1. Helical/Spiral CT

2. 2-4 slice 8-16 slice 16-32 slice 32-64 slice Helical/Spiral CT

3. Arterial Calcification on Plain X-Rays

4. Arterial Calcification Increases Mortality Risk ‡ Carotid artery, abdominal aorta, iliofemoral axis, and legs P<0.0001 for each increase in number of arteries calcified n=110 1 Follow-up (months) 0 0.25 0.5 0.75 020406080 Probability of survival 0 arteries ‡ calcified 1 artery calcified 2 arteries calcified 3 arteries calcified 4 arteries calcified 73% mortality in patients with 4 arterial sites calcified Blacher J, Guerin AP, Pannier B et al. Hypertension 2001;38:938-942

5. Other Types of Calcification Predict Risk in CKD-5 Wang A, JASN 2003

6. Valve Calcification Predicts All-Cause Mortality and Cardiovascular Mortality in Peritoneal Dialysis Patients Wang AYM et al. JASN 2003 P<0.0005  All-Cause Mortality  Cardiovascular Mortality

7. How Do these Methods Correlate?

8. Abdominal Aorta X-ray Score ROC characteristics for a + abdominal X-ray score predicting a CACS> 30 Sensitivity= 0.74 Specificity= 0.77 L1 L2 L3 L4 Bellasi A. et al, KI 2006

9. Impacting Outcome in CKD

10. Sevelamer attenuates the progression of coronary artery and aorta calcification in hemodialysis patients Chertow GM, Burke SK, Raggi P, and the Treat to Goal Working Group Kidney Int Vol 62; 2002

11. Treat-to-Goal Study Study Design BL EBCT Titrate dose: P=3.0-5.0 mg/dL Ca <10.5 mg/dL 26 wk EBCT Titrate dose: P=3.0-5.0 mg/dL Ca < 10 mg/dL PTH 150-300 pg/mL Vitamin D if PTH >300 pg/mL If P >5.5 mg/dL 2 weeks 12 weeks 40 weeks Calcium binder Extended treatmentWashout Extended treatmentSevelamerWashout 52 wk EBCT Chertow GM et al. Kidney Int 2002;62:245-252 Randomize

12. Treat-to-Goal Study Baseline Demographics Smoker Diabetes BMI (kg/m 2 ) Sex (% male) Time on dialysis (years) Age (years) 8% 33% 26 ± 5 66% 2.9 56 ± 16 Calcium 3% 32% 26 ± 5 64% 3.6 57 ± 14 Sevelamer Race (% white) 66% 71% Chertow GM et al. Kidney Int 2002;62:245-252

13. Mean serum phosphorus (mg/dL) Treatment (weeks) -3012345678910111216202428323640444852 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 Sevelamer (S): 6.5 g/day (~8 800 mg tablets) Calcium acetate (C): 4.6 g/day (~7 667 mg tablets) S=5.1 C=5.1 Treat-to-Goal Study Serum Phosphorus Chertow GM et al. Kidney Int 2002;62:245-252

14. Treat-to-Goal Study Serum Calcium Study (weeks) -203691216202428323640444852 10.5 10.0 9.5 9.0 8.5 S=9.50 C=9.70 S = 9.40 C = 9.30 Sevelamer Calcium Chertow GM et al. Kidney Int 2002;62:245-252 Mean serum calcium (mg/dL)

15. Serum Ca x P Product Study Week -203691216202428323640444852 Serum Calcium x Phosphorus Product (mmol 2 /L 2 ) 3.5 4.0 4.5 5.0 5.5 6.0 6.5 S=5.72 C=5.59 S=3.88 C=4.00 Calcium Sevelamer

16. Treat-to-Goal Study Coronary Artery and Aortic Calcification Calcium Sevelamer Coronary arteryAorta *Within treatment P<0.0001; between treatment groups P=0.02 Chertow GM et al. Kidney Int 2002;62:245-252 0 6 14* 25* 0 5 10 15 20 25 30 Week 26Week 52 Median % change 1 5 24* 28* 0 5 10 15 20 25 30 35 Week 26Week 52 Median % change

17. Between group: P=0.03 (coronary), P=0.01 (aorta) Sevelamer Calcium Median change (%) -7% 0 10 20 30 40 60 70 90 20% 83% 66% -10 -5 50 80 Coronary artery Aorta P=NS P<0.0001 Treat-to-Goal Study: 2-Year European Data Coronary Artery and Aortic Calcification Asmus HG et al. NDT 2005; 20:1653-1661

18. “RIND trial”

19. Objective The primary aims of this study were To assess the degree of coronary artery calcification in a cohort of patients new to hemodialysis, and To compare the impact of Sevelamer versus calcium containing phosphate binders on the development and progression of coronary artery calcification. Block G et al Kidney International, Vol68(4): 1815-1824 (2005)

