Copeptin in Adolescent Participants With Type 1 Diabetes and Early Renal Hemodynamic Function

NCT03618420 | Completed Phase 1 Results FDA Drug

• 1 other identifier: 17-0820
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

Over 1.25 million Americans have type 1 diabetes (T1D), increasing risk for early death from cardiorenal disease. The strongest risk factor for cardiovascular disease (CVD) and mortality in T1D is diabetic kidney disease (DKD). Current treatments, such as control of hyperglycemia and hypertension, are beneficial, but only partially protect against DKD. Hyperfiltration is common in youth with T1D, and predicts progressive DKD. Hyperfiltration is also associated with early changes in intrarenal hemodynamic function, including increased renal plasma flow (RPF) and glomerular pressure. Intrarenal hemodynamic function is strongly influenced by the renin-angiotensin-aldosterone system (RAAS), which is also considered a key player in the pathogenesis of DKD. Preliminary data demonstrate differences in intrarenal hemodynamic function and RAAS activation in early and advanced DKD in T1D. However, the pathophysiology contributing to the differences observed in RAAS activation and intrarenal hemodynamic function in T1D are poorly defined Animal research demonstrates that arginine vasopressin (AVP) acts directly to modify intrarenal hemodynamic function, but also indirectly by activating RAAS. Preliminary data suggest that elevated copeptin, a marker of AVP, which predicts DKD in T1D adults, independently of other risk factors. However, no human studies to date have examined how copeptin relates to intrarenal hemodynamic function in early DKD in T1D. A better understanding of this relationship is critical to inform development of new therapies targeting the AVP system in T1D. Accordingly, in this study, the investigators propose to define the relationship between copeptin and intrarenal hemodynamics in early stages of DKD, by studying copeptin levels, renal plasma flow, and glomerular filtration in youth (n=50) aged 12-21 y with T1D duration \< 10 y.

Conditions

Diabetes Mellitus, Type 1; Nephropathy; Diabetic Nephropathies; Juvenile Diabetes; Diabetes Mellitus Complication; Autoimmune Diabetes; Type 1 Diabetes Mellitus

Outcome Measures

Primary Outcomes (3)

• Copeptin Levels

  Measured by fasting blood draw; Copeptin will be measured by ultrasensitive assays on KRYPTOR Compact Plus analyzers using the commercial sandwich immunoluminometric assays (Thermo Fisher Scientific, Waltham, MA). The copeptin assay has a lower limit of detection of 0.9 pmol/L, and a sensitivity of \<2pmol/L. Elevated copeptin will be defined as \>13pmol/L, which is \>97.5th percentile for healthy adults (68).

  4 hours

• Effective Renal Plasma Flow (ERPF)

  Measured by para-aminohippurate (PAH) clearance; An intravenous (IV) line was placed, and participants were asked to empty their bladders. Spot plasma and urine samples were collected prior PAH infusion. PAH (2 g/10 mL, prepared at the University of Minnesota, with a dose of \[weight in kg\]/75 × 4.2 mL; IND #140129) was given slowly over 5 min followed by a continuous infusion of 8 mL of PAH and 42 mL of normal saline at a rate of 24 mL/h for 2 h. After an equilibration period, blood was drawn at 90 and 120 min, and ERPF was calculated as PAH clearance divided by the estimated extraction ratio of PAH, which varies by the level of GFR (13). We report absolute ERPF (mL/min) in the main analyses because the practice of indexing ERPF for body surface underestimates hyperperfusion, and body surface area (BSA) calculations introduce noise into the clearance measurements.

  4 hours

• Glomerular Filtration Rate (GFR)

  Measured by iohexol clearance; An intravenous (IV) line was placed, and participants were asked to empty their bladders. Spot plasma and urine samples were collected prior to iohexol infusion. Iohexol was administered through bolus IV injection (5 mL of 300 mg/mL; Omnipaque 300, GE Healthcare). An equilibration period of 120 min was used and blood collections for iohexol plasma disappearance were drawn at +120, +150, +180, +210, +240 min (11). Because the Brøchner-Mortensen equation underestimates high values of GFR, the Jødal-Brøchner-Mortensen equation was used to calculate the GFR (12). We report absolute GFR (mL/min) in the main analyses because the practice of indexing GFR for body surface underestimates hyperfiltration, and body surface area (BSA) calculations introduce noise into the clearance measurements.

