ckd-mbd in children/adults - era-edtackd-mbd in children/adults . markus ketteler ....

CKD-MBD in children/adults

Markus Ketteler

markus.ketteler@klinikum-coburg.de

ESPN 2014 Porto, September 19, 2014

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…