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Novel Aspects of Renal Bone Disease:
Current guidelines
Günter Klaus, Marburg, Germany
Review Parts of ...
• European Guidelines (Klaus et al, 2006)
• K/DOQI Clinical Practice guidelines for Bone Metabolism and Disease in children with Chronic Kidney Disease 2005
(kdoqi/guidelines_pedbone)
Guideline 1: Biochemical and radiological markerMarker Frequency at GFR
59-30 29-15 < 15
Aim
calcium 6 3 1 normal range
phosphate 6 3 1 normal range for age band
Ca x Pi 6 3 1 target range 3.3-4.4, 5.0 mmol2/l2 ,
AP 6 3 1
Normal range (age band)
S-HCO3- 6 3 1 normal range, at least: bicarbonate >
22mmol/l, base excess > -5 mmol/l
PTH 6 3 1 within normal range in moderate CRF (GFR>29ml/min/1.73m2)
2-3 times upper limit of normal in advanced CRF or on dialysis
25-(OH) D3 as indicated > 20 pg/ml
left hand / wrist X-ray
6-12 no radiological signs of sHPT, Looser zones or osteopenia
Case 1 (2002)• 2y old girl• CKD due to fetofetal Transfusion Syndrome
(shock)• CCR 7.8 ml/min/1.73m2• SDS Height –3,04, weight –2.15, BMI –0,08• Treatment:
erythropoietin 1000 U/w s.c.iron supplementssodium bicarbonate (BE-0.8)1,25(OH)2D3 0.15µg/d in the morning
Calcium-Phosphate-Vitamin D
• Ca 2.6 mmol/l (2.2-2.7)
• Phosphate 1.9 mmol/l (1.25-2.1)
• 25(OH)D 10 nmol/l (10-20)
• PTH 105 pg/ml (19-80)
• X-ray left wrist: no periosteal resorption zones, no metaphyseal abnormalities
Recommendation 7:
Vitamin D deficiency should be avoided (Klaus et al, 2006)
• Common, deficiency (<10ng/ml), insufficency (< 30 ng/ml)> 80% adult dialysis patients (Sadlier 2007, Del Vale 2007)
• In early CRF: PTH-levels ~ 25(OH)D-Conc. (Reichel 1991)
• Same after TPL (good renal function) dto. ( Lomonte 2005)
• Vit D Substitution in pts. with 25(OH)D3 in the range 20 to 50 nmol/l lowers iPTH (Van der Wielen, 1995)
• sHPT in CRF-Pts. 38% with 25(OH)D > 20ng/ml 68% with 25(OH)D < 20ng/ml (Holick 2005)
• extra-renal 1-OHase is substrate dependent
• 25(OH)D3 but not 1,25(OH)2D3 affects muscle phosphate content and muscle function (Birge SJ 1975; Eastwood JB 1977)
OHHO
OH
25-(OH)-Vitamin D and PTH
CKD 2-3(-4), n=57
77 % Vit D Insufficiency
Supplementation with Ergocalciferol
2000 IE insufficiency4000 IE deficiency
decrease of PTH in treated 122±83 to 80±59ng/ml
Increase in untreated 119 ± 93 to 143 ± 104
(p < 0.001)
Prior to ergocalciferol treatment:
Menon et al., Pediatr Nephrol 2008
Vitamin D SupplementationDose?
• 500 Units/d (Marburg, 66.6 % sufficency, no deficiency in CKD 3-5)
• 2000 IE/d x 12 weeks in insufficency4000 IE/d x 12 weeks in deficiency 8000 IE/d x 4 weeks, then 4000 IE/d x 8 weeks severe deficiency (DOQI)
Calcium-Phosphate
• Ca 2.6 mmol/l (2.2-2.7)Phosphate 1.9 mmol/l (1.25-2.1)
• 25(OH)D 35 nmol/l (10-20)
• PTH 105 pg/ml (19-80)
• X-ray left wrist: no periosteal resorption zones, no metaphyseal abnormalities
??
