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Saudi Journal of Kidney Diseases and Transplantation
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RENAL DATA FROM THE ARAB WORLD  
Year : 2018  |  Volume : 29  |  Issue : 1  |  Page : 127-135
Renal anemia syndromes in iraqi hemodialysis patients according to iron status


1 Nephrology and Renal Transplantation Center, Medical City Teaching Hospital, Baghdad, Iraq
2 Nephrology and Dialysis Unit, Thi qar Health Directorate, Thi qar, Iraq

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Date of Web Publication15-Feb-2018
 

   Abstract 

Anemia is common in patients on hemodialysis (HD). Adequate iron stores are essential for achieving the best hemoglobin level through maximum benefit from erythropoiesis-stimulating agents (ESA). Decreased iron stores or decreased availability of iron are the most common reasons for resistance to the effect of these agents. Our objective was to categorize a group of Iraqi HD patients according to absolute or functional iron deficiency anemia (IDA); this study was conducted in the HD unit of the Baghdad Teaching Hospital from October 2012 to January 2013. Seventy prevalent adult HD Iraqi patients were enrolled. All patients were tested for full blood counts and iron parameters. They were categorized as nonanemic and those with absolute or functional iron deficiency. The patients were also tested for serum albumin, C-reactive protein (CRP), parathyroid hormone, and serum hepcidin levels. Data were expressed as mean ± standard deviation, and frequencies (number) and proportions (%). The mean age of the study group was 49.8 ± 12.3 years. Diabetes was the primary cause of end-stage renal disease, seen in 30 patients (42.8%). Majority of the HD patients were anemic, [51 (82.9%)] and among them, 39 (76.4%), had functional IDA. The mean serum iron, serum ferritin, and transferrin saturation were significantly higher in patients with functional IDA than those with absolute IDA (P <0.05). The mean highly sensitive CRP, parathormone and hepcidin values were also significantly higher in functional IDA patients than in those with absolute IDA and the nonanemic group (P <0.05). More than half of the study patients had functional IDA, and this can explain ESA hyporesponsiveness. This is besides the interplay of other factors including inflammation, inadequate dialysis, and secondary hyperparathyroidism. It is essential to diagnose functional IDA early, before the initiation of unnecessary iron therapy.

How to cite this article:
Ali A, Salih RM. Renal anemia syndromes in iraqi hemodialysis patients according to iron status. Saudi J Kidney Dis Transpl 2018;29:127-35

How to cite this URL:
Ali A, Salih RM. Renal anemia syndromes in iraqi hemodialysis patients according to iron status. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2021 Mar 1];29:127-35. Available from: https://www.sjkdt.org/text.asp?2018/29/1/127/225182

   Introduction Top


Anemia is one of the most significant consequences of chronic kidney disease (CKD). It has been defined by the World Health Organization (WHO) as a hemoglobin (Hb) concentration below 13.0 g/dL for adult males and postmenopausal women, and Hb below 12.0 g/dL for premenopausal women.[1]

Anemia is almost universal in the end-stage renal disease (ESRD) and based on the WHO definition, nearly 90% of patients with a glomerular filtration rate (GFR) <25–30 mL/min would have anemia and many with Hb levels below 10 g/dL.[2],[3]

The pathophysiology of anemia of CKD involves the interaction of multiple factors in which, erythropoietin (EPO) plays the central role. Blood loss and nutritional deficiencies add to the severity of renal anemia. The uremic milieu and uremic toxins add to the complexity of understanding renal anemia and the development of the therapeutic intervention. Uremic red blood cells are fragile and more prone to premature lysis, and there are many uremic inhibitors of erythropoiesis.[4]

