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

Diabetes Clinical Trial

— CROCODILE  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04074668
• Other study ID #: 19-1282
• Status: Completed
• Start date: January 1, 2020
• Est. completion date: November 15, 2022

Study information

• Verified date: February 2023
• Source: University of Colorado, Denver
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 58
• Est. completion date: November 15, 2022
• Est. primary completion date: May 15, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 30 Years

Eligibility

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

Related Conditions & MeSH terms

• Autoimmune Diabetes
• Diabetes
• Diabetes Complications
• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Diabetes, Autoimmune
• Diabetic Kidney Disease
• Diabetic Nephropathies
• Insulin Resistance
• Juvenile Diabetes
• Kidney Diseases
• Type 1 Diabetes
• Type 1 Diabetes Mellitus
• Type1diabetes

Intervention

Drug:
• Aminohippurate Sodium Inj 20%
Diagnostic aid/agent used to measure effective renal plasma flow (ERPF)
• Iohexol Inj 300 milligrams/milliliter (mg/ml)
Diagnostic aid/agent used to measure glomerular filtration rate (GFR)

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.

Locations

Country	Name	City	State
United States	Children's Hospital Colorado	Aurora	Colorado

Sponsors (2)

Lead Sponsor	Collaborator
University of Colorado, Denver	Juvenile Diabetes Research Foundation

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Podocyte numerical density and number per glomerulus	Measured by light microscopy from tissue obtained by renal biopsy	4 hours
Other	Foot process width of glomeruli	Measured by electron microscopy from tissue obtained by renal biopsy	4 hours
Other	Detachment and endothelial fenestration of glomeruli	Measured by electron microscopy from tissue obtained by renal biopsy	4 hours
Other	Podocyte volume of glomeruli	Measured by electron microscopy from tissue obtained by renal biopsy	4 hours
Other	Number and identity of RNA in kidney cells	Measured from tissue obtained by renal biopsy	4 hours
Other	Epigenetic profiling	Measured from tissue obtained by renal biopsy	4 hours
Primary	Renal Oxygenation	Blood oxygen level dependent (BOLD) MRI	30 minutes
Primary	Renal Perfusion	Arterial Spin Labeling (ASL) MRI	30 minutes
Primary	Renal Oxygen Consumption	11-C Acetate PET/CT	30 minutes
Primary	Insulin Sensitivity	Hyperinsulinemic-Euglycemic Clamp	4.5 hours
Primary	Mitochondrial Function	Blood draw for mitochondrial DNA copy number	5 minutes
Primary	Mitochondrial Function	Blood draw for untargeted metabolite assessment of the tricyclic acid (TCA) cycle	5 minutes
Primary	Mitochondrial Function	Blood draw for targeted assessment and quantification of glucose oxidation using an established metabolite panel	5 minutes
Primary	Mitochondrial Function	Blood draw for untargeted metabolite assessment of Free Fatty Acid (FFA) oxidation	5 minutes
Secondary	Glomerular Filtration Rate (GFR)	Iohexol Clearance Study	3 hours
Secondary	Effective Renal Plasma Flow (ERPF)	PAH Clearance Study	2.5 hours
Secondary	Renin-Angiotensin-Aldosterone-System Activity	Blood draw for Plasma Renin levels	5 minutes
Secondary	Renin-Angiotensin-Aldosterone-System Activity	Blood draw for Angiotensin II levels	5 minutes
Secondary	Renin-Angiotensin-Aldosterone-System Activity	Blood draw for Copeptin levels	5 minutes
Secondary	Kidney Injury Biomarkers	Blood draw for Tyrosine Lysine Leucine-40 (YKL-40) levels	5 minutes
Secondary	Kidney Injury Biomarkers	Blood draw for Neutrophil gelatinase-associated lipocalin (NGAL) levels	5 minutes
Secondary	Kidney Injury Biomarkers	Blood draw for Kidney Injury Marker 1 (KIM-1) levels	5 minutes
Secondary	Kidney Injury Biomarkers	Blood draw for Interleukin-18 (IL-18) levels	5 minutes
Secondary	Kidney Injury Biomarkers	Blood draw for Tumor Necrosis Factor Receptor 1/2 (TNF-R 1/2) levels	5 minutes