Secondary hyperparathyroidism in dialysis patients

Secondary hyperparathyroidism in dialysis patients ( a critical approach of pharmacological treatments) Dominique JOLY Néphrologie Hôpital NECKER, Paris

DFG Finn WF. J Am Soc Nephrol. 24;15:271A.

Ca ++ Phosphates Calcitriol Ca SR? VDR VDR PTH

Ca ++ Phosphates Calcitriol Ca SR? VDR VDR PTH Secretion Synthesis Number of cells Hyperplasia Nodules

PTH High turnover Low turnover PTH

Low turnover PTH Target PTH : 15-3 pg/ml PTH High turnover

Low turnover PTH Target PTH : 15-3 pg/ml PTH High turnover Barreto KI. 28;73:771

Low turnover PTH Target PTH : 15-3 pg/ml PTH High turnover Fracture-free survival 1..9.8.7.6.5 2 4 6 8 1 12 PTH 196-5 > 51 66-195 < 65 (mois) Coco & Rush, AJKD 2;36:1115

High turnover PTH Target PTH : 15-3 pg/ml Low turnover PTH

Low turnover PTH Target PTH : 15-3 pg/ml PTH High turnover PO -- 4 Ca ++ PO -- 4 -- Ca ++ Ca x P elevated

Mortality 1.8 * RR of death 1.6 1.4 1.2 * * * 1..8 * * *.6. < 8. 8. 8.5 8.5 9. 9. 9.5 9.5 1. 1. 1.5 1.5 11. > 11. 2.2 * 2. * RR of death 1.8 1.6 1.4 1.2 * * * 1..8. 1.8 < 3. 3. 4. 4. 5. 5. 6. 6. 7. 7. 8. 8. 9. > 9. RR of death 1.6 1.4 1.2 1. *.8.6. < 15 15 3 3 6 6 Block J Am Soc Nephrol. 24;15:228-2218.

Mortality 1.8 * RR of death 1.6 1.4 1.2 * * * 1..8 * * *.6. 2.2 < 8. 8. 8.5 8.5 9. 9. 9.5 9.5 1. 1. 1.5 1.5 11. > 11. * Ca 9.5 8.5 RR of death 2. 1.8 1.6 1.4 1.2 1..8. 1.8 * * * * < 3. 3. 4. 4. 5. 5. 6. 6. 7. 7. 8. 8. 9. > 9. PTH 8 Ph 5.5 3.5 3 PTHi 15 1.6 RR of death 1.4 1.2 * 1..8.6. < 15 15 3 3 6 6 Block J Am Soc Nephrol. 24;15:228-2218.

Calcifications

Calcifications CAC score (EBCT)

CAC Score of dialysis patients

CAC Score of dialysis patients (1) Elevated 2,5 2, 1,5 1, 5 Contro l Coronary artery disease On Dialysis Ag e 28 39 4 49 5 59 6 69 Braun et al. AJKD. 1996;27:394-41.

CAC Score of dialysis patients (1) Elevated 2,5 2, 1,5 1, 5 Contro l Coronary artery disease On Dialysis Ag e 28 39 4 49 5 59 6 69 Braun et al. AJKD. 1996;27:394-41. Blacher et al. Hypertension. 21;38:938. London et al. NDT 23;18:1731. (2) Predicts mortality SURVIVAL 1..75.5 Calcification score: Calcification score: 1 Calcification score: 2 Calcification score: 3.25 Calcification score: 4. 2 4 6 8 mois

CAC Score of dialysis patients (3) Increased by hyperca ++ - phosphatemia 163 174 8 39 Braun et al. AJKD. 1996;27:394-41. Blacher et al. Hypertension. 21;38:938. London et al. NDT 23;18:1731. Chertow et al. NDT. 24;19:1489-1496. Block GA et al, KI 25;68:1815-24 35 3 25 2 15 1 5 Coronaire (P =.1) s Ph< 5.5 (4) Modified by treatments T Calciu msevelame r 6 m 12 m 18 m Aorte (P =.16) Ph 5.5 mg/dl

Ca x P Calcifications Mortalite «There is a link» Moe S et al, KI 26;69:1945-53

Ca x P Calcifications Mortalite «There is a link» Moe S et al, KI 26;69:1945-53 «Causality?»