Altered iron metabolism and chronic inflammation are also implicated in the pathogenesis leading to better categorization of renal anemia syndromes and improving decisions of its management. The identification of hepcidin as a key regulator of iron homeostasis in normal conditions and anemia of chronic disease has redefined our understanding of iron homeostasis in CKD.[5] Hepcidin is a small peptide hormone secreted by hepatocytes to regulate plasma iron concentration and distribution in different tissues.[6] It is a negative regulator of iron absorption and mobilization; high hepcidin concentrations turn off both duodenal iron absorption as well as the release of iron from macrophages, while low hepcidin concentrations promote iron absorption and heme iron recycling or iron mobilization from macrophages. Thus, hepcidin concentrations are expected to be high in iron-overload states and diminished in iron-deficient states. Hepcidin production can be induced by type II acute inflammatory reactions, which are mediated by interleukin-(IL-6) thus, providing a mechanism for inflammation to affect iron availability.[7],[8]

Patients with ESRD and anemia can be classified according to their iron status into true (absolute) iron deficiency where iron level and stores are decreased and functional iron deficiency. The latter occurs when the iron is being rapidly utilized for erythropoiesis while the total iron stores may not be depleted.[9] This classification was refined clinically in view of malnutrition or inflammation in uremic patients.

In spite of such understanding of the pathophysiology of renal anemia, it is still difficult to find clear-cut definitions for the diagnosis of functional iron deficiency or inflammatory block. In addition, the discovery of hepcidin and its role added a little as a diagnostic utility. Clinically, a distinction can be made by the response to iron therapy. Functional iron deficiency usually responds to iron therapy, while inflammatory iron block may not respond as briskly. The response to erythropoiesis-stimulating agents and/or parenteral iron may help distinguish between these two entities.[10]

The aims of this study are to categorize a group of Iraqi hemodialysis (HD) patients according to definition of anemia into absolute iron deficiency anemia (IDA) or functional IDA and to study some factors contributing to it.


   Patients and Methods Top


This cross-sectional study was conducted at the HD unit of the Baghdad Teaching Hospital, Medical City Complex in Baghdad from October 2012 to January 2013. It was approved by the scientific and ethical committees of research at the Medical City Directorate. The aim of the study was explained thoroughly to all participants and their companions, and written consent was taken.

Patients

Seventy adult Iraqi patients who were diagnosed with ESRD and were on regular HD were enrolled in this study. There were 38 males and 32 females.

Inclusion criteria

Patients with ESRD on maintenance HD for more than three months and <1 year were enrolled in this study. The maintenance HD schedule was three sessions per week, each of 4 h duration. All underwent HD using a bio-compatible Fresenius Polysulfone® dialysis membrane through an arteriovenous fistula (AVF) as vascular access. All patients received EPO alfa 50–100 IU/kg twice a week and oral folate 5 mg/day. All patients were on intravenous iron naïve. Relevant clinical and biochemical data were retrieved from the patients’ records. None of the study patients were on angiotensin-converting enzyme inhibitors of angiotensin II receptor blockers.

Exclusion criteria

  1. HD for <3 months
  2. Patients with acute kidney injury (AKI)
  3. Patients with vascular access other than AVF
  4. Previous treatment with immunosuppressive drugs
  5. Active inflammatory disease
  6. Clinical signs of acute infection
  7. Presence of liver disease
  8. Presence of malignancy
  9. Evidence of blood loss or gastrointestinal bleeding.


AKI was excluded according to patients’ historic data and the referral notes of the treating nephrologists. In addition, imaging studies and abdominal ultrasound were performed to assess the renal size and to exclude obstruction.

Protocol

Initially, all patients were tested for complete blood count and iron parameters [serum iron, ferritin, and total iron binding capacity (TIBC)]. They were then categorized accordingly into two categories; absolute and functional IDA.

Absolute IDA was defined[11] as the percentage transferrin saturation (TSAT) below 20%, and the serum ferritin concentration of <200 ng/mL among HD patients.

The functional IDA was defined[10] as TSAT ≤ 20%, and elevated ferritin level (typically >200 ng/mL). All patients were then tested further for serum albumin, highly sensitive C-reactive protein (hs-CRP), bio-intact parathyroid hormone (iPTH), and serum hepcidin levels.

Sample collection and determination

Blood samples were collected before the start of HD. Tubes with EDTA anticoagulants were used for hematology samples and no anticoagulants were used for other biochemical tests. CBC was tested by Celltac Es MEK-7300 hematology automatic analyzer by Nihon Kohden, Japan. It included Hb; mean cell volume; mean cell hemoglobin concentration, and red cell distribution width (RDW).

