Effect of Statins on Sympathetic Activity in Hypertensive Patients with Chronic Kidney Disease: a Randomized trial 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 (ACE) inhibitors 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 atorvastatin 20mg/day combined to standard antihypertensive
treatment on sympathetic nerve activity.

The central hypothesis of this project is that atorvastatin (added on standard
antihypertensive treatment ARB) causes a substantial decrease in MSNA in
hypertensive patients with CKD.

First visit:
ACE inhibitor or ARB is considered *standard* treatment in CKD patients.
Therefore, all eligible patients will be on such medication. The patient will
be asked to provide written informed consent form and his/her eligibility for
enrolment into the trial will be checked. Physical examination will be
performed. Their regular ACE inhibitor or ARB will be replaced by Losartan
100mg/day and their regular statin will be replaced by atorvastatin 20mg/day.
If all inclusion criteria and no exclusion criteria are fulfilled, the patients
will be randomized into two groups:

Group 1) patients will receive losartan 100mg/day for 6 weeks (and no
atorvastatin), followed by the first set of MSNA measurements. Then,
atorvastatin 20mg/day will be prescribed (on top of losartan 100mg/day) for 6
weeks, followed by a second set of MSNA measurements.
Or:
Group 2) patients start with atorvastatin 20mg/day and losartan 100mg/day for 6
weeks, followed by the first set of MSNA measurements. Then, atorvastatin
20mg/day will be stopped for 6 weeks (losartan 100mg/day will be continued),
followed by a second set of MSNA measurements.

In both groups, blood samples will be drawn during this visit to test the
kidney function and PRA. The amount of blood sample needed is 6ml.

Group 1

Second visit group 1: this visit will take place six weeks after the first
visit.
During this visit the first MSNA measurement will be done. Blood pressure and
heart rate will be measured and blood samples will be drawn during this visit
to test the kidney function and PRA. The amount of blood sample needed is 6ml.
Then atorvastatin 20mg/day will be added on ARB.

Third visit group 1: This visit will be planned six weeks after the second
visit. During this visit the second MSNA measurement will be done. Blood
pressure and heart rate will be measured and blood samples will be drawn during
this visit to test the kidney function and PRA. The amount of blood sample
needed is 6ml. In addition, the possible side effects of the drug will
explicitly be asked (See CRF).

Group 2

Second visit group 2: this visit will take place six weeks after the first
visit. The first MSNA measurement will be done during this visit and the
possible side effects of the drug will explicitly be asked (See CRF). Blood
pressure and heart rate will be measured and blood samples will be drawn during
this visit to test the kidney function and PRA. The amount of blood sample
needed is 6ml. Patients will be ask to stop atorvastatin and continue other
medications including ARB.

Third visit group 2: this visit will take place six weeks later than the second
visit. The second MSNA measurement will be done during this visit. Blood
pressure and heart rate will be measured and blood samples will be drawn during
this visit to test the kidney function and PRA. The amount of blood sample
needed is 6ml.

In both groups: All medication, including phosphate binders, vitamin D
derivatives, erythropoietin etc will be continued during the whole study.
Importantly, also diuretics are continued throughout the study in order to
maintain normovolemia. Patients will be weighed before each MSNA measurement in
order to test the volume status.

Their regular ACE inhibitor or ARBs will be replaced by Losartan 100mg/day and
their regular statin will be replaced by atorvastatin 20mg/day. If all
inclusion criteria and no exclusion criteria are fulfilled, the patients will
be randomized into two groups:

Group 1) patients will receive losartan 100mg/day for 6 weeks (and no
atorvastatin), followed by the first set of MSNA measurements. Then,
atorvastatin 20mg/day will be prescribed (on top of losartan 100mg/day) for 6
weeks, followed by a second set of MSNA measurements.
Or:
Group 2) patients start with atorvastatin 20mg/day and losartan 100mg/day for 6
weeks, followed by the first set of MSNA measurements. Then, atorvastatin
20mg/day will be stopped for 6 weeks (losartan 100mg/day will be continued),
followed by a second set of MSNA measurements.

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.

De safety of atorvastatin 20mg/day is studied among 1035 patients. The
incidence of side effects was comparable to the placebo group.