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

**PP=0.03 =0.03 ****PP<0.0001 (N=6407)<0.0001 (N=6407)

1.00

1.25

1.50

0.36-1.45 1.49-1.78 1.81-2.10 2.13-2.52 2.55-5.46

Serum Phosphorus Quintile (mmol/L)

Rela

tive

Mor

talit

y Ri

sk (R

R)

1.00 1.001.02

1.18*

1.39**

1.00

1.25

1.50

1.13-3.39 3.47-4.20 4.28-4.84 4.92-5.81 5.89-10.65

Ca x P Product Quintile (mmol2/L2)Re

lativ

e M

orta

lity

Risk

(RR)

1.061.08

1.13

1.34*

1.00

HyperphosphataemiaHyperphosphataemia

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

<0.97 mmol

>2.90 mmol

Block et al. 2005

<2.20 mmol

>2.75 mmol

Block et al. 2005

• 433 patients starting ESRD therapy433 patients starting ESRD therapy

• 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”

Tom PetersTom Peters

Metastatic Calcification & OssificationMetastatic Calcification & Ossification

Amorphous(CaMg)3(PO4)2

Soft tissue Heart Lungs Kidneys

HydroxyapatiteCa10(PO4)6(OH)2

Vascular Valvular Joints Ocular

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

- nodular hyperplasia- nodular hyperplasia

- hyperphosphataemia- hyperphosphataemia

- calcimimetics- calcimimetics

Renal Osteodystrophy - GuidelinesRenal Osteodystrophy - Guidelines

K-DOQI K-DOQI Guidelines.mhtGuidelines.mht

GB Renal Association GuidelinesGB Renal Association Guidelines

EDTA GuidelinesEDTA Guidelines

Sponsors of the k/DOQI Bone & Mineral GuidelinesSponsors of the k/DOQI Bone & Mineral Guidelines

Paricalcitol

Cinacalcet

Renagel

USA k/DOQI Guidelines 2004USA k/DOQI Guidelines 2004

Serum phosphateSerum phosphate 1.13 – 1.78 mmol/L (3.5 – 5.5 mg/dL) 1.13 – 1.78 mmol/L (3.5 – 5.5 mg/dL) OpinionOpinion

Serum calciumSerum calcium Preferably lower end of normalPreferably lower end of normal OpinionOpinion

(8.4 – 9.5 mg/dl, 2.10 – 2.37 mmol/L)(8.4 – 9.5 mg/dl, 2.10 – 2.37 mmol/L)

Ca x PO4 productCa x PO4 product < 4.5 mmol< 4.5 mmol22/L/L22 (< 55mg (< 55mg22/dL/dL22) ) EvidenceEvidence

Target PTH levelTarget PTH level 150 – 300 pg/ml (16 – 33 pmol/L) 150 – 300 pg/ml (16 – 33 pmol/L) EvidenceEvidence

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)

Suboptimal phosphate-binding abilitySuboptimal phosphate-binding ability

Optimum binding occurs at pH 7 which is not the pH at the absorption siteOptimum binding occurs at pH 7 which is not the pH at the absorption site

May affect concomitant vitamin K, and D treatmentMay affect concomitant vitamin K, and D treatment

High doses are associated with gastrointestinal problems High doses are associated with gastrointestinal problems

Relatively high costRelatively high cost

Around US$3000 per year Around US$3000 per year

Can we improve on sevelamer?Can we improve on sevelamer?

• High affinity for binding phosphorous High affinity for binding phosphorous - low dose required- low dose required

• Rapid phosphate bindingRapid phosphate binding

• Low solubilityLow solubility

• Low systemic absorptionLow systemic absorption (preferably none) (preferably none)

• Non toxicNon toxic

• Solid oral dose formSolid oral dose form

• Palatable - encourages compliancePalatable - encourages compliance

Characteristics of an IdealCharacteristics of an IdealOral Phosphate BinderOral Phosphate Binder

• A rare earth elementA rare earth element

• Atomic number 57Atomic number 57

• Atomic weight 139Atomic weight 139

• Valency 3, binds phosphate ionicallyValency 3, binds phosphate ionically

• Present in tap water (very low levels)Present in tap water (very low levels)

• Various salts bind phosphate avidlyVarious salts bind phosphate avidly

• Lanthanum phosphate very insolubleLanthanum phosphate very insoluble

• Lanthanum carbonate least soluble saltLanthanum carbonate least soluble salt

LanthanumLanthanum

Lanthanum vs Calcium - 301: DesignLanthanum 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 13 weeks

Part 25 weeks

Part 36 months

Part 46 months

Part 52 years

Hutchison AJ. Hutchison AJ. NephronNephron Clin PractClin Pract 2005;100:c8–19 2005;100:c8–19

N=767

Ser

um

ph

os

ph

ate

(mm

ol/

L)

