New Approaches to the Treatment of Hyperphosphataemia

1
New Approaches to the Treatment of
Hyperphosphataemia
Dr. Alastair J. Hutchison MBChB, FRCP,
MD Manchester Institute of Nephrology
Transplantation, UK
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Cardiac Risk Dramatically Increased in HD Patients
9.2

• Risk factors include

• Hypertension
• Lipid abnormalities
• LVH
• Glucose intolerance
• Cardiovascular and valvular calcification

0.3
Foley RN, et al. Am J Kidney Dis.
199832S112-S119
3
Elevated Serum phosphate and Ca x Pi Increases
Mortality Risk

P0.03 Plt0.0001 (N6407)
Block GA, et al. Am J Kidney Dis.
199831607-617.
4
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.
5
Young et al. Kidney Int 2005671179-1187
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Young et al. Kidney Int 2005671179-1187
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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 2004152208-18
10
gt2.90 mmol
lt0.97 mmol
Block et al. 2005
11
gt2.75 mmol
lt2.20 mmol
Block et al. 2005
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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. 199616(5)386-93

• 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 lt
  8.8 mg/dl.

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Hypocalcemia, morbidity, and mortality in ESRD

• 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 lt 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 lt
  0.001) recurrent ischemic heart disease (RR
  2.46, p 0.006) de novo cardiac failure (RR
  2.64, p lt 0.001) recurrent cardiac failure (RR
  3.30, p lt 0.001).

Foley et al. Am J Nephrol. 199616(5)386-93
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If youre not confused, youre not paying
attention Tom Peters
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Metastatic Calcification Ossification
Calcium and phosphate are deposited in one of two
forms

• Amorphous
• (CaMg)3(PO4)2
• Soft tissue
• Heart
• Lungs
• Kidneys

• Hydroxyapatite
• Ca10(PO4)6(OH)2
• Vascular
• Valvular
• Joints
• Ocular

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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

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Phosphate Control in ESRD
Average daily intake of phosphorous 1000mg Appr
oximately 50 absorbed 500mg Dialysis
removes around 300mg Daily net positive
balance 200mg
Therefore oral phosphate binders needed to
reduce phosphate absorption by at least 200mg
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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

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Phosphate Control in the 21st CenturyProblems
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

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Phosphate Control in the 21st CenturyProblems
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

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Renal Osteodystrophy - Guidelines

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

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Sponsors of the k/DOQI Bone Mineral Guidelines
Paricalcitol
Cinacalcet
Renagel
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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 lt 4.5 mmol2/L2 (lt
55mg2/dL2) 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?
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Hypocalcemia, morbidity, and mortality in ESRD

• 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 lt 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 lt
  0.001) recurrent ischemic heart disease (RR
  2.46, p 0.006) de novo cardiac failure (RR
  2.64, p lt 0.001) recurrent cardiac failure (RR
  3.30, p lt 0.001).

Foley et al. Am J Nephrol. 199616(5)386-93
25
Effects of sevelamer and calcium on coronary
artery calcification in patients new to
hemodialysis

• 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

Block et al. 2005681815-1824
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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 gt30
  over 18 months
• Subjects with a CACS gt 30 at baseline showed
  progressive increases in CACS in both treatment
  arms (P lt 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. 2005681815-1824
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Effects of sevelamer and calcium on coronary
artery calcification in patients new to
hemodialysis
Block et al. 2005681815-1824
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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 US3000 per year

Can we improve on sevelamer?
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Characteristics of an IdealOral 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

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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

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Lanthanum vs Calcium - 301 Design
N767
La treatment group 66
Enrolment
Titration phase
Maintenance phase
Open-label extension
Optional extension phase
Washout
Ca treatment group 34
Weeks of treatment
3
1
0
5
25
48
154
Part 1 3 weeks
Part 2 5 weeks
Part 3 6 months
Part 46 months
Part 52 years
Hutchison AJ. Nephron Clin Pract 2005100c819
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Mean ( SD) serum phosphate levels
Titration phase
Dose-maintenance phase
3.1
2.6
2.1
Serum phosphate (mmol/L)
1.6
1.1
0
2
4
6
8
10
12
14
16
18
20
22
24
26
Time (weeks)
Hutchison AJ. Nephron Clin Pract 2005100c819
33
Hypercalcaemic events (gtULN) by Week 26
Hutchison AJ. Nephron Clin Pract 2005100c819
34
Ca ? P Product Reduction
2.0
P 0.009
1.8
P 0.961
P 0.061
1.6
Mean Ca x P reduction (mmol2/L2)
1.4
1.2
1.0
End of titration (Week 5)
Mid-maintenance (Week 17)
End of maintenance (Week 25)
Study phase
Hutchison AJ. Nephron Clin Pract 2005100c819
35
European One Year Paired Bone Biopsy Study
A. HUTCHISON
H-H. NEUMAYER
W. SULOWICZ
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.
M. DE BROE
S. SULKOVA
M. LAVILLE
A. BALDUCCIG. COEN
A. FERREIRA
L. DJUKANOVICM. POPOVICS. PEJANOVIC
A. TORRES
A. SIKOLEG. SPASOVSKI
C. SWAENEPOEL
Kidney Int 200385s73-78
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Categorisation of bone histology
Kidney Int 200385s73-78
2994
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Long-term observational populationTwo year
extension
LAM-IV-301
40 patients
LAM-IV-303
1 patient
SDP405-309 N 93 total 41 EU, 52 US
48 patients
LAM-IV-307
4 patients
LAM-IV-308
Provides up to 6 years observation in a small
number of patients.
Hutchison AJ Pratt R. ASN 2005
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Expected remaining lifetimes (years) of the
general U.S. population of dialysis
transplant patients
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Demographics
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Lanthanum Exposure by Total Daily Dose
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Serum Phosphate Levels Throughout Treatment With
Lanthanum Carbonate
42
Serum PTH Levels Throughout Treatment With
Lanthanum Carbonate
kDOQI target
43
Liver enzymes ALT/AST Levels (U/L)
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Plasma Lanthanum Levels During Overall Lanthanum
Exposure
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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?
46
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 2004651099-1104
• Could be used as an adjunct to oral phosphate
  binders?

47
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?

48
Phosphate absorption blockade

• 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

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New compounds in the management of renal
osteodystrophy
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Achieving K/DOQI bone metabolism disease goals
with cinacalcet

• 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

Moe et al. KI 2005
51
56 vs 10
65 vs 36
46 vs 33
49 vs 24
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Our futures are entirely predictable by a quick
retrospective cross-sectional study of our past
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I wanted a perfect endingnow I've learned, the
hard way, that some poems don't rhyme, and some
stories don't have a clear beginning, middle, and
end. Life is about not knowing, having to
change, taking the moment and making the best of
it, without knowing what's going to happen
next Gilda Radner