A Study to Evaluate Homocysteine Metabolism and Endothelial Function in ADPKD

Study Overview
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Brief Summary
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The purpose of this study is to assess homocysteine metabolism and systemic endothelial function at the early stages of the disease and determine the prognostic value of homocysteine, related metabolites, and markers of endothelial function and injury to estimate renal disease severity and progression in patients with early Autosomal Dominant Polycystic Kidney Disease (ADPKD).

Detailed Description
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ADPKD is a devastating systemic disorder characterized by progressive development and enlargement of bilateral renal cysts, often leading to renal failure. Disease severity and progression vary widely among patients. Large phenotypic variability, incomplete understanding of underlying mechanisms, and lack of suitable biomarkers challenge potential therapies' identification, implementation, and evaluation. In ADPKD, systemic endothelial dysfunction (ED), characterized by an imbalance between vasodilating (particularly nitric oxide, NO) and vasoconstricting substances, develops early and correlates with renal disease severity. It has been previously associated with decreased NO availability, but NO abnormalities' mechanisms are still poorly understood. Endothelium-dependent, NO-mediated vasodilation is impaired in subjects with hyperhomocysteinemia, suggesting that NO availability is decreased in these subjects. Increased plasma levels of homocysteine have been reported in patients with ADPKD and preserved kidney function, likely contributing to a reduction in NO bioavailability. The mechanisms underlying increased homocysteine in ADPKD are not known. Furthermore, whether systemic endothelial function and injury or homocysteine levels can predict renal disease severity and progression in patients is unknown. The investigators' broad objective is to assess homocysteine metabolism and systemic endothelial function at the early stages of the disease and determine the prognostic value of homocysteine, related metabolites, and markers of endothelial function and injury to estimate renal disease severity and progression in patients with early ADPKD. Participants in this study will have a blood and a urine sample collected to determine biomarkers of oxidative stress, endothelial function and injury, homocysteine, and related metabolite levels. In addition, peripheral arterial tonometry (PAT) will determine systemic endothelial function, and an abdominal MRI will be performed to determine the patient's total kidney volume (TKV).

Official Title
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Role of Homocysteine Metabolism, Endothelial Function and Microvascular Rarefaction on Renal Disease Severity and Progression in ADPKD

Conditions
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Autosomal Dominant Polycystic Kidney Disease

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and Female subjects, 15-40 years of age, inclusive Previous diagnosis of ADPKD (Based on Ravine et al. criteria) Class 1 according to imaging classification Estimated GFR>70 mL/min/1.73m^2(CKD-EPI) Ability to provide written, informed consent. Exclusion Criteria: Class 2 according to imaging classification A concomitant systemic disease affecting the kidney Diabetes mellitus Predicted urine protein excretion in urinalysis >1 g/24 hrs Subjects having contraindications to or interference with MRI assessments Patients that are part of an interventional study or taking tolvaptan Female subjects that are pregnant

Ages Eligible for Study
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Minimum Age: 15 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 |
| --- | --- |
| Patients with a previous diagnosis of ADPKD<br>Patients that have been diagnosed with ADPKD and meet the study's inclusion criteria | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in height adjusted Total kidney volume (htTKV) | TKV determined by MRI | Baseline to 24 months | 
| Baseline endothelial function, homocysteine and related metabolite levels as predictors of change in TKV | Endothelial function determined by PAT and biochemical markers, TKV determined by MRI | Baseline to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in systemic endothelial function | Endothelial function determined by PAT | Baseline to 24 months | 
| Change in biochemical markers related to endothelial function and injury | Determined by ELISA and/or biochemical assays | Baseline to 24 months | 
| Change in homocysteine and related metabolite levels | Determined by 1HNMR, Mass spect, ELISA | Baseline to 24 months | 
| Change in Renal blood flow (RBF) | Determined by MRI | Baseline to 24 months | 
| Change in estimated Glomerular filtration rate (GFR) | eGFR determined by CKD-epi equation | Baseline to 24 months | 
| NADPH oxidase 4 (NOX4) expression/activity | Determined by ELISA | Baseline to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autosomal Dominant Polycystic Kidney Disease (ADPKD), Endothelial function, Endothelial dysfunction, Homocysteine metabolism, Oxidative stress, NADPH oxidase 4 (NOX4)