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

Recruiting

• Conditions: Diabetic Kidney Disease; Adolescent Obesity; Kidney Hypoxia; Puberty; Type 2 Diabetes Mellitus; Pre Diabetes
• Interventions: Drug: Aminohippurate Sodium Inj 20%; Drug: Iohexol Inj 300 MG/ML; Drug: Dextran 40

• Registration Number: NCT05008276
• Lead Sponsor: University of Colorado, Denver

Brief Summary

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.

Detailed Description

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/or elevated hemoglobin A1c (HbA1c ≥6%) \[n=60\], and healthy normoglycemic 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/or HbA1c ≥6.0% to represent youth ranging from those at magnified risk of developing T2D to those recently diagnosed.

Study Timeline

• Study First Submitted: 2021-08-09
• Study First Submitted QC: 2021-08-09
• Study First Posted: 2021-08-17
• Study Start: 2021-09-27
• Status Verified: 2024-04
• Last Update Submitted: 2024-04-09
• Last Update Posted: 2024-04-11
• Primary Completion: 2027-12-01
• Study Completion: 2027-12-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 100

Inclusion Criteria

• HbA1c ≥6.0% for untreated high-risk group
• BMI ≥ 95th %ile for high-risk group
• Normal HbA1c ≤5.6% for control group
• Type 1 diabetes (T1D) Antibody negative

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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

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Youth with overweight/obesity and/or newly diagnosed T2D and elevated HbA1c	Dextran 40	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
Youth with overweight/obesity and/or newly diagnosed T2D and elevated HbA1c	Aminohippurate Sodium Inj 20%	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
Healthy normal-weight controls	Aminohippurate Sodium Inj 20%	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
Youth with overweight/obesity and/or newly diagnosed T2D and elevated HbA1c	Iohexol Inj 300 MG/ML	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
Healthy normal-weight controls	Iohexol Inj 300 MG/ML	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
Healthy normal-weight controls	Dextran 40	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

Primary Outcome Measures

Name	Time	Method
Effective renal plasma flow (ERPF)	3 Hours	Measured by PAH Clearance
Glomerular Filtration Rate (GFR)	3 hours	Measured by iohexol clearance

Secondary Outcome Measures

Name	Time	Method
Insulin Sensitivity	3 hours	Measured by IV glucose tolerance test (IVGTT)
Renal oxygenation	60 min	Blood oxygen level dependent (BOLD) MRI
Renal perfusion	10 min	Arterial spin labeling (ASL) MRI

Trial Locations

Locations (1)

Children's Hospital Colorado; 🇺🇸 Aurora, Colorado, United States