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Objectives: To evaluate the serum iron and ferritin oncentrations in patients with chronic kidney disease (CKD) predialysis and its relation with stages of CKD and some other features. Subjects and methods: A cross-sectional study on a group of 175 patients with CKD stage 3 - 5 and a control group of 51 healthy people at Department of Nephrology and Hemodialysis, 103 Military Hospital.
JOURNAL OF MILITARY PHARMACO-MEDICINE N09-2017 SURVEY OF SERUM IRON AND FERRITIN CONCENTRATIONS IN PATIENTS WITH STAGE TO CHRONIC KIDNEY DISEASE Nguyen Van Hung*; Nguyen Cao Luan**; Le Viet Thang*** SUMMARY Objectives: To evaluate the serum iron and ferritin concentrations in patients with chronic kidney disease (CKD) predialysis and its relation with stages of CKD and some other features Subjects and methods: A cross-sectional study on a group of 175 patients with CKD stage - and a control group of 51 healthy people at Department of Nephrology and Hemodialysis, 103 Military Hospital Results: The average concentrations of serum iron in study group was significantly lower than control group (12.87 ± 6.85 µmol/L versus 16.57 ± 5.83 µmol/L), but the average concentrations of serum ferritin in study group was higher than in the control group (308.59 ± 178.41 ng/mL versus 159.89 ± 87.98 ng/mL) with p < 0.01 Serum iron and ferritin concentrations were significantly associated with the stages of CKD (p < 0.05) Ferritin levels were positively correlated with serum creatinine levels (r = 0.256; p < 0.01) and hs-CRP levels (r = 0.383; p < 0.001) Conclusion: Patients with stage - CKD, predialysis had lower serum iron and higher serum ferritin concentrations compared to control group There was significant correlation between serum iron, ferritin with serum creatinine concentrations and hs-CRP levels * Keywords: Chronic kidney disease; Serum iron; Serum ferritin; Predialysis INTRODUCTION Chronic kidney disease is a worldwide public health problem with an increasing incidence and prevalence, poor outcomes and high cost Chronic kidney disease causes not only kidney failure but also complications of decreased kidney function and cardiovascular disease [5] Anaemia of chronic kidney disease (CKD) is widely common in patients with renal impairment and is associated with significant morbidity and mortality Deficient erythropoietin (EPO) production and reduced bioavailability of iron ultimately lead to absolute or functional iron deficiency anaemia Anaemia of endstage renal disease can be managed successfully by recombinant human EPO Iron administration plays a central role in enhancing anaemia responsiveness to EPO Serum ferritin concentrations and iron saturation ratio are among the two most commonly used markers of iron status in maintenance dialysis patients [4] Absolute iron deficiency, the iron deficiency that is characterized by low orabsent bone marrow staining for iron, is to be distinguished from functional or * Transport Hospital ** Bachmai Hospital ** 103 Military Hospital Corresponding author: Nguyen Van Hung (hunggttw@gmail.com) Date received: 04/10/2017 Date accepted: 22/11/2017 163 JOURNAL OF MILITARY PHARMACO-MEDICINE N09-2017 relative iron deficiency, which is defined within last days; did not agree to participate as a response to intravenous iron with an in the study increase in hemoglobin (Hb) or a decrease Methods in erythropoiesis-stimulating agent (ESA) * Study design: A cross-sectional requirement [8] Therefore, we conducted this research aiming: To assess the descriptive study serum iron and ferritin concentrations in - Serum iron concentrations measurement: patients with stage - CKD and its Quantification of serum iron concentrations relation with stages of CKD, serum creatinine by color comparison following the principle: concentrations and hs-CRP Fe3+ is released from the transferrin-Fe SUBJECTS AND METHODS complex at pH < 2.0; Fe3+ in the acid environment will be reduced to Fe2+ Fe2+ Subjects combined with ferrozine buffers to form a The study was conducted on a group of 175 patients with CKD stage - 5, predialysis and a control group of 51 healthy people at Department of Nephrology and color complex After that, the test is conducted on the Cobas 6,000 system with Roche's kit - Hemodialysis, 103 Military Hospital * Excluding criteria: Blood transfusion, acute bleeding, some acute diseases, being performed surgery within months Serum ferritin concentrations measurement: Quantification of serum ferritin by immunohistochemistry on the Cobas 6,000 system with Roche's kit prior to study period; taking iron products * Diagnostic criteria: Table 1: Stages of CKD: K/DOQI 2002 [1] Stage Description ≥ 90 Kidney damage with normal or increase GFR Kidney damage with mild decrease GFR 60 - 90 Moderate decrease GFR 30 - 59 Severe decrease GFR 15 - 29 Kidney failure - Serum