Hypertension and Urine Protease Activity in Preeclampsia (HUPP)

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by Odense University Hospital
Sponsor:
Collaborators:
The Danish Council for Strategic Research
Lundbeck Foundation
Danish Data Protection Agency
South Denmark Regional Council
Information provided by (Responsible Party):
Lise Hald Nielsen, Odense University Hospital
ClinicalTrials.gov Identifier:
NCT01828138
First received: April 5, 2013
Last updated: March 14, 2014
Last verified: March 2014
  Purpose

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 not known 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 is able to activate the epithelial sodium channel ( ENaC ) in renal collecting duct cells. The investigators suggest that the 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.

The aldosterone in normal pregnant women circulates in a significant higher concentration through their pregnancies. PE is characterized by low aldosterone levels (a discovery the investigators have also confirmed) and by an underdeveloped placenta. In established PE, suppression of aldosterone can possibly contribute to an underdeveloped placenta other than a primary disturbance.

Study Aim: To test specific hypothesis regarding established PE´s pathophysiological mechanisms.

Study Hypothesis:

  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. The degree of aldosterone suppression in PE determines placental development

Condition Intervention
Preeclampsia
Hypertension
Proteinuria
Pregnancy
Dietary Supplement: Sodium
Dietary Supplement: Placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: HUPP-study -Hypertension and Urine Protease Activity in Preeclampsia

Resource links provided by NLM:


Further study details as provided by Odense University Hospital:

Primary Outcome Measures:
  • urine Plasmin/plasminogen correlation to the severity of preeclampsia [ Time Frame: 3 years ] [ Designated as safety issue: No ]

    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.



Secondary Outcome Measures:
  • correlation between RAAS components in urine and severity of preeclampsia [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Degree of aldosterone suppression in PE determines placental development [ Time Frame: 3 years ] [ Designated as safety issue: No ]

    PE is characterized by low aldosterone levels and by an underdeveloped placenta. In established PE, suppression of aldosterone can possibly contribute to an underdeveloped placenta.

    A causal link between the degree of aldosterone suppression and morphological placenta abnormalities is not yet established. We compare blood levels of aldosterone to flow in a. umbilicalis and a.uterine by ultrasound.



Other Outcome Measures:
  • Correlation between ENaC peptide fragments in urine and severity of preeclampsia [ Time Frame: 3 years ] [ Designated as safety issue: No ]

    PE patients with comparable heavy proteinuria have shown that urokinase plasminogen activator (uPA) in the urine has the ability to activate abnormal filtered plasminogen to plasmin. Active plasmin in urine from patients with nephrotic syndrome and PE is able to activate the epithelial sodium channel ( ENaC ) in renal collecting duct cells by proteolytic cleavage - either directly or by the protease prostatin.

    Hyperactive ENaC causes primary renal sodium retention with secondary suppression of the renin-angiotensin-aldosterone system.



Estimated Enrollment: 30
Study Start Date: May 2013
Estimated Study Completion Date: February 2016
Estimated Primary Completion Date: February 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Preeclampsia

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
supplemental sodium tablets 150-200 mmol/day in 5 days
Dietary Supplement: Placebo
Placebo are given in 5 days
Placebo Comparator: Controls

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
supplemental sodium tablets 150-200 mmol/day in 5 days
Dietary Supplement: Placebo
Placebo are given in 5 days

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 45 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Cases:

Inclusion Criteria:

  1. Pregnancy week 28-36 (exclusion of patients with previously severe preeclampsia).
  2. Singleton pregnancy
  3. Preeclampsia- hypertension: repetitive high blood pressures (> 140/80 mm Hg) measured in the consultation and proteinuria (dip test, albumin).
  4. 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.

It is still possible to test our hypothesis with possible comorbidity such as diabetes, SLE(systemic lupus erythematosus), rheumatoid arthritis and therefore not a reason for exclusion.

Exclusion Criteria:

  1. Hypertension in pregnancy without proteinuria.
  2. Pregestational nephropathy by other unknown reasons.
  3. Early severe preeclampsia.
  4. Organic or systemic disease of clinical relevance, such as malignancy.

Pregnant controls-

Inclusion Criteria:

  1. pregnancy week 28-36
  2. Singleton pregnancy
  3. Uncomplicated pregnancy

Exclusion Criteria:

  1. Hypertension
  2. Any kind of nephropathy
  3. Organic or systemic disease of clinical relevance, such as malignancy.

Non-pregnant controls:

Inclusion Criteria:

  1. woman, not pregnant
  2. Matched by age and BMI

Exclusion Criteria:

  1. Hypertension
  2. Any kind of nephropathy
  3. Organic or systemic disease of clinical relevance, such as malignancy.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01828138

Contacts
Contact: Lise H Nielsen, doctor 0045+53347735 lihn@ki.au.dk
Contact: Per Ovesen, doctor 0045+61669728 Per.Ovesen@dadlnet.dk

Locations
Denmark
Gynelogical Obstetrical Department Recruiting
Skejby, Aarhus, Denmark, 8200
Contact: Ellen M Daugaard, Nurse       Merete.daugaard@skejby.rm.dk   
Principal Investigator: Lise H. Nielsen, Doctor         
Sponsors and Collaborators
Odense University Hospital
The Danish Council for Strategic Research
Lundbeck Foundation
Danish Data Protection Agency
South Denmark Regional Council
Investigators
Study Director: Boye L. Jensen, Professor cardiovascular and renal research department, Odense University Hospital
  More Information

Additional Information:
No publications provided

Responsible Party: Lise Hald Nielsen, doctor, Ph.D student, Odense University Hospital
ClinicalTrials.gov Identifier: NCT01828138     History of Changes
Other Study ID Numbers: 9-5510
Study First Received: April 5, 2013
Last Updated: March 14, 2014
Health Authority: Denmark: Danish Dataprotection Agency

Keywords provided by Odense University Hospital:
Proteinuria
Pregnancy
Hypertension
Plasmin
Plasminogen
Aldosterone
Angiotensin
Renin
sodium chloride
epithelial sodium channel
Placenta

Additional relevant MeSH terms:
Proteinuria
Hypertension
Pre-Eclampsia
Vascular Diseases
Cardiovascular Diseases
Hypertension, Pregnancy-Induced
Pregnancy Complications
Urination Disorders
Urologic Diseases
Urological Manifestations
Signs and Symptoms

ClinicalTrials.gov processed this record on July 24, 2014