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Effect van fosfaat verlaging op FGF23 en bloedvaten.
Effect of phosphate reduction on FGF23 and bloodvessel function.



- candidate number8179
- NTR NumberNTR2383
- ISRCTNISRCTN wordt niet meer aangevraagd.
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR23-jun-2010
- Secondary IDsNL31055.029.09 CCMO
- Public TitleEffect van fosfaat verlaging op FGF23 en bloedvaten.
Effect of phosphate reduction on FGF23 and bloodvessel function.
- Scientific TitlePilot 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).
- ACRONYM
- hypothesisOver 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
- Healt Condition(s) or Problem(s) studiedChronic renal failure, Sevelamer-carbonate
- Inclusion criteria1. Patients with eGFR 30-60 ml/min/1,73 m2;
2. Serum phosphorus level <1,49 mmol/L and >1,0 mmol/L;
3. Age >18 year;
4. Informed consent.
- Exclusion criteria1. Known allergy or intolerance for sevelamer-containing drugs;
2. Patients with heart failure;
3. Use of phosphate binder therapy;
4. Patients dependent on tube-feeding or those with malabsorption syndrome;
5. Rapidly deteriorating renal function;
6. Pregnant woman.
- mec approval receivedyes
- multicenter trialno
- randomisedno
- groupParallel
- TypeSingle arm
- Studytypeintervention
- planned startdate 23-jun-2010
- planned closingdate1-okt-2010
- Target number of participants20
- InterventionsPatients will be treated with sevelamer-carbonate (RenvelaŽ) 2,4 g before breakfast and diner for 8 weeks. Patients remain on their usual diet.
- Primary outcomeSerum FGF23 and phosphaturia before and after 8 weeks of treatment with sevelamer-carbonate.
- Secondary outcomePulse Wave Velocity measured before and after the treatment with Sevelamer.
- TimepointsTotal duration of the studie is 12 weeks.
Time points in weeks:
1. Time point -2: Measurement of PWV, baseline laboratory investigations of bloodsamples en urinesamples and x-ray lateral abdomen;
2. Time point 0: Measurement of PWV and laboratory investigations of blood- and urinesamples (patients acts as their own control in this way). Start of tratment 8 weeks with sevelamer -carbonate;
3. Time point 1: Measurement of serum phosphate;
4. Time point 8: Stop tratment wiht Sevelamer-carbonate. Measurement PWV and laboratory investigation of bloodsamples and urinesamples (after treatment);
5. Time point 10: Measurement PWV and laboratory investigation of bloodsamples and urinesamples (after wash-out).
- Trial web sitewww.ccmo.nl
- statusopen: patient inclusion
- CONTACT FOR PUBLIC QUERIES Annet Bouma-de Krijger
- CONTACT for SCIENTIFIC QUERIESProf. Dr. P.M. Wee, ter
- Sponsor/Initiator VU University Medical Center
- Funding
(Source(s) of Monetary or Material Support)
Genzyme Corporation, VU University Medical Center
- PublicationsN/A
- Brief summaryOver 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.
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, Fibroblast Growth Factor 23 (FGF-23) was identified as a novel and important hormone in phosphate metabolism. FGF-23 was identified as an independent risk factor for mortality.
We aim to further explore the role of FGF-23 in the cardiovascular morbidity of these patients. We hypothesize that targeting FGF-23 is a legitimate goal for treatment to reduce cardiovascular morbidity. In the current pilot we expect to demonstrate that it is possible to lower FGF-23 pharmacologically, using phosphate binders.
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 we want to evaluate vascular function bij measuring Pulse Wave Velocity.
- Main changes (audit trail)
- RECORD23-jun-2010 - 7-jul-2010


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