![10
Vitamin D (25[OH]D) status in CKD
>30 ng/mL 10-30 ng/mL <10 ng/mL
Decrease in intestinal
calcium absorption and
an increase in PTH in
patients with 25(OH)D
levels < 30ng/mL
(<75nmol/L)](https://image-private.slidesharecdn.com/cozzolino-180805101337/85/slide-10-320.jpg?hdnea=acl=/cozzolino-180805101337/85/slide-10-320.jpg*~exp=1769606021~hmac=ebea1592d4d530f51585812319bc162adc056181155463740dc69ea563f9e862&cb=1533465230)
![30
Kaplan Meier curve for sudden cardiac death according to 25-hydroxyvitamin D groups
Vitamin D status and
CVD mortality
Pilz S, et al. Nephrology, Dialysis and Transplantation, 2011 Mar 4. [Epub ahead of print]
Patients with eGFR <60 mL/min/1.73m² (n=444)
During a median follow up of 9.4 years 159 CVD deaths occurred
25(OH)D levels
>30 ng/ml
20-29.99 ng/ml
10-19.99 ng/ml
<10 ng/ml
Adjusted HR: Severe deficient vs.
sufficient 5.61 (1.89-16.6)](https://image-private.slidesharecdn.com/cozzolino-180805101337/85/slide-30-320.jpg?hdnea=acl=/cozzolino-180805101337/85/slide-30-320.jpg*~exp=1769606021~hmac=34fb3db89856034f14bbbaef08bd32a09d2aa291451985231aa5483795c88a7e&cb=1533465230)
![Kim, KI 2011
• Observational prospective study: oral cholecalciferol 40,000 U/wk mo
• 49 DM Tp2 pts with low 25(OH)D levels
• eGFR= 4215
• ACR= 16.4 (9.7–27.4) mg/mmol [MAU range: 3.5-35]](https://image-private.slidesharecdn.com/cozzolino-180805101337/85/slide-41-320.jpg?hdnea=acl=/cozzolino-180805101337/85/slide-41-320.jpg*~exp=1769606021~hmac=03dec15d6518f21bf8deb4e7873ef2593318bf1928862109e800fa60b65f6bd9&cb=1533465230)
![• 6-month prospective, controlled, intervention study
• 101 non-dialysis CKD patients (eGFR 39) with Ualb (254 mg/g) under anti-RAS
• Experimental group: patients with low 25(OH) vitamin D [25(OH)D] and high
PTH that received oral Cholecalciferol (666 IU/day)
• Control group: patients without high PTH that did not receive cholecalciferol
Molina, NDT 2014
Evolution of the uACR at a 6-month follow-up
All patients Subgroup with unchanged
antihypertensive Tx
In treated pts, the 41% reduction in uACR correlated to
the 53% increase in 25(OH)D levels](https://image-private.slidesharecdn.com/cozzolino-180805101337/85/slide-42-320.jpg?hdnea=acl=/cozzolino-180805101337/85/slide-42-320.jpg*~exp=1769606021~hmac=dd4766ad19a622ce7bff488ff0c99549ef1538e49749b5972a380b730f416811&cb=1533465230)
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Supplementazioni nutrizionali nel disordine minerale e osseo nell'insufficienza renale cronica (CKD-MBD)
Approccio multidisciplinare alla gestione del paziente osteoporotico sarcopenico Milano, 12 maggio 2018 Supplementazioni nutrizionali nel disordine minerale e osseo nell'insufficienza renale cronica (CKD-MBD) Mario Cozzolino, MD, PhD, FERA, FASN
Supplementazioni nutrizionali nel disordine minerale e osseo nell'insufficienza renale cronica (CKD-MBD)
- 1. SUPPLEMENTAZIONI NUTRIZIONALI NELDISORDINE MINERALE E OSSEO NELL’INSUFFICIENZA RENALE CRONICA (CKD-MBD) Mario Cozzolino, MD, PhD, FERA, FASN Dipartimento di Scienze della Salute Università degli Studi di Milano UOC Nefrologia e Dialisi, ASST Santi Paolo e Carlo, Milano Milano, 12 Maggio 2018 Approccio multidisciplinare alla gestione del paziente osteoporotico sarcopenico
- 3. 3 OUTLINE Basics and backgroundon vitamin D metabolism in CKD Vitamin D deficiency and cardiovascular diseases and its risk factors Natural vitamin D treatment in CKD Perspectives & Conclusions
- 4. 4 OUTLINE Basics and backgroundon vitamin D metabolism in CKD Vitamin D deficiency and cardiovascular diseases and its risk factors Natural vitamin D treatment in CKD Perspectives & Conclusions
- 5.
- 6.
