Clinical trial NCT03584217: Renal HEIR Study: Renal Hemodynamics, Energetics and Insulin Resistance in Youth Onset Type 2 Diabetes Study
Official title: Renal HEIR Study: Renal Hemodynamics, Energetics and Insulin Resistance in Youth Onset Type 2 Diabetes Study
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Type 2 Diabetes Mellitus
Obesity
Nephropathy
Adolescent Obesity
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
First posted: 2018-07-12
Enrollment: 100
Sex: ALL
Minimum age (years): 12
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

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.


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)

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

Primary outcomes:
measure: Effective renal plasma flow (ERPF)
timeFrame: 4 hours
measure: Glomerular filtration rate (GFR)
timeFrame: 4 hours
Secondary outcomes:
measure: Insulin sensitivity
timeFrame: 4 hours
measure: Renal oxygenation
timeFrame: 60 min
measure: Renal perfusion
timeFrame: 10 min
Other outcomes:
measure: Podocyte numerical density and number per glomerulus
timeFrame: 4 hours
measure: Foot process width of glomeruli
timeFrame: 4 hours
measure: Detachment and endothelial fenestration of glomeruli
timeFrame: 4 hours
measure: Podocyte volume of glomeruli
timeFrame: 4 hours
measure: Number and identity of RNA in kidney cells
timeFrame: 4 hours
measure: Epigenetic profiling
timeFrame: 4 hours
Locations:
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
Study officials:
affiliation: University of Colorado School of Medicine
name: Petter Bjornstad, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.