Salt Loading and Thiazide Intervention Study (SALTI)

• ClinicalTrials.gov Identifier: NCT00896389
• Recruitment Status: Completed
• First Posted: May 11, 2009
• Results First Posted: May 31, 2018
• Last Update Posted: November 5, 2019
• Sponsor: University of Maryland, Baltimore
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Information provided by (Responsible Party): Yen-Pei Christy Chang, University of Maryland, College Park

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Hypertension	Procedure: Salt loading; Drug: Hydrochlorothiazide (HCTZ)	Phase 4

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 124 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: The Relationship Between Serine Threonine Kinase 39 (STK39) Genotypes, Salt Sensitivity, Thiazide Diuretics-induced Blood Pressure Response
• Study Start Date: October 2009
• Actual Primary Completion Date: December 2012
• Actual Study Completion Date: March 2013

Arms and Interventions

Arm

Intervention/treatment

Salt-loading and thiazide diuretic (HCTZ); Salt loading:2 L of 0.9% NaCl. HCTZ:12.5/ 25 mg of HCTZ for 1 week

Procedure: Salt loading; 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.; Drug: Hydrochlorothiazide (HCTZ); 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.; Other Names: Hydrochlorothiazide; HCTZ; Apo-Hydro; Aquazide H; Dichlotride; Hydrodiuril; HydroSaluric; Microzide; Esidrex; Oretic.

Outcome Measures

Primary Outcome Measures :

1. Blood Pressure Change During Salt Loading [ Time Frame: Every 15 minutes for 4 hours ]

   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.

2. Blood Pressure Change After 7 Days of Low Dose (12.5 mg) of HCTZ [ Time Frame: 24-hr Ambulatory blood pressure were measured every hour on day 0 and day 8 ]
   Blood pressure change is defined as SBP or DBP average over the 24 hour period, Day 8 subtracts Day 0.
3. Blood Pressure Change After 7 Days of High Dose (25 mg) of HCTZ [ Time Frame: 24-hr Ambulatory blood pressure were measured every hour on day 0 and day 8 ]
   Blood pressure change is defined as SBP or DBP average over the 24 hour period, Day 8 subtracts Day 0.
4. Fasting Glucose Change After 7 Days of Low Dose (12.5 mg) of HCTZ [ Time Frame: Fasting glucose was measured on day 0 and day 8 ]
   Values on Day 8 subtracts Day 0.
5. Fasting Glucose Change After 7 Days of High Dose (25mg) of HCTZ [ Time Frame: Fasting glucose was measured on day 0 and day 8 ]
   Values on Day 8 subtracts Day 0.

Secondary Outcome Measures :

1. Change in Plasma Aldosterone Level Due to Salt-loading [ Time Frame: Aldosterone was measured from blood collected pre and post 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
2. Change in Plasma Renin Activity Due to Salt-loading [ Time Frame: Renin was measured from blood collected pre and post 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
3. Change in Plasma Sodium/Potassium Level Due to Salt-loading [ Time Frame: Plasma sodium and potassium measured from blood collected pre and post salt loading ]
   Na/K ratio is a function of kidney function
4. Change in Plasma Sodium/Potassium Level During Low Dose of HCTZ [ Time Frame: Plasma sodium and potassium measured from blood collected pre and post salt loading ]
   Na/K ratio is a function of kidney function
5. Change in Plasma Sodium/Potassium Level During High Dose of HCTZ [ Time Frame: Plasma sodium and potassium measured from blood collected pre and post salt loading ]
   Na/K ratio is a function of kidney function

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Locations

United States, Pennsylvania

Amish Research Clinics

Lancaster, Pennsylvania, United States, 17607

Sponsors and Collaborators

University of Maryland, Baltimore

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Yen Pei C. Chang, Ph.D.; University of Maryland, Baltimore

More Information

Publications:

Wang Y, O'Connell JR, McArdle PF, Wade JB, Dorff SE, Shah SJ, Shi X, Pan L, Rampersaud E, Shen H, Kim JD, Subramanya AR, Steinle NI, Parsa A, Ober CC, Welling PA, Chakravarti A, Weder AB, Cooper RS, Mitchell BD, Shuldiner AR, Chang YP. From the Cover: Whole-genome association study identifies STK39 as a hypertension susceptibility gene. Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):226-31. doi: 10.1073/pnas.0808358106. Epub 2008 Dec 29.

Delpire E, Gagnon KB. SPAK and OSR1: STE20 kinases involved in the regulation of ion homoeostasis and volume control in mammalian cells. Biochem J. 2008 Jan 15;409(2):321-31. Review.

Chiga M, Rai T, Yang SS, Ohta A, Takizawa T, Sasaki S, Uchida S. Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone. Kidney Int. 2008 Dec;74(11):1403-9. doi: 10.1038/ki.2008.451. Epub 2008 Sep 17.

• Responsible Party: Yen-Pei Christy Chang, Associate Professor, University of Maryland, College Park
• ClinicalTrials.gov Identifier: NCT00896389
• Other Study ID Numbers: HP-00040712; R21DK084566 ( U.S. NIH Grant/Contract )
• First Posted: May 11, 2009
• Results First Posted: May 31, 2018
• Last Update Posted: November 5, 2019
• Last Verified: May 2018

Keywords provided by Yen-Pei Christy Chang, University of Maryland, College Park:

hypertension; hydrochlorothiazide; HCTZ; Salt sensitivity; Hydrochlorothiazide induced hyperglycemia

Additional relevant MeSH terms:

Hypertension; Vascular Diseases; Cardiovascular Diseases; Hydrochlorothiazide; Antihypertensive Agents; Diuretics; Natriuretic Agents; Physiological Effects of Drugs; Sodium Chloride Symporter Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action