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Strategie terapeutiche per il controllo ottimale dell’IPTS: lo Studio IMPACT

Strategie terapeutiche per il controllo ottimale dell’IPTS: lo Studio IMPACT. Mario Cozzolino , MD, PhD Dipartimento di Scienze della Salute Università di Milano UO Nefrologia e Dialisi Laboratorio di Nefrologia Sperimentale AO San Paolo, Milano NephroCare, 17 Annual Meeting

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Strategie terapeutiche per il controllo ottimale dell’IPTS: lo Studio IMPACT

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  1. Strategie terapeutiche per il controllo ottimale dell’IPTS: lo Studio IMPACT Mario Cozzolino, MD, PhD Dipartimento di Scienze della Salute Università di Milano UO Nefrologia e Dialisi Laboratorio di Nefrologia Sperimentale AO San Paolo, Milano NephroCare, 17 Annual Meeting Napoli, 24 Novembre

  2. IMPACT SHPT: Improved Management of iPTH with Paricalcitol-centered Therapy vs. Cinacalcet Therapy with Low-dose Vitamin D in Hemodialysis Patients with Secondary Hyperparathyroidism (SHPT)

  3. Overview: CV Mortality in ESRD AgeGender Altered tensile stress(hypertension) Altered shear stress(change in blood flow) Left ventricular hypertrophy Vascular calcification Genetic factors Diabetes Vascular calcification Arteriosclerosis Atherosclerosis Local growth factors/inhibitors Chronic renal failure Anemia Endothelial dysfunction Inflammation Smoking Calcification inhibitors Dyslipidemia Lp(a) Oxidative stress Diminished VDR activation Lipoprotein modifications: oxidation; glycation, AGE, AOPP Ca, P, PTH NO, ADMA, homocysteine

  4. Adverse events REDUCED VDR ACTIVATION Bover and Cozzolino,Kidney Int . 2011; 1,122–129

  5. The vitamin D System:a Crosstalk between the Heart and the Kidney VDR activators Cardiovascular Modulation Outcome • Inactive vitamin D • Ergocalciferol • Cholecalciferol • 1α-hydroxyvitamin D • Alfacalcidol • Doxercalciferol • 1,25-dihydroxyvitamin D • Calcitriol • Selective 1,25D • Paricalcitol • Maxacalcitol Hormone • Decreased • Hypertension • Heart weight • LV hypertrophy • Posterior wall thickness • Left ventricular end-diastolic pressure • BNP, ANF, ANP • Renin and angiotensin • VEGF • PAI-1 • Tissue factor • Increased • Fractional shortening • Vascular relaxation • Thrombomodulin VDR Acute RepairIntegrity restored Heart VDR Morbidity/Mortality Improved Vasculature VDR Chronic RepairDamage limitation Kidney VDR Immunecells VDR Other effects ANF, atrial natriuretic factor; ANP, atrial natriuretic protein; BMP-2, bone morphogenetic protein-2; BNP, brain natriuretic protein; IL-1β, interleukin-1β; LV, left ventricular; MGP, matrix Gla protein; PAI-1, plasminogen activator inhibitor-1; TGF-β, tumour growth factor-β; TNF-α, tumour necrosis factor-α; VEGF, vascular endothelial growth factor Cozzolino M, et al. Eur J Heart Failure 2010

  6. The vitamin D System:a Crosstalk between the Heart and the Kidney VDR activators Cardiovascular Modulation Outcome VDR activators • Inactive vitamin D • Ergocalciferol • Cholecalciferol • 1α-hydroxyvitamin D • Alfacalcidol • Doxercalciferol • 1,25-dihydroxyvitamin D • Calcitriol • Selective 1,25D • Paricalcitol • Maxacalcitol Hormone • Decreased • Hypertension • Heart weight • LV hypertrophy • Posterior wall thickness • Left ventricular end-diastolic pressure • BNP, ANF, ANP • Renin and angiotensin • VEGF • PAI-1 • Tissue factor • Increased • Fractional shortening • Vascular relaxation • Thrombomodulin VDR Acute RepairIntegrity restored Heart VDR • Inactive vitamin D • Ergocalciferol • Cholecalciferol • 1α-hydroxyvitamin D • Alfacalcidol • Doxercalciferol • 1,25-dihydroxyvitamin D • Calcitriol • Selective 1,25D • Paricalcitol • Maxacalcitol Morbidity/Mortality Improved Vasculature VDR Chronic RepairDamage limitation Kidney VDR Immunecells VDR Other effects ANF, atrial natriuretic factor; ANP, atrial natriuretic protein; BMP-2, bone morphogenetic protein-2; BNP, brain natriuretic protein; IL-1β, interleukin-1β; LV, left ventricular; MGP, matrix Gla protein; PAI-1, plasminogen activator inhibitor-1; TGF-β, tumour growth factor-β; TNF-α, tumour necrosis factor-α; VEGF, vascular endothelial growth factor Cozzolino M, et al. Eur J Heart Failure 2010

