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: [email protected]
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