Kidney-Bone and Beyond: An Academic Career

Transcription

1 Kidney-Bone and Beyond: An Academic Career Isidro B. Salusky, M.D. Distinguished Professor of Pediatrics Chief, Division of Pediatric Nephrology Director, Clinical Translational Research Center Associate Dean of Clinical Research David Geffen School of Medicine at UCLA

2 Holick MF, Lancet 6:357, 2001

3 Normal Metabolic Pathway OH OH LIVER KIDNEY HO VITAMIN D 2 HO 25 (OH)D 2 HO 1,25 D 2 OH Active Vitamin D Hormone In Kidney Failure OH LIVER KIDNEY FAILURE No Active Vitamin D Hormone HO VITAMIN D 2 HO 25 (OH)D 2 With Hectorol (doxercalciferol) Therapy OH 1.25 D 2 Major Active Vitamin D Hormone HO OH LIVER HO HO HECTOROL OH 1.24 D 2 Minor Active Vitamin D Hormone HO OH

4 Reduced Kidney Function and SHPT Reduced Renal Mass Decreased Serum 1,25(OH) 2 D (Active Vitamin D Calcitriol) Increased Serum Phosphate Hypocalcemia Increased PTH Secretion Decreased Vitamin D Receptors Decreased Ca-Sensing Receptors Parathyroid Glands National Kidney Foundation. Am J Kidney Dis. 2003;42:S1-S201. Cheng S, et al. Ther Clin Risk Manag. 2006;2:

5 Alteration of Parathyroid Gland Function Progressive loss of kidney function 1 -Hydroxylase VDR Expression CaSR Expression Partial 1,25(OH) 2 D resistance Normal Diffuse Early Nodular Nodular Hyperplasia Adenomatous Hyperplasia Progression to Renal Failure Progressive loss of 1,25(OH) 2 D has a profound effect on the structure and function of the parathyroid glands Murayama A, Takeyama K, Kitanaka S, et al. Endocrinology. 1999;140(5): ; Fukagawa M, Yi H, Fukuda N, et al. Artif Organs. 1995;19(12): ; Satomura K, Seino Y, Yamaoka K, et al. Kidney Int. 1988; 34:

6 Spectrum of Renal Osteodystrophy Calcium, Vitamin D Low turnover PTH Vascular Calcification Process High turnover Adynamic Osteomalacia Normal bone formation Mild Osteitis fibrosa Al +3 Mixed lesion

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11 Therapeutic Options for the Treatment of Renal Osteodystrophy Phosphate Binders Sevelamer: Ca free Metal Free A Lanthanum Ca: Ca free - Metal + Oxacalcitrol - Japan Paracalcitol - USA Stage 5 Doxercalciferol - USA Stage 3-5 Cinacalcet Active Vitamin D Analogues Calcimimetic Drugs

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13 Change in Plasma Al levels During the Course of the Study

14 Change in Plasma Aluminum Levels after DFO

15 Extra-Skeletal Calcification in Chronic Renal Failure Courtesy of Kevin Martin, M.D.

16 Lumen Intimal Atherosclerotic Plaque

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18 Coronary Arteries with Vascular Calcifications

19 Process of Vascular Calcification (Giachelli et al 2004)

20 New Definition of ROD: CKD-MBD A systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following: Abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism Abnormalities in bone turnover, mineralization, volume, linear growth, or strength Vascular or other soft tissue calcification Moe et al Kidney International June 2006

21 Mean Coronary Artery Calcium Score* Risk of Cardiovascular Calcification Is Increased in Dialysis Patients Nondialysis, No CAD (n = 22) Nondialysis, CAD (n = 80) Dialysis (n = 49) Very high CV risk Age (years) *Determined by EBT. CAD = coronary artery disease; CV = cardiovascular. Rumberger JA, et al. Mayo Clin Proc. 1999;74: Braun J, et al. Am J Kidney Dis. 1996;27:

22 Calcification Score* Coronary Artery Calcification in Young Dialysis Patients N=39 Calcification scores doubled in patients with positive initial scan when rescanned at 20 months Age (years) *Determined by EBT. Goodman WG, et al. N Engl J Med. 2000;342:

23 Risk Factors Associated With Increased Risk for Cardiac Calcification in Young Dialysis Patients Coronary No Calcification Calcification Factor (n=14) (n=25) P Value Ca from 6456 ± ± calcium binders (mg/day)* Serum P (mg/dl) 6.9 ± ± Ca P product (mg 2 /dl 2 )* 65.0 ± ± Age (years) 26 ± 3 15 ± 5 <0.001 Mean duration of dialysis (years) 14 ± 5 4 ± 4 <0.001 * Modifiable. Serum calcium was not significant. Goodman WG, et al. N Engl J Med. 2000;342:

24 Coronary Artery Calcification by Presence of CKD and Diabetes: The Dallas Heart Study Population Total No CKD (n=2449) Stage 1-2 CKD (n =170) Stage 3-5 CKD (n = 41) Non-Diabetic No CKD (n = 2182) Stage 1-2 CKD (n = 108) Stage 3-5 CKD (n = 28) Diabetic No CKD (n = 267) Stage 1-2 CKD (n = 62) Stage 3-5 CKD (n = 13) CAC 10 CAC CAC CAC >400 Kramer et al. J Am Soc Nephrol. 2005;16: % 20% 40% 60% 80% 100%

25 C hange i n Scor e C hange i n Scor e Change in EBCT Scores in the Coronaries at 52 Weeks Medi an M e a n * 200 *p< *p< * Calcium ( n=70) Sevelamer ( n=62) Chertow et al. KI 62:245, 2002

26 C hange i n Scor e Changes in EBCT Scores in the Aorta at 52 Weeks C hange i n Scor e M e a n * 200 *p< *p< * M e d ia n Calcium ( n=70) Sevelamer ( n=62) Chertow et al. KI 62:245, 2002

27 Vascular Calcification in Patients With CKD Patients with Stage 5 CKD are at high risk for vascular calcification Vascular calcifications are present in almost 50% of patients with stage 4 CKD and new dialysis patients Vascular calcification can be quantified Vascular calcification is associated with modifiable risk factors Ca intake from calcium-based binders S-P, S-Ca and Ca P product Therapy with vitamin D Vascular calcification results in arterial stiffening and increased pulse pressure and adynamic bone disease Goodman WG, et al. N Engl J Med. 2000;342: Guérin AP, et al. Nephrol Dial Transplant. 2000;15: Ribeiro S, et al. Nephrol Dial Transplant. 1998;13: Raggi P, et al. J Am Coll Cardiol. 2002b;39:

28 Annual CVD mortality (%) Cardiovascular disease (CVD) mortality general population versus ESRD patients GP male GP female GP black GP white dialysis male dialysis female dialysis black dialysis white >85 Age (years) GP=general population Foley et al. Am J Kidney Dis. 1998;32:S112-S119

29 Charles Nolan, MD

30 Clinical Features of Childhood ROD Height < -2 SD 153 (61.9%) Clinical manifestations of bone disease 91 (36.8%) Deformities 63 (25.5%) Pathological fractures 33 (13.4%) Aseptic bone necrosis 32 (13.0%) Mild disabling bone disease 26 (10.5%) Severe disabling bone disease 18 (7.3%) Invalidating bone disease (all) 44 (17.8%) Groothoff JW KI 63 (2003)

31 Feedback Loops in SHPT Decreased Vitamin D Receptors and Ca-Sensing Receptors PTH PTH Bone Disease Fractures Bone pain Marrow fibrosis Erythropoietin resistance Serum P Ca ++ 1,25D Calcitriol 25D Systemic Toxicity CVD Hypertension Inflammation Calcification Immunological Renal Failure Ca = calcium; CVD = cardiovascular disease; P = phosphorus. Courtesy of Kevin Martin, MB, BCh.

