PTH - Chronic Renal Failure

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  • PTH - Chronic Renal Failure

    1. 1. <ul><li>Learning Objectives: </li></ul><ul><li>Describe the physiology of PTH and mineral metabolism in patients with CKD </li></ul><ul><li>Discuss the available therapies for the disorders of PTH and mineral metabolism in patients with CKD </li></ul><ul><li>Apply this information to the clinical management of patients with CKD </li></ul>PTH and Mineral Disorders in Patients With CKD: A Practical Case-Based Approach for Renal Dietitians
    2. 2. Patient Case <ul><li>53-year-old male with history of stage 5 CKD 2 º AD PKD recently started on hemodialysis after failed renal transplant </li></ul><ul><li>History of deceased donor renal transplant, 11/95 </li></ul><ul><li>Previously on hemodialysis, 6/95–11/95 </li></ul><ul><li>History of CVD, s/p CABG x 3 in 02/04 </li></ul><ul><li>History HTN; history basal cell carcinoma </li></ul><ul><li>Social history: works as car mechanic; no history of alcohol, tobacco; married 21 years; 1 daughter, age 19 </li></ul><ul><li>Family history ADPKD on maternal side </li></ul>
    3. 3. Patient Case (cont) <ul><li>Presents with mild itching, bone pain </li></ul><ul><li>No history of fractures </li></ul><ul><li>Medications: </li></ul><ul><ul><li>Calcium acetate: 667 mg 3 tab tid </li></ul></ul><ul><ul><li>B-complex with C: 1 tab qd </li></ul></ul><ul><ul><li>Atorvastatin: 20 mg qd </li></ul></ul><ul><ul><li>Metoprolol: 50 mg bid </li></ul></ul><ul><ul><li>Prednisone: 2.5 mg qd </li></ul></ul><ul><li>Laboratory values: </li></ul><ul><ul><li>Phosphorus: 8.0 mg/dl </li></ul></ul><ul><ul><li>Corrected calcium: 8.3 mg/dl </li></ul></ul><ul><ul><li>Intact PTH: 670 pg/ml </li></ul></ul><ul><ul><li>Ca x P: 66.4 </li></ul></ul>
    4. 4. <ul><li>Concentration in blood/plasma is tightly regulated by PTH and vitamin D </li></ul><ul><li>Calcium ions serve a variety of functions </li></ul><ul><ul><li>Signal transduction: 1st and 2nd messengers </li></ul></ul><ul><ul><li>Nerve and muscle function </li></ul></ul><ul><ul><li>Major component of bone </li></ul></ul><ul><li>Serum calcium does not reflect total body calcium content </li></ul>Overview of Calcium Physiology
    5. 5. Regulation of Plasma Calcium Adapted from E Nemeth. PT glands CaSR PTH bone PO 4 reabsorption Ca reabsorption kidney PT glands CaSR PO 4 resorption Ca resorption Low plasma Ca 2+ plasma Ca 2+ intestine 1,25-dihydroxy- vitamin D 3 PO 4 absorption Ca absorption
    6. 6. Liver Kidney Skin Pre-vitamin D Vitamin D 7-dehydrocholesterol 25-OH calcidiol 1  -hydroxylase 1,25 (OH) 2 D calcitriol most potent metabolite Low PO 4 Low Ca High PTH + - High PO 4 High Ca Low PTH Vitamin D Metabolism Diet Adapted from WG Goodman.
