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CKD-MBD: New Insights into Pathogenesis and Current Aspects of
Treatment
Isidro B. Salusky, M.D.Distinguished Professor of Pediatrics
Chief, Division of Pediatric NephrologyDirector, Clinical Translational Research Center
Associate Dean of Clinical ResearchDavid Geffen School of Medicine at UCLA
New Definition of Renal Osteodystrophy CKD-Mineral Bone Disease (CKD-MBD)
A systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following:• Abnormalities of calcium, phosphorus, PTH or
vitamin D metabolism • Abnormalities in bone turnover, mineralization,
volume, linear growth, or strength• Vascular or other soft tissue calcification
Moe et al KI 2006
KDIGO—Definition of Renal Osteodystrophy
“…an alteration of bone morphology in patients with CKD. It is one measure of the skeletal component of the systemic disorder of CKD-MBD that is quantifiable by histomorphometry of bone biopsy..."
New Classification of ROD
Mineralization
NormalAbnormal
TurnoverHigh
NormalLow
VolumeHigh
NormalLow
Slide courtesy of Susan Ott
KI 2006 69(11):1945-53
TMV ClassificationHistologic Classification of Renal Osteodystrophy Based on TMV (Turnover/Mineralization/Volume)
KI 2006 69(11):1945-53
Osteitis fibrosa
Mild 2oHPT
Osteomalacia
Mixed uremic osteodystrophy
Adynamic bone
Prevalence of Abnormal Turnover and Mineralization Across CKD 2-4
(n=14)
Stage 4
Patie
nts
with
Abn
orm
al
Hist
olog
y (%
)
BFR/BS
O.Th
Stage 3Stage 2
(n=24)
(n=14)
OMT
Wesseling K et al. CJASN 2012
Traditional Pathogenesis of Secondary Hyperparathyroidism in CKD
Decreased Vitamin D Receptors
Decreased Ca-Sensing Receptors
Parathyroid Glands
Increased PTH Secretion
Hypocalcemia
Reduced Renal Mass
Decreased Serum 1,25(OH)2D
(Active Vitamin D Calcitriol)
Increased Serum Phosphate
National Kidney Foundation. Am J Kidney Dis. 2003;42:S1-S201.Cheng S, et al. Ther Clin Risk Manag. 2006;2:297-301.
FGF23 and Rickets
ADHR (Autosomal Dominant Hypophosphatemic rickets)
TIO (Tumor Induced Osteomalacia)
XLH (X-linked hypophosphatemia)
ARHP (Autosomal Recessive Hypophosphatemia)
HypophosphatemiaRenal phosphate wastingLow (or inappropriately normal) 1,25DNormal serum Ca levels
Increased FGF-23 values
FGF-23 is Produced in Osteocytes and Regulates Phosphorus and Vitamin D
Osteoblast Osteocyte
DMP-1
MEPE-ASARM
PHEX
FGF-23
1,25(OH)2D Pi
Dietary animals + humans +CKD
PituitaryChoroid
DCT PCT
Klotho
OBOC
BONE MARROW
OCY
BONE OSTEOID
OCY
Traditional Bone Histomorphometry
Osteocytes: Regulators of phosphate, vitamin D and bone metabolism
Feng et al Curr Opin.Nephrol.Hypertens (2009) 18:285
MARKER
Phex Early and lateosteocytes
Phosphate metabolism
OF45/MEPE Late osteoblastthrough osteocytes
Inhibitor of bone formation/regulator of phosphate metabolism
DMPI Early and matureosteocytes
Sclerostin Late embeddedosteocyte
Inhibitor of bone formation
FGF23 Early and matureosteocytes
Induceshypophosphatemia
Phosphatemetabolism andmineralization
EXPRESSION FUNCTION
Osteocytes
Adapted Feng JQ. et al (2006-2007)
Calcium, Phosphorus & PTH by iGFR in 447 Children with CKD
Ser
um
Cal
ciu
m (
mg
/dl)
Ser
um
Ph
osp
ho
rus
(mg
/dl)
Inta
ct P
TH
(p
g/m
l)
Iohexol GFR (ml/min/1.73 m2)
>70 60-69 50-59 40-49 30-39 20-29 <200
2
4
6
8
10
12
0
60
120
180
Corrected Calcium Phosphorus iPTH
**
*
*
*vs GFR >70, P<0.05 by ANOVA
Portale A et al CJASN in press
25OHD, 1,25(OH)2D, & FGF23 by iGFR in 447 Children with CKDS
eru
m 2
5OH
D (
ng
/dl)
Ser
um
1,2
5(O
H) 2
D (
pg
/dl)
FG
F23
(R
U/m
l)
Iohexol GFR (ml/min/1.73 m2)
>70 60-69 50-59 40-49 30-39 20-29 <200
10
20
30
40
0
100
200
300
400
500
25OHD 1,25(OH)2D FGF23
*
**
*
*
*
Median valuesVitamin D, N=370
*vs GFR >70, P<0.05 by ANOVA
FGF23 & Phosphorus SD Scores by iGFR in 447 CKiD Children
Ph
osp
ho
rus
SD
Ph
osp
ho
rus
SD
Iohexol GFR (ml/min/1.73 m2)Iohexol GFR (ml/min/1.73 m2)
-3
-2
-1
0
1
2
3
0
100
200
300
400
500
Phosphorus FGF23
Median values
*
*
>70 69-60 59-50 49-40 39-30 29-20 <20
*
**
*
*
*
FG
F23
(R
U/m
l)
Portale A et al CJASN in press
>70 60-69 50-59 40-49 30-39 20-29 <200
10
20
30
40
50
60
70
80
90
100 Phos >95% iPTH >65 pg/ml FGF23 >100 RU/ml
GFR (ml/min/1.73 m2)
Increased Serum Pi, PTH and FGF23 by GRF in 447 CKiD Children
Increased Serum Pi, PTH and FGF23 by GRF in 447 CKiD Children
Pe
rce
nta
ge
Glomerular Non-Glomerular P (n=91) (n=356)
Age, years 14 ± 3 11 ± 4 <0.001GFR, ml/min/1.73 m2 49 ± 21 45 ± 17 NSSerum calcium, mg/dl 9.3 ± 0.4 9.4 ± 0.4 NSSerum phosphorus, mg/dl 4.4 ± 1.0 4.6 ± 0.8 <0.05*Serum iPTH, pg/ml 50 (28-116) 52 (30-84) NSPlasma FGF23, RU/ml 169 (96-273) 131 (90-192) 0.005*Serum 25OHD, ng/ml 18 ± 12 29 ± 11 <0.001Serum 1,25(OH)2D, pg/ml 27 ± 12 31 ± 11 0.001
Data are means ± SD or medians (25th-75th percentile)
Mean (median) values were compared using the t-test or *Wilcoxon rank-sum test
Comparison of Glomerular vs Non-Glomerular Disease
FGF23 in CKD-MBD
• FGF23 is the first detectable abnormality in mineral metabolism
• Early increases in serum FGF23 concentrations reduced S-P levels and subsequently maintain serum P levels within the normal range until advanced CKD stages
• Early increases in FGF23 account for early decreases in 1,25D and the development of 2oHPT
• Phosphate balance is neutral in CKD stages 2-3
FGF23 and Progressive Renal Dysfunction
Fliser D. et al. JASN 18:2600, 2007
FGF23 Associated with LVH in Patients with CKD (Faul C et al. JCI 2012)
Prevalence of LVH by FGF23 Quartile in 317 CKiD Children
FGF23 QuartileFGF23 Quartile
LVH
Pe
rce
nta
geLV
H P
erc
ent
age
<90 90-135 135-200 >2000
5
10
15
20
25P for linear trend = 0.038
Data from Visit 1b
Determinants of LVH
Odds Ratio [95% CI] P
Systolic BP %tile (AGH) 1.02 [1.02 – 1.03] 0.002
