ROD study group K. Cransberg, N. Godefroid, L. Koster, K. N Schoenmaker and M. Van Dyck

1.Renal osteodystrophy 2.First report 3.Research questions 4.CKD and bone health 5.Proposal add-on studies

Part 1 Renal osteodystrophy

NKF/DOQI CKD-MBD A systemic disorder of mineral and bone maturuation due to CKD manifested by either one or a combination of the following - abnl Ca, P, PTH and vit D metabolism - abnl in bone turnover, mineralization, volume, linear growth, or strength - vascular or soft-tissue calcification Renal osteodystrophy An alteration of bone morpholgy low turnover, high turnover, mixed lesions

Secundary osteoporosis Hormonal therapy glucosteroids, thyroid hormone aromatase inhibitors, ovarian suppressing agents androgen deprivation therapy, thiazolidiniones Psychotropic and anticonvulsant therapy selective serotonin reuptake inhibitors anticonvulsants Drugs used for cardiovascular diseases heparin, oral AC, loop diuretics Drugs targeted the immune system calcineurin inhibitors, anti-retroviral therapy Drugs used for gastro-intestinal diseases proton pump inhibitors Maziotti G et al. The American Journal of Medicine 2010;123:

Guidelines NKF/DOQI CKD 5 monthly Ca, P, bic, AP, PTH 25(OH) vit D at least annually Rx Bone every 6-12 months Stages 1-5 T 25 OH and then based on level of treatments (2C) EPDWG

DXA scan Z score (corrected for age and sex) > -1,5 = no signs -1,5 and -2 = osteopenia >-2 = osteoporosis or osteopenia with fractures References, devices Small children Zemel B et al, 2007 Henwood 2009

A BC Mass (gm) A = B = C Density (gm/cm 3 ) A = B = C Strength [  (R P 4 - R E 4 )] A << B << C Cortical Bone: Geometry & Strength

25 OH Vit D storage levels normal values 25 (OH)D serum <10 ng/ml (25nmol/l) severe deficient <30 ng/ml (75nmol/l) deficiency >30 ng/ml (75nmol/l) desirable for optimal growth (30-50) >80 ng/ml (200 nmol/l) toxic > hyperCa Vit D deficiency is a worldwide health problem >> skeletal disorders + cardiovascular disease Vit D deficiency is a risk factor for hyperparathyroidism (independent of 1.25 OH 2 D)

Part 2 First report - treatment policy - available data ? - first results

Policies ROD 2007: Management policies No questions asked about ROD 2011: What do we want to know? How are we working on ROD?

Patients (n=245) Entry rich-q HD: 80 PD: 111 Tx : 54 August 2011 HD: 40 PD: 47 Tx: 158 prevalent 122, incident 123 Incident 0-3 mo RRT at MO New prevalent3-12 mo RRT at MO Old prevalent> 12 mo RRT at MO

Growth (M0) only caucasian, dialysis: GroupLength <-2.5 SD Growth hormone use incident16/61= 26%15/61=24% Prevalent new10/33= 30% 8/33=24% Prevalent old20/44= 45%22/45=49%

X ray hand (dialysis) GroupROD signs incident10/57= 18% Prevalent new 6/37= 16% Prevalent old22/61= 36%

DXA scan (nl Z Scores) DialysisIncidentPrevalent femur 5 (83%)21/26 (77%) Lumbar spine 5 (100%)31/38 (82%) Total body 012 /15 (86%) Transplantation Femur 4 (100%)9/18 (50%) Lumbar spine 5 (63%)24/33 (73%) Total body 3 (50%)7/13 (54%)

Femur z score vs PTH in dialysis R=0.12 Femur z score vs phosphate in dialysis R=-0.08 Lumbal Z score wv Alkaline phosphatase (dialyse M0) n=11! Alk.phos. Vs Calcium R= Alk.phos. Vs iPTH, dialyse R= 0.37

Phosphate binder Phosphate binders Incident N (%) Prevalent N (%) Both10 (14%)30 (27%) Only Ca based21 (29%)26 (23%) Only non calcium based 17 (24%)35 (31%) None24 (33%)21 (19%)

Vitamin D (dialysis) Vitamin DIncident N (%) Prevalent N (%) Multi vit28 (53%)44 (45%) Vit D/ D cure /dagravit 5 (9%) 6 ( 6%) Vit D3 (etalpha etc) 59 (82%)88 (79%)

Part 3 Research Questions

Diagnosis; Does your centre check Vitamin D regularly? How often? DEXA scan: How often is a DEXA scan preformed? Which type of DEXA scan is used? How are the results reported?: BMD/ Z score/ T score/ other? Which normal values are used? X ray hand: How often is a Hand X ray performed? For children treated with PD? HD? Tx? How are the results reported? Open text or for example “no signs of ROD” Definition of no/moderate/ severe signs of ROD? Other diagnostic tools?

