Osman YEŞİLBAŞ, Harika ALPAY, Nurdan YILDIZ, Özgür BAYKAN

Diyaliz gereksinimi olmayan kronik böbrek hastalıklı çocuklarda hepsidin ile anemi ve kemik mineral metabolizması ilişkili midir?

Amaç: İnflamasyona ikincil fonksiyonel demir eksikliği ve artmış hepsidin düzeyleri kronik böbrek hastalığı olan çocuklarda eritropoetin dirençli anemiye neden olmaktadır. Vitamin D eksikliği, parathormon ve fosfor da kronik inflamasyon ve anemiye katkıda bulunabilmektedir. Bu çalışmanın amacı, diyaliz ihtiyacı olmayan kronik böbrek hastalıklı çocuklarda hepsidin ile anemi ve kemik mineral metabolizmasının ilişkisini araştırmaktır. Gereç ve Yöntemler: Evre 2–4 kronik böbrek hastalığı olan 35 çocuk ile 35 sağlıklı çocuk çalışmaya alındı. Serum kreatinin, kan üre nitrojeni, ürik asit, C-reaktif protein, interlökin-6, hepsidin, tam kan sayımı, ferritin, kalsiyum, fosfor, parathormon, 25-hidroksivitamin D, 1,25- hidroksivitamin D ve fibroblast büyüme faktörü-23 düzeyleri iki grup arasında karşılaştırıldı. Bulgular: Ferritin, C-reaktif protein, kan üre nitrojeni, kreatinin ve ürik asit düzeyleri ile retikülosit yüzdesi kontrol grubuna göre anlamlı yüksek idi (p0,05). Hasta grubundaki serum hepsidin düzeyi ile anemi belirteçleri, fibroblast büyüme faktörü-23, fosfor, ürik asit, C-reaktif protein, 25-hidroksivitamin D ve parathormon düzeyleri korele değildi (p>0,05). Bununla birlikte serum hepsidin düzeyleri ile 1,25- hidroksivitamin D ve interlökin-6 düzeylerinin korelasyon gösterdiği görüldü (sırasıyla p=0,013 ve p=0,002). Çıkarımlar: Diyaliz ihtiyacı olmayan kronik böbrek hastalıklı çocuklarda, C-reaktif protein ve interlökin-6 gibi inflamasyon belirteçlerindeki artışa rağmen serum hepsidin düzeyleri anlamlı olarak artmayabilir. Demir desteği ve eritropoetin ile etkin anemi tedavisi ile fosfat bağlayıcılar ve aktif vitamin D ile ikincil hiperparatiroidizmin etkin tedavi edilerek serum parathormon ve fibroblast büyüme faktörü-23 düzeylerinin düşürülmesi bu hastalardaki inflamasyonu kontrol altına alarak serum hepsidinin artmasını engelleyebilir.

Is hepcidin related with anemia and bone mineral metabolism in children with non-dialysis chronic kidney disease?

Aim: Functional iron deficiency secondary to inflammation and increased serum hepcidin lead to erythropoietin-resistant anemia in children with chronic kidney disease. Vitamin D deficiency, parathyroid hormone, and phosphate can also participate in chronic inflammation and anemia. The aim of this study was to evaluate the association between hepcidin, bone mineral metabolism, and anemia in non-dialysis pediatric patients with chronic kidney disease. Material and Methods: Thirty-five patients with stage 2–4 chronic kidney disease and 35 healthy subjects were enrolled in the study. Serum creatinine, blood urea nitrogen, uric acid, C-reactive protein, interleukin-6, hepcidin, complete blood count, ferritin, calcium, phosphorus, parathyroid hormone, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and fibroblast growth factor-23 levels were compared between the groups. Results: Ferritin, C-reactive protein, interleukin-6, blood urea nitrogen, creatinine, uric acid levels, and percentages of reticulocytes were significantly higher than in the controls (p0.05). Serum hepcidin levels were not correlated with anemia parameters, serum fibroblast growth factor-23, phosphorus, uric acid, C-reactive protein, parathyroid hormone, and 25-hydroxyvitamin D levels (p>0.05). However, serum hepcidin levels were correlated with 1,25-dihydroxyvitamin D and interleukin-6 levels (p=0.013 and p=0.002, respectively). Conclusion: Serum hepcidin levels may not increase significantly in non-dialysis pediatric patients with chronic kidney disease despite high levels of inflammatory markers such as C-reactive protein and interleukin-6. The increase of serum hepcidin levels may be inhibited by effective treatment of anemia with iron supplementation and erythropoietin, and the treatment of secondary hyperparathyroidism with phosphate binders and the active form of vitamin D, which decrease serum parathyroid hormone and fibroblast growth factor-23 levels, and control inflammation to some extent.

