Uric Acid, Klotho and Salt Sensitivity in Young Adults Born Preterm (PEPC3)

The purpose of this research is to learn about how salt in the diet influences blood pressure in young adults who were born prematurely.

Study Overview

• Status: Recruiting
• Conditions: Blood Pressure Disorders; Salt; Excess
• Intervention / Treatment: Drug: Allopurinol; Other: Dietary Intervention

Detailed Description

Premature birth is an emerging and important risk factor for hypertension and cardiovascular disease, as both preterm birth rates and infant survival increase worldwide. Hypertension and cardiovascular disease begin in early adulthood in individuals born prematurely, but the reasons especially in regard to the role of preterm birth are unknown. An improved understanding of why hypertension and cardiovascular disease occur in early adulthood in individuals born preterm will enable the development of prevention and treatment strategies to mitigate the burden of cardiovascular disease. Investigators propose to investigate these relationships mechanistically in a clinical trial of subjects born preterm to establish the SSBP (salt sensitivity of blood pressure) phenotype and study its relationship to CVD (cardiovascular disease) compared to a control group of healthy term- born peers. Investigators will then propose to determine if blocking UA (uric acid) formation improves SSBP and cardiovascular function in subjects born preterm.

• Study Type: Interventional
• Enrollment (Estimated): 165
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Hossam Shaltout, PhD; Phone Number: 336-716-1251; Email: hshaltou@wakehealth.edu

Study Locations

• United States
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Recruiting
      • Wake Forest University Health Sciences
      • Contact: Hossam Shaltout, PhD; Phone Number: 336-716-1251; Email: hshaltou@wakehealth.edu
      • Principal Investigator: Hossam Shaltout, PhD
      • Sub-Investigator: Andrew South, MD, MS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 24 years to 32 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Born 1990-1998
• Singleton birth
• Born at less than 34 weeks gestational age (preterm cohort)
• Born at greater than 36 weeks gestational age (term cohort)

Exclusion Criteria:

• Twin birth
• Congenital anomalies or genetic syndromes
• Currently pregnant or breast feeding
• Subject-reported history of hypertension
• Current use of antihypertensive medications
• Active cancer
• Chronic kidney disease
• Heart failure
• Liver failure

