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Trial registered on ANZCTR


Registration number
ACTRN12621000898853
Ethics application status
Approved
Date submitted
25/05/2021
Date registered
9/07/2021
Date last updated
9/07/2021
Date data sharing statement initially provided
9/07/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Developing a non-invasive method for the diagnosis and monitoring of kidney transplant rejection
Scientific title
Urinary proteomics in renal transplant rejection
Secondary ID [1] 304303 0
Nil known
Universal Trial Number (UTN)
Trial acronym
INSIGhT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
End stage kidney disease 322043 0
Kidney transplantation 322044 0
Kidney transplant rejection 322045 0
Condition category
Condition code
Renal and Urogenital 319769 319769 0 0
Kidney disease

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
There are two arms to this observational study.
Cohort 1 - Incident patients undergoing live donor or deceased donor kidney transplantation.
Patients will provide a urine sample for assessment by proteomics at regular intervals post-transplant (weekly at 0-3 months, 2 weekly at 3-6 months, 3 weekly at 6-9 months, 4 weekly at 9-12 months) and at the time of any surveillance or indication transplant kidney biopsy. Patients will also be invited to provide an optional kidney transplant biopsy sample for assessment by MMDx molecular microscope. The period of observation is up to 12 months post-transplant.

Cohort 2 - Kidney transplant patients not recruited into Cohort 1 who are having an indication transplant kidney biopsy.
Patients will provide a single urine sample for assessment by proteomics at the time of their biopsy. Patients will also be invited to provide an optional kidney transplant biopsy sample for assessment by MMDx molecular microscope. The period of observation is a single time point at the time of their biopsy.
Intervention code [1] 320647 0
Not applicable
Comparator / control treatment
No control group - observational study
Control group
Uncontrolled

Outcomes
Primary outcome [1] 327628 0
Changes in the urinary proteome associated with kidney transplant rejection:

The urinary proteome will be assessed by shot-gun mass spectrometry with changes in the proteome associated with kidney transplant rejection determined by correlation with kidney transplant biopsy results assessed as per the BANFF diagnostic criteria.
Timepoint [1] 327628 0
Cohort 1:
0-3 months post-transplant: weekly
3-6 months post-transplant: every 2 weeks
6-9 months post-transplant: every 3 weeks
9-12 months post-transplant: every 4 weeks

Cohort 2:
A single sample at the time of an indication kidney transplant biopsy
Secondary outcome [1] 395987 0
Changes in the urinary proteome associated with BK nephropathy:

The urinary proteome will be assessed by shot-gun mass spectrometry with changes in the proteome associated with BK nephropathy determined by correlation with kidney transplant biopsy results assessed as per the BANFF diagnostic criteria.
Timepoint [1] 395987 0
Cohort 1:
0-3 months post-transplant: weekly
3-6 months post-transplant: every 2 weeks
6-9 months post-transplant: every 3 weeks
9-12 months post-transplant: every 4 weeks

Cohort 2:
A single sample at the time of an indication kidney transplant biopsy
Secondary outcome [2] 395988 0
Changes in the urinary proteome associated with bacterial pyelonephritis:

The urinary proteome will be assessed by shot-gun mass spectrometry with changes in the proteome associated with bacterial pyelonephritis determined by correlation with kidney transplant biopsy results assessed as per the BANFF diagnostic criteria.
.
Timepoint [2] 395988 0
Cohort 1:
0-3 months post-transplant: weekly
3-6 months post-transplant: every 2 weeks
6-9 months post-transplant: every 3 weeks
9-12 months post-transplant: every 4 weeks

Cohort 2:
A single sample at the time of an indication kidney transplant biopsy
Secondary outcome [3] 398090 0
Changes in the urinary proteome associated with recurrent glomerular disease:

The urinary proteome will be assessed by shot-gun mass spectrometry with changes in the proteome associated with recurrent glomerular disease determined by correlation with kidney transplant biopsy results assessed as per the BANFF diagnostic criteria.
Timepoint [3] 398090 0
Cohort 1:
0-3 months post-transplant: weekly
3-6 months post-transplant: every 2 weeks
6-9 months post-transplant: every 3 weeks
9-12 months post-transplant: every 4 weeks

Cohort 2:
A single sample at the time of an indication kidney transplant biopsy
Secondary outcome [4] 398091 0
Changes in the urinary proteome associated with acute tubular necrosis :

