New Approaches to the Treatment New Approaches to the Treatment of Hyperphosphataemia of Hyperphosphataemia Dr. Alastair J. Hutchison MBChB, FRCP, MD Dr. Alastair J. Hutchison MBChB, FRCP, MD Manchester Institute of Nephrology & Transplantation, UK Manchester Institute of Nephrology & Transplantation, UK
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New Approaches To The Treatment Of Hyperphosphataemia (CRF)
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New Approaches to the Treatment of New Approaches to the Treatment of HyperphosphataemiaHyperphosphataemia
Dr. Alastair J. Hutchison MBChB, FRCP, MDDr. Alastair J. Hutchison MBChB, FRCP, MDManchester Institute of Nephrology & Transplantation, UKManchester Institute of Nephrology & Transplantation, UK
Risk factors include;Risk factors include;
Foley RN, et al. Am J Kidney Dis. 1998;32:S112-S119
Cardiac Risk Dramatically Increased in HD Patients
• HypertensionHypertension• Lipid abnormalities Lipid abnormalities • LVHLVH• Glucose intolerance Glucose intolerance • Cardiovascular and Cardiovascular and
valvular calcificationvalvular calcification0%
2%
4%
6%
8%
10%
An
nu
al R
isk
of
CV
Dea
th
GeneralPopulation
HemodialysisPatients
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
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;67:1179-1187Young et al. Kidney Int 2005;67:1179-1187
Young et al. Kidney Int 2005;67:1179-1187Young et al. Kidney Int 2005;67:1179-1187
Mineral Metabolism, Mortality, and Mineral Metabolism, Mortality, and Morbidity in Maintenance HemodialysisMorbidity in Maintenance Hemodialysis
• Study of Fresenius database from patients identified in 1997Study of Fresenius database from patients identified in 1997• Over 40,500 patients studied with long-term follow-upOver 40,500 patients studied with long-term follow-up• Found mortality associated with increased serum phosphateFound mortality associated with increased serum phosphate• Also similar but less marked increase associated with serum CaAlso similar but less marked increase associated with serum Ca• Hyperphos and hyperPTH associated with hospitalisation for Hyperphos and hyperPTH associated with hospitalisation for
cardiac disease and bone fracturecardiac disease and bone fracture• ““These results support the hypothesis that disorders of mineral These results support the hypothesis that disorders of mineral
metabolism contribute to the burden of CVS disease in the metabolism contribute to the burden of CVS disease in the ESRD population”ESRD population”
Block et al. J Am Soc Nephrol 2004;15:2208-18Block et al. J Am Soc Nephrol 2004;15:2208-18
• Followed Followed prospectivelyprospectively for average 41 months for average 41 months
• Serum calcium and other parameters measured monthlySerum calcium and other parameters measured monthly
• The mean calcium levels were 9.4 +/- 0.7 mg/dlThe mean calcium levels were 9.4 +/- 0.7 mg/dl
• 23% of the patients had mean calcium levels < 8.8 mg/dl.23% of the patients had mean calcium levels < 8.8 mg/dl.
Hypocalcemia, morbidity, and mortality in ESRDHypocalcemia, morbidity, and mortality in ESRD
Foley R, Parfrey P, Harnet J, et al. Division of Nephrology, Memorial Foley R, Parfrey P, Harnet J, et al. Division of Nephrology, Memorial University, St. John's, Nfld, Canada.University, St. John's, Nfld, Canada.
Am J Nephrol. 1996;16(5):386-93Am J Nephrol. 1996;16(5):386-93
• After adjusting for numerous other variables, lower serum calcium After adjusting for numerous other variables, lower serum calcium was strongly associated with mortality (RR 2.10, p = 0.006 for a mean was strongly associated with mortality (RR 2.10, p = 0.006 for a mean calcium level < 8.8 mg/dl).calcium level < 8.8 mg/dl).
• Association with mortality similar in;Association with mortality similar in;hemodialysis (RR 2.10, p = 0.006)hemodialysis (RR 2.10, p = 0.006)and peritoneal dialysis patients (2.67, p = 0.034).and peritoneal dialysis patients (2.67, p = 0.034).
