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5. Regulation of Plasma Calcium Adapted from E Nemeth. PT glands CaSR PTH bone PO 4 reabsorption Ca reabsorption kidney PT glands CaSR PO 4 resorption Ca resorption Low plasma Ca 2+ plasma Ca 2+ intestine 1,25-dihydroxy- vitamin D 3 PO 4 absorption Ca absorption

6. Liver Kidney Skin Pre-vitamin D Vitamin D 7-dehydrocholesterol 25-OH calcidiol 1  -hydroxylase 1,25 (OH) 2 D calcitriol most potent metabolite Low PO 4 Low Ca High PTH + - High PO 4 High Ca Low PTH Vitamin D Metabolism Diet Adapted from WG Goodman.

8. Acute and Chronic Regulation of PTH Output Ca 2+ /CaSR PO 4 weeks, months, years Tissue hyperplasia Vit D / VDR  VDRE Ca 2+  CaRE low Ca ( ↑ half-life) low PO 4 ( ↓ half-life) hours, days Gene expression Transcription mRNA stability Ca 2+ /CaSR minutes PTH secretion FACTORS TIME FRAME PROCESS

10. Phosphorus Homeostasis 1200 mg 500 mg 130 mg 700 mg (< 1%) (85%) (15%) Soft tissues Plasma Bone Kidney Intestine 700 mg Adapted from: Goodman WG. Med Clin North Am . 2005;89:631-647.

15. Pathophysiology of sHPT in CKD Adapted from Skorecki K, et al. Harrison’s Principles of Internal Medicine . 15th ed. 2001:1551-1562. ↓ 1,25(OH) 2 D 3 ↑ P ↑ PTH ↓ Ca 2+

16. Risk of Death by Quarterly Varying iPTH 1 1.5 2 0.9 All-Cause Death Hazard Ratio Serum iPTH (pg/mL) KDOQI recommended range: 150-300 pg/mL < 100 100-200 200-300 300-400 400-500 500-600 600-700  700 Time-dependent Case-Mix and MICS model Kalantar-Zadeh K, et al. Kidney Int. 2006;70:771-780.

17. Corrected Serum Calcium (mg/dL) < 8.0 8.0 to 8.5 8.5 to 9.0 9.0 to 9.5 9.5 to 10.0 10.0 to 10.5 10.5 to 11  11.0 0.7 2 3 1 All-Cause Death Hazard Ratio 8.0 to 0.7 2 3 1 0.7 2 3 1 0.7 1.5 2 3 1 Risk of Death by Quarterly Varying Albumin-Adjusted Calcium KDOQI recommended range 8.4-9.5 mg/dL Time-dependent Case-Mix and MICS model Kalantar-Zadeh K, et al. Kidney Int. 2006;70:771-780.

18. Risk of Death by Quarterly Varying Phosphorus Serum Phosphorus (mg/dL) 2 3 4 1 2 3 4 1 2 3 4 1 < 3.0 3.0 to 3.99 4.0 to 4.99 5.0 to 5.99 6.0 to 6.99 7.0 to 7.99 8.0 to 8.99  9.0 KDOQI recommended range: 3.5-5.5 mg/dL All-Cause Death Hazard Ratio Kalantar-Zadeh K, et al. Kidney Int. 2006;70:771-780. Time-dependent Case-Mix and MICS model 0.7 2 3 4 1

20. Forms of Vascular Calcification London GM et al. Curr Opin Nephrol Hypertens. 2005;14:525–531. Arterial Calcification Intimal Calcification Atherosclerosis Stenosis, occlusions Infarction, ischemia Medial Calcification Arteriosclerosis Stiffening Systolic and pulse pressures, early return of wave reflections Altered coronary perfusion, left-ventricular hypertrophy

22. Vascular Calcification in ESRD Intimal Calcification Atherosclerosis Medial Calcification Arteriosclerosis Available at: http://library.med.utah.edu/WebPath/CVHTML/CV007.html. Accessed May 2007.

23. Impact of Arterial Calcification in Stable Hemodialysis Patients with ESRD London GM, et al. Nephrol Dial Transplant. 2003;18:1731. Cardiovascular Survival  2 = 34.9; P < 0.0001 Time (months) NC P < 0.01 P < 0.001 AMC AIC  2 = 44.3; P < 0.00001 All-Cause Survival NC P < 0.001 P < 0.01 AMC AIC 0 25 50 75 100 0.00 0.75 0.50 0.25 1.00 0 25 50 75 100 0.00 0.75 0.50 0.25 1.00

24. Probability of Survival Decreases With Increasing Arterial Calcification 0 0.25 0.5 0.75 1 0 20 40 60 80 Follow-up (months) Probability of Survival 0 Arteries Calcified 1 Artery Calcified 2 Arteries Calcified 3 Arteries Calcified 4 Arteries Calcified N = 110 stable dialysis patients with ESRD P < 0.0001 comparison among groups Blacher J, et al. Hypertension . 2001;38:938-942.