Ca x P Calcifications Mortalite «There is a link» Moe S et al, KI 26;69:1945-53 «Causality?» «Intervention studies are necessary» Vitamin D Calcimimetic agents Phosphate binders

1. Vitamin D Stock (calciferol, ergocalciferol) sun, food 1 generation: calcitriol (1, 25-(OH) 2 -D3) 2 generation : alfacalcidol (1-α OH-D3) doxercalciferol (Hectorol, 1-αOH-D2) 3 generation : paricalcitol (Zemplar, 19-Nor-1-α-25 (OH) 2 -D2) other

Calcitriol VDR VDR PTH Synthesis ipth P Ca Ca x P New vitamin D Calcitriol/ Alfacalcidol

Do 3 generation vitamins D have a «better biological profile»? (prospective randomized study)

Do 3 generation vitamins D have a «better biological profile»? (prospective randomized study) PTH (pg/ml) Calcitriol (n = 133) 1 Paricalcitol (n = 13) 9 8 7 6% of patients: > 5% reduction of PTH Paricalcitol : quicker Paricalcitol : fewer hypercalcemia / Ca x P 6 5 4 3 2 1 2 4 6 8 1 12 14 16 18 2 22 24 26 28 3 32 34w Sprague Kidney Int. 23;63:1483-149.

Are 2 /3 generation vitamin D associated with a better survival in HD patients? (historical cohorts, retrospective, observation of 2-3y mortality, multivariate adjusted)

Are 2 /3 generation vitamin D associated with a better survival in HD patients? (historical cohorts, retrospective, observation of 2-3y mortality, multivariate adjusted) 67 399 HD (prevalent) survival : paricalcitol > calcitriol Paricalcitol => mortality -16 % (,79-,9) Teng, NEJM 23; 349:446-56

Vitamine D use is associated with a reduced all-cause mortality (historical cohorts, retrospective, observation of 2-3y mortality, multivariate adjusted)

Vitamine D use is associated with a reduced all-cause mortality (historical cohorts, retrospective, observation of 2-3y mortality, multivariate adjusted) Teng M et al, JASN 25 51 37 HD (prevalent) 37 173 under vitamin D (IV calcitriol or paricalcitol) 13 864 no vitamine D HR Death =.8 (.76-.83) Tentori, KI 26; 7:1858-65 14 967 HD (incident) 46,9 % no vitamin D (calcitriol or paricalcitol) HR Death =.8 (.7-.9) Melamed, KI 26; 7:351-57 17 HD/DP (incident) HR Death =.74 (.56-1)

Does vitamin D use explain «better survival of HD black patients?» (prospective cohort of incident HD, 1 y mortality observation, multivariate adjustement) n Mortality (1 y) PTH (pg/ml) 25 OH (ng/ml) Vitamin D active Dose/TT White 511 23 % 173 23,2 71%,6 µg Black 3214 16 % 279 16,2 88 % 1 µg Black - Hispanic White

Vitamin D Pleiotropic effects VDR is ubiquitary Vitamin D deficiency is associated with extra-skeletal complications Insulin-resistance, Diabetes HTA, SRAA Activation, cardiac failure, stroke Cancer (prostate, colon, breast) Wang, circulation 27; 117:53 VDR and diabetic nephropathy Progression Zhang, KI 28; 73:163 Glycemia Proteinuria VDR -/- Glomerulosclérosis VDR +/+

Vitamin D Ongoing studies OBSERVATION INTERVENTION Native Active VD and Myopathy in HD patients

2. Calcimimetic agents Small organic compounds that are administered orally Act as allosteric activators rather than ligands to the CaSR Increase sensitivity of the CaSR to extracellular Ca ions Suppress PTH secretion without elevating serum calcium and phosphorus levels

Calcimimetic agents Cinacalcet [Ca 2+ ] Ca SR PTH Secretion Synthesis Number of cells Hyperplasia

Calcimimetic agents Cinacalcet [Ca 2+ ] Increase calcium sensitivity 1 Control Cinacalcet Ca SR Serum PTH (% of maximum) 8 6 4 2 Secretion PTH Synthesis Number of cells Hyperplasia.5 1. 1.5 2. Serum ionized calcium (mm) de Francisco, NDT 23 AVRIL 28

Calcimimetic agents Placebo Cinacalcet Biological Effects 7 6 5 4 3 2 1 PTH KDOQI Target B 2 4 6 8 1 12 14 16 18 2 22 24 26 Week 1.2 1. 9.8 9.6 9.4 9.2 9. 8.8 8.6 8.4 8.2 Calcium KDOQI Target B 2 4 6 8 1 12 14 16 18 2 22 24 26 Week 6.4 6.2 6. Phosphate 65 6 Ca x P 5.8 5.6 55 5.4 5.2 5 5. 4.8 4.6 KDOQI Target B 2 4 6 8 1 12 14 16 18 2 22 24 26 Week 45 4 KDOQI Target B 2 4 6 8 1 12 14 16 18 2 22 24 26 Week Moe SM, et al. Kidney Int. 25;67:76-771.

