any of the secondary end points. There was an increased risk of resistant infection among isolates usually sensitive to quinolones in the levofloxacin group vs placebo (14/24 [58.3%] vs 15/45 [33.3%], respectively; risk ratio, 1.75; 95% CI, 1.01-2.98) as well as a nonsignificant increased risk of suspected tendinitis (6/76 [7.9%] vs 1/78 [1.3%]; risk ratio, 6.16; 95% CI, 0.76-49.95). CONCLUSIONS AND RELEVANCE: Among kidney transplant recipients, a 3-month course of levofloxacin initiated early following transplantation did not prevent BK viruria. Levofloxacin was associated with an increased risk of adverse events such as bacterial resistance. These findings do not support the use of levofloxacin to prevent posttransplant BK virus infection. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01353339.

Differential association of body mass index with access to kidney transplantation in men and women.

BACKGROUND AND OBJECTIVES: Obese patients encounter barriers to medical care not encountered by lean patients, and inequities in access to care among obese patients may vary by sex. This study aimed to determine the association of body mass index (BMI) with access to kidney transplantation in men and women. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this retrospective analysis of 702,456 incident ESRD patients aged 18-70 years (captured in the US Renal Data System between 1995 and 2007), multivariate time-to-event analyses were used to determine the association of BMI with likelihood of transplantation from any donor source, transplantation from a living donor, and transplantation from a deceased donor, as well the individual steps in obtaining a deceased donor transplant (activation to the waiting list, and transplantation after wait-listing). RESULTS: Among women, a BMI ≥ 25.0 kg/m(2) was associated with a lower likelihood of transplantation from any donor source (hazard ratio [HR], 0.75; 95% confidence interval [95% CI], 0.73 to 0.77), transplantation from a living donor (HR, 0.75; 95% CI, 0.72 to 0.77), and transplantation from a deceased donor (HR, 0.74; 95% CI, 0.72 to 0.77). By contrast, among men, a BMI of 25.0-34.9 kg/m(2) was associated with a higher likelihood of the outcomes of transplantation from any donor source (HR, 1.08; 95% CI, 1.06 to 1.11), transplantation from a living donor (HR, 1.18; 95% CI, 1.13 to 1.22), and transplantation from a deceased donor (HR, 1.05; 95% CI, 1.02 to 1.07). Among men, the level beyond which BMI was associated with a lower likelihood of transplantation from any donor source or a living donor was ≥ 40.0 kg/m(2), and ≥ 35.0 kg/m(2) in the case of deceased donor transplantation. CONCLUSIONS: The association of BMI with access to transplantation varies between men and women. The reasons for this difference should be further studied.

The effect of race and income on living kidney donation in the United States.

Studies of racial disparities in access to living donor kidney transplantation focus mainly on patient factors, whereas donor factors remain largely unexamined. Here, data from the US Census Bureau were combined with data on all African-American and white living kidney donors in the United States who were registered in the United Network for Organ Sharing (UNOS) between 1998 and 2010 (N=57,896) to examine the associations between living kidney donation (LKD) and donor median household income and race. The relative incidence of LKD was determined in zip code quintiles ranked by median household income after adjustment for age, sex, ESRD rate, and geography. The incidence of LKD was greater in higher-income quintiles in both African-American and white populations. Notably, the total incidence of LKD was higher in the African-American population than in the white population (incidence rate ratio [IRR], 1.20; 95% confidence interval [95% CI], 1.17 to 1.24]), but ratios varied by income. The incidence of LKD was lower in the African-American population than in the white population in the lowest income quintile (IRR, 0.84; 95% CI, 0.78 to 0.90), but higher in the African-American population in the three highest income quintiles, with IRRs of 1.31 (95% CI, 1.22 to 1.41) in Q3, 1.50 (95% CI, 1.39 to 1.62) in Q4, and 1.87 (95% CI, 1.73 to 2.02) in Q5. Thus, these data suggest that racial disparities in access to living donor transplantation are likely due to socioeconomic factors rather than cultural differences in the acceptance of LKD.

Quinolone prophylaxis for the prevention of BK virus infection in kidney transplantation: study protocol for a randomized controlled trial.

