CKD-MBD

Masafumi Fukagawa, MD, PhD

Tokai University School of Medicine

Isehara, Japan

APSN Continuing Medical Education (CME)7/3/2014 Yokohama

I have the following relationships to disclose.Potential Financial Conflicts of Interest

(1) Employment: No

(2) Stock ownership or options: No

(3) Patent royalties/licensing fees: No

(4) Research funding: Kyowa Hakko-Kirin

(5) Honoraria: Bayer, Kyowa Hakko-Kirin

(6) Manuscript fees: Chugai

(7) Advisory board: JT, Kyowa Hakko-Kirin, Astellas

The 14th Asian Pacific

Congress of Nephrology

ＣＯＩ disclosure

presenter：

CME Session on CKD-MBD

• Regulation of calcium and phosphate metabolism

• Difinition and Pathogenesis of CKD-MBD

– Phosphorus

– FGF23

• Control of Severe Hyperparathyroidism

– Cinacalcet

• CKD-MBD and Survival

Phosphorus

FGF23

Extracellular CALCIUM CONCENTRATION

Total 10mg/dl

Ionized 5 mg/dl

Protein bound 4mg/dl

Complex 1mg/dl

2.5 mEq/L1.25 mmol/L

PTH

Ca

P

1,25(OH)2D

– –

ミネラル代謝の制御システム

0 10 20 30

100

200

300

400

Days

2μg/day 3μg/day

1α-OHD3

6

7

8

9

10 Plasm

a Ca (m

g/d

l)

4 5 6 7 8 9 10 11

0.1

0.2

0.3

0.4

0.5

SERUM Ca, mg/dl

UR

INE

Ca,

mg

/hr

-D-PTH

+D-PTH

-D+PTH

+D+PTH

Yamamoto M et al, JCI

Phosphorus as a Potential Risk

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60

day

su

rv

ivo

rsh

ip(%

) LP

CP

HP

Phosphorus intake and survival

Males

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60

day

LP

CP

HP

Females

maximum lifespan

30 40 50 60

HP

CP

LP

day

Males

Females

*

*

*

*

*p ≦0.05

n=5

15 % longer than

control diet

17% longer than

control diet

Life span (day) Life span (day)

Courtesy of Miyamoto K-I, PhD

Kuro-o M, et al. Mech Ageing Dev. 2010;131:270-275.

1. Klotho-/-mouce2. Mouse3. Rat17. Human18. Human （100y）

（Tonelli M, Circulation 2005)

In general population even within normal range

Impact of hyperphosphataemia on mortality

Note: 1 mg/dL = 0.32 mmol/L. Data subject to multivariable adjustment.

Redrawn from 1. Block GA et al. J Am Soc Nephrol 2004;15:2208–18

2. Eknoyan et al. Am J Kidney Dis 2003;42(Suppl 3):1–201

Relative risk of death increases as serum phosphorus

concentrations increase (N = 40,538)1

Taniguchi M, et al. Ther Apher Dial 2013:17; 221-228.

Analyses of JSDT Registry Data

B model

TD model

TA model

Phosphorus（mg/dL）

All Cause Mortality H

azard Ratio

5

4

3

2

1

0

50,000

40,000

30,000

20,000

10,000

0

Intact PTH（pg/mL）

～60

～120

～180

～240

～300

～360

～420

～480

～540

～600

～700

～800

>800

Corrected Ca（mg/dL）

>11.5

～11.5

～11.0

～10.5

～10.0

～9.5

～9.0

～8.5

～8.0

～7.5

>9.0

～9.0

～8.0

～7.0

～6.5

～6.0

～5.5

～5.0

～4.5

～4.0

～3.5

～3.0

Bone

Absorption

Dietary PhosphorusDietary calcium

Vitamin DPTH

FGF23

Intestinal

Absorption Tubular

Reabsorption

Regulation of Pi Balance

Systemic Pi Balance

12 3

ADHRXLHTIO

HypophosphatemiaLow 1,25D level

Rickets/osteomalacia

Resistant to Degradation

OverproductionBy Tumor Tissue

Mutation of PHEX

Excessive activity of FGF-23

FGF-23: A Newly-Discovered Phosphaturic Factor

1 24 25 251

Signal seq.

FGF-homology domain

Unique seq.

Promotes urinary phosphate excretion

FGF23:A Peptide Hormone Secreted from Osteocytes

Suppresses vitamin D activation in the kidney

Suppresses PTH secretion

Target Organ: Kidney, Parathyroid, Colloid Plexus

Nature. 2006 Dec 7;444(7120)

FGF23/Klotho system

PTH

Ca P

1,25(OH)2D

– –

副甲状腺

骨腎臓

腸

FGF23

Osteitis fibrosa

PTH level and Bone abnormalities

Calcium, Vitamin D

PTHLow turnover High turnover

Adynamic

osteomalacia

NormalBone turnover

Al +3

mixed type

Vascular calcification

median areamedian area

Masson Von Kossa

Paradigm shift in renal bone

disease

• Renal Osteodystrophy (ROD)

– Bone disease

– Diagnosis based on bone biopsy

• CKD-Mineral and Bone Disorder (CKD-

MBD)

– Systemic disease

Chronic Kidney Disease

Phosphorus

Retention

Low Levels

1,25(OH)2D3

Hypocalcemia

Secondary

Hyperparathyroidism

?

FGF23

Proteinuria

Vitamin Ddeficiency

0

50

100

150

200

250

300

350

FG

F23

(n

g/l

)

0 25 50 75 100 125 150 175 200 225 250

Ccr(ml/min)

FGF23 and Kidney Function

0

1

2

3

4

Tm

p/C

cr

0 10 20 30 40 50 60 70

FGF23(ng/l)

R2 = .167

0

1

2

3

4

Tm

p/C

cr

FGF23(ng/l)

0 100 200 300 400

0

1

2

3

4

Tm

p/C

cr

FGF23(ng/l)

0 100 200 300 400

FGF23 and TmP/GFR

Ccr<30ml/min Ccr>80ml/min

1,2

5D

(p

g/m

l)

FGF23 (ng/l)

10

20

30

40

50

60

70

80

10 15 20 25 3035 40 45 50 55 60 65

R2 = .434

0

10

20

30

40

50

60

70

80

90

100

110

1,2

5D

(p

g/m

l)

0 50 100 150 200 250 300 350

FGF23 (ng/l)

Serum FGF23 and 1,25dihydroxyvitamin D level

Ccr>80ml/minn

Shigematsu et al: AJKD, 2004

Ccr<30ml/min

Role of FGF-23 in predialysis patients

-hypothesis-

FGF-23

1,25D

activation

Pi

Pi

suppression

FGF-23

1,25D

activation

Pi

Pi

healthy uremia

-100

-50

0

50

100

sevelamer+CaCO3 CaCO3

p<.01

(%)

-100

-50

0

50

100

sevelamer+CaCO3 CaCO3

p<.01

(%)

The percent relative change of serum FGF 23 levels between two groups

F Koiwa, et al TAD 9: 336, 2005

The percent relative change= FGF 23 (after)-FGF 23 (before) /

FGF 23 (before)

After: after the treatment (week 8)Before: before the treatment

(week 4)

2000

−500

−80 20

1500

1000

500

0

−1000

−1500

0−60 −40 −20 6040

ΔFGF-23 (RU/ml)

(mg

/d)

Δ24hr Ur.Pi excretion

Ferrari SL et al, JCEM, 2005

Isakova T, et al. Kidney Int 79, 2011

Down-regulation of Klotho first?

John GB et al. Am J Kidney Dis, 2012

Increased phosphorus Load per nephron?

Prevention from Early Stages

• Supplement Klotho?

• Block FGF23 action?

• Decrease phosphorus load per nephron?

