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Multicentre randomised controlled trial protocol of urine CXCL10 monitoring strategy in kidney transplant recipients.

ABSTRACT: INTRODUCTION:Subclinical inflammation is an important predictor of death-censored graft loss, and its treatment has been shown to improve graft outcomes. Urine CXCL10 outperforms standard post-transplant surveillance in observational studies, by detecting subclinical rejection and early clinical rejection before graft functional decline in kidney transplant recipients. METHODS AND ANALYSIS:This is a phase ii/iii multicentre, international randomised controlled parallel group trial to determine if the early treatment of rejection, as detected by urine CXCL10, will improve kidney allograft outcomes. Incident adult kidney transplant patients (n~420) will be enrolled to undergo routine urine CXCL10 monitoring postkidney transplant. Patients at high risk of rejection, defined as confirmed elevated urine CXCL10 level, will be randomised 1:1 stratified by centre (n=250). The intervention arm (n=125) will undergo a study biopsy to check for subclinical rejection and biopsy-proven rejection will be treated per protocol. The control arm (n=125) will undergo routine post-transplant monitoring. The primary outcome at 12?months is a composite of death-censored graft loss, clinical biopsy-proven acute rejection, de novo donor-specific antibody, inflammation in areas of interstitial fibrosis and tubular atrophy (Banff i-IFTA, chronic active T-cell mediated rejection) and subclinical tubulitis on 12-month surveillance biopsy. The secondary outcomes include decline of graft function, microvascular inflammation at 12?months, development of IFTA at 12?months, days from transplantation to clinical biopsy-proven rejection, albuminuria, EuroQol five-dimension five-level instrument, cost-effectiveness analysis of the urine CXCL10 monitoring strategy and the urine CXCL10 kinetics in response to rejection therapy. ETHICS AND DISSEMINATION:The study has been approved by the University of Manitoba Health Research Ethics Board (HS20861, B2017:076) and the local research ethics boards of participating centres. Recruitment commenced in March 2018 and results are expected to be published in 2023. De-identified data may be shared with other researchers according to international guidelines (International Committee of Medical Journal Editors [ICJME]). TRIAL REGISTRATION NUMBER:NCT03206801; Pre-results.

SUBMITTER: Ho J

PROVIDER: S-EPMC6500325 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Multicentre randomised controlled trial protocol of urine CXCL10 monitoring strategy in kidney transplant recipients.

Ho Julie J Sharma Atul A Kroeker Kristine K Carroll Robert R De Serres Sacha S Gibson Ian W IW Hirt-Minkowski Patricia P Jevnikar Anthony A Kim S Joseph SJ Knoll Greg G Rush David N DN Wiebe Chris C Nickerson Peter P

BMJ open 20190411 4

<h4>Introduction</h4>Subclinical inflammation is an important predictor of death-censored graft loss, and its treatment has been shown to improve graft outcomes. Urine CXCL10 outperforms standard post-transplant surveillance in observational studies, by detecting subclinical rejection and early clinical rejection before graft functional decline in kidney transplant recipients.<h4>Methods and analysis</h4>This is a phase ii/iii multicentre, international randomised controlled parallel group trial ...[more]

PMID: 30975673

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Project description:BackgroundCalcineurin inhibitors, including tacrolimus, remain a cornerstone of immunosuppressive therapy after kidney transplantation. However, the therapeutic window is narrow, and nephrotoxic side effects occur with overdose, while the risk of alloimmunization and graft rejection increases with underdose. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) allows quantification of tacrolimus in biological samples from patients. This study investigates the feasibility of quantifying tacrolimus in scalp hair from kidney transplant (KT) recipients and correlates hair tacrolimus concentrations with tacrolimus dosage and blood trough levels. The aim was to provide proof-of-principle for hair tacrolimus drug monitoring in KT recipients.MethodSingle-center prospective study between September 9, 2021 and December 4, 2021, including KT recipients under tacrolimus. Minors, patients with active skin or hair diseases, and patients with scalp hair shorter than 4 cm were excluded from participation. Scalp hair was collected from the posterior vertex of patients, cut into segments, and analyzed for tacrolimus by LC-MS/MS. Patients filled out a questionnaire on hair treatments and washing habits. In parallel, tacrolimus trough levels were measured in whole blood and correlated with hair tacrolimus concentrations.ResultsIn total, 39 consenting KT recipients were included, and hair samples were collected at 53 visits. Tacrolimus was detected in 98% of hair samples from patients exposed to the drug. Tacrolimus hair levels and whole blood trough levels were correlated with a beta coefficient of 0.42 (95% CI: -0.22-1.1, p = n.s.). Age and dark hair affected hair tacrolimus measurements, while different tacrolimus formulations (immediate release vs. extended release), hair washes, and permanent coloring did not. Longitudinal measurements in a subgroup of patients indicate that long-term measurement of hair tacrolimus levels is feasible.ConclusionMeasuring tacrolimus in hair is a potentially reliable method to monitor drug exposure in KT patients. Rapid wash-in effects and consistent concentrations over time indicate that tacrolimus is incorporated into the hair matrix, allowing temporal resolution in the analysis of recent exposure and exposure history. This method provides a simple and low-risk alternative to regular blood sampling, sparing patients from frequent hospital visits through the self-collection of hair samples.