Calcimimetic agents Clinical Effects Changes in relative risk (%)* 2-2 -4-6 -8 PTX Fracture -54 Hospitalization CV -39 Mortality -19-1 -93 Cunningham J et al, KI 25;68:1793-8

Calcimimetic agents Clinical Effects Changes in relative risk (%)* 2-2 -4-6 -8 PTX Fracture -54 Hospitalization CV -39 Mortality -19 DNS -1-93 Cunningham J et al, KI 25;68:1793-8

Calcimimetic agents Clinical Effects Meta-analysis 8 studies comparing cinacalcet vs placebo n = 1429 patients End of treatment values of PTH, Ca, Ph are lower with calcimimetics No significant effects on patient-based endpoints were demonstrated Benefits of calcimimetics remain uncertain until futher RCT become available Strippoli AJKD 26;47:715

Calcimimetic agents Clinical Effects IN PROGRESS EVOLVE (Evaluation of Cinacalcet to Lower Clinical Events)

Calcimimetic agents Clinical Effects IN PROGRESS EVOLVE (Evaluation of Cinacalcet to Lower Clinical Events) Prevalent HD N=19 PTH > 3 Ca > 2.1 mm N=19 Ca x P > 3.6 mm 2 Placebo ± P binders ± vit D Cinacalcet ± P binders ± vit D

Calcimimetic agents Clinical Effects While EVOLVE results are awaited I personnaly use calcimimetic agents in selected patients

Calcimimetic agents Clinical Effects While EVOLVE results are awaited I personnaly use calcimimetic agents in selected patients M PTH 15 Ca x P > 1 mg 2 /dl 2 Zerbi et al. JCEM 28 1121

Calcimimetic agents Clinical Effects While EVOLVE results are awaited I personnaly use calcimimetic agents in selected patients M Cinacalcet 3-6 mg/j M6 PTH 15 Ca x P > 1 mg 2 /dl 2 35 6 Zerbi et al. JCEM 28 1121

3. Phosphorus Hennig Bland (1669) The Discovery of Phosphorus Joseph Wright

Phosphate? PTH HD patients General Population 2.2 Risque relatif de décès 2. 1.8 1.6 1.4 1.2 1..8. < 3. 3. 4. 4. 5. 5. 6. 6. 7. 7. 8. 8. 9. > 9. Block JASN 24;15:228-2218. Dhingra Arch Intern Med 27;167:879-885.

Phosphate balance in HD patients Intake 1.2 g/kg => 1 mg P Absorption 6% => 42 mg P/w Dialysis Extraction => 8 mg x 3/w Accumulation => 2 mg P /day

Phosphate balance in HD patients Intake 1.2 g/kg => 1 mg P Absorption 6% => 42 mg P/w Dialysis Extraction => 8 mg x 3/w Accumulation => 2 mg P /day Diet appropriate diet prevents l hyperparathyroïdism Slatopolski et al, JCI 1971 5:492

Phosphate balance in HD patients Intake 1.2 g/kg => 1 mg P Absorption 6% => 42 mg P/w Dialysis Extraction => 8 mg x 3/w Accumulation => 2 mg P /day Diet Phosphate Binders appropriate diet prevents l hyperparathyroïdism Calcium (carbonate / acetate) Résines Sevelamer Lanthanum Slatopolski et al, JCI 1971 5:492

Phosphate binders Serum P (mg/dl) 8.5 8 7.5 7 6.5 6 Ca * Ca *** Sevelamer * Lanthanum ** 5.5 K/DOQI 5 4.5 4 8 12 16 2 24 28 32 36 4 44 48 52 Weeks * TTG: Chertow GM. KI 22 ** Hutchison WCN 3. Berlin *** Qunibi W. Kidney Int. 24 65: 1914

Phosphate binders «CARE Study» The Calcium Acetate Renagel Evaluation Qunibi W. Kidney Int. 24 65: 1914

Phosphate binders «CARE Study» The Calcium Acetate Renagel Evaluation n = 1 HD Double blind 8 weeks Titration : P<5.5 Phosphate Ca x P P < 5.5 mg/dl Calcium Acetate OR = 2.37 CaP < 55 mg 2 /dl 2 Calcium Acetate OR = 2.16 Calcium Hypercalcémie Calcium Acetate OR = 6.1 Qunibi W. Kidney Int. 24 65: 1914

Phosphate binders «CARE Study» The Calcium Acetate Renagel Evaluation n = 1 HD Double blind 8 weeks Titration : P<5.5 PTH DNS HCO3- P <,1 Tolerance DNS

Phosphate binders «CARE Study» The Calcium Acetate Renagel Evaluation n = 1 HD Double blind 8 weeks Titration : P<5.5 Calcium Acetate 732 $ Sevelamer 4283 $ «superior efficacy» «in occasional patients»

