1. CKD-MBD Update Shin Byung-Chul Division of Nephrology, Chosun University Hospital 인공신장실 세미나 2016 년 3 월 7 일 ( 월 )

2. 10 th Nephrology Board Review Course 2016 Jan30-31 2016

3. Updating Clinical Practice Guideline Ketteler M. et al. KI 2015

5. CASE 45/M Problem : increased iPTH level P/Ix: 2011 년 CGN 에 의한 ESRD 진단 하에 HD 중인 자로 iPTH 상승에 대한 검사와 치료를 위해 방문. P/Hx : HTN(+) Labw ㅗㅅ

6. 위 환자에서 CKD-MBD 평가를 위해 실시해야 할 Laboratory test 로 적절하기 않는 것은 ? 1)Calcium 2)Phosphorus 3)Alkaline phosphatase 4)1,25-(OH) 2 D3 5)Intact PTH

7. Chronic Kidney Disease- Metabolic Bone Disorder CKD-MBD: systemic disorder Trinity: bone abnormalities, laboratory abnormalities, & vascular calcification Hard outcomes: fractures, cardiovascular morbidity, & mortality.

8. Guideline CKD-MBD 1.1 Guideline 1.1 CKD-MBD: Monitoring of biochemical parameters We suggest that serum levels of calcium, phosphate, alkaline phosphatase, PTH and calcidiol (25(OH) D3) should be monitored in patients with CKD stage 3-5, and patients on dialysis, with a frequency based on stage, rate of progression and whether specific therapies have been initiated. In general, it is recommended that therapeutic decisions are based on the clinical situation, and trends in parameters, rather than a single laboratory value, as part of the entire available dataset, (not graded). Steddon D. et al. Oxford 2015

9. Biomarkers in CKD-MBD Phosphorus Calcium PTH Vitamin D : Calcidiol (25-OH D 3 ) Bone turnover markers : alkaline phosphatase (ALP) FGF23 Klotho ? Sclerostin ?

10. FGF23 effects in ESRD Perazella MA, et al. Nat Rev Nephrol 2013

11. FGF23 and Outcomes Kovesdy C.P. and Quarles L.D. Nephrol Dial Transplant 2013;28:2228-2236

12. CASE 45/M Problem : increased iPTH level P/Ix: 2011 년 CGN 에 의한 ESRD 진단 하에 PD 중인 자로 iPTH 상승에 대한 검사와 치료를 위해 방문. P/Hx : HTN(+) Lab CBC: WBC/Hb/Hct/Plt : 4,790/ 10.5/ 31.1%/ 166*10 3 Blood Chemistry BUN/Cr : 43/7.9 mg/dL TP/Alb : 6.61/ 3.46 g/dL AST/ALT : 34/4 IU/L ALP : 356 (35-123 mg/dL) Na/K/Cl : 134/4.8/100 mEq/L T-chol/TG : 173/ 98 mg/dL P/Ca : 3.9/ 7.92 mg/dL iPTH: 1361 pg/mL 25-(OH) Vit D3: < 4.0 ng/mL

13. Target levels of serum Ca, P and PTH Phosphorus (mg/dL) Calcium (mg/dL)iPTH (pg/mL) KDIGO(2009)Normal range 2-9 X normal range (130-585) ERBP(2010)2.4-4.5Normal range100-800 UKRA(2011)2.78-4.648.8-10.0Not mentioned CARI(2006) ~4.958.5-10.5100-470 KDOQI(2003)3.5-5.58.4-9.5150-300 JSDT(2013)3.5-6.08.4-10.060-240 Hwang E et al. Kidney Res Clin Pract 2015:34;4-12

14. Corrected Ca concentration The total, but not ionized (biologically active), serum Ca concentration may be lowered by hypoalbuminemia. KDIGO method: Corrected total Ca (mg/dL) = measured Ca (mg/dL) + 0.8 X [4 – serum albumin (g/dL)]. JSDT method: Corrected total Ca (mg/dL) = measured Ca (mg/dL) + [4 – serum albumin (g/dL)]. Hwang E et al. Kidney Res Clin Pract 2015:34;4-12

15. Measurement frequency and range in CKD-5D Serum parameters Measurement frequency Recommended range CalciumOnce per mo8.4-9.6 mg/dL PhosphorusOnce per mo2.4-5.0 mg/dL Parathyroid hormoneOnce every 3 mo100-300 pg/dL Hwang E et al. Kidney Res Clin Pract 2015:34;4-12 Our recommendation on the frequency of serum mineral measurements and their target ranges

16. 이 환자는 CKD-MBD 분류 중 어디에 해당하는가 ? 1)Osteomalacia 2)Adynamic bone disease 3)Osteitis fibrosa 4)Mild Hyperparathyroidism 5)Mixed uremic osteodystrophy

17. Diagnosis of CKD-MBD: bone Chapter 3.2: Diagnosis of CKD-MBD: bone This mainly concerns the performance and utility of bone biopsy and histological/histomorphometric diagnosis and classification of CKD-MBD. As such, it is unlikely to alter clinical practice in the UK. Steddon S & Sharples E. Renal Association. UK 2015