32 Prevalence of Normal Corrected Calcium Levels > <20 (N=61) (N=117) (N=230) (N=396) (N=355) (N=358) (N=204) (N=93) (N=5) (N=20) (N=36) (N=393) (N=354) (N=357) (N=202) (N=96) Low (< 8.4 mg/dl) Normal ( mg/dl) High (>10.2 mg/dl) Levin et al KI(2007) 31-38

33 Prevalence of Normal Phosphorus Levels > <20 (N=61) (N=117) (N=230) (N=396) (N=355) (N=358) (N=204) (N=93) (N=5) (N=20) (N=37) (N=396) Low (< 2.7 mg/dl) Normal ( mg/dl) (N=355) (N=358) (N=204) High (> 4.6 mg/dl) (N=93) Levin et al KI(2007) 31-38

34 PTH Level Vitamin D Levels Mean Values of ipth, 1,25(OH) 2 D 3 and 25(OH) 2 D 3 by egfr * * > <20 N = 61 N=117 N=230 N=396 N=355 N=358 N=204 N=93 egfr Interval ipth 1,25 Vitamin D 25 (OH) Vitamin D N = 1814 *p< 0.001

35 FGF-23 and Rickets Hypophosphatemia Renal phosphate wasting Low (or inappropriately normal) 1,25D Normal serum Ca levels Increased FGF-23 values ADHR (Autosomal Dominant Hypophosphatemic rickets) TIO (Tumor Induced Osteomalacia) XLH (X-linked hypophosphatemia) ARHP (Autosomal Recessive Hypophosphatemia)

36 Phosphatonins/FGF23 Regulate Multiple Aspects of Mineral Metabolism Cause phosphaturia Inhibit 25-hydroxyvitamin D 1-hydroxylase activity Possible interfere with mineralization

37 Phosphatonins/FGF 23 in CRF FGF 23 is increased in CRF What role does it play in the pathogenesis of Renal osteodystrophy independent of PTH Altered vitamin D metabolism Vascular calcification

38 FGF-23 is Produced in Osteocytes and Regulates Phosphorus and Vitamin D Osteoblast Osteocyte Klotho DMP-1 FGF-23 PHEX 1,25(OH) 2 D Pi MEPE-ASARM Dietary animals + humans + CKD DCT PCT Pituitary Choroid

39 Bone-Kidney-Parathyroid Feedback Loop Ca 2+ FGF23 Klotho FGFR Vit D serum PTH FGFR Klotho 1,25(OH) 2 D synthesis phosphaturia 1,25(OH) 2 D synthesis phosphaturia Ben-Dov IZ, et al ASN & JCI 2007:117;4003

40 FGF-23 According to CKD Stage Mean: 436 Mean: 86.2 Gutierrez, et al JASN 2005

41 Serum Biochemical Parameters Across the Spectrum of CKD 11 8 S-Ca (mg/dl) S-Phos (mg/dl) PTH (pg/ml) CKD Stage * * C-term FGF-23 (RU/ml) CKD Stage * * * CKD Stage CKD Stage 4

42 Traditional Bone Histomorphometry BONE MARROW OC OB OCY OCY BONE OSTEOID

43 Connections between blood vessels and osteocyte-lacunocanaliculi Novel Regulators of Phosphate and Bone Metabolism MARKER Phex OF45/MEPE DMPI Sclerostin FGF23 EXPRESSION Early and late osteocytes Late osteoblast through osteocytes Early and mature osteocytes Late embedded osteocyte Early and mature osteocytes FUNCTION Phosphate metabolism Inhibitor of bone formation/regulator of phosphate metabolism Phosphate metabolism and mineralization Inhibitor of bone formation Induces hypophosphatemia Feng JQ. et al. Curr Opin.Nephrol.Hypertens. 18:285, 2009

44 Bone FGF-23 Expression (50x) Healthy Control CKD (Stage 2) Pereira RC et al Bone 2009 in press

45 Bone DMP1 Expression (200x) Healthy Control CKD (Stage 2) Pereira RC et al Bone 2009 in press

46 Bone FGF-23 and DMP1 Expression Across the Spectrum of CKD Bone FGF-23/B.Ar Bone FGF-23 Expression * * Control CKD 2-4 Dialysis Bone DMP1/B.Ar Bone DMP1 Expression * * Control CKD 2-4 Dialysis (Pereira R et al. ASN 2009) * p<0.05 from controls

47 Conclusions Osteocyte function is altered early in the course of CKD Increases in serum FGF-23 values may represent the first detectable biomarker of osteocytic changes

48 Analyte concentration Temporal aspects of disordered mineral metabolism in CKD cfgf-23 (RU/mL) 1,25D (pg/ml) PTH (pg/ml) P (mg/dl) >10, Increased 2. Gradually FGF-23 increasing is the earliest FGF-23 3.This alteration levels frees cause PTH in mineral from 4. All these changes early occur feedback decline metabolism in inhibition, 1,25D CKD levels leading long before increases in to SHPT serum P levels are evident Normal PTH range Normal P range Dialysis > >12 cfgf-23, C-terminal Fibroblast Growth Factor-23 GFR (ml/min/1.73 m 2 ) Wolf M. J Am Soc Nephrol 2010;21. [Epub ahead of print] Time post-transplant (months)

49 New Therapeutic Options for the Treatment of Renal Osteodystrophy Phosphate Binders Sevelamer: Ca free Metal Free A Lanthanum Ca: Ca free - Metal + Oxacalcitrol - Japan Paracalcitol - USA Stage 5 Doxercalciferol - USA Stage 3-5 Cinacalcet Active Vitamin D Analogues Calcimimetic Drugs

50 STUDY DESIGN Calcitriol + CaCO 3 1- D 2 + CaCO 3 Calcitriol + Sevelamer 1- D 2 + Sevelamer

51 Endpoints of the Study Primary Bone formation rate assessed by double tetracycline labeling Secondary S-Ca, PO 4, alkaline phosphatase, 1 st PTH-IMA Dose of vitamin D sterols Bone histological variables