hs-CRP > mg/L: diagnosed as increase * Statistical analysis: Statistical analyses were conducted using SPSS 20.0 164 GFR (mL/min/1.73m ) < 15 (or dialysis) JOURNAL OF MILITARY PHARMACO-MEDICINE N09-2017 RESULTS AND DISCUSSION The study group with an average age of 53.26 years old, 69.1% male, 30.9% female There was not significant difference compared to those of control group Table 2: Iron and ferritin concentrations between study group and control group Indexes Iron* (µmoL/L) Ferritin* (ng/mL) Control group (n = 51) Study group (n = 175) p average 16.57 ± 5.83 12.87 ± 6.85 < 0.01 7.8 2.0 max 41.8 38.7 average 159.89 ± 87.98 308.59 ± 178.41 10.6 35.1 max 501.8 698.6 < 0.001 In our study, the average concentrations weight of about 450 kDa, containing of serum iron in study group was significant heavy (H) and light (L) subunits Serum lower than control group (12.87 µmol/L ferritin is slightly different than tissue versus 16.57 µmol/L) with p < 0.01 The ferritin and contains little or no iron While average concentrations of serum ferritin in tissue ferritin clearly plays a role in study group was higher than in the control intracellular iron handling, the role of group with p < 0.01 (308.59 ng/mL versus serum ferritin is less clearly understood 159.89 ng/mL) The study by Malyszko J The level of ferritin in plasma represents also showed that the average concentrations the balance between its secretion, which of serum iron and ferritin in chronic kidney is directly related to intracellular iron synthesis failure was significantly lower than control and its clearance, mainly in liver and other group (with p < 0.05 and 0.001, respectively) organs [3] However, liver dysfunction and [7] Serum ferritin is a frequently used inflammatory factors may interfere with marker of iron status in CKD patients the synthesis and clearance of ferritin, Serum ferritin concentration results from thereby increasing serum ferritin levels the leakage of tissue ferritin, an intracellular due to circumstances unrelated to iron iron storage protein shell with a molecular metabolism 165 JOURNAL OF MILITARY PHARMACO-MEDICINE N09-2017 Table 3: Relationship between iron, ferritin concentrations and stages of CKD in study group (n = 175) Stages of CKD Iron (µmol/L) X ± 2SD Ferritin (ng/mL) X ± 2SD (n = 31) 16.31 ± 6.56 197.46 ± 50.85 (n = 35) 13.88 ± 6.26 261.70 ± 141.19 (n = 109) 11.57 ± 6.77 355.25 ± 194.51 < 0.01 < 0.001 pANOVA Our results showed that serum iron and ferritin concentrations were significantly associated with the stages of CKD (p < 0.01) Patients with stage CKD had the highest levels of serum iron and the lowest levels of serum ferritin, while the patients with stage CKD had the lowest iron concentrations and the highest serum ferritin concentrations Table 4: Correlation between serum iron, ferritin concentrations and serum creatinine (n = 175) Creatinine (µmol/l) Indexes Correlation equation r p Iron (µmol/L) -0.103 > 0.05 Ferritin (ng/mL) 0.256 < 0.01 Serum iron concentrations was not correlated with serum creatinine concentrations, whereas ferritin levels were positively correlated with serum creatinine levels (r = 0.256; p < 0.01) Our results in table and showed that serum iron and ferritin concentrations were significantly associated with the stage of CKD as well as the serum creatinine concentration These results were similar to those by Fishbane S’ (the same subjects): among women, there was a trend toward lower decreasing mean TSAT for progressively lower levels of renal function (p < 0.02) and a statistically significant trend toward increasing serum 166 Ferritin = 0.121 x creatinine + 240.46 ferritin for progressively lower levels of renal function (p < 0.0001) [2] Iron is a vital element for numerous body functions, most notably as an ingredient of hemoglobin (Hb) Most healthy people can achieve a stable iron balance, managing to ingest the required amount of iron in the diet to compensate for the small amount of daily loss iron from the gut However, many patients with advanced CKD are in negative iron balance as a result of reduced dietary intake, impaired absorption from the gut and increased loss iron, so serum iron concentrations mostly decreased In our study, there was an increase in serum ferritin JOURNAL OF MILITARY PHARMACO-MEDICINE N09-2017 concentrations It is likely due to the effect of inflammation It is well known that occult inflammation is commonly present in CKD and may increase with progressive disease [6] Inflammation has a profound effect on iron indices Previously, in hemodialysis, hs-CRP, an indicator of inflammation, was found to be highly correlated with serum ferritin values [2] Ferritin = 0.121xCreatinine + 240.46 800 700 600 Ferritin 500 400 300 200 100 Creatinine 500 1000 1500 2000 2500 Chart 1: Correlation between serum ferritin concentration and serum creatinine Table 5: Relationship