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Preterm Group; Subjects with very low birth weight (<37 completed weeks' gestation and birth weight <1500 g) will receive a dietary intervention (high/low salt diet) and FDA approved drug, Allopurinol	Drug: Allopurinol; Study Part 2- Preterm group only: After Visit 5 preterm born participants will start allopurinol 200 mg daily PO for 6 weeks. The 1 week high and low salt diets and assessments will be repeated while on allopurinol.; Other Names: Zyloprim; Other: Dietary Intervention; High-Na+ (250 mmol/d) and low-Na+ (50 mmol/d) standard isocaloric K+ diets (75 mmol/1000 kcal/d) for 1 week each as 3 meals and 1 snack a day provided by the Clinical Research Unit Metabolic Kitchen. Part 2 preterm only- the diets will be repeated while the participant is taking allopurinol.
Active Comparator: Term-born control group; Subjects with birth weight ≥2500 g will receive a dietary intervention (high/low salt diet)	Other: Dietary Intervention; High-Na+ (250 mmol/d) and low-Na+ (50 mmol/d) standard isocaloric K+ diets (75 mmol/1000 kcal/d) for 1 week each as 3 meals and 1 snack a day provided by the Clinical Research Unit Metabolic Kitchen. Part 2 preterm only- the diets will be repeated while the participant is taking allopurinol.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion with salt sensitivity of blood pressure at baseline via ABPM	Defined as a ≥8 mmHg decrease in mean arterial blood pressure when moving from the high-Na+ to the low-Na+ phase, as measured on 24-hour ambulatory blood pressure monitoring (ABPM).	Day 7 to 14
Proportion with salt sensitivity of blood pressure after allopurinol via ABPM	A ≥8 mmHg decrease in mean arterial blood pressure when moving from the high-Na+ to the low-Na+ phase while taking allopurinol, as measured on 24-hour ambulatory blood pressure monitoring (ABPM).	Day 49 to 56
Salt sensitivity index at baseline	The ratio between the change in 24-hour mean arterial pressure, as measured on 24-hour ambulatory blood pressure monitoring, and the change in 24-hour urine Na+ concentration when moving from the high-Na+ phase to the low-Na+ phase.	Day 7 to 14
Salt sensitivity index after allopurinol	The ratio between the change in 24-hour mean arterial pressure, as measured on 24-hour ambulatory blood pressure monitoring, and the change in 24-hour urine Na+ concentration when moving from the high-Na+ phase to the low-Na+ phase while taking allopurinol	Day 49 to 56
Proportion with salt sensitivity of blood pressure at baseline via casual blood pressure	A >=5 mmHg decrease in mean arterial blood pressure measured in clinic when moving from the high-Na+ phase to the low-Na+ phase. Casual blood pressure measured 3 consecutive times via auscultation with the average of the 3 mean arterial blood pressure measurements recorded.	Day 7 to 14
Proportion with salt sensitivity of blood pressure after allopurinol via casual blood pressure	A >=5 mmHg decrease in mean arterial blood pressure measured in clinic when moving from the high-Na+ phase to the low-Na+ phase while taking allopurinol. Casual blood pressure measured 3 consecutive times via auscultation with the average of the 3 mean arterial blood pressure measurements recorded.	Day 49 to 56
High blood pressure at baseline via ABPM	Proportion with 24-hour mean systolic or diastolic blood pressure ≥115/75 mmHg, awake mean systolic or diastolic blood pressure ≥120/80 mmHg, or asleep mean systolic or diastolic blood pressure ≥100/65 mmHg, measured with ambulatory blood pressure monitoring (ABPM).	Day 0
Hypertension at baseline via ABPM	Proportion with 24-hour mean systolic or diastolic blood pressure ≥125/75 mmHg, awake mean systolic or diastolic blood pressure ≥130/80 mmHg, or asleep mean systolic or diastolic blood pressure ≥110/65 mmHg, measured with ambulatory blood pressure monitoring (ABPM).	Day 7
High blood pressure at baseline via casual blood pressure	Proportion with mean systolic or diastolic blood pressure ≥120/80 mmHg, measured via 3 consecutive auscultated measurements (averaged) at each of 3 separate study visits.	First 3 study visits
Hypertension at baseline via casual blood pressure	Proportion with mean systolic or diastolic blood pressure ≥130/80 mmHg, measured via 3 consecutive auscultated measurements (averaged) at each of 3 separate study visits	First 3 study visits
Serum uric acid at baseline	Serum uric acid concentration at baseline	Day 0
Change in serum uric acid with dietary Na+ intervention	The change in serum uric acid levels when moving from high-Na+ phase to the low-Na+ phase	Day 7 to 14
Change in serum uric acid with dietary Na+ intervention on allopurinol	The change in serum uric acid levels when moving from high-Na+ phase to the low-Na+ phase while on allopurinol	Day 42 to 56
Pulse wave velocity at baseline	Carotid femoral pulse wave velocity will be measured at baseline with the SphygmoCor XCEL device	Day 0
Augmentation index at baseline	Augmentation index will be measured at baseline with the SphygmoCor XCEL device	Day 0
Heart rate variability at baseline	Heart rate variability will be measured at baseline using continuous heart rate recording using the CNAP™ Monitor 500i	Day 0
Baroreflex sensitivity at baseline	Baroreflex sensitivity will be measured at baseline using continuous blood pressure and heart rate using the CNAP™ Monitor 500i	Day 0
Angiotensin-(1-7) at baseline	Plasma angiotensin-(1-7) concentration and urine angiotensin-(1-7)/creatinine at baseline	Day 0
Angiotensin II at baseline	Plasma angiotensin II concentration and urine angiotensin II/creatinine at baseline	Day 0
Klotho at baseline	Plasma klotho concentration and urine klotho/creatinine at baseline.	Day 0
Creatinine at baseline	Serum creatinine concentration at baseline	Day 0
Cystatin C at baseline	Serum cystatin C concentration at baseline	Day 0
eGFR at baseline	Estimated glomerular filtration rate (eGFR) at baseline.We will calculate the eGFR by the CKD-EPI Creatinine-Cystatin C 2012 equation and by 24 hour creatinine	Day 0

