The antihypertensive effect of spironolactone in oligo-anuric haemodialysis patients.

The adrenocortical hormone aldosterone causes a rise in blood pressure through
stimulation of renal water and salt reabsorption, via, among other mechanisms,
the upregulation of the epithelial sodium channel (eNac) in the distal renal
tubule. Inhibition of these effects with aldosterone-receptor-antagonists such
as spironolactone has gained an important place in the treatment of
hypertension. There is, however, growing evidence that aldosterone also acts
outside the kidney. Aldosterone has been shown to increase blood pressure via
other, extrarenal, mechanisms and the antihypertensive actions of
spironolactone could in part be attributable to extrarenal effects.
In humans, however, it is hardly impossible to identify these effects separate
from the diuretic actions. An exception is formed by patients with end-stage
renal failure with no (relevant) remaining diuresis. These patients form an
ideal model to study the extrarenal actions of antihypertensive drugs. A study
in eight oligoanuric patients showed a significant decrease in blood pressure
after a two weeks treatment with spironolactone. In this project the potential
mechanisms behind this effect are further explored. Our hypothesis is that the
decline in blood pressure is caused by affecting other neurohormonal systems,
such as the sympathetic nervous system and the pituitary-adrenal-axis.

If the decrease in blood pressure is indeed mediated outside the kidney, an
inhibitor of eNaC should have no effect on blood pressure in these patients. To
test this assumption a treatment arm with triamterene, an eNaC inhibitor, is
included in the protocol.

1. to study the effect of spironolacton and triamterene on blood pressure in
anuric hemodialysis patients.

2. to study the effect of treatment on body weight, serum elektrolytes,
24-hours sodium excretion, plasma aldosterone and renin concentrations

3. to identify potential mechanisms by studying changes in sympathetic tone,
endothelin-1 concentrations, hypothamalic-pituitary-adrenal, and thyroid axis.

The design is a placebo-controlled cross-over study consisting of three
treatment periods: spironolactone, triamterene, and placebo.

1. Phase 0: preparation
After inclusion a 3-week preparation phase starts. If patients are on an
angiotensin-converting-enzyme (ACE) inhibitor, angiotensin-receptor blocker
(ARB),or potassium-sparing diuretic these will be discontinued. In case of an
unacceptable rise in blood pressure a calciumantagonist of alphablocker will be
added to the antihypertensive regimen. After three weeks baseline parameters
are measured, such as blood pressure, neuroendocrine profile, and serum
elektrolytes.

2. Phase 1
Phase 1 consists of a double-blinded, placebo-controlled, randomized cross-over
trial comparing treatment with spironolactone 50 mg (twice daily) with
triamterene (50 mg twice daily), and placebo. Each treatment period has a
duration of two weeks followed by a 2-week washout period. The last treatment
period is not followed by a washout period. The treatment order is determined
by randomisation.
On baseline, day 7, and day 14 the following parameters are determined:

-blood pressure by automatic blood pressure monitoring for 30 minutes.
-on day 14 collection of blood samples for assessment of renin and aldosterone
concentations, adrenocorticotropic hormone (ACTH), plasma cortisol,
noradrenalin, and endothelin-1. These samples are drawn after installation of
the dialysis device followed by a 30-minute resting period in sitting position.
-on day 13 a 24-hours ambulatory blood pressure measurement (24-hrs ABPM) is
performed.
-on day 14 24-hours sodium excretion is determined in a 24-hours urine sample.
At every hemodialysis session during the study body weight, and serum
elektrolyte concentrations are measured.

All patients will be treated with spironolactone, triamterene and placebo for a
2-week period. During the whole study, all subjects will continue their own
antihypertensive drugs as described earlier.

If the subjects are on ACE-inhibitor, angiotensin-receptor-blocker, or
potassium-sparing diuretic therapy this will be discontinued at the start of
the study. If this results in an unacceptable rise in blood pressure, a
calciumantagonist of alphablocker will be added to the antihypertensive
regimen. Blood pressure will be measured three times a week during
haemodialysis which will guarantee an early detection of an unacceptable rise
in blood pressure.

Important side effects of spironolactone are its anti-androgenic and
progestagenic actions, such as gynaecomastia, erectile and menstrual disorders.
These side effects are mainly relevant during longterm treatment and are
considered to be of minor importance during shortterm treatment such as in this
protocol.
Another serious side effect of spironolactone and triamterene is the occurence
of hyperkalemia. Patients with renal failure are especially at risk for this.
This is related to the impaired renal potassium excretion. However, in
oligo-anuric patients the renal potassium excretion is largely absent. An
additonal risk of hyperkalemia is therefore not te be expected. Several studies
have indeed shown spironolactone in low doses can be used safely in
hemodialysis patients.

Theoretically, treatment responses can be characterized by hypotension. Because
the frequency of dialysis in this population (three times weekly) adverse
events will be recognized in an early stage.

The burden for participants is considered acceptable. No relevant changes will
be made to their dialysis schedule. Once weekly the dialysis session will be
half an hour longer of duration because of an automatic blood pressure
measurement and the collection of blood samples for hormone assays.
Furthermore, a 24-hour ambulatory blood pressure measurement will be performed
four times. This is a noninvasive procedure that is sometimes experienced as
dreadful.