1. Uncontrolled secondary hyperparathyroidism in a haemodialysis patient Jordi Bover, MD, PhD Fundació Puigvert Barcelona, Spain © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

2. Objectives ●The systemic manifestations of chronic kidney disease- mineral bone disorder (CKD-MBD) ●The treatment of uncontrolled secondary hyperparathyroidism in CKD CKD: chronic kidney disease; CKD-MBD: chronic kidney disease-mineral and bone disorder © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

3. Chronic kidney disease-mineral and bone disorder ●Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a systemic disorder of mineral and bone metabolism due to CKD manifested by either one or more of the following: ●Abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism ●Abnormalities in bone turnover, mineralisation, volume, linear growth, or strength ●Vascular or soft tissue calcification ●Several biochemical abnormalities of CKD-MBD are associated with reduced survival in dialysis patients ●Calcium, phosphate, PTH, Ca x P, alkaline phosphatase, FGF-23 ●Combinations of high-low PTH, calcium and phosphate ●Time on target Ca x P: calcium/phosphate product; CKD: chronic kidney disease; CKD-MBD: chronic-kidney disease-mineral and bone disorder; FGF-23: fibroblast growth factor-23; PTH: parathyroid hormone KDIGO CKD-MBD Work Group. Kidney Int. 2009 [Supp113]:S1–130 © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

4. Secondary hyperparathyroidism in CKD ●Secondary hyperparathyroidism is a common complication of impaired renal function ●Secondary hyperparathyroidism is associated with clinical complications involving the bones and other tissues ●Bone disease (renal osteodystrophy) is present in at least 70% of CKD patients starting dialysis, although different patterns have been observed over time ●Increased PTH is also associated with several “uraemic” conditions ●Treatment in secondary hyperparathyroidism aims to manage levels of calcium, phosphate and PTH ●Conventional therapy includes dietary reduction of phosphate intake, the use of phosphate binders, hydroxylated vitamin D sterols or the synthetic vitamin D analogue paricalcitol, and modification of the dialysis regimen ●Calcimimetics increase the sensitivity of calcium-sensing receptors to extracellular calcium ions, thereby inhibiting the release and synthesis of PTH ●Can be used as part of a therapeutic regimen including phosphate binders and/or vitamin D sterols, as appropriate CKD: chronic kidney disease; PTH: parathyroid hormone National Institute for Health and Clinical Excellence. January 2007 © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

5. Patient presentation A 72-year-old female patient —CKD stage 5D since 2007 —Uncontrolled secondary hyperparathyroidism Current therapy —Paricalcitol: 10  g/haemodialysis —Sevelamer: 4800 mg/day Haemodialysis treatment (early morning shift) —Kt/V ≈ 1.4 —Dialysate calcium: 3 mEq/L CKD: chronic kidney disease © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

6. Multiple choice question 1 According to the KDIGO 2009 guidelines and the KDOQI US Commentary on the 2009 KDIGO Clinical Practice Guidelines, which of the following is an important laboratory parameter for monitoring secondary hyperparathyroidism in patients with CKD stage 5D? A.Corrected serum calcium B.Serum phosphorus C.Alkaline phosphatase D.Intact parathyroid hormone E.All of the above © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

7. Laboratory values for key secondary hyperparathyroidism parameters ParameterValueKDOQI 2003 Goals KDIGO 2009 Range Corrected calcium (mg/dL)10.18.4-9.5N Phosphate (mg/dL)5.63.5-5.5“towards” N Calcium/phosphate product (mg 2 /dL 2 ) 56.6<55 - iPTH (pg/mL)820150-300>2-<9 ULN iPTH: intact parathyroid hormone; KDOQI: Kidney Disease Outcomes Quality Initiative. KDIGO: Kidney Disease: Improving Global Outcomes; N: normal; ULN: upper limit of normal National Kidney Foundation. Am J Kidney Dis. 2003;42(suppl 3):S1-S201; KDIGO CKD-MBD Work Group. Kidney Int. 2009 [Supp113]:S1–130 © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

8. Additional laboratory values ParameterValue Alkaline phosphatase (U/L)160 Calcidiol (25-OH-vitamin D)* (ng/mL)28 CalcitriolN/A Albumin (g/L)41 Bicarbonate (mEq/L)20 *With native vitamin D supplementation © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

