Characterization of the Nrf2 Response in Patients With Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Sponsor

Mayo Clinic (Other)

Overall Status

Recruiting

CT.gov ID

NCT04344769

Collaborator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)

Enrollment

Location

44.9

Anticipated Duration (Months)

0.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to characterize oxidative stress and the Nrf2 antioxidant response in early stages of Autosomal Dominant Polycystic Kidney Disease (ADPKD), while identifying candidate biomarkers.

Condition or Disease	Intervention/Treatment	Phase
Autosomal Dominant Polycystic Kidney Disease

Detailed Description

Intracellular Reactive Oxygen Species (ROS) concentration is a major determinant of cellular fate and is finely regulated by the cell's antioxidant systems. While low levels of ROS are required for pro-survival signaling, cell proliferation, growth, and energy metabolism, the excess of ROS or oxidative stress leads to inflammation, cell death, and disease/injury progression. Indeed, oxidative stress is commonly observed in several renal diseases including ADPKD. On the other hand, a surplus of antioxidants will not only neutralize ROS, but may result in the antithesis of oxidative stress, which is known as reductive stress. The Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a transcription factor that integrates cellular stress signals and responds by regulating the expression of several antioxidant proteins. Activation of the Nrf2-mediated antioxidant defense pathway enhances ROS detoxification, conferring a more reduced intracellular environment that can promote cell survival and proliferation, a distinctive feature in ADPKD that underlies cyst formation and enlargement. Therefore, a better characterization of ROS levels and antioxidant response in ADPKD patients would allow development of more specific and effective therapies, while providing additional related biomarkers.

The investigators broad objective is to characterize oxidative stress and the Nrf2 antioxidant response in early stages of ADPKD, while identifying candidate biomarkers.

Participants in this study will have a blood and a urine sample collected to determine biomarkers of oxidative status and antioxidant response to study redox balance at early stages of the disease. In addition, an abdominal MRI will be performed to determine patient's total kidney volume (TKV).

Study Design

Study Type:

Observational

Anticipated Enrollment :

40 participants

Observational Model:

Case-Control

Time Perspective:

Prospective

Official Title:

Characterization of the Nrf2 Response in Patients With Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Actual Study Start Date :

Oct 4, 2019

Anticipated Primary Completion Date :

Jul 1, 2023

Anticipated Study Completion Date :

Jul 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
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

Outcome Measures

Primary Outcome Measures

Assessment of Oxidative Status [Baseline]
Determination of common biomarkers of oxidative damage including but not limited to: 8-oxodeoxyguanosine, F2-isoprostanes, from urine and plasma samples
Assessment of Antioxidant Response [Baseline]
Determination of antioxidants including but not limited to: Heme Oxygenase 1 (HO-1), Superoxide dismutase (SOD), catalase, glutathione reductase (GSR), glutathione peroxidase (GPx), and NAD(P)H dehydrogenase [quinone] 1 (NOQ1), glutathione, Nrf2 from urine and plasma samples
Total kidney volume (TKV) [Baseline]
Determined by MRI

Secondary Outcome Measures

Assessment of Kidney Injury [Baseline]
Determination of kidney injury biomarkers including but not limited to: Kidney Injury Molecule 1 (KIM-1), Neutrophil gelatinase-associated lipocalin (NGAL), Monocyte chemotactic protein-1 (MCP-1), Transforming growth factor-β1 (TGF-β1),

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 30 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria (ADPKD Subjects):

ADPKD (based on Ravine et al. criteria)
Class 1 B-E according to our imaging classification
Male and female subjects 18 - 30 years of age, inclusive
Estimated GFR> 60 mL/min/m2 (CKD-EPI equation)
Ability to provide written, informed consent.

Exclusion Criteria (ADPKD Subjects):

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

Inclusion Criteria (Healthy Subjects):

Male and female subjects 18 - 30 years of age, inclusive
Estimated GFR> 60 mL/min/m2 (CKD-EPI equation)
Ability to provide written, informed consent.

Exclusion Criteria (Healthy Subjects):

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