PTH - Chronic Renal Failure

Learning Objectives: Describe the physiology of PTH and mineral metabolism in patients with CKD Discuss the available therapies for the disorders of PTH and mineral metabolism in patients with CKD Apply this information to the clinical management of patients with CKD PTH and Mineral Disorders in Patients With CKD: A Practical Case-Based Approach for Renal Dietitians

Patient Case 53-year-old male with history of stage 5 CKD 2 º AD PKD recently started on hemodialysis after failed renal transplant History of deceased donor renal transplant, 11/95 Previously on hemodialysis, 6/95–11/95 History of CVD, s/p CABG x 3 in 02/04 History HTN; history basal cell carcinoma Social history: works as car mechanic; no history of alcohol, tobacco; married 21 years; 1 daughter, age 19 Family history ADPKD on maternal side

Patient Case (cont) Presents with mild itching, bone pain No history of fractures Medications: Calcium acetate: 667 mg 3 tab tid B-complex with C: 1 tab qd Atorvastatin: 20 mg qd Metoprolol: 50 mg bid Prednisone: 2.5 mg qd Laboratory values: Phosphorus: 8.0 mg/dl Corrected calcium: 8.3 mg/dl Intact PTH: 670 pg/ml Ca x P: 66.4

Concentration in blood/plasma is tightly regulated by PTH and vitamin D Calcium ions serve a variety of functions Signal transduction: 1st and 2nd messengers Nerve and muscle function Major component of bone Serum calcium does not reflect total body calcium content Overview of Calcium Physiology

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

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.

Principal Biological Effects of Vitamin D Increases absorption of Ca and P Maintains bone mineralization and turnover Indirectly reduces synthesis of calcitriol Reduces synthesis of PTH

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

Phosphorus Metabolism Normal PO 4 levels in plasma: 2.5–4.5 mg/dL 1 Total body PO 4 content: 500–700 g 1 (85% in bone) Dietary Reference Intake 2 : 700 mg Typical US dietary intake 2 : 1200 mg GI absorption Mainly passive, through Na/Pi transporter Fractional absorption 60–70% Enhanced by vitamin D Kidney is major regulator 3 Mediated by brush border Na/Pi transporter PTH – increases excretion Vitamin D – decreases excretion 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.

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.

Physiology Summary PTH and vitamin D are central regulators of plasma Ca Calcium regulates serum PTH through the parathyroid CaSR PTH production is controlled at several levels: Kidney is crucial for calcitriol synthesis and phosphate secretion Calcitriol increases serum calcium through increased intestinal absorption Hyperplasia mRNA level Secretion Vitamin D Calcium

Secondary HPT Pathophysiology: Overview CKD disrupts calcium homeostasis High PTH Low calcitriol Reduced intestinal calcium absorption Low serum calcium at low GFR High serum phosphorus at low GFR Excess PTH synthesis and secretion Inhibition of PTH transcription is deficient Hyperplasia and parathyroid gland enlargement contribute to elevated serum PTH

Serum Analytes Vary With Stage of Kidney Disease Craver L, et al. Nephrol Dial Transpl . 2007;22:1171-1176. . 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

Serum Analytes Vary With Stage of Kidney Disease (cont) Craver L, et al. Nephrol Dial Transpl . 2007;22:1171-1176. 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

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+

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.

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.

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

Clinical Consequences of Mineral Dysregulation Renal osteodystrophy Hyperphosphatemia Cardiovascular calcification Extraskeletal calcification Endocrine disturbances Neurobehavioral changes Compromised immune system Altered erythropoiesis

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

Risk Factors for Soft Tissue Calcification Hyperphosphatemia Increased Ca x P product Excessive calcium load Secondary hyperparathyroidism Local tissue injury Rise in tissue pH Decreased levels of calcification inhibitors Systolic hypertension (average 1 year systolic bp 160 mm Hg vs 120) Adipose tissue (calcific uremic arteriolopathy)

Vascular Calcification in ESRD Intimal Calcification Atherosclerosis Medial Calcification Arteriosclerosis Available at: http://library.med.utah.edu/WebPath/CVHTML/CV007.html. Accessed May 2007.

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

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.

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.

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

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.

Vascular Calcification, Cardiovascular Complications, and CKD Vascular Calcification Associated With: Accelerated risk of stroke, amputation, MI Left ventricular hypertrophy Poor coronary artery perfusion Increased pulse wave velocity Increased pulse pressure Contributory Factors: Deranged bone and mineral metabolism Decreased levels of inhibitors of calcification such as fetuin-A Stimulation of osteogenic pathways in endothelial cells by uremic “toxins” Impaired endothelial repair mechanisms 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.

