Beyond phosphate control: Pleiotropic effects of sevelamer€¦ · LDL HDL TG Percent...
Transcript of Beyond phosphate control: Pleiotropic effects of sevelamer€¦ · LDL HDL TG Percent...
Beyond phosphate control: Pleiotropic effects of sevelamer
Ziad A. Massy
INSERM ERI-12, Amiens University hospital , University of Picardie - Jules Verne, Amiens, France
Vanholder, Massy, al. Nephrol Dial Transplant 2005Vanholder, Massy, al. Nephrol Dial Transplant 2005
0
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
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
Nikolov et al. KI 2006
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
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%
AURORANEJM 2009
AURORANEJM 2009
Houslay Heart 2006
Microinflammation, oxidative stress and Uremic toxins
Uremic Toxins
Inflammation
Oxidative stress
Dialysis
Phan et al. Circulation 2005
Nitrotyrosine
Microinflammation, oxidative stress and Uremic toxins
Uremic Toxins
Inflammation
Oxidative stress
Dialysis
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
Barreto et al. Clin JASN 2009 Oct;4(10):1551-8
Serum indoxyl sulfate is associated with vascular disease and mortality in CKD patients
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
Adijiang et al. NDT 2008; 23:1892
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
Brandenburg et al. NDT 2010
Effects of Sevelamer hydrochloride
Brandenburg et al. NDT 2010
Effects of Sevelamer hydrochloride
Garg Arthritis Rheum 2005
- Long-term effects of Sevelamer hydrochloride (TTG study) -
Brandenburg et al. NDT 2010
Effects of Sevelamer hydrochloride
FGF23, Bone and CKDLoss of Filtering Function: CKD (+) Phosphate Balance
FGF23
1,25-dihydroxyvitamin D
NPT2a
NPT2c (Pit-1)
Phosphaturia
Reduction in (+) Pi Balance
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)
Koiwa et al. Ther Apher Dial 2005
Microinflammation, oxidative stress and Uremic toxins
Uremic Toxins
Inflammation
Oxidative stress
Dialysis
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 (%)
Brandenburg et al. NDT 2010
Effects of Sevelamer hydrochloride
Sevelamer increases Fetuin A
Brandenburg KI 2009 76 Sup 114: S26-33
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
Endotoxins in CKD patients
Endotoxins
Sun et al. KI 2009 76 Sup114 S20-5
Endotoxins
Sun et al. KI 2009 76 Sup114 S20-5
Endotoxins
Follow-up: 6 months; switch from CaCo3 to sevelamer
Endotoxins
Follow-up: 6 months; switch from CaCo3 to sevelamer
Stinghen AE, Blood Purif 2010;29(4):352-356[
Endotoxins
Sun et al. KI 2009 76 Sup114 S20-5
Nikolov et al. KI 2006
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
Oka et al. Ther Apher Dial 2007
Nikolov et al. KI 2006
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 (%)
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
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
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
Nikolov et al. KI 2006
Schepers et al. Blood Purif 2010
The Gut: The Forgotten Organ in Uremia
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)
INSERM ER12 Team
Collaboration with Tilman B Drueke
Former and current Fellows: Igor Nikolov, Nobuhiko Joki, Olivier Phan, Ognen Ivanovski, Julien Maizel
EUTox group