52 PTH [1 st PTH-IMA] (pg/ml) Effects on Serum PTH Levels * 1-α (OH)D 2 + CaCO 3 1-α (OH)D 2 + Sevelamer 1,25 (OH) 2 D 3 + CaCO 3 1,25 (OH) 2 D 3 + Sevelamer * p < 0.01 from baseline Time (months) Wesseling K. et al KI 2010

53 Bone Formation Rate (um 2 /mm 2 /day) Effects of Therapy on Bone Turnover Initial Final * * * * α(oh)d α(oh)d 2 + 1,25(OH) 2 D 3 + CaCO 3 Sevelamer CaCO 3 1,25(OH) 2 D 3 + Sevelamer * p<0.001 Wesseling K. et al KI 2010

54 cfgf-23 Quartiles and Mortality in Dialysis Patients (Gutierrez et al. NEJM 2008)

55 FGF-23 and Moratlity in Long-term Hemodialyis Patients Jean G et al NDT 24:286, 2009

56 1 st PTH-IMA (pg/ml) C-terminal FGF-23 (% Baseline) Bone Formation Rate (um 2 /mm 2 /day) A Treatment Paradox? * * * * 1 α(oh)d 2 + CaCO 3 1 α(oh)d 2 + Sevelamer 1,25(OH) 2 D 3 + CaCO 3 1,25(OH) 2 D 3 + Sevelamer 1200 * * Time (months) Time (months)

57 Survival (%) Paricalcitol Associated with Improved Survival Compared to Calcitriol in Patients on Hemodialysis Paricalcitol Calcitriol P < Months Teng M, et al. N Engl J Med. 2003;349:

58 Survival Kaplan-Meier Survival Curves Vitamin D Calcitriol Doxercalciferol Paricalcitol Months on IV vitamin D

59 Pathophysiology of CKD-MBD GFR PO 4 Calcitriol FGF-23 Skeletal Resistance to PTH Ca 2 PTH Vascular Calcification Hyperparathyroid bone Disturbed mineralization

60 Collaborators UCLA Renata Pereira, Ph.D., Pediatrics Joel Hernandez M.D., Pediatrics Barbara Gales, R.N., Pediatrics Jonathan Goldin, M.D.,Ph.D., Radiology Robert Elashoff, Ph.D, Biomathematics Katherine Wesseling, M.D., Pediatrics Immutopics Jeffrey Lavigne Richard Zahranik Loma Linda Med. Ctr. Shobha Sahney, M.D. Mass. General Hospital Harald Jüppner, M.D. Support: NIDDK, NCRR

61 ES/BS (%) Response of Eroded Surface/Bone Surface to Therapy * * * p<0.05 from baseline αD 2 + 1αD ,25D ,25D CaCO 3 Sevelamer CaCO 3 Sevelamer Wesseling K. et al KI 2010

62 Vitamin D dose (μg) Vitamin D Dose During Therapy 12 1αD 2 + Sevelamer 1αD 2 + CaCO 3 calcitriol + Sevelamer calcitriol + CaCO 3 (yellow) 9 6 p< p< Time (months) Wesseling K. et al KI 2010

63 S-Calcium (mg/dl) Effects on Serum Calcium Levels α (OH)D 2 + CaCO 3 1-α (OH)D 2 + Sevelamer 1,25 (OH) 2 D 3 + CaCO 3 1,25 (OH) 2 D 3 + Sevelamer * p < 0.01 between and * p < 0.01 between and 9.5 * * Time (months) Wesseling K. et al KI 2010

64 Conclusions Combined therapy of sevelamer with 1α(OH)D 2 or 1,25 (OH) 2 D 3 controls the biochemical and skeletal features of 2 HPT without inducing changes in S-Ca. Sevelamer allows the use of higher doses of vitamin D 1α(OH)D 2 may have greater suppressive effect on osteoclastogenesis and indices of mineralization

65 Intact FGF-23 (% baseline) 1aD2 + Ca 1aD2 + ren 1,25 + Ca 1,25 + ren Time (month) Wesseling K. et al KI 2010

66 Paricalcitol vs No Paricalcitol Time-Dependent Covariates/All-Cause Mortality All patients Race Caucasian Black Asian Hispanic Diabetes mellitus Diabetic Non-diabetic Gender Female Male Age <65 years 65 years Vintage <6 months 6-24 months 2-5 years >5 years Serum albumin 3.8 g/dl >3.8 g/dl Protein intake 1.0 g/kg/day >1.0 g/kg/day Calcium <8.4 mg/dl mg/dl 9.5 mg/dl Phosphorus < 3.5 mg/dl mg/dl 5.5 mg/dl Cal*Phos Product <55 mg 2 /dl 2 55 mg 2 /dl 2 Alk. Phos. < 100 U/L 100 U/L PTH < 150 pg/ml pg/ml pg/ml 600 pg/ml Lee GH et al. J Ren Nutr. In press. 0.4 Paricalcitol improves survival Paricalcitol worsens survival All-Cause Death Hazard Ratio Unadjusted Adjusted

67 Prevalence of AVD (%) Atherosclerotic Vascular Disease Is Increased in Hemodialysis Patients With Increased Coronary Calcification N=205 83% of patients had evidence of coronary calcification >1000 Coronary Calcium Score* *Determined by EBT. AVD = atherosclerotic vascular disease. Raggi P, et al. J Am Coll Cardiol. 2002;39: ,

68 Prevalence of Vascular Calcification IN CKD-IV, Patients New to Dialysis and Established Patients 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 83% 57% 40% Russo et al RIND TTG Russo et al AJKD 2004 (CrCl =33 ml/min) Spiegel D et al. Hemod Internat 2004;8:265 Chertow et al KI 2002

69 Rate of Death From Any Cause* Rates of Death and Cardiovascular Events in Patients According to GFR < N = 1,120,295 adults. CV = cardiovascular. *Age-standardized rates per 100 person-years; CV event defined as hospitalization for coronary heart disease, heart failure, ischemic stroke, and peripheral arterial disease per 100 person-years. Go et al. N Engl J Med. 2004;351: Rate of CV Events egfr (ml/min/1.73 m 2 ) <15

70 Cardiovascular Disease Contributing Factors Hypertension Diabetes Anemia Inflammation Alterations in lipid metabolism Infrequent use of aspirin beta-adrenergic antagonists lipid lowering agents estrogen replacement Disturbances in mineral metabolism

71 Relative mortality risk (RR) Elevated serum phosphorus increases mortality risk ** * Serum phosphorus quintiles (mg/dl) * P=0.03 ** P< (n=6407) Adapted from Block GA, et al. Am J Kidney Dis. 1998;31:

72 Mineral Metabolism and Mortality in Patients Treated with Maintenance Hemodialysis N=40,538 N=40,538 Block et al JASN 15:2208, 2004

73 Mineral Metabolism and Mortality in Patients Treated with Maintenance Hemodialysis N=40,538 Block et al JASN 15:2208, 2004

74 Calcium amount(mg/mg) Protein Calcium Induces Calcification in HFSMC 250 Normal P / High Ca High P / High Ca High P / Normal Ca / / /2.8 (3.71/7.21) (3.71/9.64) (3.71/11.22) 2/1.8 (6.19/7.21) 2/2.0 2/2.2 2/2.4 (6.19/8.02) (6.19/8.82) (6.19/9.64) 1.6/ /1.8 (4.96/7.21) (7.43/7.21) mm (mg/dl) Phosphate/Ca treatment mm or (mg/dl) Yang et al K.I 66:2293, 2004.