Recommendation 8: Marked hyperparathyroidism should be prevented
in children with CRF prior to dialysis
Low doses of active Vitamin D Metabolites
Normal PTH with strictly controlled Pi (GFR> 30):normal iPTH/whole PTHnormal AP (Waller 2003)
Waller S 2006crea. 140µmol/lphosphate 0.84 ULNheight SDS -1.73
Recommendation 10: If PTH is elevated in CRF stage 3 or
more than 2-3 times normal in stage 4-5 in the presence of Pi < 2 mmol/l,
active vitamin D metabolites should be
administered orally
.... in the evening (Tsuruoka 2003) less hypercalcemia more effective suppression of PTH
..... 20-40 ng/kg/d (lowest effective dose)
Concept: Why elevated PTH in CKD V?
• PTHRmRNA reduced in bone and growth cartilage cells Picton ML 2000, Sanchez 1998
• ADBD with PTH levels up to 3x ULN Kuizon 1998
• Risk of hypercalcemia with low normal PTH Klaus 1991
Treatment with active Vitamin D-Metabolites: PTH-levels (pg/ml)
CKD-Stage EPDWG K/DOQI Dose(k/DOQI)
2-3 10-65 35-704 130-195 70-110 < 10kg 0.05µg/48h (2-3x ULN) -20 kg 0.1-0.15 µg/d
> 20kg 0.25µg/d
5 130-195 200-300 0.0075-0.025µg/kg (2-3x ULN) (3-5x ULN) max 1µg/d
European Dose : ..... 20-40 ng/kg/d (lowest effective dose)
Control of Mineral Metabolism in 620 Children on PD% patients meeting pediatric KDOQI guidelines
0
10
20
30
40
50
60
70
%
Ca Pi PTH
Below targetWithin target
Above target
r=-0.04p=ns
Mean PTH (pg/ml)
20 30 50 200 300 500 200010 100 1000
HS
DS
ch
an
ge
pe
r ye
ar
-6
-4
-2
0
2
4
6 non-GHGH
PTH and Growth in Children on Chronic PD
Bone Histology prior to RRTWaller et al, Pediatr Nephrol 2008
• N=11, follow-up prior histolgy 1.1 year
• Policy: phosphate control 50.pc, PTH within normal range
• Results:Low turnover PTH within normal range, n=2mixed lesions PTH 1.1-1.4 ULN, n=4high tunover PTH > 2.9 ULN, n=4
0
0,5
1
1,5
2
2,5
3
3,5
4
4,5
5
0
200
400
600
800
1000
1200
1400
1600
P
EUDOQI
Pi, A
P x U
LN
Ca m
mol/l, C
alcidiol µ
g
PTH pg/ml
Case: 2 y-old, PD, PEG
GH
Calcimimetics
• Persistent decrease of PTH levels in comb. with Vitamin D• upregulates decreased calcium-sensing receptor expression
level in parathyroid glands Mizobuchi 2004
• Reduced CVR expected- decreases extraosseous calcifications in uremic rats treated with calcitriol Lopez 2006 - marked and sustained antihypertensive effect (rat)
Odenwald 2006
• Risk of hypocalcemia• First data in pediatric patients
Effect of cinacalcet on PTH in children
Muscheites 2008
Calcium-Phosphate 1 year later
• Ca 2.3 mmol/l (2.2-2.7)Phosphate 2.1 mmol/l (1.0-1.95)
• PTH 151 pg/ml (19-80)
• AP 335 (-281)
High Phosphate is a risk factor
• Myocardial fibrosis
• Hyperparathyroidism
• Parathyroid adenoma
• Soft tissue calcificationCardiovascular mortality
Effect of Phosphate on Vascular Calcification
In vitro
calcification of smooth muscle Expression of osteoblastic markers (Jono S., Circulation Res 2000)
in vivo:
calcification of the media (Ibels LS et al., Am J Med 1979)
+ expression of osteoblastic markers (Moe SM., Kidney Int 2002)
Recommendation 4: If plasma phosphate is elevated, phosphate
intake should be limited to the recommended levels
• Dietary counselling by a trained dietician• Protein intake reduced to recommended
levels (Coleman 2001) rule of thumb: normal + 50% in PD
• Dietary training with patients and parents
Recommendation 5: In case of hyperphosphatemia, the dialysis
efficacy should be optimised
• increase dwell volume to 1000-1400 ml/m2 BSA • avoide a too short dwell time• a daytime dwell should be added • prolong time on dialysis (PD)• increase frequency (daily HD)
