A Study to Evaluate Homocysteine Metabolism and Endothelial Function in ADPKD (HCY)

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

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).

Study Overview

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

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).

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

• Study Contact: Name: Maria V Irazabal, M.D., Ph.D; Email: irazabalmira.maria@mayo.edu
• Study Contact Backup: Name: Ahmed Abdelfattah; Phone Number: 507-266-2108; Email: Abdelfattah.Ahmed@mayo.edu

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Recruiting
      • Mayo Clinic
      • Contact: Ahmed Abdelfattah; Phone Number: 507-266-2108; Email: Abdelfattah.Ahmed@mayo.edu
      • Contact: Maria V Irazabal, M.D.;Ph.D.; Phone Number: 507-293-6388; Email: irazabalmira.maria@mayo.edu
      • Principal Investigator: Maria V Irazabal, M.D.; Ph.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 40 years (Child, Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Male and female patients with a previous diagnosis of ADPKD that meet the inclusion criteria.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

1

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Maria V Irazabal, M.D.;Ph.D., Mayo Clinic

Publications and helpful links

Helpful Links

• Study information

Study record dates

Study Major Dates

• Study Start (Actual): September 14, 2021
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: January 3, 2022
• First Submitted That Met QC Criteria: January 3, 2022
• First Posted (Actual): January 18, 2022

Study Record Updates

• Last Update Posted (Actual): April 9, 2024
• Last Update Submitted That Met QC Criteria: April 8, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Oxidative stress; Endothelial dysfunction; Endothelial function; NADPH oxidase 4 (NOX4); Autosomal Dominant Polycystic Kidney Disease (ADPKD); Homocysteine metabolism
• Additional Relevant MeSH Terms: Urologic Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Abnormalities, Multiple; Kidney Diseases, Cystic; Ciliopathies; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant
• Other Study ID Numbers: 20-005312; 1R01DK128017-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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