75 Cardiovascular Disease in CKD Disorders of Ca-P Metabolism Abnormal Bone Turnover and Its Treatment Classic CV Risk Factors Nonatherosclerotic Arterial Disease Atherosclerosis HTN, TC, DM Family history, tobacco use Obesity Medial Calcification Intimal Calcification Abnormal Cardiac/ Vascular Physiology Vessel Occlusion Valvular and Visceral Calcification (+) CV Morbidity and Mortality Ca = calcium; P = phosphorus; VSMC = vascular smooth muscle cell; LDL = low-density lipoprotein. Adapted from Block et al. Semin Dial. 2003;16:

76 NKF-K/DOQI TM Guidelines for Treating Patients with ESRD

77 New Therapeutic Options for the Treatment of Renal Osteodystrophy Phosphate Binders Sevelamer: Ca free Metal Free Lanthanum Ca: Ca free - Metal + Oxacalcitrol - Japan Paracalcitol - USA Stage 5 Doxercalciferol - USA Stage 3-5 Cinacalcet Active Vitamin D Analogues Calcimimetic Drugs

78 Total Elemental Calcium Intake (average g/wk) Reducing Calcium Load With a Calcium-Free, Metal-Free Phosphate Binder *Calcium acetate g/wk Calcium Binder* Bleyer AJ, et al. Am J Kidney Dis. 1999;33: Hsu CH. Am J Kidney Dis. 1997;29: g/wk Calcium-Free, Metal-Free Binder Binder* (dose 5 g/day) Dialysate (2.5 meq/l) Diet (550 mg/day)

79 Ser um Phosphor us ( mmol / L) Time ( weeks) Sevelamer Calcium Chertow et al. KI 62:245, 2002

80 Serum Calcium Levels 2.6 Serum Calcium (mmol/l) R=2.34 C=2.33 R=2.36 C=2.43 Renagel Calcium Study Week

81 C hange i n Scor e C hange i n Scor e Change in EBCT Scores in the Coronaries at 52 Weeks Medi an M e a n * 200 *p< *p< * Calcium ( n=70) Sevelamer ( n=62) Chertow et al. KI 62:245, 2002

82 C hange i n Scor e Changes in EBCT Scores in the Aorta at 52 Weeks C hange i n Scor e M e a n * 200 *p< *p< * M e d ia n Calcium ( n=70) Sevelamer ( n=62) Chertow et al. KI 62:245, 2002

83 Elemental Calcium Intake (g/day) Calcium Intake and Calcification Score 2.5 N=120 P=0.001 (ANOVA) Calcification Score* *Determined by ultrasonography. Guérin AP, et al. Nephrol Dial Transplant. 2000;15:

84 Renagel In New Dialysis Maintain Dialysate Ca=2.5 meq/l USUAL Clinical Practice RANDOMISE w/in 90 days of HD Sevelamer CALCIUM BINDER Extended Treatment Extended Treatment Extended Treatment Block et al ASN 04 0 EBCT Scan Titrate Dose P 3.0 to 5.0 mg/dl Ca++ < 10 mg/dl 6 mo 12 mo 18 mo EBCT Scans Titrate Dose P 3.0 to 5.0 mg/dl Ca++ < 10 mg/dl PTH pg/ml

85 Calcium Score Progression Baseline vs 18 Months P=0.02 Sevelamer Ca Salts 0 Sevelamer Ca Salts RIND, ASN 2004

86 Clinical Implications of Vascular Calcification Coronary Arteries Correlated with Coronary Artery Disease and Atherosclerotic Plaque Burden Correlated with high ischemic heart disease rates in ESRD population Associated with Sudden Cardiac Death Promotes dissection following angioplasty Calcified, Atherosclerotic Coronary Artery from webpath

87 New Therapeutic Options for the Treatment of Renal Osteodystrophy Phosphate Binders Sevelamer: Ca free Metal Free Lanthanum Ca: Ca free - Metal + Oxacalcitrol - Japan Paracalcitol - USA Stage 5 Doxercalciferol - USA Stage 3-5 Cinacalcet Active Vitamin D Analogues Calcimimetic Drugs

88 Aim of the Study To determine whether the use of non-calcemic vitamin D sterol (doxercalciferol) and calciummetal free phosphate binder (Sevelamer) modify the skeletal response during the treatment of 2 o HPT

89 STUDY DESIGN Calcitriol + CaCO 3 1- D 2 + CaCO 3 Calcitriol + Sevelamer 1- D 2 + Sevelamer

90 Entry Criteria Secondary hyperparathyroidism documented by bone histomorphometry Undergoing treatment with peritoneal dialysis

91 End Points of the Study Primary: Bone formation rate assessed by double tetracycline labeling Secondary: S-Ca, S-PO 4, Ca x P, PTH, Alk.P Tase, dose of vitamin D, dose of binders and lipids

92 Therapeutic Targets Serum phosphorus < 6.0 mg/dl Serum calcium < 10.2 mg/dl Serum PTH pg/ml (1 st generation immunometric assay)

93 Vitamin D Dosage Oral Calcitriol: PTH < 600 pg/ml, 1,25-D 0.5 µ/dose 3 x/week PTH > 600 pg/ml, 1,25-D 1 µ/dose 3 x/week Oral 1- -D 2 : PTH < 600 pg/ml, 1- -D µ 3 x/week PTH > 600 pg/ml, 1- -D 2 5 µ/dose 3 x/week The dose of calcitriol or 1- -D 2 was adjusted every month according to S-Ca, P and PTH levels

94 Serum PO 4 Levels According to Type of Phosphate Binder Salusky et al. JASN in press

95 Skeletal Effects of Therapy with Vitamin D According to Type of Phosphate Binder (Salusky el. JASN in press)

96 Effects of Intermittent Calcitriol and CaCO 3 Therapy on Bone Formation Rate Salusky et al KI 54:907, 1998

97 Serum Ca levels According to Type of Phosphate Binder (Salusky et al. JASN in press)

98 Percent Change in S-Ca Levels During the Study (Salusky et al. JASN in press)

99 Serum PTH Levels According to Type of Phosphate Binder (Salusky et al. JASN in press)

100 Percent Change in S-PTH Levels During the Study Baseline PTH: pg/ml (sevelamer) and pg/ml (calcium) (Salusky et al. JASN in press)