between serum iron, ferritin concentrations and hs-CRP (n = 175) hs-CRP status Iron (µmol/L) X ± 2SD Ferritin (ng/mL) X ± 2SD hs-CRP > mg/L (n = 52) 11.71 ± 6.97 411.03 ± 177.65 hs-CRP ≤ mg/L (n = 123) 13.36 ± 6.77 265.28 ± 160.75 > 0.05 < 0.001 p In patients with elevated hs-CRP levels, serum iron concentrations were significantly lower than those without elevated hs-CRP, but the difference was not statistically significant (p > 0.05) By contrast, serum ferritin concentrations in patients who elevated hs-CRP was significantly higher than non elevated hs-CRP group with p < 0.001 167 JOURNAL OF MILITARY PHARMACO-MEDICINE N09-2017 Table 6: Correlation between serum iron, ferritin concentrations and hs-CRP (n = 175) hs-CRP (mg/l) Indexes Correlation equation r p Iron (µmol/L) -0.117 > 0.05 Ferritin (ng/mL) 0.383 < 0.001 Ferritin = 23.52 x CRP + 223.26 There was no correlation between serum iron concentrations and hs-CRP levels, but there was a positive correlation between ferritin and hs-CRP levels (r = 0.383; p < 0.001) Ferritin = 0.121xCreatinine + 240.46 800 700 600 Ferritin 500 400 300 200 100 0 500 Creatinine 1000 1500 2000 2500 Chart 2: Correlation between serum ferritin concentration and hs-CRP In table and 6, we found that serum ferritin concentration in patients who elevated hs-CRP was significantly higher than non elevated hs-CRP group and there was a positive correlation between ferritin and hs-CRP levels The study by KalantarZadeh K also showed that there was a possitive correlation between serum ferritin and serum hs-CRP concentration (r = 0.31; p = 0.005) [4] Inflammation has been implicated in several complications in CKD, including malnutrition and accelerated 168 atherosclerosis It also blunts the iron utilization and induces resistance to erythropoietin therapy The exact pathway which the inflammatory cascade results in erythropoietin resistance is not completely understood It has been hypothesized that inflammatory activators have a pro-apoptotic effect on erythroid progenitor cells and compete with the anti-apoptotic effect of erythropoietin, the end result being erythropoietin resistance Serum ferritin is also an acute phase reactant which may JOURNAL OF MILITARY PHARMACO-MEDICINE N09-2017 also be elevated during an inflammation Thus, an elevation of serum ferritin can be due to an increase in body iron stores or an inflammation, both of which are hazardous in patients with CKD CONCLUSIONS In our study, the average concentration of serum iron in study group was significantly lower than that in the control group (12.87 ± 6.85 µmol/L versus 16.57 ± 5.83 µmol/L), but the average concentration of serum ferritin in study group was higher than that in the control group (308.59 ± 178.41 ng/mL versus 159.89 ± 87.98 ng/mL) with p < 0.01 Serum iron and ferritin concentrations were significantly associated with the stages of CKD (p < 0.01) Ferritin levels were positively correlated with serum creatinine levels (r = 0.256; p < 0.01) and hs-CRP levels (r = 0.383; p < 0.001) REFFERENCES K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification Am J Kidney Dis 2002 39 (2 Suppl 1), pp.S1-266 Fishbane S et al Iron indices in chronic kidney disease in National Health and Nutritional Examination Survey 1988 - 2004 Clin J Am Soc Nephrol 2009 (1), pp.57-61 Kalantar-Zadeh K et al Serum ferritin is a marker of morbidity and mortality in hemodialysis patients Am J Kidney Dis 2001, 37 (3), pp.564-572 Kalantar-Zadeh K, R.A Rodriguez, M.H Humphreys Association between serum ferritin and measures of inflammation, nutrition and iron in haemodialysis patients Nephrol Dial Transplant 2004 19 (1), pp.141-149 Krishnan A et al Anaemia of chronic kidney disease: What We Know Now 2017, Vol 1, 11 Landray M.J et al Inflammation, endothelial dysfunction and platelet activation in patients with chronic kidney disease: the chronic renal impairment in Birmingham (CRIB) study Am J Kidney Dis 2004, 43 (2), pp.244-253 Malyszko J et al Hepcidin, iron status and renal function in chronic renal failure, kidney transplantation and hemodialysis Am J Hematol 2006, 81 (11), pp.832-837 Wish J.B Assessing iron status: beyond serum ferritin and transferrin saturation Clin J Am Soc Nephrol 2006, 1, Suppl 1, pp.S4-S8 169 ... serum iron and ferritin concentrations in - Serum iron concentrations measurement: patients with stage - CKD and its Quantification of serum iron concentrations relation with stages of CKD, serum. .. between iron, ferritin concentrations and stages of CKD in study group (n = 1 75) Stages of CKD Iron (µmol/L) X ± 2SD Ferritin (ng/mL) X ± 2SD (n = 31 ) 16 .31 ± 6 .56 197.46 ± 50 . 85 (n = 35 ) 13. 88... between serum iron, ferritin concentrations and serum creatinine (n = 1 75) Creatinine (µmol/l) Indexes Correlation equation r p Iron (µmol/L) -0.1 03 > 0. 05 Ferritin (ng/mL) 0. 256 < 0.01 Serum iron concentrations