25. Valvular Calcification and Mortality † P < 0.0005 vs no valvular calcification 0 0.2 0.4 0.6 0.8 1.0 0 6 12 18 24 30 36 Overall Survival Both Mitral and Aortic (n = 14) Either Mitral or Aortic (n = 48) Neither (n = 130) Follow-Up Time (months) † Wang A, et al. J Am Soc Nephrol. 2003;14:159-168.

26. CAC Is Associated With Increased Mortality Block GA, et al. Kidney Int . 2007;71:438-441. 0 6 12 18 CAC = 0 CAC1 – 400 CAC  400 24 0.00 0.25 0.50 0.75 1.00 30 36 42 48 54 60 66 P = 0.002 Months Survival Distribution Function

27. Calcification in Vascular Smooth Muscle Cells Osteo/Chondrocytic VSMC Death Signal VSMC Damage “Uremic Milieu” Apoptotic Bodies Matrix Vesicles + MGP / BMP7 + fetuin-A + PPi - MGP/ BMP2 - fetuin-A - PPi/+ALK + Ca/P Clearance Calcification Phagocytosis Delayed or Impaired Phagocytosis Elastin Shanahan CM. Curr Opin Nephrol Hypertens. 2005 ; 14:361–367.

29. KDOQI ™ Goals for Stage 5 CKD National Kidney Foundation. Am J Kidney Dis . 2002;39(Suppl 1):S1-S266. KDOQI guidelines recommend that Ca 2+ and P should be monitored monthly and PTH quarterly after stabilization. < 55 mg 2 /dL 2 Ca x P Product 3.5 – 5.5 mg/dL Serum P 8.4 – 9.5 mg/dL Serum Ca (albumin-corrected) 150 – 300 pg/mL Serum PTH

34. Therapeutic Interventions for Managing Secondary HPT Intervention Result Ca PO 4 PTH Phosphate Binders (Ca-based) Adapted from Goodman WG. Nephrol Dial Transplant. 2003;18(suppl 3):iii2-iii8.

35. Managing Mineral Balance: Phosphate Binders Sevelamer label: http://www.renagel.com/docs/renagel_pi.pdf Block GA, et al. Kidney Int. 2007;71(5):438-441. Serum Phosphate Sevelamer Calcium Mortality Phosphorus Change Study Week 0 2 6 10 14 18 22 26 30 34 38 42 46 52 -5 -4 -3 -2 -1 0 1 2 1.00 0.75 0.50 0.25 0.00 0 6 12 18 24 30 36 42 48 54 60 66 P = 0.016 Survival Fraction Sevelamer Calcium Months

37. Phosphate Binders: Summary Cannata-Andia JB. Dial Trans . 2002;17(Suppl 11):16–19; Ritz EJ. J Nephrol. 2005;18;221-228. Goodman WG. Neph Dial Trans. 2003;18(Suppl 3):iii2-iii8; Block GA, et al. Kidney Int. 2007; 71(5):438-441. Hyper-Mg; no long term studies Potential to minimize Ca load Magnesium carbonate Cost; Taste fatigue; Unknown long term impact; Tolerability Good potency; Minimal absorption; Not Hyper-Ca; Low pill burden Lanthanum carbonate High pill burden (moderate potency); Cost; Tolerability Less vascular calcification than Ca-containing binders; lower mortality? Reduction of TC & LDL Sevelamer Hyper-Ca, calcification risk; High pill burden Effective; Widely used Calcium-containing Tissue accumulation; Bone disease, encephalopathy, anemia Effective Aluminum-containing Disadvantages Advantages Binder

39. Therapeutic Interventions for Managing Secondary HPT Intervention Result Ca PO 4 PTH Vitamin D analog Adapted from Goodman WG. Nephrol Dial Transplant. 2003;18(suppl 3):iii2-iii8.

40. Vitamin D Repletion in Stage 3 & 4 with Ergocalciferol: KDOQI TM Recommendation National Kidney Foundation. Am J Kidney Dis. 2003;42(4 suppl 3):S1-S201. 50,000/mo 50,000/wk X 4 wks, then monthly 500,000 once 50,000/wk X 12 wks; then monthly Dose (IU) Assure pt adherence; assay 25(OH)D at 6 months im 6 po Insufficiency 16-30 Assay 25(OH)D after 6 months 6 po Mild deficiency 5-15 Assay 25(OH)D after 6 months 6 po Severe deficiency < 5 Comment Duration (months) Route Vitamin D Status Serum 25(OH)D (ng/mL)

41. Vitamin D Analogs Suppress PTH Sprague SM, et al. Kidney Int. 2003;63:1483-1490. Time (weeks) PTH (pg/mL) 0 100 200 300 400 500 600 700 800 900 1000 Paricalcitol (n = 130) Calcitriol (n = 133) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

