New Approaches To The Treatment Of Hyperphosphataemia (CRF)

New Approaches to the Treatment of Hyperphosphataemia Dr. Alastair J. Hutchison MBChB, FRCP, MD Manchester Institute of Nephrology & Transplantation, UK

Risk factors include; Cardiac Risk Dramatically Increased in HD Patients Foley RN, et al. Am J Kidney Dis. 1998;32:S112-S119 Hypertension Lipid abnormalities LVH Glucose intolerance Cardiovascular and valvular calcification 0.3% 9.2%

Block GA, et al. Am J Kidney Dis. 1998;31:607-617. Elevated Serum phosphate and Ca x Pi Increases Mortality Risk * P =0.03 ** P <0.0001 (N=6407)

Hyperphosphataemia The Silent Killer Amann K, Gross ML, London GM, Ritz E: Hyperphosphatemia - a silent killer of patients with uremia. NDT , 1999,14,2085-2087 .

Young et al. Kidney Int 2005;67:1179-1187

Mineral Metabolism, Mortality, and Morbidity in Maintenance Hemodialysis Study of Fresenius database from patients identified in 1997 Over 40,500 patients studied with long-term follow-up Found mortality associated with increased serum phosphate Also similar but less marked increase associated with serum Ca Hyperphos and hyperPTH associated with hospitalisation for cardiac disease and bone fracture “ These results support the hypothesis that disorders of mineral metabolism contribute to the burden of CVS disease in the ESRD population” Block et al. J Am Soc Nephrol 2004;15:2208-18

<0.97 mmol >2.90 mmol Block et al. 2005

<2.20 mmol >2.75 mmol Block et al. 2005

433 patients starting ESRD therapy Followed prospectively for average 41 months Serum calcium and other parameters measured monthly The mean calcium levels were 9.4 +/- 0.7 mg/dl 23% of the patients had mean calcium levels < 8.8 mg/dl. Hypocalcemia, morbidity, and mortality in ESRD Foley R, Parfrey P, Harnet J, et al. Division of Nephrology, Memorial University, St. John's, Nfld, Canada. Am J Nephrol. 1996;16(5):386-93

After adjusting for numerous other variables, lower serum calcium was strongly associated with mortality (RR 2.10, p = 0.006 for a mean calcium level < 8.8 mg/dl). Association with mortality similar in; hemodialysis (RR 2.10, p = 0.006) and peritoneal dialysis patients (2.67, p = 0.034). Using similar covariate adjustment, lower serum calcium was associated with; de novo ischemic heart disease (RR 5.23, p < 0.001) recurrent ischemic heart disease (RR 2.46, p = 0.006) de novo cardiac failure (RR 2.64, p < 0.001) recurrent cardiac failure (RR 3.30, p < 0.001). Hypocalcemia, morbidity, and mortality in ESRD Foley et al. Am J Nephrol. 1996;16(5):386-93

“ If you’re not confused, you’re not paying attention” Tom Peters

Metastatic Calcification & Ossification Amorphous (CaMg) 3 (PO 4 ) 2 Soft tissue Heart Lungs Kidneys Hydroxyapatite Ca 10 (PO 4 ) 6 (OH) 2 Vascular Valvular Joints Ocular Calcium and phosphate are deposited in one of two forms;

Phosphate removal by dialysis – difficult! Phosphate is mostly found intracellularly Has a large sphere of hydration Cleared rapidly from serum in first 2 hours of HD Rebounds significantly at 3 - 4 hours post – HD Consequently slightly better clearance by PD Excellent clearance by daily home HD

Phosphate Control in ESRD Average daily intake of phosphorous = 1000mg Approximately 50% absorbed = 500mg Dialysis removes around 300mg Daily net positive balance = +200mg Therefore oral phosphate binder s needed to reduce phosphate absorption by at least 200mg

Osteodystrophy and Vascular Disease What can we manipulate? Serum phosphate – new non-calcaemic binders Serum calcium – new vitamin D analogues, dialysate Serum PTH – vitamin D analogues, calcimimetics

