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.

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.

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

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.

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.

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).

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).

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.

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

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.

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.

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).

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).

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.

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

The change in serum uric acid levels when moving from high-Na+ phase to the low-Na+ phase while on allopurinol

Heart rate variability will be measured at baseline using continuous heart rate recording using the CNAP™ Monitor 500i

Baroreflex sensitivity will be measured at baseline using continuous blood pressure and heart rate using the CNAP™ Monitor 500i

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

Proportion of mean 24-hour systolic blood pressures ≥125 mmHg, measured with ambulatory blood pressure monitors

Proportion of mean 24-hour diastolic blood pressures ≥75 mmHg, measured with ambulatory blood pressure monitors.

Proportion of mean awake systolic blood pressures ≥130 mmHg, measured with ambulatory blood pressure monitors

Proportion of mean awake diastolic blood pressures ≥80 mmHg, measured with ambulatory blood pressure monitors

Proportion of mean asleep systolic blood pressures ≥110 mmHg, measured with ambulatory blood pressure monitors

Proportion of mean asleep diastolic blood pressures ≥65 mmHg, measured with ambulatory blood pressure monitors

Percent change in mean awake to mean asleep systolic blood pressure, measured with ambulatory blood pressure monitors

Percent change in mean awake to mean asleep diastolic blood pressure, measured with ambulatory blood pressure monitors

Measured 3 consecutive times via auscultation with the average of the 3 systolic blood pressure measurements recorded

Measured 3 consecutive times via auscultation with the average of the 3 diastolic blood pressure measurements recorded

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

The change in augmentation index will be measured with the SphygmoCor XCEL device when moving from high-Na+ phase to the low-Na+ phase

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.

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

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

The change in baroreflex sensitivity will be measured using the CNAP™ Monitor 500i when moving from high-Na+ phase to the low-Na+ phase

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

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

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

The change in plasma angiotensin II concentration and urine angiotensin II/creatinine when moving from the high-Na+ phase to the low-Na+ phase

The change in plasma klotho concentration and urine klotho/creatinine when moving from the high-Na+ phase to the low-Na+ phase

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

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

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

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

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

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

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

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

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

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

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

Proteinuria at baseline, defined as urine protein/creatinine >0.2 mg/mg on first-morning urine sample

The change in serum angiotensinogen concentration and urine angiotensinogen/creatinine when moving from the high-Na+ phase to the low-Na+ phase

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

Carotid-femoral (CF) pulse wave velocity will be measured at baseline with the SphygmoCor XCEL device

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

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

The change in plasma angiotensin II:angiotensin-(1-7) when moving from the high-Na+ phase to the low-Na+ phase

The change in plasma angiotensin II:angiotensin-(1-7) when moving from the high-Na+ phase to the low-Na+ phase 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

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

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.