(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