!! CKD$MBD’in’children’ -...
Transcript of !! CKD$MBD’in’children’ -...
CKD-‐MBD in children
Rukshana Shroff
Great Ormond Street Hospital for Children and Ins6tute of Child Health
London, UK
Disclosures
Speaker: Gambro, Baxter, Genzyme, Amgen Educational / Research support: Gambro
Children are not small adults
• Children have higher Ca and P requirements
• Total skeletal Ca increases from ~25g at birth to ~1000g in an adult
• Buffering capacity of the growing skeleton Age, years Calcium threshold (mg/
day) Balance per day (mg/
day)
0-‐1 1090 503±91
2-‐8 1390 246±126
9-‐17 1480 396±164
18-‐30 957 114±133
Matkovic V; Am J Nutri2on 1992
Calcium balance is positive throughout childhood
Paediatric CKD-MBD studies
• No RCTs • Registry reports • Longitudinal studies in pre-dialysis and dialysis
• No ‘hard’ end-points for vascular studies
• Surrogate measures of vascular disease • Ex vivo changes in vessels
‘Clean population’ • no pre-existing CVD • rarely have diabetes or underlying inflammatory disease • some studies have selected children without uncontrolled
HT or dyslipidaemia
Outline • CKD-MBD evolution in children
• Paediatric CVD and MBD • single / multicentre studies • Registry reports • Longitudinal studies on progression of vascular and bone disease
• Vessel and bone biopsy data
USRDS 2011 report
CKD-MBD in children
Vascular changes begin pre-dialysis
700 children; age 6 – 18 years eGFR 10 – 45ml/min/1.73m2
586 children; age 1-‐16 years eGFR 30-‐90 mL/min/1.73 m2
Increased cIMT in pre-dialysis CKD
Brady et al; CJASN 2012
• 100 children with a median GFR 43 ml/min/1.73 m2
• Increased cIMT was associated with HT and dyslipidemia
Increased cIMT & PWV pre-dialysis
Height [cm]90 100 110 120 130 140 150 160 170 180 190
cIM
T [m
m]
0,3
0,4
0,5
0,6
0,7
0,8
InCma Media Thickness
height (cm)100 120 140 160 180
PW
V (
m/s
)
3
4
5
6
7
8
Pulse Wave Velocity
N = 700 eGFR 10 – 45ml/min/1.73m2 Slide courtesy of Prof Schaefer
Systolic BP SDS 0.42 0.126 0.126 <.0001
25OH Vitamin D -0.025 0.032 0.158 0.0002
S-Phosphate 0.52 0.014 0.171 0.0115
iPTH 0.006 0.007 0.179 0.0675
Beta Partial R2 Model R2 p
Systolic BP SDS 0.17 0.029 0.029 0.0005
S-Phosphate 0.55 0.028 0.056 0.0005
S-Calcium -1.03 0.022 0.078 0.0016
25OH Vitamin D -0.02 0.014 0.092 0.012
IMT SDS
PWV SDS
Predictors of cIMT and PWV
Slide courtesy of Prof Schaefer
Studies in dialysis patients
KDOQI CKD-‐MBD Guideline Adherence Rates
n = 890 pa6ents
10
45
45
30
64
6
24
60
16
8
63
30
19
81
0%
20%
40%
60%
80%
All < 1 1 to 5 5 to 11 12+
High P levels in 45% of PD patients
1 Above Within
Below KDOQI age-‐specific target range
0
100
200
300
400
500
600
Net
herla
nds
Fra
nce
Gre
ece
Pol
and
Ger
man
y
UK
Can
ada
Kor
ea
Cze
ch R
ep
Indi
a
Tur
key
Italy
Chi
na
US
A
Chi
le
Uru
guay
Bra
zil
Arg
entin
a
Me
dia
n s
eru
m iP
TH
leve
l (p
g/m
l) PTH levels in PD patients
KDIGO 2009
KDOQI 2003 EPDWG 2003
Authors / Journal
Number of dialysis pts
Vascular measures
Clinical / biochemical associations with cIMT
Oh / Circulation 2002
39 cIMT CAC
- dialysis duration - mean serum P - PTH levels
Litwin / JASN 2005
37 cIMT - dialysis duration - mean serum P
- Mean calcitriol dose
Mitsnefes / JASN 2005
16 cIMT distensibility
- dialysis duration - mean serum Ca x P - Mean calcitriol dose - mean PTH levels
Shroff / JASN 2007
85 cIMT PWV CAC
- dialysis duration - mean serum P and Ca x P - Mean calcitriol dose - mean PTH levels
