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

NCT ID: NCT04074668

Last Updated: 2023-02-09

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 58 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2020-01-01
• Study Completion Date: 2022-11-15

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.

Conditions

Diabetic Kidney Disease; Type 1 Diabetes; Diabetes; Diabetes Mellitus; Diabetes Complications; Diabetic Nephropathies; Type1diabetes; Diabetes, Autoimmune; Autoimmune Diabetes; Juvenile Diabetes; Type 1 Diabetes Mellitus

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: CROSS_SECTIONAL

Study Groups

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).

Aminohippurate Sodium Inj 20%

Intervention Type: DRUG

Diagnostic aid/agent used to measure effective renal plasma flow (ERPF)

Iohexol Inj 300 milligrams/milliliter (mg/ml)

Intervention Type: DRUG

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

PET/CT Scan

Intervention Type: RADIATION

Imaging used to visualize the kidneys and quantify renal metabolic activity

Renal Biopsy

Intervention Type: PROCEDURE

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).

Aminohippurate Sodium Inj 20%

Intervention Type: DRUG

Diagnostic aid/agent used to measure effective renal plasma flow (ERPF)

Iohexol Inj 300 milligrams/milliliter (mg/ml)

Intervention Type: DRUG

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

PET/CT Scan

Intervention Type: RADIATION

Imaging used to visualize the kidneys and quantify renal metabolic activity

Renal Biopsy

Intervention Type: PROCEDURE

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

Interventions

Aminohippurate Sodium Inj 20%

Diagnostic aid/agent used to measure effective renal plasma flow (ERPF)

Intervention Type: DRUG

Iohexol Inj 300 milligrams/milliliter (mg/ml)

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

Intervention Type: DRUG

PET/CT Scan

Imaging used to visualize the kidneys and quantify renal metabolic activity

Intervention Type: RADIATION

Renal Biopsy

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

Intervention Type: PROCEDURE

Other Intervention Names

Sodium 4-amino hippurate (PAH) inj 20% 2 grams (g)/10 milliliters (mL); Para-aminohippurate; Aminohippuric acid; omnipaque 300

Eligibility Criteria

Inclusion Criteria

• 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

• 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

• 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

• 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

• 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 30 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Juvenile Diabetes Research Foundation

OTHER

Sponsor Role: collaborator

University of Colorado, Denver

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Children's Hospital Colorado

Aurora, Colorado, United States

Countries

United States

References

Choi YJ, Richard G, Zhang G, Hodgin JB, Demeke DS, Yang Y, Schaub JA, Tamayo IM, Gurung BK, Naik AS, Nair V, Birznieks C, MacDonald A, Narongkiatikhun P, Gross S, Driscoll L, Flynn M, Tommerdahl K, Nadeau KJ, Shah VN, Vigers T, Snell-Bergeon JK, Kendrick J, van Raalte DH, Li LP, Prasad P, Ladd P, Chin BB, Cherney DZ, McCown PJ, Alakwaa F, Otto EA, Brosius FC, Saulnier PJ, Puelles VG, Goodrich JA, Street K, Venkatachalam MA, Ruiz A, de Boer IH, Nelson RG, Pyle L, Blondin DP, Sharma K, Kretzler M, Bjornstad P. Attenuated kidney oxidative metabolism in young adults with type 1 diabetes. J Clin Invest. 2024 Oct 22;134(24):e183984. doi: 10.1172/JCI183984.

Reference Type: DERIVED

PMID: 39436695 (View on PubMed)

Bjornstad P, Richard G, Choi YJ, Nowak KL, Steele C, Chonchol MB, Nadeau KJ, Vigers T, Pyle L, Tommerdahl K, van Raalte DH, Hilkin A, Driscoll L, Birznieks C, Hopp K, Wang W, Edelstein C, Nelson RG, Gregory AV, Kline TL, Blondin D, Gitomer B. Kidney Energetics and Cyst Burden in Autosomal Dominant Polycystic Kidney Disease: A Pilot Study. Am J Kidney Dis. 2024 Sep;84(3):286-297.e1. doi: 10.1053/j.ajkd.2024.02.016. Epub 2024 Apr 15.

Reference Type: DERIVED

PMID: 38621633 (View on PubMed)

Other Identifiers

19-1282

Identifier Type: -

Identifier Source: org_study_id