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