Molecular Analysis of Diabetic Kidney Disease Biopsies

Diabetic Nephropathies Clinical Trial

Official title:

Molecular Analysis of Diabetic Kidney Disease Biopsies

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04029402
• Other study ID #: 16-118
• Status: Recruiting
• Start date: July 1, 2019
• Est. completion date: December 2025

Study information

• Verified date: April 2021
• Source: Unity Health Toronto
• Contact: Richard Gilbert, MD PhD
• Phone: 416-864-3747
• Email: richard.gilbert[@]utoronto.ca
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 500
• Est. completion date: December 2025
• Est. primary completion date: December 2022
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria (diabetic kidney disease cases):

• 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)

Exclusion Criteria (diabetic kidney disease cases):

• less than 3 eGFR values post-biopsy

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

Inclusion Criteria (healthy controls):

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

Related Conditions & MeSH terms

• Diabetic Nephropathies
• Kidney Disease, Chronic
• Kidney Diseases
• Renal Insufficiency, Chronic

Intervention

Other:
• RNA sequencing
Transcriptomic analysis of kidney biopsy tissue, and linking with slope of eGFR decline

Locations

Country	Name	City	State
Canada	University of Ottawa	Ottawa	Ontario
Canada	St. Michael's Hospital	Toronto	Ontario
Canada	University of British Columbia	Vancouver	British Columbia
Canada	University of Manitoba	Winnipeg	Manitoba

Sponsors (4)

Lead Sponsor	Collaborator
Unity Health Toronto	University of British Columbia, University of Manitoba, University of Ottawa

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Interstitial fibrosis	Extent of interstitial fibrosis in kidney biopsy assessed using a semi-quantitative scale on light microscopy of biopsy sections	Baseline biopsy
Primary	Glomerulosclerosis	Extent of glomerulosclerosis in kidney biopsy assessed using a semi-quantitative scale on light microscopy of biopsy sections	Baseline biopsy
Primary	Renal function change	Slope of eGFR decline	Baseline biopsy