101 CONCLUSIONS Therapy with CaCO 3 or sevelamer efficiently controlled serum phosphorus levels and the biochemical and skeletal manifestations of 2 o HPT when combined with active vitamin D sterols Sevelamer however, widened the safety margin of treating 2 o HPT with active vitamin D sterols by maintaining S-Ca levels within the lower end of the normal physiological range as recently recommended (K/DOQI)

102 Mineral Metabolism and Mortality in Patients Treated with Maintenance Hemodialysis N=40,538 Block et al JASN 15:2208, 2004

103 New Therapeutic Options for the Treatment of Renal Osteodystrophy Phosphate Binders Sevelamer: Ca free Metal Free Lanthanum Ca: Ca free - Metal + Oxacalcitrol - Japan Paracalcitol - USA Stage 5 Doxercalciferol - USA Stage 3-5 Cinacalcet Active Vitamin D Analogues Calcimimetic Drugs

104 Lanthanum Carbonate Mineral free Metal-based compound It has been shown to be an effective and safe phosphate binder when compared with placebo Lanthanum carbonate is associated with a significantly lower incidence of hypercalcemia than calcium-based phosphate binders Recently approved by FDA

105 Lanthanum Clinical Studies Treatment Baseline P Final P % of patients achieving target Dose Joy AJKD 43: (2003) n=94, 6 weeks of titration + 4 weeks of double-blind, placebo-controlled, maintenance phase Lanthanum 7.69 mg/dl 2.48 mmol/l 5.94 mg/dl 1.92 mmol/l 65% P<5.9 mg/dl <1.9mmol/l 71%: >2.25g/day of elemental La (3.75 g/day La 3 (CO 3 ) 3 )?? Placebo 7.39 mg/dl 2.4 mmol/l 7.85 mg/dl 2.53 mmol/l D Haese KI 63 (sup 85):s73-s78 (2003) n=30 in Ca and 33 in La. 1 year, bone biopsy study. Lanthanum 5.57 mg/dl 1.8 mmol/l 5.57 mg/dl 1.8 mmol/l N/A Median: 1.25 g of lanthanum/day CaCO mg/dl 1.6 mmol/l 4.34 mg/dl 1.4 mmol/l N/A Median: 2 g of calcium carbonate/day Hutchison NDT 19: (2004) n=59, 2 weeks of washout+ 4 weeks of open label titration Lanthanum 6.99 mg/dl 2.26 mmol/l 5.26 mg/dl 1.70 mmol/l 70% P<5.6 mg/dl <1.8mmol/l 56%: >1.50g/day of Lanthanum 37.3% g/d 18.6% g/d Hutchison WCN. Berlin 2003 N=805, 6 month, multicenter, randomized, active comparatorcontrolled, parallel-group trial Lanthanum 8.36 mg/dl 2.7 mmol/l 5.26 mg/dl 1.7 mmol/l 66% P<5.6mg/dl <1.8 mmol/l Median: 2.25 g/day CaCO mg/dl 2.7 mmol/l 5.26 mg/dl 1.7 mmol/l N/A Median: 3.00 g/day

106 Changes in Bone Histology According to Binder D Haese et al. KI 63:S-73, 2003

107 Changes in Bone Histology According to Binder (D Haese et al. KI 63:S-73, 2003)

108 Short-term studies: No al-like adverse effects with La Bone No negative short-term (1-year) effects in 2 controlled studies 1,2 : No increase in osteomalacia No increase in low bone turnover osteopathies Central nervous system No negative effects after 2 years 3 1. D Haese et al. Kidney Int 2003;63(suppl 85):S73-S78 2. Malluche HH, et al. Abstract F-PO945, ASN St. Louis, Altmann P, Finn WF. Abstract F-PO950, ASN St. Louis, 2004

109 La (ng/g wet weight) Effects of oral lanthanum carbonate vs. placebo on tissue La concentrations in control rats and CRF rats Liver La Placebo *** *** 365 *** Control Adenine Surgical Nx 2.7 Control. non-crf rats; adenine. adenine-induced CRF Surgical Nx. 5/6th nephrectomy-induced CRF Lacour et al KI in press

110 La (ng/g wet weight) Effects of oral lanthanum carbonate vs. placebo on tissue La concentrations in control rats and CRF rats Femur La Placebo *** 250 *** Control Adenine Surgical Nx Control. non-crf rats; adenine. adenine-induced CRF Surgical Nx. 5/6th nephrectomy-induced CRF Lacour et al KI in press

111 Liver Weight (g) Potential Concern of Liver Toxicity? /6 Nephrectomy 12% 21%* Observed decrease In liver weight Adenine Placebo Lanthanum *P<.05 (Lacour et al KI in press)

112 Lanthanum based Products-Absorption Uremic rats treated with lanthanum carbonate for 28 days had increased levels of lanthanum in: 65 Brain (167-fold increase) Liver (60-fold increase) Lung (20-fold increase) Bone lanthanum increased more than 4-fold in uremic rats after 12 weeks of treatment with lanthanum carbonate 63 Bone lanthanum increased an additional >50% after a 2- week washout period 63 In rats, lanthanum chloride has been shown to bind to chondroitin sulfate, a major component of cartilage 66

113 Lanthanum Carbonate and Long-term Safety Effective calcium-free phosphate binder The drug is well tolerated Available BBx data in dialysis pts treated for up to 4 yrs. indicate low level bone deposition (DeBroe et al. 2004) Animals studies demonstrated tissue aluminum accumulation

114 Lanthanum Carbonate FDA (Packet Insert) Studies in mice, rats and dogs, lanthanum concentrations in many tissues increased over time and were several orders of magnitude higher than plasma concentrations Relatively high levels of lanthanum remained in these tissues for longer than 6 months after cessation of dosing in dogs Lanthanum was deposited into developing bone including growth plate

115 Renal Osteodystrophy and Cardiovascular Disease Atherosclerosis Optimize Overall Patient Survival Vitamin D/PTH Axis Vascular Calcification Bone Health

116 Progression of CKD and Indices of Bone Metabolism Martinez I et al. NDT S-11 3:22-28, 1996, Walters et al, D&I, 31: 735, 2002

117 Median Percentage Change Median Percentage Change in Coronary And Aorta Scores at 104 Weeks 90 82%* 70 61%* % Cors Aorta Calcium -7%* Cors Aorta Sevelamer * Between treatment groups P< (Patients with a baseline score >30)

118 CALCIUM DIET 1,000 mg 300 mg ECF Ca mg FECES 825 mg 175 mg 125 mg 9,825 mg 900 mg 500 mg 10,000 mg URINE 175 mg

119 PHOSPHORUS DIET 1,400 mg 1,100 mg ECF Pi 350 mg FECES 500 mg 900 mg 200 mg 6,100 mg 550 mg 350 mg 7,000 mg URINE 900 mg

