Effect of Statin Treatment on Urinary AQP2 (uAQP2/01) (uAQP2/01)

August 11, 2015 updated by: piero portincasa, University of Bari

Urinary AQP2 Excretion in Hypercholesterolemic Patients as a Measure of Effect of Statin Therapy

The purpose of this study is to test the hypothesis that the function and/or regulation of urinary aquaporin 2 in hypercholesterolemic humans is affected by standard statin therapy, as compared with diet alone

Study Overview

Status

Completed

Conditions

Detailed Description

Statins are the first-line recommended pharmacological therapy in patients with dyslipidemias and play a key role in both primary and secondary prevention of coronary heart disease. By decreasing plasma total and low-density lipoprotein cholesterol (LDL-C) concentrations, statins decrease the risks for atherosclerotic cardiovascular disease and associated morbidity and mortality. Statins occupy part of the active binding site of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) and inhibit its enzymatic activity in the liver, a key step leading to the reduction of cellular sterol pool. Statins also have beneficial effects on the vascular wall by stabilizing the atherosclerotic plaques, ameliorating impaired endothelial function, and reducing vascular inflammation.

Besides the well-known metabolic and cardiovascular effects, it has been recently shown that statins increase the plasma membrane expression of the renal water channels Aquaporin 2 (AQP2). Water reabsorption in the kidney connecting tubule and collecting duct is regulated by the antidiuretic hormone arginine vasopressin (AVP), which promotes plasma membrane expression of the water channe aquaporin 2 (AQP2), the rate-limiting step controlling reabsorption of water, thus urine concentration, in this segment of the nephron. The investigators reported a number of evidences showing that statins accumulate AQP2 at the apical membrane of collecting duct cells by a AVP-independent mechanism. The effect of statins on AQP2 is independent of classical cholesterol homeostasis but rather depends on depletion of mevalonate-derived intermediates of cholesterol synthetic pathways, i.e. isoprenoid intermediates, including farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP).

Water balance disorders are often associated with defects of AQP2 trafficking. Nephrogenic Diabetes Insipidus (NDI) is characterized by the inability of the kidney to respond to AVP stimulation and is caused by either mutations in AQP2 or vasopressin type-2 receptor (AVPR2) genes. Mutations in the AVPR2 gene lead to X-linked NDI (X-NDI). This cause of 90% of all diagnosed congenital NDI cases.

Conventional treatment of X-NDI patients consists in low-sodium, low-protein diet and the administration on thiazide diuretics sometimes in combination with indomethacin or amiloride. Although these drugs cause some relief of X-NDI symptoms, they most often do not eliminate them. Due to the partial beneficial effect of conventional treatments, much effort has been spent in the past years to uncover new and alternative methods to induce antidiuresis in X-NDI patients.

In this regard, the investigators recently reported that statins, in particular fluvastatin, accumulate AQP2 at the apical membrane of collecting duct cells by a AVP-independent mechanism and increase water reabsorption in both wild type and X-NDI mice.

The effect of statins on AQP2 trafficking in humans, however, deserves further investigation, also considering the potential efficacy of statins in patients with X-NDI. This was the reason to embark on the present study in which the investigators monitored the time-dependent effects of statin therapy on the urine excretion of AQP2, diuresis and urine osmolality in a cohort of hypercholesterolemic subjects initiating simvastatin therapy for three months. Two other groups of patients serve as controls: patients already on statin treatment and patients choosing to undergo an initial program with a standard hypolipidemic "mediterranean" style diet.

Study Type

Observational

Enrollment (Actual)

37

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Bari, Italy, 70124
        • Department of Biomedical Sciences Human Oncology - Clinica Medica "A. Murri"

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

40 years to 75 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

Behavioral: diet Drug: statins, as required according to the ACC/AHA guidelines Diagnostic: anthropometric data, abdominal and carotid ultrasonography, serum (lipids, renal function) and urinary (AQP2, osmolality) dosages at enrollment and during a 3-months follow up (week 0, 1, 4, 12)

Description

Inclusion criteria:

  • patients on primary prevention requiring moderate reduction of LDL-cholesterol according to the ACC/AHA Guidelines
  • age 40 to 75 years
  • estimated 10-year ASCVD risk ≥7.5%

Exclusion criteria:

  • concomitant type 1 or type 2 diabetes
  • blood hypertension
  • concomitant use of diuretics or other drugs interfering with simvastatin

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Naïve-S
Patients with hypercholesterolemia starting statin treatment for primary or secondary prevention of cardiovascular diseases.
ONC-S
Patients with hypercholesterolemia who had been treated with statin for at least one year and continued their previous therapy during the study period
Naïve-MC
Patients with mild hypercholesterolemia either refusing initial statin treatment or intolerant to standard statin treatment and starting with monacolin K
Naïve-Diet
Patients refusing an initial pharmacologic treatments and choosing the hypolipidic diet

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
uAQP2
Time Frame: 0, 1, 4, 12 weeks
Urinary AQP2 excretion during therapy (statin or diet)
0, 1, 4, 12 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cholesterolemia
Time Frame: 0, 1, 4, 12 weeks
Serum cholesterol during therapy (statin or diet)
0, 1, 4, 12 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Bari

Investigators

  • Principal Investigator: Piero Portincasa, University of Bari Medical School

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2013

Primary Completion (Actual)

May 1, 2014

Study Completion (Actual)

July 1, 2015

Study Registration Dates

First Submitted

August 10, 2015

First Submitted That Met QC Criteria

August 11, 2015

First Posted (Estimate)

August 14, 2015

Study Record Updates

Last Update Posted (Estimate)

August 14, 2015

Last Update Submitted That Met QC Criteria

August 11, 2015

Last Verified

August 1, 2015

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • uAQP2/01
  • MRAR08P011 (Other Identifier: Italian Agency of Drug (AIFA))

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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