Response to angiotensin II in formerly preeclamptic women. RETAP study.

Preeclampsia (PE) is characterized by hypertension and proteinuria in the
second half of pregnancy and complicates about 5% of pregnancies. In the
Netherlands (pre)eclampsia represents the number one cause of maternal
mortality. Moreover, recent data show that pregnancy complicated by PE is also
a risk factor for long-term cardiovascular, cerebrovascular and renal disease.
The pathogenesis of PE is unknown but it is likely to be multifactorial. Its
pathophysiology involves activation of the inflammatory response including
endothelial cell activation and dysfunction, immune mechanisms and altered
activity of the renin angiotensin aldosterone system (RAAS). During PE there is
an increased sensitivity for angiotensin II. This maladaptation of the renin
angiotensin aldosteron system is one of the main factors altered during PE.
This increased sensitivity for angiotensin II might be involved in the
increased cardiovascular and renal risk after PE.

Primary Objective:
Primary endpoints will be renal (ERPF, GFR and FF) response to angiotensin II
after low and high sodium diet in formerly preeclamptic patients compared to
healthy controls.

Secondary Objectives:
Secondary endpoint will be systemic respons (blood pressure) to angiotensin II
after low and hogh sodium diet in formerly preeclamptic patients compared to
healthy controls.
Secondary endpoints will be renal function after preeclampsia, expressed as
glomerular filtration rate (GFR), effective renal plasma flow (ERPF),
filtration fraction (FF) and extracellular volume (ECV) and changes in
RAAS-parameters (plasma renine activity, aldosteron, angiotensins,
ACE-activity) in relation to sodiumintake, in formely preeclamptic patients
compared to healthy controls.

Gender specific differences in renal hemodynamics and bloodpressure in response
to dietary sodium intake and angiotensin II infusion will be analysed using our
previous studies. The exact same protocol is performed in healthy young male
subjects. This will allow us to perform analysis on gender differences.

The study design of this study is a patient-control, cross over study, with a
study day after a week of low sodium intake and a week of high sodium intake,
with four weeks in between. There will be one visit for inclusion before the
first dietary period with the investigator, including a physical examination
and explanation of the dietary sodium diets. During their mid follicular phase
women will use a low sodium diet during one week (50 mmol sodium/day, 1.2 gram)
followed by a week of high sodium diet (200 mmol sodium/day, 4.8 gram), with
four weeks in between. On day 3 and day 6 of each dietary period subjects will
collect 24-hour urine to assess dietary compliance and achievement of stable
sodium balance. At the end of each week a day of renal function measurements
will follow. Baseline blood pressure and renal function will be measured. GFR,
ERPF, FF and ECV will be measured by constant infusion of radioactive-labelled
tracers: 125-I-iothalamate and 131-I-hippurate. Blood samples will be drawn for
the measurement of RAAS parameters (plasma renine activity, angiotensins,
ACE-activity). In the afternoon angiotensine II will be infused at a rate of
0.3, 1 and 3 ng/kg/hour all during one hour. Both blood pressure and renal
hemodynamics will be measured during angiotensin II infusion.

During one week women will use a low sodium diet (50 mmol sodium/day, 1.2
gram). This will be followed by a week of high sodium diet (200 mmol
sodium/day, 4.8 gram) (with four weeks in between). On day 3 and day 6 of each
dietary period subjects will collect 24-hour urine to assess dietary compliance
and achievement of stable sodium balance.

At the end of both the low and the high sodium diet week, a day of renal
function measurements will follow. Baseline blood pressure and renal function
will be measured. GFR, ERPF, FF and ECV will be measured by constant infusion
of radioactive-labelled tracers: 125-I-iothalamate and 131-I-hippurate. In the
afternoon ang II will be infused at a rate of 0.3, 1 and 3 ng/kg/min all during
one hour. Both blood pressure and renal hemodynamics will be measured during
ang II infusion

The subject has to come three times to the clinic, one short visit for intake
and two eight hours visits for renal function measurements and angiotensin II
infusion. In total, during the entire study, a maximum of 250 ml of blood
samples will be drawn. The subjects will follow one week of low sodium diet and
one week of high sodium diet, with in total four times 24-hour urine
collection. This study can only be conducted in healthy women and women with a
history of preeclampsia to answer the research questions. During the study days
radioactive tracers (in total 0,2 mSv) and angiotensin II will be infused. All
substances are safe; and our research group has extensive experience with
similar experiments in healthy subjects and patients with diabetes mellitus
using similar study designs.