120 K/DOQI guidelines on bone and mineral metabolism Phosphorus is measured less frequently in CKD stages 3-4 CKD Stage GFR Range (ml/min/1.73 m 2 ) Measurement of PTH Measurement of Calcium/Phosphorus At least every Every 12 months 12 months At least every 3 months Every 3 months 5 <15 or dialysis At least every 3 months Every month K/DOQI Clinical Practice Guidelines on Bone Metabolism

121 Framingham Heart Study: Coronary Artery Calcification (CAC) increases as GFR declines

122 K/DOQI guidelines on bone and mineral metabolism Bone and Mineral Targets for CKD Phosphorus (mg/dl) Calcium (mg/dl) Intact PTH (pg/ml) CKD Stage 3 CKD Stage 4 CKD Stage Normal Normal ; Hypercalcemia > * *Evidence

123 Guideline 1. Evaluation of Calcium and Phosphorus Metabolism and Bone Disease (Continued) The target range of plasma levels of intact PTH in the various stages of CKD are: CKD Stage GFR Range (ml/min/1.73 m 2 ) Target intact PTH pg/ml (OPINION) pg/ml (OPINION) 5 <15 or dialysis pg/ml (EVIDENCE)

124 Bone Disease and Cardiovascular Risk Clinical Consequences Current Therapy Elevated PTH Current Therapy Renal Osteodystrophy Non-skeletal Effects Unintended Consequences Adynamic Bone Disease Growth Retardation osteitis fibrosa demineralization fractures bone pain bone deformities growth retardation Systemic and Arterial Effects Ca P O 4 Ca PO 4 Increased Mortality?

125 Deaths per 1000 patient (years) Cardiovascular disease is the most common cause of death in dialysis patients all cardiac cerebrovascular infection/ malignancy all others Age (years) USRDS Annual Data Report 2002

126 Prevalence of Vascular Calcification IN CKD- IV, Patients New to Dialysis and Established Patients 90% 83% 80% 70% 57% 60% 50% 40% 40% 30% 20% 10% 0% Russo et al RIND TTG Russo et al AJKD 2004 (CrCl =33 ml/min) Spiegel D et al. Hemod Internat 2004;8:265 Chertow et al KI 2002

127 Cardiovascular Disease Contributing Factors Hypertension Diabetes Anemia Inflammation Alterations in lipid metabolism Infrequent use of aspirin beta-adrenergic antagonists lipid lowering agents estrogen replacement Disturbances in mineral metabolism

128 Relative mortality risk (RR) Elevated Ca P Product Increases Mortality Risk * Ca P Product Quintile (mg 2 /dl 2 ) *P=0.01 (n=2669) Adapted from Block GA, et al. Am J Kidney Dis. 1998;31:

129 Elemental Calcium Intake (g/day) Calcium Intake and Calcification Score 2.5 N=120 P=0.001 (ANOVA) Calcification Score* *Determined by ultrasonography. Guérin AP, et al. Nephrol Dial Transplant. 2000;15:

130 Lanthanum Carbonate Mineral free Metal-based compound It has been shown to be an effective and safe phosphate binder when compared with placebo Lanthanum carbonate is associated with a significantly lower incidence of hypercalcemia than calcium-based phosphate binders Recently approved by FDA

131 La (ng/g wet weight) Effects of oral lanthanum carbonate vs. placebo on tissue La concentrations in control rats and CRF rats Liver La Placebo *** *** 365 *** Control Adenine Surgical Nx 2.7 Control. non-crf rats; adenine. adenine-induced CRF Surgical Nx. 5/6th nephrectomy-induced CRF Lacour et al KI in press

132 La (ng/g wet weight) Effects of oral lanthanum carbonate vs. placebo on tissue La concentrations in control rats and CRF rats Femur La Placebo *** 250 *** Control Adenine Surgical Nx Control. non-crf rats; adenine. adenine-induced CRF Surgical Nx. 5/6th nephrectomy-induced CRF Lacour et al KI in press

133 Lanthanum Carbonate FDA (Packet Insert) Studies in mice, rats and dogs, lanthanum concentrations in many tissues increased over time and were several orders of magnitude higher than plasma concentrations Relatively high levels of lanthanum remained in these tissues for longer than 6 months after cessation of dosing in dogs Lanthanum was deposited into developing bone including growth plate

134 Relative risk of death* Mineral metabolism, mortality, and morbidity in maintenance hemodialysis 2 N = 40,538 P = < >11.0 Adjusted Serum Calcium Concentration (mg/dl) *Multivariable Adjusted Block G, J Am Soc Nephrol 2004;15:

135 CV Survival Decreased CV Survival in Patients With Soft Tissue Calcification P<0.01 NC AMC 0.50 P< χ 2 = 34.9; P< AIC Femoral AMC Follow-Up (mo) CV = cardiovascular; NC = noncalcification; AMC = artery media calcification; AIC = artery intima calcification. London et al. Nephrol Dial Transplant. 2003;18: Femoral AIC

136 Medial Calcification in Patients on Dialysis Is Associated With Ca-Based P-Binders Variable Patients With No Calcification Patients With Medial Calcification P Value 1,25(OH) 2 D 3 dose (mg/d) NS PTH (pg/ml) NS CaCO 3 dose (g/d) Serum CRP (mg/l) Serum Ca P (mmol 2 /L 2 ) Serum PO 4 (mmol/l) Patients matched for duration of hemodialysis and exclusion of diabetes. NS = not significant; CRP = C-reactive protein. London et al. Nephrol Dial Transplant. 2003;18:

137 Phosphorus link to mortality in CKD Kestenbaum, JASN February 2005 Serum phosphate levels and mortality risk among persons with chronic kidney disease Study Overview: Retrospective VA data 6730 CKD subjects, 3490 eligible (phosphate measurement during previous 18 months) Primary endpoint all cause mortality Secondary endpoints acute MI, combined MI plus death

138 Phosphorus link to mortality in CKD N= 3,490 Mortality rates by phosphate category >5.0 Phosphorus (mg/dl) Mortality risk increased linearly with each subsequent 0.5 mg/dl increase in serum phosphate levels Kestenbaum et al.

139 Phosphorus management in CKD Possibly link to mortality? Correct management goal mg/dl? should patients be managed to low normal? any effect of phosphorus accumulation before it shows up in the serum? Will your management strategies change for this population?

