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Control of Renal Oxygen Consumption, Mitochondrial Dysfunction, and Insulin Resistance (CROCODILE)

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ClinicalTrials.gov Identifier: NCT04074668
Recruitment Status : Recruiting
First Posted : August 30, 2019
Last Update Posted : May 4, 2020
Sponsor:
Collaborator:
Juvenile Diabetes Research Foundation
Information provided by (Responsible Party):
Petter Bjornstad, 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.


Condition or disease Intervention/treatment
Diabetic Kidney Disease Type 1 Diabetes Diabetes Diabetes Mellitus Diabetes Complications Diabetic Nephropathies Type1diabetes Diabetes, Autoimmune Autoimmune Diabetes Juvenile Diabetes Type 1 Diabetes Mellitus Drug: Aminohippurate Sodium Inj 20% Drug: Iohexol Inj 300 milligrams/milliliter (mg/ml) Radiation: PET/CT Scan Procedure: Renal Biopsy

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Study Type : Observational
Estimated Enrollment : 50 participants
Observational Model: Cohort
Time Perspective: Cross-Sectional
Official Title: CROCODILE Study: Control of Renal Oxygen Consumption, Mitochondrial Dysfunction, and Insulin Resistance
Actual Study Start Date : January 1, 2020
Estimated Primary Completion Date : October 31, 2021
Estimated Study Completion Date : March 31, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Oxygen Therapy

Group/Cohort Intervention/treatment
Type 1 Diabetes
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).
Drug: Aminohippurate Sodium Inj 20%
Diagnostic aid/agent used to measure effective renal plasma flow (ERPF)
Other Names:
  • Sodium 4-amino hippurate (PAH) inj 20% 2 grams (g)/10 milliliters (mL)
  • Para-aminohippurate
  • Aminohippuric acid

Drug: Iohexol Inj 300 milligrams/milliliter (mg/ml)
Diagnostic aid/agent used to measure glomerular filtration rate (GFR)
Other Name: omnipaque 300

Radiation: PET/CT Scan
Imaging used to visualize the kidneys and quantify renal metabolic activity

Procedure: Renal Biopsy
Minimally invasive outpatient procedure to obtain renal tissue after ultrasound visualization.

Healthy Controls
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).
Drug: Aminohippurate Sodium Inj 20%
Diagnostic aid/agent used to measure effective renal plasma flow (ERPF)
Other Names:
  • Sodium 4-amino hippurate (PAH) inj 20% 2 grams (g)/10 milliliters (mL)
  • Para-aminohippurate
  • Aminohippuric acid

Drug: Iohexol Inj 300 milligrams/milliliter (mg/ml)
Diagnostic aid/agent used to measure glomerular filtration rate (GFR)
Other Name: omnipaque 300

Radiation: PET/CT Scan
Imaging used to visualize the kidneys and quantify renal metabolic activity

Procedure: Renal Biopsy
Minimally invasive outpatient procedure to obtain renal tissue after ultrasound visualization.




Primary Outcome Measures :
  1. Renal Oxygenation [ Time Frame: 30 minutes ]
    Blood oxygen level dependent (BOLD) MRI

  2. Renal Perfusion [ Time Frame: 30 minutes ]
    Arterial Spin Labeling (ASL) MRI

  3. Renal Oxygen Consumption [ Time Frame: 30 minutes ]
    11-C Acetate PET/CT

  4. Insulin Sensitivity [ Time Frame: 4.5 hours ]
    Hyperinsulinemic-Euglycemic Clamp

  5. Mitochondrial Function [ Time Frame: 5 minutes ]
    Blood draw for mitochondrial DNA copy number

  6. Mitochondrial Function [ Time Frame: 5 minutes ]
    Blood draw for untargeted metabolite assessment of the tricyclic acid (TCA) cycle

  7. Mitochondrial Function [ Time Frame: 5 minutes ]
    Blood draw for targeted assessment and quantification of glucose oxidation using an established metabolite panel

  8. Mitochondrial Function [ Time Frame: 5 minutes ]
    Blood draw for untargeted metabolite assessment of Free Fatty Acid (FFA) oxidation


