- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05319990
Pathogenesis of Kidney Disease in Type 1 Diabetes: a Modern Kidney Biopsy Cohort (The PANDA Study) (PANDA)
April 9, 2024 updated by: University of Colorado, Denver
Diabetic kidney disease (DKD) occurs in up to 40% of people with type 1 diabetes (T1D), often leading to kidney failure and markedly magnifying risks of cardiovascular disease and premature death.
Landmark T1D kidney biopsy studies identified the classic pathological lesions of DKD, which have been attributed largely to hyperglycemia.
Recent advances in continuous glucose monitoring (CGM) and automated insulin delivery have facilitated improved glycemic control, but the residual risk of DKD continues to be high.
In addition, obesity and insulin resistance (IR) have accompanied intensive glycemic therapy and may promote mitochondrial dysfunction and inflammation.
Deciphering the molecular underpinnings of DKD in modern-day T1D and identifying modifiable risk factors could lead to more effective and targeted therapies to prevent DKD.
Study Overview
Status
Recruiting
Conditions
Detailed Description
The overall goal of this project is to characterize the molecular, morphometric, and metabolic features of DKD over the modern clinical course of T1D.
The investigators hypothesize that perturbed kidney energetics and hypoxia are central metabolic pathways in the development of DKD.
Kidney hypoxia stems from a mismatch between increased renal energy demand (e.g., increased glomerular filtration rate [GFR] and tubular reabsorption of sodium) and impaired substrate metabolism (e.g., IR and mitochondrial dysfunction) and results in activation of the hypoxia-inducible factor (HIF) system.
Although upregulation of HIF1α confers favorable short-term effects, sustained activation promotes cellular injury.
Supporting these hypotheses, data from our group and others have shown that obesity, IR, and The investigators also found that youth with T1D exhibit kidney hypoxia by MRI that strongly associates with IR and mitochondrial dysfunction.
Moreover, our preliminary single-cell RNA sequencing (scRNA-seq) data from kidney biopsies demonstrate upregulated tubular expression of HIF1α in adults with T1D vs. healthy controls.
The investigators propose to build a unique new longitudinal kidney biopsy cohort (N=100) spanning the critical duration of T1D over which DKD initiates and progresses (5-30 years).
Participants will be enrolled from our existing CROCODILE study (adding longitudinal follow-up to completed kidney biopsies and baseline data and biosample acquisition) and from new enrollment at the University of Colorado and University of Washington.
Normative kidney biopsy data will be provided from our existing cohort of healthy controls (N=20) and the Kidney Precision Medicine Project (KPMP).
The investigators will implement state-of-the-art molecular (scRNA-seq) and morphometric interrogation of kidney tissue and rigorous metabolic phenotyping to include kidney magnetic resonance imaging (MRI), direct measurements of glycemia (continuous glucose monitoring), intraabdominal fat (dual-energy X-ray absorptiometry), estimation of insulin sensitivity by a T1D-validated equation, and (in a subset) GFR (iohexol clearance) and renal plasma flow (p-aminohippurate clearance).
Participants will be followed longitudinally for DKD outcomes.
A subset of 20 participants will undergo repeat kidney biopsies and associated procedures 3 years after baseline kidney biopsy.
Study Type
Observational
Enrollment (Estimated)
100
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Contact
- Name: Petter M Bjornstad, MD
- Phone Number: 720-777-4659
- Email: Petter.M.Bjornstad@cuanschutz.edu
Study Contact Backup
- Name: Carissa Birznieks, MS
- Phone Number: 720-777-4659
- Email: Carissa.Birznieks@childrenscolorado.org
Study Locations
-
-
Colorado
-
Aurora, Colorado, United States, 80045
- Recruiting
- Children's Hospital Colorado
-
Contact:
- Petter M Bjornstad, MD
- Phone Number: 720-777-4659
- Email: Petter.M.Bjornstad@cuanschutz.edu
-
Contact:
- Carissa Birznieks, MS
- Phone Number: 720-777-4659
- Email: Carissa.Birznieks@childrenscolorado.org
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years and older (Adult, Older Adult)
Accepts Healthy Volunteers
No
Sampling Method
Probability Sample
Study Population
The investigators propose to address the specific aims of this study in a cross-sectional project with 70 newly enrolled adults with T1D and 30 former CROCODILE participants (COMIRB #19-1282).