• Using similar covariate adjustment, lower serum calcium was Using similar covariate adjustment, lower serum calcium was associated with;associated with;
de novo ischemic heart disease (RR 5.23, p < 0.001)de novo ischemic heart disease (RR 5.23, p < 0.001)recurrent ischemic heart disease (RR 2.46, p = 0.006)recurrent ischemic heart disease (RR 2.46, p = 0.006)de novo cardiac failure (RR 2.64, p < 0.001)de novo cardiac failure (RR 2.64, p < 0.001)recurrent cardiac failure (RR 3.30, p < 0.001). recurrent cardiac failure (RR 3.30, p < 0.001).
Hypocalcemia, morbidity, and mortality in ESRDHypocalcemia, morbidity, and mortality in ESRD
Foley et al. Am J Nephrol. 1996;16(5):386-93Foley et al. Am J Nephrol. 1996;16(5):386-93
““If you’re not confused, you’re not paying attention”If you’re not confused, you’re not paying attention”
Calcium and phosphate are deposited in one of two forms;Calcium and phosphate are deposited in one of two forms;
Phosphate removal by dialysis – difficult!Phosphate removal by dialysis – difficult!
• Phosphate is mostly found intracellularlyPhosphate is mostly found intracellularly
• Has a large sphere of hydrationHas a large sphere of hydration
• Cleared rapidly from serum in first 2 hours of HDCleared rapidly from serum in first 2 hours of HD
• Rebounds significantly at 3 - 4 hours post – HDRebounds significantly at 3 - 4 hours post – HD
• Consequently slightly better clearance by PDConsequently slightly better clearance by PD
• Excellent clearance by daily home HDExcellent clearance by daily home HD
Average daily intake of phosphorous = 1000mg
Approximately 50% absorbed = 500mg
Dialysis removes around 300mg
Daily net positive balance = +200mg
Therefore oral phosphate binders needed to reducephosphate absorption by at least 200mg
Phosphate Control in ESRDPhosphate Control in ESRD
Osteodystrophy and Vascular DiseaseOsteodystrophy and Vascular Disease
What can we manipulate?What can we manipulate?
• Serum phosphate – new non-calcaemic bindersSerum phosphate – new non-calcaemic binders
• Serum calcium – new vitamin D analogues, dialysateSerum calcium – new vitamin D analogues, dialysate
• Serum PTH – vitamin D analogues, calcimimeticsSerum PTH – vitamin D analogues, calcimimetics
Phosphate Control in the 21Phosphate Control in the 21stst Century; Century;Problems of knowledgeProblems of knowledge
Phosphate metabolismPhosphate metabolism- uptake, phosphatonins- uptake, phosphatonins- mechanism of effect on PTH, bone, vascular tissue- mechanism of effect on PTH, bone, vascular tissue
Persisting Bone AbnormalitiesPersisting Bone Abnormalities- ‘normal turnover’ at elevated PTH - ‘normal turnover’ at elevated PTH - PTH assays- PTH assays- cytokines- cytokines- adynamic bone lesion- adynamic bone lesion
Oestrogens and BoneOestrogens and Bone- osteoporosis and oestrogen analogues- osteoporosis and oestrogen analogues
Genetics and bone diseaseGenetics and bone disease- genetic polymorphisms and bone mass, - genetic polymorphisms and bone mass,
receptors, susceptibility to PTH stimulation receptors, susceptibility to PTH stimulation- genetic factors in calcification- genetic factors in calcification
Phosphate Control in the 21Phosphate Control in the 21stst Century; Century;Problems of treatmentProblems of treatment
Better phosphate controlBetter phosphate control
- main problem is complex Pi kinetics- main problem is complex Pi kinetics
- under-dialysis (cf long slow dialysis)- under-dialysis (cf long slow dialysis)
- most of current Pi binders are unsatisfactory- most of current Pi binders are unsatisfactory
Relative inefficacy of active Vitamin DRelative inefficacy of active Vitamin D
Calcium dosageCalcium dosage Less than 1500mg elemental calciumLess than 1500mg elemental calcium OpinionOpinion
Is this good advice?Is this good advice?