  7. Cardiovascular Hormone VDR Heart VDR Vasculature VDR Kidney VDR Immunecells The vitamin D System:a Crosstalk between the Heart and the Kidney VDR activators Cardiovascular Modulation Outcome • Inactive vitamin D • Ergocalciferol • Cholecalciferol • 1α-hydroxyvitamin D • Alfacalcidol • Doxercalciferol • 1,25-dihydroxyvitamin D • Calcitriol • Selective 1,25D • Paricalcitol • Maxacalcitol • Decreased • Hypertension • Heart weight • LV hypertrophy • Posterior wall thickness • Left ventricular end-diastolic pressure • BNP, ANF, ANP • Renin and angiotensin • VEGF • PAI-1 • Tissue factor • Increased • Fractional shortening • Vascular relaxation • Thrombomodulin Hormone VDR Acute RepairIntegrity restored Heart VDR Morbidity/Mortality Improved Vasculature VDR Chronic RepairDamage limitation Kidney VDR Immunecells VDR Other effects VDR ANF, atrial natriuretic factor; ANP, atrial natriuretic protein; BMP-2, bone morphogenetic protein-2; BNP, brain natriuretic protein; IL-1β, interleukin-1β; LV, left ventricular; MGP, matrix Gla protein; PAI-1, plasminogen activator inhibitor-1; TGF-β, tumour growth factor-β; TNF-α, tumour necrosis factor-α; VEGF, vascular endothelial growth factor Cozzolino M, et al. Eur J Heart Failure 2010

  8. The vitamin D System:a Crosstalk between the Heart and the Kidney VDR activators Cardiovascular Modulation Outcome Modulation • Inactive vitamin D • Ergocalciferol • Cholecalciferol • 1α-hydroxyvitamin D • Alfacalcidol • Doxercalciferol • 1,25-dihydroxyvitamin D • Calcitriol • Selective 1,25D • Paricalcitol • Maxacalcitol Hormone • Decreased • Hypertension • Heart weight • LV hypertrophy • Posterior wall thickness • Left ventricular end-diastolic pressure • BNP, ANF, ANP • Renin and angiotensin • VEGF • PAI-1 • Tissue factor • Increased • Fractional shortening • Vascular relaxation • Thrombomodulin VDR Acute RepairIntegrity restored Heart • Decreased • Hypertension • Heart weight • LV hypertrophy • Posterior wall thickness • Left ventricular end-diastolic pressure • BNP, ANF, ANP • Renin and angiotensin • VEGF • PAI-1 • Tissue factor • Increased • Fractional shortening • Vascular relaxation • Thrombomodulin VDR Morbidity/Mortality Improved Vasculature VDR Chronic RepairDamage limitation Kidney VDR Immunecells VDR Other effects ANF, atrial natriuretic factor; ANP, atrial natriuretic protein; BMP-2, bone morphogenetic protein-2; BNP, brain natriuretic protein; IL-1β, interleukin-1β; LV, left ventricular; MGP, matrix Gla protein; PAI-1, plasminogen activator inhibitor-1; TGF-β, tumour growth factor-β; TNF-α, tumour necrosis factor-α; VEGF, vascular endothelial growth factor Cozzolino M, et al. Eur J Heart Failure 2010

  9. The vitamin D System:a Crosstalk between the Heart and the Kidney VDR activators Cardiovascular Modulation Outcome Outcome • Inactive vitamin D • Ergocalciferol • Cholecalciferol • 1α-hydroxyvitamin D • Alfacalcidol • Doxercalciferol • 1,25-dihydroxyvitamin D • Calcitriol • Selective 1,25D • Paricalcitol • Maxacalcitol Hormone • Decreased • Hypertension • Heart weight • LV hypertrophy • Posterior wall thickness • Left ventricular end-diastolic pressure • BNP, ANF, ANP • Renin and angiotensin • VEGF • PAI-1 • Tissue factor • Increased • Fractional shortening • Vascular relaxation • Thrombomodulin VDR Acute RepairIntegrity restored Acute RepairIntegrity restored Heart VDR Morbidity/Mortality Improved Morbidity/Mortality Improved Vasculature VDR Chronic RepairDamage limitation Chronic RepairDamage limitation Kidney VDR Immunecells VDR Other effects ANF, atrial natriuretic factor; ANP, atrial natriuretic protein; BMP-2, bone morphogenetic protein-2; BNP, brain natriuretic protein; IL-1β, interleukin-1β; LV, left ventricular; MGP, matrix Gla protein; PAI-1, plasminogen activator inhibitor-1; TGF-β, tumour growth factor-β; TNF-α, tumour necrosis factor-α; VEGF, vascular endothelial growth factor Cozzolino M, et al. Eur J Heart Failure 2010