    7. 7. Principal Biological Effects of Vitamin D <ul><li>Increases absorption of Ca and P </li></ul><ul><li>Maintains bone mineralization and turnover </li></ul><ul><li>Indirectly reduces synthesis of calcitriol </li></ul><ul><li>Reduces synthesis of PTH </li></ul>
    8. 8. Acute and Chronic Regulation of PTH Output Ca 2+ /CaSR PO 4 weeks, months, years Tissue hyperplasia Vit D / VDR  VDRE Ca 2+  CaRE low Ca ( ↑ half-life) low PO 4 ( ↓ half-life) hours, days Gene expression Transcription mRNA stability Ca 2+ /CaSR minutes PTH secretion FACTORS TIME FRAME PROCESS
    9. 9. Phosphorus Metabolism <ul><li>Normal PO 4 levels in plasma: 2.5–4.5 mg/dL 1 </li></ul><ul><li>Total body PO 4 content: 500–700 g 1 (85% in bone) </li></ul><ul><li>Dietary Reference Intake 2 : 700 mg </li></ul><ul><li>Typical US dietary intake 2 : 1200 mg </li></ul><ul><li>GI absorption </li></ul><ul><ul><li>Mainly passive, through Na/Pi transporter </li></ul></ul><ul><ul><li>Fractional absorption 60–70% </li></ul></ul><ul><ul><li>Enhanced by vitamin D </li></ul></ul><ul><li>Kidney is major regulator 3 </li></ul><ul><ul><li>Mediated by brush border Na/Pi transporter </li></ul></ul><ul><ul><li>PTH – increases excretion  </li></ul></ul><ul><ul><li>Vitamin D – decreases excretion </li></ul></ul>1. Merck Manual . 2006;Sec 2:Ch 12. 2. Food & Nutrition Board, Institute of Medicine. Washington D.C.: National Academy Press; 1997:146-189. 3. Takeda E, et al. Adv Enzyme Regul . 2000;40:285-302.
    10. 10. Phosphorus Homeostasis 1200 mg 500 mg 130 mg 700 mg (< 1%) (85%) (15%) Soft tissues Plasma Bone Kidney Intestine 700 mg Adapted from: Goodman WG. Med Clin North Am . 2005;89:631-647.
    11. 11. Physiology Summary <ul><li>PTH and vitamin D are central regulators of plasma Ca </li></ul><ul><li>Calcium regulates serum PTH through the parathyroid CaSR </li></ul><ul><li>PTH production is controlled at several levels: </li></ul><ul><li>Kidney is crucial for calcitriol synthesis and phosphate secretion </li></ul><ul><li>Calcitriol increases serum calcium through increased intestinal absorption </li></ul>Hyperplasia mRNA level Secretion Vitamin D Calcium
    12. 12. Secondary HPT Pathophysiology: Overview <ul><li>CKD disrupts calcium homeostasis </li></ul><ul><ul><li>High PTH </li></ul></ul><ul><ul><li>Low calcitriol </li></ul></ul><ul><ul><li>Reduced intestinal calcium absorption </li></ul></ul><ul><ul><li>Low serum calcium at low GFR </li></ul></ul><ul><ul><li>High serum phosphorus at low GFR </li></ul></ul><ul><li>Excess PTH synthesis and secretion </li></ul><ul><ul><li>Inhibition of PTH transcription is deficient </li></ul></ul><ul><ul><li>Hyperplasia and parathyroid gland enlargement contribute to elevated serum PTH </li></ul></ul>
    13. 13. Serum Analytes Vary With Stage of Kidney Disease <ul><li>Craver L, et al. Nephrol Dial Transpl . 2007;22:1171-1176. </li></ul><ul><li>. </li></ul>50 40 30 20 10 0 CKD1 CKD2 CKD3 CKD4 CKD5 N = 15 87 221 156 43 1,25-(OH) 2 D (pg/mL) i PTH (pg/mL) CKD1 CKD2 CKD3 CKD4 CKD5 N = 174 341 856 354 111 0 200 100 * * * * * * * * P < 0.05 LLN ULN LLN
    14. 14. Serum Analytes Vary With Stage of Kidney Disease (cont) <ul><li>Craver L, et al. Nephrol Dial Transpl . 2007;22:1171-1176. </li></ul>CKD1 CKD2 CKD3 CKD4 CKD5 N = 174 341 856 354 111 9.7 9.6 9.5 9.4 9.3 9.2 9.1 9.0 8.9 Serum Calcium (mg/dL) CKD1 CKD2 CKD3 CKD4 CKD5 N = 174 341 856 354 111 Serum Phosphate (mg/dL) 5.5 5.0 4.5 4.0 3.5 3.0 * * P < 0.05 * * All calcium values within normal range ULN
    15. 15. Pathophysiology of sHPT in CKD Adapted from Skorecki K, et al. Harrison’s Principles of Internal Medicine . 15th ed. 2001:1551-1562. ↓ 1,25(OH) 2 D 3 ↑ P ↑ PTH ↓ Ca 2+
    16. 16. Risk of Death by Quarterly Varying iPTH 1 1.5 2 0.9 All-Cause Death Hazard Ratio Serum iPTH (pg/mL) KDOQI recommended range: 150-300 pg/mL < 100 100-200 200-300 300-400 400-500 500-600 600-700  700 Time-dependent Case-Mix and MICS model Kalantar-Zadeh K, et al. Kidney Int. 2006;70:771-780.