140 Parfitt (1969) Arora (1975) Abnormalities in Mineral Metabolism and Vascular Calcifications Rostand (1988) Straumann (1992) Goldsmith (1997) Ribeiro (1998) - PO 4 & soft tissue calcifications - Ca x PO 4 in myocardial calcification - Ca x PO 4 correlated with myocardial Ca content & poor LVEF - S-Alk.P tase correlated with AS - 2 o HPT, PO 4, vitamin D level correlated with vascular calcification - Ca x PO 4 correlated with mitral valve calcification

141 Bone and mineral metabolism management CKD Stage 5

142 2003 CKD Stage 5 patients and expected growth Total WW population: 1.3 million (7-8% growth rate) (11% growth rate) (5-6% growth rate) North America Europe/Middle East/Africa Asia Pacific Latin America (5% growth rate) NOTE: Does not include transplanted patients (n= worldwide) 2003 Fresenius Annual Report

143 Deaths/100 patient years Mortality in dialysis patients Year of ESRD incidence

144 Relative risk Relative risk of cardiac mortality in chronic hemodialysis patients *** ** * RR=1.21 for all causes combined * n= year f/u CAD Sudden Other Cardiac CVA Infect. Other known Unknown Missing Cause of death *P<0.05; **P<0.005; *** P< Ganesh SK et al J Am Soc Nephrol 2001;12:

145 Mineral metabolism, mortality and morbidity in maintenance hemodialysis Phosphorus categories (mg/dl) Relative risk of death per 1 mg/dl increase of serum calcium P Block G. J Am Soc Nephrol 2004

146 Increase in RR of All-Cause & CV Hospitalization by Serum Phosphorus Percent Increase in RR All Cause CV >9.0 Serum Phosphorus Block G, J Am Soc Nephrol 2004;15:

147 Calcium amount(mg/mg) Protein Calcium Induces Calcification in HFSMC 250 Normal P / High Ca High P / High Ca High P / Normal Ca / / /2.8 (3.71/7.21) (3.71/9.64) (3.71/11.22) 2/1.8 (6.19/7.21) 2/2.0 2/2.2 2/2.4 (6.19/8.02) (6.19/8.82) (6.19/9.64) 1.6/ /1.8 (4.96/7.21) (7.43/7.21) mm (mg/dl) Phosphate/Ca treatment mm or (mg/dl) Yang et al K.I 66:2293, 2004.

148 Why are CKD patients at increased risk? Disorders of mineral metabolism (including abnormalities of calcium, phosphorus, vitamin D and parathyroid hormone) represent cardiovascular risk factors unique to patients with CKD 1 There is increasing evidence that disturbances of calcium and phosphate metabolism may play important roles in uraemic cardiovascular disease 2 A growing body of evidence suggests a major cause of increased morbidity and mortality is cardiovascular calcification 1 Block G, Port FK. Sem in Dial. 2003;16: Rostand SG, Drueke TB. Kidney Int. 1999;56;

149 Wolf, J Am Soc Nephrol 2010

150 Vascular Calcification in Patients With CKD Patients with Stage 5 CKD are at high risk for vascular calcification Vascular calcifications are present in almost 50% of patients with stage 4 CKD and new dialysis patients Vascular calcification can be quantified Vascular calcification is associated with modifiable risk factors Ca intake from calcium-based binders S-P, S-Ca and Ca P product Therapy with vitamin D Vascular calcification results in arterial stiffening and increased pulse pressure and adynamic bone disease Goodman WG, et al. N Engl J Med. 2000;342: Guérin AP, et al. Nephrol Dial Transplant. 2000;15: Ribeiro S, et al. Nephrol Dial Transplant. 1998;13: Raggi P, et al. J Am Coll Cardiol. 2002b;39:

151 Final

152 CVD in CKD patients What can be done? What do you see as traditional and non-traditional risk factors for patients? Do you see changes / improvements over time? How can we affect outcomes?

153 Disturbances in mineral and bone metabolism Disturbances in mineral and bone metabolism are common in patients with chronic kidney disease (CKD) These include hyperphosphatemia, hyperparathyroidsim, and vitamin D deficiency and exert important long term effects including increased morbidity and mortality In particular the negative consequences of cardiovascular calcification are now being recognized Significant improvements in care may be obtained by prevention and management of these disturbances National Kidney Foundation. Am J Kidney Dis. 2003;42(suppl 3):S1-S201 Collins AJ, et al. Am J Kidney Dis. 2001;38(suppl 1):S26-S29

154 Consequences of hyperphosphatemia Pi Ca ** PTH resistance Calcitriol calcitriol resistance PTH secretion Parathyroid cell growth Increased risk of bone disease Increased risk of bone disease

155 Consequences of hyperphosphatemia Pi Ca ** PTH resistance Calcitriol calcitriol resistance PTH secretion Parathyroid cell growth Increased risk of Uremic Calcification Increased Mortality

156 Death Hazard Ratio MICS Confounds Associations between Serum Phosphorus and Mortality in HD Patients 2-Year Mortality According to Serum Phosphorus in 57,069 MHD Patients ( ) Malnutrition-inflammation adjusted <3 3 to 4 4 to 5 5 to 6 6 to 7 7 to 8 8 to 9 >9 Seum Phosphorus Groups (mg/dl) 2-year (7/01-6/03) cohort of 57,069 MHD pts from virtually all DaVita facilities in the USA. Both the unadjusted and multivariate adjusted hazard ratios (and their 95% CI) for case-mix (gender, race, diabetes, vintage, Kt/V, standardized mortality ratio, incident quarter, marital status, and insurance, serum PTH, vitamin D dose) and for above covariates plus MICS (body mass index, npna, albumin, creatinine, TIBC, ferritin, WBC, lymphocyte, and hemoglobin) were calculated in 8 groups divided according to phosphorus and calcium levels (Phos: <3, 9 and 1 mg/dl increments inbetween; Ca: <8.0, 11.0 and 0.5 mg/dl increments in-between) Kuwae & Kalantar-Zadeh, ASN 2004

157 Aortic stiffness and mortality A) Probability of overall survival PWV < 9.4 m/s 9.4 PWV 12.0 m/s B) Probability of event-free survival PWV < 9.4 m/s 9.4 PWV 12.0 m/s PWV > 12.0 m/s Duration of follow-up (months) PWV > 12.0 m/s Duration of follow-up (months) N = 241 Blacher J. Circ. J 1999 (99)

158 Pulse wave reflection in young and old persons Young compliant arteries : Normal PW velocity (8 m/sec) Systole Diastole Calcified/Elderly stiff arteries: Increased PW velocity (12 m/sec) Systole Increases vascular afterload with a propensity to develop LVH Decreases coronary perfusion pressure Increases myocardial oxygen demand and subendocardial ischemia Increases endothelial dysfunction and atherogenesis Adapted from P. Klassen, MD, slide gift of Geoff Block

159 Probability of Survival Arterial Calcification Increases Mortality Risk 1 N=110 0 Arteries Calcified Artery Calcified 2 Arteries Calcified 3 Arteries Calcified 4 Arteries Calcified Follow-Up (months) *Determined by ultrasonography. Carotid artery, abdominal aorta, iliofemoral axis, and legs. P< for each increase in number of arteries calcified. Blacher J, et al. Hypertension. 2001;38(4):

