PErfusioN, OxyGen ConsUmptIon and ENergetics in ADPKD (PENGUIN) (PENGUIN)

PENGUIN: PErfusioN, OxyGen ConsUmptIon and ENergetics in ADPKD

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of end-stage kidney disease (ESKD). The disorder is characterized by development and continued growth of multiple cysts requiring renal replacement therapy in 50% of patients by age 60 years. However, ADPKD is also a complex metabolic disorder defined by insulin resistance (IR) and mitochondrial dysfunction which may be causally related to cyst expansion, kidney function decline and contribute to reduced life expectancy. Renal hypoxia, stemming from a potential metabolic mismatch between increased renal energy expenditure and impaired substrate utilization, is proposed as a novel unifying early pathway in the development and expansion of renal cysts in ADPKD. By examining the interplay between renal O2 consumption and energy utilization in young adults with and without ADPKD, the investigators hope to identify novel therapeutic targets to impede development of cyst expansion in future trials.

The investigators propose to address the specific aims in a cross-sectional study with 20 adults with ADPKD (50% female, ages 18-40 years). Comparative data will be provided from healthy adults from an ongoing study with similar study design and methods (CROCODILE Study: Control of Renal Oxygen Consumption, Mitochondrial Dysfunction, and Insulin Resistance). 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) to assess body composition, and a 11C-acetate positron emission tomography (PET/CT) scan to quantify renal O2 consumption. After the PET/CT, participants will undergo a hyperinsulinemic-euglycemic clamp while fasting 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.

Study Overview

• Status: Completed
• Conditions: Polycystic Kidney, Autosomal Dominant; Polycystic Kidney Disease, Adult
• Intervention / Treatment: Drug: Aminohippurate Sodium Inj 20%; Radiation: PET/CT Scan; Drug: Iohexol Inj 300 milligrams per milliliter (MG/ML)

• Study Type: Observational
• Enrollment (Actual): 22

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 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

The investigators propose to address the specific aims in a cross-sectional study with 20 adults with ADPKD (50% female, ages 18-40 years). Comparative data will be provided from healthy adults from an ongoing study with similar study design and methods.

Description

Inclusion Criteria:

• Patients with Autosomal dominant polycystic kidney disease
• Age 18-40 years
• BMI >= 18.5 and <30 kg/m2
• Weight <350 lbs

Exclusion Criteria:

• Diabetes mellitus, based on previous diagnosis
• Albuminuria (≥30mg/g) or estimated glomerular filtration rate (eGFR) <75ml/min/1.73m2
• Pregnancy or nursing
• Anemia
• Allergy to shellfish or iodine
• Vaptan therapy (e.g. tolvaptan)
• Uncontrolled hypertension (average ≥140/90 mmHg)

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Adults with autosomal dominant polycystic kidney disease; All participants will undergo DXA scan, 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: •- Sodium 4-amino hippurate (PAH) inj 20% 2g/10 milliliter (mL) • Para-aminohippurate • Aminohippuric acid; Radiation: PET/CT Scan; Imaging used to visualize the kidneys and quantify renal metabolic activity; Drug: Iohexol Inj 300 milligrams per milliliter (MG/ML); Diagnostic aid/agent used to measure glomerular filtration rate (GFR); Other Names: omnipaque 300
Healthy Controls; Comparative data will be provided from healthy adults from an ongoing study with similar study design and methods (CROCODILE Study: Control of Renal Oxygen Consumption, Mitochondrial Dysfunction, and Insulin Resistance).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin Sensitivity	Hyperinsulinemic-Euglycemic Clamp	4.5 hours
Renal oxygen consumption	11-C Acetate PET/CT	30 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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 Neutrophil gelatinase-associated lipocalin (NGAL) 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
Kidney Injury Biomarkers	Chitinase-3-like protein 1 (YKL-40) levels	5 minutes
Kidney Injury Biomarkers	Blood draw for Kidney Injury Molecule 1 (KIM-1) levels	5 minutes
Kidney Injury Biomarkers	Blood draw for monocyte chemoattractant protein-1 (MCP-1) levels	5 minutes

Collaborators and Investigators

• Sponsor: University of Colorado, Denver

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2020
• Primary Completion (Actual): October 13, 2022
• Study Completion (Actual): October 13, 2022

Study Registration Dates

• First Submitted: May 19, 2020
• First Submitted That Met QC Criteria: May 27, 2020
• First Posted (Actual): May 29, 2020

Study Record Updates

• Last Update Posted (Actual): February 3, 2023
• Last Update Submitted That Met QC Criteria: February 1, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urologic Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Abnormalities, Multiple; Kidney Diseases, Cystic; Ciliopathies; Kidney Diseases; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant
• Other Study ID Numbers: 20-0277

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