Objectives: To evaluate the relationship between serum iron and ferritin concentrations with some characteristics of chronic kidney diseases. Subjects and methods: A cross-sectional study with a study group of 124 stage 3 - 5 chronic kidney disease patients, and a control group of 66 healthy people at Department of Nephrology and Hemodialysis, 103 Military Hospital.
Journal of military pharmaco-medicine n09-2018 SURVEY ON THE RELATIONSHIP BETWEEN SERUM CONCENTRATION OF IRON, FERRITIN AND SOME CHARACTERISITICS IN PATIENTS WITH STAGE TO CHRONIC PREDIALYSIS KIDNEY DISEASE Nguyen Van Hung1, Nguyen Cao Luan2; Le Viet Thang3 SUMMARY Objectives: To evaluate the relationship between serum iron and ferritin concentrations with some characteristics of chronic kidney diseases Subjects and methods: A cross-sectional study with a study group of 124 stage - chronic kidney disease patients, and a control group of 66 healthy people at Department of Nephrology and Hemodialysis, 103 Military Hospital Results: The mean concentrations of serum iron in study group was significantly lower than control group (10.7 µmol/L versus 15.81 µmol/L), but the mean concentrations of serum ferritin in study group was higher than control group (403.73 ng/mL versus 198.45 ng/mL) with p < 0.01 Serum ferritin concentration was significantly related with the stage of chronic kidney diseas (p < 0.05) Iron level was positively correlated with serum creatinine level (r = 0.201; p < 0.05) and negatively correlated with hs-CRP level (r = -0.229; p < 0.05) Conclusion: Patients with stage - chronic kidney diseas, predialysis had lower serum iron and higher serum ferritin concentrations than control group There were significant correlations between serum iron with serum creatinine concentrations and hs-CRP levels * Keywords: Chronic kidney disease; Serum iron; Serum ferritin INTRODUCTION Anemia of chronic kidney disease (CKD) is widely prevalent in patients with renal impairment and is associated with significant morbidity and mortality [6] Deficient erythropoietin (EPO) production and reduced bioavailability of iron ultimately lead to absolute or functional iron deficiency anaemia Anaemia of end-stage renal disease can be managed relatively successf ully by recombinant human erythropoietin 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 [1, 5] Absolute iron deficiency, the iron deficiency that is characterized by low or absent bone marrow staining for iron, is distinguished from functional or relative iron deficiency, Transport Hospital Bachmai Hospital 103 Military Hospital Corresponding author: Nguyen Van Hung (hunggttw@gmail.com) Date received: 15/09/2018 Date accepted: 12/11/2018 114 Journal of military pharmaco-medicine n09-2018 which is defined as a response to intravenous iron with an increase in hemoglobin (Hb) or a decrease in erythropoiesis-stimulating agent (ESA) requirement [9] Therefore, we conducted this research in order: To find the relationship between serum iron, ferritin concentrations and stage of CKD, serum creatinine and hs-CRP level SUBJECTS AND METHODS Subjects The study was conducted with a study group of 124 stage - chronic kidney diseas (CKD) patients, prediaysis and a control group of 66 healthy people at Department of Nephrology and Hemodialysis, 103 Military Hospital * Criteria exclusion: Blood transfusion, active bleeding, some acute diseases, undergoing surgery within months prior to study period; taking iron products within last days; did not agree to participate in the study Methods * Study design: A cross-sectional descriptive study * Serum iron concentrations measurement: Quantification of serum iron concentrations by color comparison following the principle: Fe3+ is released from the transferrin-Fe complex at pH < 2.0; Fe3+ in the acid environment will be reduced to Fe2+ Fe2+ combine with ferrozine buffers to form a color complex After that, the test is conducted on the Cobas 6000 system with Roche's kit * Serum ferritin concentrations measurement: Quantification of serum ferritin by immunohistochemistry on the Cobas 6000 system with Roche's kit * Diagnostic criteria: - Stages of CKD: K/DOQI 2002 [2]: Table 1: Stage Description GFR (mL/min/1.73m ) Kidney damage with normal or increase GFR ≥ 90 Kidney damage with mild decrease GFR 60 - 90 Moderate decrease GFR 30 - 59 Severe decrease GFR 15 - 29 Kidney failure < 15 (or dialysis) - Serum hs-CRP > mg/L: diagnosed as increase * Statistical analysis: Statistical analyses were conducted using SPSS 20.0 115 Journal of military pharmaco-medicine n09-2018 RESULTS The study group with average age was 52.65 years old, there were 72.6% male; 27.4% female, mean glomerular filtration rate was 8.3 mL/min Table 2: Iron and ferritin concentrations between study group and control group Indexes Control group (n = 66) Study group (n = 124) p Median 15.81 (11.56 - 19.26) 10.7 (6.62 - 15.25) < 0.001 Min 7.3 2.1 Max 31.4 41.6 Median 198.45 (68.05 - 255.22) 403.73 (211.36 - 548.42) Min 16.5 31 Max 383.4 1070.1 Iron (µmoL/L) Ferritin (ng/mL) < 0.001 The concentrations of serum iron in study group was significantly lower than control group (10.7 µmoL/L versus 15.81 µmoL/L) with p < 0.001 The concentrations of serum ferritin in study group was higher than control group with p < 0.001 (403.73 ng/mL versus 198.45 ng/L) Table 3: Relation between iron, ferritin concentrations and stage of CKD in study group (n = 124) Stage of CKD Iron (µmoL/L) (median) Ferritin (ng/mL) (median) + (n = 25) 10.16 (7 - 14.58) 252.6 (177.89 - 437) (n = 99) 10.7 (6.6 - 15.6) 435.5 (250.49 - 557.68) > 0.05 < 0.05 p Our results showed that serum ferritin concentrations were