Salt Loading and Thiazide Intervention Study

Study Overview
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Brief Summary
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The investigators of this study propose to examine the relationships between STK39 (Serine Threonine Kinase 39) genotypes and responses to salt loading and to thiazide diuretics, hydrochlorothiazide. The investigators hypothesize that STK39 genotypes will be associated with the outcome of both interventions and can contribute to personalized care for hypertension.

Detailed Description
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Although hypertension can be easily diagnosed and there are many medications available to treat hypertension, this condition is poorly managed in many patients and is a leading cause of morbidity and mortality worldwide. Because a newly identified hypertension susceptibility gene, STK39 (Serine Threonine Kinase 39), plays a central role in kidney sodium transport, the investigators propose a pharmacogenetics study to examine the relationships between STK39 genotypes and blood pressure responses to salt loading and to thiazide diuretics, hydrochlorothiazide. In addition, STK39 genotypes may also predict those hypertension patients more likely to develop thiazide-induced hyperglycemia. The investigators hypothesize that STK39 genotypes of those single nucleotide polymorphisms (SNPs) that are associated with baseline systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension status, will be associated with the outcome of both interventions. Therefore these SNPs can act as markers and contribute to personalized care for hypertension by identifying patients most likely to effectively control their blood pressure by adopting salt-reducing diet versus patients most likely to effectively and safely control their blood pressure by taking thiazide diuretics.

Official Title
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The Relationship Between Serine Threonine Kinase 39 (STK39) Genotypes, Salt Sensitivity, Thiazide Diuretics-induced Blood Pressure Response

Conditions
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Hypertension

Intervention / Treatment
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* Procedure: Salt loading
* Drug: Hydrochlorothiazide (HCTZ)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Old Order Amish Age 18 to 65 Have systolic blood pressure between 120 and 160 and diastolic blood pressure between 80 and 100 Exclusion Criteria: History of myocardial infarction, stroke, congestive heart failure, liver disease Known cause of secondary hypertension Diabetes or Fasting glucose > 100 mg/dL Women who are pregnant, on oral contraceptives, or menstruating Used hydrochlorothiazide (HCTZ) in the last 8 weeks or known allergy to HCTZ Taking non-steroidal anti-inflammatory drugs Estimated glomerular filtration rate < 80 mL/m Intention to alter dietary habit during the study Abuse of alcohol or drug

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Salt-loading and thiazide diuretic (HCTZ)<br>Salt loading:2 L of 0.9% NaCl. HCTZ:12.5/ 25 mg of HCTZ for 1 week | Procedure: Salt loading<br>* Subjects will arrive at the Amish Research Clinics after overnight fasting. After taking height, weight, BP, and body temperature, subjects will receive 2 liters (L) of 0.9% sodium chloride (NaCl) saline over 4 hours while their blood pressure is monitored every 15 minutes. Blood pressure will be taken every 15 minutes during this procedure. Blood and urine samples will be collected from all subjects pre- and post-infusion.<br>Drug: Hydrochlorothiazide (HCTZ)<br>* We will perform short-term HCTZ intervention on the same 120 subjects. After overnight fasting and having their height, weight, and BP measured, subjects are given seven 12.5 mg HCTZ tablets and instructed to take 1 tablet daily for one week. Ambulatory blood pressure will be measured and blood and urine will be collected on both day 1 and day 8. After a minimum 6-week wash-out period, the subjects will repeat the 7-day HCTZ intervention, taking 25 mg of HCTZ instead. Subjects with plasma potassium levels below 3.6 mmol/L on day 8 of 12.5 mg HCTZ will be given a daily supplement of 16 milliequivalents of potassium to prevent harmful loss of potassium while taking HCTZ.<br>* Other names: Oretic.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Pressure Change During Salt Loading | Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured every 15 minutes for 4 hours. Blood pressure change is calculated by the trapezoid method. Essentially we use the average of blood pressure at each pair of time points (for example, DBP 30min + DBP 15min)/2 + (DBP 45min + DBP 30min)/2 + … up to 4 hours.) normalized by baseline SBP/DBP. | Every 15 minutes for 4 hours | 
| Blood Pressure Change After 7 Days of Low Dose (12.5 mg) of HCTZ | Blood pressure change is defined as SBP or DBP average over the 24 hour period, Day 8 subtracts Day 0. | 24-hr Ambulatory blood pressure were measured every hour on day 0 and day 8 | 
| Blood Pressure Change After 7 Days of High Dose (25 mg) of HCTZ | Blood pressure change is defined as SBP or DBP average over the 24 hour period, Day 8 subtracts Day 0. | 24-hr Ambulatory blood pressure were measured every hour on day 0 and day 8 | 
| Fasting Glucose Change After 7 Days of Low Dose (12.5 mg) of HCTZ | Values on Day 8 subtracts Day 0. | Fasting glucose was measured on day 0 and day 8 | 
| Fasting Glucose Change After 7 Days of High Dose (25mg) of HCTZ | Values on Day 8 subtracts Day 0. | Fasting glucose was measured on day 0 and day 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Plasma Aldosterone Level Due to Salt-loading | Aldosterone is a hormone that plays a critical role in homeostatic regulation of blood pressure. Change is defined as the post-salt loading values minus the pre-salt loading values | Aldosterone was measured from blood collected pre and post salt loading | 
| Change in Plasma Renin Activity Due to Salt-loading | Renin is an enzyme that mediates extracellular fluid and regulates blood pressure. Plasma renin activity (PRA) is a measure of the activity of the plasma enzyme renin. PRA is measured in the laboratory by incubating plasma at physiologic temperature in a buffer that facilitates its enzymatic activity. The natural substrate for the enzyme renin is angiotensinogen. Exogenous angiotensinogen is not added to the reaction mixture. This means that, in effect, the PRA results reported are dependent on both renin concentration and the concentration of its substrate in the patient's plasma. Renin cleaves angiotensinogen to produce a decapeptide, angiotensin I, the concentration of which is assayed using liquid chromatography accompanied by tandem mass spectroscopic detection (LC/MS/MS). PRA levels are reported as the amount of angiotensin I generated per unit of time. Change is defined as the post-salt loading values minus the pre-salt loading values | Renin was measured from blood collected pre and post salt loading | 
| Change in Plasma Sodium/Potassium Level Due to Salt-loading | Na/K ratio is a function of kidney function | Plasma sodium and potassium measured from blood collected pre and post salt loading | 
| Change in Plasma Sodium/Potassium Level During Low Dose of HCTZ | Na/K ratio is a function of kidney function | Plasma sodium and potassium measured from blood collected pre and post salt loading | 
| Change in Plasma Sodium/Potassium Level During High Dose of HCTZ | Na/K ratio is a function of kidney function | Plasma sodium and potassium measured from blood collected pre and post salt loading | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hypertension, hydrochlorothiazide, HCTZ, Salt sensitivity, Hydrochlorothiazide induced hyperglycemia