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NCT Number: NCT04026776

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

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

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Key information

Conditions

Salt; Excess Blood Pressure Disorders

Age range

22 year–33 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Early Phase 1

Primary location

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157, United States

Location status: Recruiting

Location contact

Andrew South, MD, MS

SUB_INVESTIGATOR

Hossam Shaltout, PhD

CONTACT

[email protected]

336-716-1251

Hossam Shaltout, PhD

PRINCIPAL_INVESTIGATOR

About this study

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.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • 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

Treatment and study plan

Allopurinol

Drug

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

Dietary Intervention

Other

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.

Primary outcomes

  1. Proportion with salt sensitivity of blood pressure at baseline via ABPM

    Time frame: Day 7 to 14

    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).

  2. Proportion with salt sensitivity of blood pressure after allopurinol via ABPM

    Time frame: Day 49 to 56

    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).

  3. Salt sensitivity index at baseline

    Time frame: Day 7 to 14

    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.

  4. Salt sensitivity index after allopurinol

    Time frame: Day 49 to 56

    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

  5. Proportion with salt sensitivity of blood pressure at baseline via casual blood pressure

    Time frame: Day 7 to 14

    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.

  6. Proportion with salt sensitivity of blood pressure after allopurinol via casual blood pressure

    Time frame: Day 49 to 56

    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.

  7. High blood pressure at baseline via ABPM

    Time frame: Day 0

    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).

  8. Hypertension at baseline via ABPM

    Time frame: Day 7

    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).

  9. High blood pressure at baseline via casual blood pressure

    Time frame: First 3 study visits

    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.

  10. Hypertension at baseline via casual blood pressure

    Time frame: First 3 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

  11. Serum uric acid at baseline

    Time frame: Day 0

    Serum uric acid concentration at baseline

  12. Change in serum uric acid with dietary Na+ intervention

    Time frame: Day 7 to 14

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

  13. Change in serum uric acid with dietary Na+ intervention on allopurinol

    Time frame: Day 42 to 56

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

  14. Pulse wave velocity at baseline

    Time frame: Day 0

    Carotid femoral pulse wave velocity will be measured at baseline with the SphygmoCor XCEL device

  15. Augmentation index at baseline

    Time frame: Day 0

    Augmentation index will be measured at baseline with the SphygmoCor XCEL device

  16. Heart rate variability at baseline

    Time frame: Day 0

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

  17. Baroreflex sensitivity at baseline

    Time frame: Day 0

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

  18. Angiotensin-(1-7) at baseline

    Time frame: Day 0

    Plasma angiotensin-(1-7) concentration and urine angiotensin-(1-7)/creatinine at baseline

  19. Angiotensin II at baseline

    Time frame: Day 0

    Plasma angiotensin II concentration and urine angiotensin II/creatinine at baseline

  20. Klotho at baseline

    Time frame: Day 0

    Plasma klotho concentration and urine klotho/creatinine at baseline.

  21. Creatinine at baseline

    Time frame: Day 0

    Serum creatinine concentration at baseline

  22. Cystatin C at baseline

    Time frame: Day 0

    Serum cystatin C concentration at baseline

  23. eGFR at baseline

    Time frame: Day 0

    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

Secondary outcomes

  1. Ambulatory systolic blood pressure 24-hour mean at baseline

    Time frame: Day 0

    Average systolic blood pressure over 24 hours, measured with ambulatory blood pressure monitors

  2. Ambulatory diastolic blood pressure 24-hour mean at baseline

    Time frame: Day 0

    Average diastolic blood pressure over 24 hours, measured with ambulatory blood pressure monitors

  3. Ambulatory mean arterial pressure 24-hour mean at baseline

    Time frame: Day 0

    Average mean arterial pressure over 24 hours, measured with ambulatory blood pressure monitors

  4. Ambulatory systolic blood pressure awake mean at baseline

    Time frame: Day 0

    Average systolic blood pressure while awake, measured with ambulatory blood pressure monitors

  5. Ambulatory diastolic blood pressure awake mean at baseline

    Time frame: Day 0

    Average diastolic blood pressure while awake, measured with ambulatory blood pressure monitors

