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

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

Detailed Description
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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.

Official Title
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Uric Acid, Klotho and Salt Sensitivity in Young Adults Born Preterm

Conditions
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Salt; Excess, Blood Pressure Disorders

Intervention / Treatment
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* Drug: Allopurinol
* Other: Dietary Intervention


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 24 Years
Maximum Age: 32 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: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Preterm Group<br>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<br>* 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.<br>* Other names: Zyloprim;Other: Dietary Intervention<br>* 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.<br>|
| Active Comparator: Term-born control group<br>Subjects with birth weight ≥2500 g will receive a dietary intervention (high/low salt diet) | Other: Dietary Intervention<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Uric Acid sensitivity, Salt sensitivity, Blood Pressure Influences