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Beyond phosphate control: Pleiotropic effects of sevelamer
Ziad A. Massy
INSERM ERI-12, Amiens University hospital , University of Picardie - Jules Verne, Amiens, France
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Vanholder, Massy, al. Nephrol Dial Transplant 2005Vanholder, Massy, al. Nephrol Dial Transplant 2005
0
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Adapted from Massy Pediatr Nephrol 2005
Vascular and valvular Calcifications
All-cause and Cardiovascular
mortality
Uremic Toxins (e.g. Phosphate, Indoxyl Sulfate, Inflammation, and Oxidative Stress)
Bone disease
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Comparing phosphate binders –Efficacy
4.7
8.6
0
Weeks
Ca (TTG)1
Renagel® (TTG)1
Seru
m P
hosp
horu
s (m
g/dL
)
4 8 12 16 20 24 28 32 36 40 44 48 52
Lanthanum2
Ca (CARE)3
7.8
7.0
6.3
5.5
4.5
1. Chertow GM. Kidney Int 2002;62(1):245-252.2. Hutchison A. 2003 World Congress of Nephrology; Berlin, Germany.3. Qunbi W et al. Kidney Int 2004;65:1914-1926.
K/DOQI Limit
Adapted from references 1–3
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Nikolov et al. KI 2006
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Decrease in serum LDL-cholesterol by sevelamer depends on baseline values
LDL HDL TG
Per
cent
Cha
nge
-60
-40
-20
0
20
40
< 100 mg/dL 100-130 mg/dL 130-160 mg/dL > 160 mg/dL
Chertow et al Nephrol Dial Transplant 1999, 14: 2907-14
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Sevelamer – consistent effect on lipidsStudy Patient
sTreatment Duration Total
cholesterolLDL HDL Triglycerid
esChertow 1997
36 HD Sevelamer vs placebo
8 weeks - 10% + 5%
Bleyer 1999 84 HD Sevelamer vs calcium acetate
8 weeks,crossover
- 26% - 25% 0% - 7%
Chertow** 1999
192 HD Sevelamer 46 weeks - 30% + 18% 0%
Slatopolsky 1999
172 HD Sevelamer 8 weeks - 15% - 26% 0% 0%
Goldberg 1998
48 HD Sevelamer 8 weeks - 25% - 23% + 1% - 12%
Wilkes 1998 15 HD Sevelamer 8 weeks - 23% - 36% -35% LDL/HDL ratio
Sadek2003
42 HD Sevelamervs CaCO3
5 weeks -12% -18% 0% -6%
Chertow 2002
200 HD Sevelamer vs Ca Acetate or CaCO2
1 year -22% -36% -2% -7%
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AURORANEJM 2009
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AURORANEJM 2009
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Houslay Heart 2006
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Microinflammation, oxidative stress and Uremic toxins
Uremic Toxins
Inflammation
Oxidative stress
Dialysis
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Phan et al. Circulation 2005
Nitrotyrosine
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Microinflammation, oxidative stress and Uremic toxins
Uremic Toxins
Inflammation
Oxidative stress
Dialysis
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Barreto et al. Clin JASN 2009 Oct;4(10):1551-8
Serum indoxyl sulfate is associated with vascular disease and mortality in CKD patients
Normal control levels 0.113 +/- 0.06 mg/100ml
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Barreto et al. Clin JASN 2009 Oct;4(10):1551-8
Serum indoxyl sulfate is associated with vascular disease and mortality in CKD patients
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Barreto et al. Clin JASN 2009 Oct;4(10):1551-8
Serum indoxyl sulfate is associated with vascular disease and mortality in CKD patients
2,00
1,00
0,00
-1,00
-2,00
-3,00
Indo
xyl s
ulph
ate
(loga
rithm
ic tr
ansf
orm
ed)
14121086420
Aortic calcification - CT (%)
r2=0.051
p=0.010
A
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Adijiang et al. NDT 2008; 23:1892
