Hypertension and Urine Protease Activity in Preeclampsia (HUPP)
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|ClinicalTrials.gov Identifier: NCT01828138|
Recruitment Status : Completed
First Posted : April 10, 2013
Last Update Posted : October 16, 2015
|First Submitted Date ICMJE||April 5, 2013|
|First Posted Date ICMJE||April 10, 2013|
|Last Update Posted Date||October 16, 2015|
|Study Start Date ICMJE||May 2013|
|Actual Primary Completion Date||October 2015 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||urine Plasmin/plasminogen correlation to the severity of preeclampsia [ Time Frame: 3 years ]
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.
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT01828138 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Outcome Measures ICMJE
||Correlation between ENaC peptide fragments in urine and severity of preeclampsia [ Time Frame: 3 years ]
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.
|Original Other Outcome Measures ICMJE||Same as current|
|Brief Title ICMJE||Hypertension and Urine Protease Activity in Preeclampsia|
|Official Title ICMJE||HUPP-study -Hypertension and Urine Protease Activity in Preeclampsia|
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.
Selection of patients:
The selection of patients is based on outpatients with preeclampsia and patients with normal pregnancies recruited from gynecological-obstetric department, Aarhus University Hospital - Skejby, Denmark. Non- pregnant woman are recruited by posting notices at the workplace. Specifically by office facilities, canteen and in gynecological department at Skejby hospital, Aarhus.
Registration of date of birth, sex, weight, height, abdominal circumference, and smoking status will be noted.
Furthermore, we will register current antihypertensive-, diuretic-, antidiabetic- and antiepileptic medicine and other current use of medicine. Also post-partum registration of gestation length, placentas weight and the infant weight will be noted.
Weight, height, BMI, abdominal circumference. Blood pressure (systolic, diastolic, mean arterial pressure). Weight of placenta, gestation length, Infant weight
Measurements in blood tests:
Se-creatinine, p-Na+, p-K+. P-plasminogen. P-albumin. P-renin concentration (not activity!), angiotensin II, aldosterone and arterial natriuretic peptide (ANP).
Measurements in 50 ml newly "spot urine":
Plasmin, plasminogen, ENaC peptide fragment (analyses in location of development), Proteolytic activity, Prostatin, Creatinine, Na+, K+.
If findings dictate it we may have to examine the following on chosen urine tests:
Measurements in 24- hour urine samples:
Na+/K+ - concentration. Creatinine clearance. Albumin.
The three groups, "cases" (patients with preeclampsia) and "pregnant controls" (patients with normal pregnancies) and non pregnant controls ( non pregnant woman), are provided with 10 days of a healthy fully diet with a fixed low- normal NaCl content of 50 -60 mmol Na+/ day. The diet has the same content of calories per kg body weight and has the same content of potassium as far as possible. In this period of time the patients must only consume this diet and regularly drink water. Besides the fixed diet the patients are given a supplement with either sodium or placebo. The sequence is double randomized. The participants ingests either sodium tablets (150-200 mmol /day) or a corresponding number of placebo tablets. On the fifth day, the participants switch their daily supplement, so they now take placebo instead of sodium or the other way around.
Day number 1 is a Monday and day number 5 is a Friday where the measurements are to be done. 24-h urine samples are collected from Thursday 7 a.m. till Friday morning. On the 5th day the participants meet from 9 a.m. to 10 a.m. They are placed in a chair with elevated legs and relaxed for an hour in calm surroundings.
From 7 a.m. they ingest 200 ml water per hour. Spot urine tests are collected. Blood pressure is measured with an automatic oscillometric device. Intravenous access is made and blood samples are taken to decide the plasma hormone concentration (renin, angiotensin, aldosterone, ANP) and albumin, plasminogen and electrolytes. Cardiac output is measured non-invasive by impedance cardiography. Placenta flow is measured by ultrasound. The procedure lasts approximately 2 hours.
Hereafter a fixed, fully diet is given either with a sodium supply, a total of 250 mmol/day (corresponding to a high average sodium intake in Denmark) or placebo tablets. This diet is given in 4 days and measurements are made on the 5th day as described above.
A fixed sodium intake is given to:
Data- analysis methods:
This is an interventional double blinded case-control, cross-over study which includes 10 patients with preeclampsia, 10 patients with normal pregnancies and 10 non pregnant woman.
Population size evaluation:
The settings for a Ph.D. study makes it impossible to accomplish a fixed sodium diet intervention in 10 days with the amount of patients required to get a relevant change in the blood pressure detection.
With a paired design it is estimated that to achieve an expected change in blood pressure at approximately 15 mmHg in the individual and a clinical relevant different in blood pressure at 8 mmHg the sample size must include 40 patients (5% percentage point - 90% strength). Therefore we have chosen that blood pressure is not the primary variable of the outcome, instead we choose the RAAS components.
In previously similar designs we have measured hypertensive vs. normotensive patients and had enough statistic strength to detect differences in plasma concentrations of renin-angiotensin-aldosterone components and ANP by using 10 patients in each group.
|Study Type ICMJE||Interventional|
|Study Phase||Not Applicable|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Actual Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Actual Study Completion Date||October 2015|
|Actual Primary Completion Date||October 2015 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
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.
|Ages||18 Years to 45 Years (Adult)|
|Accepts Healthy Volunteers||Yes|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Denmark|
|Removed Location Countries|
|NCT Number ICMJE||NCT01828138|
|Other Study ID Numbers ICMJE||9-5510|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||Not Provided|
|Responsible Party||Lise Hald Nielsen, Odense University Hospital|
|Study Sponsor ICMJE||Odense University Hospital|
|PRS Account||Odense University Hospital|
|Verification Date||October 2015|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP