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(Renal osteodystrophy)
Chronic Kidney Disease-
Metabolic and Bone Disorder
Dr Simon Waller Consultant Paediatric Nephrologist
Evelina Childrens’ Hospital
London, UK
• CKD-MBD
• Bone – the basics
• Extra-skeletal (Cardiovascular) calcification
• The Calcium, Phosphate, VitD and PTH axis
• Renal Osteodystrophy – Metabolic Bone – Investigation (PTH) and Management
• Growth data & PTH levels
• FGF23
• Practical guidelines
CKD-Metabolic and Bone disorder
• KDIGO Kidney Disease: improving global
outcomes – 2006
Definition
Loss of cortical outline with
subperiosteal bone resorption.
Multiple erosions, metaphyseal
fracture
�
Extra skeletal calcification
Coronary Artery Calcification
Coronary Artery Calcification
Bones
• Osteoblasts and Bone Formation
– Produce osteoid
– PTH, vitamin D and oestrogen receptors
• Osteoclast and Bone Resorption
– Multinucleated cell
– Howship’s lacunae
• Osteocytes
– later
Remodelling
A-R-F
• Activation
• Osteoclast resorption
• Reversal
• Pre-osteoblast migration and
differentiation
• Osteoblast matrix (osteoid) formation
• Mineralisation
Osteoclasts
Periosteal erosions
Electron micrograph of (650 magnification)
of a single trabecula of vertebral TB with deep Howship
lacunae caused by excessive osteoclastic resorption
causing stresses that will eventually lead to mechanical
failure
Osteoid
Osteoblasts
No osteoid or osteoblasts
Increased
osteoclasis
CKD-MBD
Metabolic Bone disease and
Vascular Calcification
• Bone disease and vascular calcification
– Multifactorial
– Mineral metabolic disturbance due to CKD may
not be primary/only aetiology
– Link between VC and CKD being established
Am J Kidney Dis 32[Suppl 3]: S115, 1998
Cardiovascular Mortality, by age, sex and race
in the general population and dialysis patients
Coronary-Artery Calcification in Children and Young Adults with ESRF on Dialysis
W Goodman NEJM Volume 342. Number 20.1479
Cardiovascular disease:
Arterial Vascular Disease
TYPE OF CVD (Pathology) Clinical Presentation
Atherosclerosis IHD (MI, Angina, Cardiac
Arrest), CerebroVD, PVD, HF
Arteriosclerosis: dilated and non- IHD, HF
compliant large vessels
Fishbien and Fishbien. Arch Pathol Lab Med—Vol 133, August 2009
Mineral disturbance
CKD and Secondary Hyperparathyroidism
• Hyperphosphataemia
• Hypocalcaemia
• Vitamin D deficiency
• FGF23 activation
CKD phosphate
PTH
calcium
CKD phosphate Vit D
PTH
calcium
Renal mass
Diet
Mobility/activity
Latitude
Phosphate
FGF23
CKD phosphate Vit D
PTH
calcium
CKD phosphate Vit D
PTH
calcium
CKD phosphate Vit D
PTH
calcium
Skeletal resistance to PTH
Ureamia/acidosis
FGF23
VDR, PTH/PTHrP, CaSR expression altered
PTH fragments
Hyperplasia of PT gland and altered function
CKD phosphate Vit D
calcium
Skeletal resistance to PTH
Ureamia/acidosis
VDR, PTH/PTHrP, CaSR
expression altered
Hyperplasia of PT gland and
altered function
SECONDARY
HYPERPARATHYROIDISM
PTH as a Surrogate Marker
Renal Osteodystrophy
• High Turnover Bone Disease
– Persistently high PTH levels activate both
osteoclasts and osteoblasts
Salusky IB, Goodman WG et al . Kidney Int 1994;45:253-8
Kuizon BD, Goodman WG, Salusky IB et al. Kidney Int 1998;53:205-11
Renal Osteodystrophy
• High Turnover Bone Disease
– Persistently high PTH levels activate both
osteoclasts and osteoblasts
• Low Turnover Bone Disease
– Adynamic
– Osteomalacia
• Mixed ROD
Salusky IB, Goodman WG et al . Kidney Int 1994;45:253-8
Kuizon BD, Goodman WG, Salusky IB et al. Kidney Int 1998;53:205-11
TMV Classification
• Underlining the contribution of parameters
other than turnover to bone health
Three Key Histologic descriptors
• Turnover
• Mineralisation (before development of 2ary hyperparathyroidism)
• Volume
Clinical manifestations
•Fracture rates
•Bony deformities
•Poor growth
•Chronic bone pain
TMV Classification
Investigation and Management of
ROD
• Biopsy with histomorphometry mainly research
tool
• Calcium, phosphate, 25(OH)VitD, ALP, & PTH
• BMD, X-ray
• Anthropometry
• BS-ALP, FGF23
Management of ROD
• via control of PTH levels
– via phosphate control
• phosphate restriction
Management of ROD
• via control of PTH levels
– via phosphate control
• phosphate restriction
• phosphate binders
Management of ROD
• via control of PTH levels
– via phosphate control
• phosphate restriction
• phosphate binders
–aluminum hydroxide
–calcium carbonate/acetate
–Sevelamer hydrochloride/carbonate
– lanthanum carbonate
Management of ROD
• via control of PTH levels
– via phosphate control
• phosphate restriction
• phosphate binders
• calcium carbonate/acetate
– Calcium and phosphate concerns
– Dose related to serum levels and CaxP
– Is phosphate a vascular toxin?
– ?related to CV disease
Management of ROD
• via control of PTH levels
– via phosphate control
• phosphate restriction
• phosphate binders
– Vitamin D
• 1 α calcidol, calcitriol
• New analogues
Management of ROD
• via control of PTH levels
– via phosphate control
• phosphate restriction
• phosphate binders
– Vitamin D
– (Calcimimetics)
What level of PTH?
• Lack of evidence
• Different strategies Europe/N.America
Haffner D, Schaefer F.
Pediatr Nephrol. 2013 Apr;28(4):537-45.
Dilemma-PTH levels
Adynamic bone disease PT gland hyperplasia
-Calcium buffer -High turnover ROD
-Growth? -Growth
-CV disease
Under suppression Over suppression
What PTH level should we aim for ?
GFR KDIGO EPDWG
30-60 35-70
(ULN 65)
Normal
range
15-30 70-110 Normal
range
<15 or
Dialysis
3-5 x ULN 1.7-3 x ULN
Haffner D, Schaefer F.
Pediatr Nephrol. 2013 Apr;28(4):537-45.
Why should
supraphysiological PTH levels
be required?
•Ureamic toxins
•Assays
•Long carboxyl-terminal PTH fragments (C-PTH)
•PT Gland function uncontrolled
C-PTH
• Levels increase with worsening renal failure,
explaining the need for higher levels of ‘intact’ PTH
to prevent low turnover bone disease.
• Antagonises the biological actions of 1-84 PTH
• 7-84 PTH acts at a specific C-terminal PTH receptor,
inhibits resorption induced by 1-84 PTH
• 7-84 PTH is present in the parathyroid gland
Divieti P, et al. Endocrinology 2001:142(2); 916-925
What PTH level should we aim for?
• Histomorphometry, new PTH assays
and growth
• Growth data in relationship to PTH
• Relationship between 1-84 PTH, C-PTH
and growth
Growth
• Retrospective analysis of 99 patients
• Median age at entry 1.6 years (pre-pubertal)
• GFR < 41 mls/min/m2, (median 22)
• Data collected for mean of 3.6 yrs
– Until renal replacement therapy
– Initiation of growth hormone
– Lack of data or aged 10 years
Waller S, et al.
Pediatr Nephrol. 2003 Dec;18(12):1236-41
Growth
• Height SDS at entry –1.77 (p<0.001)
• Median PTH equal to upper limit of
normal
• Significant increase in Height SDS
– Independent of age and PTH levels
Change in Height SDS per year (Error bars = 95% Confidence Interval)
-0.08
-0.04
0
0.04
0.08
0.12
0.16
0.2
0.24
0.28
0.32
Year 1
n=94
Year 2
n=83
Year 3
n=51
Year 4
n=32
Year 5
n=29
Overall
n=99
De
lta
he
igh
t S
DS
pe
r ye
ar
p=0.004
(Ave. 3.6 yrs)
Ratio 1-84 PTH : C-PTH Methods: Patients
Number Age
years (range)
Mean GFR
mls/min/m2
(range)
CRF 127 7.7 (0.3-16.9) 34 (7-60)
Dialysis 26 13.3 (2.8-16.9)
Transplant 41 13.6 (3.8-17.1) 38 (13-60)
Waller SC. et al.Kidney Int. 2005 Jun;67(6):2338-45
Results
• Median follow-up (range) 1.1 (0.5-1.7)
years
• Clinic visits: 5 (3-15)
Mean (Range)
• Calcium : 2.36 (1.93-2.72) mmol/L
• Phosphate: 1.44 (0.65-2.59) mmol/L
• Ca x Phos: 42.2 (19.6-79.3) mg2/dL2
Mean PTH Levels (Range)
• CAP-PTH: 28.3 (1.7-403) pg/mL (Normal Range 5-39)
• ‘intact’PTH: 44.6 (5-596) pg/mL (Normal Range 14-66)
Height
• Change in Height SDS: -0.01 (-1.1-1.0)
41134N =
Change in Ht SDS per Year by CAP-PTH Level
Cha
ng
e in
Ht
SD
S p
er
Yea
r
.2
.1
-.0
-.1
-.2
-.3
Normal Range Above Normal Range
CAP-PTH CAP-PTH
(Error bars represent 95 % confidence interval for mean)
p=0.018
Change in Height SDS
N= 134 41
0.2
0.0
-0.2
Change in
Height
SDS per
Year
39120N =
.6
.5
.4
.3
.2
4
3
2
Mean Ratio
(Log Scale)
Mean 1-84 PTH:C-PTH Ratio
Normal Range Above Normal Range
CAP-PTH CAP-PTH (Error bars represent 95 % confidence interval for mean)
p=0.01 Control
Patients
N= 120 39
545454N =
Change in Ht SDS per Year by