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Barreto et al. Clin JASN 2009 Oct;4(10):1551-8
Serum indoxyl sulfate is associated with vascular disease and mortality in CKD patients
Days of Follow up0 200 400 600 800
IS 1st tertile 46 45 44 23 8
IS 2nd tertile 46 44 38 17 9
IS 3rd tertile 47 44 37 24 21
Kaplan-Meyer estimates of overall and CV mortality for patients as a function of tertiles for serum IS levels
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Brandenburg et al. NDT 2010
Effects of Sevelamer hydrochloride
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Brandenburg et al. NDT 2010
Effects of Sevelamer hydrochloride
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Garg Arthritis Rheum 2005
- Long-term effects of Sevelamer hydrochloride (TTG study) -
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Brandenburg et al. NDT 2010
Effects of Sevelamer hydrochloride
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FGF23, Bone and CKDLoss of Filtering Function: CKD (+) Phosphate Balance
FGF23
1,25-dihydroxyvitamin D
NPT2a
NPT2c (Pit-1)
Phosphaturia
Reduction in (+) Pi Balance
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Gutierrez OM et al, NEJM 2008; 359: 584-92
Independent association of high cFGF-23 with RR of mortality in 400 HD
patients(cFGF-23 level
quartiles)
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Koiwa et al. Ther Apher Dial 2005
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Microinflammation, oxidative stress and Uremic toxins
Uremic Toxins
Inflammation
Oxidative stress
Dialysis
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Caglar Clin JASN. 2007;3:61-68
Fetu
in-A
(g/l)
hsC
RP
(mg/
l)FM
D (%
)
Before NS After Before p<0.001 After
Ca-acetate Sevelamer
Before NS After
Before NS After
Before p<0.001 After
Before p<0.001 After
0.27 g/l 0.28 g/l 0.27 g/l 0.35 g/l
14 mg/l 14 mg/l 15 mg/l 10 mg/l
5.8 (%) 6.8 (%)6.0 (%)6.0 (%)
Fetu
in-A
(g/l)
hsC
RP
(mg/
l)FM
D (%
)
Before NS After Before p<0.001 After
Ca-acetate Sevelamer
Before NS After
Before NS After
Before p<0.001 After
Before p<0.001 After
0.27 g/l 0.28 g/l 0.27 g/l 0.35 g/l
14 mg/l 14 mg/l 15 mg/l 10 mg/l
5.8 (%) 6.8 (%)6.0 (%)6.0 (%)
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Brandenburg et al. NDT 2010
Effects of Sevelamer hydrochloride
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Sevelamer increases Fetuin A
Brandenburg KI 2009 76 Sup 114: S26-33
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Free oxygen radicals(O2)
Endogenouscauses
Exogenouscauses
• LPSEndotoxinDialysate
• Vascular accessGore-Tex
• Catheter• Dialysis membrane
NFκB
Gene activation
Nucleus
CRPVCAM-1, ICAM-1E-SelectionIL-6IL-1MCP-1, M-CSF
VirusHomocysteineLipoprotein(a)
Gingivitis
Cytokine
Ang-II
LPS‘Leaky gut’
AGEs
mLDL
Nikolov et al. KI 2006
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Endotoxins in CKD patients
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Endotoxins
Sun et al. KI 2009 76 Sup114 S20-5
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Endotoxins
Sun et al. KI 2009 76 Sup114 S20-5
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Endotoxins
Follow-up: 6 months; switch from CaCo3 to sevelamer
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Endotoxins
Follow-up: 6 months; switch from CaCo3 to sevelamer
Stinghen AE, Blood Purif 2010;29(4):352-356[
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Endotoxins
Sun et al. KI 2009 76 Sup114 S20-5
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Nikolov et al. KI 2006