    17. 17. Corrected Serum Calcium (mg/dL) < 8.0 8.0 to 8.5 8.5 to 9.0 9.0 to 9.5 9.5 to 10.0 10.0 to 10.5 10.5 to 11  11.0 0.7 2 3 1 All-Cause Death Hazard Ratio 8.0 to 0.7 2 3 1 0.7 2 3 1 0.7 1.5 2 3 1 Risk of Death by Quarterly Varying Albumin-Adjusted Calcium KDOQI recommended range 8.4-9.5 mg/dL Time-dependent Case-Mix and MICS model Kalantar-Zadeh K, et al. Kidney Int. 2006;70:771-780.
    18. 18. Risk of Death by Quarterly Varying Phosphorus Serum Phosphorus (mg/dL) 2 3 4 1 2 3 4 1 2 3 4 1 < 3.0 3.0 to 3.99 4.0 to 4.99 5.0 to 5.99 6.0 to 6.99 7.0 to 7.99 8.0 to 8.99  9.0 KDOQI recommended range: 3.5-5.5 mg/dL All-Cause Death Hazard Ratio Kalantar-Zadeh K, et al. Kidney Int. 2006;70:771-780. Time-dependent Case-Mix and MICS model 0.7 2 3 4 1
    19. 19. Clinical Consequences of Mineral Dysregulation <ul><li>Renal osteodystrophy </li></ul><ul><li>Hyperphosphatemia </li></ul><ul><li>Cardiovascular calcification </li></ul><ul><li>Extraskeletal calcification </li></ul><ul><li>Endocrine disturbances </li></ul><ul><li>Neurobehavioral changes </li></ul><ul><li>Compromised immune system </li></ul><ul><li>Altered erythropoiesis </li></ul>
    20. 20. Forms of Vascular Calcification London GM et al. Curr Opin Nephrol Hypertens. 2005;14:525–531. Arterial Calcification Intimal Calcification Atherosclerosis Stenosis, occlusions Infarction, ischemia Medial Calcification Arteriosclerosis Stiffening Systolic and pulse pressures, early return of wave reflections Altered coronary perfusion, left-ventricular hypertrophy
    21. 21. Risk Factors for Soft Tissue Calcification <ul><li>Hyperphosphatemia </li></ul><ul><li>Increased Ca x P product </li></ul><ul><li>Excessive calcium load </li></ul><ul><li>Secondary hyperparathyroidism </li></ul><ul><li>Local tissue injury </li></ul><ul><li>Rise in tissue pH </li></ul><ul><li>Decreased levels of calcification inhibitors </li></ul><ul><li>Systolic hypertension (average 1 year systolic bp 160 mm Hg vs 120) </li></ul><ul><li>Adipose tissue (calcific uremic arteriolopathy) </li></ul>
    22. 22. Vascular Calcification in ESRD Intimal Calcification Atherosclerosis Medial Calcification Arteriosclerosis Available at: http://library.med.utah.edu/WebPath/CVHTML/CV007.html. Accessed May 2007.
