Transformative Research in Diabetic Nephropathy 2.0 (TRIDENT 2)

Transformative Research in Diabetic Nephropathy 2.0: A Proof of Principle Study of SGLT2 Inhibitors (TRIDENT 2.0)

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

Study Overview

• Status: Recruiting
• Conditions: Kidney Diseases; Diabetes Mellitus, Type 2; Renal Insufficiency, Chronic; Diabetic Nephropathies
• Intervention / Treatment: Drug: Sodium-glucose cotransporter 2 inhibitors (SGLT2i); Drug: Renin-angiotensin-aldosterone system blockade; Drug: Glucagon-like peptide-1 receptor agonists (GLP 1 RA); Drug: Mineralocorticoid Receptor Antagonists(MRAs)

Detailed 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.

• Study Type: Observational
• Enrollment (Estimated): 200

Contacts and Locations

• Study Contact: Name: Gaia Coppock, MD; Phone Number: 2673030158; Email: Gaia.Coppock@pennmedicine.upenn.edu
• Study Contact Backup: Name: Mohammed Al Dulaimee, BS; Phone Number: 5853589733; Email: mohammed.aldulaimee@pennmedicine.upenn.edu

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Penn Presbyterian Medical Center
      • Contact: Gaia Coppock, MD; Phone Number: 2673030158; Email: Gaia.Coppock@pennmedicine.upenn.edu
      • Contact: Mohammed Al Dulaimee, BS; Phone Number: 5853589733; Email: mohammed.aldulaimee@pennmedicine.upenn.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

TRIDENT 2.0 will enroll approximately 200 participants across multiple sites. Eligible participants include:

• Patients with diabetic kidney disease (DKD) confirmed by clinically indicated biopsy.
• Patients with other kidney diseases (disease controls).
• Living kidney donors (donor biopsy tissue).
• Patients undergoing nephrectomy (non-tumor, adjacent normal tissue when available).

All participants must provide informed consent for release of one H&E slide from their clinical biopsy or surgical specimen and for abstraction of relevant clinical data.

Description

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.

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Biopsy-confirmed Diabetic Kidney Disease Cohort; 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.	Drug: Sodium-glucose cotransporter 2 inhibitors (SGLT2i); Standard-of-care exposure to sodium-glucose cotransporter 2 inhibitors documented from medication history. Participants are not assigned therapy. Exposure status is used for observational comparisons of kidney tissue molecular and histopathologic features.; Other Names: SGLT2 inhibitors; Drug: Renin-angiotensin-aldosterone system blockade; Standard-of-care exposure to renin-angiotensin-aldosterone system blockade documented from medication history for observational comparisons.; Drug: Glucagon-like peptide-1 receptor agonists (GLP 1 RA); Standard-of-care exposure documented from medication history for observational comparisons.; Other Names: GLP-1 receptor agonists; Drug: Mineralocorticoid Receptor Antagonists(MRAs); Standard-of-care exposure documented from medication history for observational comparisons.; Other Names: MRAs
Disease Control Kidney Disease Cohort; 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.	Drug: Sodium-glucose cotransporter 2 inhibitors (SGLT2i); Standard-of-care exposure to sodium-glucose cotransporter 2 inhibitors documented from medication history. Participants are not assigned therapy. Exposure status is used for observational comparisons of kidney tissue molecular and histopathologic features.; Other Names: SGLT2 inhibitors; Drug: Renin-angiotensin-aldosterone system blockade; Standard-of-care exposure to renin-angiotensin-aldosterone system blockade documented from medication history for observational comparisons.; Drug: Glucagon-like peptide-1 receptor agonists (GLP 1 RA); Standard-of-care exposure documented from medication history for observational comparisons.; Other Names: GLP-1 receptor agonists; Drug: Mineralocorticoid Receptor Antagonists(MRAs); Standard-of-care exposure documented from medication history for observational comparisons.; Other Names: MRAs
Living Kidney Donor Cohort; 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.	Drug: Sodium-glucose cotransporter 2 inhibitors (SGLT2i); Standard-of-care exposure to sodium-glucose cotransporter 2 inhibitors documented from medication history. Participants are not assigned therapy. Exposure status is used for observational comparisons of kidney tissue molecular and histopathologic features.; Other Names: SGLT2 inhibitors; Drug: Renin-angiotensin-aldosterone system blockade; Standard-of-care exposure to renin-angiotensin-aldosterone system blockade documented from medication history for observational comparisons.; Drug: Glucagon-like peptide-1 receptor agonists (GLP 1 RA); Standard-of-care exposure documented from medication history for observational comparisons.; Other Names: GLP-1 receptor agonists; Drug: Mineralocorticoid Receptor Antagonists(MRAs); Standard-of-care exposure documented from medication history for observational comparisons.; Other Names: MRAs
Nephrectomy Control Cohort; 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.	Drug: Sodium-glucose cotransporter 2 inhibitors (SGLT2i); Standard-of-care exposure to sodium-glucose cotransporter 2 inhibitors documented from medication history. Participants are not assigned therapy. Exposure status is used for observational comparisons of kidney tissue molecular and histopathologic features.; Other Names: SGLT2 inhibitors; Drug: Renin-angiotensin-aldosterone system blockade; Standard-of-care exposure to renin-angiotensin-aldosterone system blockade documented from medication history for observational comparisons.; Drug: Glucagon-like peptide-1 receptor agonists (GLP 1 RA); Standard-of-care exposure documented from medication history for observational comparisons.; Other Names: GLP-1 receptor agonists; Drug: Mineralocorticoid Receptor Antagonists(MRAs); Standard-of-care exposure documented from medication history for observational comparisons.; Other Names: MRAs

