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

NCT ID: NCT03584217

Last Updated: 2023-08-15

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 100 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-10-01
• Study Completion Date: 2023-10-30

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

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.

Group Type: OTHER

Aminohippurate Sodium Inj 20%

Intervention Type: DRUG

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

Iohexol Inj 300 MG/ML

Intervention Type: DRUG

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

Renal Biopsy

Intervention Type: PROCEDURE

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

Interventions

Aminohippurate Sodium Inj 20%

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

Intervention Type: DRUG

Iohexol Inj 300 MG/ML

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

Intervention Type: DRUG

Renal Biopsy

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

Intervention Type: PROCEDURE

Other Intervention Names

Sodium 4-amino hippurate (PAH) inj 20% 2g/10mL; Para-aminohippurate; Aminohippuric acid; omnipaque 300; Kidney Biopsy

Eligibility Criteria

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)

• 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

• Minimum Eligible Age: 12 Years
• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Colorado, Denver

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Petter Bjornstad, MD

Role: PRINCIPAL_INVESTIGATOR

University of Colorado School of Medicine

Locations

Children's Hospital Colorado

Aurora, Colorado, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 35507146 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32737116 (View on PubMed)

Other Identifiers

16-1752

Identifier Type: -

Identifier Source: org_study_id