Phosphate Control in the 21 st Century; Problems of knowledge Phosphate metabolism - uptake, phosphatonins - mechanism of effect on PTH, bone, vascular tissue Persisting Bone Abnormalities - ‘normal turnover’ at elevated PTH - PTH assays - cytokines - adynamic bone lesion Oestrogens and Bone - osteoporosis and oestrogen analogues Genetics and bone disease - genetic polymorphisms and bone mass, receptors, susceptibility to PTH stimulation - genetic factors in calcification

Phosphate Control in the 21 st Century; Problems of treatment Better phosphate control - main problem is complex Pi kinetics - under-dialysis (cf long slow dialysis) - most of current Pi binders are unsatisfactory Relative inefficacy of active Vitamin D - nodular hyperplasia - hyperphosphataemia - calcimimetics

Renal Osteodystrophy - Guidelines K-DOQI Guidelines.mht GB Renal Association Guidelines EDTA Guidelines

Sponsors of the k/DOQI Bone & Mineral Guidelines Paricalcitol Cinacalcet Renagel

USA k/DOQI Guidelines 2004 Serum phosphate 1.13 – 1.78 mmol/L (3.5 – 5.5 mg/dL) Opinion Serum calcium Preferably lower end of normal Opinion (8.4 – 9.5 mg/dl, 2.10 – 2.37 mmol/L) Ca x PO4 product < 4.5 mmol 2 /L 2 (< 55mg 2 /dL 2 ) Evidence Target PTH level 150 – 300 pg/ml (16 – 33 pmol/L) Evidence Calcium dosage Less than 1500mg elemental calcium Opinion Is this good advice?

Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis Block et al. 2005;68:1815-1824 129 patients new to hemodialysis in Denver, Colorado Randomized to receive calcium containing phosphate binders or sevelamer Subjects underwent electron beam computed tomography scanning (EBCT) at entry into the study and again at 6, 12, and 18 months 109 underwent baseline + at least one additional assessment of coronary calcification

Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis At baseline: 37% of sevelamer treated and 31% of calcium treated patients had no evidence of coronary calcification No subject with a zero coronary artery calcium score (CACS) at baseline progressed to a CACS > 30 over 18 months Subjects with a CACS > 30 at baseline showed progressive increases in CACS in both treatment arms ( P < 0.05 for each time point in both groups) Subjects treated with calcium containing phosphate binders showed more rapid and more severe increases in CACS when compared with those receiving sevelamer hydrochloride ( P = 0.056 at 12 months, P = 0.01 at 18 months). Subjects with diabetes progressed more rapidly Block et al. 2005;68:1815-1824

Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis Block et al. 2005;68:1815-1824

Limitations of sevelamer Dosing and formulation Average prescribed dose is 4.8 g/day (6 x 800 mg tablets daily) Suboptimal phosphate-binding ability Optimum binding occurs at pH 7 which is not the pH at the absorption site May affect concomitant vitamin K, and D treatment High doses are associated with gastrointestinal problems Relatively high cost Around US$3000 per year Can we improve on sevelamer?

Characteristics of an Ideal Oral Phosphate Binder High affinity for binding phosphorous - low dose required Rapid phosphate binding Low solubility Low systemic absorption (preferably none) Non toxic Solid oral dose form Palatable - encourages compliance

Lanthanum A rare earth element Atomic number 57 Atomic weight 139 Valency 3, binds phosphate ionically Present in tap water (very low levels) Various salts bind phosphate avidly Lanthanum phosphate very insoluble Lanthanum carbonate least soluble salt

Lanthanum vs Calcium - 301: Design Weeks of treatment – 3 – 1 0 5 25 48 154 Enrolment Washout La treatment group 66% Titration phase Maintenance phase Open-label extension Optional extension phase Ca treatment group 34% Part 1 3 weeks Part 2 5 weeks Part 3 6 months Part 4 6 months Part 5 2 years Hutchison AJ. Nephron Clin Pract 2005;100:c8–19 N=767

