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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2015  |  Volume : 26  |  Issue : 1  |  Page : 34-38
Comparison of serum levels of hepcidin and pro-hepcidin in hemodialysis patients and healthy subjects


1 Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran
2 Department of Epidemiology, Digestive Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran
3 Department of Nephrology, 5th Azar Hospital, Golestan University of Medical Sciences, Gorgan, Iran
4 Department of Clinical Biochemistry, Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran

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Date of Web Publication8-Jan-2015
 

   Abstract 

Hepcidin prevents absorption of iron from the intestine and inhibits release of iron from macrophages and hepatocytes. For this reason, it seems that high levels of hepcidin are a predisposing factor for anemia in chronic inflammatory conditions such as chronic kidney disease and dialysis patients. This study was designed to determine the role of changes in the level of serum hepcidin in the management of hemodialysis patients. This study included 44 dialysis patients and 44 controls. The hepcidin and pro-hepcidin levels were measured by the enzymelinked immunosorbent assay method. The serum ferritin level was measured by the chemiluminescence method. The mean hepcidin level was 999.3 ± 996.7 ng/mL in the case group and 770.4 ± 815.9 ng/mL in the control group (P = 0.25). The mean pro-hepcidin level was, respectively, 186.1 ± 220.3 pg/mL and 150.87 ± 207.7 pg/mL, in the case group and control groups (P = 0.45). The mean (standard deviation) ferritin level was 816.4 ± 379.4 ng/mL in the case group and 193 ± 171.8 ng/mL in the control group (P < 0.001). In the case group, the correlation between serum ferritin and hepcidin was not significant (r = 0.6, P = 0.08). Also, there was no significant correlation between serum ferritin and pro-hepcidin levels (r = 0.6, P = 0.08). A positive correlation was seen between pro-hepcidin and hepcidin levels (r = 0.92, P < 0.01). In this study, the results showed that the serum hepcidin levels are high in dialysis patients and that there was no correlation with the serum ferritin levels.

How to cite this article:
Taheri N, Gh Roshandel, Mojerloo M, Hadad M, Mirkarimi H, Nejad R K, Joshaghani H R. Comparison of serum levels of hepcidin and pro-hepcidin in hemodialysis patients and healthy subjects. Saudi J Kidney Dis Transpl 2015;26:34-8

How to cite this URL:
Taheri N, Gh Roshandel, Mojerloo M, Hadad M, Mirkarimi H, Nejad R K, Joshaghani H R. Comparison of serum levels of hepcidin and pro-hepcidin in hemodialysis patients and healthy subjects. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2021 Feb 25];26:34-8. Available from: https://www.sjkdt.org/text.asp?2015/26/1/34/148730

   Introduction Top


Chronic renal failure (CRF) is a severe debilitating disease and is associated with many systemic complications, and anemia is one of them. [1] Renal anemia is considered as a form of anemia of chronic diseases that is often of the normochromic normocytic type. Anemia of chronic diseases is seen in many diseases associated with inflammation, such as cancer, chronic infections and autoimmune diseases. [2]

Anemia is a major factor in many of the symptoms associated with decreased renal function. These complications cause a significant increase in mortality due to cardiovascular disease in dialysis patients. [3] The kidneys are the primary site for the synthesis of erythropoietin (EPO) in adults. Interleukin-6 is the most important cytokine involved in the production of hepcidin and the inflammatory condition axis of hepcidin-interleukin (IL)-6 is responsible for iron deficiency during inflammation. [4],[5]

Hepcidin is a low molecular weight protein that has recently been discovered and plays an important role in iron metabolism. It is a regulator of renal iron homeostasis. [6] Pre-prohepcidin, with 84 amino acids, is produced in the hepatocytes and is then broken down to 60 amino acid pro-hepcidin that appears in the plasma. [7] Hepcidin prevents the release of iron from the macrophages and decreases iron absorption in the intestine. [8] Various physiological and pathological conditions are effective in the synthesis of hepcidin. On the other hand, synthesis of hepcidin increases in infections and inflammatory processes. [9]

Hepcidin is considered as one of the acute phase proteins. It is believed that this effect can lead to anemia of chronic disease, which is caused by a decrease of circulating iron available for erythropoiesis, despite normal iron stores. [10] The hepcidin level increases in patients with CRF and hemodialysis (HD) patients. [11],[12] Hepcidin is cleared only in some patients during dialysis. Exactly why this happens is not clear yet, but it may be due to differences in the membranes of various dialyzers, state of kidney function or induction of hepcidin during the process of HD. [6] Hepcidin may be associated with resistance to factors triggering the production of EPO and an imbalance in iron metabolism in CRF patients. In addition, hepcidin can also be discussed as a therapeutic agent as decreasing the levels of hepcidin can lead to improved iron uptake from the intestine and macrophages; thus, antihepcidin therapy can be a substitute for intravenous iron therapy. [13] The aim of this study was to evaluate the level of pro-hepcidin and hepcidin in patients with CRF on HD.


   Materials and Methods Top


In this study, 44 HD patients and 44 healthy controls were sampled. Before dialysis, 6 mL of blood was taken from each patient and, after separation, the sera were stored in the freezer at -70°C. Subjects with active infection (fever or other evidence of infection) were excluded. The control subjects were healthy individuals with normal serum urea and creatinine. Hepcidin (IBL) and pro-hepcidin (Glory Science) were measured by the enzyme-linked immunosorbent assay method. The serum ferritin was measured by the luminescence quantitative method (Monobind).

To investigate the correlation between different variables and eliminate confounding variables in the subjects of the study, we used multivariate analysis (logistic regression). For this purpose, variables that had a P-value < 0.2 on univariate analysis were entered into the multivariate analysis. For comparison of the mean of variables that was not normally distributed, the Mann-Whitney test was used and for variables that had normal distribution, the Student t-test was used. The chi-square test was used to evaluate the qualitative variables and the t-test was used to compare the quantitative variables between the two groups. A P value < 0.05 was considered significant. This study was performed with the approval of the Research Ethics Committee of the Golestan University of Medical Sciences.


   Results Top


In each of the groups, 54.5% of the participants were male (P = 0.58). 31.8% of the patient group and 27.3% of the control group had age below 50 years (P = 0.41). The mean pro-hepcidin level in the case and control groups was 186.1 ± 220.3 pg/mL and 150.87 ± 207.7 pg/mL, respectively (P = 0.45). The the normal controls was 999.3 ± 996.7 ng/mL and 770.4 ± 815.9 ng/mL, respectively (P = 0.25). In CRF patients, the mean pro-hepcidin level was 168.2 ± 226 pg/mL in males and 207.7 ± 216.9 pg/mL in females (P = 0.54) and the mean hepcidin was 816.8 ± 840.6 ng/mL in males and 1218.2 ± 1140.4 ng/mL in females (P = 0.77). In the control group, the mean pro-hepcidin was 123.6 ± 161.5 pg/mL in males and 182.5 ± 252 pg/mL in females (P = 0.84) and the mean hepcidin was702.3 ± 757.2 ng/mL in males and 849.2 ± 893.4 ng/mL in females (P = 0.73) [Table 1].
Table 1: The mean hepcidin and pro-hepcidin levels in the two age-groups studied.

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The mean serum ferritin was 816.4 ± 379.4 ng/mL in the case group and 193 ± 171.8 ng/ml in the control group (P (0.001>. In the case group, no significant correlation was observed between serum ferritin and hepcidin and pro-hepcidin levels (r = 0.6, P = 0.08). Also, in this group, a significant positive correlation was observed between pro-hepcidin and hepcidin levels (r = 0.92, P < 0.01). In the control group, no significant correlation was seen between serum ferritin and hepcidin (r = 0.4, P = 0.14) and pro-hepcidin levels (r = 0.7, P = 0.06). Also, in this group, a significant correlation was seen between pro-hepcidin and hepcidin levels (r = 0.8, P (0.01>). The level of hepcidin had a direct correlation with the duration on dialysis in the case group, but it was not significant (r = 0.3, P = 0.06). Also, a direct correlation was observed between duration on dialysis and pro-hepcidin levels (r = 0.3, P = 0.09). On multivariate regression analysis of the variables such as age and ferritin, pro-hepcidin and hepcidin levels, the only variable that was significantly associated with the risk of anemia was ferritin levels (P < 0.001).


   Discussion Top


This study was conducted to evaluate the normal subjects. In our study, the mean prohepcidin level had no significant difference in the case and control groups. Tomosug et al, in a study in 2006, measured the hepcidin levels in patients with CRF and found that the hepcidin level was approximately two to three-times higher than in the control group. In contrast, serum levels of β2-microglobulin, which is a low molecular weight protein that is controlled almost totally by glomerular filtration, there was a 20-30-times increase in the levels. Thus, glomerular filtration has little effect on hepcidin level that theoretically may explain the presence of an unknown carrier in the circulation for hepcidin, which can cause decreased renal clearance of this molecule. [14]

Young et al in a study in 2009 showed that the pro-hepcidin level increases in dialysis patients and correlates inversely with the glomerular filtration rate (GFR). However, prohepcidin has minimal interaction with iron or inflammatory parameters in dialysis patients; also, it seems that pro-hepcidin is an intermediate metabolite and without physiological activity and its level is not associated with the active production of hepcidin. [15] In the study performed by Zaritsky et al in 2009, the serum ferritin level in children with CRF was higher than in adults with CRF. [16] In our study, there was no significant correlation between ferritin and hepcidin and pro-hepcidin levels.