18. Bone Strength Bone strength => the capacity of bone to resist mechanical stresses Bone Strength Bone Density Bone Quality =+ BMD DEXA = limited utility in CKD 1.Turnover 2.Mineralization 3.Architecture (volume) 4.Material properties Bone biopsy= rarely obtained in CKD patients

19. Classification of CKD-MBD: TMV OM = Osteomalcia AD = Adynamic OF = Osteitis Fibrosa MUO = Mixed Uremic ODR Mild = Mild HPT

20. KDIGO – guideline for CKD-MBD PDHD

21. Neck Sono and CT

22. Parathyroid MIBI scan / SPECT CT

23. Diagnosis of CKD-MBD: vascular calcification Chapter 3.3: Diagnosis of CKD-MBD: vascular calcification It is recommended that lateral abdominal radiographs are used to assess the burden of vascular calcification. This is unlikely to alter current UK clinical practice, but may be a relatively simple tool for clinical research. The role of screening (and management strategies) for vascular calcification remain uncertain. Steddon S & Sharples E. Renal Association. UK 2015

24. 50/M, ESRD with HD Chest PA HRCT

25. Bone scan : 진단명 ?

26. Musso CG et al, Saudi J Kidney Dis Transpl (2009)

27. 이 환자에서 적절한 치료는 무엇인가 ? 1)Sevelamer 2)Paricalcitol 3)Calcitriol pulse Tx 4)Cinacalcet plus low dose calcitriol 5)Parathyroidectomy

28. Acute effects of dialysate calcium levels Blood pressure during hemodialysis Arterial compliance Cardiac arrhythmias

29. Chronic effects of dialysate calcium levels Uremic bone disease (Renal osteodystrophy) Hyperparathyroid bone disease Adynamic bone disease Vascular calcification and CV morbidity (?) Ca x P

30. Lower dialysate calcium concentration (2.5 mEq/L) Advantages 1. Reduces risk of hypercalcemia 2. Allows greater use of vitamin D and calcium-containing phosphate binders 3. Benefit in adynamic bone disease Disadvantages 1. Potential for negative calcium balance and stimulation of PTH 2. Increase in intra-dialytic hypotension

31. Higher dialysate calcium concentration (3.5 mEq/L) Advantages 1. Improves hemodynamic stability 2. Suppression of PTH Disadvantages 1. Greater risk of hypercalcemia 2. Limits use of vitamin D and calcium based binders 3. Possible risk of vascular calcification

32. Consideration of dialysate Ca concentration  Recommendation  Dialysate Ca: 2.5 – 3.0 mEq/L  Individual dietary intake of Ca  Use of phosphate binder, VDRAs, and Cinacalcet

33. Management of CKD-MBD  Treatment of hyperphosphatemia  Dietary phosphate restriction  Phosphate binder  Vitamin D supplement: Calcitriol (iPTH>200 pg/mL)  Treatment of abnormal PTH levels  Selective VDRA: Paricalcitol  Calcimimetics: Canacalcet  Parathyroidectomy

34. Dietary P restriction P > 4.5 mg/dL, limited < 800 mg Dietary P content Dietary P (mg) = 78 + 11.8 X protein intake (g) P < 2.4 mg/dL : P & protein intake encouraged Hwang E et al. Kidney Res Clin Pract 2015

35. Phosphate binder  Aluminum containing : only for limited periods  Calcium containing  Calcium acetate: less hypercalcemic  Calcium carbonate  Non-calcium containing (NCPB)  Sevelamer: cholesterol & uric acid↓, anti-inflammatory  Lanthanum: bone toxicity d/t accumulation  Magnesium-based binders  Iron-based binders  Ferric citrate (JTT-751): reduction in ESA/IV iron usage  Sucroferric oxyhydroxide (PA21)

36. Restrict dose of Calcium-based phosphate binder  Hypercalcemia  Vascular calcification  Low iPTH level  Adynamic bone disease

37. Equivalent dosage for dialysis patient Switching from calcium acetate to sevelamer or lanthanum Calcium acetate 667 mg Sevelamer hydrochloride 400 mg Sevelamer hydrochloride 800 mg Lanthanum carbonate 500 mg 1 tablet2 tablet1 tablet0.5 tablet 2 tablet3 tablet2 tablet1 tablet 3 tablet5 tablet3 tablet1.5 tablet Daugirdas JT et al. Semin Dial 2011, Hwang E et al. Kidney Res Clin Pract 2015

38. Definition of Vitamin D status Vitamin D status25(OH)D Deficiency< 15 ng/mL< 37 nmol/L Insufficiency15-30 ng/mL37-75 nmol/L Sufficiency30-100 ng/mL75-250 nmol/L Excess100-150 ng/mL250-375 nmol/L Intoxication> 150 ng/mL> 375 nmol/L WHO, NKF/K-DOQI 2003, KDIGO 2009