The urinary proteome will be assessed by shot-gun mass spectrometry with changes in the proteome associated with acute tubular necrosis determined by correlation with kidney transplant biopsy results assessed as per the BANFF diagnostic criteria.
Timepoint [4] 398091 0
Cohort 1:
0-3 months post-transplant: weekly
3-6 months post-transplant: every 2 weeks
6-9 months post-transplant: every 3 weeks
9-12 months post-transplant: every 4 weeks

Cohort 2:
A single sample at the time of an indication kidney transplant biopsy
Secondary outcome [5] 398092 0
Changes in the urinary proteome associated with interstitial fibrosis/tubular atrophy:

The urinary proteome will be assessed by shot-gun mass spectrometry with changes in the proteome associated with interstitial fibrosis/tubular atrophy determined by correlation with kidney transplant biopsy results assessed as per the BANFF diagnostic criteria.
Timepoint [5] 398092 0
Cohort 1:
0-3 months post-transplant: weekly
3-6 months post-transplant: every 2 weeks
6-9 months post-transplant: every 3 weeks
9-12 months post-transplant: every 4 weeks

Cohort 2:
A single sample at the time of an indication kidney transplant biopsy
Secondary outcome [6] 398093 0
Changes in the urinary proteome associated with healthy kidney transplants:

The urinary proteome will be assessed by shot-gun mass spectrometry with changes in the proteome associated with normal kidney transplant function determined by correlation with kidney transplant biopsy results assessed as per the BANFF diagnostic criteria.
Timepoint [6] 398093 0
Cohort 1:
0-3 months post-transplant: weekly
3-6 months post-transplant: every 2 weeks
6-9 months post-transplant: every 3 weeks
9-12 months post-transplant: every 4 weeks

Cohort 2:
A single sample at the time of an indication kidney transplant biopsy

Eligibility
Key inclusion criteria
(1) Incident patients undergoing live donor or deceased donor kidney transplantation at the Royal Melbourne Hospital; OR
(2) Patients not recruited at the time of transplant but undergoing a ‘for-cause’ transplant kidney biopsy
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
(1) Patients who are unable or unwilling to provide consent to participate in the study.

(2) Patients who will not be able to attend this centre (Royal Melbourne Hospital) for follow up over the study period (cohort 1 only).

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
This is an initial observational study that seeks to determine whether changes in the urine proteome of kidney transplant recipients are correlated with diagnoses made on kidney biopsies, and to understand how those changes arise over time. Within the 300 patients that we will recruit into this study, we estimate that there will be approximately 60 episodes of rejection (40 cell mediated and 20 antibody mediated), 30 episodes of acute tubular necrosis, 10 episodes of BK nephropathy and 30 cases of interstitial fibrosis/tubular atrophy alone.
Categorical variables will be presented as frequencies and percentages and compared using Chi-squared test. Continuous variables will be presented as mean +/- sd and compared using two-tailed Student t-test. 2-tailed p-value of < 0.05 will be considered as statistically significant, adjusting for potential confounding variables. Multiple hypothesis testing correction will be applied for the protein biomarkers. Longitudinally collected samples. (Cohort 1) will be analysed as a repeated-measurement experiment, with a repeated measures ANOVA to test for proteins with changed expression across time points .
For predictive biomarker discover, machine-learning models will be used, where data are split into training and test sets. Specificity and sensitivity of the constructed models will be assessed.

In addition, we will establish common temporal profiles for measured proteins using fuzzy clustering (Futschik et al. "Noise-robust soft clustering of gene expression time-course data." Journal of bioinformatics and computational biology 3.04, 2005: 965-988.). Correlation between different temporal profiles and diagnoses will be investigated.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 19525 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment postcode(s) [1] 34134 0
3050 - Parkville

