Hypertension and Urine Protease Activity in Preeclampsia

NCT01828138 | Completed DMC

• 1 other identifier: 9-5510
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 1

Brief Summary

Preeclampsia (PE) is a common disorder of pregnancy that complicates 4-7% of all pregnancies. It is a serious condition with acute proteinuria and hypertension and varying degrees of edema after 20 weeks of gestation. PE leads to a severe risk of low birth weight because of prematurity with inherent complications. The pathogenesis is unknown but is assumed to involve placental ischemia.The primary placental disorder results in renal glomerular injury. Established PE is associated with paradoxical suppression of the renin-angiotensin-aldosterone system, RAAS. Despite suppressed RAAS, patients with PE retain NaCl(sodium chloride) after an intravenous isotonic NaCl overload compared to healthy pregnant women on a low NaCl diet. The investigators believe to have data that provide a possible explanation for the overall relationship between proteinuria, NaCl retension, suppression of RAAS, hypertension and underdevelopment of placenta. Earlier data, which the investigators have confirmed, shows abnormal glomerular loss of the enzyme plasmin/plasminogen from plasma to the urine in PE. Active plasmin in urine from patients with nephrotic syndrome and PE activates the epithelial sodium channel ( ENaC ) in renal collecting duct cells. The investigators hypothesize that loss of plasmin/plasminogen are shared for the diseases with proteinuria, including PE, and that plasmin- driven ENaC (epithelial sodium channel) activation is a causal factor in the pathophysiology of established PE. Hyperactive ENaC causes primary renal sodium retention with secondary suppression of the renin-angiotensin-aldosterone system. Aldosterone is recently established as a placental growth factor. Plasma-aldosterone levels are significant higher in normal pregnant women. PE is characterized by low aldosterone levels (a discovery the investigators have also confirmed) and by placental underdevelopment. Study Aim: To test specific hypothesis regarding established PE´s pathophysiological mechanisms. Study Hypothesis:

1. 1.Excretion of urine proteases (plasmin/plasminogen) in PE leads to an activation of ENaC and hence RAAS is less NaCl sensitive while the blood pressure is more NaCl sensitive compared to healthy pregnant women.
2. 2.The degree of aldosterone suppression in PE determines placental development

Conditions

Preeclampsia; Hypertension; Proteinuria; Pregnancy

Keywords

Proteinuria; Pregnancy; Hypertension; Plasmin; Plasminogen; Aldosterone; Angiotensin; Renin; sodium chloride; epithelial sodium channel; Placenta

Outcome Measures

Primary Outcomes (1)

• urine Plasmin/plasminogen correlation to the severity of preeclampsia

  We suggest that the loss of plasmin/plasminogen are shared for the diseases with proteinuria, including PE, and that plasmin- driven ENaC activation is a causal factor in the pathophysiology of established PE. We believe that high concentrations of plasmin/plasminogen in the urine correlates to the severity og preeclampsia. -Another outcome measure is the correlation between plasma aldosterone and the placental (under)development.

  3 years

Secondary Outcomes (2)

• correlation between RAAS components in urine and severity of preeclampsia

  3 years

• Degree of aldosterone suppression in PE determines placental development

  3 years

Other Outcomes (1)

• Correlation between ENaC peptide fragments in urine and severity of preeclampsia

  3 years

Study Arms (3)

Preeclampsia

OTHER

patients with preeclampsia are given a diet with a fixed content of sodium chloride ( 50-60 mmol/day ) plus a supplement of sodium chloride tablets ( 150-200 mmol/day) OR they are given placebo tablets. After 5 days they switch their supplement.

Dietary Supplement: Sodium; Dietary Supplement: Placebo

Controls

OTHER

Controls are given a diet with a fixed content of sodium chloride ( 50-60 mmol/day ) plus a supplement of sodium chloride tablets ( 150-200 mmol/day) OR they are given placebo tablets. After 5 days they switch their supplement

Dietary Supplement: Sodium; Dietary Supplement: Placebo

not-pregnant women

OTHER

This arm is also a control- group. Controls are given a diet with a fixed content of sodium chloride ( 50-60 mmol/day ) plus a supplement of sodium chloride tablets ( 150-200 mmol/day) OR they are given placebo tablets. After 5 days they switch their supplement

Dietary Supplement: Sodium; Dietary Supplement: Placebo

Interventions

Sodium DIETARY_SUPPLEMENT

supplemental sodium tablets 150-200 mmol/day in 5 days

Controls; Preeclampsia; not-pregnant women

Placebo DIETARY_SUPPLEMENT

Placebo are given in 5 days

Controls; Preeclampsia; not-pregnant women

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Singleton pregnancy
• Preeclampsia- hypertension: repetitive high blood pressures (\> 140/80 mm Hg) measured in the consultation and proteinuria (dip test, albumin).
• Pregnant with microalbuminuria and proteinuria, but without hypertension (and therefore do not meet the diagnostic criteria for preeclampsia) can also be included. Proteinuria is the most important factor.

You may not qualify if:

• Hypertension in pregnancy without proteinuria.
• Pregestational nephropathy by other unknown reasons.
• Early severe preeclampsia.
• Organic or systemic disease of clinical relevance, such as malignancy.
• Pregnant controls-
• pregnancy week 28-36
• Singleton pregnancy
• Uncomplicated pregnancy
• Hypertension
• Any kind of nephropathy
• Organic or systemic disease of clinical relevance, such as malignancy.
• Non-pregnant controls:
• woman, not pregnant
• Matched by age and BMI
• Hypertension

Sponsors & Collaborators

• Odense University Hospital: lead
• The Danish Council for Strategic Research: collaborator
• Lundbeck Foundation: collaborator

Study Sites (1)

Gynelogical Obstetrical Department

Skejby, Aarhus, 8200, Denmark

Location

Related Links

• webpage of the research group and related projects

MeSH Terms

Conditions

Pre-Eclampsia; Hypertension; Proteinuria

Interventions

Sodium

Condition Hierarchy (Ancestors)

Hypertension, Pregnancy-Induced; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Vascular Diseases; Cardiovascular Diseases; Urination Disorders; Urologic Diseases; Female Urogenital Diseases; Male Urogenital Diseases; Urological Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Metals, Alkali; Elements; Inorganic Chemicals; Metals, Light; Metals

Study Officials

• Boye L. Jensen, Professor

  cardiovascular and renal research department, Odense University Hospital

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: doctor, Ph.D student

Study Record Dates

• First Submitted: April 5, 2013
• First Posted: April 10, 2013
• Study Start: May 1, 2013
• Primary Completion: October 1, 2015
• Study Completion: October 1, 2015
• Last Updated: October 16, 2015

Record last verified: 2015-10

Locations

DK (1)