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1. Malyszko J, Mysliwiec M. Hepcidin in anemia and inflammation in chronic kidney disease. Kidney Blood Press Res 2007; 30: 15−30. [CrossRef]
2. Zaritsky J, Young B, Wang HJ, et al. Hepcidin--a potential novel biomarker for iron status in chronic kidney disease. Clin J Am Soc Nephrol 2009; 4: 1051−6. [CrossRef]
3. Atkinson MA, Kim JY, Roy CN, Warady BA, White CT, Furth SL. Hepcidin and risk of anemia in CKD: a crosssectional and longitudinal analysis in the CKiD cohort. Pediatr Nephrol 2015; 30: 635−43. [CrossRef]
4. Young B, Zaritsky J. Hepcidin for clinicians. Clin J Am Soc Nephrol 2009; 4: 1384−7. [CrossRef]
5. Mercadal L, Metzger M, Haymann JP, et al. The relation of hepcidin to iron disorders, inflammation and hemoglobin in chronic kidney disease. PLoS One 2014; 9: e99781. [CrossRef]
6. Navarro-González JF, Mora-Fernández C, Muros M, Herrera H, García J. Mineral metabolism and inflammation in chronic kidney disease patients: a cross-sectional study. Clin J Am Soc Nephrol 2009; 4: 1646−54. [CrossRef]
7. Carvalho C, Isakova T, Collerone G, et al. Hepcidin and disordered mineral metabolism in chronic kidney disease. Clin Nephrol 2011; 76: 90−8. [CrossRef]
8. Bacchetta J, Zaritsky JJ, Sea JL, et al. Suppression of ironregulatory hepcidin by vitamin D. J Am Soc Nephrol 2014; 25: 564−72. [CrossRef]
9. Smith EM, Alvarez JA, Kearns MD, et al. High-dose vitamin D reduces circulating hepcidin concentrations: A pilot, randomized, double-blind, placebo-controlled trial in healthy adults. Clin Nutr 2017; 36: 980−5. [CrossRef]
10. Zughaier SM, Alvarez JA, Sloan JH, Konrad RJ, Tangpricha V. The role of vitamin D in regulating the iron-hepcidinferroportin axis in monocytes. J Clin Transl Endocrinol 2014; 1: 19−25. [CrossRef]
11. Munoz Mendoza J, Isakova T, Ricardo AC, et al. Chronic Renal Insufficiency Cohort. Fibroblast growth factor 23 and inflammation in CKD. Clin J Am Soc Nephrol 2012; 7: 1155−62. [CrossRef]
12. Lukaszyk E, Lukaszyk M, Koc-Zorawska E, BodzentaLukaszyk A, Malyszko J. Fibroblast growth factor 23, iron and inflammation - are they related in early stages of chronic kidney disease? Arch Med Sci 2017; 13: 845−50.
13. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis 2012; 39: S1−266.
14. Schwartz GJ, Brion LP, Spitzer A. The use of plasma creatinin concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am 1987; 34: 571−90. [CrossRef]
15. Panwar B, Gutiérrez OM. Disorders of iron metabolism and anemia in chronic kidney disease. Semin Nephrol 2016; 36: 252−61. [CrossRef]
16. Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 2003; 101: 2461−3.
17. Uehata T, Tomosugi N, Shoji T, et al. Serum hepcidin-25 levels and anemia in non-dialysis chronic kidney disease patients: a cross-sectional study. Nephrol Dial Transplant 2012; 27: 1076−83. [CrossRef]
18. Atkinson MA, White CT. Hepcidin in anemia of chronic kidney disease: review for the pediatric nephrologist. Pediatr Nephrol 2012; 27: 33−40. [CrossRef]
19. Kakimoto-Shino M, Toya Y, Kuji T, Fujikawa T, Umemura S. Changes in hepcidin and reticulocyte hemoglobin equivalent levels in response to continuous erythropoietin receptor activator administration in hemodialysis patients: A randomized study. Ther Apher Dial 2014; 18: 421−6. [CrossRef]
20. Onuma S, Honda H, Kobayashi Y, et al. Effects of longterm erythropoiesis-stimulating agents on iron metabolism in patients on hemodialysis. Ther Apher Dial 2015; 19: 582−9. [CrossRef]
21. Ashby DR, Gale DP, Busbridge M, et al. Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease. Kidney Int 2009; 75: 976−81. [CrossRef]
22. Kulaksiz H, Gehrke SG, Janetzko A, et al. Pro-hepcidin: expression and cell specific localization in the liver and its regulation in hereditary haemochromatosis, chronic renal insufficiency, and renal anemia. Gut 2004; 53: 735−43. [CrossRef]
23. Ganz T, Olbina G, Girelli D, Nemeth E, Westerman M. Immunoassay for human serum hepcidin. Blood 2008; 112: 4292−7. [CrossRef]
24. Kato A, Tsuji T, Luo J, Sakao Y, Yasuda H, Hishida A. Association of prohepcidin and hepcidin-25 with erythropoietin response and ferritin in hemodialysis patients. Am J Nephrol 2008; 28: 115−21. [CrossRef]
25. Camaschella C, Pagani A, Nai A, Silvestri L. The mutual control of iron and erythropoiesis. Int J Lab Hematol 2016; 38: 20−6. [CrossRef]
26. Kalantar-Zadeh K, McAllister CJ, Lehn RS, Lee GH, Nissenson AR, Kopple JD. Effect of malnutrition-inflammation complex syndrome on EPO hyporesponsiveness in maintenance hemodialysis patients. Am J Kidney Dis 2003; 42: 761−73. [CrossRef]
27. Kiss Z, Ambrus C, Almasi C, et al. Serum 25(OH)-cholecalciferol concentration is associated with hemoglobin level and erythropoietin resistance in patients on maintenance hemodialysis. Nephron Clin Pract 2011; 117: c373−8.
28. Braithwaite V, Prentice AM, Doherty C, Prentice A. FGF23 is correlated with iron status but not with inflammation and decreases after iron supplementation: a supplementation study. Int J Pediatr Endocrinol 2012; 2012: 27. [CrossRef]
29. Mehta R, Cai X, Hodakowski A, et al; CRIC Study Investigators. Fibroblast growth factor 23 and anemia in the chronic renal insufficiency cohort study. Clin J Am Soc Nephrol 2017; 12: 1795−803.