RENAL GRAND ROUNDS. Vitamin D- Beyond the bone. Dr Krishna Pakkivenkata. 9 th April 2010.

Transcription

1 RENAL GRAND ROUNDS Vitamin D- Beyond the bone Dr Krishna Pakkivenkata. 9 th April 2010.

2 Brief history Secosteroid s-exposure to sunlight prevented rickets structure of Vit D was discovered s-metabolic pathway of Vit D.

3 Synthesis and Metabolism of Vitamin D in the Regulation of Calcium, Phosphorus, and Bone Metabolism Holick M. N Engl J Med 2007;357:

4 Brief history s-vit D receptor presence was discovered in other tissues VDR was cloned.

5 Meta-analysis of data on all-cause mortality in 18 randomized controlled trials with vitamin D Autier, P. et al. Arch Intern Med 2007;167:

6 Rate Ratios of All-Cause and CVD Mortality by 25(OH)D Quartiles in Participants of NHANES IIIa Melamed, M. L. et al. Arch Intern Med 2008;168:

7 Restricted cubic spline analysis Melamed, M. L. et al. Arch Intern Med 2008;168:

8 Vitamin D receptor UVR Skin 7 dehydroxycholesterol Vitamin D 3 1α hydroxylase Kidney Liver 1,25(OH) 2 D 3 25(OH)D 3 Prostate 25(OH)D 3 Other tissues 1,25(OH) 2 D 3 VDR Retinoid X receptor Target cell nucleus VDRE Transcription

9 Vitamin D Receptor Gene Chr 12q13 9 exons, alternatively spliced promoter region Binding domains: DNA binding domain binds VDRE Ligand binding domain 1,25(OH) 2 Vit D 5 3 1f 1e 1a 1d 1b 1c UTR Promoter region DNA Binding domain Ligand Binding domain

10 Single Nucleotide Polymorphism in the VDR gene 5 3 1f 1e 1a 1d 1b 1c UTR Cdx-2 GATA Fok1 Taq Apa1 Poly A Human VDR >470 reported SNPs Many have low allele frequencies and not suited for genetic studies

11 Target organs for vitamin D. Valdivielso, J. M. et al. Am J Physiol Renal Physiol 297: F1502-F ; doi: /ajprenal Copyright 2009 American Physiological Society

12 Pleotropic effects OF Vit D Cancer. Osteoarthritis. Depression. Epilepsy. Polycystic Ovaries. Musculoskeletal Pain. Autoimmune Disease. Multiple Sclerosis. Falls in the Elderly. Pregnancy and Lactation.

13 Pleotropic effects of vitamin D Vit D and renoprotective and immunomodulatory effects. Vit D- Cardiometabolic actions.

14 Vit D and renoprotective effects Vit D and proteinuria. Vit D and RAS. Vit D and anti inflammatory effect. Vit D and immunomodulatory effects.

15 Overview of the potential renoprotective effects of active vitamin D in the damaged kidney Doorenbos, C. R. C. et al. (2009) Possible renoprotection by vitamin D in chronic renal disease: beyond mineral metabolism Nat. Rev. Nephrol. doi: /nrneph

16 Hypertension Aug;52(2): Randomized double blind pilot study. Included 24 CKD patients - >18yrs,GFR >30, Taking ACE or ARB. Divided into 3 groups Randomly receiving placebo, 1mcg or 2mcg paricalcitol for 1month. Primary endpoint- evaluate for endothelial function and inflammation. Secondary end points-hemodynamic effects by measuring BP,GFR and urinary albumin. Being a small study power calculations were not performed to determine minimal sample size.

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18 Placebo-1.5 times the baseline CPR. 1mcg- 0.8 times. 2mcg- 0.5 times. Hypertension Aug;52(2):249-55

19 > 35% <48% <46% Hypertension Aug;52(2):249-55

20 Summary Paricalcitrol may reduce albuminuria and inflammation in CKD patients. No significant effect on endothelial function, GFR, or BP.

21 Kidney International (2006) 70, VDR + vs VDR MICE. Substances-1,25 (OH)D, atra, dexamethasone, cytokines podocytes are terminally differentiated cells with little mitogenic potential, which does not allow for establishment of stable cell lines required for in vitro assays-the authors conditionally immortalized reporter podocytes REPON for sensitive, continuous monitoring of nephrin gene expression.

22 Vitamin D and nephrin expression. secreted alkaline phosphatase (SEAP)gene was fused to the promoter of the nephrin gene and introduced into conditionally immortalized podocytes. K Yamauchi et al.:kidney International (2006) 70,

23 Vitamin D and nephrin.. K Yamauchi et al.:kidney International (2006) 70,

24 Vitamin D and nephrin Immunohistochemistry A-Normal B-Nephrotic syndrome C-Low 22-oxacalcitriol D-High 22-oxacalcitriol E-low 1α,25(OH)2D3 F-High 1α,25(OH)2D3 Matsui et al. Nephrol Dial Transplant (2009) 24:

25 Vitamin D and podocin. Immunohistochemistry A-Normal B-Nephrotic syndrome C-Low 22-oxacalcitriol D-High 22-oxacalcitriol E-low 1α,25(OH)2D3 F-High 1α,25(OH)2D3 Matsui et al. Nephrol Dial Transplant (2009) 24:

26 Vitamin D and desmin Immunohistochemistry A-Normal B-Nephrotic syndrome C-Low 22-oxacalcitriol D-High 22-oxacalcitriol E-low 1α,25(OH)2D3 F-High 1α,25(OH)2D3 Matsui et al. Nephrol Dial Transplant (2009) 24:

27 Summary Vit D by altering the expression of nephrin podocin and desmin is thought to reduce protienuria in diseased kidneys.

28 Vit D and renoprotective effects Vit D and proteinuria. Vit D and RAS. Vit D and anti inflammatory effect. Vit D and immunomodulatory effects.

29 Vitamin D and Renin 184 healthy normotensive individuals. High sodium balance. No DM,CKD, CAD or active malignancy. 25(OH) VIT D and PRA was measured. RPF was calculated by PAH assays.

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31 When adjusted for age race and BMI PRA was greater by0.17+/ ng/ml in Vit D deficiency when restricted to whites the levels were similar.

32 Angiotensin and renal Plasma flow

33 Vit D Status and incidence of hypertension Ann Intern Med Mar 2;152(5):307-14

34 Vit D Status and incidence of hypertension Ann Intern Med Mar 2;152(5):307-14

35 Vit D Status and incidence of hypertension Ann Intern Med Mar 2;152(5):307-14

36 Vit D supplementation and hypertension

37 Vit D supplementation and hypertension

38 Vit D supplementation and hypertension

39 Kidney international (2008) 73, If vit D provides reno protection, mice lacking VDR are more susceptible to hyperglycemia induced renal injury

40 Kidney Int Jan;73(2): Epub 2007 Oct 10.

41 Kidney international (2008) 73,

42 Kidney international (2008) 73,

43 Kidney international (2008) 73,

44 Kidney international (2008) 73,

45 Vit D and renoprotective effects Vit D and proteinuria. Vit D and RAS. Vit D and anti inflammatory effects. Vit D and immunomodulatory effects

46 Total of 174 CKD patients Checked both 25 (OH)D and 1,25 (OH)D levels Checked Urinary MCP (Macrophage chemoattractant protien) and index of chronic renal damage 111 patients had kidney biopsy (frozen available for PCR analysis) Kidney International (2008) 74,

47 Kidney International (2008) 74,

48 Kidney International (2008) 74,

49 MCP-macrophage chemoattractant protein 1,25(OH) VIT D 25(OH)VIT D Kidney International (2008) 74,

50 Kidney International (2008) 74,

51 Kidney International (2008) 74,

52 Vit D and renoprotective effects Vit D and proteinuria. Vit D and RAS. Vit D and anti inflammatory effect. Vit D and immunomodulatory effects.

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55 Summary Down regulates T helper 1 cell assciated cytokines- IL-2 and IFN-Y. Up regulates T helper 2 cell associated cytokines- IL-4 and IL-5. Experiments in VDR KO mice produced high IL-2,IFN-Y and low IL4-IL-5. T helper 1 cells T helper 2 cells.

56 Overview of the potential renoprotective effects of active vitamin D in the damaged kidney Doorenbos, C. R. C. et al. (2009) Possible renoprotection by vitamin D in chronic renal disease: beyond mineral metabolism Nat. Rev. Nephrol. doi: /nrneph

57 Pleotropic effects of vitamin D Vit D and renoprotective and immunomodulatory effects. Vit D- Cardiometabolic actions.

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59 Vit D and incidence of diabetes Ann Intern Med Mar 2;152(5):307-14

60 Vit D and incidence of diabetes Ann Intern Med Mar 2;152(5):307-14

61 Vit D and incidence of diabetes Ann Intern Med Mar 2;152(5):307-14

62 Vit D supplementation and diabetes Ann Intern Med Mar 2;152(5):307-14

63 Vit D supplementation and diabetes Ann Intern Med Mar 2;152(5):307-14

64 Vit D supplementation and diabetes Ann Intern Med Mar 2;152(5):307-14

65 Vit D supplementation and diabetes

66 VIT D status and incidence of CVD Ann Intern Med Mar 2;152(5):307-14

67 VIT D status and incidence of CVD Ann Intern Med Mar 2;152(5):307-14

68 VIT D status and incidence of CVD Ann Intern Med Mar 2;152(5):307-14

69 VIT D status and incidence of CVD Ann Intern Med Mar 2; (5):3

70 Vit D supplementation and CVD Ann Intern Med Mar 2;152(5):307-14

71 Vit D supplementation and CVD Ann Intern Med Mar 2;152(5):307-14

72 Vit D supplementation and CVD Ann Intern Med Mar 2;152(5):307-14

73 Conclusion There is a lot of promise regarding the beneficial effects of Vit D. Decent animal models showing the pleotrophic effects. More convincing data is required from human studies.

74 THANK YOU