Control of Renal Oxygen Consumption, Mitochondrial Dysfunction, and Insulin Resistance

CROCODILE Study: Control of Renal Oxygen Consumption, Mitochondrial Dysfunction, and Insulin Resistance

Sponsors

Lead Sponsor: University of Colorado Denver School of Medicine Barbara Davis Center

Collaborator: Juvenile Diabetes Research Foundation

Source University of Colorado Denver School of Medicine Barbara Davis Center
Brief Summary

Type 1 diabetes (T1D) is a complex metabolic disorder with many pathophysiological disturbances including insulin resistance (IR) and mitochondrial dysfunction which are causally related to the development of diabetic kidney disease (DKD) and which contribute to reduced life expectancy. Renal hypoxia, stemming from a potential metabolic mismatch between increased renal energy expenditure and impaired substrate utilization, is increasingly proposed as a unifying early pathway in the development of DKD. By examining the interplay between factors responsible for increased renal adenosine triphosphate (ATP) consumption and decreased ATP generation in young adults with and without T1D, this study hopes to identify novel therapeutic targets to impede the development of DKD in future trials.

The investigators propose to address the specific aims in a cross-sectional study with 30 adults with T1D and 20 controls without a diagnosis of diabetes. For this protocol, participants will complete a one day study visit at Children's Hospital Colorado. Patients will undergo a Dual-energy X-Ray Absorptiometry (DXA) scan to assess body composition, renal Magnetic Resonance Imaging (MRI) to quantify renal oxygenation and perfusion, and a Positron Emission Tomography/Computed Tomography (PET/CT) scan to quantify renal O2 consumption. After the PET and MRI, participants will undergo a hyperinsulinemic-euglycemic clamp to quantify insulin sensitivity. Glomerular Filtration Rate (GFR) and Effective Renal Plasma Flow (ERPF) will be measured by iohexol and PAH clearances during the hyperinsulinemic-euglycemic clamp. To further investigate the mechanisms of renal damage in T1D, 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.

Overall Status Recruiting
Start Date January 1, 2020
Completion Date March 31, 2022
Primary Completion Date October 31, 2021
Study Type Observational
Primary Outcome
Measure Time Frame
Renal Oxygenation 30 minutes
Renal Perfusion 30 minutes
Renal Oxygen Consumption 30 minutes
Insulin Sensitivity 4.5 hours
Mitochondrial Function 5 minutes
Mitochondrial Function 5 minutes
Mitochondrial Function 5 minutes
Mitochondrial Function 5 minutes
Secondary Outcome
Measure Time Frame
Glomerular Filtration Rate (GFR) 3 hours
Effective Renal Plasma Flow (ERPF) 2.5 hours
Renin-Angiotensin-Aldosterone-System Activity 5 minutes
Renin-Angiotensin-Aldosterone-System Activity 5 minutes
Renin-Angiotensin-Aldosterone-System Activity 5 minutes
Kidney Injury Biomarkers 5 minutes
Kidney Injury Biomarkers 5 minutes
Kidney Injury Biomarkers 5 minutes
Kidney Injury Biomarkers 5 minutes
Kidney Injury Biomarkers 5 minutes
Enrollment 50
Condition
Intervention

Intervention Type: Drug

Intervention Name: Aminohippurate Sodium Inj 20%

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

Intervention Type: Drug

Intervention Name: Iohexol Inj 300 milligrams/milliliter (mg/ml)

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

Other Name: omnipaque 300

Intervention Type: Radiation

Intervention Name: PET/CT Scan

Description: Imaging used to visualize the kidneys and quantify renal metabolic activity

Intervention Type: Procedure

Intervention Name: Renal Biopsy

Description: Minimally invasive outpatient procedure to obtain renal tissue after ultrasound visualization.

Eligibility

Sampling Method: Probability Sample

Criteria:

Inclusion Criteria -- Type 1 Diabetes:

- Antibody positive Type 1 Diabetes with duration > 5 years

- BMI between 18.5 and 30 kg/m2

- Weight < 350 lbs

- HbA1c < 11%

- Hemoglobin >= 12 g/dl

Exclusion Criteria -- Type 1 Diabetes:

- Recent diagnosis (within 3 months) of Diabetic Ketoacidosis (DKA)

- Severe illness

- Pregnancy, nursing

- Anemia

- Allergy to shellfish or iodine

- Claustrophobia or implantable metal devices (MRI contraindications)

- High blood pressure (greater than 130/80 mm Hg)

- Elevated Urine Albumin-to-Creatinine Ratio (UACR) (>30 mg/g) or estimated Glomerular Filtration Rate (eGFR) <90 ml/min/1.73 m2

- Taking ACE inhibitors (ACEis), Angiotensin receptor blockers (ARBs), diuretics, Sodium Glucose Transporter (SGLT) 1/2 blockers

Inclusion Criteria -- Healthy Controls:

- No diagnosis of Type 1 or Type 2 Diabetes

- BMI between 18.5 and 30 kg/m2

- Weight < 350 lbs

- HbA1c < 11%

- Hemoglobin >= 12 g/dl

Exclusion Criteria -- Healthy Controls:

- Severe illness

- Pregnancy, nursing

- Anemia

- Allergy to shellfish or iodine

- Claustrophobia or implantable metal devices (MRI contraindications)

- High blood pressure (greater than 130/80 mm Hg)

- Elevated UACR (>30 mg/g) or eGFR <90 ml/min/1.73 m2

- Taking ACE inhibitors (ACEis), Angiotensin receptor blockers (ARBs), diuretics, SGLT 1/2 blockers

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

Gender: All

Minimum Age: 18 Years

Maximum Age: 30 Years

Healthy Volunteers: Accepts Healthy Volunteers

Overall Contact

Last Name: Carissa Vinovskis, MS

Phone: 720-777-2660

Email: [email protected]

Location
Facility: Status: Contact: Contact Backup: Children's Hospital Colorado Petter Bjornstad, MD 720-777-4659 [email protected]
Location Countries

United States

Verification Date

April 2020

Responsible Party

Type: Principal Investigator

Investigator Affiliation: University of Colorado Denver School of Medicine Barbara Davis Center

Investigator Full Name: Petter Bjornstad

Investigator Title: Asisstant Professor of Medicine and Pediatrics

Has Expanded Access No
Condition Browse
Arm Group

Label: Type 1 Diabetes

Description: All participants will undergo DXA scan, magnetic resonance imaging (MRI) studies of the kidneys, PET/CT using 11-C acetate to measure renal oxygen consumption, hyperinsulinemic-euglycemic clamp to quantify insulin sensitivity, and renal clearance testing using iohexol and para-aminohippurate (PAH) to quantify glomerular filtration rate (GFR) and effective renal plasma flow (ERPF).

Label: Healthy Controls

Description: All participants will undergo DXA scan, magnetic resonance imaging (MRI) studies of the kidneys, PET/CT using 11-C acetate to measure renal oxygen consumption, hyperinsulinemic-euglycemic clamp to quantify insulin sensitivity, and renal clearance testing using iohexol and para-aminohippurate (PAH) to quantify glomerular filtration rate (GFR) and effective renal plasma flow (ERPF).

Acronym CROCODILE
Patient Data Undecided
Study Design Info

Observational Model: Cohort

Time Perspective: Cross-Sectional

Source: ClinicalTrials.gov