• After adjusting for numerous other variables, lower serum calcium After adjusting for numerous other variables, lower serum calcium was strongly associated with mortality (RR 2.10, p = 0.006 for a mean was strongly associated with mortality (RR 2.10, p = 0.006 for a mean calcium level < 8.8 mg/dl).calcium level < 8.8 mg/dl).
• Association with mortality similar in;Association with mortality similar in;hemodialysis (RR 2.10, p = 0.006)hemodialysis (RR 2.10, p = 0.006)and peritoneal dialysis patients (2.67, p = 0.034).and peritoneal dialysis patients (2.67, p = 0.034).
• Using similar covariate adjustment, lower serum calcium was Using similar covariate adjustment, lower serum calcium was associated with;associated with;
de novo ischemic heart disease (RR 5.23, p < 0.001)de novo ischemic heart disease (RR 5.23, p < 0.001)recurrent ischemic heart disease (RR 2.46, p = 0.006)recurrent ischemic heart disease (RR 2.46, p = 0.006)de novo cardiac failure (RR 2.64, p < 0.001)de novo cardiac failure (RR 2.64, p < 0.001)recurrent cardiac failure (RR 3.30, p < 0.001). recurrent cardiac failure (RR 3.30, p < 0.001).
Hypocalcemia, morbidity, and mortality in ESRDHypocalcemia, morbidity, and mortality in ESRD
Foley et al. Am J Nephrol. 1996;16(5):386-93Foley et al. Am J Nephrol. 1996;16(5):386-93
Effects of sevelamer and calcium on coronary Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysisartery calcification in patients new to hemodialysis
Block et al. 2005;68:1815-1824Block et al. 2005;68:1815-1824
• 129 patients new to hemodialysis in Denver, Colorado129 patients new to hemodialysis in Denver, Colorado
• Randomized to receive calcium containing phosphate binders or sevelamerRandomized to receive calcium containing phosphate binders or sevelamer
• Subjects underwent electron beam computed tomography scanning (EBCT) Subjects underwent electron beam computed tomography scanning (EBCT)
at entry into the study at entry into the study
and again at 6, 12, and 18 monthsand 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 Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysiscalcification in patients new to hemodialysis
At baseline:At baseline:
• 37% of sevelamer treated and 31% of calcium treated patients had no evidence 37% of sevelamer treated and 31% of calcium treated patients had no evidence
of coronary calcificationof coronary calcification
• No subject with a zero coronary artery calcium score (CACS) at baseline No subject with a zero coronary artery calcium score (CACS) at baseline
progressed to a CACS progressed to a CACS >>30 over 18 months30 over 18 months
• Subjects with a CACS Subjects with a CACS > > 30 at baseline showed progressive increases in 30 at baseline showed progressive increases in
CACS in both treatment arms (CACS in both treatment arms (P < P < 0.05 for each time point in both groups)0.05 for each time point in both groups)
• Subjects treated with calcium containing phosphate binders showed more Subjects treated with calcium containing phosphate binders showed more
rapid and more severe increases in CACS when compared with those rapid and more severe increases in CACS when compared with those
receiving sevelamer hydrochloride (receiving sevelamer hydrochloride (P P = 0.056 at 12 months, = 0.056 at 12 months, P P = 0.01 at 18 = 0.01 at 18
months).months).