20. Materials and methods Sevelamer Extended treatment RANDOMIZE w/in 90 days of HD 0 EBCT scan Titrate dose P <6.5 mg/dL Ca 2+ <10.2 mg/dL USUAL clinical practice Calcium binder Extended treatment 6 mo 12 mo 18 mo EBCT scans Titrate dose P <6.5 mg/dL Ca 2+ <10.2 mg/dL PTH 150-300 pg/mL Maintain dialysate Ca=2.5 mEq/L Renagel patients can receive Ca supplementation at night. Dialysate Ca concentration was maintained at 2.5 mEq/l (1.25 mmol/l) throughout the study period. Block G et al Kidney International, Vol68(4): 1815-1824 (2005)

21. Patients New to Dialysis and Established Patients Prevalence of Coronary Calcification in CKD *Russo D et al Am J Kidney Dis 2004;44:1024-1030 (CrCl =33 ml/min) **Spiegel D et al. Hemod Internat 2004: 8:265 *** Chertow GM et al. Kidney Int 2002;62:245-252 40%* 57%** 83%*** 0% 20% 40% 60% 80% 100% Russo et alRINDTTG

22. Results: medication P-binders use: –Of the 55 patients in the calcium arm, 38 received calcium carbonate only, 3 received calcium acetate only, and 14 received both medications during the 18-month study period. –The average dose of Sevelamer was 8 g/day (10 pills), and the average dose of calcium was 5.75 g of CaCO3 or 9.2 g of Ca- acetate Vitamin D use: slightly higher use in the Sevelamer group, but not statistically significant. Average doses were similar in both groups. Statins: There were no statistically significant differences in the use of statins between the two groups. Block G et al Kidney International, Vol68(4): 1815-1824 (2005)

23. Average Phosphorus Control by Binder Block, GA et al. Kidney Int 2005; 68:1815-1824 average dose 8 g/day average dose elemental Ca 2.3 g/day

24. Mean Serum Calcium Level by Binder 8.5 8.7 8.9 9.1 9.3 9.5 9.7 0123456789101112131415161718 Study month Serum calcium (alb.corrected) RenagelCalcium Block, GA et al. Kidney Int 2005; 68:1815-1824

25. Results: Coronary Calcification 0 20 40 60 80 100 120 140 SevelamerCa Salts Sevelamer Ca Salts P<0.002 Block G et al Kidney International, Vol68(4): 1815-1824 (2005) 11x greater increase

26. Results: Median Coronary Artery Calcium Score N=45 N=54 N=55 N=51 N=53 N=45 N=47 N=40 N=45 Block G et al Kidney International, Vol68(4): 1815-1824 (2005)

27. Median Change in Total Coronary Artery Calcium Score by Diabetic Status-RIND Diabetes Median Change in Total CACS No Diabetes PTH=293PTH=229 P=0.038 P=0.015 Galassi A et al NDT 2006

28. Russo D, Kid Int, Advance Online, 5 September 2007 Progression of coronary artery calcification in predialysis patients with CaCO3 or Sevelamer 800 P=0.001 P NS Initial Final 750 650 550 450 350 250 150 700 600 500 400 300 200 100 50 0 Controls (n=29) Sevelamer (n=27) Calcium carbonate (n=28) TCS Figure 2: Initial (white bars) and final (dark bars) absolute TCS in controls (n = 29) and in patients assigned to calcium carbonate (n = 28) and sevelamer (n =27). Numbers are mean and s.e.

29. Russo D, Kid Int, Advance Online, 5 September 2007 Annual progression of coronary artery calcification in predialysis patients Controls (n=29) Sevelamer (n=27) Calcium carbonate (n=28) TCS 0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 320 300 Figure 3: Annualized progression of TCS in controls (n = 29) and in patients assigned to calcium carbonate (n = 28) and sevelamer (n = 27). Numbers are mean and s.e.

30. RIND mortality

31. Baseline Coronary Artery Score Is a Strong Predictor of Mortality Days 03657301095146018252190 n=129 P=0.0035 Zero <400 >400 Block GA et al. KI 2007

32. Increased Mortality in Patients Randomized to Calcium vs Sevelamer 0 20 40 60 80 100 Percent Survival Days 03657301095146018252190 n=129 P=0.0214 Sevelamer Calcium Cox Proportional Hazard Regression Model Age Race Gender Diabetes Baseline CCS Calcium vs. Sevelamer p=0.02 (HR 2.2) Block GA et al. KI 2007

33. The Dialysis Clinical Outcomes Revisited (DCOR) Trial Suki WN et al. Effects of Sevelamer and Calcium-Based Phosphate Binders on Mortality in Hemodialysis Patients Kidney Int 2007;online Aug 29th

