Journal Club: Hepcidin, Vitamin D and Anemia of CKD
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Hepcidin, Vitamin D and Anemia of CKD
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Journal Club: Hepcidin, Vitamin D and Anemia of CKD
- 1. Suppression of Iron-Regulatory Hepcidin by Vitamin D Wisit Cheungpasitporn March 28, 2013
- 3. Objective • To discuss on the role of vitamin D in regulation of hepcidin and anemia of chronic kidney disease.
- 4. Background • Patients with CKD require iron supplementation and erythropoiesis stimulating agents (ESAs) to correct disease-associated anemia.
- 5. Background • ESA hyporesponsiveness ~ 5-10% (in HD pts)1. • Hepcidin (encoded by the HAMP gene) emerging as a possible culprit. 1 Icardi A, et.al. Nephrol Dial Transplant. 2013 Jul;28(7):1672-9..
- 6. • 25 aa peptide hormone. • Chromosome 19. • Synthesized by hepatocytes. • Intrinsic antimicrobial activity. Hepcidin
- 7. Background • Elevated plasma hepcidin: • Common in CKD or inflammation • causes intracellular sequestration of iron and increases risk of anemia. • Patients with hemochromatosis or iron deficiency exhibit decreased hepcidin.
- 8. Zaritsky J. Clin J Am Soc Nephrol. 2009 Jun;4(6):1051-6.
- 9. Diseases of Hepcidin Dysregulation Hereditary haemochromatosis Iron-loading Anaemias Anaemia of Inflammation Iron-refractory iron-deficiency anaemia Hepcidin-secreting tumors HepcidinIron Normal homeostasis Ganz T. J Am Soc Nephol. 2007;18:394-400. Ganz T, Nemeth E. Am J Physiol Gastrointest Liver Physiol. 2006;290:G199-G203.
- 10. Background • Hepcidin suppresses membrane expression of ferroportin, the only known exporter of intracellular iron.
- 11. Fpn Fe ferritin Low Hepcidin High Hepcidin Fe hepcidin ferritin Iron release into plasma Iron-exporting cells (duodenal enterocytes, macrophages, hepatocytes) X Fpn Iron uptakeIron uptake Nemeth E, et al. Science. 2004;306:2090-2093.
- 12. Spleen Liver Duodenum Hepcidin Fpn Fpn Fpn Plasma Fe-Tf How Hepcidin Regulates Iron Bone marrow and other sites of iron usage Nemeth E, et al. Science. 2004;306:2090-2093.
- 13. Icardi A, et.al. Nephrol Dial Transplant. 2013 Jul;28(7):1672-9..
- 14. 142 HD patients Kiss Z, et.al. Nephron Clin Pract. 2011;117(4):c373-8.
- 15. N = 153 All CKD not on dialysis Lac PT, et.al. Clin Nephrol. 2010 Jul;74(1):25-32. at 4 mo
- 16. Carvalho C. et al. Clin Nephrol. 2011 Aug;76(2):90-8. N = 125 CKD not on dialysis
- 17. Background • Vitamin D: a potent inducer of antimicrobial proteins such as cathelicidin antibacterial protein (encoded by the cathelicidin [CAMP] gene). • Hepcidin: described as an antimicrobial peptide (encoded by the gene for hepcidin antibacterial protein, HAMP) Liu PT et. el. Science 311: 1770–1773, 2006
- 18. JASN March 2014 vol. 25 no. 3 564-572 Bacchetta J. et. el. J Am Soc Nephrol. 2014 Mar;25(3):564-72.
- 19. HYPOTHESIS • Vitamin D can act to regulate expression of hepcidin, in a similar fashion to its effects on other antimicrobial proteins. • To test this hypothesis, vitamin D–mediated changes in hepcidin and cathelicidin were compared using in vitro and in vivo models.
