Assessment of Longitudinal Changes in Endothelial Function and Oxidative Stress in Normotensive Patients With ADPKD

Assessment of Longitudinal Changes in Endothelial Function and Oxidative Stress in Normotensive Patients With Autosomal Dominant Polycystic Kidney Disease (ADPKD) - A Pilot Study

The purpose of this study is to determine whether patients with autosomal dominant polycystic kidney disease (ADPKD) present with abnormal endothelial function, increased levels of NOX4 activity and mitochondrial abnormalities, contributing to oxidative stress from early stages that correlate with disease severity.

Study Overview

• Status: Completed
• Conditions: Autosomal Dominant Polycystic Kidney Disease

Detailed Description

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic and the fourth cause of end-stage renal disease (ESRD) in adults worldwide. Cardiovascular diseases are the most important non-cystic complications and continue to be the leading cause of premature mortality in these patients. Hypertension (HTN) is present in approximately 50% of the patients at early stages, and increases to nearly 100% at ESRD. Furthermore, HTN contributes to the underlying renal disease progression. Nitric oxide (NO) associated endothelium-dependent vasorelaxation has been shown to be impaired in small subcutaneous resistance vessels from patients with ADPKD before the development of HTN. However, the principal contributors to vascular dysfunction remain unclear.

The investigators broad objective is to evaluate the presence and extent of endothelial dysfunction and its association with oxidative stress in young normotensive patients with ADPKD, with the long term goal of timely intervention to slow the progression of the disease in these patients.

Participants in this study will have their endothelial function assessed using a non-invasive technique, peripheral arterial tonometry (PAT), which has been shown to be a useful, highly reproducible, and non-operator dependent method for non-invasive assessment of vascular health. The investigators will assess longitudinal changes in endothelial function using PAT with the intention of establishing if this methodology offers the potential of non-invasive measures of early vascular disease in young normotensive patients with ADPKD. Biochemical markers of endothelial dysfunction will be assessed concomitantly. In addition, the investigators will assess oxidative stress levels in these patients, with the intention of determining the association with endothelial dysfunction.

• Study Type: Observational
• Enrollment (Actual): 18

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

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

Male and female patients with a previous diagnosis of ADPKD that meet the inclusion criteria. In addition, patients will be matched 2:1 to age and gender healthy controls. Exclusion criteria are listed in for ADPKD patients and healthy controls.

Description

Inclusion Criteria:

ADPKD Patients:

• ADPKD (based on Ravine et al. criteria)
• Class 1 B-D according to our imaging classification
• Male and female subjects 18 - 40 years of age, inclusive
• Estimated GFR> 60 mL/min/m2 (CKD-Epi equation)
• Systolic BP≤130mmHg without taking HTN medications
• Ability to provide written, informed consent

Healthy controls:

• Male and female subjects 18 - 40 years of age, inclusive
• estimated GFR> 60 mL/min/m2 (CKD-EPI equation)
• Systolic BP≤130mmHg without taking HTN medications
• Ability to provide written, informed consent

Exclusion Criteria:

ADPKD Patients:

• Class 2 according to our imaging classification
• Concomitant systemic disease in the kidney (e.g. lupus, hepatitis B or C, amyloidosis)
• Diabetes mellitus (fasting glucose > 126 mg/dL or treatment with insulin or oral hypoglycemics).
• Predicted urine protein excretion in urinalysis >1 g/24 hrs
• Abnormal urinalysis suggestive of concomitant glomerular disease
• Subjects having contraindications to, or interference with MRI assessments. [For example: ferromagnetic metal prostheses, aneurysm clips, severe claustrophobia, large abdominal/back tattoos, etc].
• Female subjects that are pregnant

Healthy controls:

• Previous personal or family history of kidney disease
• Concomitant systemic disease in the kidney (e.g. lupus, hepatitis B or C, amyloidosis)
• Diabetes mellitus (fasting glucose > 126 mg/dL or treatment with insulin or oral hypoglycemics).
• Presence of proteinuria
• Abnormal urinalysis suggestive glomerular disease
• Subjects having contraindications to, or interference with MRI assessments. [For example: ferromagnetic metal prostheses, aneurysm clips, severe claustrophobia, large abdominal/back tattoos, etc]
• Female subjects that are pregnant

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Patients with a previous diagnosis of ADPKD; Patients that have been diagnosed with ADPKD and meet the study's inclusion criteria
Healthy individuals as controls; Age and gender-matched healthy controls

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of endothelial function by Peripheral Artery Tonometry (PAT)	PAT is a novel non-invasive technology which records volume changes in the microcirculation of the digits in response to hyperemia, to measure peripheral vasodilator response as a measure for endothelial dysfunction.	18 months
NADPH oxidase 4 (NOX4) expression/activity	Determined by ELISA from plasma and urine	18 months
Mitochondrial DNA copy number	Plasma and urine levels of the mitochondria encoded genes cytochrome-c oxidase-3 (COX3) and nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit-1 (ND1) determined by quantitative real-time polymerase chain reaction	18 months
Total kidney volume (TKV)	Determined by MRI	18 months
Renal blood flow (RBF)	Determined by MRI	18 months
Glomerular filtration rate (GFR)	Determination of iothalamate clearance	18 months

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: University of Kansas Medical Center
• Investigators: Principal Investigator: Maria V Irazabal, M.D., Mayo Translational PKD Center, Mayo Clinic

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2017
• Primary Completion (Actual): January 17, 2020
• Study Completion (Actual): January 17, 2020

Study Registration Dates

• First Submitted: March 23, 2018
• First Submitted That Met QC Criteria: April 3, 2018
• First Posted (Actual): April 11, 2018

Study Record Updates

• Last Update Posted (Actual): August 16, 2022
• Last Update Submitted That Met QC Criteria: August 15, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Oxidative stress; Endothelial dysfunction; ADPKD; Mitochondria; NADPH oxidase 4 (NOX4)
• 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: 17-005944

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No