ANZCTR - Registration

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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]

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

Kidney transplantation

Kidney transplant rejection

Condition category

Condition code

Renal and Urogenital

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]

Not applicable

Comparator / control treatment

No control group - observational study

Control group

Uncontrolled

Outcomes

Primary outcome [1]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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

Sex

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

12/07/2021

Actual

Date of last participant enrolment

Anticipated

30/06/2023

Actual

Date of last data collection

Anticipated

30/06/2024

Actual

Sample size

Target

300

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Royal Melbourne Hospital - City campus - Parkville

Recruitment postcode(s) [1]

3050 - Parkville

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Department of Nephrology, Royal Melbourne Hospital

Address [1]

Royal Melbourne Hospital
300 Grattan Street
Parkville
Victoria 3050

Country [1]

Australia

Primary sponsor type

Hospital

Name

Royal Melbourne Hospital

Address

300 Grattan Street
Parkville
Victoria 3050

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Other collaborator category [1]

Other Collaborative groups

Name [1]

Walter and Eliza Hall Institute

Address [1]

1G Royal Parade
Parkville
Victoria 3052

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Melbourne Health Human Research Ethics Committee

Ethics committee address [1]

Office for Research
The Royal Melbourne Hospital
Level 2 South West
300 Grattan Street
Parkville VIC 3050

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

25/01/2021

Approval date [1]

22/04/2021

Ethics approval number [1]

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

A/Prof Peter Hughes

Address

Department of Nephrology
Royal Melbourne Hospital
300 Grattan Street
Parkville
Victoria 3050

Country

Australia

Phone

+61 3 93427143

Fax

+61 3 93471420

Email

Peter.Hughes@mh.org.au

Contact person for public queries

Name

Kevin Chow

Address

Department of Nephrology
Royal Melbourne Hospital
300 Grattan Street
Parkville
Victoria 3050

Country

Australia

Phone

+61 3 93427143

Fax

+61 3 93471420

Email

Kevin.Chow@mh.org.au

Contact person for scientific queries

Name

Kevin Chow

Address

Department of Nephrology
Royal Melbourne Hospital
300 Grattan Street
Parkville
Victoria 3050

Country

Australia

Phone

+61 3 93427143

Fax

+61 3 93471420

Email

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 Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

No additional documents have been identified.