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Clinical Trial Details — Status: Active, not recruiting

Administrative data

NCT number NCT03620773
Other study ID # 18-0704
Secondary ID
Status Active, not recruiting
Phase Phase 1/Phase 2
First received
Last updated
Start date October 1, 2018
Est. completion date October 1, 2024

Study information

Verified date April 2024
Source University of Colorado, Denver
Contact n/a
Is FDA regulated No
Health authority
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. Early DKD is characterized by changes in intrarenal hemodynamic function, including increased renal plasma flow (RPF) and glomerular pressure with resultant hyperfiltration, is common in Y-T2D, and predicts progressive DKD. Studies evaluating the two currently approved medications for treating T2D in youth (metformin and insulin) have shown these medications are not able to improve β-cell function over time in the youth. However, recent evidence suggests that bariatric surgery in adults is associated with improvements in diabetes outcomes, and even T2D remission in many patients. Limited data in youth also supports the benefits of bariatric surgery, regarding weight loss, glycemic control in T2D, and cardio-renal health. While weight loss is important, the acute effect of bariatric surgery on factors such as insulin resistance likely includes weight loss-independent mechanisms. A better understanding of the effects of bariatric surgery on pancreatic function, intrarenal hemodynamics, renal O2 and cardiovascular function is critical to help define mechanisms of surgical benefits, to help identify potential novel future non-surgical approaches to prevent pancreatic failure, DKD and cardiovascular disease. The investigators' overarching hypotheses are that: 1) Y-T2D is associated with IR, pancreatic dysfunction, intrarenal hemodynamic dysfunction, elevated renal O2 consumption and cardiovascular dysfunction which improve with bariatric surgery, 2) The early effect of bariatric surgery on intrarenal hemodynamics is mediated by improvement in IR and weight loss. To address these hypotheses, the investigators will measure GFR, RPF, glomerular pressure and renal O2, in addition to aortic stiffness, β-cell function and insulin sensitivity in youth ages 12-21 with T2D (n=30) before and after vertical sleeve gastrectomy (VSG). To further investigate the mechanisms of renal damage in youth with T2D, two optional procedures are included in the study prior to vertical sleeve gastrectomy: 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 30
Est. completion date October 1, 2024
Est. primary completion date October 1, 2024
Accepts healthy volunteers No
Gender All
Age group 12 Years to 21 Years
Eligibility Inclusion Criteria: - Obese youth with and without T2D (=50 kg) scheduled for VSG - Weight <550 lbs. - BMI = 35 kg/m2 - Age 12-21 years - HbA1c = 12% Exclusion Criteria: - T2D onset (diagnosis) > 18 years of age - Prepubertal - Anemia - Seafood or iodine allergy - Pregnancy or breastfeeding - Claustrophobia, implantable devices (MRI contraindications) - Recent diabetic ketoacidosis or hyperosmolar hyperglycemia - Other causes of diabetes other than T2D - Diuretics, sodium-glucose co-transport (SGLT) 2 or 1 blockers, daily NSAIDs or aspirin, sulfonamides, procaine, thiazolsulfone or probenecid, atypical antipsychotics or regular use of oral steroids 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

Study Design


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:
Vertical Sleeve Gastrectomy
Participants will undergo vertical sleeve gastrectomy surgery, a laparoscopic bariatric surgery procedure designed for weight loss in obese patients
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 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 Pancreatic ß-cell function Measured by Mixed Meal Tolerance Test (MMTT) 4 hours (MMTT)
Primary Pancreatic ß-cell function Measured by blood draws during/after hyperglycemic clamp 4 hours (hyperglycemic clamp)
Primary Effective Renal Plasma Flow (ERPF) Measured by PAH clearance 4 hours
Primary Glomerular Filtration Rate (GFR) Measured by iohexol clearance 4 hours
Secondary Renal Perfusion Measured by Arterial Spin Labeling (ASL) MRI 10 min
Secondary Renal Oxygenation Measured by Blood Oxygen Level Dependent (BOLD) MRI 60 min
Secondary Aortic Stiffness & Wall Shear Stress Measured by Aortic MRI 30 min
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