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

Patient Case Review/Update Medications: Calcium acetate: 667 mg 3 tab tid B-complex with C: 1 tab qd Atorvastatin: 20 mg qd Metoprolol: 50 mg bid Prednisone: 2.5 mg qd Laboratory values: Phosphorus: 8.0 mg/dl Corrected calcium: 8.3 mg/dl Intact PTH: 670 pg/ml Ca x P: 66.4

Nutrition Guidelines 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 Limit elemental calcium from calcium-based binders to ≤ 1500 mg/d Limit total (dietary and medication) elemental calcium to ≤ 2000 mg/d Avoid calcium fortified foods as directed Moderate application of cardiovascular dietary recommendations, not to the detriment of nutrition status National Kidney Foundation. Am J Kidney Dis . 2002;39(Suppl 1):S1-S266.

Lifestyle Guidelines Exercise training Identify and address psychological issues (eg, depression) No smoking (help prevent CVD?)

Patient Case Review/Update Patient started on sevelamer HCl 800 mg 2 tablets tid with meals, Ca acetate discontinued to reduce vascular calcification risk Repeat labs after 2 weeks: Phosphorus: 6.5 mg/dl Corrected calcium: 8.3 mg/dl Ca x P: 54 Diet reviewed; sevelamer increased to 3 tablets with meals, 2 tablets with snacks

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.

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

Use of Phosphate Binders Ca-based binder should not be used if patient has hypercalcemia or PTH < 150 pg/mL Non-Ca-based binder preferred if vascular or soft-tissue calcification is appreciable 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

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

At 1 month, labs are checked Phosphorus: 5.5 mg/dL Corrected calcium: 8.3 mg/dL Ca x P: 46 Intact PTH: 601 pg/mL 25-hydroxy vitamin D: 18 ng/mL Started on Vitamin D Ergocalciferol: 50,000 IU/month Active analog Patient Case Update

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.

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)

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

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 *

Which Vitamin D Do We Use and Why? Calcitriol (Calcijex ® , Rocaltrol ® ) active vitamin D Increased calcium and phosphorus absorption Increased serum levels Loses effectiveness with high serum P Paricalcitol (Zemplar ® ) active vitamin D analog Less calcemic Doxercalciferol (Hectorol ® ) Less calcemic

Recommended Vitamin D Dosing Serum Ca > 10.2 : stop all D, minimize Ca load Ca = 9.5-10.2: change to non Ca-containing binder Ca < 9.5: continue D or modify with P algorithm P > 6.0: stop vitamin D P = 5.5–6.0: increase binders, decrease Vitamin D P < 5.5: continue or modify using Ca or PTH algorithm 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

Laboratory data in one month: Phosphorus: 6.1 mg/dl Calcium: 9.3 mg/dl Ca x P product: 57 Intact PTH: 489 pg/ml Patient started on cinacalcet HCl 30 mg qd Patient Case Update

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.

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.

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

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

Cinacalcet Reduction of iPTH for 3 Years Moe SM, et al. Nephrol Dial Transplant . 2005;20:2186-2193. Placebo n = 17 Cinacalcet n = 16

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

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.

Lab values checked at 1 week: Phosphorus: 5.4 mg/dL Corrected calcium: 8.7 mg/dL Patient complains of mild nausea Advised to take cinacalcet with evening meal No other changes made at this time Patient Case Update

Labs rechecked at 1 month Phosphorus: 5.4 mg/dL Corrected calcium: 8.7 mg/dL Intact PTH: 290 pg/ml Ca x P product: 47 Nausea resolved No further changes warranted at present Patient Case Update (cont)

Developing a Treatment Algorithm Promote patient safety and incorporate strategies for the fewest side effects Be consistent with current, valid research and update regularly as new information is available Reflect team consensus and consider facility needs or limitations Provide a schedule for changes (dose, meds, route of admin) Provide logical, easy steps Allow for therapy response time before making additional changes Minimize paperwork Include mechanism to inform patient and team of progress Define limits and provide mechanism to return management to MD if treatment outside parameters is needed Identify outcome measures and provide tracking mechanisms

Therapeutic Options for Secondary HPT: Conclusions New phosphate binders offer options for phosphorus reduction without increasing serum calcium Vitamin D analogs lower PTH and increase bone mineralization, but also raise calcium and phosphorus Cinacalcet can be used to lower PTH despite elevations in calcium and/or phosphorus Dialysis is a critical tool for managing ESRD Parathyroidectomy can be useful for lowering PTH when pharmacologic intervention fails

PTH - Chronic Renal Failure

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