• Subjects with diabetes progressed more rapidlySubjects with diabetes progressed more rapidlyBlock et al. 2005;68:1815-1824Block et al. 2005;68:1815-1824
Effects of sevelamer and calcium on coronary artery Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysiscalcification in patients new to hemodialysis
Block et al. 2005;68:1815-1824Block et al. 2005;68:1815-1824
Limitations of sevelamerLimitations of sevelamer
Dosing and formulationDosing and formulation
Average prescribed dose is 4.8 g/day (6 x 800 mg tablets daily)Average prescribed dose is 4.8 g/day (6 x 800 mg tablets daily)
Hutchison AJ. Hutchison AJ. NephronNephron Clin PractClin Pract 2005;100:c8–19 2005;100:c8–19
Time (weeks)
La Ca
Hypercalcaemic events (>ULN) by Week 26
Hypercalcaemic Hypercalcaemic episodesepisodes
La (La (nn = 510) = 510)
nn (%) (%)
Ca (Ca (nn = 257) = 257)
nn (%) (%)
00 480 (94.3)480 (94.3) 159 (62.1)159 (62.1)
11 16 (3.1)16 (3.1) 59 (23.0)59 (23.0)
22 6 (1.2)6 (1.2) 20 (7.8)20 (7.8)
33 3 (0.6)3 (0.6) 8 (3.1)8 (3.1)
44 3 (0.6)3 (0.6) 7 (2.7)7 (2.7)
55 1 (0.2)1 (0.2) 2 (0.8)2 (0.8)
66 00 1 (0.4)1 (0.4)
Hutchison AJ. Hutchison AJ. NephronNephron Clin PractClin Pract 2005;100:c8–19 2005;100:c8–19
Ca Ca P Product Reduction P Product Reduction
Hutchison AJ. Hutchison AJ. NephronNephron Clin PractClin Pract 2005;100:c8–19 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)
Mea
n C
a x
P r
edu
ctio
n
(mm
ol2
/L2)
Study phase
La Ca
98 patients, age 5598 patients, age 55 ± ±14.314.3 yr, yr,
59 males59 males
Recruited from dialysis Recruited from dialysis
centrescentres in 12 countries. in 12 countries.
In 63 a histomorphometric In 63 a histomorphometric
analysis of baseline analysis of baseline andand
follow-up bone biopsies was follow-up bone biopsies was
performed.performed.
C. SWAENEPOEL
A. TORRES
A. FERREIRA
A. HUTCHISON
M. DE BROE
M. LAVILLE
H-H. NEUMAYER W. SULOWICZ
S. SULKOVA
A. BALDUCCIG. COEN
L. DJUKANOVICM. POPOVIC
S. PEJANOVIC
A. SIKOLEG. SPASOVSKI
Kidney Int 2003;85:s73-78Kidney Int 2003;85:s73-78
European One Year Paired Bone Biopsy StudyEuropean One Year Paired Bone Biopsy Study
Categorisation of bone histologyCategorisation of bone histology
2994
Lanthanum
n=33
Norm al
Adynam icbone
M ixed
Hyperpara-thyroidism
Baseline
Osteo-m alacia
Norm al
Adynam icbone
Hyperpara-thyroidism
One year
M ixed
Osteo-m alacia
Calcium
n=30
Norm al
Adynam icbone
M ixed
Hyperpara-thyroidism
Baseline
Osteo-m alacia
Norm al
Adynam icbone
Hyperpara-thyroidism
One year
M ixed
Osteo-m alacia
Kidney Int 2003;85:s73-78
Long-term observational populationLong-term observational populationTwo year extensionTwo 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 2005Hutchison AJ & Pratt R. ASN 2005
Provides up to 6 years observation in a small number of patients….Provides up to 6 years observation in a small number of patients….
Expected remaining lifetimes (years) of the general Expected remaining lifetimes (years) of the general U.S. population & of dialysis & transplant patientsU.S. population & of dialysis & transplant patients
General US population, General US population, 20022002
• Shown to reduce PO4 levels in 65 HD patients over 12 weeksShown to reduce PO4 levels in 65 HD patients over 12 weeks• Replaced calcium based binderReplaced calcium based binder• No adverse effects reportedNo adverse effects reported• HDL increased and LDL decreasedHDL increased and LDL decreased
Takahashi et al. Kidney Int Takahashi et al. Kidney Int 2004;65:1099-11042004;65:1099-1104
Could be used as an adjunct to oral phosphate binders?Could be used as an adjunct to oral phosphate binders?