Log FGF23 1.54 [1.03 – 2.33] 0.038
Multivariable logistic regression of LVH as categorical variable. (N=317)
Odds Ratio [95% CI] P
Systolic BP %tile (AGH) 1.01 [1.02 – 1.03] 0.007
Log FGF23 1.34 [0.87 – 2.06] 0.178
Serum Phos Z score 1.29 [1.05 – 1.57] 0.014
Bone FGF23 Expression (50x)
Healthy Control CKD (Stage 2)
Pereira RC et al Bone 2009
Bone DMP1 Expression (200x)
Healthy Control CKD (Stage 2)
Pereira RC et al Bone 2009
Therapeutic Options for the Treatment of CKD-MBD
Cinacalcet
Calcitriol
Paricalcitol
DoxercalciferolErgocalciferol
Sevelamer:Ca free – Metal Free
Ca-Salts
Lanthanum Ca:Ca free - Metal +
0
200
400
600
800
1000
1200
0 1 2 3 4 5 6 7 8
Effects on Serum PTH Levels
Time (months)
PTH
[1st P
TH-IM
A] (p
g/m
l)
1-α (OH)D2 + CaCO3
1-α (OH)D2 + Sevelamer
1,25 (OH)2D3 + CaCO3
1,25 (OH)2D3 + Sevelamer
p < 0.01 from baseline*
*
Wesseling K. et al KI 2010
500
3500
2500
1500
Bo
ne
Fo
rmat
ion
Rat
e (
um
2/m
m2/d
ay)
1 α(OH)D2 +CaCO3
1,25(OH)2D3 +CaCO3
1 α(OH)D2 +Sevelamer
1,25(OH)2D3 +Sevelamer
Effects of Therapy on Bone Turnover
6000
Initial
Final
* *
*
*
* p<0.001
Wesseling K. et al KI 2010
Effects of 1,25(OH)2D3 Therapy on Bone Turnover, Mineralization and FGF23 in
Dialyzed Patients with 2oHPT
Wesseling-Perry K et al. KI 79:112, 2011
(n=51)
Effects of 1,25(OH)2D3 Therapy on Bone Osteocytic Proteins in Dialyzed Patients
(Pereira R et al. ASN 2011)
Temporal aspects of disordered mineral metabolism in CKD
An
alyt
e co
nce
ntr
atio
n
>10,000
1000
90
60
30
40>90 75 60 45 30 15 0 3 6 >12
GFR (mL/min/1.73 m2)
Time post-transplant (months)
1,25D(pg/mL)
cFGF-23(RU/mL)
1 2 3
4
Dialysis
Wolf M. J Am Soc Nephrol 2010;21. [Epub ahead of print]
cFGF-23, C-terminal Fibroblast Growth Factor-23
PTH(pg/mL)
Normal PTH range
P(mg/dL)
Normal P range
1. Increased FGF-23 is the earliest alteration in mineral
metabolism in CKD
2. Gradually increasing FGF-23 levels cause early
decline in 1,25D levels
3 .This frees PTH from feedback inhibition, leading to
SHPT
4. All these changes occur long before increases in
serum P levels are evident
Oliveira CJASN 2010;5:286-291
Effects of Sevelamer and CaCO3 on 2oHPT and FGF23 in CKD 2-4
UCLA
Katherine Wesseling, M.D., Pediatrics
Renata Pereira, Ph.D., Pediatrics
Joshua Zaritsky, M.D., Pediatrics
Barbara Gales, R.N., Pediatrics
Justine Bacchetta, M.D., Pediatrics
Robert Elashoff, Ph.D, Biomathematics
Children’s Hospital Los Angeles. Kevin Lemley, M.D.
CollaboratorsMass. General HospitalHarald Jüppner, M.D.
Immutopics Jeffrey LavigneRichard Zahranik
UCSFTony Portale, M.D.
Northwestern U. M. Wolf, M.D.
Loma Linda Med. Ctr. Shobha Sahney, M.D.
Support: NIDDK, NCRR
Thank You
UCLA Renata Pereira
Joshua Zaritsky
Navdeep TumberBarbara GalesGina RamosOra YadinIsidro Salusky
Mass Gen HospitalHarald Jüppner
ImmutopicsJeff Lavigne
Richard ZaradnikChris Harkins
Loma Linda UniversityShoba Sahney