Pilot study to investigate whether oral phosphorus binders can reduce FGF23 levels and can influence vascular function as measured by pulse wave velocity in patiens with chronic kidney disease stage 3 (eGFR 30-60 ml/min/1,73 m2).

Over the last decade it has become clear that patients with end-stage renal
disease and patients with chronic kidney disease have a severely enhanced risk
for cardiovascular morbidity and mortality. This elevated risk cannot be
explained completely by traditional factors like hypertension and
hyperlipidemia, well-known to be present in this patient population.

In the search for factors that might contribute to this enhanced
cardiovascular risk, the role of renal disease-induced abnormalities in
calcium-phosphorus metabolism have become apparent. Recently it was shown that
levels of serum phosphorus, calcium and parathormone (PTH) all have U-shape
relationships with survival in dialysis patients. In addition there is
demonstration that vascular calcification, especially of the coronary artery
system, is positively associated with cardiovascular mortality. Likewise in
patients with CKD, phosphorus level is associated with cardiovascular
outcome. Furthermore, in large observational studies the use of active vitamin
D, both in dialysis patients and in predialysis patients, correlates with
improved mortality rates.

Recently, Fibroblast Growth Factor 23 (FGF-23) was identified as a novel and
important hormone in phosphate metabolism. FGF-23 decreases phosphate
reabsorption in the kidney, due to by down regulation of the expression of
Sodium-Phosphate co-transporters in the proximal tubule. In addition, FGF-23
also inhibits 1α-hydroxylase expression, resulting in decreased synthesis of
1,25-dihydroxy vitamin D which could lead to decreased intestinal calcium
reabsorption and hypocalcemia, as well as impaired vitamin D-mediated
suppression of PTH, and possibly attenuate beneficial pleiotropic effects of
activation of the vitamin D recepter. On top of this, it was recently shown
that FGF-23 upregulates 24-hydroxylase, which catabolizes all vitamin D
metabolites, further inducing a vitamin D deficient state. Vitamin D deficiency
(both 25- and 1,25 hydroxylized cholecalciferol) is associated with
cardiovascular malfunction.

Recently, FGF-23 was identified as an independent risk factor for mortality in
a large hemodialysis cohort. Preliminary data demonstrated exactly the same in
predialysis patients with or without diabetes. We aim to further explore the
role of FGF-23 in the cardiovascular morbidity of these patients. Since there
is epidemiological evidence that FGF-23 level is independently associated with
clinical outcome, and because there is biological plausibility that FGF-23
actually modulates the natural history of cardiovascular disease of uremia, we
hypothesize that targeting FGF-23 is a legitimate goal for treatment. In the
current pilot proposal we expect to demonstrate that it is possible to lower
FGF-23 pharmacologically, using phosphate binders, as has been shown
convincingly in mice. This could pave the way to proceed with an interventional
trial, targeting FGF-23, aiming to improve cardiovascular endpoints.
As mentioned FGF-23 is independently associated with cardiovascular outcome.
This association remains after correction of phosphate and also remains if
patients use 1,25-dihydroxy vitamin D. (Gutierrez et al. NEJM 2008). The
mechanism in which FGF-23 influences cardiovascular status is not yet known.
Our hypotheses is that FGF-23 might have a direct influence on the vesselwall
since it is known that there is a FGF-23 receptor on the vessel wall. For this
reason, and for the reason that vascular function can be influenced over a
short time period (eg Kelly et al. Hypertension 2001), whe want to evaluate
vascular function bij measuring Pulse Wave Velocity

Aim of this study proposal
· To establish whether oral phosphorus binding is able to reduce FGF23 levels
in patients with CKD stage 3.
· To evaluate if a reduction of serum phosphate and FGF23 improves vascular
function as measured by pulse-wave-velocity (PWV)

Design
Pilot study in which 20 patients with CKD stage 3 (eGFR 30-60 ml/min/1,73 m2)
with high normal serum phosphorus levels will be treated with
sevelamer-carbonate (Renvela®) 2,4 g before breakfast and diner for 8 weeks.
Patients remain on their usual diet.

Laboratory investigations:
* Two weeks and immediately before, after 8 week sevelamer-carbonate treatment
as well as two weeks after stopping sevelamer-carbonate:
- in plasma: creatinine, urea, potassium, calcium, phosphate, c-term FGF23,
25OH vitamin D, 1,25 (OH)2-vitamin D, PTH
- in 24h urine collection: phosphaturia, calciuria, creatinine clearance,
total protein, urea.
* during the sevalamer-carbonate treatment after one week:
-serum phosphate

Pulse-wave-velocity:
-Two measurement in the the period of two weeks before starting the treatment
with Sevelamer. One measurement immediately after stopping the treatment with
sevelamer and again one after the two weeks wash out.
(this takes four times half an hour, maximum one hour. The measurement is an
painless procedure)

The use of once to twice daily the study medicine (powder for oral suspencion)
Renvela. Renvela is a phosphate binder. Phosphatebinders can cause intestinal
complaints such as nausea, vomiting, pain in the upper abdomen and
constipation. Further sometimes dyspepsia or diarrea. Very rare (< 0,01%) are
some cases of intestinal obstruction or ileus.

An X-ray of the abdomen to evaluate the possible existence of vascular
calcification. This burdens the patiënt with X-radiation. For one X-ray, the
radiation burden is 0,2 mSV. In comparison with the yearly burden of natural
sources, which is between 2 to 5 mSv, this is relatively low. For a low dose of
radiation, the incidence of mortality through cancer caused by radiaton is
estimated 0,04 to 0,07 per sievert (0,00004 to 0,00007 per milliSievert).