Effect of Aliskiren on Muscle Sympathetic Nerve Activity (MSNA) in hypertensive patients with chronic kidney disease

Cardiovascular (CV) morbidity and mortality are frequently occurring problems
in chronic kidney disease (CKD) patients. Apart from the so called traditional
risk factors, also risk factors more or less specific to CKD contribute in the
pathogenesis of these problems. There is strong evidence that the sympathetic
hyperactivity, which often characterizes CKD, is one such factor. Previously,
we have shown that angiotensin converting enzyme inhibitors (ACEi) and
angiotensin II receptor blockers (ARB) reduce but not normalize this
sympathetic hyperactivity. We re-analysed the cohort of patients who were
investigated in the past and subsequently treated according to present
guidelines. The results show that, despite of treatment, the unfavourable
relation between sympathetic hyperactivity and clinical outcome still exits.
This might mean that treatment is insufficient. In present study, we want to
study the effect of Aliskiren 300mg on sympathetic nerve activity.

The central hypothesis of this project is that Aliskiren causes a substantial
decrease in MSNA in hypertensive patients with CKD.

This study is designed as a randomized trial. We collect data on activity of
MSNA at two different conditions:

1. At baseline when participants are taken off antihypertensive medication
while other medications will be continued.
2. After 6 weeks treatment of participants with Aliskiren 300mg/day and no ACE
inhibitor or ARB is given. Other medication, including phosphate binders,
vitamine D derivatives, erythropoietine etc will be continued during the whole
study. Importantly, also diuretics are continued throughout the study in order
to maintain normovolemia, which is evidenced by extracellular volume assessment
(bromide distribution).


During the first visit the patient will be randomized into two groups:

o Group 1: Take off ACE inhibitor and ARB for 4 weeks AND after 4 weeks
"off-treatment" start with Aliskiren 300mg/day for 6 weeks

o Group 2: Take off ACE inhibitor and ARB and start directly with Aliskiren
300mg/day for 6 weeks. After 6 weeks of Aliskiren the participants will be put
in "off-treatment" period i.e. no ACE inhibitor or ARB and no Aliskiren

See Protocol, the FLOWCHART on page 19, for an overview of the study design.

Patients will be asked to take off ACE inhibitors and ARB and start directly
with Aliskiren 300mg/day for 6 weeks. The first MSNA measurement will be done.
After 6 weeks of treatment with only Aliskiren patients will be place in
"off-treatment" period i.e. no ACE inhibitor, no ARB and no Aliskiren for 4
weeks. The second MSNA measurement will be done.

OR

The order of treatment will be randomized:

Patients will be put in "off-treatment" period first, the first MSNA
measurement will be done. Then patients will start with Aliskiren 300mg/day and
still no ACE inhibitor or ARB. The second MSNA measurement will be done.

The risks associated with participation in this study are very limited.

Microneurography: there are no risks associated with this procedure. Usually,
nerve recordings cause minimal discomfort and negligible, transient
after-effects, when studies are done by an experienced technician.

Aliskiren: de safety of Aliskiren 300mg is studied among 7.800 patients. The
incidence of side effects was comparable to the placebo group. In general the
side effects were mild and spontanously disapeared. The most common side
effects are diarrhea and skin rash. See our study protocol "SUMMARY OF KNOWN
AND POTENTIAL RISKS" for more information.