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ambulatory systolic blood pressure 24-hour mean at baseline	Average systolic blood pressure over 24 hours, measured with ambulatory blood pressure monitors	Day 0
Ambulatory diastolic blood pressure 24-hour mean at baseline	Average diastolic blood pressure over 24 hours, measured with ambulatory blood pressure monitors	Day 0
Ambulatory mean arterial pressure 24-hour mean at baseline	Average mean arterial pressure over 24 hours, measured with ambulatory blood pressure monitors	Day 0
Ambulatory systolic blood pressure awake mean at baseline	Average systolic blood pressure while awake, measured with ambulatory blood pressure monitors	Day 0
Ambulatory diastolic blood pressure awake mean at baseline	Average diastolic blood pressure while awake, measured with ambulatory blood pressure monitors	Day 0
Ambulatory mean arterial pressure awake mean at baseline	Average mean arterial pressure while awake, measured with ambulatory blood pressure monitors	Day 0
Ambulatory systolic blood pressure asleep mean at baseline	Average systolic blood pressure while asleep, measured with ambulatory blood pressure monitors	Day 0
Ambulatory diastolic blood pressure asleep mean at baseline	Average diastolic blood pressure while asleep, measured with ambulatory blood pressure monitors	Day 0
Ambulatory mean arterial pressure asleep mean at baseline	Average mean arterial pressure while asleep, measured with ambulatory blood pressure monitors	Day 0
Ambulatory systolic blood pressure 24-hour load at baseline	Proportion of mean 24-hour systolic blood pressures ≥125 mmHg, measured with ambulatory blood pressure monitors	Day 0
Ambulatory diastolic blood pressure 24-hour load at baseline	Proportion of mean 24-hour diastolic blood pressures ≥75 mmHg, measured with ambulatory blood pressure monitors.	Day 0
Ambulatory systolic blood pressure awake load at baseline	Proportion of mean awake systolic blood pressures ≥130 mmHg, measured with ambulatory blood pressure monitors	Day 0
Ambulatory diastolic blood pressure awake load at baseline	Proportion of mean awake diastolic blood pressures ≥80 mmHg, measured with ambulatory blood pressure monitors	Day 0
Ambulatory systolic blood pressure asleep load at baseline	Proportion of mean asleep systolic blood pressures ≥110 mmHg, measured with ambulatory blood pressure monitors	Day 0
Ambulatory diastolic blood pressure asleep load at baseline	Proportion of mean asleep diastolic blood pressures ≥65 mmHg, measured with ambulatory blood pressure monitors	Day 0
Ambulatory systolic blood pressure nocturnal dipping at baseline	Percent change in mean awake to mean asleep systolic blood pressure, measured with ambulatory blood pressure monitors	Day 0
Ambulatory diastolic blood pressure nocturnal dipping at baseline	Percent change in mean awake to mean asleep diastolic blood pressure, measured with ambulatory blood pressure monitors	Day 0
Casual systolic blood pressure at baseline	Measured 3 consecutive times via auscultation with the average of the 3 systolic blood pressure measurements recorded	Day 0
Casual diastolic blood pressure at baseline	Measured 3 consecutive times via auscultation with the average of the 3 diastolic blood pressure measurements recorded	Day 0
Change in pulse wave velocity with dietary Na+ intervention	The change in carotid femoral pulse wave velocity will be measured with the SphygmoCor XCEL device when moving from high-Na+ phase to the low-Na+ phase	Day 7 to 14
Change in augmentation index with dietary Na+ intervention	The change in augmentation index will be measured with the SphygmoCor XCEL device when moving from high-Na+ phase to the low-Na+ phase	Day 7 to 14
Change in pulse wave velocity with dietary Na+ intervention while on allopurinol	The change in carotid femoral pulse wave velocity will be measured with the SphygmoCor XCEL device when moving from high-Na+ phase to the low-Na+ phase while on allopurinol.	Day 49 to 56
Change in augmentation index with dietary Na+ intervention while on allopurinol	The change in augmentation index will be measured with the SphygmoCor XCEL device when moving from high-Na+ phase to the low-Na+ phase while on allopurinol	Day 49 to 56
Change in heart rate variability with dietary Na+ intervention	The change in heart rate variability will be measured using the Continuous noninvasive arterial pressure (CNAP™) Monitor 500i when moving from high-Na+ phase to the low-Na+ phase	Day 7 to 14