- 7. TOP 10 MedicalBreakthroughs 2007 Adapted from Time Magazine, US Edition 2007 (Dec 24);26:170 Benefits of Vitamin D • Bone strength • Diabetes • Gum disease • Multiple sclerosis • Cancer (in particular colon cancer)
- 8. 8 Vitamin D Vitamin Dmetabolism Vitamin D sources Nutrition UV-B induced vitamin D production in the skin 80-90% 10-20%
- 9. 9 Vitamin D metabolism PilzS, et al. Nature Reviews Cardiology 2009, 6: 621-630 Pathophysiology ng/ml HL~1 month pg/ml HL<1 day Serum 1,25(OH)2D: Derived from the kidney Tissue 1,25(OH)2D: Produced from serum 25(OH)D
- 10. 10 Vitamin D (25[OH]D)status in CKD >30 ng/mL 10-30 ng/mL <10 ng/mL Decrease in intestinal calcium absorption and an increase in PTH in patients with 25(OH)D levels < 30ng/mL (<75nmol/L)
- 11. 11 Reduced 25D/1,25D OccursEarly in CKD Levin A, et al. Kidney Int 2007;71:31–8 †p<0.001 iPTH (pg/mL) 1,25D (pg/mL) 25D (ng/mL) *as measured by 1,25D n=61 n=117 n=230 n=396 n=355 n=358 n=204 n=93 † 79–70 69–60 59–50 49–40 39–30 29–20 <20 eGFR Interval (mL/min/1.73 m2) 0 ≥80 5 10 15 20 25 30 35 40 45 50 1,25D(pg/mL) 25D(ng/mL) † 0 50 100 150 iPTHlevel(pg/mL) (n=1814)
- 13. 13 OUTLINE Basics and backgroundon vitamin D metabolism in CKD Vitamin D deficiency and cardiovascular diseases and its risk factors Natural vitamin D treatment in CKD Perspectives & Conclusions
- 14. Hypothesis: Mechanisms ofVDR Activation Impact on CV Outcomes ↓ Atherosclerosis and vascular calcification Li YC, et al. J Clin Invest 2002;110:229–38; Mathieu C, et al. Trends Mol Med 2002;8:174–9 VDR activation ↓ Inflammation ↓ Heart failure ↓ Morbidity and mortality ↓ RAAS ↓ LVH ↑ Cardiomyocyte remodeling
- 15. System Tissue Gastrointestinal Esophagus,stomach, small intestine, large intestine, Hepatic Liver parenchyma cells Endocrine Parathyroid, pancreatic β-cells, thyroid C-cells Exocrine Parotid gland, sebaceous gland Reproductive Testis, spermatocytes, ovary, placenta, uterus, endometrium, yolk sac Immune Thymus, bone marrow, B cells, T cells Respiratory Lung alveolar cells Skeletal Osteoblasts, osteocytes, chondrocytes Muscle Striated muscle Epidermis/appendage Skin, breast, hair follicles Central nervous system Brain neurons Connective tissue Fibroblasts, stroma VDR Distribution in the Body Cardiovascular Vascular smooth muscle cells, endothelial cells, cardiomyocytes Renal Proximal and distal tubules, collecting duct, podocytes
- 16. Endothelial cells haveVDR and express 1-alpha hydroxylase Merke, et al. JCI 1989 VSMC cells have VDR Kawashima H. BBRC. 1987 and express 1-alpha hydroxylase Somjen D, Circulation 2005 Vitamin D and the vasculature
- 17. Lack of VDRinduces senescence in VSMCs Absence of VDR in mouse VSMC induces an arrest in G1 phase and a decrease in proliferation levels, probably due to a development of a premature cellular senescence Valcheva P, et al. Nephrol Dial Transplant 2008;1(Suppl 2):132. #SP313 Growth curve of VSMC in 10% FBS DMEM 100000 200000 300000 400000 500000 0 0 10 20 30 40 50 60 KO y=108924e0.0154x R2=0.9486 WT y=87445e0.0322x R2=0.9362 Cellnumber Time (hours) WT KO
- 18. 18 Vitamin D effectson the cardiovascular system VITAMIN D EFFECTS ON THE CARDIOVASCULAR SYSTEM EFFECTS ON THE MYOCARDIUM Antihypertrophic effects Modulation of calcium flux and contractility Renin suppression Modulation of extracellular matrix turnover EFFECTS ON THE VESSELS Anti-atherosclerotic effects Inhibition of vascular calcification Improvement of endothelial function EFFECTS ON CARDIOVASCULAR RISK FACTORS Reno-protective effects Anti-hypertensive effects Anti-diabetic effects PTH suppression Anti-inflammatory effects Anti-oxidative effects
- 19. 19 OUTLINE Basics and backgroundon vitamin D metabolism in CKD Vitamin D deficiency and cardiovascular diseases and its risk factors Natural vitamin D treatment in CKD Perspectives & Conclusions
- 20. 20 Vitamin D inCKD Pilz S, et al. Nature Reviews Cardiology 2009, 6: 621-630 Low serum levels of 1,25(OH)2D Low serum levels of 25(OH)D Natural (nutritional) vitamin D treatment Pathophysiology Active vitamin D treatment: 1,25(OH)2D (=calcitriol) or Selective VDR agonists (ie paricalcitol, doxercalciferol, maxacalcitol, falecalcitriol )
- 21. 21 PTH effects onthe cardiovascular system PTH receptors are widely expressed throughout the cardiovascular system including the myocardium PTH infusions increase blood pressure in healthy volunteers and PTH modifies contractile functions of the myocardium PTH levels were highlighted as a cardiovascular risk factor in epidemiological studies Schlüter KD et al. Cardiovasc Res 1998,37:34-41 Fitzpatrick LA et al. Curr Osteoporos Rep 2008,6:77-83 Hagström E et al. Circulation 2009,119:2765-2771
- 22.
