Kein Folientitel

1
Principles and Problems of Renal Replacement
Therapy Management and treatment of renal
osteodystrophy
Günter Klaus, on behalf of EPDWG
Marburg, Germany
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Interrelationships between Ca, Pi, 1,25(OH)2D3
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Guideline 1 Biochemical and radiological marker
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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
• Treatmenterythropoietin 1000 U/w s.c.iron
  supplementssodium bicarbonate (BE-0.8)1,25(OH)2D
  3 0.15µg/d in the morning

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Calcium-Phosphate

• 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

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Recommendation 7 Vitamin D deficiency should be
avoided

• Common
• In early CRF PTH levels 25(OH)D levels (Reichel
  1991)
• Substitution in patients with 25(OH)D3 between 20
  and 50 nmol/l decreased iPTH (Van der Wielen,
  1995)
• sHPT in CKD Patients 38 with 25(OH)D gt
  20ng/ml 68 with 25(OH)D lt 20ng/ml (Holick
  2005)
• extra-renal 1a-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)

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Action

• Supplementation of Vitamin D3500 Units/d

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Calcium-Phosphate

• 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

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Recommendation 8 Marked hyperparathyroidism
should be prevented in children with CRF prior to
dialysis
Low doses of active Vitamin D Normal PTH with
strictly controlled Pi (GFRgt 30)normal
iPTH/whole PTHnormal AP (Waller 2003)
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Waller S 2006
crea. 140µmol/lphosphate 0.84 ULNheight
SDS -1.73
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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 lt 2 mmol/l, active
vitamin D metabolites should be administered
orally
.... in the evening (Tsuruoka 2003) ..... 20-40
µg/kg/d
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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

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Growth Hormone?
Height SDS 3.04
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Recommendation 11 Treatment with growth hormone
should not be started in presence of severe
hyperparathyroid bone disease

• iPTH levels as well as calcium and phosphate
  should be treated towards the recommended levels
  prior to administration of GH
• after start of GH increased iPTH
  observed (Berard 1998, Picca 2004)
• no increased frequency of epiphyseal slipping
  associated with the use of growth hormone
  (Fine 2003)

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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)

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Control of HPT by Low-Phosphorus Diet in advanced
CRF
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PTHmRNA in CRF
Phosphate regulates the parathyroid independent
of calcium and calcitriol
Phosphate modulates PTH gene translation, PTH
sekretion and parathyroid cell proliferation S-Pi
correlates with increase in PTH and cell
proliferation (Hayakawa Y et al, Endocr J 1999)
Pi
Kilav et al., J Clin Invest 1995
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Rapid modulation of PTH secretion by phosphorus
in the rat
Martin 2005
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Effect of Phosphate on Vascular Calcification
In vitro Þ calcification of smooth muscle Þ
Expression of osteoblastic markers (Jono S.,
Circulation Res 2000) in vivo Þ calcification
of the media (Ibels LS et al., Am J Med 1979)Þ
expression of osteoblastic markers (Moe SM.,
Kidney Int 2002)
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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

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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 25higher
  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

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Action

• Phosphate Binder (Ca-Carbonate, -Acetate)
• 500mg per 200mg phosphate content of the
  diet0-1 years 1-2x 500mg, 1-4 years
  2-3x500mg/d, 5-8 years 3-4x500mg/d, 9-18 years
  5x500mg
• alternative approachstart dose of approximately
  50 mg/kg/d
• dietary training

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September 2005 Start of PD

• Ca 2.3 mmol/l (2.2-2.7) Phosphate 1.3 mmol/l
  (0.95-1.85)
• PTH 105 pg/ml (19-80)
• AP 333 (-269)

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Biochemistry renal osteodystrophy
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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)

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35 children, 0.1-17 yrs on automated PD 3-13
night-time exchanges, 998110 ml/m² fill volume
gt 56 24h clearances and PETs
CP Schmitt
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Online HDF 34 h 5-63 h
n5, 4-41 month of intensified HDF
Weekly Kt/V urea 4.2 ? 9.1 nPCR
(g/kg) 1.28 ? 1.43 Serum phosphate
(mmol/l) 2.03 ? 1.39 Serum ß2
microglobulin (mg/l) 27.5 ? 24.1 Serum
homocysteine (µmol/l) 21.6 ?
13.4 Fischbach 2005
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Recommendation 13 The calcium phosphorus
product should be kept within the normal range,
at least below 5.0 mmol2/l2 (60 mg2/dl2).
Ca X Pi
lt 5,0 mmol2/l2
gt 5,0 mmol2/l2
PTH low -low normal
PTH1-3 x normal
PTH elevated above target range
PTH low - low-normal
PTH normal - elveated
PTH grossly elevated
persisting
stop active vit. D
continue current phos-binder
increase active vitamin D
consider ADBD
Phosphate
consider subtotal
use low-calcium dialysate
and active vit D therapy
Calcium
parathyroidektomy
reduce Ca-cont. phos-binder
stopp active Vitamin D
Phosphate high
use low calcium dialysate
use Ca-free phos-binder
increase phos-binder
dietary counselling
stop active Vit D
Calcium high
stop active Vit. D
use Ca-free Phos binder
use low Ca-Dialysate
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Soft Tissue Calcification and Cardiac Disease in
Dialysis Patients
Cardiovascular disease mortality

• Ca x P
• gt 60mg2/l2 (5 mmol2/l2) is associated with soft
  tissue calcification Velentzas et
  al, 1978)
• Pi gt 2.09 RR death 1.24
• gt 72mg2/l2 (5.9 mmol2/l2) RR of death 1.34
  Block GA 1998

Foley et al., 1998
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Mortality start of CRF in childhood

• pts. with CRF for 275,9 years
• 20 cardiovascular mortality

Oh et al., Circulation 2002
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Effect of Sevelamer on progression of arterial
calcification
N 200 Adults- HD Compared to Ca-Acetat
Chertow GM et al., Kidney Int 2002
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Ca
Effects of Calcimimetics AMG 073 in HPT
Pi
CaXPi
Quarles D et al., J Am Soc Nephrol 2003
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Biochemistry renal osteodystrophy
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Recommendation 14 Parathyroidectomy has to be
considered in case of severe, therapy-refractory
hyperparathyroidism with radiological signs in
combination with hypercalcemia and/or elevated
calcium phosphorus product
parathyroid gland larger than 0.5 cm3 or 1.0 cm
in diameter usually no response to vitamin D
(adults) Subtotal PTX and or autotransplantation
Calcimimetics?
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Calcimimetics

• Persistent decrease of PTH levels in comb. with
  vit.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
• No data in pediatric patients

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Action
Calcimimetics? Parathyroid adenoma?
Klaus_at_med.uni-marburg.de
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Secondary hyperparathyroidism
PTH
Diet
Phosphate Binders
Active Vitamin D (-Analogues)
Calcimimetics
Parathyroidectomy
Fukagawa 2003, modifed