Renal Hemodynamics, Energetics and Insulin Resistance: A Follow-up Study

Study Overview
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Brief Summary
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The current protocol plans to enroll participants with youth-onset Type 2 Diabetes (T2D) as well as obese and lean controls from the Renal-HEIR - Renal Hemodynamics, Energetics and Insulin Resistance in Youth Onset Type 2 Diabetes Study (n=100) [COMIRB #16-1752] in a prospective investigation that seeks to 1) define the changes in kidney function by gold standard techniques and energetics by functional Magnetic Resonance Imaging (MRI) in adolescents with and without T2D as they transition to young adulthood; 2) quantify kidney oxidative metabolism by 11C-acetate Positron Emission Tomography (PET) in a subset of participants who are ≥18 years of age with youth-onset T2D and/or obesity; 3) determine peripheral arterial stiffness by SphygmoCor. Mechanistic insight will be provided by transcriptomic analyses of repeat biopsies 3-years after their initial biopsy for eligible participants with youth-onset T2D, as well as molecular analysis of tissue obtained from J-wire endovascular biopsies. This study will also leverage this well-characterized cohort of youths to define youth-onset T2D-related changes in brain morphology and function by structural MRI and resting-state functional MRI and through the assessment of cognitive function (fluid and crystallized intelligence) using the NIH Toolbox Cognitive Battery (NIHTB-CB), as an exploratory objective. All enrollees in Renal-HEIR have consented to be contacted for future research opportunities.

Official Title
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Renal Hemodynamics, Energetics and Insulin Resistance in Youth Onset Type 2 Diabetes: A Follow-up Study

Conditions
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Type 2 Diabetes, Diabetes Type 2, Diabetic Nephropathies, Nephropathy, Obesity, Adolescent Obesity, Diabetic Kidney Disease

Intervention / Treatment
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* Drug: Aminohippurate Sodium Inj 20%
* Drug: Iohexol Inj 300 MG/ML
* Drug: Dextran 40
* Procedure: Renal Biopsy
* Radiation: Positron Emission Tomography


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Obese youth with and without Type 2 Diabetes + lean controls who were previously enrolled in the Renal HEIR Study Participants who will undergo a PET Scan: ≥ 18 years Exclusion Criteria: Anemia Seafood, iodine, or penicillin allergy Pregnancy MRI Scanning contraindications (claustrophobia, implantable devices, >550 lbs) History of bleeding or clotting disorders, thrombocytopenia, warfarin and/or heparin use Taking sulfonamides, procaine, thiazolsulfone or probenecid

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 26 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Lean Controls (previously enrolled in the Renal HEIR Study)<br> | Drug: Aminohippurate Sodium Inj 20%<br>* Diagnostic aid/agent used to measure effective renal plasma flow (ERPF)<br>* Other names: Aminohippuric acid;Drug: Iohexol Inj 300 MG/ML<br>* Diagnostic aid/agent used to measure glomerular filtration rate (GFR)<br>* Other names: omnipaque 300;Drug: Dextran 40<br>* Diagnostic aid/agent used to measure glomerular size selectivity<br>* Other names: LMD;|
| Obese Youth without Type 2 Diabetes (previously enrolled in the Renal HEIR Study)<br> | Drug: Aminohippurate Sodium Inj 20%<br>* Diagnostic aid/agent used to measure effective renal plasma flow (ERPF)<br>* Other names: Aminohippuric acid;Drug: Iohexol Inj 300 MG/ML<br>* Diagnostic aid/agent used to measure glomerular filtration rate (GFR)<br>* Other names: omnipaque 300;Drug: Dextran 40<br>* Diagnostic aid/agent used to measure glomerular size selectivity<br>* Other names: LMD;Radiation: Positron Emission Tomography<br>* Imaging study performed to study renal oxidative metabolism<br>* Other names: PET Scan;|
| Obese Youth with Type 2 Diabetes (previously enrolled in the Renal HEIR Study)<br> | Drug: Aminohippurate Sodium Inj 20%<br>* Diagnostic aid/agent used to measure effective renal plasma flow (ERPF)<br>* Other names: Aminohippuric acid;Drug: Iohexol Inj 300 MG/ML<br>* Diagnostic aid/agent used to measure glomerular filtration rate (GFR)<br>* Other names: omnipaque 300;Drug: Dextran 40<br>* Diagnostic aid/agent used to measure glomerular size selectivity<br>* Other names: LMD;Procedure: Renal Biopsy<br>* Minimally invasive outpatient procedure in interventional radiology to obtain renal tissue cores.<br>* Other names: Kidney Biopsy;Radiation: Positron Emission Tomography<br>* Imaging study performed to study renal oxidative metabolism<br>* Other names: PET Scan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effective Renal Plasma Flow (ERPF) | Measured by PAH clearance | 4 Hours | 
| Glomerular Filtration Rate | Measured by Iohexol Clearance | 4 Hours | 
| Glomerular Size Selectivity | Measured by Dextran sieving | 4 hours | 
| Renal Oxygen Availability | Measured by functional kidney MRI | 1 hour | 
| Renal Perfusion | Measured by functional kidney MRI + PET Scan | 1 hour | 
| 11-C Acetate Tracer Uptake | Measured by PET Scan | 1 Hour | 
| Renal Oxidative Metabolism | Measured by PET Scan | 1 Hour | 
| Blood Volume Fraction | Measured by PET Scan | 1 Hour | 
| Glomerular Basement Membrane Width | Measured by Renal Biopsy | 1 Hour | 
| Mesangial Expansion | Measured by Renal Biopsy | 1 Hour | 
| Interstitial Fibrosis | Measured by Renal Biopsy | 1 Hour | 
| Renal Arteriosclerosis | Measured by Renal Biopsy | 1 Hour | 
| Spatial Transcriptomics | Measured by Renal Biopsy | 1 Hour | 
| Spatial Metabolomics | Measured by Renal Biopsy | 1 Hour | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pulse Wave Velocity between Carotid and Femoral Artery | Measured by PWV | 10 minutes | 
| Whole brain gray matter volume | Measured by brain MRI | 1 Hour | 
| Whole brain cortical thickness | Measured by brain MRI | 1 Hour | 
| Whole brain resting-state network connectivity | Measured by brain MRI | 1 Hour | 
| Age-corrected composite fluid cognition score | Measured by brain MRI | 1 Hour |