Autosomal Dominant Polycystic Kidney Disease
Conditions
Keywords
ADPKD, Endothelial dysfunction, Oxidative stress, NADPH oxidase 4 (NOX4), Mitochondria
Brief summary
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.
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.
Interventions
None listed
Sponsors
University of Kansas Medical Center
Mayo Clinic
Study design
Observational model
CASE_CONTROL
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of endothelial function by Peripheral Artery Tonometry (PAT) | 18 months | 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. |
| NADPH oxidase 4 (NOX4) expression/activity | 18 months | Determined by ELISA from plasma and urine |
| Mitochondrial DNA copy number | 18 months | 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 |
| Total kidney volume (TKV) | 18 months | Determined by MRI |
| Renal blood flow (RBF) | 18 months | Determined by MRI |
| Glomerular filtration rate (GFR) | 18 months | Determination of iothalamate clearance |
Countries
United States
Outcome results
None listed