ckd-mbd in children/adults - era-edtackd-mbd in children/adults . markus ketteler ....
TRANSCRIPT
Pathogenesis of secondary hyperparathyroidism
VDR CaR
Ca2+
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)
Normal kidney function
Normal Ca2+- levels keep PTH secretion/synthesis under control
PTH secretion
PTH synthesis
Cell proliferation
PTH
VDR CaR
Calcitriol
Phosphate
Ca2+
PTH secretion
PTH synthesis
Cell proliferation
PTH
Slatopolsky E et al. Kidney Int 1999;73:S14–9
Pathogenesis of secondary hyperparathyroidism
Normal Diffuse
Early nodules
Nodular transformation
solitary nodes
Gla
nd v
olum
e
secretory cells
Ref: Tominaga Y et al. Curr Opin Nephrol Hypertens 1996;5:336–41
VDR
CaR
Normal very high PTH
VDR
CaR
Pathogenesis of secondary hyperparathyroidism
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 (?)
Leonard MB et al. NEJM 2004; 351:868
Minimal Change GN: Glucocorticoids and bone metabolism
Leonard MB et al. NEJM 2004; 351:868
Minimal Change GN: Glucocorticoids and bone metabolism
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
Bone density and structure: Influence of age and CKD stage
Adapted from: Time Magazine, US Edition 2007 (December 24);26:170
Vitamin D and • Bone metabolism • Diabetes • CV disorders • Multiple sclerosis • Rheumatoid arthritis • Cancer • Infections
Vitamin D – deficiency / insufficiency
24-H
ydro
xyla
se
24,25(OH)2D3 and 1α,24,25(OH)2D3
Plants: Ergosterol D2 (Ergocalciferol)
Skin: 7-Dehydrocholesterol
Vitamin D3
1α,25(OH)2 Vitamin D3
(Calcitriol, endogenous VDR- activator, 1,25D)
25(OH) Vitamin D3
LIVER
Liver or fatty fish: D3 (Cholecalciferol)
Nutrition
HO
CH2
OH HO
CH2
OH
HO
CH2
OH
NIERE (Calcidiol, 25D)
(Cholecalciferol)
UVB
24-Hydroxylase
Inactivation
Vitamin D – deficiency / insufficiency
Grant WB, Holick MF. Altern Med Rev 2005; 10:94-111 Institute of Medicine (IOM), Report November 2010 / Rosen CJ. N Engl J Med 2011; 364:248-54
Vitamin D – deficiency / insufficiency
Grant WB, Holick MF. Altern Med Rev 2005; 10:94-111 Institute of Medicine (IOM), Report November 2010 / Rosen CJ. N Engl J Med 2011; 364:248-54
20 – 60 ng/ml 600 – 4.000 IU per day
Vitamin D – deficiency / insufficiency
2.4
2.6
2.8
3.0
3.2
QiN Daten
0.8
1
1.2
1.4
1.6
1.8
2
2.2
<3 3-4 4-5 5-6 6-7 7-8 8-9 >9
S-Phosphate [mg/dl] (mmol :3,1)
Rela
tive
mor
talit
y ri
sk
<3 3-4 4-5 5-6 6-7 7-8 8-9 >9
40538 Patients Fresenius Medical Care North America Patient Statitics Multivariate analysis
Block GA et al., JASN 2004
Serum phosphate vs. mortality risk in hemodialysis patients
0.8
1
1.2
1.4
1.6
1.8
2
2.2
2.4
2.6
2.8
3.0
3.2 14435 Patients QiN-Register 3 different analyses unadjusted multivariate limited multivariate adjusted Stoffels et al., unpublished
Mediasclerosis • Non-inflammatory • No lipid deposition • Usually asymptomatic • pseudohypertension
Atherosclerosis • Inflammatory • Lipid deposition • ischemia-related,
occlusion
Pathomechanisms of extraosseous calcification Giachelli C. Kidney Int 2009
Coronary artery calcifications are observed in childhood-onset dialysis patients
Goodman et al., NEJM (2000) 342:1478-83
Chronic dialysis patients 60 controls (20-30-y-old)
Alter (Jahre)
CAC
Circulation 2002
Coronary artery calcifications are observed in childhood-onset dialysis patients
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
Calcium and the bone-vascular-axis
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
Wan et al. NDT 2013; 28:153
FGF23 and other bone biomarkers in CKD: Stage dependency in children
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 ?
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.
http://ec.europa.eu/food/food/fAEF/additives/index_en.htm
„LookForPhos“: Dialysis patients received a magnifying glass and instructions concerning better choices in fast-food-restaurants and supermarkets = Net phosphate lowering: 0.6 mg/dl
Sehgal AR, ASN Philadelphia 2011
From dietary phosphate restriction to dietary phosphate additive restriction ?
Sehgal AR, ASN Philadelphia 2011
From dietary phosphate restriction to dietary phosphate additive restriction ?
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
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.
Ketteler M et al., Kidney Int 2014 (in press)
CKD-MBD Controversies Conference | October 25-27, 2013 | Madrid, Spain
CKD-MBD GL Update 2015
JSDT Congress │ June 15, 2014 │ Kobe, Japan
Sausage is so expensive, boy! Just be so kind to eat your phosphate pure today…