Mean (± SD) serum phosphate levels Serum phosphate (mmol/L) Titration phase Dose-maintenance phase 3.1 2.6 2.1 1.6 1.1 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Hutchison AJ. Nephron Clin Pract 2005;100:c8–19 Time (weeks) La Ca

Hypercalcaemic events (>ULN) by Week 26 Hutchison AJ. Nephron Clin Pract 2005;100:c8–19 1 (0.4) 0 6 2 (0.8) 1 (0.2) 5 7 (2.7) 3 (0.6) 4 8 (3.1) 3 (0.6) 3 20 (7.8) 6 (1.2) 2 59 (23.0) 16 (3.1) 1 159 (62.1) 480 (94.3) 0 Ca ( n = 257) n (%) La ( n = 510) n (%) Hypercalcaemic episodes

Ca  P Product Reduction Hutchison AJ. Nephron Clin Pract 2005;100:c8–19 P = 0.961 P = 0.009 P = 0.061 1.0 1.2 1.4 1.6 1.8 2.0 End of titration (Week 5) Mid-maintenance (Week 17) End of maintenance (Week 25) Mean Ca x P reduction (mmol 2 /L 2 ) Study phase La Ca

98 patients, age 55 ± 14.3 yr, 59 males Recruited from dialysis centres in 12 countries. In 63 a histomorphometric analysis of baseline and follow-up bone biopsies was performed. C . SWAENEPOEL A . TORRES A . FERREIRA A. HUTCHISON M. DE BROE M. LAVILLE H-H . NEUMAYER W. SULOWICZ S. SULKOVA A. BALDUCCI G. COEN L. DJUKANOVIC M. POPOVIC S. PEJANOVIC A. SIKOLE G. SPASOVSKI Kidney Int 2003;85:s73-78 European One Year Paired Bone Biopsy Study

Categorisation of bone histology 2994 Kidney Int 2003;85:s73-78 Lanthanum Calcium

Long-term observational population Two year extension LAM-IV-301 LAM-IV-303 LAM-IV-307 LAM-IV-308 SDP405-309 N = 93 total 41 EU, 52 US 40 patients 1 patient 48 patients 4 patients Hutchison AJ & Pratt R. ASN 2005 Provides up to 6 years observation in a small number of patients….

Expected remaining lifetimes (years) of the general U.S. population & of dialysis & transplant patients ESRD patients, 2003 General US population, 2002 Transplant Dialysis 15.9 14.6 15.1 5.4 5.6 5.5 26.6 23.4 25.2 Overall 1.8 1.7 1.8 4.5 3.8 4.3 85+ 2.2 2.2 2.2 8.3 6.9 7.8 80 –84 7.7 6.2 6.7 2.7 2.6 2.6 11.1 9.3 10.4 75 –79 8.9 7.4 7.9 3.1 3.1 3.1 14.4 12.0 13.4 70 –74 10.6 9.1 9.6 3.7 3.6 3.7 18.0 15.2 16.8 65 –69 12.5 11.0 11.5 4.4 4.3 4.3 21.9 18.7 20.4 60 –64 14.7 13.2 13.8 5.0 5.0 5.0 26.0 22.5 24.4 55 –59 17.2 15.7 16.3 5.9 6.0 5.9 30.4 26.6 28.6 50 –54 19.8 18.5 19.0 6.7 7.0 6.8 34.9 30.8 33.0 45 –49 22.7 21.5 21.9 7.6 8.0 7.8 39.5 35.2 37.5 40 –44 25.8 24.8 25.2 8.7 9.2 9.0 44.2 39.8 42.1 35 –39 28.9 28.3 28.5 10.0 10.8 10.5 49.0 44.4 46.8 30 –34 Female Male All Female Male All Female Male All Age

Demographics 24 (25.8%) 0 24 (46.2%) Black 61 (65.6%) 40 (97.6%) 21 (40.4%) Caucasian 64 (68.8%) 28 (68.3%) 36 (69.2%) Male 1 (1.1%) 1 (2.4%) 0 Other 7 (7.5%) 0 7 (13.5%) Hispanic 29 (31.2%) 13 (31.7%) 16 (30.8%) Female 53.2  14.3 51.7  13.0 54.5  15.2 Mean Age Total N = 93 EU N = 41 US N = 52