34. Study Design Primary study endpoint –all-cause mortality Secondary study endpoints –cause-specific mortality (cardiovascular, infection, and other causes), and –all-cause hospitalizations Treatment interactions with each of the pre-defined prognostic factors were assessed: race, age (<65 or ≥65 years), sex, diabetes, primary cause of ESRD, and dialysis vintage –a statistically significant interaction was required as a gating step prior to strata-specific subset analysis

35. Patient Disposition *Did not discontinue from study prior to death or study cessation. In addition, 11 sevelamer patients and 18 calcium patients who discontinued early died during the 90-day follow-up period and were included in the mortality analyses (sevelamer, N=562; calcium, N=535). Randomized N = 2103 Sevelamer N = 1053 Calcium-based binder N = 1050 Terminated Early (N=533) Consent withdrawn (n=83) Investigator decision (n=151) Lost to follow-up (n=99) Adverse event (n=50) Renal transplant (n=46) Changed dialysis modality (n=26) Clinical site closure (n=19) Other (n=70) Completed study* N = 517 Terminated Early (N=502) Consent withdrawn (n=69) Investigator decision (n=94) Lost to follow-up (n=108) Adverse event (n=81) Renal transplant (n=59) Changed dialysis modality (n=22) Clinical site closure (n=22) Other (n=47) Completed study* N = 551

36. All-Cause Mortality Overall Study Population Time (Years) Cumulative Incidence of All-Cause Mortality Calcium Sevelamer 1050 640 430 161 1053 656 449 196 No. at Risk 12340 0.0 0.1 0.2 0.3 0.4 0.5 0.6 Sevelamer Calcium p = 0.40 HR = 0.93 (0.79 - 1.10) For patients on treatment for  2 years, a difference between groups appears to emerge (time-treatment interaction, p = 0.02)

37. All-Cause Mortality 01234 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 Time (Years) Cumulative Incidence of All-Cause Mortality p = 0.02 HR = 0.77 (0.61- 0.96) Patients  65 Years Time (Years) 12340 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 Sevelamer Calcium p = 0.21 HR = 1.18 (0.91- 1.53) Patients <65 Years Sevelamer Calcium Sevelamer 472 274 185 62 455 275 196 97 No. at Risk 578 366 245 99 598 381 253 99

38. A Comparison of Sevelamer and Calcium-Based Phosphate Binders on Hospitalization in Hemodialysis: Secondary Analysis of DCOR Using Claims Data SevelamerCalcium Unadjusted RR (referent: calcium) 0.90, P=0.03 Adjusted RR* (referent: calcium) 0.89, P=0.02 *Adjusted for demographic variables and prestudy cardiovascular comorbidity. St. Peter W, Liu J, Weinhandl E, et al. AJKD 2008;51:445-454

39. SevelamerCalcium Unadjusted RR (referent: calcium) 0.88, P=0.05 Adjusted RR* (referent: calcium) 0.88, P=0.03 *Adjusted for demographic variables and prestudy cardiovascular comorbidity. St. Peter W, Liu J, Weinhandl E, et al. AJKD 2008;51:445-454 A Comparison of Sevelamer and Calcium-Based Phosphate Binders on Hospitalization in Hemodialysis: Secondary Analysis of DCOR Using Claims Data

40. What happened to the BONE?

41. Treat-to-Goal Study Serum Intact Parathyroid Hormone Study (weeks) -201216202428323640444852 0 50 100 150 200 250 300 350 400 Sevelamer Calcium PTH below target S=30% C=57% P=0.001 Chertow GM et al. Kidney Int 2002;62:245-252 Median serum iPTH (pg/dL)

42. Time 01 & 2 Years f/u

43. Change in vertebral bone density -8 -6 -4 -2 0 2 4 6 Sevelamer Calcium salts Trabecular Cortical * * *P<0.05 % change (hounsfield units) 5% 2% -7% -2% Raggi P. J Bone Min Res 2005;20:764-772

44. Total Hip Bone Mass Predicts Survival in Patients with CKD Stage 5 Survival (d) 1400 1200 1000 800 600 400 200 0 0 Cumulative Survival 1.0 0.8 0.6 0.4 0.2 Normal Osteopenia (T-score -1.0 – 2.5 SD) Osteoporosis (T-score >-2.5 SD) N=88 P=0.03 N=88 P=0.03 Taal et al. Kidney Int. 2003;63: 1116-1120

