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Novel Aspects of Renal Bone Disease: Current guidelines

Novel Aspects of Renal Bone Disease: Current guidelines. Günter Klaus, . Marburg, Germany. Review Parts of ... . European Guidelines (Klaus et al, 2006)

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Novel Aspects of Renal Bone Disease: Current guidelines

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  1. Novel Aspects of Renal Bone Disease: Current guidelines Günter Klaus, Marburg, Germany

  2. 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)

  3. Guideline 1: Biochemical and radiological marker

  4. 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

  5. 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

  6. OH OH HO 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 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)

  7. Prior to ergocalciferol treatment: Menon et al., Pediatr Nephrol 2008 25-(OH)-Vitamin D and PTH • CKD 2-3(-4), n=57 • 77 % Vit D Insufficiency • Supplementation with Ergocalciferol 2000 IE insufficiency 4000 IE deficiency • decrease of PTH in treated 122±83 to 80±59ng/ml • Increase in untreated 119 ± 93 to 143 ± 104 (p < 0.001)

  8. 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)

  9. 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 ? ?

  10. 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)

  11. crea. 140µmol/lphosphate 0.84 ULNheight SDS -1.73 Waller S 2006

  12. 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)

  13. 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

  14. Treatment with active Vitamin D-Metabolites: PTH-levels (pg/ml) CKD-Stage EPDWG K/DOQI Dose(k/DOQI) 2-3 10-65 35-70 4 130-195 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)

  15. Control of Mineral Metabolism in 620 Children on PD % patients meeting pediatric KDOQI guidelines

  16. PTH and Growth in Children on Chronic PD

  17. 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

  18. Case: 2 y-old, PD, PEG PTH pg/ml Pi, AP x ULNCa mmol/l, Calcidiol µg GH DOQI EU

  19. 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

  20. Effect of cinacalcet on PTH in children Muscheites 2008

  21. 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)

  22. High Phosphate is a risk factor • Myocardial fibrosis • Hyperparathyroidism • Parathyroid adenoma • Soft tissue calcification • Cardiovascular mortality

  23. 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: • calcification of the media (Ibels LS et al., Am J Med 1979)Þ + expression of osteoblastic markers (Moe SM., Kidney Int 2002)

  24. 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

  25. 1.0 0.8 0.6 [Phosphate] D/D0 0.4 0.2 0 0 60 120 180 240 time (min) 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)

  26. 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

  27. Ca-containing PB • Efficacy • Established • Risks • High dose=high calcium load • Adynamic bone disease • Hypercalcemia (less with CaAcetate) • Vascular calcification • Benefits • cheapest PB • Reduction of sHPT • Correction of hypocalcemia

  28. Effect of Type of Phosphate Binder on Mortality Block GA 2007

  29. 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

  30. 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 < 5,0 mmol2/l2 > 5,0 mmol2/l2 PTH low -low normal PTH=1-3 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

  31. cIMT and CaxPi • Transplanted children (n=24) • IMT ~ with time on dialysis CaxPi product before transplantation Bilginer 2007

  32. Effect of cinacalcet on CaxPi Muscheites 2008

  33. Summary/Perspective Prevention 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

  34. 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 Klaus@med.uni-marburg.de

  35. < 5.0 mmol2/l2 PTH low -low normal PTH=1-3 x ULN PTH elevated above target range stop active vit. D continue current phos-binder increase active vitamin D use low-calcium dialysate and active vit D therapy reduce Ca-cont. phos-binder CaxPi-Product

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