Neutralizing Antibody to FGF23 in CKD Rats

Shalhoub V. J Clin Invest. 2012;122(7):2543–2553. 35

Copyright ©2010 American Society of Nephrology

Oliveira, R. B. et al. Clin J Am Soc Nephrol 2010;5:286-291

Figure 2. Percentage change in serum FGF23 and PTH levels in patients treated with sevelamer hydrochloride

({square}) or calcium acetate ({blacksquare}) over a 6-wk period

Decrease Phosphorus Load from Early Stage!

Progression of Vascular Calcification?

Block G A et al. JASN doi:10.1681/ASN.2012030223

©2012 by American Society of Nephrology

Control of Phosphorus

• Avoid high phosphorus content foods

– Tasty foods contain more phosphorus

• Needs strict protein restriction?

Mortality predictability of the difference of the percentiles of the changes in dietary protein intake, represented by nPNA (nPCR), and serum P concentration in 30,075 MHD patients.

Kalantar-Zadeh K et al. CJASN 2010;5:519-530

Decrease phosphorus load without strictly decreasing protein intake!!

Source of Phosphorus 1

• Inorganic phosphate or organic phosphate?

• From meat or from plant? (Moe: KI 2009, CJASN2011)

Fukagawa et al, CJASN 2011

Phytate

Phosphorus from plant

Source of Phosphorus 2

• Food additives – Easily absorbable

– Not shown in the food facts

– Contained in enhanced foods and in drinks

Sherman R A , Mehta O CJASN 2009;4:1370-1373

Phosphorus derived from food additives

Patient-education on food additives

Sullivan et al, JAMA, 2009

From serum phosphorus level to dietary phosphorus load,

then to bioavailability

Fukagawa M: CJASN, 2011

Phosphate Binders

Estimating phosphate balance

HD Patient (mg/d) PD Patient

1000 1000

+600 +600

−343c −315d

+257 +285Net + phosphate balance

GI absorption (60%)1,b

Dietary phosphate intakea

Removal by dialysis

1552

+931

−315

+616

PD patient

achieving

recommended

protein nutrition

GI, gastrointestinal; PD, peritoneal dialysis. aKDOQI-recommended dietary phosphate intake. bIntestinal phosphate

absorption may range from 60% to 86%, depending on vitamin D status. cBased on HD removing 800 mg phosphate per

treatment (three treatments per week).2 dBased on PD removing 315 mg phosphate per day.2

1. Ramirez JA et al. Kidney Int 1986;30:753–9;

2. Eknoyan G et al. Am J Kidney Dis 2003;42(Suppl 3):S1–201

They need phosphate binders!

Phosphate Binders

• Ca-containing binders– Calcium carbonate

– Calcium acetate

– Ca-Mg

• Non Ca containing binders– Sevelamer hydrochloride(carbonate)

– Lanthanum carbonate

– bixalomer

– Iron citrate

Phosphate Binders

• Phosphate binding capacity

• Effects on vascular calcification

• Effects on survival

• Other beneficial effects

Mean

Calcium Sevelamer-75

-50

-25

0

25

50

75

100

125

150

175

200

Median

Calcium Sevelamer

Sco

re

-75

-50

-25

0

25

50

75

100

125

150

175

200

Coronary Mean and Median Change at 52 Weeks

151 56*

-46 88

37*

0

*Within treatment P<0.001.

Sco

re (

Ch

an

ge

S

E)

(n=70) (n=62) (n=62)(n=70)

Chertow GM et al: Kidney Int; 62: 245-252, 2002.

1.00

0.75

0.50

0.25

0.000 6 12 18 24 30 36 42 48 54 60 66

P =0.016

Surv

ival dis

trib

ution function

CalciumSeverlmer

No. at risk4642

4241

4240

3936

3432

1814

41

Months

CalciumSevelamer

Block: Kidney Int, 2007

Phosphate Binders and Survival

Effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease:

an updated systematic review and meta-analysis

Sophie A Jamal, Lancet.Published online July 19, 2013

Phosphate Binders on FGF23

Block GA, et al. J Am Soc Nephrol. 2012;23:1407-1415.