1-84 PTH: C-PTH Ratio Tertiles
Cha
ng
e in
Ht
SD
S p
er
Ye
ar
.3
.2
.1
0.0
-.1
-.2
1-84 PTH: C-PTH 1st 2nd 3rd Tertile
Ratio <1.85 1.85-2.75 >2.75
(Error bars represent 95 % confidence interval for mean)
p=0.039 (ANOVA)
p=0.033
Change in Height SDS by
1-84 PTH: C-PTH Ratio Tertiles
Change in
Height SDS per
Year
0.2
0.0
-0.2
N= 54 54 54
Summary
• In children with CKD strict serum phosphate and calcium control aimed at normalising serum PTH levels allowed good growth along the centiles
• Patients with normal range PTH levels grew better than those with supraphysiological PTH levels
Summary
• 1-84 PTH: C-PTH ratio was higher with
normal range PTH levels
• Better growth was associated with
higher 1-84 PTH: C-PTH ratio
Conclusions
• Normal range PTH levels are safe and
appropriate in children with CKD
• Measurement of C-PTH levels may
provide clinically useful information
FGF23
• Secreted from osteocytes
• Target kidney
• Phosphaturic
CKD phosphate Vit D
PTH FGF23
FGF23
• Phosphaturic & decreased enteral absorption
– reduced expression of
• a phosphate transporter in proximal tubules
• 1--hydroxylase
– promotes expression
• 24-hydroxylase
• Associated with
– Vascular dysfunction, calcification & CVD
FGF23
• Increases early in children with CKD – As early as CKD 2
– PTH, Calcium, Phosphate & VitD: Normal
• Associated with improved height SDS BUT…
• Independent risk factor for CV mortality in adults.
• Non-calcium based phosphate binders decrease FGF23 levels with increased VitD and decreased PTH & stable phosphate
Wesseling-Perry K.
Pediatr Nephrol. 2013 Apr;28(4):569-76.
Mx of CKD-MBD KDOQI(wallerised)
Target Serum Phosphorus Levels
• CKD patients (Stages 1-5); serum level of
phosphorus should be maintained at mid-point of the age-appropriate normal range
• Dietary phosphorus should be decreased to the Dietary Reference Intake for age when the serum PTH concentration is above the target range for the stage of CKD and serum phosphorus is within the
target range or elevated for age
KDOQI(wallerised)
CKD 2-4
• If serum phosphorus levels cannot be controlled within the target range despite dietary phosphorus restriction, phosphate binders should be prescribed.
• Calcium-based phosphate binders are effective in lowering serum phosphorus levels – they should be used as the initial binder therapy
CKD 5
– calcium-based phosphate binders should be used as primary therapy in infants and young children .
– In older children and adolescents, either calcium and/or non-calcium based binders may be used.
KDOQI(wallerised)
In CKD Stages 2-4 • If serum PTH is above normal range serum 25-hydroxyvitamin D should
be measured.
– Periodic assessment is warranted thereafter if dietary or lifestyle changes
have occurred in the patient.
• If the serum level of 25-hydroxyvitamin D is deficient/insufficient
(<50-60nmol/L), supplementation with ergocalciferol or cholecalciferol
should be initiated
In CKD Stage 5:
• Therapy with an active vitamin D sterol (1α-calcitol) should be provided if
the serum levels of PTH are significantly raised (>3xULN)
Summary
• CKD-MBD
• Bones and CV calcification
• The Calcium, Phosphate, Vitamin D and PTH axis – CKD and secondary hyperparathyroidism
• Renal Osteodystrophy – Metabolic Bone – Ix and Mx; phosphate and PTH control
• PTH levels – Assays
– C-PTH
– Growth
• FGF23
CKD 2-4: Normal PTH levels
Normal PTH levels;
Appropriate
Safe
• (Normal 1-84 PTH: C-PTH)
• Improved/good Growth Velocity