- 20. Vitamin D metabolite suppression of HAMP
- 21. HAMP: Hepcidin Vitamin D suppresses expression of hepcidin (HAMP) in human monocytes and hepatocytes. In vitro effect of vitamin D
- 22. CAMP: Cathelicidin vitamin D catabolic enzyme CYP24A1 Vitamin D increased expression of Cathelicidin and CYP24A1 in monocytes but not hepatocytes In vitro effect of vitamin D
- 23. In vivo effect of vitamin D PBMCm Wild type C57BL/6 No change in Hamp expression following 6 hr treatment with 25D or 1,25 D No change in mouse Hamp expression following 24 hr treatment with increased doses of vit D Mouse Monocyte cell line J774
- 24. In vivo effect of vitamin D 12-wk C57BL/6 mice on vitamin D-deficient diet * 6 wk 4 ppm iron diet for 1 week Treated with 25D,1,25 D, saline IP injection HAMP mRNA expression
- 25. Vitamin D receptor-mediated transcriptional repression of HAMP
- 26. In human cells, the suppression of HAMP expression by 1,25D or 25D appears to be due to direct inhibition of HAMP transcription - ChIP assay using human PBMC monocytes - 1,25D decreased 0.5-fold for HAMP promoters in VDR enrichment - 1,25D enhanced CAMP and CYP24A1 promoters in VDR and RNA pol II enrichment
- 27. Luciferase promoter- reporter construct transfected into VDR- expressing MC3T3 cells -24% decrease in transcription with 1,25D -In absence of 1α hydroxylase activity in MC3T3, 25 D had no effect HAMP Target gene activity
- 28. Vitamin D-induced suppression of HAMP is associated with changes in ferroportin and ferritin expression
- 29. The effect of vitamin D on ferroportin expression in Human monocytes and hepatocytes 25D and 1,25D had no effect on level of ferroportin mRNA 25 and 1,25D increased ferroportin protein expression Western blot Effect of vitamin D on ferroportin - Post-transcriptional action
- 30. 25D and 1,25D decreased ferritin mRNA level 25D and 1,25D decreased ferritin protein expression Immunohistochemistry
- 31. Effect of vitamin D supplementation on circulating Hepcidin in healthy volunteers
- 32. - Single arm PK study - 7 healthy volunteers (4 Men, median age 42 years) - Before and after a single dose of vitamin D2 100,000 IU Increase in 25D serum levels No change in 1,25D serum levels
- 33. Circulating hepcidin levels decreased by 34% at 24 hr and 33% at 72 hr
- 34. Result • Baseline and +72 hr after vitamin D supplement • Increase in FGF23 (62.57 vs 74.71 RU/ml, p=0.03) • Increase in phosphate (3.27 vs 3.61mg/dl, p<0.001) • Decrease in PTH (58.86 vs 51.29 pg/ml, p=0.06) • No significant Ca (9.19 vs 9.07 mg/dl, p=0.36)
- 35. Discussion • Vitamin D is a potent regulator of the iron-regulatory protein hepcidin in both monocytes and hepatocytes • Direct transcriptional suppression of the HAMP gene proximal promoter by 1,25D bound to its nuclear receptor,VDR • Suppression of HAMP by 25D or 1,25D was not observed in murine models
- 36. Discussion • In all three cell types studied, regulation of HAMP was observed after treatment with either active 1,25D or inactive 25D • suggesting an intracrine mode of action • PBMC monocytes, THP1 cells, and HepG2 cells express mRNA for the enzyme that catalyzes conversion of 25D to 1,25D, 1a-hydroxylase/ CYP27B1, as well as the VDR • Intracrine responses to vitamin D appear to be exquisitely sensitive to the availability of substrate 25D • hepcidin-ferroportin homeostasis system may be influenced by serum vitamin D
- 37. Vitamin D and Hepcidin-ferroportin iron-regulatory axis
- 38. Discussion • Elevated serum concentrations of 25D (but not 1,25D) after a single oral dose of vitamin D2 produced a 34% decrease in serum hepcidin concentrations that persisted for 72 hours • the regulation of serum hepcidin after vitamin D supplementation in vivo was at least as sensitive as more established markers of serum 25D status such as PTH, suggesting that hepcidin may be a useful marker of vitamin D function for future studies.
- 39. Discussion • Low vitamin D status may be a contributing factor to the anemia of chronic disease. • It is proposed that by acting to suppress expression of hepcidin in hepatocytes and monocytes, simple vitamin D supplementation may provide a cost-effective and safe adjuvant therapy for managing the anemia associated with this disease.
- 40. Questions & Discussion Clinical implication – Future studies?
Editor's Notes
- This was an analysis of cross-sectional data from the NHANES in 2007–2008 and 2009–2010. A total of 12,077 adults participated in the interview and examination components of the NHANES surveys in 2007–2008 and 2009–2010.
- ●The National Kidney Foundation (NKF) Dialysis Outcomes Quality Initiative (DOQI) guidelines for the anemia of CKD were initially published in 1997, with revisions in 2001 and 2006 [22-24]. The 2007 update for the Hgb target recommended that the selected Hgb target should generally be in the range of 11 to 12 g/dL in all patients with CKD [25]. They also recommended that the Hgb target should not exceed 13 g/dL. However, these guidelines were issued prior to Food and Drug Administration (FDA) dosing modification published in 2011 [15].●The 2012 Kidney Disease Improving Global Outcomes (KDIGO) guidelines suggested that ESAs not be started among adult nondialysis CKD patients with Hgb concentrations ≥10 g/dL [26]. For non-dialysis CKD patient with Hgb <10 g/dL, the decision to start ESAs should be individualized based upon the rate of fall in Hgb concentration, prior response to iron therapy, risk of needing a transfusion, the risks related to ESA therapy, and the presence of symptoms. Among dialysis patients, KDIGO suggests initiating ESAs when the Hgb concentration is <10 g/dL.●The KDIGO 2012 guidelines suggest that ESAs should generally not be used to maintain Hgb concentrations >11.5 g/dL, but that individualization of therapy will be necessary as some patients may have improvements in quality of life at Hgb ≥11.5 g/dL and will be prepared to accept the risks [26]. The KDIGO guidelines recommended that ESAs not be used to maintain Hgb ≥13 g/dL.●The 2012 KDIGO guidelines recommended that ESAs be used with great caution, if at all, in CKD patients with active malignancy, especially if cure is anticipated, or with a history of stroke or a history of malignancy.
- 5-15%
- Fig. 1. Box-whisker plot showing the maximum epoetin doserequired during the stabilization phase. Epoetin dose (IU/kg/week)is shown for patients in the low-haemoglobin (Hb) and high-Hbgroups who had dosing information during the stabilization phaseand required an epoetin dose at the start of the maintenance phase,and for the responsive and hyporesponsive patients in the high-Hbgroup. Of the 93 patients in the high-Hb group, 14 received amaximum epoetin dose >100 IU/kg/week during the stabilizationphase. Of the 23 patients in the low-Hb group, only one receivedan epoetin dose >100 IU/kg/week during the stabilization phase.The upper and lower boundaries of the box represent the 75thand 25th percentiles, respectively. Whiskers above and belowthe box indicate the 90th and 10th percentiles, respectively.The solid line within the box marks the median and the dashedline marks the mean. Outlying data points represent extreme values.
- Fig. 1 Suggested approach topatients with erythropoiesisstimulatingagents (ESA) hyporesponsiveness.ACEi, angiotensinconvertingenzyme inhibitors; CRP,C-reactive protein; HRC, hypochromicred cells; LDH, lactate dehydrogenase;SC, subcutaneous; TIBC,total iron-binding capacity; URR,urea reduction ratio.
- Figure 1. Serum hepcidin across chronic kidney disease (CKD)stages. Box plots represent second quartile, median, and thirdquartile of each group. Error bars denote the 10th and 90thpercentile. Hepcidin levels in each group of CKD patients weresignificantly elevated compared with respective age controls byANOVA analysis. Additionally, each group of CKD patientshad significantly different hepcidin levels (see text).
- (A) The hormone hepcidin is produced by the liver and controlsthe flow of iron into plasma from enterocytes that absorb dietary iron, from macrophages of the spleen and liverthat recycle old red blood cells (RBCs), and from hepatocytes that store iron. In inflammation and several otherconditions, hepcidin production is elevated. This causes iron restriction and contributes to the development ofanemia.
- Hepcidin binds to ferroportin and induces its internalization and degradation. By this mechanism, the interaction of hepcidin with ferroportin regulates the flow of iron into plasma, and thereby regulates the distribution of iron in the body.
- Scatter plot…association hepcidin inversely associated with vitamin D level.Correlation coefficient. Cross sectional.
- In silico analyses identified consensus vitamin D response elements (VDREs) within a 1071-bp HAMP proximal promoter DNA sequence.
- Previous studies have shown that transcriptional regulation of CAMP by 1,25D-VDR is primate specific