Civilibal / Ped Neph 2007
37 cIMT FMD
ECHO
- mean serum P - total & LDL cholesterol - mean calcitriol dose
Reusz / Ped Neph 2009
11 PWV - mean serum Ca x P - mean calcitriol dose
PTH is associated with calcification
Controls PTH < 2xULN PTH > 2xULN0.2
0.3
0.4
0.5
0.6
0.7
0.8
n = 33 n = 41 n = 44
p < 0.0001R2 = 0.65
0.38 ± 0.010.39 ± 0.01
0.58 ± 0.02
Intim
a M
edia
Thi
ckne
ss (m
m)
Shroff et al, JASN 2007
Controls PTH < 2xULN PTH > 2xULN0
3
6
9
12
15
p = 0.03
5.8 ± 1.2
8.6 ± 2.3
n = 33 n = 41 n = 44
5.6 ± 1.8
Puls
e w
ave
velo
city
(m/s
ec)
PTH <2 ULN n = 41
PTH >2 ULN n = 44
p
Total 5 (12%) 12 (27%) <0.01 Calcification score
7.8
(0 – 98) 85.3
(0 – 2039) 0.001
Age (years)10 15 20 25 30 35 40 45 50
Goodman et al., NEJM 2000
Oh et al., Circula6on 2002
Civilibal et al., Pediatr Nephrol 2006
36%
92%
15%
Eifinger et al., NDT 2000 46%
Shroff et al., JASN 2007 17%
0
Predictors of CAC -‐ age -‐ dialysis dura6on -‐ serum P -‐ PTH -‐ hs-‐CRP -‐ Higher Ca intake from binders
CAC in children and young adults
Effects of vitamin D supplementation
Vitamin D No Vitamin D
PW
V S
DS
-2
-1
0
1
2
3
*<0.0001
Vitamin D No Vitamin D
IMT
SD
S
0
1
2
3
*<0.008
Vit D supplements (Ergo/ cholecalciferol) in pre-dialysis CKD
InCma Media Thickness Pulse Wave Velocity
Slide courtesy of Prof Schaefer
Shroff et al; CJASN 2012
0 3 6 9 12 15 18 21 240
4040
50
60
70
80
90
100
Number at risk Ergocalciferol 20 20 19 17 16 12 9 5 Placebo 20 20 15 13 12 8 5 4
Ergocalciferol
Placebo
p = 0.05
Time (months)
Ergocalciferol in CKD2-4 delays the onset of secondary hyperparathyroidism
% develop
ing high PTH
Authors / Journal
Number of dialysis pts
Vascular measures
Clinical / biochemical associations with cIMT
Oh / Circulation 2002
39 cIMT CAC
- dialysis duration - mean serum P - PTH levels
Litwin / JASN 2005
37 cIMT - dialysis duration - mean serum P
- Mean calcitriol dose
Mitsnefes / JASN 2005
16 cIMT distensibility
- dialysis duration - mean serum Ca x P - Mean calcitriol dose - mean PTH levels
Shroff / JASN 2007
85 cIMT PWV CAC
- dialysis duration - mean serum P and Ca x P - Mean calcitriol dose - mean PTH levels
Civilibal / Ped Neph 2007
37 cIMT FMD
ECHO
- mean serum P - total & LDL cholesterol - mean calcitriol dose
Reusz / Ped Neph 2009
11 PWV - mean serum Ca x P - mean calcitriol dose
A
A
Bimodal effect of 1,25 dihydroxy D
0 50 100 150 200 2500.2
0.3
0.4
0.5
0.6
0.7
0.8 p < 0.0001
1,25 dihydroxy Vit D (pmol/L)
Car
otid
IMT
(mm
)
Shroff et al; JASN 2008
0 50 100 150 200 2500.1
1
10
100
1000
10000p = 0.0002
1,25 dihydroxy Vit D (pmol/L)
Cal
cifi
cati
on
sco
re(l
og
axi
s)
Log calcifica6o
n score
A
1
10
100
1000
hs-CRP (mg/L) <10 >10 <10 >10 <10 >10p
1,25(OH)2D (pmol/L) low normal high
n = 8 14 18 10 5 6
Cal
cific
atio
n sc
ore
(log
axis
)
AssociaCon with FGF23
Wan and Shroff; NDT 2012
Progression of vascular disease
Goodman et al; NEJM 2000
P levels determine progression of coronary calcification
Civilibal et al; Ped Nephrol 2010
Dependent variable Independent variable β R2 P
Final CACS Final Ca×P product 0.880 0.736 0.004 CAC progressiona Final albumin −0.811 0.601 0.009
CORONARY-ARTERY CALCIFICATION IN YOUNG ADULTS WHO ARE UNDERGOING DIALYSIS
Volume 342 Number 20
·
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and a calcified atheroma near the ostium of the rightcoronary artery was detected by echocardiographyin the other.
CT scanning was repeated in 22 patients a meanof 22±7 months later. Among 12 patients who hadno evidence of coronary-artery calcification on theinitial scan, 2 had evidence of calcification on fol-low-up scanning. Among the 10 of these 22 patientswho had evidence of coronary-artery calcification onthe initial scan, 9 had a higher calcification score onfollow-up scanning; the values nearly doubled (from125±104 to 249±216) over a mean period of 20±3months (P=0.02) (Fig. 3). Serum concentrations ofphosphorus and the calcium–phosphorus ion prod-uct were positively correlated with the change in cal-cification scores at follow-up.
DISCUSSION
Our results indicate that coronary-artery calcifica-tion, as measured by electron-beam CT, is commonin women and men who are 30 years old or youngerand who have end-stage renal disease for which theyare undergoing regular dialysis. It is quite uncom-mon, however, in normal subjects who are 20 to 30years of age. Indeed, only 10 percent of women and25 percent of men between the ages of 40 and 49years who have normal renal function have coronary-artery calcification,
19
whereas in our study, seven ofeight women (88 percent) and seven of eight men(88 percent) who were 20 to 30 years of age had cal-cification. Thus, coronary-artery calcification occursmore frequently in young adults with end-stage re-
nal disease than in either normal subjects of thesame age and sex or older adults with normal renalfunction.
Several established risk factors for coronary arterydisease, such as elevated levels of systolic and diastol-ic blood pressure, male sex, and the presence of di-abetes mellitus, were not associated with coronary-artery calcification in this relatively small study ofyoung patients who were undergoing dialysis. Onlyone patient had diabetes, reflecting the low preva-lence of diabetes among young adults who are un-dergoing dialysis.
22
Among those with coronary-arterycalcification, serum cholesterol concentrations werelower and serum albumin concentrations and body-mass index were higher than in the patients withoutcalcification. These findings do not support the viewthat malnutrition has a role in the development ofcoronary artery disease in young persons treated withdialysis, as has been suggested in the case of olderadults.
23
The duration of treatment with dialysis was sub-stantially longer, however, in the patients with coro-nary-artery calcification than in those without calci-fication. All had undergone regular dialysis for at leastfive years, and most started dialysis as children or ad-olescents. Indeed, the age at which dialysis was start-ed averaged 13±4 years among those with coro-nary-artery calcification.
The relation between coronary-artery calcificationscores and clinically important coronary-artery le-sions is controversial.
24
In persons older than 50 yearsof age, calcification scores of more than 10 but lessthan 100 are considered to reflect the presence ofminimal or mild luminal stenosis.
19
Values of 100 to400 suggest the presence of nonobstructive coro-
Figure 2.
Prevalence of Coronary-Artery Calcification among 39Patients with End-Stage Renal Disease, According to the Dura-tion of Treatment with Dialysis.Coronary-artery calcification was assessed by electron-beamcomputed tomography. The stepped dashed line indicates theproportion of patients with evidence of coronary-artery calcifi-cation within each interval of approximately four years. Thecurved line reflects estimates derived by logistic-regressionanalysis. All patients were 30 years of age or younger whenthey were first evaluated by electron-beam computed tomogra-phy. The duration of dialysis excludes intervals of adequate re-nal function as a result of renal transplantation in 27 patients.
0.0
1.0
0 24
0.2
0.4
0.6
0.8
4 8 12 16 20
Duration of Dialysis (years)
Pro
po
rtio
n w
ith
!C
alci
fica
tio
n
Figure 3.
Coronary-Artery Calcification Scores in 10 Patientswith Evidence of Coronary-Artery Calcification on the InitialScan and in 2 Patients in Whom Calcification Was Detectedduring Follow-up.Coronary-artery calcification was assessed by electron-beamcomputed tomography. The mean interval between the scanswas 20 months (range, 12 to 41). All patients underwent regulardialysis, and all were 20 to 30 years of age at the time of thefirst scan.
0
700
First scan Second scan
204060
100
300
500
Cal
cifi
cati
on
Sco
re
The New England Journal of Medicine Downloaded from nejm.org on April 11, 2012. For personal use only. No other uses without permission.
Copyright © 2000 Massachusetts Medical Society. All rights reserved.
Serum P posi6vely correlated with doubling of calcifica6on scores within 20 months
PWV Progression within1 Year of Follow-up
-2
-1
0
1
2
Δ P
WV
(m
/s)
Evolution of cIMT and PWV
0 12 24
Slide courtesy of Prof Schaefer
0 12 24
IMT Progression within 1 Year of Follow-up
-0.15
-0.10
-0.05
0.00
0.05
0.10
0.15
0.20
-4
-2
0
2
4
Δ IMT (mm) Δ IMT SDS
Months
0 12 24
SDS
-1,5
-1,0
-0,5
0,0
0,5
1,0
1,5
2,0
2,5
CKDDialysisTx
An arterial biopsy model
Shroff et al, Circulation 2008; JASN 2010; JASN 2013
Ca accumulation in vessels begins in pre-dialysis CKD
Normal Pre-dialysis Dialysis0
10
20
30
40
50p = 0.02
p = 0.0005
n = 6 n = 10 n = 24
Ca
load
in th
e ve
ssel
wal
l (µ
gm/µ
L)
HydroxyapaCte crystals
Histological changes in the Vessels were only seen in dialysis patients
Shroff et al; Circula2on 2008
No inflammaCon
A
CalcificaCon is associated with Ca x P levels
00
10
20
30
40
50
Mean time-integrated Ca x P product (mMol2/L2)3 4 5 6 7
p = 0.007r2 = 0.41
pre-dialysis n = 10Dialysis n = 24
Ca
load
in th
e ve
ssel
(µg/µ L
)
Ca load correlates with carotid IMT
Pulse wave velocity In 2 /31 patients Coronary calcification on CT scan In 2 /31 patients
50
40
30
20
10
0 0.0 0.3 0.4 0.5 0.6 0.7
Carotid Intima Media Thickness (mm)
Ca
load
in th
e ve
ssel
(µg/µL
)
Pre-dialysis n=9 Dialysis n=22
P=0.01 R2=0.42
Shroff et al; Circula2on 2008
Calcification progression is determined by vessel calcium load
Baseli
ne
von k
ossa
positi
ve
Baseli
ne
von k
ossa
nega
tive
0.1
0.20.25
0.30
0.35
0.40
0.45
0.50
0.55
0.60
0.65
0.70
0.75 p = 0.01 p = 0.08
Caro
tid in
tima-
med
ia th
ickne
ss (m
m)
Von Kossa stain
10
-0.10
-0.05
0.00
0.05
0.10
0.15
0.20
0.25
25 30 35 40 45 50
p = 0.004R2 = 0.59
Vessel Ca load (µg/µL)
Del
ta c
hang
e in
cIM
T
Associations with cIMT progression • Baseline vessel Ca load r = 0.47 • Baseline 25-OH D level r = -0.22 • Mean time-averaged P r = 0.61 • Δ PTH r = 0.17 • Δ Fetuin-A levels r = 0.11
No associations with • Serum calcium • FGF-23 or s-klotho • Osteoprotegerin
p = 0.004 r = 0.47
Conclusions – vascular studies
• Vascular changes begin in pre-dialysis CKD stage 3b (or earlier) and progress rapidly on dialysis
• Serum phosphate is associated with progression
of vascular disease (cIMT and calcification)
• 4C and CKiD studies may soon provide markers of CVD progression
Bone disease in children with CKD
KDIGO 2009 We recommend that infants with CKD 2-5D have their lengths measured at least quarterly, while children with CKD 2-5D should be assessed for linear growth at least annually (1B)
High Ca*P Osteodystrophy Limb deformities Osteopenia Tissue calcification Bone pain
% p
atie
nts
0
5
10
15
20
25
PTH (pg/ml)
0-100 100-200 200-300 300-500 500-1000 >1000
% p
atie
nts
with
com
plic
atio
ns
0
10
20
30
40
50
60
aba
ab
c
bc
d
IPPN Registry data - Borzych et al. Kidney Int 2010
Bone disease in PD patients
PTH levels and MBD
↑Ca
↓ Longitudinal growth
Clinical & radiological symptoms
n = 900 children on PD
Bakkaloglu SA et al; CJASN 2010
Turnover (BFR/BS)
MineralizaCon (OV/BV + OMT)
Serum Calcium (mg/dl)
Serum Phosphorus (mg/dl)
Alkaline Phosphatase
(IU/L) PTH (pg/ml)
Low (n = 7)
Normal (n = 5)
9.6 ± 0.4 8.2 ± 0.6 197 ± 26 116 ± 15
Abnormal (n = 2)
8.1 ± 2.0 8.2 ± 2.2 250 ± 160 282 ± 162
Normal (n = 62)
Normal (n = 39)
9.6 ± 0.1 6.0 ± 0.2 198 ± 16 286 ± 38
Abnormal (n = 23)
8.9 ± 0.2 5.9 ± 0.3 243 ± 41 477 ± 68
High (n = 92)
Normal (n = 39)
9.2 ± 0.2 6.2 ± 0.2 340 ± 31 587 ± 58
Abnormal (n = 53)
8.8 ± 0.1 6.5 ± 0.2 506 ± 39 924 ± 67
Associations with abnormal mineralization
Bone biopsies in 161 children on peritoneal dialysis ↓ serum calcium and ↑ PTH in paCents with defecCve mineralizaCon, irrespecCve of bone turnover
Wesseling-Perry et al; cJASN 2012
N=14 N=24 N=14
Bone biopsies - ↓ Ca and ↑ PTH are associated with defective mineralization
PTH
FGF23
MineralizaCon
Turnover
Bone biopsies in 52 children with CKD 2-4 Age - 2 to 21 years
Abnormal mineralization ↓ serum calcium ↑ PTH FGF-‐23: NS Acidosis: NS
β (95% CI) p-‐value
Calcium (per 1 mg/dl)
0.31 (0.08, 0.54) 0.01
25(OH)D (per 10 ng/ml)
0.18 (0.01, 0.34) 0.04
1,25(OH)2D (per 10%)
-‐0.07 (-‐0.10, -‐0.04) < 0.001
PTH (per 10%)
-‐0.02 (-‐0.04, -‐0.01) 0.002
FGF23, underlying renal disease and acidosis were not significant.
Cross-sectional - 171 patients, age 5-21 yrs - CKD 2-5D
Denburg, et al. JCEM 2013
Decline in corCcal BMD Z-‐scores:
Higher baseline 1,25(OH)2D
↑ΔPTH
↑Δ Calcium -‐ ↑ cor6cal BMD
(especially in growing children)
Lower cor6cal BMD – increased fracture risk (HR 1.75)
Tibia QCT - ↓ Ca and ↑ PTH are associated with decline in cortical BMD
Longitudinal - After 12 months - 89 patients
Tsampalieros, et al. Kidney Int 2012
Tibia QCT - Trabecular BMD
Limitations of DXA in CKD
Confounding by short stature 2D measurement of superimposed cor6cal and trabecular bone Superimposed vascular calcifica6ons Failure to dis6nguish between PTH effects on trabecular and
cor6cal bone
KDIGO 2009 and ISCD 2007 – recommends against rouCne DXA BMD tesCng in CKD3-‐5 BMD does not differenCate the type of renal osteodystrophy
Whole Body DXA in transplant recipients
-4
-2
0
2
Z-sc
ores
Baseline 3 6 12Months Since Transplantation
Whole Body BMC
-4
-2
0
2
Z-sc
ores
Baseline 3 6 12Months Since Transplantation
Lean MassBone Mineral Content
Tsampalieros, et al; Am J Transplant 2013
Whole body BMC Z-‐scores were correlated with pQCT cor6cal area Z-‐scores (R = 0.77, p < 0.0001) rather than cor6cal BMD.
Greater linear growth was associated with greater increases in WB-‐BMC Z-‐scores (p = 0.01).
Greater glucocor6coid exposure was associated with greater declines in WB-‐BMC Z-‐scores (p < 0.001).
-2
0
2
4
-2
0
2
4
Baseline 3 6 12 Baseline 3 6 12
Baseline age <13 yrs Baseline age ³13 yrs
LS-B
MD
Z-s
core
s
Months Since Transplantation
Renal Transplant: Lumbar Spine DXA
Tsampalieros, et al; Am J Transplant 2013
Changes in LS-‐BMD correlated with changes in pQCT trabecular BMD (R = 0.47) Decrease in LS-‐BMD -‐ ↓PTH levels -‐ ↑ Steroid exposure
Conclusions – bone studies
• Abnormal bone mineralisation occurs early (CKD2) and is associated with low serum calcium and high PTH
• Non-invasive assessment by qCT and DXA may be useful tools in evaluating children with CKD
Do we need new guidelines? Do we need to change existing recommendations / grading of existing recommendations?
Separate paediatric guidelines or
More precisely address paediatric management within any new guidelines
?
In the context of paediatric CKD-MBD