Funding & Sponsors
Funding source category [1] 308679 0
Hospital
Name [1] 308679 0
Department of Nephrology, Royal Melbourne Hospital
Address [1] 308679 0
Royal Melbourne Hospital
300 Grattan Street
Parkville
Victoria 3050
Country [1] 308679 0
Australia
Primary sponsor type
Hospital
Name
Royal Melbourne Hospital
Address
300 Grattan Street
Parkville
Victoria 3050
Country
Australia
Secondary sponsor category [1] 309558 0
None
Name [1] 309558 0
Address [1] 309558 0
Country [1] 309558 0
Other collaborator category [1] 281804 0
Other Collaborative groups
Name [1] 281804 0
Walter and Eliza Hall Institute
Address [1] 281804 0
1G Royal Parade
Parkville
Victoria 3052
Country [1] 281804 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308601 0
Melbourne Health Human Research Ethics Committee
Ethics committee address [1] 308601 0
Office for Research
The Royal Melbourne Hospital
Level 2 South West
300 Grattan Street
Parkville VIC 3050
Ethics committee country [1] 308601 0
Australia
Date submitted for ethics approval [1] 308601 0
25/01/2021
Approval date [1] 308601 0
22/04/2021
Ethics approval number [1] 308601 0
2021.012

Summary
Brief summary
Kidney transplantation is the best form of treatment for patients with kidney failure, however transplant recipients are at risk of allograft rejection, because the recipient’s immune system recognises the transplanted organ as foreign. Up to 20% of kidney transplant recipients experience at least one episode of rejection. This remains a major cause of kidney transplant failure. Most episodes of rejection are diagnosed by performing a kidney biopsy on patients who have been found to have abnormalities on their blood test results. However, a significant proportion of patients have rejection despite not having abnormal blood test results. In order to detect these cases of “sub-clinical” rejection, the majority of transplant recipients are subjected to surveillance kidney biopsies at pre-determined time points, even in the absence of any clinical problems. Kidney transplant biopsies are invasive, uncomfortable and carry some risk, but remain the only reliable way of diagnosing rejection, especially sub-clinical rejection. Because surveillance biopsies are only performed at a few predetermined time points it is also possible for subclinical rejection to be present weeks or months before it is detected by such a biopsy or becomes clinically evident.
Assessment of the pattern of proteins or protein fragments excreted into the urine of kidney transplant recipients may provide an alternative, non-invasive method of understanding the condition and health of the kidney. If a panel of urinary proteins that changes in the setting of kidney transplant rejection could be identified, it could potentially allow for the detection of patients with or at risk of subclinical rejection, therefore avoiding the need to subject large numbers of patients to surveillance biopsies. It might also allow earlier detection of subclinical rejection meaning that it can be treated with before damage is done to the kidney.
This pilot study will be performed in collaboration between the Royal Melbourne Hospital and the Walter and Eliza Hall Institute of Medical Research . Kidney transplant recipients at the Royal Melbourne Hospital will have urine samples prospectively collected at pre-determined time points in the first year post-transplantation. These samples will be analysed at the Advanced Technology and Biology Division at the Walter and Eliza Hall Institute of Medical Research (WEHI). Urine protein patterns will be correlated with outcome data obtained in the course of routine clinical care in order to determine the existence of any patterns that correlate with rejection. Serial samples will be analysed to determine whether identification of these proteins at earlier time points can identify patients who ultimately develop rejection. Whether the lack of expression of these proteins can also identify patients who are not at risk of rejection (therefore not requiring surveillance biopsies will also be analysed.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 111286 0
A/Prof Peter Hughes
Address 111286 0
Department of Nephrology
Royal Melbourne Hospital
300 Grattan Street
Parkville
Victoria 3050
Country 111286 0
Australia
Phone 111286 0
+61 3 93427143
Fax 111286 0
+61 3 93471420
Email 111286 0
Peter.Hughes@mh.org.au
Contact person for public queries
Name 111287 0
Dr Kevin Chow
Address 111287 0
Department of Nephrology
Royal Melbourne Hospital
300 Grattan Street
Parkville
Victoria 3050
Country 111287 0
Australia
Phone 111287 0
+61 3 93427143
Fax 111287 0
+61 3 93471420
Email 111287 0
Kevin.Chow@mh.org.au
Contact person for scientific queries
Name 111288 0
Dr Kevin Chow
Address 111288 0
Department of Nephrology
Royal Melbourne Hospital
300 Grattan Street
Parkville
Victoria 3050
Country 111288 0
Australia
Phone 111288 0
+61 3 93427143
Fax 111288 0
+61 3 93471420
Email 111288 0
Kevin.Chow@mh.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
This is a pilot study. No IPD will be available.
What supporting documents are/will be available?
No other documents available
Summary results
No Results