Iron studies included serum iron, TIBC, and serum ferritin. TSAT was calculated as serum iron × 100/TIBC.

Other measurements included quantitative test for hs-CRP, serum albumin, iPTH, and serum hepcidin levels.

The CRP was measured by ELISA using a Demeditec CRP ELISA DEZ40001 Kit by Demeditec Diagnostics GmbH, Germany. The normal values for the general population are <5 mg/L.

Albumin was measured with ALB Flex reagent cartridge, Cat. No. DF13 by dimension clinical chemistry system, Germany, using bromocresol purple dye-binding method.

For intact PTH, morning blood samples were collected from patients in plain tubes. The concentrations were measured using the COBAS Elecsys® PTH immunoassay (Roche Diagnostics, GmbH, Germany) on Cobas e411.

Serum levels of hepcidin were measured using commercially available ELISA kits (Cusabio Biotech, China). Non-fasting blood samples (2.5 mL each, taken in heparinized tubes with immediate centrifugation) were collected 48 h after the 3rd weekly HD session in which the patients received their second EPO dose.


   Statistical Analysis Top


The data were analyzed using the Statistical Package for Social Sciences (SPSS) version 22.0 (Armonk NY: IBM Corp.). Data are expressed as mean ± standard deviation (SD), and frequencies (number) and proportions (%). We used Student ’ s t-test and one-way analysis of variance to compare means. Chi-square test was used to compare frequencies. P <0.05 was considered to be statistically significant.


   Results Top


[Table 1] shows the baseline characteristics of the study group. The mean age of the study group was 49.8 ± 12.3 years. Diabetes mellitus was the cause of ESRD in 30 patients (42.9%). The mean duration of the dialysis sessions was 210 +7.13 min.
Table 1: The baseline characteristics of the study group.

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Diabetes was more frequent in patients with functional IDA (56.7%) than the nonanemic patients (40%) and those with absolute IDA (3.3%) and this was statistically significant (P <0.05).

[Table 2] shows that 51/70 study patients (72.8%) had anemia. Among them, 39/51 (76.4%) had functional IDA and 12/51 patients (23.6%) had absolute IDA.
Table 2: The frequency of distribution of the study group by definitions of anemia.

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[Table 3] shows the difference in the mean values of iron parameters between patients with absolute and functional IDA. The mean serum iron level was significantly higher in patients with functional IDA than those with absolute IDA; 76.3 ± 35.2 μg/dL versus 38.8 ± 6.6 μg/dL, (P <0.001). The mean serum ferritin was higher in the functional IDA group than those with absolute IDA and the non-anemic patients. This difference was statistically significant (P <0.05). HD patients with functional IDA had higher mean TSAT levels (31.5 ± 12.9%) than those with absolute IDA (15.5 ± 3.7%), and this was statistically significant (P <0.05).
Table 3: The mean values of iron parameters in the absolute and functional iron deficiency states.

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[Table 4] shows the difference in the mean values of iPTH, albumin, hs-CRP, and hepcidin between nonanemic patients and those with absolute and functional iron deficiency states.
Table 4: The mean values of inflammatory markers of the study group.

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The mean iPTH of the functional anemia patients (239.1 ± 26.7) pg/mL was higher than in patients with IDA (137.2 ± 81.3) and the non-anemic group (150.1 ± 23.6); this was statistically significant (P >0.05).

The mean CRP value of the functional anemia patients (22.1 ± 13.3) was higher than patients with absolute iron deficiency and the non-anemic group. This difference was statistically significant (P <0.05).

The mean albumin values showed no statistically significant differences between both categories of anemia or those in the non-anemic group.

Patients with functional IDA had much higher mean hepcidin level, (358.9 ± 26.7 ng/mL), when compared to patients with absolute IDA, (161.8 ± 36.5), P <0.001, or nonanemic patients (172.3 ± 12.4), P <0.001.

