Transformative Research in Diabetic Nephropathy 2.0: A Proof of Principle Study of SGLT2 Inhibitors (TRIDENT 2.0)
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 200
- 试验地点
- 1
- 主要终点
- Change in Kidney Tissue molecular fingerprint
研究概览
简要总结
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
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: Glucagon-like peptide-1 receptor agonists (GLP 1 RA) (Drug)
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.
干预措施: Glucagon-like peptide-1 receptor agonists (GLP 1 RA) (Drug)
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.
干预措施: Mineralocorticoid Receptor Antagonists(MRAs) (Drug)
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.
干预措施: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) (Drug)
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.
干预措施: Renin-angiotensin-aldosterone system blockade (Drug)
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.
干预措施: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) (Drug)
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.
干预措施: Renin-angiotensin-aldosterone system blockade (Drug)
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.
干预措施: Glucagon-like peptide-1 receptor agonists (GLP 1 RA) (Drug)
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.
干预措施: Mineralocorticoid Receptor Antagonists(MRAs) (Drug)
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.
干预措施: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) (Drug)
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.
干预措施: Renin-angiotensin-aldosterone system blockade (Drug)
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.
干预措施: Glucagon-like peptide-1 receptor agonists (GLP 1 RA) (Drug)
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.
干预措施: Mineralocorticoid Receptor Antagonists(MRAs) (Drug)
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.
干预措施: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) (Drug)
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.
干预措施: Renin-angiotensin-aldosterone system blockade (Drug)
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.
干预措施: Mineralocorticoid Receptor Antagonists(MRAs) (Drug)
结局指标
主要结局
Change in Kidney Tissue molecular fingerprint
时间窗: Baseline enrollment to 18 months.
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.
次要结局
- Change in urine protein/creatinine ratio(Baseline to 6 months.)
- Change in estimated glomerular filtration rate (eGFR)(Baseline to 18 months)
- Descriptive histopathology features and spatial gene expression patterns across cohorts(At enrollment/baseline (Single assessment on the archived clinical specimen slide))
- Associations between histopathological features and clinical outcomes(Up to 3 years (longitudinal outcome abstraction, including dialysis/transplant/kidney failure/mortality as captured).)
- Associations between histopathological features and prior medication exposures(Baseline (prior/current medication exposure history at enrollment).)
- Feasibility metrics(During study accrual and specimen acquisition (up to 3 years).)
研究者
Katalin Susztak
MD, PhD
University of Pennsylvania