  10. The vitamin D System:a Crosstalk between the Heart and the Kidney VDR activators Cardiovascular Modulation Outcome • Inactive vitamin D • Ergocalciferol • Cholecalciferol • 1α-hydroxyvitamin D • Alfacalcidol • Doxercalciferol • 1,25-dihydroxyvitamin D • Calcitriol • Selective 1,25D • Paricalcitol • Maxacalcitol Hormone • Decreased • Hypertension • Heart weight • LV hypertrophy • Posterior wall thickness • Left ventricular end-diastolic pressure • BNP, ANF, ANP • Renin and angiotensin • VEGF • PAI-1 • Tissue factor • Increased • Fractional shortening • Vascular relaxation • Thrombomodulin VDR Acute RepairIntegrity restored Heart VDR Morbidity/Mortality Improved Vasculature VDR Chronic RepairDamage limitation Kidney VDR Immunecells VDR Other effects ANF, atrial natriuretic factor; ANP, atrial natriuretic protein; BMP-2, bone morphogenetic protein-2; BNP, brain natriuretic protein; IL-1β, interleukin-1β; LV, left ventricular; MGP, matrix Gla protein; PAI-1, plasminogen activator inhibitor-1; TGF-β, tumour growth factor-β; TNF-α, tumour necrosis factor-α; VEGF, vascular endothelial growth factor Cozzolino M, et al. Eur J Heart Failure 2010

  11. KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) VOLUME 76 | SUPPLEMENT 113 | AUGUST 2009

  12. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease Immediate Target Maintain PTH within appropriate targets Prevent parathyroid gland hyperplasia Maintain normal serum phosphorus and calcium levels Maintain normal skeletal function Long-term Target Reduce risk of renal osteodystrophy Reduce risk of CV morbidity and mortality Am J Kidney Dis 2003:42:S1-201

  13. KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of CKD-MBD Reduce elevated phosphate levels toward the normal range Maintain normal calcium levels Use a dialysate calcium concentration between 1.25 and 1.50 mmol/L (2.5–3.0 mEq/L) Maintain iPTH levels in the range of approximately 2 to 9 times the upper normal limit for the assay Mark changes in iPTH levels in either direction within this range prompt an initiation or change in therapy to avoid progression to levels outside of this range

  14. Proposed K/DOQI Guidelines: Target Range for PTH K/DOQI PTHTarget (pg/mL) 300 150 100 500 KDIGO 2-9 times • Low bone turnover • Adynamic bone disease • High bone turnover • Bone pain • Cardiovascular disease • Cognitive impairment

  15. Proposed K/DOQI – KDIGO Guidelines: Target Range for PTH K/DOQI PTHTarget (pg/mL) 300 150 100 500 KDIGO 2-9 times Selective VDRA Calcimimetic

  16. Primary Efficacy Analysis:Proportion of Subjects with Mean iPTH Value Between 150 to 300 pg/mL During Evaluation Period (Weeks 21 to 28) IV Stratum Oral Stratum P=0.016 P=0.260 57.7% 54.4% 43.4% 32.7% 30/52 16/49 31/57 23/53 Paricalcitol Cinacalcet Ketteler M et al, NDT 2012.

  17. Secondary Efficacy Analysis:- proportion of subjects achieving at least 30% reduction from baseline in iPTH - proportion of subjects achieving at least 50% reduction from baseline in iPTH Ketteler M et al, NDT 2012.

  18. Secondary efficacy analysis:Proportion of Subjects with Mean Calcium < 8.4 mg/dL (2.09 mmol/L) or >10.5 mg/dL (2.63 mmol/L) During the Evaluation Period IV Stratum Oral Stratum Proportion Achieving Hypocalcemia and Hypercalcemia Endpoints Paricalcitol Cinacalcet Ketteler M et al, NDT 2012.

  19. Cozzolino M et al, NDT 2013, submitted.

  20. Cozzolino M et al, NDT 2013, submitted.

  21. Proposed K/DOQI – KDIGO Guidelines: Target Range for PTH K/DOQI PTHTarget (pg/mL) 300 150 100 500 KDIGO 2-9 times Selective VDRA Calcitriol

  22. Initial Dose for VDRAs by Serum Levels of iPTH, Ca, and P Ca=calcium, P=phosphate, PTH=parathyroid hormone. Cozzolino M Personal Opinion.

  23. Mean (SD) Values of PTH, Ca, and P During the Survey. Ca=calcium, P=phosphate, PTH=parathyroid hormone.

  24. Kaplan-Meier Survival Estimates by PTH Levels (Varying at Each Visit) 1.00 The cumulative probability of death for any cause was higher for HD patients with serum PTH levels ≤150 pg/mL 0.90 Cumulative probability PTH >150 pg/mL 0.80 P<.01; log rank test PTH 150 pg/mL 0.70 0 6 12 18 24 Months Since Enrollment Cozzolino et al, Nephrol Dial Transplant, 2012

  25. 1.00 0.90 0.80 Untreated Calcitriol Paricalcitol 0.70 0.60 0 6 12 18 24 Months Since Enrollment Kaplan-Meier Survival Estimates by VDRA Treatment in HD Patients with PTH ≤ 150 pg/ml Cumulative probability P<.01; log rank test Cozzolino et al, Nephrol Dial Transplant, 2012

  26. FARO-2 Messa, Cozzolino, Mazzaferro et al, submitted 2013

  27. FARO-2 Cozzolino, Messa, Mazzaferro et al, NDT submitted 2013

  28. FARO-2 Cozzolino, Messa, Mazzaferro et al, NDT submitted 2013

  29. Il paracalcitolo in emodialisi: quando e cosa trattare?

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