C-Terminal FGF23 Intact FGF23

Decrease of FGF23 by Phosphorus Restriction and Lanthanum Carbonate

(Isakova et al.Clin J Am Soc Nephrol. (2013)

Urinary Phosphsphate Excretion Serum FGF23 Level

Yokoyama K, et al. Clin J Am Soc Nephrol. 2014;9:543-552.

Iron Citrate on Phosphorus and FGF23in ND Patients

Calcium Load and FGF23

Other drugs for phosphorus management

Na/Pi transporter Inhibitor

Inhibitor of intestinal phosphate absorption

Control of Severe Hyperparathyroidism

• Supplementation of native or oral active vitamin D sterols

• Intravenous active vitamin D analogues (VDRA)– Calcitriol

– Maxacalcitol

– Paricalcitol

– Not effective in severe cases

– Increase serum Ca and P

Progression

of Parathyroid Hyperplasia

Normal Parathyroid

Diffuse Hyperplasia

Early Nodularity

in diffuse Hyperplasia

Nodular

Hyperplasia

Single Nodular

Gland

Volume ＞0.5cm3

PTH> 500pg/ml

Decrease

VDR

CaR

FGFR-klotho

Komaba H, Fukagawa M, Kidney Int, 2010

Calcimimetics

PTH Synthesis

核

Cell Proliferation

PTH Secretion

Ca-sensing receptor

（-）

（-）

（-） ： suppression

PTH

Cinacalcet

Parathyroid

Ca2+

レグパラ®

Fukagawa M, et al. Nephrol Dial Transplant 23, 2008

Clinical Trial in Japan

Fukagawa M, et al. Nephrol Dial Transplant 23, 2008

Clinical Trial in Japan

Komaba H, Fukagawa M et al. Ther Apher Dial 12, 2008

Achievement of JSDT Target RangeP

rop

ort

ion

of

pat

ien

ts a

chie

vin

g th

e ta

rget

(%)

80

70

60

50

40

30

20

10

26%

65%68%

17%

1% 0%

45% 47%

P = 0.015P = 0.009

P < 0.001

P < 0.001

Placebo

Cinacalcet

intact PTH60-180 pg/ml

Calcium8.4-10.0 mg/dl

Phosphorus3.5-6.0 mg/dl

All 3 targets

Mean percentage change from baseline

intact PTH, calcium, and phosphorus

Komaba H, Fukagawa M et al. Clin J Am Soc Nephrol, 2010

Mean absolute change in parathyroid gland volume

from baseline to wk-52

Komaba H, Fukagawa M et al. Clin J Am Soc Nephrol, 2010

Case1: take Cinacalcet 25mg orally

Control group

Tunel Stain×400

Tuneｌ stain: positive rate (TPR): 0.3% (Mean)

Tuneｌ stain: positive rate: 0.3% (Mean)

Case1: take Cinacalcet 25mg orally

Case1: take Cinacalcet 50 mg orally

(Tatsumi, Kakuta, Fukagawa, Nephron Clin Prac 2014)

Schematic representation of the postulated morphological effect of cinacalcet on the

hyperplastic parathyroid gland.

Komaba H , and Fukagawa M Nephrol. Dial. Transplant.