- 24. Cozzolino M, etal. Eur J Heart Failure 2010 Impact of VDR activators on CV endpoints and patient outcome Kidney fibrosis VDR effect • Interstitial volume • Glomerulosclerosis • TGF-β1 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 VDR activators Cardiovascul ar Modulation Outcome Inactive vitamin D • Ergocalciferol • Cholecalciferol 1α-hydroxyvitamin D • Alfacalcidol • Doxercalciferol 1,25-dihydroxyvitamin D • Calcitriol Selective 1,25D • Paricalcitol • Maxacalcitol Hormone Heart Vasculature Kidney VDR VDR VDR VDR Immune cellsVDR 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 Acute Repair Integrity restored Chronic Repair Damage limitation Morbidity/ Mortality Improved Calcification VDR effect Inducers • BMP-2 • Type 1 collagen • IL-1β and TNF-α Inhibitors • MGP • Osteopontin • Type IV collagen Other effects
- 25. Cozzolino M, etal. Eur J Heart Failure 2010 Impact of VDR activators on CV endpoints and patient outcome Kidney fibrosis VDR effect • Interstitial volume • Glomerulosclerosis • TGF-β1 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 VDR activators Cardiovascul ar Modulation Outcome Inactive vitamin D • Ergocalciferol • Cholecalciferol 1α-hydroxyvitamin D • Alfacalcidol • Doxercalciferol 1,25-dihydroxyvitamin D • Calcitriol Selective 1,25D • Paricalcitol • Maxacalcitol Hormone Heart Vasculature Kidney VDR VDR VDR VDR Immune cellsVDR 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 Acute Repair Integrity restored Chronic Repair Damage limitation Morbidity/ Mortality Improved Calcification VDR effect Inducers • BMP-2 • Type 1 collagen • IL-1β and TNF-α Inhibitors • MGP • Osteopontin • Type IV collagen Other effects VDR activators Inactive vitamin D •Ergocalciferol •Cholecalciferol 1α-hydroxyvitamin D •Alfacalcidol •Doxercalciferol 1,25-dihydroxyvitamin D •Calcitriol Selective 1,25D •Paricalcitol •Maxacalcitol
- 26. Cozzolino M, etal. Eur J Heart Failure 2010 Impact of VDR activators on CV endpoints and patient outcome Kidney fibrosis VDR effect • Interstitial volume • Glomerulosclerosis • TGF-β1 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 VDR activators Cardiovascul ar Modulation Outcome Inactive vitamin D • Ergocalciferol • Cholecalciferol 1α-hydroxyvitamin D • Alfacalcidol • Doxercalciferol 1,25-dihydroxyvitamin D • Calcitriol Selective 1,25D • Paricalcitol • Maxacalcitol Hormone Heart Vasculature Kidney VDR VDR VDR VDR Immune cellsVDR 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 Acute Repair Integrity restored Chronic Repair Damage limitation Morbidity/ Mortality Improved Calcification VDR effect Inducers • BMP-2 • Type 1 collagen • IL-1β and TNF-α Inhibitors • MGP • Osteopontin • Type IV collagen Other effects Cardiovascular Hormone Heart Vasculature Kidney VDR VDR VDR VDR Immune cellsVDR
- 27. Cozzolino M, etal. Eur J Heart Failure 2010 Impact of VDR activators on CV endpoints and patient outcome Kidney fibrosis VDR effect • Interstitial volume • Glomerulosclerosis • TGF-β1 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 VDR activators Cardiovascul ar Modulation Outcome Inactive vitamin D • Ergocalciferol • Cholecalciferol 1α-hydroxyvitamin D • Alfacalcidol • Doxercalciferol 1,25-dihydroxyvitamin D • Calcitriol Selective 1,25D • Paricalcitol • Maxacalcitol Hormone Heart Vasculature Kidney VDR VDR VDR VDR Immune cellsVDR 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 Acute Repair Integrity restored Chronic Repair Damage limitation Morbidity/ Mortality Improved Calcification VDR effect Inducers • BMP-2 • Type 1 collagen • IL-1β and TNF-α Inhibitors • MGP • Osteopontin • Type IV collagen Other effects Modulation 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
