Kidney Transplant; Complications, Rejection of Renal Transplant
Conditions
Keywords
Urine biomarker, CXCL10 chemokine, Post-transplant monitoring, Protocol biopsy
Brief summary
This is a Phase II-III multi-center prospective randomized controlled clinical trial of incident adult renal transplant patients. The primary objective of this study is to determine if the early treatment of rejection, as detected by urinary CXCL10, will improve renal allograft outcomes.
Detailed description
This is a Phase II-III multi-center prospective randomized controlled clinical trial of incident adult renal transplant patients. Patients will be screened for eligibility (n≈485) and n≈420 will be enrolled and undergo post-transplant surveillance with urinary CXCL10. Two hundred and fifty patients deemed at high risk for rejection based on a confirmed elevated urine CXCL10 will undergo 1:1 randomization to the intervention and control arms, stratified by center. The total study duration is approximately 5 years; and there two main phases - screening and intervention. All eligible, enrolled patients will undergo the Screening Phase (n≈420). Routine urine CXCL10 screening will be done from 2 weeks - 9 months post-transplant. We have previously shown that urine CXCL10 is elevated in ischemia-reperfusion injury, so screening will commence at 2 weeks (+/- 4 days) to exclude this as a potential confounding factor (60). If patient develops a confirmed elevated urine CXCL10 level and is considered high risk for rejection, they will proceed to Randomization in the Intervention Phase, which can occur anytime between 2 weeks - 9 months post-transplant. Participants in the Intervention Arm will undergo renal biopsy to check for rejection. Biopsy-proven subclinical rejection will be treated per study protocol. Participants in the Control Arm will continue routine post-transplant surveillance with serum creatinine and proteinuria; serial urine samples will continue to be collected and analyzed (blinded), but not used to direct care. All randomized participants will undergo a 12-month study exit visit with protocol biopsy to determine primary, secondary and long-term outcomes. Enrolled patients with persistently low urine CXCL10 and low risk of rejection from 2 weeks - 9 months post-transplant will be considered Off-Study (not randomized). They will undergo a 12-month study exit visit (+/- 7 days) to determine secondary and long-term outcomes.
Interventions
PROCEDUREKidney transplant biopsy
Elevated urine CXCL10 will trigger a study biopsy in patients randomized to the intervention arm. Subclinical rejection will be treated per protocol.
Sponsors
University of Manitoba
Canadian Institutes of Health Research (CIHR)
Canadian National Transplant Research Program
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SCREENING
Masking
SINGLE (Outcomes Assessor)
Masking description
The assessor of the primary outcome will be masked. As the intervention involves a study biopsy, based on an elevated urine CXCL10, it is not possible to blind the participant, care provider or investigator.
Intervention model description
This is a Phase II-III multi-center prospective randomized controlled clinical trial of incident adult renal transplant patients. Patients with elevated urine CXCL10 will be randomized 1:1 to the intervention and control arms, stratified by center (\ 420 enrolled to urine CXCL10 screening for n=250 randomized participants).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Participants must be able to understand and provide written informed consent 2. Stated willingness to comply with all study procedures and availability for the duration of the study 3. All ethnic and gender groups will have equal access to the study 4. Incident adult (age ≥18) renal transplant patients with a living or deceased donor kidney transplant 5. Confirmed elevated urine CXCL10:Cr without a urinary tract infection or gross hematuria.
Exclusion criteria
1. Primary non-function 2. Blood group (ABO) incompatible 3. Pre-transplant donor specific antibody (DSA) positive (MFI\>1000 OR positive flow crossmatch) 4. Human leukocyte (HLA) 0 HLA antigen D-related (DR) + 0 major HLA class 2 (DQ) mismatch 5. Presence of other transplanted organ or co-transplanted organ 6. Medical contraindication to biopsy or rejection treatment 7. Followed outside of investigational center 8. Participation in other interventional trials within 4-weeks post-transplant or anytime post-transplant till study end at 12-months 9. Intention to not use a maintenance immunosuppression regimen consisting of calcineurin inhibitor (CNI) and anti-proliferative agents 10. Any condition that, in the opinion of the investigator, would pose risk to the subject's safe participation, or interfere with their ability to comply with the study requirements, or may impact the quality of interpretation of the data.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Death-censored graft loss | 2 weeks-12 months post-transplant | Return to dialysis or re-transplant |
| Clinical indication biopsy-proven acute rejection | 2 weeks-12 months post-transplant | Clinical rejection, Banff criteria |
| De novo donor specific antibody development | 2 weeks-12 months post-transplant | De novo human leukocyte antibody (HLA) antibodies, donor specific |
| Subclinical tubulitis | 12-month study exit biopsy | Subclinical rejection, Banff criteria |
| Interstitial fibrosis and inflammation (IFTA + i) | 12-month study exit biopsy | IFTA + i, defined by Mayo criteria |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Renal allograft function | 6, 12, 24 and 60 months post-transplant | Change in eGFR (slope, ∆) and graft function (eGFR) (absolute, mL/min) |
| Microvascular inflammation | 12-month study exit biopsy | Banff ptc, g, c4d, cg |
| Development IFTA from implantation to 12-months | 12-month study exit biopsy | Banff ∆ ci, ct, cv |
| Days from transplantation to clinical-biopsy proven rejection | 2 weeks-12 months post-transplant | Time to biopsy proven rejection |
| Albuminuria >300mg/day | 6, 12, 24 and 60 months post-transplant | Urine albumin: Cr ratio |
| Cost-effectiveness of urine CXCL10 monitoring strategy | 2 weeks-12 months post-transplant | Costs of urine CXCL10 screening |
| Quality of life | 6 and 12 months post-transplant | EuroQOL (EQ-5DL) |
| Urine CXCL10 kinetics | 2 weeks-12 months post-transplant | Change in urine CXCL10 levels in response to rejection therapy |
Countries
Australia, Canada
Contacts
PRINCIPAL_INVESTIGATORJulie Ho, MD
University of Manitoba
Outcome results
None listed