    23. 23. Impact of Arterial Calcification in Stable Hemodialysis Patients with ESRD London GM, et al. Nephrol Dial Transplant. 2003;18:1731. Cardiovascular Survival  2 = 34.9; P < 0.0001 Time (months) NC P < 0.01 P < 0.001 AMC AIC  2 = 44.3; P < 0.00001 All-Cause Survival NC P < 0.001 P < 0.01 AMC AIC 0 25 50 75 100 0.00 0.75 0.50 0.25 1.00 0 25 50 75 100 0.00 0.75 0.50 0.25 1.00
    24. 24. Probability of Survival Decreases With Increasing Arterial Calcification 0 0.25 0.5 0.75 1 0 20 40 60 80 Follow-up (months) Probability of Survival 0 Arteries Calcified 1 Artery Calcified 2 Arteries Calcified 3 Arteries Calcified 4 Arteries Calcified N = 110 stable dialysis patients with ESRD P < 0.0001 comparison among groups Blacher J, et al. Hypertension . 2001;38:938-942.
    25. 25. Valvular Calcification and Mortality † P < 0.0005 vs no valvular calcification 0 0.2 0.4 0.6 0.8 1.0 0 6 12 18 24 30 36 Overall Survival Both Mitral and Aortic (n = 14) Either Mitral or Aortic (n = 48) Neither (n = 130) Follow-Up Time (months) † Wang A, et al. J Am Soc Nephrol. 2003;14:159-168.
    26. 26. CAC Is Associated With Increased Mortality Block GA, et al. Kidney Int . 2007;71:438-441. 0 6 12 18 CAC = 0 CAC1 – 400 CAC  400 24 0.00 0.25 0.50 0.75 1.00 30 36 42 48 54 60 66 P = 0.002 Months Survival Distribution Function
    27. 27. Calcification in Vascular Smooth Muscle Cells Osteo/Chondrocytic VSMC Death Signal VSMC Damage “Uremic Milieu” Apoptotic Bodies Matrix Vesicles + MGP / BMP7 + fetuin-A + PPi - MGP/ BMP2 - fetuin-A - PPi/+ALK + Ca/P Clearance Calcification Phagocytosis Delayed or Impaired Phagocytosis Elastin Shanahan CM. Curr Opin Nephrol Hypertens. 2005 ; 14:361–367.
    28. 28. Vascular Calcification, Cardiovascular Complications, and CKD <ul><li>Vascular Calcification Associated With: </li></ul><ul><ul><li>Accelerated risk of stroke, amputation, MI </li></ul></ul><ul><ul><li>Left ventricular hypertrophy </li></ul></ul><ul><ul><li>Poor coronary artery perfusion </li></ul></ul><ul><ul><li>Increased pulse wave velocity </li></ul></ul><ul><ul><li>Increased pulse pressure </li></ul></ul><ul><li>Contributory Factors: </li></ul><ul><ul><li>Deranged bone and mineral metabolism </li></ul></ul><ul><ul><li>Decreased levels of inhibitors of calcification such as fetuin-A </li></ul></ul><ul><ul><li>Stimulation of osteogenic pathways in endothelial cells by uremic “toxins” </li></ul></ul><ul><ul><li>Impaired endothelial repair mechanisms </li></ul></ul>Adapted from Lederer E and Ouseph R. Am J Kidney Dis. 2007;49:162-171. Block GA, et al. Kidney Int. 2007;71(5):438-441.