39. Paricalcitol Vitamin D receptor activator (VDRA) Paricalcitol ↓ Bone disease↓ Inflammation ↓ Vascular calcification ↓ Congestive heart failure ↓ Left ventricular hypertrophy ↓ Proteinuria↓ Hypertension ↓ Visceral calcification

40. Optimal Paricalcitol IV Dosing money saved Initial low dose: iPTH/120Once-weekly dosing: safe and effective Weekly paricalcitol Dose (µg/week) iPTH level Ca x P (mmol 2 /L 2 ) Baseline*Week 4Week 8 HD patient: iPTH300-600600-1,200>1,200 Initial dose5 ug7 ug (7-7-7 or 5-10-5)10 ug Maintenance dose300-600: 5 ug, 100-300: 2 ug, <100: hold PD patient6-15 ug/week Mitsopoulos E. et al, Am J Kidney Dis 2006, Staniforth, Cheng, & Coyne. Clin Nephrol, 2005

41. Cinacalcet Calcimimetics: increase sensitivity of parathyroid calcium sensing receptor (CaSR): iPTH > 300 pg/mL, Ca> 9.0 mg/dL (stop when Ca < 7.5 mg/dL) initial dosage 25mg (every 3-4 weeks max 100mg) during dinner Sx: hypocalcemia, GI symptoms (nausea, vomiting, diarrhea) ECHO observational study Urena P. et al, Nephrol Dial Transplant, 2009

42. Mean iPTH during treatment by stratum (IV or oral) and treatment group Ketteler M et al, Nephrol Dial Transplant 2012

43. Comparative Properties of Cinacalcet and Vitamin D CinacalcetVitamin D Acts on cell surface receptor Acts via intracellular receptor on PTH gene Inhibits PTH secretionInhibits PTH synthesis Rapid onset (min) and recovery (hrs or days) Slow onset and recovery (days to weeks) Decrease Ca X P productIncrease Ca X P product

44. Treatment strategy for SHPT Hwang E et al. Kidney Res Clin Pract 2015 NCPB: P> 5.5 & Ca*P ≥ 55 CalcitriolCalcitriol -> Paricalcitol Paricalcitol +/- CinacalcetCinacalcet

45. 19/M, ESRD d/t CGN with HD ( 본원 ) P/Ca: 4.02/8.72 Alb: 3.80 iPTH: 625 (cCa: 8.9)

46. 43/M, ESRD d/t CGN with HD ( 타병원 ) P/Ca: 5.16/10.2 Alb: 4.54 iPTH: 2179 (cCa: 9.8)

47. 47/M, ESRD d/t HTN with PD P/Ca: 6.0/11.8 Alb: 4.59 iPTH: 610 (cCa: 11.2)

48. CKD-MBD KDOQI Commentary 2014 Vitamin D supplementation and bisphosphonates in people with CKD 3.3.5: We suggest not to routinely prescribe vitamin D supplements or vitamin D analogs, in the absence of suspected or documented deficiency, to suppress elevated PTH concentrations in people with CKD not on dialysis. (2B) 3.3.6: We suggest not to prescribe bisphosphonate treatment in people with GFR <30 ml/min/1.73 m 2 (GFR categoriesG4-G5) without a strong clinical rationale. (2B) Inker LA. et al, Am J Kidney Dis. 2014

49. Total parathyroidectomy & autotransplantation 수술 후에 환자의 손이 저리고 무감각해졌다. P/Ca: 2.02/6.39 mg/dL iPTH: 6.1 pg/dL 진단 및 치료는 ? Parathyroidectomy indication 1)iPTH > 500 pg/mL 2)Parathyrod > 500 mm 3 as sono 3)Unmanageable hypercalcemia & hyperphosphatemia X-ray finding of bone disorder Severe bone & muscle pain Calciphylaxis, or soft tissue calcification -> 3 가지

50. Hungry Bone Syndrome Incidence: 20-70% Hypophosphatemia, hypocalcemia & hypomagnesemia Managements –Oral calcium carbonate: 1-2 g three times (between meals) a day –IV calcium: 10mL of 10% Ca gluconate (90 mg of Ca): 1-2 mg/kg/hr iCa < 3.6 mg/dL & corrected total Ca <7.2 mg/dL –Calcitriol administration –Magnesium supplementation –Correction of hypophosphatemia only if severe (<1 mg/dL) –Pamidronate: 30-45mg, 1-2days before surgery (Davenport A. et al. Nephrology 2007) Hwang E et al. Kidney Res Clin Pract 2015

51. Take Home Messages 1.Measuring serum levels of calcium, phosphate, iPTH, vitamin D (25-OH D3) and alkaline phosphatase activity in CKD stage 3b-5. 2.Early intervention to correct abnormal Ca and P metabolism are important to reduce cardiovascular morbidity and mortality. 3.Normalization of P/Ca and optimal PTH level and dietary phosphate restriction & its binder dosage. 4.Usually need paricalcitol and/or cinacalcet in CKD stage 5D.