Clinical trial NCT04029402: Molecular Analysis of Diabetic Kidney Disease Biopsies
Official title: Molecular Analysis of Diabetic Kidney Disease Biopsies
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Diabetic Nephropathies
Kidney Disease, Chronic
Lead sponsor: Unity Health Toronto
Sponsor class: OTHER
Collaborators: name: University of Ottawa
name: University of British Columbia
name: University of Manitoba
First posted: 2019-07-23
Enrollment: 500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Observational model: CASE_CONTROL
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: 1. Cases: A group of patients with diabetic kidney disease
2. Controls: A group of healthy control patients

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.

Eligibility criteria: 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

Primary outcomes:
measure: Interstitial fibrosis
timeFrame: Baseline biopsy
measure: Glomerulosclerosis
timeFrame: Baseline biopsy
measure: Renal function change
timeFrame: Baseline biopsy
Secondary outcomes:
Other outcomes:
Locations:
city: Vancouver
country: Canada
facility: University of British Columbia
state: British Columbia
city: Winnipeg
country: Canada
facility: University of Manitoba
state: Manitoba
city: Ottawa
country: Canada
facility: University of Ottawa
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
Study officials:
References: