!! 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


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

·

1481

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


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

!! ckd$mbd’in’children’ -...

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