  6. Ambulatory mean arterial pressure awake mean at baseline

    Time frame: Day 0

    Average mean arterial pressure while awake, measured with ambulatory blood pressure monitors

  7. Ambulatory systolic blood pressure asleep mean at baseline

    Time frame: Day 0

    Average systolic blood pressure while asleep, measured with ambulatory blood pressure monitors

  8. Ambulatory diastolic blood pressure asleep mean at baseline

    Time frame: Day 0

    Average diastolic blood pressure while asleep, measured with ambulatory blood pressure monitors

  9. Ambulatory mean arterial pressure asleep mean at baseline

    Time frame: Day 0

    Average mean arterial pressure while asleep, measured with ambulatory blood pressure monitors

  10. Ambulatory systolic blood pressure 24-hour load at baseline

    Time frame: Day 0

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

  11. Ambulatory diastolic blood pressure 24-hour load at baseline

    Time frame: Day 0

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

  12. Ambulatory systolic blood pressure awake load at baseline

    Time frame: Day 0

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

  13. Ambulatory diastolic blood pressure awake load at baseline

    Time frame: Day 0

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

  14. Ambulatory systolic blood pressure asleep load at baseline

    Time frame: Day 0

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

  15. Ambulatory diastolic blood pressure asleep load at baseline

    Time frame: Day 0

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

  16. Ambulatory systolic blood pressure nocturnal dipping at baseline

    Time frame: Day 0

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

  17. Ambulatory diastolic blood pressure nocturnal dipping at baseline

    Time frame: Day 0

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

  18. Casual systolic blood pressure at baseline

    Time frame: Day 0

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

  19. Casual diastolic blood pressure at baseline

    Time frame: Day 0

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

  20. Change in pulse wave velocity with dietary Na+ intervention

    Time frame: Day 7 to 14

    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

  21. Change in augmentation index with dietary Na+ intervention

    Time frame: Day 7 to 14

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

  22. Change in pulse wave velocity with dietary Na+ intervention while on allopurinol

    Time frame: Day 49 to 56

    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.

  23. Change in augmentation index with dietary Na+ intervention while on allopurinol

    Time frame: Day 49 to 56

    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

  24. Change in heart rate variability with dietary Na+ intervention

    Time frame: Day 7 to 14

    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

  25. Change in baroreflex sensitivity with dietary Na+ intervention

    Time frame: Day 7 to 14

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

  26. Change in heart rate variability with dietary Na+ intervention while on allopurinol

    Time frame: Day 49 to 56

    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

  27. Change in baroreflex sensitivity with dietary Na+ intervention while on allopurinol

    Time frame: Day 49 to 56

    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

  28. Change in angiotensin-(1-7) with dietary Na+ intervention

    Time frame: Day 7 to 14

    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

  29. Change in angiotensin II with dietary Na+ intervention

    Time frame: Day 7 to 14

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

  30. Change in klotho with dietary Na+ intervention

    Time frame: Day 7 to 14

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

  31. Change in angiotensin-(1-7) with dietary Na+ intervention while on allopurinol

    Time frame: Day 49 to 56

    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

  32. Change in angiotensin II with dietary Na+ intervention while on allopurinol

    Time frame: Day 49 to 56

    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

  33. Change in klotho with dietary Na+ intervention while on allopurinol

    Time frame: Day 49 to 56

    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

  34. ACE2 at baseline

    Time frame: Day 0

    Serum ACE2 concentration and activity and urine ACE2/creatinine and activity at baseline

  35. ACE at baseline

    Time frame: Day 0

    Serum ACE concentration and activity and urine ACE/creatinine and activity at baseline

  36. FGF23 at baseline

    Time frame: Day 0

    Plasma fibroblast growth factor 23 (FGF23) concentration and urine FGF23/creatinine at baseline

  37. Change in ACE2 with dietary Na+ intervention

    Time frame: Day 7 to 14

    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

  38. Change in ACE2 with dietary Na+ intervention while on allopurinol

    Time frame: Day 49 to 56

    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

  39. Change in ACE with dietary Na+ intervention

    Time frame: Day 7 to 14

    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

  40. Change in ACE with dietary Na+ intervention while on allopurinol

    Time frame: Day 49 to 56

    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

  41. Change in FGF23 with dietary Na+ intervention

    Time frame: Day 7 to 14

    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

  42. Change in FGF23 with dietary Na+ intervention while on allopurinol

    Time frame: Day 49 to 56

    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

  43. Neprilysin level at baseline

    Time frame: Day 0

    Serum neprilysin concentration and activity and urine neprilysin/creatinine and activity at baseline

