Urine CXCL10 Monitoring Trial in Kidney Transplant

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized Controlled Trial of Urine CXCL10 Chemokine Monitoring Post-renal Transplant

Conditions
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Kidney Transplant; Complications, Rejection of Renal Transplant

Intervention / Treatment
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* Procedure: Kidney transplant biopsy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be able to understand and provide written informed consent Stated willingness to comply with all study procedures and availability for the duration of the study All ethnic and gender groups will have equal access to the study Incident adult (age ≥18) renal transplant patients with a living or deceased donor kidney transplant Confirmed elevated urine CXCL10:Cr without a urinary tract infection or gross hematuria. Exclusion Criteria: Primary non-function Blood group (ABO) incompatible Pre-transplant donor specific antibody (DSA) positive (MFI>1000 OR positive flow crossmatch) Human leukocyte (HLA) 0 HLA antigen D-related (DR) + 0 major HLA class 2 (DQ) mismatch Presence of other transplanted organ or co-transplanted organ Medical contraindication to biopsy or rejection treatment Followed outside of investigational center Participation in other interventional trials within 4-weeks post-transplant or anytime post-transplant till study end at 12-months Intention to not use a maintenance immunosuppression regimen consisting of calcineurin inhibitor (CNI) and anti-proliferative agents 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Screening
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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).
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>Participants with high urine CXCL10 randomized to the Intervention Arm will undergo a kidney transplant biopsy to check for rejection. Biopsy-proven subclinical rejection will be treated per study protocol. | Procedure: Kidney transplant biopsy<br>* Elevated urine CXCL10 will trigger a study biopsy in patients randomized to the intervention arm. Subclinical rejection will be treated per protocol.<br>* Other names: Protocol biopsy;|
| No Intervention: Control<br>Participants with high urine CXCL10 randomized to 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. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death-censored graft loss | Return to dialysis or re-transplant | 2 weeks-12 months post-transplant | 
| Clinical indication biopsy-proven acute rejection | Clinical rejection, Banff criteria | 2 weeks-12 months post-transplant | 
| De novo donor specific antibody development | De novo human leukocyte antibody (HLA) antibodies, donor specific | 2 weeks-12 months post-transplant | 
| Subclinical tubulitis | Subclinical rejection, Banff criteria | 12-month study exit biopsy | 
| Interstitial fibrosis and inflammation (IFTA + i) | IFTA + i, defined by Mayo criteria | 12-month study exit biopsy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal allograft function | Change in eGFR (slope, ∆) and graft function (eGFR) (absolute, mL/min) | 6, 12, 24 and 60 months post-transplant | 
| Microvascular inflammation | Banff ptc, g, c4d, cg | 12-month study exit biopsy | 
| Development IFTA from implantation to 12-months | Banff ∆ ci, ct, cv | 12-month study exit biopsy | 
| Days from transplantation to clinical-biopsy proven rejection | Time to biopsy proven rejection | 2 weeks-12 months post-transplant | 
| Albuminuria >300mg/day | Urine albumin: Cr ratio | 6, 12, 24 and 60 months post-transplant | 
| Cost-effectiveness of urine CXCL10 monitoring strategy | Costs of urine CXCL10 screening | 2 weeks-12 months post-transplant | 
| Quality of life | EuroQOL (EQ-5DL) | 6 and 12 months post-transplant | 
| Urine CXCL10 kinetics | Change in urine CXCL10 levels in response to rejection therapy | 2 weeks-12 months post-transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Post-transplant monitoring, Urine biomarker, CXCL10 chemokine, Protocol biopsy