2009;24:707-709

© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights

reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Annual number of PTx for 2HPT in Japan

* JSDT guideline

** Cinacalcet*

↓

**

↓

0

200

400

600

800

1000

1200

1400

1600

1800

04 05 06 07 08 09 10 11

1144 1166

1391

1763

1055

505 464 411

(operations)

Tominaga Y et al

75

Changes in Prescription Patterns

Cinacalcet VDRA category*

No Decreased

No Stable

No Increased

Starting Decreased

Starting Stable

Starting Increased

* decreased: <-25%, stable:-25% to 25%, increased: >25%

Fukagawa M, et al. Kidney Week 2011(ASN) SA-

76

Association between prescription patterns and improvement in intact PTH

IncreasedStarting

StableStarting

DecreasedStarting

IncreasedNo

StableNo

DecreasedNo

VDRA doseCinacalcet

Prescription Pattern

IncreasedStarting

StableStarting

DecreasedStarting

IncreasedNo

StableNo

DecreasedNo

VDRA doseCinacalcet

Prescription Pattern

-10% 10% 30% 50% -10% 10% 30% 50%

Unadjusted model

Adjusted for age, gender, dialysis vintage, intact PTH, phosphorus, calcium, calcium-based phosphate binder, non-calcium based phosphate binder, sp Kt/V and dialysate calcium conc.

R

(PD, 95%CI)

Adjusted model

(PD, 95%CI)

R

Fukagawa M, et al. Kidney Week 2011(ASN) SA-PO2314

Fukagawa M et al. CJASN 2012;7:1473-1480

77

Association between prescription patterns and improving hyperphosphatemia and hypercalcemia toward the target range

IncreasedStarting

StableStarting

DecreasedStarting

IncreasedNo

StableNo

DecreasedNo

VDRA doseCinacalcet

Prescription Pattern

IncreasedStarting

StableStarting

DecreasedStarting

IncreasedNo

StableNo

DecreasedNo

VDRA doseCinacalcet

Prescription Pattern Improvement Hyperphosphatemia

Adjusted for age, gender, dialysis vintage, intact PTH, phosphorus/ calcium, calcium-based phosphate binder, non-calcium based phosphate binder, sp Kt/V and dialysate calcium conc.

-20% 10% 40% -20% 10% 40%

R

(PD, 95%CI)

Improvement Hypercalcemia

(PD, 95%CI)

R

Fukagawa M, et al. Kidney Week 2011(ASN) SA-PO2314

Fukagawa M et al. CJASN 2012;7:1473-1480

Abbreviations; ↑, initiation or increase; ↓, reduce or discontinuation; CaCO3, Ca carbonate; NCaPB, non-Ca containing phosphate binder;

VDRA, vitamin D receptor activator.

If serum PTH value were * high or ** low, initiation or discontinuation of cinacalcet is considered.

10.0

8.4

CaCO3 ↓

NCaPB ↓

VDRA ↓

NCaPB ↓

CaCO3 ↓

VDRA ↑

NCaPB ↓

CaCO3 between meals

VDRA ↑

Cinacalcet ↓ **

CaCO3 ↓

change to NCaPB

VDRA ↓

Cinacalcet ↑ *

CaCO3 ↑

CaCO3 between meals

VDRA ↑

Cinacalcet ↓ **

CaCO3 ↓

NCaPB ↑

VDRA ↓

Cinacalcet ↑ *

NCaPB ↑

CaCO3 ↑

VDRA ↓

Cinacalcet ↑ *

CaCO3 ↑

NCaPB ↑

Cinacalcet ↓ **

Serum phosphte

value (mg/dl)

Serum adjusted

Ca value(mg/dl)

6.03.5

Serum

P and Ca

targets

Adequate amount of hemodialysis

Restriction of dietary phosphate

Consider change

of

dialysate calcium

Assessment of

nutritional state

Examine cause of

hypercalcemia

Consider change of

dialysate calcium

58 2

69 3

47 1

Management of CKD-MBD

Cinacalcet ↑*

Lag-censoring analysis of the primary composite

outcome and its components.

Shown are Kaplan-Meier curves comparing cinacalcet with placebo for the time to the first primary composite outcome （Panel A）, death （Panel B）, first myocardial infarction （Panel C）, first hospitalization for unstable angina （Panel D）, first episode of heart failure （Panel E）, and first episode of a peripheral vascular event （Panel F）.