- 28. Cozzolino M, etal. Eur J Heart Failure 2010 Impact of VDR activators on CV endpoints and patient outcome Kidney fibrosis VDR effect • Interstitial volume • Glomerulosclerosis • TGF-β1 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 VDR activators Cardiovascul ar Modulation Inactive vitamin D • Ergocalciferol • Cholecalciferol 1α-hydroxyvitamin D • Alfacalcidol • Doxercalciferol 1,25-dihydroxyvitamin D • Calcitriol Selective 1,25D • Paricalcitol • Maxacalcitol Hormone Heart Vasculature Kidney VDR VDR VDR VDR Immune cellsVDR 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 Outcome Acute Repair Integrity restored Chronic Repair Damage limitation Morbidity/ Mortality Improved Calcification VDR effect Inducers • BMP-2 • Type 1 collagen • IL-1β and TNF-α Inhibitors • MGP • Osteopontin • Type IV collagen Other effects Outcome Acute Repair Integrity restored Chronic Repair Damage limitation Morbidity/ Mortality Improved
- 29. 29 Vitamin D statusand sudden cardiac death in hemodialysis patients
- 30. 30 Kaplan Meier curvefor sudden cardiac death according to 25-hydroxyvitamin D groups Vitamin D status and CVD mortality Pilz S, et al. Nephrology, Dialysis and Transplantation, 2011 Mar 4. [Epub ahead of print] Patients with eGFR <60 mL/min/1.73m² (n=444) During a median follow up of 9.4 years 159 CVD deaths occurred 25(OH)D levels >30 ng/ml 20-29.99 ng/ml 10-19.99 ng/ml <10 ng/ml Adjusted HR: Severe deficient vs. sufficient 5.61 (1.89-16.6)
- 32. 128 CKD 2-5Patients
- 36. 36 OUTLINE Basics and backgroundon vitamin D metabolism in CKD Vitamin D deficiency and cardiovascular diseases and its risk factors Natural vitamin D treatment in CKD Perspectives & Conclusions
- 37.
- 38. • Observational prospectivestudy to investigate whether there is an association of 25 (OH) vitamin D deficiency with disease progression in type II diabetic nephropathy • 25 (OH) vitamin D levels measured at baseline and 4 and 12 months in 103 patients • primary composite endpoint: 50% increase in baseline serum creatinine, ESRD, or death
- 39. Molina P, WorldJ Nephrol 2016. • N=470 ND-CKD stage 3-5 • 3-year follow-up Participants with 25(OH)D levels <20 ng/ml had a 2.5-fold greater incidence of ESRD than those with levels ≥20 ng/ml. log rank test, p<0.001 Low Vitamin D status is an independent predictor of ESRD in CKD population
- 40. Renoprotective effects ofvitamin D
- 41. Kim, KI 2011 •Observational prospective study: oral cholecalciferol 40,000 U/wk mo • 49 DM Tp2 pts with low 25(OH)D levels • eGFR= 4215 • ACR= 16.4 (9.7–27.4) mg/mmol [MAU range: 3.5-35]
- 42. • 6-month prospective,controlled, intervention study • 101 non-dialysis CKD patients (eGFR 39) with Ualb (254 mg/g) under anti-RAS • Experimental group: patients with low 25(OH) vitamin D [25(OH)D] and high PTH that received oral Cholecalciferol (666 IU/day) • Control group: patients without high PTH that did not receive cholecalciferol Molina, NDT 2014 Evolution of the uACR at a 6-month follow-up All patients Subgroup with unchanged antihypertensive Tx In treated pts, the 41% reduction in uACR correlated to the 53% increase in 25(OH)D levels
- 44.
- 45.
- 47. 47 Take home messages Thecardiovascular and renal systems are target tissues for vitamin D and a poor vitamin D status, which is present in the majority of CKD patients, is a risk factor for cardiovascular morbility and mortality, and for renal disease progression. It is suggested to test for and treat reduced 25(OH)D concentrations with natural vitamin D: this therapy is safe, cheap and simple, reduces PTH levels and might also reduce cardiovascular events and delay CKD progression