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Kidney Tissue molecular fingerprint	Change/differences in kidney tissue molecular "fingerprint" (molecular pathways / spatial gene expression signatures derived from archived kidney tissue) comparing participants exposed to sodium-glucose cotransporter 2 inhibitors versus controls and participants on other therapies. Tissue profiling includes single-cell spatial transcriptomics with differential expression and pathway analyses stratified by therapy exposure.	Baseline enrollment to 18 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in estimated glomerular filtration rate (eGFR)	Change in eGFR calculated using the 2021 race-free CKD-EPI equation.	Baseline to 18 months
Change in urine protein/creatinine ratio	Change in urine protein/creatinine ratio over follow-up.	Baseline to 6 months.
Descriptive histopathology features and spatial gene expression patterns across cohorts	Descriptive histopathological features (fibrosis, sclerosis, inflammation, vascular changes) and spatial gene expression patterns evaluated across diabetic kidney disease, disease controls, donor, and nephrectomy cohorts.	At enrollment/baseline (Single assessment on the archived clinical specimen slide)
Associations between histopathological features and clinical outcomes	Associations between histopathological features and clinical outcomes including eGFR slope, proteinuria, kidney failure, and transplant.	Up to 3 years (longitudinal outcome abstraction, including dialysis/transplant/kidney failure/mortality as captured).
Associations between histopathological features and prior medication exposures	Associations between histopathological features and prior medication exposures, including SGLT2 inhibitors, renin-angiotensin-aldosterone system blockade, glucagon-like peptide-1 receptor agonists, mineralocorticoid receptor antagonists, and other therapies.	Baseline (prior/current medication exposure history at enrollment).
Feasibility metrics	Accrual rate by cohort, proportion of slides successfully retrieved, and slide quality metrics.	During study accrual and specimen acquisition (up to 3 years).

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: Novo Nordisk A/S; GlaxoSmithKline; AstraZeneca; Genentech, Inc.; Boehringer Ingelheim; Regeneron Pharmaceuticals
• Investigators: Principal Investigator: Katalin Susztak, MD, PhD, University of Pennsylvania

Study record dates

Study Major Dates

• Study Start (Actual): November 12, 2025
• Primary Completion (Estimated): May 30, 2027
• Study Completion (Estimated): November 12, 2028

Study Registration Dates

• First Submitted: February 24, 2026
• First Submitted That Met QC Criteria: February 24, 2026
• First Posted (Actual): March 2, 2026

Study Record Updates

• Last Update Posted (Actual): March 2, 2026
• Last Update Submitted That Met QC Criteria: February 24, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Chronic kidney disease; Diabetic kidney disease; Diabetic nephropathy; Spatial transcriptomics; Sodium-glucose cotransporter 2 inhibitors; Kidney-protective therapy
• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Pathologic Processes; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Chronic Disease; Disease Attributes; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Diabetes Complications; Renal Insufficiency; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Diabetes Mellitus, Type 2; Kidney Diseases; Renal Insufficiency, Chronic; Diabetic Nephropathies; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Diuretics; Natriuretic Agents; Diuretics, Potassium Sparing; Pharmacologic Actions; Chemical Actions and Uses; Sodium-Glucose Transporter 2 Inhibitors; Glucagon-Like Peptide-1 Receptor Agonists; Mineralocorticoid Receptor Antagonists
• Other Study ID Numbers: 849580

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No