    29. 29. KDOQI ™ Goals for Stage 5 CKD National Kidney Foundation. Am J Kidney Dis . 2002;39(Suppl 1):S1-S266. KDOQI guidelines recommend that Ca 2+ and P should be monitored monthly and PTH quarterly after stabilization. < 55 mg 2 /dL 2 Ca x P Product 3.5 – 5.5 mg/dL Serum P 8.4 – 9.5 mg/dL Serum Ca (albumin-corrected) 150 – 300 pg/mL Serum PTH
    30. 30. Patient Case Review/Update <ul><li>Medications: </li></ul><ul><ul><li>Calcium acetate: 667 mg 3 tab tid </li></ul></ul><ul><ul><li>B-complex with C: 1 tab qd </li></ul></ul><ul><ul><li>Atorvastatin: 20 mg qd </li></ul></ul><ul><ul><li>Metoprolol: 50 mg bid </li></ul></ul><ul><ul><li>Prednisone: 2.5 mg qd </li></ul></ul><ul><li>Laboratory values: </li></ul><ul><ul><li>Phosphorus: 8.0 mg/dl </li></ul></ul><ul><ul><li>Corrected calcium: 8.3 mg/dl </li></ul></ul><ul><ul><li>Intact PTH: 670 pg/ml </li></ul></ul><ul><ul><li>Ca x P: 66.4 </li></ul></ul>
    31. 31. Nutrition Guidelines <ul><li>Limit dietary phosphorus to 800-1000 mg/d with consideration for protein needs, ie, as low as possible while allowing for a recommended level of protein intake </li></ul><ul><li>Limit elemental calcium from calcium-based binders to ≤ 1500 mg/d </li></ul><ul><li>Limit total (dietary and medication) elemental calcium to ≤ 2000 mg/d </li></ul><ul><li>Avoid calcium fortified foods as directed </li></ul><ul><li>Moderate application of cardiovascular dietary recommendations, not to the detriment of nutrition status </li></ul>National Kidney Foundation. Am J Kidney Dis . 2002;39(Suppl 1):S1-S266.
    32. 32. Lifestyle Guidelines <ul><li>Exercise training </li></ul><ul><li>Identify and address psychological issues (eg, depression) </li></ul><ul><li>No smoking (help prevent CVD?) </li></ul>
    33. 33. Patient Case Review/Update <ul><li>Patient started on sevelamer HCl 800 mg 2 tablets tid with meals, Ca acetate discontinued to reduce vascular calcification risk </li></ul><ul><li>Repeat labs after 2 weeks: </li></ul><ul><ul><li>Phosphorus: 6.5 mg/dl </li></ul></ul><ul><ul><li>Corrected calcium: 8.3 mg/dl </li></ul></ul><ul><ul><li>Ca x P: 54 </li></ul></ul><ul><li>Diet reviewed; sevelamer increased to 3 tablets with meals, 2 tablets with snacks </li></ul>
    34. 34. Therapeutic Interventions for Managing Secondary HPT Intervention Result Ca PO 4 PTH Phosphate Binders (Ca-based) Adapted from Goodman WG. Nephrol Dial Transplant. 2003;18(suppl 3):iii2-iii8.
    35. 35. Managing Mineral Balance: Phosphate Binders Sevelamer label: http://www.renagel.com/docs/renagel_pi.pdf Block GA, et al. Kidney Int. 2007;71(5):438-441. Serum Phosphate Sevelamer Calcium Mortality Phosphorus Change Study Week 0 2 6 10 14 18 22 26 30 34 38 42 46 52 -5 -4 -3 -2 -1 0 1 2 1.00 0.75 0.50 0.25 0.00 0 6 12 18 24 30 36 42 48 54 60 66 P = 0.016 Survival Fraction Sevelamer Calcium Months
    36. 36. Use of Phosphate Binders <ul><li>Ca-based binder should not be used if patient has hypercalcemia or PTH < 150 pg/mL </li></ul><ul><li>Non-Ca-based binder preferred if vascular or soft-tissue calcification is appreciable </li></ul>National Kidney Foundation. Am J Kidney Dis . 2002;39(Suppl 1):S1-S266. Al-OH up to 4 wks Ca-based and other binder Dietary P restriction, Ca-based or other binder Stage 5 Ca-based binder Dietary P restriction Stage 3/4 3 rd line 2 nd line 1 st line