Description
Inclusion Criteria:
- Age ≥ 18 years at enrollment (rationale: this study focuses on determinants of early DKD over the course of T1D in adults)
- T1D duration >5 years (rationale: DKD in T1D rarely manifests prior to 5 years of disease duration)
- HbA1c <11% (rationale: HbA1c ≥ 11% exceeds the average HbA1c at most academic center and would limiting the generalizability of our study findings)
Exclusion Criteria:
- T2D and monogenic diabetes (rationale: our study focuses on T1D)
- Recent diabetic ketoacidosis, i.e., <1 month (rationale: safety and insulin resistance and tubular dysfunction of DKA can confound study findings)
- eGFR < 30 ml/min/1.73m2 or dialysis treatment (rationale: to reduce the likelihood of identifying secondary pathways that are not specific to kidney injury from T1D)
- Kidney transplant recipients (rationale: molecular confounding from immunosuppression)
Kidney biopsy contraindications (rationale: safety - kidney biopsy):
- Evidence of bleeding disorder or complications from bleeding
- Use of aspirin, Nonsteroidal anti-inflammatory drugs (NSAIDS) or other blood thinner that cannot be safely stopped for a sufficient time before and after the biopsy to avoid additional risk of bleeding.
- INR > 1.4
- Hemoglobin (Hgb) < 10 mg/dL (Colorado) [altitude]
- Hemoglobin (Hgb) < 9 mg/dL (Washington)
- Platelet count < 100,000 / µL
- Uncontrolled or difficult to control hypertension (> 150/90 mmHg at the day of biopsy)
- Single kidney (either by history, documented by prior imaging or ultrasound performed prior to the biopsy)
- Kidney size: One or both kidneys < 8 cm
- Hydronephrosis or other important renal ultrasound findings such as significant stone disease
- Any evidence of a current urinary tract infection as indicated on day of biopsy
- Clinical evidence of non-diabetic renal disease
- Positive urine pregnancy test or pregnancy
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
Cohorts and Interventions
Group / Cohort |
Intervention / Treatment |
---|---|
PANDA, T1D
New participants with T1D will be enrolled at the University of Colorado and University of Washington.
|
|
PANDA Sub Study, Former CROCODILE Participants
Participants will be enrolled from the existing CROCODILE study (COMIRB # 19-1282), adding longitudinal follow-up to completed kidney biopsies and baseline data and biosample acquisition.
|
PAH (Basic Pharma, Geleen, Netherlands) has been used to measure ERPF in human research for 7 decades, and is very well tolerated and generally recognized as safe with low toxicity.
Other Names:
Iohexol (Omnipaque 300, GE Healthcare, Chicago, IL) is a nonionic, low osmolar contrast agent with a history of extensive use in Radiology practice (for contrast x-rays) that shares many qualities of an ideal GFR marker, like inulin, such as not being absorbed, metabolized, or secreted by the kidney.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Insulin Sensitivity
Time Frame: 4.5 hours
|
Hyperinsulinemic-Euglycemic Clamp
|
4.5 hours
|
Renal Oxygenation
Time Frame: 30 min
|
Blood oxygen level dependent (BOLD) MRI
|
30 min
|
Renal Perfusion
Time Frame: 30 min
|
Arterial Spin Labeling (ASL) MRI
|
30 min
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Glomerular Filtration Rate (GFR)
Time Frame: 3 hours
|
Iohexol Clearance Study
|
3 hours
|
Effective Renal Plasma Flow (ERPF)
Time Frame: 2.5 hours
|
PAH Clearance Study
|
2.5 hours
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
March 9, 2022
Primary Completion (Estimated)
June 30, 2027
Study Completion (Estimated)
December 31, 2027
Study Registration Dates
First Submitted
April 1, 2022
First Submitted That Met QC Criteria
April 1, 2022
First Posted (Actual)
April 11, 2022
Study Record Updates
Last Update Posted (Actual)
April 10, 2024
Last Update Submitted That Met QC Criteria
April 9, 2024
Last Verified
April 1, 2024
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Glucose Metabolism Disorders
- Metabolic Diseases
- Immune System Diseases
- Autoimmune Diseases
- Urologic Diseases
- Endocrine System Diseases
- Female Urogenital Diseases
- Female Urogenital Diseases and Pregnancy Complications
- Urogenital Diseases
- Male Urogenital Diseases
- Diabetes Mellitus
- Kidney Diseases
- Diabetes Mellitus, Type 1
- Diabetic Nephropathies
- Diabetes Complications
Other Study ID Numbers
- 22-0250
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
UNDECIDED
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Yes
Studies a U.S. FDA-regulated device product
No
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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