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Completed

NCT Number: NCT04074668

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

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.

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Key information

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Aminohippurate Sodium Inj 20%

Drug

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

Iohexol Inj 300 milligrams/milliliter (mg/ml)

Drug

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

Other names: omnipaque 300

PET/CT Scan

Radiation

Imaging used to visualize the kidneys and quantify renal metabolic activity

Renal Biopsy

Procedure

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

Primary outcomes

  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 outcomes

  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 outcomes

  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

Sponsors and collaborators

Lead sponsor

University of Colorado, Denver

Other

Collaborators

  • Juvenile Diabetes Research Foundation

Registry information

Official study title

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

Acronym: CROCODILE

Important dates

Study start
2020
Primary completion
2022
Study completion
2022
First posted
Aug 30, 2019
Registry last updated
Feb 9, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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