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SYMPOSIUM. Novel aspects of renal bone disease

F Santos ESPN – Lyon 2008. SYMPOSIUM. Novel aspects of renal bone disease. Control of hyperparathyroidism and growth Fernando Santos Hospital Universitario Central de Asturias University of Oviedo Oviedo, Spain. F Santos ESPN – Lyon 2008. Control of hyperparathyroidism and growth.

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SYMPOSIUM. Novel aspects of renal bone disease

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  1. F Santos ESPN – Lyon 2008 SYMPOSIUM. Novel aspects of renal bone disease Control of hyperparathyroidism and growth Fernando Santos Hospital Universitario Central de Asturias University of Oviedo Oviedo, Spain

  2. F Santos ESPN – Lyon 2008 Control of hyperparathyroidism and growth • Clinical information • Basic science data on the effect of PTH on longitudinal growth

  3. K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. 2005. Guideline 14A. Hyperparathyroid (High-Turnover) Bone Disease “The relationship among iPTH, PTH fragments, vitamin D therapies, and linear growth needs to be established in children with CKD” F Santos ESPN – Lyon 2008 Guideline 1. Evaluation of Calcium and Phosphorus Metabolism

  4. K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. 2005. F Santos ESPN – Lyon 2008 Guideline 14C. Adynamic Bone Disease In CKD Stage 5, adynamic bone disease not related to aluminum (as determined either by bone biopsy or suggested by PTH <150 pg/mL) should be treated by allowing serum levels of PTH to rise in order to increase bone turnover. (OPINION) “adynamic bone disease appears to be associated with further impairment in longitudinal growth in children with CKD Stage 5 after treatment with calcium-containing binders and intermittent calcitriol therapy”(Kuizon BD, Goodman WG, Juppner H, Boechat I, Nelson P, Gales B, Salusky IB Diminished linear growth during intermittent calcitriol therapy in children undergoing CCPD. Kidney Int 1998; 53:205–211)

  5. Recommendation 8 Marked hyperparathyroidism should be prevented in children with CRF prior to dialysis (evidence). “In children with moderate renal failure (GFR >30 ml/min/1.73 m2) … slight catch-up growth with PTH levels at the upper limit of normal was reported (Waller S, Ledermann S, Trompeter R, van’t Hoff W, Ridout D, Rees L Catch-up growth with normal parathyroid hormone levels in chronic renal failure. Pediatr Nephrol 2003; 18:1236–1241). In a sub-group analysis, improved growth was restricted to patients with enteral feeding tubes” G Klaus, A Watson, A Edefonti, M Fischbach, K Rönnholm, F Schaefer, E Simkova, CJ Stefanidis, V Strazdins, J Vande Walle, C Schröder, A Zurowska · M Ekim Prevention and treatment of renal osteodystrophy in children on chronic renal failure: European guidelines. Pediatr Nephrol 2006 21:151-9 F Santos ESPN – Lyon 2008 Abstract The PTH levels should be within the normal range in chronic renal failure (CRF) and up to 2–3 times the upper limit of normal levels in dialysed children. Prevention of ROD is expected to result in improved growth and less vascular calcification.

  6. G Klaus, A Watson, A Edefonti, M Fischbach, K Rönnholm, F Schaefer, E Simkova, CJ Stefanidis, V Strazdins, J Vande Walle, C Schröder, A Zurowska · M Ekim Prevention and treatment of renal osteodystrophy in children on chronic renal failure: European guidelines. Pediatr Nephrol 2006 21:151-9 F Santos ESPN – Lyon 2008 Recommendation 9 PTH levels should be kept at two to three times the upper limit of the normal range in end-stage renal disease (evidence) Low turnover bone disease “may adversely affect growth in dialysed children” (Kuizon BD, Goodman WG, Juppner H, Boechat I, Nelson P, Gales B, Salusky IB Diminished linear growth during intermittent calcitriol therapy in children undergoing CCPD. Kidney Int 1998; 53:205–211)

  7. Kuizon B, Goodman WG, Jüppner H, Boechat I, Nelson P, Gales B, Salusky IB Diminished linear growth during intermittent calcitriol therapy in children undergoing CCPD Kidney Int 1998; 53:205-211 GROWTH Calcitriol (ng/kg/day) 3 times per wk 12 patients PTH = 660±120 Calcitriol: 39.2±7.2 4 patients PTH = 100±30 Calcitriol: 34.5±2.9 520±109 553±101 Average monthly intact PTH (pg/l) Bone biopsy: adynamic disease F Santos ESPN – Lyon 2008 Sixteen prepubertal children 15.1±3.5 38.1±5.4

