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

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

• Study Type: Observational
• Enrollment (Actual): 58

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• 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

How is the study designed?

Design Details

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

Number of groups / cohorts

2

Cohorts and Interventions

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: 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

Outcome Measure	Measure Description	Time Frame
Renal Oxygenation	Blood oxygen level dependent (BOLD) MRI	30 minutes
Renal Perfusion	Arterial Spin Labeling (ASL) MRI	30 minutes
Renal Oxygen Consumption	11-C Acetate PET/CT	30 minutes
Insulin Sensitivity	Hyperinsulinemic-Euglycemic Clamp	4.5 hours
Mitochondrial Function	Blood draw for mitochondrial DNA copy number	5 minutes
Mitochondrial Function	Blood draw for untargeted metabolite assessment of the tricyclic acid (TCA) cycle	5 minutes
Mitochondrial Function	Blood draw for targeted assessment and quantification of glucose oxidation using an established metabolite panel	5 minutes
Mitochondrial Function	Blood draw for untargeted metabolite assessment of Free Fatty Acid (FFA) oxidation	5 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glomerular Filtration Rate (GFR)	Iohexol Clearance Study	3 hours
Effective Renal Plasma Flow (ERPF)	PAH Clearance Study	2.5 hours
Renin-Angiotensin-Aldosterone-System Activity	Blood draw for Plasma Renin levels	5 minutes
Renin-Angiotensin-Aldosterone-System Activity	Blood draw for Angiotensin II levels	5 minutes
Renin-Angiotensin-Aldosterone-System Activity	Blood draw for Copeptin levels	5 minutes
Kidney Injury Biomarkers	Blood draw for Tyrosine Lysine Leucine-40 (YKL-40) levels	5 minutes
Kidney Injury Biomarkers	Blood draw for Neutrophil gelatinase-associated lipocalin (NGAL) levels	5 minutes
Kidney Injury Biomarkers	Blood draw for Kidney Injury Marker 1 (KIM-1) levels	5 minutes
Kidney Injury Biomarkers	Blood draw for Interleukin-18 (IL-18) levels	5 minutes
Kidney Injury Biomarkers	Blood draw for Tumor Necrosis Factor Receptor 1/2 (TNF-R 1/2) levels	5 minutes

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Podocyte numerical density and number per glomerulus	Measured by light microscopy from tissue obtained by renal biopsy	4 hours
Foot process width of glomeruli	Measured by electron microscopy from tissue obtained by renal biopsy	4 hours
Detachment and endothelial fenestration of glomeruli	Measured by electron microscopy from tissue obtained by renal biopsy	4 hours
Podocyte volume of glomeruli	Measured by electron microscopy from tissue obtained by renal biopsy	4 hours
Number and identity of RNA in kidney cells	Measured from tissue obtained by renal biopsy	4 hours
Epigenetic profiling	Measured from tissue obtained by renal biopsy	4 hours

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: Juvenile Diabetes Research Foundation

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 1, 2020
• Primary Completion (ACTUAL): May 15, 2022
• Study Completion (ACTUAL): November 15, 2022

Study Registration Dates

• First Submitted: August 6, 2019
• First Submitted That Met QC Criteria: August 28, 2019
• First Posted (ACTUAL): August 30, 2019

Study Record Updates

• Last Update Posted (ESTIMATE): February 9, 2023
• Last Update Submitted That Met QC Criteria: February 8, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Urologic Diseases; Endocrine System Diseases; Hyperinsulinism; Diabetes Mellitus; Kidney Diseases; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Insulin Resistance; Diabetes Complications
• Other Study ID 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