42. Vitamin D Use Is Associated With Decreased Mortality in Incident HD Patients Vitamin D (n = 37,173) No Vitamin D (n = 13,864) Teng M, et al. J Am Soc Nephrol . 2005;16:1115-1125. *P < 0.001 8 15 CV Mortality * * 14 29 0 10 20 30 40 50 2-Year Mortality Mortality per 100 Patient-Years Infectious Cause Mortality 1 3 *

46. Therapeutic Interventions for Managing Secondary HPT Intervention Result Ca PO 4 PTH Calcimimetic Adapted from Goodman WG. Nephrol Dial Transplant. 2003;18(suppl 3):iii2-iii8.

47. Targeting PTH Secretion With Cinacalcet Control Serum PTH (% of maximum) 80 60 40 20 100 0 1.5 0 0.5 1.0 2.0 Extracellular Calcium (mM) Cinacalcet Cinacalcet Increases Calcium Sensitivity [Ca 2+ ] ER [Ca i 2+ ] CaSR PTH PTH PTH Cinacalcet Adapted from Goodman WG, et al. Kidney Int . 1996;50:1834-1844.

48. Cinacalcet is Associated with a Reduction of PTH Block GA, et al. New Engl J Med. 2004;350:1516-1525. P < 0.001 Placebo Cinacalcet Dose titration Efficacy assessment Week PTH level (pg/ml) 800 700 600 500 400 300 200 100 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 ~50% reduction

49. Cinacalcet Enables Patients to Achieve the KDOQI ™ Targets Adapted from Moe SM, et al. Kidney Int. 2005;67:760-771. Median iPTH (pg/mL) KDOQI ™ Target 0 100 200 300 400 500 600 700 Week Cinacalcet HCI Placebo n = 471 n = 663 n = 366 n = 473 B 2 4 6 8 12 14 16 18 20 22 24 26 10 iPTH Week n = 471 n = 663 n = 368 n = 471 B 2 4 6 8 12 14 16 18 20 22 24 26 10 Median Serum Ca (mg/dL) 8.2 8.4 8.8 9.0 9.2 9.6 9.8 10.2 8.6 9.4 10.0 KDOQI ™ Target Serum Calcium n = 410 n = 547 n = 412 n = 555 Week n = 471 n = 662 n = 363 n = 466 B 2 4 6 8 12 14 16 18 20 22 24 26 10 Median Ca x P (mg 2 /dL 2 ) 40 45 50 55 60 65 Ca x P KDOQI ™ Target n = 408 n = 545 n = 363 n = 466 Week n = 471 n = 663 B 2 4 6 8 12 14 16 18 20 22 24 26 10 4.6 4.8 5.0 5.2 5.4 5.6 5.8 6.0 6.2 6.4 Median Serum P (mg/dL) Serum Phosphorus KDOQI ™ Target n = 409 n = 547

50. Cinacalcet Reduction of iPTH for 3 Years Moe SM, et al. Nephrol Dial Transplant . 2005;20:2186-2193. Placebo n = 17 Cinacalcet n = 16

51. Cinacalcet Is Associated With Improved Outcomes Cunningham J, et al. Kidney Int . 2005;68:1793-1800. CV Hospitalization Fractures PTX Mortality Week Event-Free Probability 0 4 8 12 16 20 24 28 32 36 40 44 48 52 0.75 0.95 1.00 Standard - 4.1 events / 100 pt yrs Cinacalcet - 0.3 events / 100 pt yrs 0.90 0.85 0.80 Event-Free Probability Week 0 4 8 12 16 20 24 28 32 36 40 44 48 52 0.75 0.95 1.00 Standard - 6.9 events / 100 pt yrs Cinacalcet - 3.2 events / 100 pt yrs 0.90 0.85 0.80 P = 0.04 Week Event-Free Probability 0 4 8 12 16 20 24 28 32 36 40 44 48 52 0.75 0.95 1.00 Standard – 7.4 deaths / 100 pt yrs Cinacalcet – 5.2 deaths / 100 pt yrs 0.90 0.85 0.80 P = NS P = 0.009 P = 0.005 Week Event-Free Probability 0 4 8 12 16 20 24 28 32 36 40 44 48 52 0.75 0.95 1.00 Standard – 19.7 events / 100 pt yrs Cinacalcet – 15.0 events / 100 pt yrs 0.90 0.85 0.80

52. Therapeutic Interventions for Managing Secondary HPT Diet/nutrition, Phosphate Binders, Vitamin D Ca PO 4 PTH Diet/nutrition, Ca-based P-binders Vitamin D Calcimimetics, Vitamin D Adapted from Goodman WG. Nephrol Dial Transplant. 2003;18(suppl 3):iii2-iii8.