9. Multiple choice question 2 Which of the following statements is NOT correct regarding vascular calcification according to the 2009 KDIGO guidelines on CKD-MBD? A.Vascular calcification is exceedingly more prevalent, more severe, and follows an accelerated course in the CKD population compared with that in the normal population. B.A lateral abdominal radiograph can not be used as an alternative to computed tomography-based imaging to detect the presence or absence of vascular calcification. C.Patients with CKD stages 3-5D with known vascular calcification should be considered at highest cardiovascular risk. D.It is reasonable to use information on vascular/valvular calcification to individualise treatment of CKD-MBD. CKD: chronic kidney disease; CKD-MBD: chronic kidney disease-mineral and bone disorder; KDIGO: Kidney Disease: Improving Global Outcomes KDIGO CKD-MBD Work Group. Kidney Int. 2009 [Supp113]:S1–130 © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

10. Radiographic evaluation Radiographic studies showed evidence of vascular calcifications in the arms (cubital and radial), hands and pelvis, as well as in a lateral lumbar spine Reprinted with permission from Dr. Bover © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

11. Additional diagnostic evaluation Sestamibi scanning —Radionuclide uptake in the parathyroid gland DEXA bone densitometry —Normal lumbar spine —Femoral osteopenia/osteoporosis DEXA: dual-energy x-ray absorptiometry Reprinted with permission from Dr. Bover © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

12. Multiple choice question 3 According to the KDIGO guidelines, which of the following can be used to lower PTH in patients with CKD stage 5D: A.Calcitriol B.Vitamin D analogues C.Calcimimetics D.Combination of calcimimetics and calcitriol/vitamin D analogues E.All of the above CKD: chronic kidney disease; KDIGO: Kidney Disease: Improving Global Outcomes; PTH: parathyroid hormone © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

13. Cinacalcet treatment: Titration and monitoring Titration phase —Week 1 Cinacalcet 30 mg/day added after lunch (main meal after HD) Day 7: Calcium 9.8 mg/dL, Phosphorus 5.3 mg/dL Day 14: Calcium 9.7 mg/dL, Phosphorus 5.4 mg/dL Day 30: iPTH 450 pg/mL; Calcium 9.8 and Phosphorus 5.3 mg/dL —Week 5 Cinacalcet ↑ to 60 mg/day + paricalcitol ↓ to 5 μg/HD Day 7: Calcium 9.1 mg/dL, phosphorus 4.9 mg/dL Day 30: iPTH 310 pg/mL Maintenance phase —Alternate regimen of cinacalcet 60/30 mg/day —Eventually sevelamer dose was decreased HD: haemodialysis; iPTH: intact parathyroid hormone © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

14. Key learning points Combination of several treatments acting on different pathways may become the best approach to the complex CKD-MBD Calcimimetics are an important option for patients with CKD-MBD and uncontrolled secondary hyperparathyroidism —Help control several biochemical markers, such as serum calcium, phosphate, Ca x P, in addition to iPTH. Recently it has been described that calcimimetics may decrease FGF-23 levels (related with mortality) —Allow some patients to decrease the need for high-dose vitamin D derivatives and phosphate binders —Provide room for vitamin D derivatives in patients prone to hypercalcaemia or hyperphosphataemia —May increase the safe therapeutic window in patients with vascular calcification —May be used in patients without severe secondary hyperparathyroidism (specially if they have high serum and phosphorus values) Ca x P: calcium/phosphate product; CKD-MBD: chronic kidney disease-mineral and bone disorder; FGF-23: fibroblast growth factor- 23; iPTH: intact parathyroid hormone National Institute for Health and Clinical Excellence. January 2007 © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

15. Conclusion In this 72-year-old calcified patient with stage 5D CKD and uncontrolled secondary hyperparathyroidism, treatment with cinacalcet normalised several biochemical abnormalities associated with CKD-MBD Calcimimetics represent a new class of drugs that control the biochemical abnormalities of patients with secondary hyperparathyroidism in dialysis —Unique mechanism of action targets the biochemical profile of CKD-MBD patients differently than other available drugs While awaiting results of new clinical studies and economical implications, calcimimetics provide an excellent therapeutic window for combination therapy CKD: chronic kidney disease; CKD-MBD: chronic kidney disease-mineral and bone disorder © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media