In a study performed by Busbridge et al in patients with inflammatory bowel disease, a direct correlation was reported between ferritin and hepcidin levels. [17] The mismatch of the results may be due to successful HD or small sample size. It is recommended that further studies should be performed with a larger sample size and the blood levels of these variables should be compared with the erythrocyte indices. In our study, no significant correlation was seen between duration on dialysis and hepcidin and pro-hepcidin levels. In a study performed by Li et al, the hepcidin level was higher in patients with renal failure and those on HD. [11] Peters et al in their study in 2010 from Holland found that the hepcidin level was higher in patients on chronic HD than in the control group. They also showed that the ferritin level in CRF and HD groups was higher than in the control group and found a significant correlation between hepcidin and ferritin levels. They concluded that the ferritin level is the only predicting factor for hepcidin level. [12]

According to studies performed in 2008 and 2010, it seems that the hepcidin level has no correlation with duration of dialysis, but the GFR is an important factor that shows correlation with the hepcidin level. [6],[12] Abbasi et al reported that the pro-hepcidin level in CRF patients was higher than in the control group. [18]

According to a study that was performed in 2011, the hepcidin level did not show a correlation with sex, race and age. [19] In our study, the mean serum ferritin was significantly higher in the dialysis group than in the control group. In a study performed by Nakanishi et al in 2011, direct and significant correlation was observed between serum ferritin and hepcidin levels. [20]


   Acknowledgment Top


This research was supported by the Deputy Head of Research and Technology of the Golestan University of Medical Sciences.

Conflict of interest: none

 
   References Top

1.
Yilmaz MI, Solak Y, Covic A, Goldsmith D, Kanbay M. Renal anemia of inflammation: The name is self-explanatory. Blood Purif 2011;32:220-5.  Back to cited text no. 1
    
2.
Zarychanski R, Houston DS. Anemia of chronic disease: A harmful disorder or an adaptive, beneficial response? CMAJ 2008;179:333-7.  Back to cited text no. 2
    
3.
KDOQI; National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis 2006;47(5 Suppl 3):S11-145.  Back to cited text no. 3
    
4.
AJ E. Erythropoietin. N Engl J Med 1999;324:339-44.  Back to cited text no. 4
    
5.
Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 2004;113:1271-6.  Back to cited text no. 5
    
6.
Swinkels DW, Wetzels JF. Hepcidin: A new tool in the management of anaemia in patients with chronic kidney disease? Nephrol Dial Transplant 2008;23:2450-3.  Back to cited text no. 6
    
7.
Pigeon C, Ilyin G, Courselaud B, et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem 2001;276:7811-9.  Back to cited text no. 7
    
8.
Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004;306:2090-3.  Back to cited text no. 8
    
9.
Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 2002;110:1037-44.  Back to cited text no. 9
    
10.
Babitt JL, Lin HY. Molecular mechanisms of hepcidin regulation: Implications for the anemia of CKD. Am J Kidney Dis 2010;55:726-41.  Back to cited text no. 10
    
11.
Li H, Rose MJ, Tran L, et al. Development of a method for the sensitive and quantitative determination of hepcidin in human serum using LC-MS/MS. J Pharmacol Toxicol Methods 2009;59:171-80.  Back to cited text no. 11
    
12.
Peters HP, Laarakkers CM, Swinkels DW, Wetzels JF. Serum hepcidin-25 levels in patients with chronic kidney disease are independent of glomerular filtration rate. Nephrol Dial Transplant 2010;25:848-53.  Back to cited text no. 12
    
13.
Coyne DW. Hepcidin: Clinical utility as a diagnostic tool and therapeutic target. Kidney Int 2011;80:240-4.  Back to cited text no. 13
    
14.
Tomosugi N, Kawabata H, Wakatabe R, et al. Detection of serum hepcidin in renal failure and inflammation by using Protein Chip System. Blood 2006;108:1381-7.  Back to cited text no. 14
    
15.
Young B, Zaritsky J. Hepcidin for clinicians. Clin J Am Soc Nephrol 2009;4:1384-7.  Back to cited text no. 15
    
16.
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.  Back to cited text no. 16
    
17.
Busbridge M, Griffiths C, Ashby D, et al. Development of a novel immunoassay for the iron regulatory peptide hepcidin. Br J Biomed Sci 2009;66:150-7.  Back to cited text no. 17
    
18.
Abbasi LR, Seyfi S, Lesan M. Correlation between Prohepcidin with serum markers in chronic hemodialysis patients: Study of 54 patients. J Med Tehran Univ Med Sci 2011;68:681-5.  Back to cited text no. 18
    
19.
Carvalho C, Isakova T, Collerone G, et al. Hepcidin and disordered mineral metabolism in chronic kidney disease. Clin Nephrol 2011; 76:90-8.  Back to cited text no. 19
    
20.
Nakanishi T, Hasuike Y, Otaki Y, Kida A, Nonoguchi H, Kuragano T. Hepcidin: Another culprit for complications in patients with chronic kidney disease? Nephrol Dial Transplant 2011;26:3092-100.  Back to cited text no. 20
    

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Correspondence Address:
Dr. H R Joshaghani
School of Paramedicine, Falsafi Building, Hirkan Boulevard, Gorgan
Iran
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DOI: 10.4103/1319-2442.148730

PMID: 25579713

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