PErfusioN, OxyGen ConsUmptIon and ENergetics in ADPKD (PENGUIN)

Study Overview
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Brief Summary
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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.

Official Title
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PENGUIN: PErfusioN, OxyGen ConsUmptIon and ENergetics in ADPKD

Conditions
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Polycystic Kidney Disease, Adult, Polycystic Kidney, Autosomal Dominant

Intervention / Treatment
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* Drug: Aminohippurate Sodium Inj 20%
* Drug: Iohexol Inj 300 milligrams per milliliter (MG/ML)
* Radiation: PET/CT Scan


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Adults with autosomal dominant polycystic kidney disease<br>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%<br>* Diagnostic aid/agent used to measure effective renal plasma flow (ERPF)<br>* Other names: •- Sodium 4-amino hippurate (PAH) inj 20% 2g/10 milliliter (mL) • Para-aminohippurate • Aminohippuric acid;Drug: Iohexol Inj 300 milligrams per milliliter (MG/ML)<br>* Diagnostic aid/agent used to measure glomerular filtration rate (GFR)<br>* Other names: omnipaque 300;Radiation: PET/CT Scan<br>* Imaging used to visualize the kidneys and quantify renal metabolic activity<br>|
| Healthy Controls<br>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?
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Primary Outcome Measures

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

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 | Chitinase-3-like protein 1 (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 Molecule 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 | 
| Kidney Injury Biomarkers | Blood draw for monocyte chemoattractant protein-1 (MCP-1) levels | 5 minutes |