Puberty, Diabetes, and the Kidneys, When Eustress Becomes Distress (PANTHER Study)

Study Overview
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Brief Summary
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Early diabetic kidney disease (DKD) occurs in 50-70% of youth with type 2 diabetes (T2D) and confers high lifetime risk of dialysis and premature death. Youth-onset T2D typically manifests during or shortly after puberty in adolescents with obesity. Epidemiological data implicate puberty as an accelerator of kidney disease in youth with obesity and diabetes and the investigators posit that the link between puberty and T2D-onset may explain the high burden of DKD in youth-onset T2D. A better understanding of the impact of puberty on kidney health is needed to promote preservation of native kidney function, especially in youth with T2D. Puberty is a complex process of physiological changes, including neuroreproductive and growth hormone activation and rapid organ growth, that may predispose organs to injury. The kidneys may be especially susceptible because they are highly metabolically active and second only to the heart with respect to oxygen consumption per tissue mass. During puberty, the kidneys almost double in size, likely increasing the kidneys' already high energy expenditure. In parallel, puberty is associated with physiologic insulin resistance (IR), which is accentuated in obesity. Our central hypothesis is that obese youth with prediabetes and T2D experience relative kidney hypoxia during puberty due to a metabolic mismatch between increased energy expenditure and impaired substrate metabolism. In turn, the kidney hypoxia results in loss of glomerular charge and size selectivity leading to increased transglomerular transport of protein and kidney dysfunction. Our preliminary data showed that pubertal adolescents with obesity and/or diabetes exhibit relative kidney hypoxia compared to normal weight controls using functional magnetic resonance imaging (MRI) and that relative kidney hypoxia is greater in late vs. early puberty. However, determining the pubertal mechanisms contributing to kidney injury in youth with obesity and T2D requires serial evaluations throughout puberty. To assess the impact of pubertal changes within a 5-year study period, the investigators propose an accelerated longitudinal study design in which the investigators will enroll adolescents (8-14 years, 50% girls) with obesity and elevated hemoglobin A1c (HbA1c ≥6%) [n=60], and healthy normal weight controls [n=40] at Tanner (pubertal) stages 1-4 and examine them at baseline, 1 and 2-years. The investigators will then compare data by Tanner stage to construct an integrated portrayal of the physiological changes that occur throughout puberty. Given the rarity of T2D prior to pubertal onset, the investigators chose to enroll a high high-risk group: youth with obesity and HbA1c ≥6.0% to represent youth ranging from those at magnified risk of developing T2D to those recently diagnosed.

Official Title
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PANTHER Study: Puberty, Diabetes, and the Kidneys, When Eustress Becomes Distress

Conditions
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Kidney Hypoxia, Type 2 Diabetes Mellitus, Diabetic Kidney Disease, Adolescent Obesity, Pre Diabetes, Puberty

Intervention / Treatment
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* Drug: Aminohippurate Sodium Inj 20%
* Drug: Iohexol Inj 300 MG/ML
* Drug: Dextran 40


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HbA1c ≥6.0% for obese group BMI ≥ 95th %ile for obese group BMI ≥ 5 and <85th %ile for control group Type 1 diabetes (T1D) Antibody negative Exclusion Criteria: History of Chronic kidney disease (CKD) or acute kidney injury (AKI) Metabolic disorder prohibiting safe fasting Iodine or penicillin allergy Pregnancy Thrombophilia MRI contraindications Hormone therapy

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 14 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Youth with obesity and elevated HbA1c<br>All participants will under go GFR (Iohexol Inj 300 MG/ML), EPRF (Aminohippurate Sodium Inj 20%), Dextran sieving (Dextran 40 Sodium Inj 0.9%), IVGTT for insulin sensitivity, in addition to BOLD and ASL Kidney MRI | 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 and selectivity<br>* Other names: Dextran Sieving;|
| Healthy normal-weight controls<br>All participants will under go GFR (Iohexol Inj 300 MG/ML), EPRF (Aminohippurate Sodium Inj 20%), Dextran sieving (Dextran 40 Sodium Inj 0.9%), IVGTT for insulin sensitivity, in addition to BOLD and ASL Kidney MRI | 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 and selectivity<br>* Other names: Dextran Sieving;|

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 | 3 Hours | 
| Glomerular Filtration Rate (GFR) | Measured by iohexol clearance | 3 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin Sensitivity | Measured by IV glucose tolerance test (IVGTT) | 3 hours | 
| Renal perfusion | Arterial spin labeling (ASL) MRI | 10 min | 
| Renal oxygenation | Blood oxygen level dependent (BOLD) MRI | 60 min |