Titration phase Dose-maintenance phase

Mean (± SD) serum phosphate levelsMean (± SD) serum phosphate levels

3.1

2.6

2.1

1.6

1.10 2 4 6 8 10 12 14 16 18 20 22 24 26

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

ESRD patients, 2003ESRD patients, 2003

DialysisDialysis TransplantTransplant

AgeAge AllAll MaleMale FemaleFemale AllAll MaleMale FemaleFemale AllAll MaleMale FemaleFemale

3030–34–34 46.846.8 44.444.4 49.049.0 10.510.5 10.810.8 10.010.0 28.528.5 28.328.3 28.928.9

3535–39–39 42.142.1 39.839.8 44.244.2 9.09.0 9.29.2 8.78.7 25.225.2 24.824.8 25.825.8

4040–44–44 37.537.5 35.235.2 39.539.5 7.87.8 8.08.0 7.67.6 21.921.9 21.521.5 22.722.7

4545–49–49 33.033.0 30.830.8 34.934.9 6.86.8 7.07.0 6.76.7 19.019.0 18.518.5 19.819.8

5050–54–54 28.628.6 26.626.6 30.430.4 5.95.9 6.06.0 5.95.9 16.316.3 15.715.7 17.217.2

5555–59–59 24.424.4 22.522.5 26.026.0 5.05.0 5.05.0 5.05.0 13.813.8 13.213.2 14.714.7

6060–64–64 20.420.4 18.718.7 21.921.9 4.34.3 4.34.3 4.44.4 11.511.5 11.011.0 12.512.5

6565–69–69 16.816.8 15.215.2 18.018.0 3.73.7 3.63.6 3.73.7 9.69.6 9.19.1 10.610.6

7070–74–74 13.413.4 12.012.0 14.414.4 3.13.1 3.13.1 3.13.1 7.97.9 7.47.4 8.98.9

7575–79–79 10.410.4 9.39.3 11.111.1 2.62.6 2.62.6 2.72.7 6.76.7 6.26.2 7.77.7

8080–84–84 7.87.8 6.96.9 8.38.3 2.22.2 2.22.2 2.22.2

85+85+ 4.34.3 3.83.8 4.54.5 1.81.8 1.71.7 1.81.8

OverallOverall 25.225.2 23.423.4 26.626.6 5.55.5 5.65.6 5.45.4 15.115.1 14.614.6 15.915.9

DemographicsDemographics

USUSN = 52N = 52

EUEUN = 41N = 41

TotalTotalN = 93N = 93

Mean Age Mean Age 54.5 54.5 15.2 15.2 51.7 51.7 13.0 13.0 53.2 53.2 14.3 14.3

Female Female 16 (30.8%)16 (30.8%) 13 (31.7%)13 (31.7%) 29 (31.2%)29 (31.2%)

Male Male 36 (69.2%)36 (69.2%) 28 (68.3%)28 (68.3%) 64 (68.8%)64 (68.8%)

CaucasianCaucasian 21 (40.4%)21 (40.4%) 40 (97.6%)40 (97.6%) 61 (65.6%)61 (65.6%)

BlackBlack 24 (46.2%)24 (46.2%) 00 24 (25.8%)24 (25.8%)

HispanicHispanic 7 (13.5%)7 (13.5%) 00 7 (7.5%)7 (7.5%)

OtherOther 00 1 (2.4%)1 (2.4%) 1 (1.1%)1 (1.1%)

Lanthanum Exposure by Total Daily DoseLanthanum Exposure by Total Daily Dose

YearYear 750 mg750 mg 1500 mg1500 mg 2250 mg2250 mg 3000 mg3000 mg TotalTotal

1 1 –– <3 <3 1 (1.1%)1 (1.1%) 5 (5.4%)5 (5.4%) 7 (7.5%)7 (7.5%) 2 (2.2%)2 (2.2%) 15 (16.1%)15 (16.1%)

3 3 –– <4 <4 00 5 (5.4%)5 (5.4%) 8 (8.6%)8 (8.6%) 9 (9.7%)9 (9.7%) 22 (23.7%)22 (23.7%)

4 4 –– <5 <5 3 (3.2%)3 (3.2%) 8 (8.6%)8 (8.6%) 12 (12.9%)12 (12.9%) 5 (5.4%)5 (5.4%) 28 (30.1%)28 (30.1%)

5 5 –– <6 <6 00 1 (1.1%)1 (1.1%) 4 (4.3%)4 (4.3%) 6 (6.5%)6 (6.5%) 11 (11.8%)11 (11.8%)

≥≥66 1 (1.1%)1 (1.1%) 8 (8.6%)8 (8.6%) 5 (5.4%)5 (5.4%) 3 (3.2%)3 (3.2%) 17 (18.3%)17 (18.3%)

TotalTotal 5 (5.4%)5 (5.4%) 27 (29.0%)27 (29.0%) 36 (38.7%)36 (38.7%) 25 (26.9%)25 (26.9%) 93 (100%)93 (100%)

Serum Phosphate Levels Throughout Serum Phosphate Levels Throughout Treatment With Lanthanum CarbonateTreatment With Lanthanum Carbonate

