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

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

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.

Study Overview

• Status: Completed
• Conditions: Obesity; Diabetic Kidney Disease; Diabetic Nephropathies; Type 2 Diabetes; Adolescent Obesity; Nephropathy; Diabetes Type 2
• Intervention / Treatment: Drug: Aminohippurate Sodium Inj 20%; Drug: Iohexol Inj 300 MG/ML; Procedure: Renal Biopsy; Drug: Dextran 40; Radiation: Positron Emission Tomography

• Study Type: Observational
• Enrollment (Actual): 57

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 26 years (Child, Adult)
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Population to be enrolled will be comprised of obese youth with and without T2D and lean controls who were previously enrolled in the Renal-HEIR (#16-1752) study.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Lean Controls (previously enrolled in the Renal HEIR Study)	Drug: Aminohippurate Sodium Inj 20%; Diagnostic aid/agent used to measure effective renal plasma flow (ERPF); Other Names: Sodium 4-amino hippurate (PAH) inj 20% 2g/10mL; Para-aminohippurate; Aminohippuric acid; Drug: Iohexol Inj 300 MG/ML; Diagnostic aid/agent used to measure glomerular filtration rate (GFR); Other Names: omnipaque 300; Drug: Dextran 40; Diagnostic aid/agent used to measure glomerular size selectivity; Other Names: Dextran; LMD
Obese Youth without Type 2 Diabetes (previously enrolled in the Renal HEIR Study)	Drug: Aminohippurate Sodium Inj 20%; Diagnostic aid/agent used to measure effective renal plasma flow (ERPF); Other Names: Sodium 4-amino hippurate (PAH) inj 20% 2g/10mL; Para-aminohippurate; Aminohippuric acid; Drug: Iohexol Inj 300 MG/ML; Diagnostic aid/agent used to measure glomerular filtration rate (GFR); Other Names: omnipaque 300; Drug: Dextran 40; Diagnostic aid/agent used to measure glomerular size selectivity; Other Names: Dextran; LMD; Radiation: Positron Emission Tomography; Imaging study performed to study renal oxidative metabolism; Other Names: PET Scan
Obese Youth with Type 2 Diabetes (previously enrolled in the Renal HEIR Study)	Drug: Aminohippurate Sodium Inj 20%; Diagnostic aid/agent used to measure effective renal plasma flow (ERPF); Other Names: Sodium 4-amino hippurate (PAH) inj 20% 2g/10mL; Para-aminohippurate; Aminohippuric acid; Drug: Iohexol Inj 300 MG/ML; Diagnostic aid/agent used to measure glomerular filtration rate (GFR); Other Names: omnipaque 300; Procedure: Renal Biopsy; Minimally invasive outpatient procedure in interventional radiology to obtain renal tissue cores.; Other Names: Kidney Biopsy; Drug: Dextran 40; Diagnostic aid/agent used to measure glomerular size selectivity; Other Names: Dextran; LMD; Radiation: Positron Emission Tomography; Imaging study performed to study renal oxidative metabolism; Other Names: PET Scan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glomerular Filtration Rate	Glomerular filtration rate measured by iohexol clearance	One-time measure collected at a single visit following screening; timing varied by participant, up to 7 months after screening
Effective Renal Plasma Flow (ERPF)	Effective renal plasma flow measured by PAH clearance	One-time measure collected at a single visit following screening; timing varied by participant, up to 7 months after screening
Renal Oxygen Availability	BOLD-MRI uses the specific paramagnetic properties of deoxyhemoglobin to assess renal tissue oxygenation. Its outcome measure is the so-called R2* value, which varies inversely with local oxygenation. This apparent relaxation rate R2* (or decay rate, defined as 1/T2* and expressed as per second) is measured voxel by voxel in each kidney by BOLD-MRI. The R2* value of each voxel is influenced by microscopic inhomogeneities in the static magnetic field, largely due to the effect of deoxyhemoglobin. As such, the decay rate R2* in a voxel will be enhanced when the local deoxyhemoglobin concentration is increased. Hence, assuming that blood pO2 is in equilibrium with tissue pO2, low R2* values indicate high tissue oxygenation, while high R2* values indicate low tissue oxygenation.	One-time measure collected at a single visit following screening; timing varied by participant, up to 7 months after screening
Renal Perfusion	Arterial spin labeling (ASL) uses magnetically labeled arterial blood water as an endogenous tracer to assess renal perfusion. Its outcome measure is renal blood flow (RBF), expressed in mL/min/100 g of tissue. In ASL, inflowing arterial blood is magnetically tagged by inverting the longitudinal magnetization of water protons proximal to the imaging plane. After a defined post-labeling delay allowing labeled blood to flow into the tissue, a labeled image is acquired and subtracted from a control image obtained without labeling. The resulting difference signal, measured voxel by voxel in each kidney, is proportional to the labeled blood water delivered during the delay. As such, the difference signal in a voxel will be enhanced when local blood delivery is increased. Hence, after quantification using tissue and blood relaxation parameters, high perfusion values indicate high renal blood flow, while low perfusion values indicate reduced renal blood flow.	One-time measure collected at a single visit following screening; timing varied by participant, up to 7 months after screening
C-11 Acetate Tracer Uptake	C-11 Acetate tracer uptake measured by PET Scan (K1)	One-time measure collected at a single visit following screening; timing varied by participant, up to 7 months after screening
Renal Oxidative Metabolism	Positron emission tomography (PET) with C-11 acetate is used to assess renal oxidative metabolism. Its outcome measure is the cortical clearance rate constant k2, expressed per minute (min^-1). Following intravenous injection, C-11 acetate is taken up by renal tissue and converted to acetyl-CoA, which enters the tricarboxylic acid (TCA) cycle and is oxidized to C-11 CO2. The washout of C-11 activity from the tissue, modeled region by region in the renal cortex, reflects the rate of this oxidative process. The clearance rate constant k2, derived from kinetic modeling of the tissue time-activity curve, will be enhanced when oxidative metabolism and TCA cycle flux are increased. Hence, assuming tracer washout is in proportion to mitochondrial oxidation, high cortical k2 values indicate high renal oxidative metabolism, while low cortical k2 values indicate reduced renal oxidative metabolism.	One-time measure collected at a single visit following screening; timing varied by participant, up to 7 months after screening

