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

NCT ID: NCT05008276

Last Updated: 2025-03-24

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 100 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2021-09-27
• Study Completion Date: 2027-12-01

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.

Conditions

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

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: CROSS_SECTIONAL

Study Groups

Youth with overweight/obesity and/or newly diagnosed T2D and elevated HbA1c

All participants will undergo 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

Aminohippurate Sodium Inj 20%

Intervention Type: DRUG

Diagnostic aid/agent used to measure effective renal plasma flow (ERPF)

Iohexol Inj 300 MG/ML

Intervention Type: DRUG

Diagnostic aid/agent used to measure glomerular filtration rate (GFR)

Dextran 40

Intervention Type: DRUG

Diagnostic aid/agent used to measure glomerular size and selectivity

Healthy normal-weight controls

All participants will undergo 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

Aminohippurate Sodium Inj 20%

Intervention Type: DRUG

Diagnostic aid/agent used to measure effective renal plasma flow (ERPF)

Iohexol Inj 300 MG/ML

Intervention Type: DRUG

Diagnostic aid/agent used to measure glomerular filtration rate (GFR)

Dextran 40

Intervention Type: DRUG

Diagnostic aid/agent used to measure glomerular size and selectivity

Interventions

Aminohippurate Sodium Inj 20%

Diagnostic aid/agent used to measure effective renal plasma flow (ERPF)

Intervention Type: DRUG

Iohexol Inj 300 MG/ML

Diagnostic aid/agent used to measure glomerular filtration rate (GFR)

Intervention Type: DRUG

Dextran 40

Diagnostic aid/agent used to measure glomerular size and selectivity

Intervention Type: DRUG

Other Intervention Names

Sodium 4-amino hippurate (PAH) inj 20% 2g/10mL; Para-aminohippurate; Aminohippuric acid; omnipaque 300; Dextran Sieving

Eligibility Criteria

Inclusion Criteria

• HbA1c ≥6.0% for untreated high-risk group
• BMI ≥ 85th %ile for high-risk group
• Normal HbA1c ≤5.6% 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

• Minimum Eligible Age: 8 Years
• Maximum Eligible Age: 14 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

Seattle Children's Hospital

OTHER

Sponsor Role: collaborator

University of Colorado, Denver

OTHER

Sponsor Role: collaborator

Petter Bjornstad

OTHER

Sponsor Role: lead

Responsible Party

Petter Bjornstad

Assistant Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Petter Bjornstad, MD

Role: PRINCIPAL_INVESTIGATOR

University of Washington - Medicine Diabetes Institute

Locations

Children's Hospital Colorado

Aurora, Colorado, United States

Site Status: RECRUITING

Seattle Children's Hospital

Seattle, Washington, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Petter Bjornstad, MD

Role: CONTACT

pettermb@uw.edu

(206) 616 3543

Facility Contacts

Megan Kelsey, MD, MS

Role: primary

Megan.Kelsey@childrenscolorado.org

720-777-0991

Petter M Bjornstad, MD

Role: primary

pettermb@uw.edu

(206) 616 3543

Other Identifiers

21-3019

Identifier Type: -

Identifier Source: org_study_id