(A) Primary composite end point

00

100

90

80

70

60

50

40Pro

po

rtio

n e

ven

t-fr

ee

Cinacalcet

Placebo

No. at Risk

4 8 12 16 20 24 28 32 36 40 44 48 52 56 60

Placebo

Cinacalcet

Hazard ratio, 0.85 （95％ CI, 0.76-0.95）p=0.003 by log-rank test

1,935 1,789 1,615 1,299 1,080 875 739 625 525 474 419 353 303 180 93 26

1,948 1,835 1,627 1,376 1,179 1,002 847 731 632 551 491 425 362 239 130 28

Study month

Chertow GM et al. N Engl J Med 367, 2012

❖Marginal structural models adjusting for the time-dependent confounders and the baseline covariates.

Ref. Ref. Ref.

Consistent use of cinacalcet is associated with improved clinical outcomes in the MBD-5D

Akizawa T et al. Abstract SAP560. 49th ERA-EDTA Congress, Paris 2012

Median (IQR) serum FGF23 (A), median (IQR) intact PTH (B), mean (±SD) serum calcium (C)

and mean (±SD) serum phosphorus (D).

Koizumi M et al. Nephrol. Dial. Transplant.

2012;27:784-790©

CKD-MBD and Survival

London GM et al. Nephrol Dial Transplant 18, 2003

Arterial intima calcification (AIC) Arterial media calcification (AMC)

Vascular calcification and mortality in ESRD

Rennenberg RJ, et al. Vasc Health Risk Manag. 2009;5:185-197.

Vascular Calcification and All-cause Motality

Blacher 2001

Fox 2003

Kemmeren 1998

Lehto 1996

London 2003

Wang 2003

Wilens 2006

Okuno 2007

Overall (95% Cl)

12.30 (3.47,43.67)

3.16 (2.19,4.55)

1.43 (1.22,1.68)

2.14 (1.64,2.81)

15.16 (5.74,40.06)

4.51 (2.24,9.07)

3.04 (1.40,6.61)

3.54 (2.13,5.89)

3.52 (2.25,5.50)

7.1

15.0

16.3

15.7

9.3

11.8

11.1

13.7

Odds ratio(95% Cl) % Weight

0.1 1 10Odds ratio

Schiffrin E et al. Circulation. 2007;116:85-97.

Mechanisms of Vascular Calcificationin CKD

Calciptotein Particle (CPP)

by Kuro-o M

CACS correlates with supernatant fetuin-A and RR but not with serum fetuin-A

concentrations.

Hamano T et al. JASN 2010;21:1998-2007

©2010 by American Society of Nephrology

Odds Ratios (and 95% CIs) for Death According to Quartile of C-Terminal Fibroblast Growth Factor 23 (cFGF-23) Levels

Gutierrez OM et al. N Engl J Med 2008;359:584-592

CRIC study: FGF-23 is associated with atherosclerotic and congestive heart

failure events.

Scialla J J et al. JASN 2014;25:349-360

FGF23 induces Ventricular Hypertrophy

Faul et al, JCI, 2011

Faul et al, JCI, 2011

Effects of FGF23 in klotho-null mice

Simplified schematic outline of how FGF23 may exert physiological and pathological responses.

Razzaque M S Nephrol. Dial. Transplant. 2009;24:4-7

Central Roles of FGF23

Wolf M. J Am Soc Nephrol. 2010;21:1427-1435.

Kuro-o: Nature Rev Nephrol, 2013

Intervention on FGF23

1. Phosphorus load

2. Calcium load

3. Active vitamin D

Increase FGF23 Deacrease FGF23

1. Phosphorus restriction

2. Non-Ca containing phosphate binders

3. Cinacalcet

PTH

1,25-(OH)2D

Ca2+

+

+-

+ -

-

+ -

Ca P Metabolism in 20thCentury

P

-+

CT（）

Ca P Metabolism in 21st Century

PTH

1,25-(OH)2D

Ca2+

+

+-

+ -

-

+ -

P

-

-FGF-23

+

+

-+

From ROD to CKD-MBD