Clinical trial NCT05193981: A Study to Evaluate Homocysteine Metabolism and Endothelial Function in ADPKD
Official title: Role of Homocysteine Metabolism, Endothelial Function and Microvascular Rarefaction on Renal Disease Severity and Progression in ADPKD
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Autosomal Dominant Polycystic Kidney Disease
Keywords: Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Endothelial function
Endothelial dysfunction
Homocysteine metabolism
Oxidative stress
NADPH oxidase 4 (NOX4)
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2022-01-18
Enrollment: 80
Sex: ALL
Minimum age (years): 15
Maximum age (years): 40
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Male and female patients with a previous diagnosis of ADPKD that meet the inclusion criteria.

Brief summary: 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: 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).

Eligibility criteria: 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

Primary outcomes:
measure: Change in height adjusted Total kidney volume (htTKV)
timeFrame: Baseline to 24 months
measure: Baseline endothelial function, homocysteine and related metabolite levels as predictors of change in TKV
timeFrame: Baseline to 24 months
Secondary outcomes:
measure: Change in systemic endothelial function
timeFrame: Baseline to 24 months
measure: Change in biochemical markers related to endothelial function and injury
timeFrame: Baseline to 24 months
measure: Change in homocysteine and related metabolite levels
timeFrame: Baseline to 24 months
measure: Change in Renal blood flow (RBF)
timeFrame: Baseline to 24 months
measure: Change in estimated Glomerular filtration rate (GFR)
timeFrame: Baseline to 24 months
measure: NADPH oxidase 4 (NOX4) expression/activity
timeFrame: Baseline to 24 months
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Maria V Irazabal, M.D.;Ph.D.
role: PRINCIPAL_INVESTIGATOR
References: