D-vitamin szerepe a krónikus betegségek megelőzésében Prof. Dr. Szabó András egyetemi tanár Semmelweis Egyetem II. Sz. Gyermekgyógyászati Klinika, Budapest

D vitamin szerepe a krónikus betegségek megelőzésében Prof. Dr. Szabó András egyetemi tanár Semmelweis Egyetem II. sz. Gyermekklinika DNN 2014. május 26.

Vitamin D Receptor Signaling 26 -Pro-apoptosis -Anti-angiogenesis -Pro-differenciation -Anti-invasion -Anti-poliferation -Cell-cycle gátlás Több mint 2700 gén szabályozása ismert 25D3 Vitamin D Receptor Signaling 125D3 125D3 VDR Actív Dimerization 125D3 125D3 SUMO1 VDR VDR UbC9 P CEBPb Cell Cycle Progression 125D3 125D3 VDR VDR CEBPa p21 (CIP1) Review: Our bones get more brittle with increasing age, and to add insult to injury, the most effective therapy for another problem that is associated with getting older, rheumatoid arthritis, often adds to the problem by causing bone resorption. The Glucocorticoid steroids, are the best available anti-inflammatories, and are used widely in the treatment of arthritis, as well as other inflammatory conditions such as dermatitis and autoimmune diseases. The Glucocorticoids, secreted by the Adrenal Cortex are powerful anti-inflammatory compounds due to their ability to inhibit all stages of the inflammatory response, from redness to wound healing to cell proliferation (Ref.1). They are powerful anti-inflammatory compounds that have the ability to inhibit all stages of the inflammatory response. They also have an essential role in cell metabolism and got the nomenclature, from their effect of raising the level of blood sugar (glucose) by stimulating gluconeogenesis in the liver: the conversion of fat and protein into intermediate metabolites that are ultimately converted into glucose. Cortisol (or Hydrocortisone) is the most important human Glucocorticoid. It is essential for life and regulates or supports a variety of important cardiovascular, metabolic, immunologic, and homeostatic functions. Corticosterone, another Glucocorticoid, helps in the regulation of the conversion of amino acids into carbohydrates and glycogen by the liver, and stimulates glycogen formation in the tissues. All the cellular responses to Glucocorticoids is attributed to their binding to the intracellular GR (Glucocorticoid Receptor) (Ref.2), that, in turn, translocates to the nucleus, that positively and negatively modulates gene expression through diverse mechanisms. The GR is the Glucocorticoid-activated member of the nuclear receptor superfamily of transcription factors. It mediates the immunosuppressive and anti-inflammatory activity of these ligands in multiple physiological systems, including the respiratory and central nervous systems. Belonging to the family of steroid hormones, Glucocorticoids are essential for development and survival of vertebrates (Ref.3). Unbound GR is associated within the cytoplasm in an inactive oligomeric complex with some regulatory proteins such as the HSP90 (Heat Shock Protein-90 KD) which binds as a dimmer to the C-terminal domain, the HSP70 (Heat Shock Protein-70 KD), the p59 immunophilin, FKBP52 and the small p23 phosphoprotein. GRs are composed of several conserved structural elements, including a COOH-terminal ligand-binding domain (which also contains residues required for dimmerization and hormone-dependent gene transactivation), a nearby hinge region containing nuclear localization signals, a central zinc-finger-containing DNA-binding domain, and an NH2-terminal variable region important for ligand-independent gene transactivation. The interaction between HSP90 and GR is required to maintain the C-terminal domain in a favourable conformation for ligand binding (Ref.4). The Gucocorticoid hormone passes through the plasma membrane into the cytoplasm where it binds to the specific, high-affinity GR. The resulting complex is the non-DNA-binding oligomer of the GR in which the receptor is complexed with other proteins. Binding of hormone agonists releases GR from its interactions with the inhibitory complex, thus inducing a conformational change which results in unmasking of the receptor nuclear localization signal. Upon activation, GR thereby translocates to the nucleus and binds as a dimmer to DNA through its central domain, which is structurally characterized by a DNA binding motif (Ref.3). The stabilization and nuclear localization of GR is facilitated by its sumoylation by SUMO1 (Small Ubiquitin Related Modifier-1). The sumoylation process is catalyzed by the SUMO1-conjugating E2 enzyme Ubc9 (Ref.5). GR interacts either with DNA by targeting specific nucleotide palindromic sequences termed GRE (Glucocorticoid Response Elements) or nGRE (Negative GRE) (Ref.6). In particular, the dimeric GR places its two DNA-binding fragments into adjacent major grooves of the DNA double helix in correspondence of appropriately spaced GRE half palindromes. Depending on the nature of the GRE, the overall process of GR binding can result in activation or repression of genes containing GR-binding sites (Ref.3). Although the activity of the GR is often thought of simply in terms of direct gene transactivation, considerable cross-talk also occurs between the GR and a cohort of molecules to mediate their function as transcriptional regulators. GRs can interact with coactivator complexes including CBP (CREB-Binding Protein), p300, ACTR (Activator of Thyroid Hormone and Retinoid Receptors), SRC1 (Steroid Receptor Coactivator-1), and PCAF (p300/CBP Associated Factor) that possess HAT (Histone Acetyltransferase) activities, and the SWI/SNF complex which possesses ATP dependent chromatin remodeling activities (Ref.3 & 7). Acetylation of core histones alters nucleosomal packing to allow increased access of transacting factors and components of the basal transcriptional machinery to the local DNA. All these complexes may act in concert to relieve chromatin-mediated gene repression, with the TRAP (Thyroid Hormone Receptor Associated Protein)-GRIP (Glucocorticoid Receptor Interacting Proteins)-ARC (Activated Recruited Cofactor) complex functioning to recruit the core transcription machinery. The latter includes the TBP (TATA Box-Binding Protein), the TAFs (TBP Associated Factors), the general transcription factors TFIIA, TFIIB, TFIIE, TFIIF, TFIIH, and the enzyme, RNA Pol II (RNA Polymerase-II). The nuclear receptors can also interact with the corepressors NCoR (Nuclear Receptor Corepressor) and SMRT (Silencing Mediator of Retinoid and Thyroid Hormone Receptor) thus leading to the recruitment of the Sin3-HDAC (Histone Deacetylase) corepressor complex, possessing histone deacetylase functions. This corepressor complex can thereby inhibit gene transcription by counteracting the actions of the coactivator complexes containing histone acetyltransferase activities (Ref.2 & 8). Alternatively, GR can also modulate the expression of genes through a GRE-independent mechanism, which is mediated in part through protein–protein interactions of GR with other sequence-specific DNA-binding factors or coactivators (Ref.9). The negative modulation of gene transcription operated by Glucocorticoids occurs through non genomic mechanisms (transrepression), mediated by inhibitory influences exerted by activated GR on the functions of several transcription factors. This contributes to the anti-inflammatory properties of the Glucocorticoids. Transrepression is due at least in part to direct, physical interactions between monomeric GR and transcription factors such as c-Jun-c-Fos and NF-KappaB (Nuclear Factor-KappaB), that synergistically coordinate the transcriptional activation of many genes involved in inflammatory diseases such as Asthma (Ref.10). In particular, the three main domains of GR may contribute to interact with the p65 subunit of NF-KappaB and with both Jun and Fos components of Activator Protein-1. The resulting reciprocal antagonism of the transcription factors engaged in these protein-protein associations causes an impairment of their transcriptional properties. However, Activator Protein-1, consisting of c-Jun homodimmers can also enhance GRE-mediated transactivation. On the other hand, Glucocorticoid-activated GR increases DNA-binding activity of CEBP-Beta via post-translational mechanisms involving phosphorylation at Thr(235) (Ref.11). GR can interact as a monomer, via direct protein-protein interactions, with transcription factors such as NF-KappaB and Activator Protein-1, activated by cytokines and other pro-inflammatory stimuli (Ref.4). The resulting mutual repression prevents both GR and the other transcription factors from binding to their respective DNA response elements. In addition, Glucocorticoids repress NF-KappaB-mediated activation of pro-inflammatory genes by reducing the levels of serine-2 phosphorylation of the carboxy-terminal domain of RNA Pol II, which is essential for the recruitment of this enzyme to the promoter region. Glucocorticoids also increase the transcription and synthesis of I-KappaB and thus may inhibit NF-KappaB by promoting its retention in the cytosol. Other products of Glucocorticoid inducible genes responsible for NF-KappaB inhibition include the two recently discovered proteins GILZ (Glucocorticoid-Induced Leucine Zipper) and GITR (Glucocorticoid-Induced Tumor Necrosis Factor Receptor Family-Related Gene), which play a crucial role in modulation of T-cell activation and apoptosis. GR can also cooperate with transcription factors, including octamer transcription factors Oct1 and Oct2; CREB (cAMP Response Element Binding Protein), and STAT5 (Signal Transducers and Activators of Transcription-5), to activate transcription. Competition for limiting co-activators of transcription is an important determinant of the fate of the cross-talk between the GR and other transcription factors. Both Activating Protein-1 and the GR are co-activated by CBP-p300, and in fact overexpression of CBP or p300 reverses the antagonism between Activator Protein-1 and the GR. Similarly, overexpression of CBP or SRC1 reverses the transcriptional antagonism between the GR and NF-KappaB (Ref.8 & 12). Glucocorticoids downregulate cell proliferation by decreasing the expression of Cyclin-D1 and the phosphorylation of Rb (Retinoblastoma) protein and by activating p21(CIP1) (Cyclin Dependent Kinase Inhibitor-p21). The antiproliferative effect of Glucocorticoids is mediated by the GR and CEBP-Alpha, and both active transcription factors are required to induce the synthesis of p21(CIP1). In human cells, including lung fibroblasts, pulmonary and bronchial smooth-muscle cells, and peripheral-blood lymphocytes, the GR forms a complex with CEBP-Alpha, which then binds to the CCAAT DNA consensus sequence in the p21(CIP1) promoter (Ref.13). The Glucocorticoid signaling interacts with other signaling pathways activated by various cytokines, thus regulating diverse biological processes through modulating the expression of target genes. GR represses TGF-â transcriptional activation of the PAI-1 (Plasminogen Activator Inhibitor-1) and other genes in a ligand-dependent manner. Glucocorticoids inhibit the TGF-â-induced expression of ECM (Extracellular Matrix) proteins including Fibronectin and Collagen, and proteinase inhibitors such as tissue inhibitors of Metalloproteinase. GR inhibits transcriptional activation by both Smad3 and Smad4 C-terminal activation domains (Ref.14). The MAPKs (Mitogen-Activated Protein Kinases) play a key role in inflammatory cell types through transducing the response from proinflammatory cytokine receptors to the transcriptional apparatus. MAPK subgroups such as JNK regulate activation of the AP-1 complex required for proinflammatory gene expression. The MAPK p38 subgroup regulates the stability of mRNAs that encode the proinflammatory molecules TNF-Alpha, IL-6, IL-8, and VEGF (Vascular Endothelial Growth Factor). Negative regulation of the MAPK family by Glucocorticoids may be an additional mechanism by which the GR exerts its antiinflammatory effects (Ref.15). The MAPK subgroups JNK, ERK1, ERK2, and p38 are all targets of negative regulation by activated GRs. For example, Glucocorticoids destabilize the mRNA of the proinflammatory enzyme COX2 (Cyclooxygenase-2) by inhibiting the activity of p38 (Ref.16). The GR represses the MAPK family by inhibiting the phosphorylation step required for their activation. The defined molecular mechanism behind this inhibition has not been fully characterized and may be cell type and stimulus specific (Ref.9). The therapeutic and prophylactic use of Glucocorticoids is widespread due to their powerful anti-inflammatory, antiproliferative and immunomodulatory activity (Ref.17). These are widely prescribed anti-inflammatory drugs, used to treat a wide variety of inflammatory diseases, including allergies, asthma, rheumatoid arthritis, and auto-immune diseases. Glucocorticoids enhance the production of other anti-inflammatory molecules such as IL-1RA (Interleukin-1 Receptor Antagonist), IL-10 (Interleukin-10), secretory leukocyte inhibitory protein and neutral endopetidase (Ref.2). Glucocorticoids are important mediators of the immune system and modulate the biological activities of inflammatory cytokines. The very effective control of airway inflammation exerted by Glucocorticoids in asthma is largely mediated by inhibition of the transcriptional activity of several different genes encoding pro-inflammatory proteins such as cytokines (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-11, IL-13, TNF-Alpha, GMCSF, IFN-Gamma), chemokines (IL-8, RANTES, MIP-1a, MCP-1, MCP-3, MCP-4, Eotaxin), adhesion molecules (ICAM1, VCAM1, E-Selectin), and mediator-synthesizing enzymes (i-NOS, COX2, cytoplasmic PLA2) (Ref.9, 10 & 16). Glucocorticoids, acting through the GR, potently modulate immune function and are a mainstay of therapy for treatment of inflammatory conditions including allergies, asthma, rheumatoid arthritis; autoimmune diseases, leukemias and lymphomas (Ref.3). Common Glucocorticoids include prednisone, dexamethasone, and hydrocortisone. Hydrocortisone is used as an anti-inflammatory in the treatment of arthritis, as well as other inflammatory conditions such as dermatitis and autoimmune disease. While Glucocorticoids are widely used as drugs to treat various inflammatory conditions, prolonged Glucocorticoid use may have adverse side effects such as immunosuppression, fluid shifts, brain changes, and psychological changes. Physicians are therefore very cautious about prescribing these medications, especially for long periods of time. The search for novel Glucocorticoids with reduced side effects has been intensified by the discovery of new molecular details regarding the function of the Glucocorticoid receptor. These new insights may pave the way for novel, safer therapies that retain the efficacy of currently prescribed steroids (Ref.18 and 19). References: 1. Miller AH Depression and immunity: a role for T cells? Brain Behav Immun. 2010 Jan;24(1):1-8. Epub 2009 Oct 8. PubMed ID: 19818725 2. De Iudicibus S, Franca R, Martelossi S, Ventura A, Decorti G. Molecular mechanism of glucocorticoid resistance in inflammatory bowel disease. World J Gastroenterol. 2011 Mar 7;17(9):1095-108. PubMed ID: 21448414 3. Marwick JA, Adcock IM, Chung KF. Overcoming reduced glucocorticoid sensitivity in airway disease: molecular mechanisms and therapeutic approaches. Drugs. 2010 May 28;70(8):929-48. doi: 10.2165/10898520-000000000-00000. PubMed ID: 20481652 4. Davies TH, Ning YM, Sanchez ER. Differential control of Glucocorticoid receptor hormone-binding function by tetratricopeptide repeat (TPR) proteins and the immunosuppressive ligand FK506. lBiochemistry. 2005 Feb 15;44(6):2030-8.l PubMed ID: 15697228 5. Chrousos GP, Kino T. Intracellular glucocorticoid signaling: a formerly simple system turns stochastic. Sci STKE. 2005 Oct 4;2005(304):pe48. PubMed ID: 16204701 6. Bhargava A, Pearce D. Mechanisms of mineralocorticoid action: determinants of receptor specificity and actions of regulated gene products. Trends Endocrinol Metab. 2004 May-Jun;15(4):147-53. PubMed ID: 15109612 7. Ruegg J, Holsboer F, Turck C, Rein T. Cofilin 1 is revealed as an inhibitor of Glucocorticoid receptor by analysis of hormone-resistant cells. Mol Cell Biol. 2004 Nov;24(21):9371-82. PubMed ID: 15485906 8. Grenier J, Trousson A, Chauchereau A, Amazit L, Lamirand A, Leclerc P, Guiochon-Mantel A, Schumacher M, Massaad C. Selective recruitment of p160 coactivators on Glucocorticoid-regulated promoters in Schwann cells. Mol Endocrinol. 2004 Dec;18(12):2866-79. PubMed ID: 15331759 9. Schoneveld OJ, Gaemers IC, Lamers WH. Mechanisms of Glucocorticoid signalling. Biochim Biophys Acta. 2004 Oct 21;1680(2):114-28. Review. PubMed ID: 15488991 10. Stellato C. Post-transcriptional and nongenomic effects of Glucocorticoids. Proc Am Thorac Soc. 2004;1(3):255-63. Review. PubMed ID: 16113443 11. Bladh LG, Liden J, Pazirandeh A, Rafter I, Dahlman-Wright K, Nilsson S, Okret S. Identification of target genes involved in the antiproliferative effect of Glucocorticoids reveals a role for nuclear factor-(kappa)B repression. Mol Endocrinol. 2005 Mar;19(3):632-43. PubMed ID: 15528271 12. Berg T, Didon L, Barton J, Andersson O, Nord M. Glucocorticoids increase C/EBPbeta activity in the lung epithelium via phosphorylation. Biochem Biophys Res Commun. 2005 Aug 26;334(2):638-45. PubMed ID: 16009338 13. Cascallana JL, Bravo A, Donet E, Leis H, Lara MF, Paramio JM, Jorcano JL, Perez P. Ectoderm-targeted overexpression of the Glucocorticoid receptor induces hypohidrotic ectodermal dysplasia. Endocrinology. 2005 Jun;146(6):2629-38. PubMed ID: 15746257 14. Roth M, Johnson PR, Borger P, Bihl MP, Rudiger JJ, King GG, Ge Q, Hostettler K, Burgess JK, Black JL, Tamm M. Dysfunctional interaction of C/EBPalpha and the Glucocorticoid receptor in asthmatic bronchial smooth-muscle cells. N Engl J Med. 2004 Aug 5;351(6):560-74. PubMed ID: 15295049 15. Li G, Wang S, Gelehrter TD. Identification of Glucocorticoid receptor domains involved in transrepression of transforming growth factor-beta action. J Biol Chem. 2003 Oct 24;278(43):41779-88. PubMed ID: 12902338 16. Bruna A, Nicolas M, Munoz A, Kyriakis JM, Caelles C. Glucocorticoid receptor-JNK interaction mediates inhibition of the JNK pathway by Glucocorticoids. EMBO J. 2003 Nov 17;22(22):6035-44. PubMed ID: 14609950 17. Brewer JA, Khor B, Vogt SK, Muglia LM, Fujiwara H, Haegele KE, Sleckman BP, Muglia LJ. T-cell glucocorticoid receptor is required to suppress COX-2-mediated lethal immune activation. Nat Med. 2003 Aug 31 [Epub ahead of print] PubMed ID: 12949501 18. Miner JN, Hong MH, Negro-Vilar A. New and improved Glucocorticoid receptor ligands. Expert Opin Investig Drugs. 2005 Dec;14(12):1527-45. PubMed ID: 16307492 19. Rosen J, Miner JN. The search for safer Glucocorticoid receptor ligands. Endocr Rev. 2005 May;26(3):452-64. PubMed ID: 15814846 ARC SWI/SNF Complex HAT1 Cell Cycle Arrest CBP Acetylation Histone TRAP GRIP1 SRC PCAF 125D3 125D3 TAFs TFIIB H4 H3 Ac TFIIF TFIIA TBP RNA Pol II VDR VDR TFIIE TFIIH VDRE TATA Histone Deacetylation Sin3 NCOR HDAC Gene Expression Qiagen, modified by Szabó.A. 3

Meta –analysis BMJ 2014;348:g1903 doi: 10. 1136/bmj Meta –analysis BMJ 2014;348:g1903 doi: 10.1136/bmj.g1903 (Published 1 April 2014) Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies Meta-analysis: 73 cohort study: n= 849412 , 22 Rand.Cont.Trial n= 30716

Az alacsony 25(OH)D3 szint halálozási kockázata Fig 1 Association of circulating 25-hydroxyvitamin D concentrations with cause specific mortality in observational cohort studies. *Pooled estimates are based on random effects meta-analysis. Using fixed effects models, for primary prevention cohorts, secondary prevention cohorts, and all cohorts, the estimates were 1.40 (1.32 to 1.47), 1.50 (1.35 to 1.66), and 1.42 (1.35 to 1.49) for cardiovascular deaths; 1.10 (1.02 to 1.17), 1.45 (1.28 to 1.65), and 1.16 (1.10 to 1.24) for cancer deaths; 1.28 (1.12 to 1.47), 1.38 (1.09 to 1.75), and 1.30 (1.16 to 1.47) for non-vascular, non-cancer deaths; and 1.45 (1.41 to 1.49), 1.49 (1.42 to 1.56), and 1.44 (1.40 to 1.47) for all cause deaths. Size of data marker is proportional to inverse of variance of relative risk; horizontal line represents Data extraction Data were extracted by two independent investigators, and a consensus was reached with involvement of a third. Study specific relative risks from 73 cohort studies (849 412 participants) and 22 randomised controlled trials (vitamin D given alone versus placebo or no treatment; 30 716 participants) were meta-analysed using random effects models and were grouped by study and population characteristics Meta analysis: 73 cohort study: n= 849412 , és 22 PCT n= 30716 BMJ 2014;348:g1903 doi: 10.1136/bmj.g1903 (Published 1 April 2014)

Az alacsony 25(OH)D3 szint cardiovascularis halálozási kockázata Fig 3 Association of circulating 25-hydroxyvitamin D concentration and risk of cardiovascular disease mortality in primary prevention cohorts, according to various characteristics. Based on available studies with relevant subgroup information. CPBA=competitive binding protein assay; +=relative risks adjusted for established cardiovascular risk factors such as age, sex, smoking status, lipids, hypertension, history of cardiometabolic disease; ++=adjusted for other potential risk factors such as physical activity, body mass index, social status; +++=adjusted for other additional variables such as bone minerals. *P<0.05 from meta-regression analyses. †Based on available studies with relevant subgroup information. ‡Based on Newcastle-Ottawa scale. No Meta analysis: 73 cohort study: n= 849412 , és 22 PCT n= 30716 BMJ 2014;348:g1903 doi: 10.1136/bmj.g1903 (Published 1 April 2014)

Mortalitási kockázat a 25(OH)D3 szint függvényében Fig 2 Association of circulating 25-hydroxyvitamin D concentrations with all cause mortality, based on primary prevention cohorts. *Indirect comparisons based on available studies with relevant information in each category; summary estimates presented were calculated using random effects models. Using fixed effects models, the estimates were 1.09 (1.06 to 1.11) for clinical cut-off of 21-29 v ≥30, 1.20 (1.15 to 1.26) for 10-20 v ≥30, 1.23 (1.20 to 1.26) for <10 v ≥30, and 1.19 (1.18 to 1.21) per 10 ng/mL decrease No <10 ng/ml 25OHD3 szint 50% mortalitási kockázat növekedéssel jár BMJ 2014;348:g1903 doi: 10.1136/bmj.g1903 (Published 1 April 2014)

<10µg/l D vitamin szint (25OHD3) prevalenciája Szérum 25OHD3 <10 µg/l Mo. HD 2006 46% Mo. 2013 21% NHANES III (1988-1994) NHANES IV (2001-2004) Arch Intern Med 2009;169(6): 626-632

Natív D vitamin supplementáció HD betegeknek   (n=5008) Age (year) 63.4 ± 14.2 Terápia (%) Calcimimeticum 259 (5.2%)   Ca tartalmú foszfátkötő 2011 (40.2%) Ca mentes foszfátkötő 947 (18.9%) Native vitamin D 166 (3.3%) Active vitamin D 2020 (40.4%) None 1349 (26.9%) Kiss Z. et. Al. BMC Nephrol. 2013; 14: 155.

D vitamin kezelés hatása a halálozásra Fig 6 Effects of vitamin D supplementation on all cause mortality when given alone, derived from available randomised control trials. *Pooled estimates are based on random effects meta-analysis. Using fixed effects models, for community dwelling, hospital based, and overall population, the estimates were 0.91 (0.81 to 1.01), 0.88 (0.77 to 1.01), and 0.90 (0.82 to 0.98) for vitamin D3 trials and 1.05 (0.94 to 1.17), 1.15 (0.63 to 2.11), and 1.03 (0.97 to 1.09) for vitamin D2 trials. Overall fixed effect estimate for all trials was 0.98 (0.94 to 1.03). Size of data marker is proportional to inverse of variance of relative risk; horizontal line represents 95% CI. Corresponding forest plots and I2 (95% CI) estimates are provided in supplementary material Fig Betegek esetén a D3 vitamin pótlás 16 %-al csökkenti a halálozás kockázatát Meta analysis: 73 cohort study: n= 849412 , és 22 RCT n= 30716 BMJ 2014;348:g1903 doi: 10.1136/bmj.g1903 (Published 1 April 2014)

D vitamin kezelés hatása a mortalitásra CKD betegekben Pooled crude hazard ratio of all-cause mortality for vitamin D treatment vs. no treatment in CKD patients. (A) baseline Cox model; (B) time-dependent Cox model.  32,6% Meta-analysis: 20 obszervációs vizsgálat (n= 491846) BMC Nephrol. 2013;14: 199

D vitamin pótlás hatása a 25OHD3 szintre 1

D vitamin kezelés hatása az EPO szükségletre n=126 5st. HD Vitamin D Treatment Period 1./ Induló érték, 2./ 4 x 50000 IU/ hét, 3./ 3 x 50000 IU / hó, 3. JNEPHROL 2011; 24(01): 98-105

D vitamin pótlás hatása a PTH szintre CKD -ben Clin J Am Soc Nephrol. 2011 January; 6(1): 50–62.b

A szérum iPTH szint mortalitás kockázata 8 % Betegek <2% 50 240 540 950 ng/L HR of serum iPTH. The graph shows the HR for mortality (dashed lines show 95% confidence interval) at 30 months after study entry derived from Cox regression models adjusted for covariate values at baseline (age, gender, history of cardiovascular disease, diabetes, dialysis vintage, body mass index, serum albumin, and Hb) and using fractional polynomials for serum iPTH (top), and number of patients (bottom). In order to model continuous variables, a fractional polynomial method uses polynomials of degree 1 or 2; the values between brackets represent the powers used for the best fit. The following equation estimates the natural logarithm of the HR; note that on the graph, the y-axis has been transformed to represent the real HR: iPTH [0.5, 1]: The k covariates are represented by . n=8577 HD beteg Nephrol Dial Transplant (2013) 28: 360-367 15

A szérum foszfát szint mortalitás kockázata 20% 8,4 % 1,1 1,67 2.2 Fig. 1. HR of serum phosphate. The graphic shows the HR for mortality (dashed lines show 95% confidence interval) at 30 months after study entry derived from Cox regression models adjusted for covariate values at baseline (age, gender, history of cardiovascular disease, diabetes, dialysis vintage, body mass index, serum albumin, and Hb) and using fractional polynomials for serum phosphate (top), and number of patients (bottom). In order to model continuous variables, a fractional polynomial method uses polynomials of degree 1 or 2; the values between brackets represent the powers used for the best fit. The following equation estimates the natural logarithm of the HR; note that on the graph, the y-axis has been transformed to represent the real HR. P [0.5, 0.5]: n=8577 HD beteg Nephrol Dial Transplant (2013) 28: 360-367 16

MGP szint és a mortalitás dializáltakban all-cause mortality cardiovascular mortality Low dp-cMGP levels predict all-cause and cardiovascular mortality in dialysis patients. Kaplan-Meier analysis of all-cause (left) and cardiovascular (right) mortality in patients with low and high levels of dp-cMGP (grouped according to median), log-rank test: P = 0.008 and P = 0.003, respectively. J Am Soc Nephrol. 2011 February; 22(2): 387–395.

K2 vitamin – Gla-proteinek Koagulaciós faktor: (II, VII, IX, X), és antikoagulációs protein (C, S, Z). Ez a Gla-protein a májban szintetizálódik és vér homeo-stasisban játszik főszerepet. Osteocalcin: Ez a fehérje az osteoblastokban szintetizálódik és nélkülözhetetlen a csontképzésben és a mineralizációban. Matrix gla protein (MGP): Ez egy kalcifikációt gátló fehérje a lágyrész szövetekben, a porcban és az artériák falában található Growth arrest-specific protein 6 (GAS6. GAS6: leukociták és endothel sejtek termelik sejtkárosodásban, segíti a sejtek túlélését, proliferációját , migrációját és az adhéziót. Proline-rich Gla-proteins (PRGP): ezek a transzmembrán Gla-protein (TMG), a Gla-rich protein (GRP) és a periostin.

Aorta kalcifikáció és az osteoporosis nőkben Schulz, E. et al. J Clin Endocrinol Metab 2004;89:4246-4253

Vesebetegek 64 %-ban volt K vitamin hiány Dialysis patients are deficient in vitamin K. Distribution of PIVKA-II in hemodialysis patients. According to the upper limit of the normal range (dotted line, 2 ng/ml30), 64% of dialysis patients display vitamin K deficiency (as indicated by increased PIVKA-II levels). n=187 CKD patient PIVKA-II = protein induced by vitamin K absence J Am Soc Nephrol. 2011 February; 22(2): 387–395.

Vitamin K2

Útravaló Tudnivaló D vitamin hiányos a felnőttek több mint 90% és a gyermekek több mint 50% <10 ng/ml D vitamin hiány 50 %-al növeli a halálozás kockzatát D vitamin pótlás jelentősen csökkenti a halálozás kockázatát, különösen betegek esetén A növényi eredetű D2 vitamin nem alkalmas a halálozás kockázatának csökkentésére, míg a D3 vitamin igen. A natív D vitamin és az aktív D vitamin is csökkenti a vesebetegek halálozási kockázatát (30 %)

Köszönöm a figyelmet

25OHD3 szintek gyermekkorban (1-18 éves, n = 3097) <10 ug/l 10-20 ug/l 20-30 ug/l >30 ug/l n=1772 n=1325 áprilistól - októberig novembertől - márciusig 5% = ca. 90000 gyermek II.sz. Gyermekklinika adatai

25OHD3 szintek 1- 3 éves gyermekekben (1-3 éves, n=400) (<1 év,n=31) <10 ug/l 10-20 ug/l 20-30 ug/l >30 ug/l 2% 10% 19% 69% n=215 n=185 áprilistól - októberig novembertől - márciusig 1% = ca. 2500 gyermek II.sz. Gyermekklinika adatai

A D vitamin optimális hatásához szükséges 25-hydroxy D vitamin szintek Szérum 25(OH)D3 (ug/L) Singapore Med J 2013; 54(5): 285-288

Szérum 25(OH)D3 szint - Calcitriol (n=176) Beteg % Norm: 30-70 μg/l 50 40 30 20 10 5 82 102 47 77 31 32 11 7 5 <10 10-20 20-30 30-40 >40 25(OH)D3 μg/l A vesebetegek >90% 30 μg/l alatt van a 25(OH)D3 szintje

Az alacsony 25(OH)D3 szint tumor halálozási kockázata Fig 4 Association of circulating 25-hydroxyvitamin D concentration and risk of cancer mortality in primary prevention cohorts, according to various characteristics. Based on available studies with relevant subgroup information. CPBA=competitive binding protein assay; +=relative risks adjusted for established cardiovascular risk factors such as age, sex, smoking status, lipids, hypertension, history of cardiometabolic disease; ++=adjusted for other potential risk factors such as physical activity, body mass index, social status; +++=adjusted for other additional variables such as bone minerals. *P<0.05 from meta-regression analyses. †Based on available studies with relevant subgroup information. ‡Based on Newcastle-Ottawa scale. No Meta analysis: 73 cohort study: n= 849412 , és 22 PCT n= 30716 BMJ 2014;348:g1903 doi: 10.1136/bmj.g1903 (Published 1 April 2014)

D vitamin szint dializált betegekben  Prevalence of vitamin D deficiency in hemodialysis. © This slide is made available for non-commercial use only. Please note that permission may be required for re-use of images in which the copyright is owned by a third party. Seminars in Dialysis Volume 26, Issue 1, pages 40-46, 27 SEP 2012 29