The values of serum iron, ferritin, TSAT, iPTH, and hepcidin in patients with various categories of anemia including those without anemia are shown in [Figure 1],[Figure 2],[Figure 3],[Figure 4],[Figure 5].
Figure 1: The mean serum iron levels according to categories of anemia.

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Figure 2: The mean transferrin saturation values according to categories of anemia.

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Figure 3: The mean serum ferritin values according to categories of anemia.

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Figure 4: The mean hepcidin levels according to categories of anemia.

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Figure 5: The mean iParathormone levels according to categories of anemia.

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   Discussion Top


In our study, more than two-thirds of patients on HD proved to be anemic. This is similar to the international data, which have stated that anemia is a universal finding in patients on HD. In the United States, half of the new patients beginning HD have Hb concentrations <10 g/dL.[12],[13]

In this study, anemia was more prevalent in patients with diabetes mellitus, and this was consistent with the international data. It is evident that patients with diabetic nephropathy have more severe anemia than patients with CKD of other etiologies, and even some diabetics with only a mildly reduced GFR had an EPO deficient anemia.[14]

The main causes of iron deficiency in CKD/ ESRD are decreased iron stores, reduced iron absorption, or inflammatory blockage of use of iron.[2] The important issue is the challenge of diagnosing absolute or functional iron deficiency due to the fact that the laboratory criteria are markedly different from those in persons with normal renal function.[15]

The first reports on functional iron deficiency dated back to 1989 by MacDougall et al[9] but still, there is no generally accepted definition. In addition, there is also no consensus in the nephrology community on the upper level of ferritin.[16] All these represented challenges to this study and many other studies in this field.

Since the discovery of hepcidin in 2001 and further understanding of how it inhibits the mobilization of iron, serum hepcidin level has been speculated to be the best predictor of iron-restricted erythropoiesis.[17] In the last few years, it had been recognized that the percentage of hypochromic red cells (%HRC) is the best-established variable for the identification of functional iron deficiency.[18] The test for percentage of %HRC is not yet available in Iraq.

In this study, significantly high ferritin and hepcidin levels were seen in patients with functional IDA compared to absolute IDA and nonanemic individuals, and these findings were consistent with other studies.[19],[20],[21] Several studies have measured hepcidin concentrations in CKD but have at times produced conflicting results. A proper interpretation of these studies must consider two caveats: (a) the degree of anemia, so a normal hepcidin in CKD can be still inappropriately high for the level of anemia and (b) the response to EPO therapy.[22],[23] The study by Ashby et al confirms that administration of EPO results in a profound and sustained suppression of circulating hepcidin, which is not mediated by reduced circulating iron. In this study, all the patients received EPO alfa 50–100 IU/kg twice/week. Accordingly, the high ferritin and hepcidin values are not enough to define functional iron deficiency. The first is an acute phase reactant and the latter would be affected by other factors.

In this study, hs-CRP values were significantly higher in patients with functional iron deficiency than those with absolute iron deficiency and the nonanemic group. hs-CRP, as a marker of inflammation, has been used with elevated serum ferritin to predict high hepcidin level in stage-5 CKD. This indicates the contribution of inflammation to the percentage of functional IDA in HD patients.[7],[24],[25]

In our study, there was no statistically significant difference in albumin levels between both patients with anemia when compared with the nonanemic group. In addition, albumin level did not correlate with hepcidin level. This is in agreement with Ali et al who postulated that hepcidin was related to albumin in CKD patients, but not in HD patients.[25]

A previous Iraqi study showed a correlation between serum hepcidin levels, ferritin, hs-CRP, and IL-6 in HD patients and those with IDA. This study recruited, for an unknown reason, only female patients who already had lower hemoglobin levels due to physiological definitions.[26]

Our study showed that iPTH level was significantly higher in those with functional IDA (P <0.001). Higher phosphate and PTH levels and lower 1,25 (OH)2D and FGF23 levels were selected as independent predictors of higher hepcidin levels.[27] The high levels of circulating PTH have multiple biological effects, including an unfavorable influence on anemia in CKD patients. Possible pathogenic mechanisms of this relationship may be PTH-related direct effect on inhibition of early erythroid progenitors, endogenous EPO synthesis and RBC survival and loss. On the other side, the most acknowledged, indirect, negative effect of PTH on bone marrow cellularity is through the induction of fibrosis.[28] At the time of conducting this study, laboratory tests for 1,25 (OH) 2D and FGF23 levels were not available in Iraq, and this may be a limitation factor.