Change in baroreflex sensitivity with dietary Na+ intervention	The change in baroreflex sensitivity will be measured using the CNAP™ Monitor 500i when moving from high-Na+ phase to the low-Na+ phase	Day 7 to 14
Change in heart rate variability with dietary Na+ intervention while on allopurinol	The change in heart rate variability will be measured using the CNAP™ Monitor 500i when moving from high-Na+ phase to the low-Na+ phase while on allopurinol	Day 49 to 56
Change in baroreflex sensitivity with dietary Na+ intervention while on allopurinol	The change in baroreflex sensitivity will be measured using the CNAP™ Monitor 500i when moving from high-Na+ phase to the low-Na+ phase while on allopurinol	Day 49 to 56
Change in angiotensin-(1-7) with dietary Na+ intervention	The change in plasma angiotensin-(1-7) concentration and urine angiotensin-(1-7)/creatinine when moving from the high-Na+ phase to the low-Na+ phase	Day 7 to 14
Change in angiotensin II with dietary Na+ intervention	The change in plasma angiotensin II concentration and urine angiotensin II/creatinine when moving from the high-Na+ phase to the low-Na+ phase	Day 7 to 14
Change in klotho with dietary Na+ intervention	The change in plasma klotho concentration and urine klotho/creatinine when moving from the high-Na+ phase to the low-Na+ phase	Day 7 to 14
Change in angiotensin-(1-7) with dietary Na+ intervention while on allopurinol	The change in plasma angiotensin-(1-7) concentration and urine angiotensin-(1-7)/creatinine when moving from the high-Na+ phase to the low-Na+ phase while on allopurinol	Day 49 to 56
Change in angiotensin II with dietary Na+ intervention while on allopurinol	The change in plasma angiotensin II concentration and urine angiotensin II/creatinine when moving from the high-Na+ phase to the low-Na+ phase while on allopurinol	Day 49 to 56
Change in klotho with dietary Na+ intervention while on allopurinol	The change in plasma klotho concentration and urine klotho/creatinine when moving from the high-Na+ phase to the low-Na+ phase while on allopurinol	Day 49 to 56
ACE2 at baseline	Serum ACE2 concentration and activity and urine ACE2/creatinine and activity at baseline	Day 0
ACE at baseline	Serum ACE concentration and activity and urine ACE/creatinine and activity at baseline	Day 0
FGF23 at baseline	Plasma fibroblast growth factor 23 (FGF23) concentration and urine FGF23/creatinine at baseline	Day 0
Change in ACE2 with dietary Na+ intervention	The change in serum ACE2 concentration and activity and urine ACE2/creatinine and activity when moving from the high-Na+ phase to the low-Na+ phase	Day 7 to 14
Change in ACE2 with dietary Na+ intervention while on allopurinol	The change in serum ACE2 concentration and activity and urine ACE2/creatinine and activity when moving from the high-Na+ phase to the low-Na+ phase while on allopurinol	Day 49 to 56
Change in ACE with dietary Na+ intervention	The change in serum ACE concentration and activity and urine ACE2/creatinine and activity when moving from the high-Na+ phase to the low-Na+ phase	Day 7 to 14
Change in ACE with dietary Na+ intervention while on allopurinol	The change in serum ACE concentration and activity and urine ACE2/creatinine and activity when moving from the high-Na+ phase to the low-Na+ phase while on allopurinol	Day 49 to 56
Change in FGF23 with dietary Na+ intervention	The change in serum fibroblast growth factor 23 (FGF23) concentration and urine FGF23/creatinine when moving from the high-Na+ phase to the low-Na+ phase	Day 7 to 14
Change in FGF23 with dietary Na+ intervention while on allopurinol	The change in serum fibroblast growth factor 23 (FGF23) concentration and urine FGF23/creatinine when moving from the high-Na+ phase to the low-Na+ phase while on allopurinol	Day 49 to 56
Neprilysin level at baseline	Serum neprilysin concentration and activity and urine neprilysin/creatinine and activity at baseline	Day 0
Change in neprilysin with dietary Na+ intervention	The change in serum neprilysin concentration and activity and urine neprilysin/creatinine and activity when moving from the high-Na+ phase to the low-Na+ phase	Day 7 to 14
Change in neprilysin with dietary Na+ intervention while on allopurinol	The change in serum neprilysin concentration and activity and urine neprilysin/creatinine and activity when moving from the high-Na+ phase to the low-Na+ phase while on allopurinol	Day 49 to 56
Urine albumin at baseline	Urine albumin/creatinine at baseline on first-morning urine sample	Day 0
Proportion with albuminuria	Albuminuria at baseline, defined as urine albumin/creatinine >30 mg/g on first-morning urine sample	Day 0