Lanthanum Exposure by Total Daily Dose 17 (18.3%) 3 (3.2%) 5 (5.4%) 8 (8.6%) 1 (1.1%) ≥ 6 93 (100%) 25 (26.9%) 36 (38.7%) 27 (29.0%) 5 (5.4%) Total Total 3000 mg 2250 mg 1500 mg 750 mg Year 11 (11.8%) 6 (6.5%) 4 (4.3%) 1 (1.1%) 0 5 – <6 28 (30.1%) 5 (5.4%) 12 (12.9%) 8 (8.6%) 3 (3.2%) 4 – <5 22 (23.7%) 9 (9.7%) 8 (8.6%) 5 (5.4%) 0 3 – <4 15 (16.1%) 2 (2.2%) 7 (7.5%) 5 (5.4%) 1 (1.1%) 1 – <3

Serum Phosphate Levels Throughout Treatment With Lanthanum Carbonate

Serum PTH Levels Throughout Treatment With Lanthanum Carbonate kDOQI target

Liver enzymes – ALT/AST Levels (U/L)

Plasma Lanthanum Levels During Overall Lanthanum Exposure Mean  SD (ng/mL) Year 0.75  0.31 6 0.97  0.69 5 0.63  0.75 4 0.67  0.64 3 0.63  0.53 2 0.52  0.60 1 0.01  0.05 Baseline

Long-term Safety Data – ASN Nov 2005 93 patients on treatment for over 5 years 22 patients on treatment for over 6 years No safety concerns identified Phosphate and PTH stable Hutchison AJ & Pratt R. ASN 2005 Other avenues for continuing research?

Phosphate absorption blockade Nicotinamide inhibits intestinal Na-dependent phosphate cotransport Shown to reduce PO4 levels in 65 HD patients over 12 weeks Replaced calcium based binder No adverse effects reported HDL increased and LDL decreased Takahashi et al. Kidney Int 2004;65:1099-1104 Could be used as an adjunct to oral phosphate binders?

Phosphate absorption blockade Phosphatonins (e.g. Fibroblast Growth Factor 23) Polypeptide hormone linked to hypophosphataemic ricketts May reduce serum phosphorus by inhibiting uptake from food, and by inhibiting sodium-dependant phosphorus re-absorption Could be manipulated as an adjunct to phosphate binders?

Phosphonoformic acid Synthetic anti-viral drug – ‘Foscarnet’ CMV treatment Inhibits sodium-dependant phosphate transport Increased phosphate excretion in normal and uraemic rats Depends on residual renal function Brooks et al J Pharmacol Exp Thera 1997 Phosphate absorption blockade

New compounds in the management of renal osteodystrophy New vitamin D analogues - Oxacalcitriol ( 22 Oxa) - Doxercalciferol (1 alpha D2)) - Paricalcitol (19 Nor,1alpha 25 OH D2) New phosphate binders Sevelamer hydrochloride Lanthanum carbonate (Hutchison 2001) – EU product license granted! Iron dextran ( Hergesell , Ritz 1999) Phosphatonins (Potential use to reduce P ) (2002, 2003) Others ( Iron derivates, Mg salts, Zirconil. Phosphonoformic acid , etc) Calcimimetics Clear reduction in serum calcium Mild reduction in serum phosphate

Achieving K/DOQI bone metabolism & disease goals with cinacalcet Moe et al. KI 2005 Combined data from three 6 month placebo-controlled RCTs Retrospective “secondary analysis” 1136 dialysis patients from 182 centres in US, EU and Aus Examined achievement of targets for iPTH phosphate calcium calcium x phosphate product

56% vs 10% 65% vs 36% 46% vs 33% 49% vs 24%

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New Approaches To The Treatment Of Hyperphosphataemia (CRF)

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