Molecular Analysis of Diabetic Kidney Disease Biopsies

NCT ID: NCT04029402

Last Updated: 2021-04-30

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 500 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2019-07-01
• Study Completion Date: 2025-12-31

Brief Summary

Despite decades of research, the pathogenesis of human diabetic kidney disease remains largely unclear. Our goal is to use archived human kidney biopsy tissue from patients with and with diabetic nephropathy to identify new molecules that drive and/or protect against disease progression. We will use RNA sequencing to identify transcriptomic changes that associate with histologic and functional outcomes.

Detailed Description

RESEARCH OBJECTIVES A. To identify differences in transcription profiles obtained from residual kidney tissue which was obtained for clinical purposes.

B. To identify differences in transcription profile between patients whose loss of kidney function progresses rapidly (eGFR decline ≥4ml/min/year) and in whom it progresses more slowly (eGFR decline <4ml/min/year).

C. To identify differences in transcription profile between predominantly glomerular and predominantly tubulointerstitial histopathological types .

D. To identify new pathogenetic pathways that may become targets for therapeutic intervention

METHODS The planned study centres on the use of archival biopsy material that is superfluous to what is or would be needed for clinical care (01/01/1995 to 31/05/2018 , n= approximately 400-500). Archived samples will be collected from St. Michael's Hospital and a number of collaborating centres, including but not limited to University of British Columbia, the University of Manitoba, and the University of Ottawa.

RNA will be extracted from the biopsy material using either the core that has been used for immunofluorescence microscopy and is stored at -80˚C, and/or the core that is formalin-fixed, embedded in paraffin wax and stored at room temperature. The RNA thereby extracted will be subjected to detailed interrogation by RNASeq to quantify the expression level of mRNAs (transcriptome) and compare differences, as indicated in the research objectives detailed above. The transcriptome will then be related to the clinical course (eGFR decline) and histopathological changes, in addition to examining potentially pathogenetically important and that are amenable to therapeutic intervention.

Histopathology will also be performed and classified according to established systems.

Clinical information that would be retrieved from patients' medical records are listed below.

Clinical data

1. Age

2. Gender

3. Ethnicity

4. Diabetes history

5. Diabetes type: 1, 2

6. Retinopathy history

7. Smoking history

8. Medications

9. Comorbidities

10. Past medical history

11. Primary nephrologist Laboratory data (prior to biopsy, at biopsy and post-biopsy)

12. Renal function measures and calculations. For example:

i. Serum creatinine, eGFR ii. Change in creatinine and eGFR iii. Urinary albumin:creatinine values and ratio (ACR) iv. Urine protein:creatinine values and ratio (PCR) v. Urinary protein excretion rate (UPEx) vi. Changes in ACR, PCR, UPEx

13. Diabetes measures and calculations. Biopsy data

14. Biopsy related data

Each site will locally maintain a confidential Master Linking Log.

De-identified data will be entered into a secure REDCap database that is hosted by St. Michael's Hospital.

Conditions

Diabetic Nephropathies; Kidney Disease, Chronic

Study Design

• Observational Model Type: CASE_CONTROL
• Study Time Perspective: RETROSPECTIVE

Study Groups

Diabetic kidney disease

Patients with archived biopsies with a pathologic diagnosis of diabetic kidney disease, interstitial fibrosis/tubular atrophy, or nephrosclerosis.

RNA sequencing

Intervention Type: OTHER

Transcriptomic analysis of kidney biopsy tissue, and linking with slope of eGFR decline

Healthy controls

Potential living donors with archived biopsies performed as part of their donor workup and with no diagnostic abnormalities

RNA sequencing

Intervention Type: OTHER

Transcriptomic analysis of kidney biopsy tissue, and linking with slope of eGFR decline

Interventions

RNA sequencing

Transcriptomic analysis of kidney biopsy tissue, and linking with slope of eGFR decline

Intervention Type: OTHER

Other Intervention Names

Histology; Slope of eGFR decline

Eligibility Criteria

Inclusion Criteria

• history of type 1 or type 2 diabetes
• at least 1 archived native kidney biopsy that demonstrates either pure diabetic kidney disease or features of non-specific vascular disease, including glomerulosclerosis, non-inflammatory vascular disease,
• sufficient remaining archived kidney biopsy tissue for RNA sequencing (100 um thick tissue section) and histologic analysis (PAS and Masson Trichrome staining)

• at least 1 native kidney disease biopsy with no diagnostic abnormality

Exclusion Criteria

• less than 3 eGFR values post-biopsy
• latest recorded eGFR values less than 6 months post-biopsy

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Ottawa

OTHER

Sponsor Role: collaborator

University of British Columbia

OTHER

Sponsor Role: collaborator

University of Manitoba

OTHER

Sponsor Role: collaborator

Unity Health Toronto

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

University of British Columbia

Vancouver, British Columbia, Canada

Site Status: NOT_YET_RECRUITING

University of Manitoba

Winnipeg, Manitoba, Canada

Site Status: NOT_YET_RECRUITING

University of Ottawa

Ottawa, Ontario, Canada

Site Status: NOT_YET_RECRUITING

St. Michael's Hospital

Toronto, Ontario, Canada

Site Status: RECRUITING

Countries

Canada

Central Contacts

Richard Gilbert, MD PhD

Role: CONTACT

richard.gilbert@utoronto.ca

416-864-3747

Facility Contacts

Sean Barbour, MD

Role: primary

Claudio Rigatto, MD

Role: primary

Kevin Burns, MD

Role: primary

Michelle Nash

Role: primary

nashm@smh.ca

416-864-6060 ext. 3692

Other Identifiers

16-118

Identifier Type: -

Identifier Source: org_study_id