Phosphate binders Treat to Goal 2 prevalent HD Calcium Acetate Calcium Carbonate International Prospective Randomized Open 52 weeks Sevelamer Primary endpoint : Ca x P difference between binders Results Primary endpoint not met (no difference between binders) Some secondary endpoints show differences: 1 hypercalcemic episode PTH suppression LDL cholesterol Aorta calcification at 52 weeks Chertow, et al. KI 22. 62:245-252

Phosphate binders Treat to Goal Progression of calcifications 3 2 5 2 1 5 1 5 Median Percent Change Sevalame r Calcium binders 1 % Aort a Week 26 24 % Week 52 5 % 28% * Chertow, et al. KI 22. 62:245-252

Phosphate binders Treat to Goal Progression of calcifications «calcium calcifies» 3 2 5 2 1 5 1 5 Median Percent Change Sevalame r Calcium binders 1 % Aort a Week 26 24 % Week 52 5 % 28% * «not so sure» In the SEVELAMER group, 1) Calcium intake was probably important in the dialysate as nighttime supplements 2) LDLc was lower Chertow, et al. KI 22. 62:245-252

Phosphate binders Treat to Goal Sevelamer (n=99) Final Calcium (n=11) Final P Phosphorus mg/dl Calcium mg/dl Hypercalcemia % Ca P mg2/dl2 Intact PTH pg/ml LDL-C mg/dl 5.1 ± 1.4 9.7 ±.7 16% 49 ± 14 138 13 ± 43.33.2.4.12.11 <.1 Chertow, et al. KI 22. 62:245-252

Phosphate binders CARE -2 Calcium Acetate /Sevelamer Evaluation Study 2 23 PREVALENT HD Calcium Acetate USA Prospective Randomized Open 52 weeks Sevelamer Ph 3.5-5.5 mg/dl LDLc <.7 g/l (± atorvastatin) Primary endpoint : CAC score (ECBT at 1 year) Hypothesis : no différence in CAC score progression

Phosphate binders CARE -2 Calcium Acetate /Sevelamer Evaluation Study 2 23 PREVALENT HD Calcium Acetate USA Prospective Randomized Open 52 weeks Sevelamer 3 3 % 29% Ph 3.5-5.5 mg/dl LDLc <.7 g/l (± atorvastatin) Median % Change 25 2 15 1 AJKD 28 in press Sevalamer Calcium binders 5 Week 52

Phosphate binders RIND study Renagel In New Dialysis Block GA et al, KI 27;71:437-441

Phosphate binders RIND study Renagel In New Dialysis 129 INCIDENTS HD Calcium Acetate Calcium Carbonate International Prospective Randomised Open 44 weeks Sevelamer Endpoints: 1) Mortality Block GA et al, KI 27;71:437-441

Phosphate binders RIND study Renagel In New Dialysis 129 INCIDENTS HD Calcium Acetate Calcium Carbonate International Prospective Randomised Open 44 weeks Renagel Endpoints: 1) Mortality Crude : 1.6/1 vs 5.3/1 (P=.5) Adjusted : HR 3.1 (p=.16) Block GA et al, KI 27;71:437-441

Phosphate binders DCOR «Dialysis Clinical Outcomes Revisited» 213 HD prévalents (75 centres, USA) Renagel (n=153) Calcium(n=15) Acetate 7% Carbonate 3% Suki et al. KI 27

Phosphate binders DCOR «Dialysis Clinical Outcomes Revisited» 213 HD prévalents Renagel (n=153) Calcium(n=15) (75 centres, USA) Acetate 7% Carbonate 3% Men 55% Black 47% Diabetes 5% HD vintage 3 y 6 y 45 months Mortality Power >8 % to detect a > 22% mortaliy réduction Suki et al. KI 27

Phosphate binders DCOR All cause Mortality Cardiovascular Mortality Suki et al. KI 27

Phosphate binders DCOR STRATIFICATION : PATIENTS > 65 ans All cause Mortality Cardiovascular Mortality Suki et al. KI 27

Phosphate binders Systematic reviews

Phosphate binders Systematic reviews Experts opinions

Phosphate binders Systematic reviews 2 -ANALYSIS AJKD 28 (March) 51 : 445 Experts opinions DCOR : many patients were lost to follow up Intention to treat analysis Using Medicare/Medicaid data Reported by Separate group of investigators Overall mortality DNS Cause specific mortality DNS Morbidity DNS Cause specific hospitalisation DNS First specific hospitalisation DNS Multiple hospitalisation rate 1.7 vs 1.9* Hospital days (patient/year) 12.3 vs 13.9 *

HPTX TREATMENTS Ca CLINICALLY RELEVANT RESULTS Morbidity Mortality Phos

HPTX TREATMENTS Ca CLINICALLY RELEVANT RESULTS Morbidity Mortality Phos Desappointing Absent Awaited To be confirmed Sevelamer Cinacalcet Vitamin D Lanthanum Nicotinic Acid Calcium / dialysate