45. Summary CVC is highly prevalent in CKD 5 CVC is linked with a poor prognosis in CKD 5 Sevelamer stopped progression of CVC in maintenance HD pts (2002) Sevelamer inhibited progression of CVC in new hemodialysis pts (2005) Sevelamer inhibited progression of CVC in pre-dialysis pts (2007) Calcium salts were associated with reduced and sevelamer with increased vertebral trabecular bone density (2005) Renvela: New sevelamer “without” HCl and GI symptoms RIND: Sevelamer reduced mortality [HR: 2.2] (2007) DCOR: Pts >65 y/o treated w/ Sevelamer had fewer deaths, fewer hospitalizations, lower overall cost of care (2008)

46. Wash-out up to 6 weeks Sevelamer +/- Atorvastatin (N= 100 patients) Ca Acetate + Atorvastatin (N= 103 patients) EBCT BaselineEBCT Week 26 1:1 randomization  Discontinuation of:  all P-binders  Ca supplements  lipid-lowering agents  vit D analogues  Randomized if:  Serum P > 5.5 mg/dl  LDL-C > 80 mg/dl  Baseline EBCT score 30- 7000  P-binder: dose titration to achieve level of 3.5-5.5 mg/dl  PTH target 150-300 pg/ml  Dialysate Ca level maintained at 2.5 mEq/L throughout study period EBCT Week 52 CARE-2 Study Design Qunibi W, Moustafa M, Muenz LR, et al. AJKD. 2008

47. Chertow GM, Burke SK, Raggi P. Treat to Goal Working Group. Kidney Int. 2002;62:245-252. 0% 6% 14% 25% 0% 5% 10% 15% 20% 25% 30% 6 months12 months Median % Change in CAC SevelamerCalcium *Within treatment P<0.001 * * Qunibi W, Moustafa M, Muenz LR, et al. AJKD. 2008; Advance On Line n = sev 100 80 68 n = ca 103 71 58 *Significant within treatment 14% 30% 20% 29% 0% 5% 10% 15% 20% 25% 30% 35% 6 months12 months Median % Change in CAC SevelamerCalcium Acetate CARE 2 * * * * Treat to Goal Change in Coronary Artery Calcium Score

48. 100 150 200 250 300 350 400 450 500 550 0 306090 120150180210240270300330360 100 150 200 250 300 350 400 450 500 550 0306090120150180210240270300330360 1. Chertow GM et al. Kidney Int. 2002;62:245-252; 2. Qunibi W et al. Am J Kidney Dis. 2008; 51:952-965. Treat to GoalCARE-2 Log Mean iPTH (pg/mL) Study day PTH Levels in TTG and CARE-2 Sevel Calcium

49. Observed increase: 2.3%/y

50. Question 2 The administration of non-calcium-based phosphate binders results in slowing of cardiovascular calcification only in de novo dialysis patients 1. True 2. False

51. Question 2 The administration of non-calcium-based phosphate binders results in slowing of cardiovascular calcification only in de novo dialysis patients 1. True 2. False - CORRECT

52. Question 4 The multivariable adjusted mortality with sevelamer treatement in RIND was: 1. 3.1-fold higher than with calcium-based binders 2. 4.7-fold lower than with calcium-based binders 3. Not significantly different compared with calcium-based binders 4. 2.2-fold lower than calcium-based binders

53. Question 4 The multivariable adjusted mortality with sevelamer treatement in RIND was: 1. 3.1-fold higher than with calcium-based binders 2. 4.7-fold lower than with calcium-based binders 3. Not significantly different compared with calcium-based binders 4. 2.2-fold lower than calcium-based binders - CORRECT

54. Question 5 In the DCOR study, the progression of vascular calcification among calcium salts and sevelamer-treated patients was the same 1. True 2. False

55. Question 5 In the DCOR study, the progression of vascular calcification among calcium salts-treated and sevelamer-treated patients was the same 1. True 2. False - CORRECT

56. Question 6 In DCOR, the survival of patients above and below age 65 was a pre-specified end-point at the time of study design 1. True 2. False

57. Question 6 In DCOR, the survival of patients above and below age 65 was a pre-specified end-point at the time of study design 1. True - CORRECT 2. False

58. Question 7 At the conclusion of this meeting: 1. I know much more about the current issues regarding dialysis patients 2. I am EXTREMELY BORED with dialysis talks 3. I am going to the pharmacy IMMEDIATELY to buy Sevelamer for my own use! 4. I am going to leave my job and get a new one with Genzyme VenCAC 5. ……I want to be like RAGGI when I grow up!

59. Question 7 At the conclusion of this meeting: 1. I know much more about the current issues regarding dialysis patients 2. I am EXTREMELY BORED with dialysis talks 3. I am going to the pharmacy IMMEDIATELY to buy Sevelamer for my own use! 4. I am going to leave my job and get a new one with Genzyme VenCAC 5. ……I want to be like RAGGI when I grow up!

60. P Evenepoel, Kidney International (2007) 71, 376–379. The Pleiotrophic Activites of Sevelamer