Secondary Outcome Measures :
  1. Glomerular Filtration Rate (GFR) [ Time Frame: 3 hours ]
    Iohexol Clearance Study

  2. Effective Renal Plasma Flow (ERPF) [ Time Frame: 2.5 hours ]
    PAH Clearance Study

  3. Renin-Angiotensin-Aldosterone-System Activity [ Time Frame: 5 minutes ]
    Blood draw for Plasma Renin levels

  4. Renin-Angiotensin-Aldosterone-System Activity [ Time Frame: 5 minutes ]
    Blood draw for Angiotensin II levels

  5. Renin-Angiotensin-Aldosterone-System Activity [ Time Frame: 5 minutes ]
    Blood draw for Copeptin levels

  6. Kidney Injury Biomarkers [ Time Frame: 5 minutes ]
    Blood draw for Tyrosine Lysine Leucine-40 (YKL-40) levels

  7. Kidney Injury Biomarkers [ Time Frame: 5 minutes ]
    Blood draw for Neutrophil gelatinase-associated lipocalin (NGAL) levels

  8. Kidney Injury Biomarkers [ Time Frame: 5 minutes ]
    Blood draw for Kidney Injury Marker 1 (KIM-1) levels

  9. Kidney Injury Biomarkers [ Time Frame: 5 minutes ]
    Blood draw for Interleukin-18 (IL-18) levels

  10. Kidney Injury Biomarkers [ Time Frame: 5 minutes ]
    Blood draw for Tumor Necrosis Factor Receptor 1/2 (TNF-R 1/2) levels


Other Outcome Measures:
  1. Podocyte numerical density and number per glomerulus [ Time Frame: 4 hours ]
    Measured by light microscopy from tissue obtained by renal biopsy

  2. Foot process width of glomeruli [ Time Frame: 4 hours ]
    Measured by electron microscopy from tissue obtained by renal biopsy

  3. Detachment and endothelial fenestration of glomeruli [ Time Frame: 4 hours ]
    Measured by electron microscopy from tissue obtained by renal biopsy

  4. Podocyte volume of glomeruli [ Time Frame: 4 hours ]
    Measured by electron microscopy from tissue obtained by renal biopsy

  5. Number and identity of RNA in kidney cells [ Time Frame: 4 hours ]
    Measured from tissue obtained by renal biopsy

  6. Epigenetic profiling [ Time Frame: 4 hours ]
    Measured from tissue obtained by renal biopsy


Biospecimen Retention:   Samples With DNA
During the study, blood and urine samples will be collected for assessment of kidney function and kidney injury markers.


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 30 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
We propose to address the specific aims of this study in a cross-sectional project with 30 adults with T1D and 20 controls (50% female, ages 18-30 yr).
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04074668


Contacts
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Contact: Carissa Vinovskis, MS 720-777-2660 carissa.vinovskis@childrenscolorado.org
Contact: Petter Bjornstad, MD 720-777-4659 petter.bjornstad@childrenscolorado.org

Locations
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United States, Colorado
Children's Hospital Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Petter Bjornstad, MD    720-777-4659    petter.bjornstad@childrenscolorado.org   
Contact: Carissa Vinovskis, MS    720-777-2660    carissa.vinovskis@childrenscolorado.org   
Sponsors and Collaborators
University of Colorado Denver School of Medicine Barbara Davis Center
Juvenile Diabetes Research Foundation
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Responsible Party: Petter Bjornstad, Asisstant Professor of Medicine and Pediatrics, University of Colorado Denver School of Medicine Barbara Davis Center
ClinicalTrials.gov Identifier: NCT04074668    
Other Study ID Numbers: 19-1282
First Posted: August 30, 2019    Key Record Dates
Last Update Posted: May 4, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Kidney Diseases
Diabetic Nephropathies
Diabetes Mellitus
Diabetes Mellitus, Type 1
Insulin Resistance
Diabetes Complications
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Urologic Diseases
Autoimmune Diseases
Immune System Diseases
Hyperinsulinism