Attivazione selettiva dei VDR nella CKD-MBD: dalla conservativa alla dialisi

Transcription

1 Attivazione selettiva dei VDR nella CKD-MBD: dalla conservativa alla dialisi Mario Cozzolino, MD, PhD, FERA Dipartimento di Scienze della Salute Università di Milano UO Nefrologia e Dialisi Laboratorio di Nefrologia Sperimentale AO San Paolo, Milano L attivazione dei VDR nella gestione del paziente nefropatico

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4 Optimal therapy of CKD-MBD: is it possible?

5 Optimal therapy of CKD-MBD: is it possible? VDR Activation in CKD patients

6 EVOLUTION OF OUR UNDERSTANDING OF VITAMIN D 1,25-(OH) 2 D 3 (Calcitriol) 1a-OH-D 3 1a-OH-D 2 (Hectorol) Vitamin D 3 19-nor-1,25-(OH) 2 D 2 (Paracalcitol) ng/day required to raise serum calcium 1 mg/100 ml in vitamin D-deficient mice Hector F DeLuca, Nutrition Reviews 2008

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8 Vitamin D and the vasculature Endothelial cells have VDR and express 1-alpha hydroxylase Merke, et al. JCI 1989 VSMC cells have VDR Kawashima H. BBRC and express 1-alpha hydroxylase Somjen D, Circulation 2005

9 3212 subjects

10 4472 Patients

11 Am J Kidney Dis 2005

12 Am J Kidney Dis 2005

13 Coyne et al, NDT 2013

14 2012 Jan;59(1):58-65

15 Mean (SD) Values of PTH, Ca, and P During the Survey. Baseline Month 6 Month 12 Month 18 P value PTH, pg/ml (292.4) (252.2) (248.1) (250.1) Ca, mg/dl 9.1 (0.8) 9.0 (1.0) 9.0 (0.7) 9.0 (0.7) P, mg/dl 5.0 (1.4) 4.9 (1.3) 5.0 (1.3) 5.0 (1.4) Ca=calcium, P=phosphate, PTH=parathyroid hormone.

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

19 Kaplan-Meier Survival Estimates by VDRA Treatment in HD Patients with PTH 150 pg/ml 1.00 Cumulative probability Untreated Calcitriol Paricalcitol 0.60 P<.01; log rank test Months Since Enrollment Cozzolino et al, Nephrol Dial Transplant, 2012

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21 Percentage of patients at target for each biomarker (all pts)

22 Cumulative probability of survival (on target at least once during the follow-up)

23 Effect of VDRA on survival in incident dialysis patients: results of the FARO-2 observational study P Messa, M Cozzolino, D Brancaccio, G Cannella, F Malberti, A M Costanzo, U di Luzio Paparatti, V Festa, G Gualberti, and S Mazzaferro, on behalf of the FARO Study Group. Prevalence of VDRA therapy during the follow-up (p<0.08) BMC Nephrology, 2015, In Press

24 BMC Nephrology, 2015, In Press VDRA administration policy

25 Decreased use of Oral Calcitriol (p<0.03) BMC Nephrology, 2015, In Press VDRA administration policy

26 Increased use of i.v. Paricalcitol (p<0.04) Decreased use of Oral Calcitriol (p<0.03) BMC Nephrology, 2015, In Press VDRA administration policy

27 Increased use of i.v. Paricalcitol (p<0.04) Decreased use of Oral Calcitriol (p<0.03) Stable use of I.V. Calcitriol BMC Nephrology, 2015, In Press VDRA administration policy

28 Cumulative probability of survival of the whole population BMC Nephrology, 2015, In Press

29 Cumulative probability of survival according to VDRA use BMC Nephrology, 2015, In Press

30 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)

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33 Cozzolino M et al, NDT 2014

34 Cozzolino M et al, NDT 2014

35 Cozzolino M et al, NDT 2014

36 The contrast in FGF23 levels between the 2 types of treatment may reflect the differences between mechanisms of action of the 2 drugs: -Cinacalcet antagonizes the CaSR, reducing PTH release and FGF23 levels; -PCT activates VDRs, promoting FGF23 production through the VDR Elements located within the FGF23 promoter

37 Cozzolino M et al, NDT 2014

38 The normalization of bone turnover markers (AP and BSAP) with PCT-centred therapy may reduce fracture risk and possibly even overall mortality given that increased AP levels have been associated with higher risk of death.

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