BACKGROUND: BK virus infection has emerged as a major complication in kidney transplantation leading to a significant reduction in graft survival. There are currently no proven strategies to prevent or treat BK virus infection. Quinolone antibiotics, such as levofloxacin, have demonstrated activity against BK virus. We hypothesize that administration of a quinolone antibiotic, when given early post-transplantation, will prevent the establishment of BK viral replication in the urine and thus prevent systemic BK virus infection. METHODS/DESIGN: The aim of this pilot trial is to assess the efficacy, safety and feasibility of a 3-month course of levofloxacin in the kidney transplant population. This is a multicenter, randomized, double-blind, placebo-controlled trial with two parallel arms conducted in 11 Canadian kidney transplant centers. A total of 154 patients with end-stage renal disease undergoing kidney transplantation will be randomized to receive a 3-month course of levofloxacin or placebo starting in the early post-transplant period. Levofloxacin will be administered at 500 mg po daily with dose adjustments based on kidney function. The primary outcome will be the time to occurrence of BK viruria within the first year post-transplantation. Secondary outcomes include BK viremia, measures of safety (adverse events, resistant infections,Clostridium difficile-associated diarrhea), measures of feasibility (proportion of transplanted patients recruited into the trial), proportion of patients adherent to the protocol, patient drop-out and loss to follow-up,and use of quinolone antibiotics outside of the trial protocol. DISCUSSION: Results from this pilot study will provide vital information to design and conduct a large, multicenter trial to determine if quinolone therapy decreases clinically meaningful outcomes in kidney transplantation. If levofloxacin significantly reduces BK viruria and urine viral loads in kidney transplantation, it will provide important justification to progress to the larger trial. If the full trial shows that levofloxacin significantly reduces BK infection and improves outcomes, its use in kidney transplantation will be strongly endorsed given the lack of proven therapies for this condition. TRIAL REGISTRATION: This trial was funded by the Canadian Institutes of Health Research (grant number:222493) and is registered at ClinicalTrials.gov (NCT01353339).

Risks and benefits of preemptive second kidney transplantation.

BACKGROUND: Information to guide the timing of a second kidney transplantation is limited. METHODS: We compared outcomes of 3509 preemptive and 14,075 nonpreemptive second kidney transplant recipients in the U.S. Renal Data System between 1995 and 2007. RESULTS: Preemptive recipients had less acute rejection (12% vs. 16%; P<0.0001) and delayed graft function (8% vs. 23%; P<0.0001). Preemptive transplantation was associated with a lower multivariate adjusted risk of allograft failure from any cause including death (hazard ratio [HR], 0.88; 95% confidence interval [95% CI], 0.81-0.96) and death with a functioning graft (HR [95% CI], 0.76 [0.66-0.87]) but a similar risk of death-censored graft loss (HR [95% CI], 0.98 [0.88-1.08]). The benefits of preemptive transplantation were evident in all patients groups with first transplant survival equal to or more than 1 year; however, a 34% increased risk of death-censored graft loss was observed in preemptive recipients when first transplant survival was less than 1 year. CONCLUSIONS: Benefits and risks of preemptive transplantation vary between primary and second transplant recipients. Benefits in second transplant recipients are primarily due to decreased death with a functioning graft, with no difference in death-censored graft survival. Preemptive transplantation was beneficial when first transplant survival was equal to or more than 1 year but associated with increased risk when graft survival was less than 1 year.

Identification of ß2-microglobulin as a urinary biomarker for chronic allograft nephropathy using proteomic methods.

PURPOSE: Chronic allograft nephropathy (CAN) remains the leading cause of renal graft loss after the first year following renal transplantation. This study aimed to identify novel urinary proteomic profiles, which could distinguish and predict CAN in susceptible individuals. EXPERIMENTAL DESIGN: The study included 34 renal transplant patients with histologically proven CAN and 36 patients with normal renal transplant function. High-throughput proteomic profiles were generated from urine samples with three different ProteinChip arrays by surface-enhanced laser-desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). Following SELDI, a biomarker pattern software analysis was performed which led to the identification of a novel biomarker pattern that could distinguish patients with CAN from those with normal renal function. RESULTS: An 11.7 kDa protein identified as ß2 microglobulin was the primary protein of this biomarker pattern, distinguishing CAN from control patients (receiver operator characteristic [ROC]=0.996). SELDI-TOF-MS comparison of purified ß2 microglobulin protein and CAN urine demonstrated identical 11.7 kDa protein peaks. Significantly, higher concentrations of 2 microglobulin were found in the urine of patients with CAN compared with the urine of normal renal function transplant recipients (p<0.001). CONCLUSIONS AND CLINICAL RELEVANCE: Although further validation in a larger more diverse patient population is required to determine if this ß2 microglobulin protein biomarker will provide a potential means of diagnosing CAN by noninvasive methods in a clinical setting, this study clearly shows a capability to stratify control and disease patients.