4.5

5

5.5

6

6.5

7

7.5

8

0 1 2 3 4 5 6

Years

Me

an

se

rum

ph

os

ph

ate

, m

g/d

L

Phosphate mg/dl

Serum PTH Levels Throughout Serum PTH Levels Throughout Treatment With Lanthanum CarbonateTreatment With Lanthanum Carbonate

100

200

300

400

500

0 1 2 3 4 5 6

Years

Ser

um

PT

H,

pg

/mL

iPTH pg/ml

kDOQItarget

Liver enzymes – ALT/AST Levels (U/L)

10

15

20

25

30

35

0 1 2 3 4 5 6

Year

AS

T (

U/L

)

10

15

20

25

30

35

0 1 2 3 4 5 6

Year

AL

T (

U/L

)

Plasma Lanthanum Levels Plasma Lanthanum Levels During Overall Lanthanum ExposureDuring Overall Lanthanum Exposure

YearYear Mean Mean SD SD

(ng/mL)(ng/mL)

BaselineBaseline 0.01 0.01 0.05 0.05

11 0.52 0.52 0.60 0.60

22 0.63 0.63 0.53 0.53

33 0.67 0.67 0.64 0.64

44 0.63 0.63 0.75 0.75

55 0.97 0.97 0.69 0.69

66 0.75 0.75 0.31 0.31

Long-term Safety Data – ASN Nov 2005Long-term Safety Data – ASN Nov 2005

• 93 patients on treatment for over 5 years93 patients on treatment for over 5 years

• 22 patients on treatment for over 6 years22 patients on treatment for over 6 years

• No safety concerns identifiedNo safety concerns identified

• Phosphate and PTH stablePhosphate and PTH stableHutchison AJ & Pratt R. ASN 2005Hutchison AJ & Pratt R. ASN 2005

Other avenues for continuing research?Other avenues for continuing research?

Phosphate absorption blockadePhosphate absorption blockade

NicotinamideNicotinamide inhibits intestinal Na-dependent phosphate cotransport inhibits intestinal Na-dependent phosphate cotransport

• 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?

Phosphate absorption blockadePhosphate absorption blockade

Phosphatonins Phosphatonins (e.g. Fibroblast Growth Factor 23)(e.g. Fibroblast Growth Factor 23)

• Polypeptide hormone linked to hypophosphataemic rickettsPolypeptide hormone linked to hypophosphataemic ricketts

• May reduce serum phosphorus by inhibiting uptake from May reduce serum phosphorus by inhibiting uptake from

food, and by inhibiting sodium-dependant phosphorus re-food, and by inhibiting sodium-dependant phosphorus re-

absorptionabsorption

Could be manipulated as an adjunct to phosphate binders?Could be manipulated as an adjunct to phosphate binders?

Phosphonoformic acidPhosphonoformic acid

• Synthetic anti-viral drug – ‘Foscarnet’ CMV treatmentSynthetic anti-viral drug – ‘Foscarnet’ CMV treatment

• Inhibits sodium-dependant phosphate transportInhibits sodium-dependant phosphate transport

• Increased phosphate excretion in normal and uraemic ratsIncreased phosphate excretion in normal and uraemic rats

• Depends on residual renal functionDepends on residual renal function

Brooks et al J Pharmacol Exp Thera 1997Brooks et al J Pharmacol Exp Thera 1997

Phosphate absorption blockadePhosphate absorption blockade

New vitamin D analoguesNew vitamin D analogues- Oxacalcitriol ( 22 Oxa) - Doxercalciferol (1 alpha D2))

- Paricalcitol (19 Nor,1alpha 25 OH D2)

New compounds in the management ofNew compounds in the management ofrenal osteodystrophyrenal osteodystrophy

New phosphate bindersNew 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)

CalcimimeticsCalcimimetics- Clear reduction in serum calcium- Mild reduction in serum phosphate

Achieving K/DOQI bone metabolism & Achieving K/DOQI bone metabolism & disease goals with cinacalcetdisease goals with cinacalcet

Moe et al. KI 2005

• Combined data from three 6 month placebo-controlled RCTsCombined data from three 6 month placebo-controlled RCTs

• Retrospective “secondary analysis”Retrospective “secondary analysis”

• 1136 dialysis patients from 182 centres in US, EU and Aus1136 dialysis patients from 182 centres in US, EU and Aus

• Examined achievement of targets for Examined achievement of targets for

iPTHiPTH

phosphatephosphate

calcium calcium

calcium x phosphate productcalcium x phosphate product

56% vs 10% 65% vs 36%

46% vs 33%

49% vs 24%

Our futures are entirely predictable bya quick retrospective cross-sectional

study of our past

““I wanted a perfect ending…now I've learned, the hard I wanted a perfect ending…now I've learned, the hard

way, that some poems don't rhyme, and some stories way, that some poems don't rhyme, and some stories

don't have a clear beginning, middle, and end.don't have a clear beginning, middle, and end.

Life is about not knowing, having to change, taking the Life is about not knowing, having to change, taking the

moment and making the best of it, without knowing moment and making the best of it, without knowing

what's going to happen next”what's going to happen next”

Gilda RadnerGilda Radner