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

University of Colorado Denver (CU Denver)

Status and phase

Active, not recruiting

Phase 2

Phase 1

Conditions

Nephropathy

Type 2 Diabetes Mellitus

Obesity

Adolescent Obesity

Treatments

Drug: Aminohippurate Sodium Inj 20%

Procedure: Renal Biopsy

Drug: Iohexol Inj 300 MG/ML

Study type

Interventional

Funder types

Other

Identifiers

NCT03584217

16-1752

Details and patient eligibility

About

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.

Enrollment

100 patients

Sex

All

Ages

12 to 21 years old

Volunteers

Accepts Healthy Volunteers

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