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

February 8, 2023 updated by: University of Colorado, Denver

CROCODILE Study: 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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
58

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Colorado
      • Aurora, Colorado, United States, 80045
        • Children's Hospital Colorado

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 30 years (ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

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).

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Cross-Sectional

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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:
  • Para-aminohippurate
  • Aminohippuric acid
  • Sodium 4-amino hippurate (PAH) inj 20% 2 grams (g)/10 milliliters (mL)
Drug: Iohexol Inj 300 milligrams/milliliter (mg/ml)
Diagnostic aid/agent used to measure glomerular filtration rate (GFR)
Other Names:
  • 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:
  • Para-aminohippurate
  • Aminohippuric acid
  • Sodium 4-amino hippurate (PAH) inj 20% 2 grams (g)/10 milliliters (mL)
Drug: Iohexol Inj 300 milligrams/milliliter (mg/ml)
Diagnostic aid/agent used to measure glomerular filtration rate (GFR)
Other Names:
  • 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.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Renal Oxygenation
Time Frame: 30 minutes
Blood oxygen level dependent (BOLD) MRI
30 minutes
Renal Perfusion
Time Frame: 30 minutes
Arterial Spin Labeling (ASL) MRI
30 minutes
Renal Oxygen Consumption
Time Frame: 30 minutes
11-C Acetate PET/CT
30 minutes
Insulin Sensitivity
Time Frame: 4.5 hours
Hyperinsulinemic-Euglycemic Clamp
4.5 hours
Mitochondrial Function
Time Frame: 5 minutes
Blood draw for mitochondrial DNA copy number
5 minutes
Mitochondrial Function
Time Frame: 5 minutes
Blood draw for untargeted metabolite assessment of the tricyclic acid (TCA) cycle
5 minutes
Mitochondrial Function
Time Frame: 5 minutes
Blood draw for targeted assessment and quantification of glucose oxidation using an established metabolite panel
5 minutes
Mitochondrial Function
Time Frame: 5 minutes
Blood draw for untargeted metabolite assessment of Free Fatty Acid (FFA) oxidation
5 minutes

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Glomerular Filtration Rate (GFR)
Time Frame: 3 hours
Iohexol Clearance Study
3 hours
Effective Renal Plasma Flow (ERPF)
Time Frame: 2.5 hours
PAH Clearance Study
2.5 hours
Renin-Angiotensin-Aldosterone-System Activity
Time Frame: 5 minutes
Blood draw for Plasma Renin levels
5 minutes
Renin-Angiotensin-Aldosterone-System Activity
Time Frame: 5 minutes
Blood draw for Angiotensin II levels
5 minutes
Renin-Angiotensin-Aldosterone-System Activity
Time Frame: 5 minutes
Blood draw for Copeptin levels
5 minutes
Kidney Injury Biomarkers
Time Frame: 5 minutes
Blood draw for Tyrosine Lysine Leucine-40 (YKL-40) levels
5 minutes
Kidney Injury Biomarkers
Time Frame: 5 minutes
Blood draw for Neutrophil gelatinase-associated lipocalin (NGAL) levels
5 minutes
Kidney Injury Biomarkers
Time Frame: 5 minutes
Blood draw for Kidney Injury Marker 1 (KIM-1) levels
5 minutes
Kidney Injury Biomarkers
Time Frame: 5 minutes
Blood draw for Interleukin-18 (IL-18) levels
5 minutes
Kidney Injury Biomarkers
Time Frame: 5 minutes
Blood draw for Tumor Necrosis Factor Receptor 1/2 (TNF-R 1/2) levels
5 minutes

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Podocyte numerical density and number per glomerulus
Time Frame: 4 hours
Measured by light microscopy from tissue obtained by renal biopsy
4 hours
Foot process width of glomeruli
Time Frame: 4 hours
Measured by electron microscopy from tissue obtained by renal biopsy
4 hours
Detachment and endothelial fenestration of glomeruli
Time Frame: 4 hours
Measured by electron microscopy from tissue obtained by renal biopsy
4 hours
Podocyte volume of glomeruli
Time Frame: 4 hours
Measured by electron microscopy from tissue obtained by renal biopsy
4 hours
Number and identity of RNA in kidney cells
Time Frame: 4 hours
Measured from tissue obtained by renal biopsy
4 hours
Epigenetic profiling
Time Frame: 4 hours
Measured from tissue obtained by renal biopsy
4 hours

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of Colorado, Denver

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Juvenile Diabetes Research Foundation

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 1, 2020

Primary Completion (ACTUAL)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
May 15, 2022

Study Completion (ACTUAL)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
November 15, 2022

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
August 6, 2019

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 28, 2019

First Posted (ACTUAL)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 30, 2019

Study Record Updates

Last Update Posted (ESTIMATE)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
February 9, 2023

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 8, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
February 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 19-1282

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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