Through better removal of uremic inhibitors of erythropoiesis, adequate dialysis will improve management of anemia. Adequately delivered dialysis duration is critical to achieve adequate dialysis dose.[29],[30] In this study, the mean dialysis duration was 210 + 7.13 min which is below the desired target of 240 min or more. This reflected on the low delivered dialysis dose with mean kt/V of 1.01, which is below the desired target. Certainly, this will contribute to anemia even in the presence of adequate iron stores.

In conclusion, functional iron deficiency is common in Iraqi HD patients. Inadequate dialysis and persistent inflammatory state are critical in such high prevalence. A model that includes a composite of multiple parameters can be used to predict functional iron deficiency independent of the iron stores, which will be beneficial to avoid unnecessary and potentially harmful iron therapy.


   Acknowledgment Top


The authors would like to thank Professor Ali M. J. Al-Mudhafar, head of Hematology Department, Faculty of Medicine, University of Baghdad and Dr. Shakir M. Muhammed the editor-in-chief of the Iraqi New Medical Journal for their help in reviewing the manuscript.

Conflict of Interest: None declared.

 
   References Top

1.
World Health Organization. Nutritional Anaemias: Report of a WHO Scientific Group. Geneva, Switzerland: World Health Organization; 1968.  Back to cited text no. 1
    
2.
Astor BC, Muntner P, Levin A, Eustace JA, Coresh J. Association of kidney function with anemia: The Third National Health and Nutrition Examination Survey (1988-1994). Arch Intern Med 2002;162:1401-8.  Back to cited text no. 2
    
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Kazmi WH, Kausz AT, Khan S, et al. Anemia: An early complication of chronic renal insufficiency. Am J Kidney Dis 2001;38:803-12.  Back to cited text no. 3
    
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Brimble KS, McFarlane A, Winegard N, Crowther M, Churchill DN. Effect of chronic kidney disease on red blood cell rheology. Clin Hemorheol Microcirc 2006;34:411-20.  Back to cited text no. 4
    
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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. 5
    
6.
Roy CN, Mak HH, Akpan I, et al. Hepcidin antimicrobial peptide transgenic mice exhibit features of the anemia of inflammation. Blood 2007;109:4038-44.  Back to cited text no. 6
    
7.
Ganz T, Olbina G, Girelli D, Nemeth E, Westerman M. Immunoassay for human serum hepcidin. Blood 2008;112:4292-7.  Back to cited text no. 7
    
8.
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. 8
    
9.
Macdougall IC, Hutton RD, Cavill I, Coles GA, Williams JD. Poor response to treatment of renal anaemia with erythropoietin corrected by iron given intravenously. BMJ 1989;299: 157-8.  Back to cited text no. 9
    
10.
Rambod M, Kovesdy CP, Kalantar-Zadeh K. Combined high serum ferritin and low iron saturation in hemodialysis patients: The role of inflammation. Clin J Am Soc Nephrol 2008; 3:1691-701.  Back to cited text no. 10
    
11.
Fernández-Rodríguez AM, Guindeo-Casasús MC, Molero-Labarta T, et al. Diagnosis of iron deficiency in chronic renal failure. Am J Kidney Dis 1999;34:508-13.  Back to cited text no. 11
    
12.
U.S. Renal Data System. USRDS 2010 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2010. p. 271.  Back to cited text no. 12
    
13.
McFarlane SI, Chen SC, Whaley-Connell AT, et al. Prevalence and associations of anemia of CKD: Kidney early evaluation program (KEEP) and National Health and Nutrition Examination Survey (NHANES) 1999-2004. Am J Kidney Dis 2008;51:S46-55.  Back to cited text no. 13
    