[Ph
osp
hat
e] D
/D0
0 600
0.81.0
240
180120
0.6
0.4
0.2
time (min)
Recommendation 6: For control of hyperphosphatemia, aluminium-
free phosphate binders should be administered Calcium containing phosphate binder• CaCO3 elemental calcium content 40%, can be crushed• CaAc, elemental calcium content 25%
higher Pi-Binding potency independent of pH• upper intake level of elemental calcium is suggested to
be 2500 mg/d for children above 4 years of age• to be taken with meals • dietary supervision and training• Check serum calcium and Ca x P
• Check compliance
Ca-containing PBEfficacy• EstablishedRisks• High dose=high calcium load• Adynamic bone disease • Hypercalcemia (less with CaAcetate)• Vascular calcificationBenefits• cheapest PB• Reduction of sHPT• Correction of hypocalcemia
Effect of Type of Phosphate Binder on Mortality
Block GA 2007
Sevelamer in Children
• crossover Sevelamer and Calcium-Acetaten=18
• Equal serum phosphate control• More metabolic acidosis with sevelamer
(p>0.005)• More hypercalcemia in CaAc (p<0.0005)• Decreased total (-27%) and LDL cholesterol (-
34%)
Pieper 2006
Recommendation 13: The calcium phosphorus product should be
kept within the normal range, at least
below 5.0 mmol2/l2 (60 mg2/dl2).
stop active vit. Duse low-calcium dialysate
reduce Ca-cont. phos-binder
PTH low -low normal
continue current phos-binderand active vit D therapy
PTH=1-3 x normal
increase active vitamin D
PTH elevated above target range
< 5,0 mmol2/l2
stopp active Vitamin Duse low calcium dialysateuse Ca-free phos-binder
consider ADBD
PTH low - low-normal
increase phos-binderdietary counsellingstop active Vit D
Phosphate high
stop active Vit. Duse Ca-free Phos binder
use low Ca-Dialysate
Calcium high
PhosphateCalcium
PTH normal - elveated
consider subtotalparathyroidektomy
PTH grossly elevatedpersisting
> 5,0 mmol2/l2
Ca X Pi
Bilginer 2007
cIMT and CaxPi
• Transplanted children (n=24)
•IMT ~ with time on dialysis CaxPi product before transplantation
Effect of cinacalcet on CaxPi
Muscheites 2008
< 5 ,0 m m o l2 /l2
s to pp a ctive V ita m in Du se low ca lciu m d ia lysa teu se C a -free p ho s -b in d er
co n s id e r A D B D
P T H lo w - lo w -n o rm a l
in c re ase ph o s -b in d erd ie ta ry co u nse lling
s to p a c tive V it D
P h osph a te h igh
s to p ac tive V it. Du se C a -free P ho s b in d er
u se lo w C a -D ia lysa te
C a lc ium h igh
P h osph a teC a lc iu m
P T H no rm a l - e lve a ted
co n sid e r su b to ta lp a ra thyro id ek to m y
P T H g ro ss ly e le va tedp e rs is t ing
> 5 ,0 m m o l2 /l2
C a X P i
Summary/PerspectivePrevention of CKD-BMD:• Vitamin D deficiency is to be avoided• Ca, Pi and CaxPi should be kept in the normal
range• Administration of a too high amount of Ca
should be prevented• New data suggest stricter control of PTH target
levels (1-2 (-3) x ULN?) (Opinion-based) guidelines are usefull to• aid in therapy• to stimulate new studies
Klaus@med.uni-marburg.de
EPDWGA.Watson, A. Edefonti, M. Fischbach, K. Rönnholm, F. Schaefer, E. Simkova, C.J. Stefanidis, V. Strazdins, J. Vande Walle, C. Schröder, A. Zurowska, M. Ekim
CaxPi-Product
stop active vit. D
use low-calcium dialysate
reduce Ca-cont. phos-binder
PTH low -low normal
continue current phos-binder
and active vit D therapy
PTH=1-3 x ULN
increase active vitamin D
PTH elevated above target range
< 5.0 mmol2/l2
Recommended