Type 2 Diabetes, Diabetes Type 2, Diabetic Nephropathies, Nephropathy, Obesity, Adolescent Obesity, Diabetic Kidney Disease
Conditions
Brief summary
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.
Interventions
Diagnostic aid/agent used to measure effective renal plasma flow (ERPF)
Diagnostic aid/agent used to measure glomerular filtration rate (GFR)
DRUGDextran 40
Diagnostic aid/agent used to measure glomerular size selectivity
PROCEDURERenal Biopsy
Minimally invasive outpatient procedure in interventional radiology to obtain renal tissue cores.
RADIATIONPositron Emission Tomography
Imaging study performed to study renal oxidative metabolism
Sponsors
University of Colorado, Denver
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
12 Years to 26 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Glomerular Filtration Rate | One-time measure collected at a single visit following screening; timing varied by participant, up to 7 months after screening | Glomerular filtration rate measured by iohexol clearance |
| Effective Renal Plasma Flow (ERPF) | One-time measure collected at a single visit following screening; timing varied by participant, up to 7 months after screening | Effective renal plasma flow measured by PAH clearance |
| Renal Oxygen Availability | One-time measure collected at a single visit following screening; timing varied by participant, up to 7 months after screening | 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. |
| Renal Perfusion | One-time measure collected at a single visit following screening; timing varied by participant, up to 7 months after screening | 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. |
| C-11 Acetate Tracer Uptake | 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 measured by PET Scan (K1) |
| Renal Oxidative Metabolism | One-time measure collected at a single visit following screening; timing varied by participant, up to 7 months after screening | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pulse Wave Velocity | One-time measure collected at a single visit following screening; timing varied by participant, up to 7 months after screening | PWV between carotid and femoral artery |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORPetter Bjornstad, MD
Children's Hospital Colorado
Participant flow
Recruitment details
Most participants will be re-recruited from the parent Renal-HEIR study (COMIRB #16-1752), who consented to be contacted for future research. New participants will also be recruited via the Lifestyle Medicine 2 clinic at Children's Hospital Colorado, by email, phone, and during clinical visits.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 34 Years STANDARD_DEVIATION 19 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Glomerular filtration rate | 149 mL/min/1.73m^2 STANDARD_DEVIATION 32 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 15 | 0 / 33 |
| other Total, other adverse events | 0 / 9 | 1 / 15 | 2 / 33 |
| serious Total, serious adverse events | 0 / 9 | 0 / 15 | 0 / 33 |
Outcome results
None listed