Excessive exercise: from quantitative categorisation to a qualitative continuum approach.

Researchers have yet to reach a consensus on the definition of excessive exercise, and many questions remain about the relationship between excessive exercise and eating disorders. Understanding of excessive exercise may be furthered by adoption of a broader, dimensional perspective. The current qualitative (grounded theory) study explored the continuum of women's exercise experiences, ranging from casual to more extreme regimens. Thirty-two women were interviewed, aged 16-77. Participants described stages in a continuum of exercise experiences. Overlaps were described between participant perceptions of 'normal' exercise, excessive exercise and exercise addiction. Excessive exercise and disturbed eating were described as arising from common concerns about the need to control the body, with exercise viewed as a more acceptable alternative to disturbed eating. The results provide support for a continuum approach to the understanding of excessive exercise, and highlight the utility of qualitative methods in this area.

Opportunities to deter transplant tourism exist before referral for transplantation and during the workup and management of transplant candidates.

Transplant tourism is a global issue, and physicians in the developed world may be in a position to actively deter this practice. To examine such opportunities, we identified 93 residents of British Columbia, Canada who had a kidney graft through tourism and determined their previous interactions with our transplant programs. These patients were mainly ethnic minorities (90%) who traveled to their country of origin for transplantation. Many tourists were transplanted early in their disease course, with 27 having a preemptive transplant. Among the 65 tourists referred for transplant, 33 failed to complete the evaluation. All tourists who completed an evaluation were placed on a waiting list in British Columbia and, after waiting a median of 2 years, pursued tourism. Most of these patients (62%) had a potential living donor, but none had an approved donor, with 13 donors found medically unsuitable, 8 ABO incompatible, and 12 who did not complete their evaluation. Thus, strategies to deter tourism should start before the development of end-stage renal disease and should be part of pretransplant workup and wait-list management, focusing on patients not progressing through their evaluation, those with a declined living donor, and those facing longer wait times, as these groups appear to be at higher risks for transplant tourism. Further studies are needed to identify individuals at risk for transplant tourism and to define effective strategies to deter these individuals.

Screening for de novo anti-human leukocyte antigen antibodies in nonsensitized kidney transplant recipients does not predict acute rejection.

BACKGROUND: The purpose of this study was to determine whether screening for anti-human leukocyte antigen (HLA) antibodies (Abs) could predict development of acute rejection (AR) before clinical evidence of kidney allograft dysfunction in nonsensitized recipients. METHODS: Eighty-four non-HLA identical kidney transplant recipients were prospectively tested for anti-HLA Abs (FlowPRA analysis and anti-HLA Ab specificity determination) at 0, 10, 20, 30, 60, 90, 180 and 365 posttransplantation, and at the time of clinical suspicion of AR. Allograft biopsies were performed at the time of engraftment, 3 and 12 months posttransplantation, when patients developed new anti-HLA Abs, or when clinically indicated. RESULTS: Among the 70 patients without preformed anti-HLA Abs, 11 developed de novo anti-HLA Abs (8 donor-specific Abs) at a median of 30 days (q1-q3=10-180 days) after transplantation. Patients with de novo anti-HLA Abs had a shorter time to AR than patients without de novo anti-HLA Abs, P=0.06. However, in all cases, de novo anti-HLA Abs developed concomitantly or after a clinically evident AR. CONCLUSIONS: Although de novo anti-HLA Abs were associated with AR, routine screening for anti-HLA Abs was not useful in identifying patients at risk for AR before clinical evidence of allograft dysfunction.