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

Obesity Clinical Trial

— Renal-HEIR  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03584217
• Other study ID #: 16-1752
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: October 1, 2018
• Est. completion date: October 30, 2023

Study information

• Verified date: August 2023
• Source: University of Colorado, Denver
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 100
• Est. completion date: October 30, 2023
• Est. primary completion date: June 30, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 12 Years to 21 Years

Eligibility

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

Related Conditions & MeSH terms

• Adolescent Obesity
• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Insulin Resistance
• Nephropathy
• Obesity
• Pediatric Obesity
• Type 2 Diabetes Mellitus

Intervention

Drug:
• Aminohippurate Sodium Inj 20%
Diagnostic aid/agent used to measure effective renal plasma flow (ERPF)
• Iohexol Inj 300 MG/ML
Diagnostic aid/agent used to measure glomerular filtration rate (GFR)

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

Locations

Country	Name	City	State
United States	Children's Hospital Colorado	Aurora	Colorado

Sponsors (1)

Lead Sponsor	Collaborator
University of Colorado, Denver

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Podocyte numerical density and number per glomerulus	Measured by light microscopy from tissue obtained by renal biopsy	4 hours
Other	Foot process width of glomeruli	Measured by electron microscopy from tissue obtained by renal biopsy	4 hours
Other	Detachment and endothelial fenestration of glomeruli	Measured by electron microscopy from tissue obtained by renal biopsy	4 hours
Other	Podocyte volume of glomeruli	Measured by electron microscopy from tissue obtained by renal biopsy	4 hours
Other	Number and identity of RNA in kidney cells	Measured from tissue obtained by renal biopsy	4 hours
Other	Epigenetic profiling	Measured from tissue obtained by renal biopsy	4 hours
Primary	Effective renal plasma flow (ERPF)	Measured by PAH clearance	4 hours
Primary	Glomerular filtration rate (GFR)	Measured by iohexol clearance	4 hours
Secondary	Insulin sensitivity	Measured by hyperinsulinemic-euglycemic clamp	4 hours
Secondary	Renal oxygenation	Blood oxygen level dependent (BOLD) MRI	60 min
Secondary	Renal perfusion	Arterial spin labeling (ASL) MRI	10 min