160 Overall Survival Overall Survival Valvular Calcification Increases Mortality Risk in Peritoneal Dialysis Patients 1.0 N= Both Mitral and Aortic (n = 14) Either Mitral or Aortic (n = 48) 0 Neither (n = 130) Follow-Up Time (months) 0.6 With VC and AVD (n = 19) With VC Only (n = 43) With AVD Only (n = 24) No VC or AVD (n = 106) Follow-Up Time (months) *Determined by echocardiography. P< vs no VC. P=0.05 vs no VC or AVD. P< vs no VC or AVD. VC = valvular calcification; AVD = atherosclerotic vascular disease. Yee-Moon Wang A, et al. J Am Soc Nephrol. 2003;14:

161 Arterial Media Calcification in ESRD London GM, et al. Nephrol Dial Transplant. 2003;18:

162 Mortality According to Arterial Calcification London GM, et al. Nephrol Dial Transplant. 2003;18:

163 Medial Calcification in Patients on Dialysis Is Associated With Ca-Based P-Binders Variable Patients With No Calcification Patients With Medial Calcification P Value 1,25(OH) 2 D 3 dose (mg/d) NS PTH (pg/ml) NS CaCO 3 dose (g/d) Serum CRP (mg/l) Serum Ca P (mmol 2 /L 2 ) Serum PO 4 (mmol/l) Patients matched for duration of hemodialysis and exclusion of diabetes. NS = not significant; CRP = C-reactive protein. London et al. Nephrol Dial Transplant. 2003;18:

164 Methods for Detecting and Quantifying Vascular Calcification X-ray Fluoroscopy B-mode ultrasonography Intravascular ultrasound imaging Magnetic resonance imaging Transthoracic/transesophageal echocardiography Conventional, helical, or electron beam computed tomography Lanzer P. Z Kardiol. 1998;87: Maehara A, Fitzgerald PJ. Z Kardiol. 2000;89(suppl 2): Schmermund A, et al. Herz. 1996;21:

165 Reduced Kidney Function and SHPT Reduced Renal Mass Decreased Serum 1,25(OH) 2 D (Active Vitamin D Calcitriol) Increased Serum Phosphate Hypocalcemia Increased PTH Secretion Decreased Vitamin D Receptors Decreased Ca-Sensing Receptors Parathyroid Glands National Kidney Foundation. Am J Kidney Dis. 2003;42:S1-S201. Cheng S, et al. Ther Clin Risk Manag. 2006;2:

166 Multivariable cox proportional hazards model of 1-year mortality * Variable Increase Parameter Estimate (SD) Hazard Ratio (95% Cl) Wald x 2 P Value Pulse pressure by 10 mm Hg 0.12 (0.02) 1.12 ( ) Albumin by 1 g/dl -1.10(0.04) 0.33 ( ) Age 10 y 0.26 (0.01) 1.30 ( ) Weight by 5kg (0.01) 0.92 ( ) Diabetes mellitus (0.03) 1.42 ( ) Urea reduction ratio by 5% -0.10(0.03) 0.90 ( ) Ferritin by 100 mg/dl 0.02 (0.003) 1.02 ( ) Calcium by 1 mg/dl 0.16 (0.02) 1.16 ( ) Women (0.03) 0.80 ( ) Systolic bp by 10 mm Hg 0.14 (0.03) 0.87 ( ) Phosphorus by 1mg/dL (0.01) 1.08 ( ) Black race (0.03) 0.82 ( ) Years receiving dialysis by 2 y 0.04 (0.01) 1.04 ( ) Hematocrit by 3% (0.02) 0.93 ( ) Parathyroid hormone by 100 mg/dl 0.02 (0.01) 1.02 ( ) Intradialytic volume change by 5% 0.16 (0.01) 1.17 ( ) *Cl indicates confidence interval. To convert phosphorous from mg/dl to mmol/l by Klassen PS. JAMA. 2002

167 Multivariable cox proportional hazards model of 1-year mortality * Variable Increase Parameter Estimate (SD) Hazard Ratio (95% Cl) Wald x 2 P Value Pulse pressure by 10 mm Hg 0.12 (0.02) 1.12 ( ) Pulse pressure by 10 mm Hg 0.12 (0.02) 1.12 ( ) Albumin by 1 g/dl -1.10(0.04) 0.33 ( ) Age 10 y 0.26 (0.01) 1.30 ( ) Weight by 5kg (0.01) 0.92 ( ) Diabetes mellitus (0.03) 1.42 ( ) Calcium by 1 mg/dl 0.16 (0.02) 1.16 ( ) Urea reduction ratio by 5% -0.10(0.03) 0.90 ( ) Ferritin by 100 mg/dl 0.02 (0.003) 1.02 ( ) Calcium by 1 mg/dl 0.16 (0.02) 1.16 ( ) Women (0.03) 0.80 ( ) Systolic bp by 10 mm Hg 0.14 (0.03) 0.87 ( ) Phosphorus by 1mg/dL (0.01) 1.08 ( ) Black race (0.03) 0.82 ( ) Phosphorus by 1mg/dL (0.01) 1.08 ( ) Years receiving dialysis by 2 y 0.04 (0.01) 1.04 ( ) Hematocrit by 3% (0.02) 0.93 ( ) Parathyroid hormone by 100 mg/dl 0.02 (0.01) 1.02 ( ) Intradialytic volume change by 5% 0.16 (0.01) 1.17 ( ) *Cl indicates confidence interval. To convert phosphorous from mg/dl to mmol/l by Klassen PS. JAMA. 2002

168 Fraction of Patients New to Dialysis vs Established Patients With Vascular Calcification 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 57% 83% 63% 87% 44% 73% Coronary Aorta >90th % Spiegel D et al. Hemod Internat 2004;8:265 Chertow et al KI 2002 RIND TTG

169 Serum Calcium (corrected) Mean Serum Calcium Levels by Binder Mean Serum Calcium by Study Month Study Month Renagel Calcium Block et al., ASN 2004

170 Serum Phosphorus Serum Phosphorus Control by Binder Mean Serum Phosphorus by Study Month Study Month Renagel Calcium Block et al., ASN 2004

171 Mean and SD Values During Study Period Sevelamer Calcium Phosphorus 5.0 (1.5) 5.2 (.95) Corrected Calcium 8.7 (2.1) 9.6 (.55) *P<0.001 CaxP 45 (13.2) 50 (9.1) PTH 291 (173) 241 (141) LDL 68 (28) 83 (24) *P<0.003 Albumin CRP RIND, ASN 2004

172 Deaths per 1000 Patient-Years Cardiovascular Disease Is the Most Common Cause of Death in Dialysis Patients All cardiac Cerebrovascular Infection/malignancy All others Age (years) USRDS Annual Data Report

173 cfgf-23 Levels (RU/ml) cfgf-23 in Cases vs. Controls in Serum Phosphate Quartiles Cases Controls * * * < > 5.5 Serum phosphate quartiles (mg/dl) Gutierrez et al N Engl J Med 2008