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