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

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

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.

Study Overview

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

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 Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

• Study Contact: Name: Petter Bjornstad, MD; Phone Number: 720-777-4659; Email: Petter.M.Bjornstad@cuanschutz.edu

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • Children's Hospital Colorado
      • Contact: Petter M Bjornstad, MD; Phone Number: 720-777-4659; Email: Petter.M.Bjornstad@cuanschutz.edu
      • Principal Investigator: Petter M Bjornstad, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 14 years (Child)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Probability Sample

Study Population

The investigators propose to address the specific aims of this study in an accelerated longitudinal project with 40 adolescents with normal HbA1c (≤5.6%) and 60 with overweight/obesity and/or newly diagnosed T2D (BMI≥95%ile) and elevated HbA1c (≥6.0%) or on anti-diabetic medications ranging from TS 1-4 (Ages 8-14 yr). They will be studied annually for 2 years.

Description

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

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Healthy normal-weight controls; 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%; 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 and selectivity; Other Names: Dextran Sieving
Youth with overweight/obesity and/or newly diagnosed T2D and elevated HbA1c; 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%; 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 and selectivity; Other Names: Dextran Sieving

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Petter Bjornstad, MD, University of Colorado School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): September 27, 2021
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: August 9, 2021
• First Submitted That Met QC Criteria: August 9, 2021
• First Posted (Actual): August 17, 2021

Study Record Updates

• Last Update Posted (Actual): April 11, 2024
• Last Update Submitted That Met QC Criteria: April 9, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Urologic Diseases; Endocrine System Diseases; Diabetes Complications; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Signs and Symptoms, Respiratory; Obesity; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Kidney Diseases; Pediatric Obesity; Diabetic Nephropathies; Prediabetic State; Hypoxia; Anticoagulants; Plasma Substitutes; Blood Substitutes; Dextrans
• Other Study ID Numbers: 21-3019

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