Download CKD-MBD in ChildrenandAdults

ESPN 2014
Porto, September 19, 2014
CKD-MBD in children/adults
Markus Ketteler
[email protected]
Pathogenesis of secondary hyperparathyroidism
CaR
Ca2+
VDR
PTH
PTH secretion
PTH synthesis
Normal kidney function
Cell proliferation
Normal Ca2+- levels keep
PTH secretion/synthesis under control
Silver J et al. Am J Physiol Renal Physiol 2002;283:F367–76
Brown EM. In: The Parathyroids – Basic and Clinical Concepts 2nd edn. 2001. Bilezikian JP et al. (eds)
Pathogenesis of secondary hyperparathyroidism
Calcitriol
CaR
Ca2+
VDR
PTH secretion
PTH synthesis
Phosphate
Slatopolsky E et al. Kidney Int 1999;73:S14–9
Cell proliferation
PTH
Pathogenesis of secondary hyperparathyroidism
solitary nodes
Gland volume
VDR
CaR
Early
nodules
secretory
Normal cells
Nodular
transformation
Diffuse
VDR
CaR
Normal
PTH
Ref: Tominaga Y et al. Curr Opin Nephrol Hypertens 1996;5:336–41
very high
Kidney Int Suppl 2009: S1-S130
Kidney Int Suppl 2009: S1-S130
Kidney Int Suppl 2009: S1-S130
Kidney Int Suppl 2009: S1-S130
Kidney Int Suppl 2009: S1-S130
CKD-MBD:
children vs. adults – a few differences…
 During growth, children require a (moderately) positive
calcium balance
 Alkaline phosphatase and phosphate serum
concentrations are increased vs. the normal laboratory
range in adults
 Interpretation of bone density may differ from adults (?)
 How about glucocorticoid therapies (?)
Minimal Change GN:
Glucocorticoids and bone metabolism
Leonard MB et al. NEJM 2004; 351:868
Minimal Change GN:
Glucocorticoids and bone metabolism
Leonard MB et al. NEJM 2004; 351:868
Bone density and structure:
Influence of age and CKD stage
Wetzsteon RJ et al. JBMR 2011; 26:2235
Bone density and structure:
Influence of age and CKD stage
Wetzsteon RJ et al. JBMR 2011; 26:2235
Vitamin D and
•
•
•
•
•
•
•
Bone metabolism
Diabetes
CV disorders
Multiple sclerosis
Rheumatoid arthritis
Cancer
Infections
Adapted from: Time Magazine, US Edition 2007 (December 24);26:170
Vitamin D – deficiency / insufficiency
UVB
Skin: 7-Dehydrocholesterol
CH2
LIVER
HO
OH
Vitamin D3
Liver or fatty fish: D3
(Cholecalciferol)
(Cholecalciferol)
CH2
Nutrition
HO
OH
NIERE
CH2
HO
OH
1α,25(OH)2 Vitamin D3
(Calcitriol, endogenous VDRactivator, 1,25D)
24-Hydroxylase
25(OH) Vitamin D3
(Calcidiol, 25D)
24-Hydroxylase
Plants: Ergosterol
 D2 (Ergocalciferol)
24,25(OH)2D3 and
1α,24,25(OH)2D3
Inactivation
Vitamin D – deficiency / insufficiency
Vitamin D – deficiency / insufficiency
Institute of Medicine (IOM), Report November 2010
Grant WB, Holick MF. Altern Med Rev 2005; 10:94-111
/
Rosen CJ. N Engl J Med 2011; 364:248-54
Vitamin D – deficiency / insufficiency
20 – 60 ng/ml
600 – 4.000 IU per day
Institute of Medicine (IOM), Report November 2010
Grant
WB, Holick
MF.
Altern
Med
Rev 2011;
2005; 364:248-54
10:94-111
/
Rosen
CJ.
N Engl
J Med
Serum phosphate vs. mortality risk in hemodialysis patients
Relative mortality risk
3.2 40538 Patients
3.0 Fresenius Medical Care
North America Patient Statitics
2.8 Multivariate analysis
2.6
Block GA et al., JASN 2004
3.2
14435 Patients
3.0
QiN-Register
3 different analyses
2.8
2.6
2.4
2.4
2.2
2.2
2
2
1.8
1.8
1.6
1.6
1.4
1.4
1.2
1.2
1
1
0.8
<3 3-4 4-5 5-6 6-7 7-8 8-9 >9
0.8
unadjusted
multivariate limited
multivariate adjusted
Stoffels et al., unpublished
QiN Daten
<3 3-4 4-5 5-6 6-7 7-8 8-9 >9
S-Phosphate [mg/dl] (mmol
:3,1)
Atherosclerosis
• Inflammatory
• Lipid deposition
• ischemia-related,
occlusion
Mediasclerosis
• Non-inflammatory
• No lipid deposition
• Usually asymptomatic
• pseudohypertension
Pathomechanisms of extraosseous calcification
Giachelli C. Kidney Int 2009
Coronary artery calcifications are observed in childhoodonset dialysis patients
CAC
Goodman et al., NEJM (2000) 342:1478-83
Alter (Jahre)
Chronic dialysis patients
60 controls
(20-30-y-old)
Coronary artery calcifications are observed in childhoodonset dialysis patients
Circulation 2002
Calcium and the bone-vascular-axis
J Am Soc Nephrol 2010; 21:103-12
Calcium and the bone-vascular-axis
J Am Soc Nephrol 2010; 21:103-12
Calcium and the bone-vascular-axis
J Am Soc Nephrol 2010; 21:103-12
Phosphate
balance in
normal kidney
function
Berndt T, Kumar R, Physiology
2009; 24:17-25
Prie et al., Kidney Int 2009; 75:882-9
FGF23, PTH and Phosphate in CKD
Isakova T et al., Kidney Int 2011
FGF23 and other bone biomarkers in CKD:
Stage dependency in children
Wan et al. NDT 2013; 28:153
Dtsch Arztebl Int. 2012 Jan;109(4):49-55.
o Phosphate additives (mostly phosphate salts) are intestinally absorbed in
up to 100%
o Absorption of natural phosphates (phosphate esters, phytates,
phospholipids, phosphoproteins) is estimated in a range of 30 – 60 %
o Restriction of phosphate additives would be feasible without a reduction of
the dietary protein content of the ingested food
o Some natural polyphosphates possess protective properties (e.g.
pyrophosphate, phytate)
o USA – RDA: 700 mg/day, EAR: 580 mg/day, UL: 4.200 mg/day
* P = GRAS („generally regarded as safe“)
From dietary phosphate restriction to
dietary phosphate additive restriction ?
http://ec.europa.eu/food/food/fAEF/additives/index_en.htm
Food additives are:
o Sweeteners to sweeten foods or in table-top sweeteners;
o Colours adding or restoring colour in a food;
o Preservatives prolonging shelf-life of foods by protecting them against
deterioration by micro-organisms;
o Antioxidants prolonging shelf-life of foods by protecting them against oxidation
e.g. fat rancidity, colour changes;
o Stabilisers to maintain the physico-chemical state of a foodstuff;
o Emulsifiers to maintain the mixture of oil and water in a foodstuff.
From dietary phosphate restriction to
dietary phosphate additive restriction ?
Sehgal AR, ASN Philadelphia 2011
„LookForPhos“:
Dialysis patients received a magnifying glass and
instructions concerning better choices in fastfood-restaurants and supermarkets
= Net phosphate lowering: 0.6 mg/dl
From dietary phosphate restriction to
dietary phosphate additive restriction
?
Sehgal AR, ASN Philadelphia 2011
LookForPhos: Flow of Participants Through the Trial
Sullivan, C. et al. JAMA 2009;301:629-635
Copyright restrictions may apply.
LookForPhos: Primary and Secondary Outcomes Among 145
Intervention and 134 Control Participants.
Sullivan, C. et al. JAMA 2009;301:629-635
Copyright restrictions may apply.
Chairpersons: Mary Leonard, Philadelphia, and Markus Ketteler, Coburg
Ketteler M et al., Kidney Int 2014 (in press)
 VC: The group also believed that there were insufficient data to support special
considerations for CKD subgroups including predialysis CKD, transplant
recipients, children, and the elderly.
 Bone quality: The working group noted that none of the studies addressing
bone therapies or DXA BMD fracture prediction included children but given the
unique characteristics of the growing skeleton, the future updating Work
Group may elect to examine this issue more closely with the hope to provide
some pediatric guidance.
 Ca + P: Studies of the impact of calcium and non-calcium containing phosphate
binders, and other therapies that impact calcium balance should consider the
special needs of the growing skeleton.
 Vitamin D + PTH: Target PTH levels may also differ during growth and
development; however, there are insufficient data to provide pediatric-specific
recommendations.
CKD-MBD GL Update 2015
CKD-MBD Controversies
Conference
| 2014
October│ 25-27,
2013
| Madrid, Spain
JSDT Congress
│ June 15,
Kobe,
Japan
Sausage is so expensive, boy!
Just be so kind to eat your phosphate
pure today…