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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03584217
Recruitment Status : Recruiting
First Posted : July 12, 2018
Last Update Posted : August 9, 2021
Information provided by (Responsible Party):
Petter Bjornstad, University of Colorado, Denver

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.

Condition or disease Intervention/treatment Phase
Type 2 Diabetes Mellitus Obesity Nephropathy Adolescent Obesity Drug: Aminohippurate Sodium Inj 20% Drug: Iohexol Inj 300 MG/ML Procedure: Renal Biopsy Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Renal HEIR Study: Renal Hemodynamics, Energetics and Insulin Resistance in Youth Onset Type 2 Diabetes Study
Actual Study Start Date : October 1, 2018
Estimated Primary Completion Date : June 2023
Estimated Study Completion Date : June 2023

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Clinical Investigation
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%
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 Name: omnipaque 300

Procedure: Renal Biopsy
Minimally invasive outpatient procedure in interventional radiology to obtain renal tissue cores.
Other Name: Kidney Biopsy

Primary Outcome Measures :
  1. Effective renal plasma flow (ERPF) [ Time Frame: 4 hours ]
    Measured by PAH clearance

  2. Glomerular filtration rate (GFR) [ Time Frame: 4 hours ]
    Measured by iohexol clearance

Secondary Outcome Measures :
  1. Insulin sensitivity [ Time Frame: 4 hours ]
    Measured by hyperinsulinemic-euglycemic clamp

  2. Renal oxygenation [ Time Frame: 60 min ]
    Blood oxygen level dependent (BOLD) MRI

  3. Renal perfusion [ Time Frame: 10 min ]
    Arterial spin labeling (ASL) MRI

Other Outcome Measures:
  1. Podocyte numerical density and number per glomerulus [ Time Frame: 4 hours ]
    Measured by light microscopy from tissue obtained by renal biopsy

  2. Foot process width of glomeruli [ Time Frame: 4 hours ]
    Measured by electron microscopy from tissue obtained by renal biopsy

  3. Detachment and endothelial fenestration of glomeruli [ Time Frame: 4 hours ]
    Measured by electron microscopy from tissue obtained by renal biopsy

  4. Podocyte volume of glomeruli [ Time Frame: 4 hours ]
    Measured by electron microscopy from tissue obtained by renal biopsy

  5. Number and identity of RNA in kidney cells [ Time Frame: 4 hours ]
    Measured from tissue obtained by renal biopsy

  6. Epigenetic profiling [ Time Frame: 4 hours ]
    Measured from tissue obtained by renal biopsy

Information from the National Library of Medicine

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Ages Eligible for Study:   12 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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)

Additional exclusion criteria for participants undergoing optional kidney biopsy:

  • 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)
  • eGFR < 40 mL/min/1.73m2
  • Single kidney (either by history, documented by prior imaging or ultrasound performed prior to the biopsy)
  • > 2 cm discrepancy between left and right kidney sizes based on largest longitudinal diameter determined by ultrasound performed prior to the biopsy.
  • Kidney size: One or both kidneys < 9 cm
  • Hydronephrosis or other important renal ultrasound findings such as significant stone disease
  • Any evidence of a current urinary tract infection as indicated on day of biopsy
  • Clinical evidence of non-diabetic renal disease
  • Positive urine pregnancy test or pregnancy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03584217

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Contact: Susan Gross, MS, RD 7207776143
Contact: Petter Bjornstad, MD 7207774659

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United States, Colorado
Children's Hospital Colorado Recruiting
Aurora, Colorado, United States, 80238
Contact: Petter Bjornstad, M.D.         
Principal Investigator: Petter Bjornstad, M.D.         
Sub-Investigator: Kristen Nadeau, M.D.         
Sponsors and Collaborators
University of Colorado Denver School of Medicine Barbara Davis Center
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Principal Investigator: Petter Bjornstad, MD University of Colorado School of Medicine
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Petter Bjornstad, Assistant Professor, University of Colorado, Denver Identifier: NCT03584217    
Other Study ID Numbers: 16-1752
First Posted: July 12, 2018    Key Record Dates
Last Update Posted: August 9, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Insulin Resistance
Pediatric Obesity
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Nutrition Disorders
Body Weight