The effectiveness of intensive treatment on sympathetic hyperactivity. A randomized, cross-over trial in patients with chronic kidney disease and hypertension

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 and need to be improved.

The primary objective is to investigate if there is an incremental inhibiting
effect on MSNA by increasing dosage valsartan above the presently advised
dosage.
We hypothesize that there will be a further decrease in MSNA as compared to the
MSNA during standard dosage valsartan.

This study is designed as a randomized cross-over trial. We prospectively
collect data on activity of MSNA at different stages of treatment by high
dosage of valsartan. It will be done in hypertensive CKD patients irrespective
of renal function as sympathetic activity is not related to kidney function.
However, patients on renal replacement therapy are excluded. Patients will be
recruited from our outpatient clinics.
At the first visit, patients who met inclusion criteria will be prescribed
160mg/day valsartan for 8 weeks. Other ACEi or ARB will be discontinued.
Diuretics are prescribed in order to maintain normovolumia. Furthermore, they
are on standard treatment, i.e. phosphate binders and vitamine D according to
guidelines. Thus the baseline dosage is 160mg/day of valsartan and the other
dosages applied in this study are 320mg/day and 640 mg/day. The first set of
measurements will be done while patients are on 160mg/day. Then patients will
be randomly allocated to receive either 640 mg/day valsartan or 320 mg/day
valsartan for the following 8 weeks. After 8 weeks the measurements will be
repeated and the groups will be switched to 320mg/day and 640mg/day
respectively. At the end the final set of measurements will be done (see study
protocol page 19 for the flowchart).
Other medication will not be changed during the entire study. In addition to
MSNA measurement, blood pressure, heart rate, PRA and other standard laboratory
tests will be done on each occasion.

Participants of this study receive 160mg/day valsartan for 8 weeks. After the
first 8 weeks the first MSNA measurement will be done. Then patients will be
randomized in group 320mg/day and group 640mg/day.
They will recieve 320mg/day or 640mg/day valsartan for 8 weeks. At the end of
this period the second MSNA measurement will be done by participants of both
groups.
Then the groups will be switched. The participants will receive 640mg/day or
320mg/day valsartan for 8 weeks. At the end the third 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.

Application of valsartan:
It has been shown that side effects induced by valsartan is relatively same as
placebo. Recent studies conducted on treatment of Valsartan 640mg/day showed
that dizziness and headache occur, relatively, more frequent in group treated
with valsartan 640mg/day (see protocol page 13). This is most likely rather an
*effect* than a *side effect*, since this is most likely explained by
(orthostatic) hypotension. Therefore, we will carefully monitor blood pressure.

The study of Weinberg (2004) indicated that dosages of 1.5 to 5 times higher
than presently maximum licensed dosage in CKD patients are safe. See protocol
"Summary of findings from non-clinical studies and clinical studies" page 11
for references.