SoFT - Sevelamer on FGF23 Trial - A clinical trial assessing the quantitative effect of phosphate binding therapy on FGF23.

CKD is associated with higher cardiovascular morbidity and mortality. The
mechanisms of vascular damage are not only explained by the traditional risk
factors. Hyperphosphatemia and deficiency of 1,25(OH)2D3 are independently
associated with mortality on dialysis patients(1). FGF-23 plays an important
role in the phosphate and vitamin D metabolism (2;3). FGF-23 levels are
increasing as early as stage 2-3, long before hyperphosphatemia is detectable
(4-7). Plasma FGF-23 continues to increase as CKD progresses (5;8). In
epidemiologic studies, increased levels of FGF-23 have been related with
progressive renal function loss in chronic kidney disease (9;10) and greater
risks of cardiovascular morbidity and mortality (8;11-13). An biological
mechanism linking high FGF-23 to cardiovascular risk is suggested in studies in
which elevated FGF-23 was associated with endothelial dysfunction (14;15),
total body atherosclerosis (16) and LVH (17-19). These small studies were not
able to prove whether FGF-23 directly contributes to an higher cardiovascular
risk or if FGF-23 rather represents an *innocent bystander* reflecting toxicity
of other factors. However, the studies of Faul et al. and Yilmaz et al. proved
that increased circulating FGF-23 in CKD induced LVH in mice and vascular
dysfunction in humans respectively (15;20;21). It*s still unknown that
improvements of circulating FGF-23 levels will translate into improved clinical
endpoints. Furthermore, there are no data that suggest a *dose-response
effects* between FGF-23 reduction and effects on intermediate or even clinical
endpoints. These important questions require placebo-controlled randomized
trials of FGF-23 reduction. Prior to executing such trials detailed knowledge
is required about dose-response effects of FGF-23 modulating interventions on
FGF-23 levels across different stages of CKD.

Some small studies suggest that FGF-23 can be reduced by dietary phosphate
restriction and/or phosphate binding therapy (22-24). However, data are still
inconsistent (24;25). In addition, data are lacking about the magnitude of
presumed sevelamer effects, the potency in different stages of CKD, and the
presence or absence of a dose-effect relationship. On top of that, as our data
(in press) showed that proteinuria is associated with FGF23 levels, it is
unknown how proteinuria interacts with FGF-23 lowering potency of
phosphate-binder therapy. Therefore, the present study is designed as a
relatively large scale clinical trial aiming to demonstrate the feasibility to
induce an effective, predictable and sustained decrease in FGF23 level in
patients with CKD stages II-IV, and stage I with proteinuria, without inducing
hypophosphatemia using a stepped treatment regimen aiming at restricting
phosphate uptake.

To demonstrate the feasibility to induce an effective, predictable and
sustained decrease in FGF23 level in CKD stage I-IV patients, without inducing
hypophosphatemia using a stepped treatment regimen aiming at restricting
phosphate uptake.

Prospective, single-center, clinical trial.

All patients will receive standard care, including blood pressure management
with use of RAAS inhibitors, sodium restriction and lipid lowering drugs as
indicated. At baseline al the patients will start on a phosphate-restricted
diet, aiming at a phosphate intake below 1000 mg/day. This will be supervised
by a dietician throughout the study protocol. At week 4 all patients start with
1600 mg sevelamercarbonate per day in divided doses, with four-weekly
increments of 1600 mg to 3200, 4800, 6400 and 8000 mg, as long as phosphate
does not drop below 0,7 mmol/l. In week 20 de highest dose sevelamer is reached
and will be sustained for 8 weeks and then in week 28 sevelamer en dietary
intervention will be stopped. In week 30 the protocol stops.

Nature and extent of the burden and risks associated with participation, and
potential benefits:
The burden and risks associated with participation in this study are:
* 11 visits to the University Medical Centers in order to take blood samples
and collect first morning spot urine.
* During the baseline visit and visit 9 extra blood will be drawn for
biobanking and for this visits and the last visit the subject has to collect
24-hours urine.
* The subject must attend a sodium- and phosphate restricted diet.
* The subject can experience side effects of sevelamer, for example nausea,
vomiting, abdominal pain and constipation or diarrhea.
* The doses sevelamer can induce hypophosphatemia.

There are no benefits in participating in this study.