  8. Kuizon B, Goodman WG, Jüppner H, Boechat I, Nelson P, Gales B, Salusky IB Diminished linear growth during intermittent calcitriol therapy in children undergoing CCPD Kidney Int 1998; 53:205-211 F Santos ESPN – Lyon 2008 r=0.71, p<001 Intermittent calcitriol therapy Daily calcitriol therapy: r = -0.38, p = NS

  9. per year Waller SC, Ridout D, Cantor T, Rees L Parathyroid hormone and growth in children with chronic renal failure Kidney Int 2005; 67:2338-45 F Santos ESPN – Lyon 2008 162 patients, 69% males, age (median = 9.9 years; range = 0.3-17.1 years), GFR < 60 ml/min/1.73m2, no GH Patients with “the highest 1-84 PTH:C-PTH ratio (a marker of bone turnover) grew better than those with the lowest ratio

  10. Daily calcitriol Intermittent calcitriol Daily calcitriol Intermittent calcitriol Schmitt CP, Ardissino G, Testa S, Appiani AC, Mehls O, The European Study Group on Vitamin D in Children with Renal Failure Growth in children with chronic renal failure on intermittent versus daily calcitriol Pediatr Nephrol 2003; 18:440-4 F Santos ESPN – Lyon 2008 29 prepubertal children with GFR < 40 ml/min/1.73m2 and PTH > 70 pg/ml, 1 year of follow-up, no GH

  11. Schmitt CP, Ardissino G, Testa S, Appiani AC, Mehls O, The European Study Group on Vitamin D in Children with Renal Failure Growth in children with chronic renal failure on intermittent versus daily calcitriol Pediatr Nephrol 2003; 18:440-4 F Santos ESPN – Lyon 2008 “The correlation between PTH and growth was weak for the entire patient group, indicating a relatively small effect of PTH on growth” “The correlation was only significant in the intermittent group (r=0.73, P<0.01), if both groups were analyzed separately … the correlation was mainly dependent on the 2 patients with the highest PTH. These were the youngest patients with an age below 2 years” “The correlation between PTH and growth velocity SDS was not significant”

  12. 566: < 2 X UNL 922: Unknown 360: > 2 X UNL F Santos ESPN – Lyon 2008 NAPRTCS 2007. CHRONIC RENAL INSUFFICIENCY 1848 patients with height Z score <-1.88 and Tanner stage I, II, III at the baseline “GH utilization was highest at baseline among patients PTH greater than twice the upper normal limit”

  13. F Santos ESPN – Lyon 2008 Control of hyperparathyroidism and growth • Some clinical data indicate that oversuppression of PTH (which means normal values in CKD stage 5) may adversely affect growth • Convincing evidence to sustain the previous statement is still missing

  14. F Santos ESPN – Lyon 2008 Control of hyperparathyroidism and growth • Clinical information • Basic science data on the effect of PTH on longitudinal growth

  15. SYSTEMIC AND LOCAL REGULATION: hormones, growth factors, … DYNAMICS Cartilage formation and progression Bone aposition F Santos ESPN – Lyon 2008 GROWTH PLATE STRUCTURE - Epiphyseal bone - Stem cells - Proliferating chondrocytes M a t r i x - Prehypertrophic chondrocytes - Hypertrophic chondrocytes - Metaphyseal bone

  16. Direct effects Indirect effects F Santos ESPN – Lyon 2008 PTH & ENDOCHONDRAL GROWTH Vitamin D – Ca – P metabolism Other hormonal systems UNLIKELY! PTH

  17. F Santos ESPN – Lyon 2008 PTH & ENDOCHONDRAL GROWTH Goltzman D, Arch Biochem Biophys 2008

  18. ? BONE RESORPTION BONE FORMATION = ≠ BODY STATUS (calcium, vitamin D, IGF-1) FORM OF PTH ADMINISTRATION F Santos ESPN – Lyon 2008 PTH & ENDOCHONDRAL GROWTH BONE REMODELING UNITS Goltzman D, Arch Biochem Biophys 2008

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