14.
Bosman DR, Winkler AS, Marsden JT, Macdougall IC, Watkins PJ. Anemia with erythropoietin deficiency occurs early in diabetic nephropathy. Diabetes Care 2001;24: 495-9.  Back to cited text no. 14
    
15.
Kalantar-Zadeh K, Streja E, Miller JE, Nissenson AR. Intravenous iron versus erythropoiesis-stimulating agents: Friends or foes in treating chronic kidney disease anemia? Adv Chronic Kidney Dis 2009;16:143-51.  Back to cited text no. 15
    
16.
Dukkipati R, Kalantar-Zadeh K. Should we limit the ferritin upper threshold to 500 ng/ml in CKD patients? Nephrol News Issues 2007; 21:34-8.  Back to cited text no. 16
    
17.
Hugman A. Hepcidin: An important new regulator of iron homeostasis. Clin Lab Haematol 2006;28:75-83.  Back to cited text no. 17
    
18.
Thomas DW, Hinchliffe RF, Briggs C, et al. Guideline for the laboratory diagnosis of functional iron deficiency. Br J Haematol 2013;161:639-48.  Back to cited text no. 18
    
19.
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.  Back to cited text no. 19
    
20.
Tomosugi N, Kawabata H, Wakatabe R, et al. Detection of serum hepcidin in renal failure and inflammation by using ProteinChip System. Blood 2006;108:1381-7.  Back to cited text no. 20
    
21.
Malyszko J, Malyszko JS, Pawlak K, Mysliwiec M. Hepcidin, iron status, and renal function in chronic renal failure, kidney transplantation, and hemodialysis. Am J Hematol 2006;81:832-7.  Back to cited text no. 21
    
22.
Macdougall IC, Malyszko J, Hider RC, Bansal SS. Current status of the measurement of blood hepcidin levels in chronic kidney disease. Clin J Am Soc Nephrol 2010;5:1681-9.  Back to cited text no. 22
    
23.
Ashby DR, Gale DP, Busbridge M, et al. Erythropoietin administration in humans causes a marked and prolonged reduction in circulating hepcidin. Haematologica 2010;95: 505-8.  Back to cited text no. 23
    
24.
Tessitore N, Girelli D, Campostrini N, et al. Hepcidin is not useful as a biomarker for iron needs in haemodialysis patients on maintenance erythropoiesis-stimulating agents. Nephrol Dial Transplant 2010;25:3996-4002.  Back to cited text no. 24
    
25.
Ali TM, Genina AM, Abo-Salem AM. The determinants of hepcidin level in chronic kidney disease and hemodialysis Saudi patients. Beni Suef Univ J Basic Appl Sci 2014; 3:133-9.  Back to cited text no. 25
    
26.
Rasheed N, Ali SH, Mazin ZM, Al Shami AM. Serum hepcidin levels in anemia of chronic kidney diseases compared to iron deficiency anemia and its correlation with serum levels of HS-C reactive protein, interlukin 6 and ferritin. GJBB 2013;2:43-50.  Back to cited text no. 26
    
27.
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. 27
    
28.
Icardi A, Paoletti E, De Nicola L, et al. Renal anaemia and EPO hyporesponsiveness associated with Vitamin D deficiency: The potential role of inflammation. Nephrol Dial Transplant 2013;28:1672-9.  Back to cited text no. 28
    
29.
Zaritsky J, Young B, Gales B, et al. Reduction of serum hepcidin by hemodialysis in pediatric and adult patients. Clin J Am Soc Nephrol 2010;5:1010-4.  Back to cited text no. 29
    
30.
Eloot S, Van Biesen W, Dhondt A, et al. Impact of hemodialysis duration on the removal of uremic retention solutes. Kidney Int 2008;73:765-70.  Back to cited text no. 30
    

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Correspondence Address:
Dr. Ala Ali
Nephrology and Renal Transplantation Center, Medical City Teaching Hospital, Baghdad
Iraq
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DOI: 10.4103/1319-2442.225182

PMID: 29456218

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    Abstract
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