Urine protein at baseline	Urine protein/creatinine at baseline on first-morning urine sample	Day 0
Proportion with proteinuria	Proteinuria at baseline, defined as urine protein/creatinine >0.2 mg/mg on first-morning urine sample	Day 0
Angiotensinogen at baseline	Serum angiotensinogen concentration and urine angiotensinogen/creatinine at baseline	Day 0
Change in angiotensinogen with dietary Na+ intervention	The change in serum angiotensinogen concentration and urine angiotensinogen/creatinine when moving from the high-Na+ phase to the low-Na+ phase	Day 7 to 14
Change in angiotensinogen with dietary Na+ intervention while on allopurinol	The change in serum angiotensinogen concentration and urine angiotensinogen/creatinine when moving from the high-Na+ phase to the low-Na+ phase while on allopurinol	Day 49 to 56
24-hour sodium excretion at baseline	Sodium excretion in the urine over 24 hours at baseline	Day 0
24-hour potassium excretion at baseline	Potassium excretion in the urine over 24 hours at baseline	Day 0
24-hour uric acid excretion at baseline	Uric acid excretion in the urine over 24 hours at baseline	Day 0
Pulse wave velocity (CF) at baseline	Carotid-femoral (CF) pulse wave velocity will be measured at baseline with the SphygmoCor XCEL device	Day 0
Change in pulse wave velocity (CF) with dietary Na+ intervention	The change in carotid-femoral (CF) pulse wave velocity will be measured with the SphygmoCor XCEL device when moving from high-Na+ phase to the low-Na+ phase	Day 7 to 14
Change in pulse wave velocity (CF) with dietary Na+ intervention while on allopurinol	The change in carotid-femoral (CF) pulse wave velocity will be measured with the SphygmoCor XCEL device when moving from high-Na+ phase to the low-Na+ phase while on allopurinol	Day 49 to 56
Angiotensin II:angiotensin-(1-7) at baseline	Plasma and urine angiotensin II:angiotensin-(1-7) at baseline	Day 0
Change in angiotensin II:angiotensin-(1-7) with dietary Na+ intervention	The change in plasma angiotensin II:angiotensin-(1-7) when moving from the high-Na+ phase to the low-Na+ phase	Day 7 to 14
Change in angiotensin II:angiotensin-(1-7) with dietary Na+ intervention while on allopurinol	The change in plasma angiotensin II:angiotensin-(1-7) when moving from the high-Na+ phase to the low-Na+ phase while on allopurinol	Day 49 to 56
ACE:ACE2 at baseline	Serum and urine ACE:ACE2 at baseline	Day 0
Change in ACE:ACE2 with dietary Na+ intervention	The change in serum and urine ACE:ACE2 when moving from the high-Na+ phase to the low-Na+ phase	Day 7 to 14
Change in ACE:ACE2 with dietary Na+ intervention while on allopurinol	The change in serum and urine ACE:ACE2 when moving from the high-Na+ phase to the low-Na+ phase while on allopurinol	Day 49 to 56
Body mass index at baseline	Body mass index at baseline	Day 0
Proportion with overweight/obesity	Overweight/obesity at baseline, defined as a body mass index >=25 kg/m2	Day 0
Proportion with obesity	Obesity at baseline, defined as a body mass index >=30 kg/m2	Day 0

Collaborators and Investigators

• Sponsor: Wake Forest University Health Sciences
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Hossam Shaltout, PhD, Wake Forest University Health Sciences

Study record dates

Study Major Dates

• Study Start (Actual): September 2, 2020
• Primary Completion (Estimated): June 1, 2025
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: July 17, 2019
• First Submitted That Met QC Criteria: July 17, 2019
• First Posted (Actual): July 19, 2019

Study Record Updates

• Last Update Posted (Actual): June 6, 2023
• Last Update Submitted That Met QC Criteria: June 5, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Uric Acid sensitivity; Salt sensitivity; Blood Pressure Influences
• Additional Relevant MeSH Terms: Immune System Diseases; Hypersensitivity; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites; Protective Agents; Antioxidants; Free Radical Scavengers; Gout Suppressants; Allopurinol
• Other Study ID Numbers: IRB00057527; 1R01HL146818-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD that underlie the results reported in this record, after deidentification.
• IPD Sharing Time Frame: Beginning 3 months and ending 5 years following publication.
• IPD Sharing Access Criteria: Proposals should be directed to hshaltou@wakehealth.edu. To gain access, data requestors will need to sign a data access agreement. Data are available for 5 years.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No