Transformative Research in Diabetic Nephropathy 2.0 (TRIDENT 2)

University of Pennsylvania

Status: Enrolling

Conditions: Diabetic Nephropathies; Kidney Diseases; Diabetes Mellitus, Type 2; Renal Insufficiency, Chronic

Treatments: Drug: Mineralocorticoid Receptor Antagonists(MRAs); Drug: Renin-angiotensin-aldosterone system blockade; Drug: Sodium-glucose cotransporter 2 inhibitors (SGLT2i); Drug: Glucagon-like peptide-1 receptor agonists (GLP 1 RA)

Study type: Observational

Funder types: Other; Industry

Identifiers

NCT07444203

849580

Details and patient eligibility

About

The goal of this observational study is to learn more about kidney health in adults with diabetic kidney disease and other groups. Researchers will study kidney tissue and other samples. They want to learn how sodium-glucose cotransporter-2 (SGLT2) inhibitors, a type of diabetes medicine, may affect the kidneys. People can join only if they are already having a kidney biopsy or kidney surgery as part of their regular medical care.

The main questions this study aims to answer are:

• Do people who take SGLT2 inhibitors show different biological patterns in kidney tissue than similar people who do not take them?
• Are these kidney tissue patterns linked with how kidney health changes over time?

Researchers will compare participants who take SGLT2 inhibitors with similar participants who do not take these medicines.

Participants will:

Let researchers use one stored slide of kidney tissue from their regular care (no extra research biopsy) Give a blood sample and a urine sample Let researchers review medical record information over time

Full description

TRIDENT 2.0 is a multicenter observational translational study that characterizes kidney molecular and histopathologic features in relation to exposure to kidney-protective therapies, with a focus on sodium-glucose cotransporter-2 (SGLT2) inhibitors. The study leverages archived clinical kidney pathology material and harmonized clinical data to support integrated molecular-histologic analyses across participating sites.

Tissue sources and central repository workflows:

Formalin-fixed, paraffin-embedded (FFPE) kidney tissue sections/slides are generated from archived clinical pathology material (including clinically indicated kidney biopsies and available donor or nephrectomy specimens) and transferred under coded identifiers to a central repository for downstream molecular assays and digital pathology.

Spatial transcriptomics and molecular profiling:

Spatially resolved transcriptomic methods are used to generate high-resolution molecular maps while preserving tissue architecture. FFPE (or fresh-frozen, when available) sections may be processed using commercially available spatial transcriptomics platforms (e.g., 10x Genomics Visium, NanoString CosMx, Xenium) or updated technologies implemented under study governance. Standard quality control procedures evaluate tissue integrity, RNA quality, capture efficiency, and resolution of major kidney compartments and cell types. Sequencing is performed on Illumina platforms with platform-appropriate depth, followed by preprocessing using platform-specific pipelines and downstream analysis in R/Python workflows (e.g., Seurat or equivalent) with normalization and batch correction as needed. Planned analyses include identification of cell-type and sub-cell-type signatures in spatial context, mapping of injury patterns (e.g., fibrosis/inflammation/vascular remodeling), and comparative molecular profiling across disease categories and therapy exposure groups with adjustment for relevant covariates.

Digital pathology and centralized histopathology review:

Digitized clinical stains and available diagnostic images are used for centralized review and standardized lesion scoring by renal pathologists. When applicable, diabetic kidney disease (DKD) is classified using established renal pathology criteria. Specimen adequacy metrics are used to guide analytic inclusion and sensitivity analyses.

Linked clinical data (high level):

Clinical data are harmonized across sites to support clinicopathologic and molecular integration, including medication exposure history and relevant laboratory and diagnostic variables. Longitudinal clinical information is used to contextualize molecular and histologic findings for downstream modeling.

Statistical and integrative analytic approach:

Analytic methods include differential expression and pathway analyses with appropriate multiple-testing control and covariate adjustment. Integrative modeling may combine molecular, histologic, and clinical domains using dimension reduction and regularized approaches to derive molecular signatures associated with disease state and therapy exposure.

Enrollment: 200 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• Age ≥18 years
• eGFR ≥10 ml/min/1.73 m2 based on the 2021 race-free CKD-EPI equation13
• Underwent a clinically indicated kidney biopsy, living donor biopsy, or nephrectomy (non-tumor adjacent tissue available).
• Able and willing to provide informed consent for release of one pathology and clinical data abstraction.

Exclusion criteria

• Inability to provide informed consent.
• Archived biopsy or surgical tissue unavailable for slide preparation.
• Any local institutional policy that prohibits release of H&E slides for research.

Trial design

200 participants in 4 patient groups

Biopsy-confirmed Diabetic Kidney Disease Cohort

Description:

Adults with diabetic kidney disease confirmed by a clinically indicated kidney biopsy. This cohort is used to evaluate kidney molecular and histopathologic features in relation to medication exposure history. Interventions/exposures of interest (observational): Primary exposure is sodium-glucose cotransporter 2 inhibitors; additional therapy exposures of interest include renin-angiotensin-aldosterone system blockade, glucagon-like peptide-1 receptor agonists, mineralocorticoid receptor antagonists, and other therapies.

Treatment:

Drug: Glucagon-like peptide-1 receptor agonists (GLP 1 RA)

Drug: Sodium-glucose cotransporter 2 inhibitors (SGLT2i)

Drug: Renin-angiotensin-aldosterone system blockade

Drug: Mineralocorticoid Receptor Antagonists(MRAs)

Disease Control Kidney Disease Cohort

Description:

Adults with other forms of kidney disease (non-DKD), included as disease controls for cross-disease comparisons of molecular and histologic patterns. Interventions/exposures of interest (observational): Medication exposure history is captured to support comparisons across therapy classes, including SGLT2 inhibitors and other disease-modifying therapies.

Treatment:

Drug: Glucagon-like peptide-1 receptor agonists (GLP 1 RA)

Drug: Sodium-glucose cotransporter 2 inhibitors (SGLT2i)

Drug: Renin-angiotensin-aldosterone system blockade

Drug: Mineralocorticoid Receptor Antagonists(MRAs)

Living Kidney Donor Cohort

Description:

Living kidney donors with available donor biopsy tissue, included as a comparator group to provide reference kidney tissue profiles. Interventions/exposures of interest (observational): Medication exposure history (including kidney-protective therapies where applicable) may be used in descriptive and comparative analyses; donors primarily serve as a reference/control tissue cohort.

Treatment:

Drug: Glucagon-like peptide-1 receptor agonists (GLP 1 RA)

Drug: Sodium-glucose cotransporter 2 inhibitors (SGLT2i)

Drug: Renin-angiotensin-aldosterone system blockade

Drug: Mineralocorticoid Receptor Antagonists(MRAs)

Nephrectomy Control Cohort

Description:

Adults undergoing nephrectomy with non-tumor, adjacent normal kidney tissue available, included as a control/reference tissue cohort. Interventions/exposures of interest (observational): Medication exposure history (including SGLT2 inhibitors and other kidney-protective therapies) may be incorporated in comparative analyses across cohorts.

Treatment:

Drug: Glucagon-like peptide-1 receptor agonists (GLP 1 RA)

Drug: Sodium-glucose cotransporter 2 inhibitors (SGLT2i)

Drug: Renin-angiotensin-aldosterone system blockade

Drug: Mineralocorticoid Receptor Antagonists(MRAs)