    37. 37. Phosphate Binders: Summary Cannata-Andia JB. Dial Trans . 2002;17(Suppl 11):16–19; Ritz EJ. J Nephrol. 2005;18;221-228. Goodman WG. Neph Dial Trans. 2003;18(Suppl 3):iii2-iii8; Block GA, et al. Kidney Int. 2007; 71(5):438-441. Hyper-Mg; no long term studies Potential to minimize Ca load Magnesium carbonate Cost; Taste fatigue; Unknown long term impact; Tolerability Good potency; Minimal absorption; Not Hyper-Ca; Low pill burden Lanthanum carbonate High pill burden (moderate potency); Cost; Tolerability Less vascular calcification than Ca-containing binders; lower mortality? Reduction of TC & LDL Sevelamer Hyper-Ca, calcification risk; High pill burden Effective; Widely used Calcium-containing Tissue accumulation; Bone disease, encephalopathy, anemia Effective Aluminum-containing Disadvantages Advantages Binder
    38. 38. <ul><li>At 1 month, labs are checked </li></ul><ul><ul><li>Phosphorus: 5.5 mg/dL </li></ul></ul><ul><ul><li>Corrected calcium: 8.3 mg/dL </li></ul></ul><ul><ul><li>Ca x P: 46 </li></ul></ul><ul><ul><li>Intact PTH: 601 pg/mL </li></ul></ul><ul><ul><li>25-hydroxy vitamin D: 18 ng/mL </li></ul></ul><ul><li>Started on Vitamin D </li></ul><ul><ul><li>Ergocalciferol: 50,000 IU/month </li></ul></ul><ul><ul><li>Active analog </li></ul></ul>Patient Case Update
    39. 39. Therapeutic Interventions for Managing Secondary HPT Intervention Result Ca PO 4 PTH Vitamin D analog Adapted from Goodman WG. Nephrol Dial Transplant. 2003;18(suppl 3):iii2-iii8.
    40. 40. Vitamin D Repletion in Stage 3 & 4 with Ergocalciferol: KDOQI TM Recommendation National Kidney Foundation. Am J Kidney Dis. 2003;42(4 suppl 3):S1-S201. 50,000/mo 50,000/wk X 4 wks, then monthly 500,000 once 50,000/wk X 12 wks; then monthly Dose (IU) Assure pt adherence; assay 25(OH)D at 6 months im 6 po Insufficiency 16-30 Assay 25(OH)D after 6 months 6 po Mild deficiency 5-15 Assay 25(OH)D after 6 months 6 po Severe deficiency < 5 Comment Duration (months) Route Vitamin D Status Serum 25(OH)D (ng/mL)
    41. 41. Vitamin D Analogs Suppress PTH Sprague SM, et al. Kidney Int. 2003;63:1483-1490. Time (weeks) PTH (pg/mL) 0 100 200 300 400 500 600 700 800 900 1000 Paricalcitol (n = 130) Calcitriol (n = 133) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
    42. 42. Vitamin D Use Is Associated With Decreased Mortality in Incident HD Patients Vitamin D (n = 37,173) No Vitamin D (n = 13,864) Teng M, et al. J Am Soc Nephrol . 2005;16:1115-1125. *P < 0.001 8 15 CV Mortality * * 14 29 0 10 20 30 40 50 2-Year Mortality Mortality per 100 Patient-Years Infectious Cause Mortality 1 3 *
    43. 43. Which Vitamin D Do We Use and Why? <ul><li>Calcitriol (Calcijex ® , Rocaltrol ® ) active vitamin D </li></ul><ul><ul><li>Increased calcium and phosphorus absorption </li></ul></ul><ul><ul><li>Increased serum levels </li></ul></ul><ul><ul><li>Loses effectiveness with high serum P </li></ul></ul><ul><li>Paricalcitol (Zemplar ® ) active vitamin D analog </li></ul><ul><ul><li>Less calcemic </li></ul></ul><ul><li>Doxercalciferol (Hectorol ® ) </li></ul><ul><ul><li>Less calcemic </li></ul></ul>