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Metabolic acidosis
Inhibition of folic acid absorption (Prof Fukagawa
personal communication; TAD 2010 in press)
Possible down regulation of 25 OH D3 levels (Oliveira et
al. CJASN 2009)
Possible up regulation of p-cresol levels (Brandenburg
et al. NDT 2010)
Sevelamer Adverse Effects
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Oka et al. Ther Apher Dial 2007
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Nikolov et al. KI 2006
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Caglar Clin JASN. 2007;3:61-68
Fetu
in-A
(g/l)
hsC
RP
(mg/
l)FM
D (%
)
Before NS After Before p<0.001 After
Ca-acetate Sevelamer
Before NS After
Before NS After
Before p<0.001 After
Before p<0.001 After
0.27 g/l 0.28 g/l 0.27 g/l 0.35 g/l
14 mg/l 14 mg/l 15 mg/l 10 mg/l
5.8 (%) 6.8 (%)6.0 (%)6.0 (%)
Fetu
in-A
(g/l)
hsC
RP
(mg/
l)FM
D (%
)
Before NS After Before p<0.001 After
Ca-acetate Sevelamer
Before NS After
Before NS After
Before p<0.001 After
Before p<0.001 After
0.27 g/l 0.28 g/l 0.27 g/l 0.35 g/l
14 mg/l 14 mg/l 15 mg/l 10 mg/l
5.8 (%) 6.8 (%)6.0 (%)6.0 (%)
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DCOR StudyDCOR StudyAllAll--Cause MortalityCause Mortality
Time on Study (Years)
Cum
ulat
ive
Inci
denc
e of
All-
Cau
se M
orta
lity
CalciumSevelamer
1007 640 430 161 1033 656 449 195
No. at Risk
1 2 3 400
0.1
0.2
0.3
0.4
0.5
0.6
SevelamerCalciumSevelamCalciumSevelamCalcium
p = 0.30
Primary endpoint results inconclusive across entire
study population
Primary endpoint results inconclusive across entire
study population
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Time on Study (Years)
Cum
ulat
ive
Inci
denc
e of
All-
Cau
se M
orta
lity
No. at RiskCalciumSevelamer
556 366 245 98 585 381 253 99
0 1 2 3 40.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
SevelamerCalcium
DCOR StudyDCOR StudyAll-Cause Mortality in Patients ≥ 65 years
SevelamCalciumSevelamCalcium
Sevelamer therapy resulted in a statistically significant
reduction in the relative risk for all-cause mortality in
pre-specified subset[RR 0.78 (0.62-0.97)]
Sevelamer therapy resulted in a statistically significant
reduction in the relative risk for all-cause mortality in
pre-specified subset[RR 0.78 (0.62-0.97)]
↓ 22%p = 0.03
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13 deaths
Renagel in New Dialysis (RIND) Study Outcomes
P = 0.016
11 deaths
Months
0 6 12 18 24 30 36 42 48 54 60 66
Surv
ival
Dis
trib
utio
n Fu
nctio
n
0.00
0.25
0.50
0.75
1.00
No. at Risk
Sevelamer HClCalcium
Sevelamer HCl 60 57 57 51 47 25 4
Calcium 67 63 60 55 45 22 5
P = 0.016
Block GA, Raggi P, Bellasi A, Kooienga L, Spiegel DM. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int. 2007;71(5):438-441.
Increased Mortality in Patients Randomized to Calcium vs Sevelamer HCl
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Nikolov et al. KI 2006
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Schepers et al. Blood Purif 2010
The Gut: The Forgotten Organ in Uremia
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Adapted from Massy Pediatr Nephrol 2005
Vascular and valvular Calcifications
All-cause and Cardiovascular
mortality
Uremic Toxins (e.g. Phosphate, Indoxyl Sulfate, Inflammation, and Oxidative Stress)
Bone disease
NEW STRATEGIES (Sevelamer or AST120)
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INSERM ER12 Team
Collaboration with Tilman B Drueke
Former and current Fellows: Igor Nikolov, Nobuhiko Joki, Olivier Phan, Ognen Ivanovski, Julien Maizel
EUTox group
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