  4 hours

Secondary Outcomes (2)

• Renal Perfusion

  10 min

• Renal Oxygenation

  60 min

Study Arms (1)

Clinical Investigation

OTHER

All participants will undergo assessment of Glomerular Filtration Rate, (Iohexol Inj 300 mg/mL) and Effective Renal Plasma Flow (Aminohippurate Sodium Inj 20%). In addition, participants will undergo imaging assessment that includes Dual X-Ray Absorptiometry (DXA), renal Blood Oxygen Level Dependent (BOLD) and Arterial Spin Labeling (ASL) MRI.

Drug: Aminohippurate Sodium Inj 20%; Drug: Iohexol Inj 300 mg/mL

Interventions

Aminohippurate Sodium Inj 20% DRUG

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

Also known as: Aminohippuric acid, Para-aminohippurate (PAH), Sodium 4-amino hippurate (PAH) inj 20% 2g/10 mL

Clinical Investigation

Iohexol Inj 300 mg/mL DRUG

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

Also known as: omnipaque 300

Clinical Investigation

Eligibility Criteria

• Age: 12 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Antibody+ T1D with \<10 yr duration
• Age 12-21 years
• BMI ≥ 5%ile
• Weight\<350 lbs and \> 57 lbs.
• No anemia
• HbA1c \<12%

You may not qualify if:

• Severe illness, recent diabetic ketoacidosis (DKA)
• Estimated Glomerular Filtration Rate (eGFR) \<60ml/min/1.73m2 or creatinine \> 1.5mg/dl or history of ACR≥300mg/g
• Anemia or allergy to shellfish or iodine
• Pregnancy or nursing
• MRI scanning contraindications (claustrophobia, implantable devices, \>350 lbs)
• Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), diuretics, sodium-glucose co-transport (SGLT) 2 or 1 blockers, daily NSAIDs or aspirin, sulfonamides, procaine, thiazolsulfone or probenecid, atypical antipsychotics and steroids

Sponsors & Collaborators

• University of Colorado, Denver: lead

Study Sites (1)

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Related Publications (3)

• Pauley ME, Vinovskis C, MacDonald A, Baca M, Pyle L, Wadwa RP, Fornoni A, Nadeau KJ, Pavkov M, Nelson RG, Gordin D, de Boer IH, Tommerdahl KL, Bjornstad P. Triglyceride content of lipoprotein subclasses and kidney hemodynamic function and injury in adolescents with type 1 diabetes. J Diabetes Complications. 2023 Feb;37(2):108384. doi: 10.1016/j.jdiacomp.2022.108384. Epub 2022 Dec 13.

  PMID: 36623423 DERIVED

• Vigers T, Vinovskis C, Li LP, Prasad P, Heerspink H, D'Alessandro A, Reisz JA, Piani F, Cherney DZ, van Raalte DH, Nadeau KJ, Pavkov ME, Nelson RG, Pyle L, Bjornstad P. Plasma levels of carboxylic acids are markers of early kidney dysfunction in young people with type 1 diabetes. Pediatr Nephrol. 2023 Jan;38(1):193-202. doi: 10.1007/s00467-022-05531-3. Epub 2022 May 4.

  PMID: 35507146 DERIVED

• Vinovskis C, Li LP, Prasad P, Tommerdahl K, Pyle L, Nelson RG, Pavkov ME, van Raalte D, Rewers M, Pragnell M, Mahmud FH, Cherney DZ, Johnson RJ, Nadeau KJ, Bjornstad P. Relative Hypoxia and Early Diabetic Kidney Disease in Type 1 Diabetes. Diabetes. 2020 Dec;69(12):2700-2708. doi: 10.2337/db20-0457. Epub 2020 Jul 31.

  PMID: 32737116 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 1; Kidney Diseases; Diabetic Nephropathies; Diabetes Complications

Interventions

p-Aminohippuric Acid; Iohexol

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Aminohippuric Acids; Hippurates; Benzamides; Amides; Organic Chemicals; para-Aminobenzoates; Aminobenzoates; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Keto Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Triiodobenzoic Acids; Iodobenzoates

Results Point of Contact

• Title: Petter Bjornstad, M.D., Assistant Professor of Pediatrics and Medicine
• Organization: University of Colorado School of Medicine

petter.bjornstad@childrenscolorado.org

7207774659

Study Officials

• Petter Bjornstad, MD

  University of Colorado School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: All study participants will receive the same intervention.

Study Record Dates

• First Submitted: August 1, 2018
• First Posted: August 7, 2018
• Study Start: October 1, 2018
• Primary Completion: October 19, 2019
• Study Completion: August 1, 2021
• Last Updated: April 20, 2022
• Results First Posted: August 31, 2021

Record last verified: 2022-03

Locations

US (1)