    44. 44. Recommended Vitamin D Dosing <ul><li>Serum Ca > 10.2 : stop all D, minimize Ca load </li></ul><ul><li>Ca = 9.5-10.2: change to non Ca-containing binder </li></ul><ul><li>Ca < 9.5: continue D or modify with P algorithm </li></ul><ul><li>P > 6.0: stop vitamin D </li></ul><ul><li>P = 5.5–6.0: increase binders, decrease Vitamin D </li></ul><ul><li>P < 5.5: continue or modify using Ca or PTH algorithm </li></ul>National Kidney Foundation. Am J Kidney Dis . 2002;39(Suppl 1):S1-S266. IV 4 – 8 mcg Oral 10 - 20 mcg 10 – 15 mcg IV 3.0-5.0 Oral 3-7 < 55 < 5.5 < 10 > 1000 IV 2 – 4 mcg Oral 5 – 10 mcg 6.0 – 10 mcg IV 1.0-3.0 Oral 1-4 < 55 < 5.5 < 9.5 600 – 1000 IV 2 mcg Oral 5 mcg 2.5 – 5.0 mcg IV 0.5 – 1.5 Oral same < 55 < 5.5 < 9.5 300 – 600 Doxercalciferol Paricalcitol Calcitriol Ca x P P Ca PTH
    45. 45. <ul><li>Laboratory data in one month: </li></ul><ul><ul><li>Phosphorus: 6.1 mg/dl </li></ul></ul><ul><ul><li>Calcium: 9.3 mg/dl </li></ul></ul><ul><ul><li>Ca x P product: 57 </li></ul></ul><ul><ul><li>Intact PTH: 489 pg/ml </li></ul></ul><ul><li>Patient started on cinacalcet HCl 30 mg qd </li></ul>Patient Case Update
    46. 46. Therapeutic Interventions for Managing Secondary HPT Intervention Result Ca PO 4 PTH Calcimimetic Adapted from Goodman WG. Nephrol Dial Transplant. 2003;18(suppl 3):iii2-iii8.
    47. 47. Targeting PTH Secretion With Cinacalcet Control Serum PTH (% of maximum) 80 60 40 20 100 0 1.5 0 0.5 1.0 2.0 Extracellular Calcium (mM) Cinacalcet Cinacalcet Increases Calcium Sensitivity [Ca 2+ ] ER [Ca i 2+ ] CaSR PTH PTH PTH Cinacalcet Adapted from Goodman WG, et al. Kidney Int . 1996;50:1834-1844.
    48. 48. Cinacalcet is Associated with a Reduction of PTH Block GA, et al. New Engl J Med. 2004;350:1516-1525. P < 0.001 Placebo Cinacalcet Dose titration Efficacy assessment Week PTH level (pg/ml) 800 700 600 500 400 300 200 100 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 ~50% reduction
    49. 49. Cinacalcet Enables Patients to Achieve the KDOQI ™ Targets Adapted from Moe SM, et al. Kidney Int. 2005;67:760-771. Median iPTH (pg/mL) KDOQI ™ Target 0 100 200 300 400 500 600 700 Week Cinacalcet HCI Placebo n = 471 n = 663 n = 366 n = 473 B 2 4 6 8 12 14 16 18 20 22 24 26 10 iPTH Week n = 471 n = 663 n = 368 n = 471 B 2 4 6 8 12 14 16 18 20 22 24 26 10 Median Serum Ca (mg/dL) 8.2 8.4 8.8 9.0 9.2 9.6 9.8 10.2 8.6 9.4 10.0 KDOQI ™ Target Serum Calcium n = 410 n = 547 n = 412 n = 555 Week n = 471 n = 662 n = 363 n = 466 B 2 4 6 8 12 14 16 18 20 22 24 26 10 Median Ca x P (mg 2 /dL 2 ) 40 45 50 55 60 65 Ca x P KDOQI ™ Target n = 408 n = 545 n = 363 n = 466 Week n = 471 n = 663 B 2 4 6 8 12 14 16 18 20 22 24 26 10 4.6 4.8 5.0 5.2 5.4 5.6 5.8 6.0 6.2 6.4 Median Serum P (mg/dL) Serum Phosphorus KDOQI ™ Target n = 409 n = 547
    50. 50. Cinacalcet Reduction of iPTH for 3 Years Moe SM, et al. Nephrol Dial Transplant . 2005;20:2186-2193. Placebo n = 17 Cinacalcet n = 16