Project description:Seventy years after its discovery, studies of the myriad properties, and potential disease associations of uromodulin are now burgeoning. Although normative ranges for serum/plasma uromodulin concentrations were established over 30 years ago, their external validation occurred only in very recent, larger studies. As tubular function indices, serum and urinary uromodulin may be more sensitive indicators of kidney graft dysfunction undetected by glomerular filtration markers, or proteinuria. Moreover, 2 sizable, just published longitudinal reports revealed that lower serum uromodulin levels were associated with cardiovascular disease (CVD) outcomes, total mortality, and infectious disease deaths, in patients with known or suspected coronary heart disease. Preliminary longitudinal studies have reported that reduced levels of plasma or serum uromodulin were linked to progression to end-stage renal disease in chronic kidney disease patients, and graft failure in kidney transplant recipients (KTRs). Conflicting data on the associations, or lack thereof, between lower urinary uromodulin concentrations and accelerated loss of renal function, or renal failure, in nontransplant chronic kidney disease patients, are perhaps due, in part, to analytical limitations in determining urine uromodulin. Potential longitudinal associations between serum and urinary uromodulin concentrations, and CVD outcomes, graft failure, and all-cause mortality, await validation in large, diverse cohorts of chronic KTRs. Taking advantage of an efficient case-cohort design scheme, we demonstrate how the completed FAVORIT clinical trial cohort might be ideally suited to evaluate these associations. Using available case-cohort sample data, statistical power simulations are provided to detect relative risk estimates of 1.50 for CVD (n = 309 events), 1.56 for graft failure (n = 223 events) or 1.50 for death from any cause (n = 320 events), comparing values below the median, to values equal to or above the median for serum uromodulin values. Edifying data such as these would advance our understanding of the hypothetical utility of uromodulin measurement in KTRs considerably.

Project description:BackgroundPrior studies have explored the use of regular reminders to improve adherence among kidney transplant recipients (KTRs), but none have included real-time alarms about drug dosage, frequency, and interval. In the present study, we aimed to evaluate the efficacy and stability of an information and communication technology (ICT)-based centralized monitoring system for increasing medication adherence among Korean KTRs.MethodsIn this prospective, multicenter, randomized controlled study, enrolled KTRs were randomized to either the ICT-based centralized monitoring group or control group. The ICT-based centralized monitoring system alerted both patients and medical staff with texts and pill box alarms if there was a missed dose or a dosage/time error. We compared the two groups in terms of medication adherence and transplant outcomes over 6 months, and evaluated patient satisfaction with the ICT-based monitoring system.ResultsAmong 114 enrolled KTRs, 57 were assigned to the ICT-based centralized monitoring group and 57 to the control group. The two groups did not significantly differ in mean adherence at each follow-up visit. The intrapatient variability of tacrolimus and mycophenolic acid levels, renal function, and adverse transplant outcomes did not differ between the intervention and control groups, or between the intervention group with feedback generation and the intervention group without feedback generation. Patients showed high overall satisfaction with the ICT-based centralized monitoring system, which significantly improved across the study period (p = 0.012).ConclusionsDue to high baseline adherence, the ICT-based centralized monitoring system did not maximize medication adherence or enhance transplant outcomes among Korean KTRs. However, patients were highly satisfied with the system. Our results suggest that the ICT-based centralized monitoring system could be successfully applied in clinical trials.Trial registrationClinicalTrials.gov, NCT03136588. Registered 20 April 2017 - Retrospectively registered.

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Multicentre randomised controlled trial protocol of urine CXCL10 monitoring strategy in kidney transplant recipients.

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Multicentre randomised controlled trial protocol of urine CXCL10 monitoring strategy in kidney transplant recipients.

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