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pulse Wave Velocity	PWV between carotid and femoral artery	One-time measure collected at a single visit following screening; timing varied by participant, up to 7 months after screening

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Investigators: Principal Investigator: Petter Bjornstad, MD, Children's Hospital Colorado

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2022
• Primary Completion (Actual): June 19, 2024
• Study Completion (Actual): June 19, 2024

Study Registration Dates

• First Submitted: September 2, 2022
• First Submitted That Met QC Criteria: September 2, 2022
• First Posted (Actual): September 7, 2022

Study Record Updates

• Last Update Posted (Actual): August 24, 2026
• Last Update Submitted That Met QC Criteria: July 1, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Nutrition Disorders; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Metabolic Diseases; Overnutrition; Body Weight; Glucose Metabolism Disorders; Diabetes Mellitus; Diabetes Complications; Overweight; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Obesity; Diabetes Mellitus, Type 2; Pediatric Obesity; Kidney Diseases; Diabetic Nephropathies; Organic Chemicals; Investigative Techniques; Hydrocarbons; Hydrocarbons, Cyclic; Carbohydrates; Carboxylic Acids; Hydrocarbons, Aromatic; Amides; Benzene Derivatives; Polymers; Macromolecular Substances; Chemistry Techniques, Analytical; Spectrum Analysis; Polysaccharides; Glucans; Acids, Carbocyclic; para-Aminobenzoates; Aminobenzoates; Benzoates; Keto Acids; Benzamides; Biopolymers; Triiodobenzoic Acids; Iodobenzoates; Aminohippuric Acids; Hippurates; Dextrans; Magnetic Resonance Spectroscopy; Iohexol; p-Aminohippuric Acid
• Other Study ID Numbers: 20-2961

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