    51. 51. Cinacalcet Is Associated With Improved Outcomes Cunningham J, et al. Kidney Int . 2005;68:1793-1800. CV Hospitalization Fractures PTX Mortality Week Event-Free Probability 0 4 8 12 16 20 24 28 32 36 40 44 48 52 0.75 0.95 1.00 Standard - 4.1 events / 100 pt yrs Cinacalcet - 0.3 events / 100 pt yrs 0.90 0.85 0.80 Event-Free Probability Week 0 4 8 12 16 20 24 28 32 36 40 44 48 52 0.75 0.95 1.00 Standard - 6.9 events / 100 pt yrs Cinacalcet - 3.2 events / 100 pt yrs 0.90 0.85 0.80 P = 0.04 Week Event-Free Probability 0 4 8 12 16 20 24 28 32 36 40 44 48 52 0.75 0.95 1.00 Standard – 7.4 deaths / 100 pt yrs Cinacalcet – 5.2 deaths / 100 pt yrs 0.90 0.85 0.80 P = NS P = 0.009 P = 0.005 Week Event-Free Probability 0 4 8 12 16 20 24 28 32 36 40 44 48 52 0.75 0.95 1.00 Standard – 19.7 events / 100 pt yrs Cinacalcet – 15.0 events / 100 pt yrs 0.90 0.85 0.80
    52. 52. Therapeutic Interventions for Managing Secondary HPT Diet/nutrition, Phosphate Binders, Vitamin D Ca PO 4 PTH Diet/nutrition, Ca-based P-binders Vitamin D Calcimimetics, Vitamin D Adapted from Goodman WG. Nephrol Dial Transplant. 2003;18(suppl 3):iii2-iii8.
    53. 53. <ul><li>Lab values checked at 1 week: </li></ul><ul><ul><li>Phosphorus: 5.4 mg/dL </li></ul></ul><ul><ul><li>Corrected calcium: 8.7 mg/dL </li></ul></ul><ul><li>Patient complains of mild nausea </li></ul><ul><li>Advised to take cinacalcet with evening meal </li></ul><ul><li>No other changes made at this time </li></ul>Patient Case Update
    54. 54. <ul><li>Labs rechecked at 1 month </li></ul><ul><ul><li>Phosphorus: 5.4 mg/dL </li></ul></ul><ul><ul><li>Corrected calcium: 8.7 mg/dL </li></ul></ul><ul><ul><li>Intact PTH: 290 pg/ml </li></ul></ul><ul><ul><li>Ca x P product: 47 </li></ul></ul><ul><li>Nausea resolved </li></ul><ul><li>No further changes warranted at present </li></ul>Patient Case Update (cont)
    55. 55. Developing a Treatment Algorithm <ul><li>Promote patient safety and incorporate strategies for the fewest side effects </li></ul><ul><li>Be consistent with current, valid research and update regularly as new information is available </li></ul><ul><li>Reflect team consensus and consider facility needs or limitations </li></ul><ul><li>Provide a schedule for changes (dose, meds, route of admin) </li></ul><ul><li>Provide logical, easy steps </li></ul><ul><li>Allow for therapy response time before making additional changes </li></ul><ul><li>Minimize paperwork </li></ul><ul><li>Include mechanism to inform patient and team of progress </li></ul><ul><li>Define limits and provide mechanism to return management to MD if treatment outside parameters is needed </li></ul><ul><li>Identify outcome measures and provide tracking mechanisms </li></ul>
    56. 56. Therapeutic Options for Secondary HPT: Conclusions <ul><li>New phosphate binders offer options for phosphorus reduction without increasing serum calcium </li></ul><ul><li>Vitamin D analogs lower PTH and increase bone mineralization, but also raise calcium and phosphorus </li></ul><ul><li>Cinacalcet can be used to lower PTH despite elevations in calcium and/or phosphorus </li></ul><ul><li>Dialysis is a critical tool for managing ESRD </li></ul><ul><li>Parathyroidectomy can be useful for lowering PTH when pharmacologic intervention fails </li></ul>

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