Diagnosis; Medications Growth standards Fracture rate Prevention ROD: What kind of babymilk is prescribed? Low phosphate? Vit D therapy, dosage, orally or IV? Vit D after transplantation?

Important questions 1.Methods of evaluation Ca-P metabolism? Ook 1,25 en vit D bepalen? hoe vaak? 2.What is the role of Vit D/ 25 (OH)D in the calcium-phosphate metabolism? 3.FGF23 is key player in CKD PTH ?

Part 4 CKD and bone health Lab measurements:pitfalls Investigation of bone health

 Accumulation of non(1-84) PTH in progressive CKD Non(1-84)PTH = 20 % in nll GFR but increases to 50 % in CKD (1-84)PTH= 20% van dit intact PTH in nl GFR, but 5% b in CKD Dr K. Van Aerschot, Prof E. Levtchenko

Bone health at adult height Results uzleuvenGroup A(GH+, n=15))Group B (GH-, n=6)P value Final Height SDS-0.5 (-2.3 to 1.0)-0.18 (-0.93 to 0.81)0.40 BMI SDS-0.5 (-2.5 to 1.0)0.22 (-0.44 to 1.79)0.05 sLBMDL2-4 (mg/cm2)1026 (859 to 1154)1045(711 to1140)0.49 T score sLBMD-1.3(-2.9 to 0.2)-1.15 (-3.8 to -0.2)0.49 % lean body mass80.7(65.2 to 86.0)72.6(57.4 to 79.6)0.01 uz Valta 2010 Abstract ESPN2011Nl values vit D and 1,25 Vit D

Part 5. Proposal Add-on studies

ROD studies in RICH-Q group Cinacalcet (AMGEN) will be started in chronic dialysis patients 6-18 yrs of age Proposal add-on studies 1.vit D in ESRD 2. bone health and FGF23 3.ROD and transplantation

Cinacalcet Cinacalcet will be started in dialysis patients 6-18 yrs of age 1. reducing the plasma PTH by 30 % 2. lowering PTH < 300 pg/ml impact on S Ca, Ca ion, Ca-P product impact on growth 60 weeks - double-blind dose titration phase(24 wks) -double-blind efficacy assessment phase(6 wks) -open-label dose titration phase (24 wks) -open-label maintenance phase (6 wks)

FGF23 Parker 2010 Van Husen 2010 Gutierrez 2010

Vit D in ESRD Rationale –Cardiovascular morbidity and mortality in ESRD –Vit D deficiency is common but no validated data in CD children –Vit deficiency is associated with endothelial dysfunction Research questions (1) - prevalence 25 OH deficiency - prevalence in black skin - association with lab (Ca, P, PTH, FGF23, Rx) MJS Oosterveld en JW Groothoff, AMC Amsterdam

Vit D in ESRD Research Questions(2) - current practice of supplementation - effect of vit D3 addition ° Ca, P, iPTH and FGF23 ° occurrence of ROD ° relation to endothelial function MJS Oosterveld en JW Groothoff, AMC Amsterdam

Body health and FGF23 in ESRD Rationale –FGF23 regulate P metabolism. In CKD both FGF23 (active and inactive)and PTH are increased. –FGF23 is a key player in the development of CKD- bone mineral disorder –FGF23 may be a predictor of adverse clinical outcomes in CKD –PTH 1-84 is a more physiological parameter in CKD M. Van Dyck, R. Lombaerts, E Levtchenko, UZ Leuven

Body health and FGF23 in ESRD Research Questions 1.relation bone health (DXA, Rx) and FGF23, vit D 2.bone health : longitudinal evolution after Tx 3.FGF23 and growth( biometry, puberal score, IGF1) FGF23 – 25-OH vit D- 1,25 OH- PTH1-84 on specimens

Part 2 study transplantation K. Cransberg

Discussion- questions