  44. Change in neprilysin with dietary Na+ intervention

    Time frame: Day 7 to 14

    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

  45. Change in neprilysin with dietary Na+ intervention while on allopurinol

    Time frame: Day 49 to 56

    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

  46. Urine albumin at baseline

    Time frame: Day 0

    Urine albumin/creatinine at baseline on first-morning urine sample

  47. Proportion with albuminuria

    Time frame: Day 0

    Albuminuria at baseline, defined as urine albumin/creatinine >30 mg/g on first-morning urine sample

  48. Urine protein at baseline

    Time frame: Day 0

    Urine protein/creatinine at baseline on first-morning urine sample

  49. Proportion with proteinuria

    Time frame: Day 0

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

  50. Angiotensinogen at baseline

    Time frame: Day 0

    Serum angiotensinogen concentration and urine angiotensinogen/creatinine at baseline

  51. Change in angiotensinogen with dietary Na+ intervention

    Time frame: Day 7 to 14

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

  52. Change in angiotensinogen with dietary Na+ intervention while on allopurinol

    Time frame: Day 49 to 56

    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

  53. 24-hour sodium excretion at baseline

    Time frame: Day 0

    Sodium excretion in the urine over 24 hours at baseline

  54. 24-hour potassium excretion at baseline

    Time frame: Day 0

    Potassium excretion in the urine over 24 hours at baseline

  55. 24-hour uric acid excretion at baseline

    Time frame: Day 0

    Uric acid excretion in the urine over 24 hours at baseline

  56. Pulse wave velocity (CF) at baseline

    Time frame: Day 0

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

  57. Change in pulse wave velocity (CF) with dietary Na+ intervention

    Time frame: Day 7 to 14

    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

  58. Change in pulse wave velocity (CF) with dietary Na+ intervention while on allopurinol

    Time frame: Day 49 to 56

    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

  59. Angiotensin II:angiotensin-(1-7) at baseline

    Time frame: Day 0

    Plasma and urine angiotensin II:angiotensin-(1-7) at baseline

  60. Change in angiotensin II:angiotensin-(1-7) with dietary Na+ intervention

    Time frame: Day 7 to 14

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

  61. Change in angiotensin II:angiotensin-(1-7) with dietary Na+ intervention while on allopurinol

    Time frame: Day 49 to 56

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

  62. ACE:ACE2 at baseline

    Time frame: Day 0

    Serum and urine ACE:ACE2 at baseline

  63. Change in ACE:ACE2 with dietary Na+ intervention

    Time frame: Day 7 to 14

    The change in serum and urine ACE:ACE2 when moving from the high-Na+ phase to the low-Na+ phase

  64. Change in ACE:ACE2 with dietary Na+ intervention while on allopurinol

    Time frame: Day 49 to 56

    The change in serum and urine ACE:ACE2 when moving from the high-Na+ phase to the low-Na+ phase while on allopurinol

  65. Body mass index at baseline

    Time frame: Day 0

    Body mass index at baseline

  66. Proportion with overweight/obesity

    Time frame: Day 0

    Overweight/obesity at baseline, defined as a body mass index >=25 kg/m2

  67. Proportion with obesity

    Time frame: Day 0

    Obesity at baseline, defined as a body mass index >=30 kg/m2

Study contacts

Contact information is provided by the study sponsor or research team.

Hossam Shaltout, PhD

CONTACT

[email protected]

336-716-1251

Sponsors and collaborators

Lead sponsor

Wake Forest University Health Sciences

Other

Collaborators

  • National Heart, Lung, and Blood Institute (NHLBI)

Registry information

Acronym: PEPC3

Important dates

Study start
2020
Primary completion
2026
Study completion
2026
First posted
Jul 19, 2019
Registry last updated
Jun 29, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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