Renal HEIR Study: Renal Hemodynamics, Energetics and Insulin Resistance in Youth Onset Type 2 Diabetes Study

NCT03584217 | Unknown Phase 1 FDA Drug

• 1 other identifier: 16-1752
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

Type 2 diabetes (T2D) in youth is increasing in prevalence in parallel with the obesity epidemic. In the US, almost half of patients with renal failure have DKD, and ≥80% have T2D. Compared to adult-onset T2D, youth with T2D have a more aggressive phenotype with greater insulin resistance (IR), more rapid β-cell decline and higher prevalence of diabetic kidney disease (DKD), arguing for separate and dedicated studies in youth-onset T2D. Hyperfiltration is common in youth with T2D, and predicts progressive DKD. Hyperfiltration may also be associated with early changes in intrarenal hemodynamic function, including increased renal plasma flow (RPF) and glomerular pressure. Despite the high prevalence and gravity of DKD in youth-onset T2D, widely effective therapeutic options are lacking. The investigators' preliminary data support a strong association between IR and hyperfiltration in youth-onset T2D, but the pathology contributing to this relationship remains unclear. A better understanding of the pathophysiology underlying hyperfiltration and its relationship with IR is critical to inform development of new therapeutics. The investigators' overarching hypotheses are that: 1) hyperfiltration in youth-onset T2D is associated with changes in intrarenal hemodynamics, resulting in increased renal oxygen demand, 2) the demand is unmet by the inefficient fuel profile associated with IR (decreased glucose oxidation and increase free fatty acid \[FFA\] oxidation), resulting in renal hypoxia and ultimately renal damage. To address these hypotheses, the investigators will measure peripheral insulin sensitivity, adipose insulin sensitivity (FFA suppression), glomerular filtration rate (GFR), RPF, and renal oxygenation in youth with T2D (n=60), obesity (n=20) and in lean (n=20) controls. To further investigate the mechanisms of renal damage in youth with T2D, two optional procedures are included in the study: 1) kidney biopsy procedure and 2) induction of induced pluripotent stem cells (iPSCs) to assess morphometrics and genetic expression of renal tissue.

Conditions

Type 2 Diabetes Mellitus; Obesity; Nephropathy; Adolescent Obesity

Outcome Measures

Primary Outcomes (2)

• Effective renal plasma flow (ERPF)

  Measured by PAH clearance

  4 hours

• Glomerular filtration rate (GFR)

  Measured by iohexol clearance

  4 hours

Secondary Outcomes (3)

• Insulin sensitivity

  4 hours

• Renal oxygenation

  60 min

• Renal perfusion

  10 min

Other Outcomes (6)

• Podocyte numerical density and number per glomerulus

  4 hours

• Foot process width of glomeruli

  4 hours

• Detachment and endothelial fenestration of glomeruli

  4 hours

Study Arms (1)

Clinical Investigation

OTHER

All participants will undergo GFR (Iohexol Inj 300 MG/ML), ERPF (Aminohippurate Sodium Inj 20%) in addition to renal BOLD and ASL MRI.

Drug: Aminohippurate Sodium Inj 20%; Drug: Iohexol Inj 300 MG/ML; Procedure: Renal Biopsy

Interventions

Aminohippurate Sodium Inj 20% DRUG

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

Also known as: Sodium 4-amino hippurate (PAH) inj 20% 2g/10mL, Para-aminohippurate, Aminohippuric acid

Clinical Investigation

Iohexol Inj 300 MG/ML DRUG

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

Also known as: omnipaque 300

Clinical Investigation

Renal Biopsy PROCEDURE

Minimally invasive outpatient procedure in interventional radiology to obtain renal tissue cores.

Also known as: Kidney Biopsy

Clinical Investigation

Eligibility Criteria

• Age: 12 Years - 21 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Obese youth with and without T2D (≥54 kg) and lean controls
• Age 12-21 years
• Weight \<300 lbs., no implanted metal devices
• HbA1c \< 11% and no recent diabetic ketoacidosis or hyperosmolar hyperglycemia
• No anemia
• BMI \>5th percentile for lean controls

You may not qualify if:

• T2D onset (diagnosis) \> 18 years of age
• Prepubertal
• eGFR \<60ml/min/1.73m2 or creatinine \> 1.5mg/dl or history of ACR≥300mg/g
• ACE inhibitors, angiotensin receptor blockers (ARB), diuretics, sodium-glucose co-transport (SGLT) 2 or 1 blockers, daily NSAIDs or aspirin, sulfonamides, procaine, thiazosulfone or probenecid.
• Seafood or iodine allergy
• Pregnancy
• MRI scanning contraindications (claustrophobia, implantable devices, \>300 lbs)
• Evidence of bleeding disorder or complications from bleeding
• Use of aspirin, NSAIDS or other blood thinner that cannot be safely stopped for a sufficient time period before and after the biopsy so as to add no additional risk of bleeding
• Blood urea nitrogen (BUN) \> 80 gm/dL
• INR \> 1.4
• PTT \> 35 seconds
• Hemoglobin (Hgb) \< 10 mg/dL
• Platelet count \< 100,000 / µL
• Uncontrolled or difficult to control hypertension (\> 150/90 mmHg at the day of biopsy)

Sponsors & Collaborators

• University of Colorado, Denver: lead

Study Sites (1)

Children's Hospital Colorado

Aurora, Colorado, 80238, United States

Location

Related Publications (2)

• Vigers T, Vinovskis C, Li LP, Prasad P, Heerspink H, D'Alessandro A, Reisz JA, Piani F, Cherney DZ, van Raalte DH, Nadeau KJ, Pavkov ME, Nelson RG, Pyle L, Bjornstad P. Plasma levels of carboxylic acids are markers of early kidney dysfunction in young people with type 1 diabetes. Pediatr Nephrol. 2023 Jan;38(1):193-202. doi: 10.1007/s00467-022-05531-3. Epub 2022 May 4.

  PMID: 35507146 DERIVED

• Vinovskis C, Li LP, Prasad P, Tommerdahl K, Pyle L, Nelson RG, Pavkov ME, van Raalte D, Rewers M, Pragnell M, Mahmud FH, Cherney DZ, Johnson RJ, Nadeau KJ, Bjornstad P. Relative Hypoxia and Early Diabetic Kidney Disease in Type 1 Diabetes. Diabetes. 2020 Dec;69(12):2700-2708. doi: 10.2337/db20-0457. Epub 2020 Jul 31.

  PMID: 32737116 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Obesity; Kidney Diseases; Pediatric Obesity

Interventions

p-Aminohippuric Acid; Iohexol

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Aminohippuric Acids; Hippurates; Benzamides; Amides; Organic Chemicals; para-Aminobenzoates; Aminobenzoates; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Keto Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Triiodobenzoic Acids; Iodobenzoates

Study Officials

• Petter Bjornstad, MD

  University of Colorado School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 28, 2018
• First Posted: July 12, 2018
• Study Start: October 1, 2018
• Primary Completion: June 30, 2023
• Study Completion: October 30, 2023
• Last Updated: August 15, 2023

Record last verified: 2023-08

Locations

US (1)