significantly related with the stages of CKD (p < 0.05) However, serum iron concentrations were not significantly related with the stages of CKD (p > 0.05) Table 4: Correlation between serum iron, ferritin concentrations and serum creatinine (n = 124) Indexes Creatinine (µmoL/L) Correlation equation r p Iron (µmoL/L) 0.201 < 0.05 Iron = 0.004 x creatinine + 9.48 Ferritin (ng/mL) 0.172 > 0.05 - Serum iron concentration was positively correlated with serum creatinine concentration (r = 0.201, p < 0.05), whereas ferritin level was not correlated with serum creatinine levels (p > 0.05) 116 Journal of military pharmaco-medicine n09-2018 Chart 1: Correlation between serum iron concentration and serum creatinine Table 5: Relation between serum iron, ferritin concentrations and hs-CRP (n = 112) hs-CRP status hs-CRP > mg/L (n = 48) hs-CRP ≤ mg/L (n = 64) p Iron (µmoL/L) Ferritin (ng/mL) (median) (median) 6.87 431.25 (4.35 - 12.34) (231.5 - 567.73) 11.9 385.2 (8.8 - 18.6) (193.1 - 544.61) < 0.001 > 0.05 In patients with elevated hs-CRP levels, serum iron concentrations were significantly lower than those without elevated hs-CRP (p < 0.001) In contrast, serum ferritin concentrations in patients who elevated hs-CRP was not significantly higher than non elevated hs-CRP group with p > 0.05 Table 6: Correlation between serum iron, ferritin concentrations and hs-CRP (n = 112) hs-CRP (mg/L) Indexes Correlation equation r p Iron (µmoL/L) -0.229 < 0.05 Iron = 12.886 - 0.073 x CRP Ferritin (ng/mL) 0.064 > 0.05 - There was no correlation between serum ferritin concentration and hs-CRP level, but there was a negative correlation between iron and hs-CRP levels (r = -0.229; p < 0.05) 117 Journal of military pharmaco-medicine n09-2018 Chart 2: Correlation between serum iron concentration and hs-CRP DISCUSSION As the results in table 1, we found that patients with stage - CKD had lower serum iron concentrations and higher serum ferritin concentrations than control group Malyszko J’s study also showed that the average concentrations of serum iron and ferritin in chronic kidney failure was lower than control group significantly (with p < 0.05 and 0.001, respectively) [8] Serum ferritin is frequently used as a marker of iron status in CKD patients Serum ferritin concentrations results from the leakage of tissue ferritin, an intracellular iron storage protein shell with a molecular weight of about 450 kDa, containing heavy (H) and light (L) subunits Serum ferritin is slightly different than tissue ferritin and contains little or no iron While tissue ferritin clearly plays a role in intracellular iron handling, the role of serum ferritin is less clearly understood The level of ferritin in plasma represents the balance between its secretion, which is directly related to intracellular iron synthesis, and its 118 clearance, mainly in liver and other organs [4] However, liver dysfunction and inflammatory factors may interfere with the synthesis and clearance of ferritin, thereby increasing serum ferritin levels due to circumstances not related to iron metabolism Our results showed that serum ferritin concentration was significantly related to the stages of CKD We also created the correlation equation between serum iron and creatinine concentrations (iron = 0.004 x creatinine + 9.48) These results were similar to Fishbane S that among women, there was a trend toward lower decreasing mean transferrin satuation for progressively lower levels of renal function (p < 0.02), and a statistically significant trend toward increasing serum ferritin for progressively lower levels of renal function (p < 0.0001) [3] Iron is a vital element for numerous bodily functions, most notably as an ingredient of hemoglobin Most healthy people can achieve a stable iron balance, managing to ingest the required Journal of military pharmaco-medicine n09-2018 amount of iron in the diet to compensate for the small amount of daily iron loss 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 iron losses, so serum iron concentrations mostly decreased In our study, it had an increasing in serum ferritin concentrations The possible explanation is the effect of inflammation It is well known that occult inflammation is commonly present in CKD and may increase in prevalence with progressive disease [7] 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 [3] In table and 5, we found that serum iron concentrations in patients who elevated hs-CRP was significantly lower than non elevated hs-CRP group, and there was no correlation between ferritin and hs-CRP levels Kalantar-Zadeh K’s study also showed that there was a positive correlation between serum ferritin and serum hs-CRP concentrations [5] Inflammation has been implicated in several complications in CKD, including malnutrition and accelerated atherosclerosis It also blunts the iron utilization and induces resistance to erythropoietin therapy The exact pathway by 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, it may also be elevated during 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 concentrations of serum iron in study group was significantly lower than control group (p < 0.001), but the concentration of serum ferritin in study group was higher than control group with p < 0.001 Serum ferritin concentration was significantly related to the stages of CKD (p < 0.05) Iron levels were positively correlated with serum creatinine level (r = 0.201; p < 0.05) and negatively correlated with hs-CRP level (r = -0.229; p < 0.05) REFFERENCES Dignass A, Farrag K, Stein J Limitations of serum ferritin in diagnosing iron deficiency in inflammatory conditions J Chronic Dis 2018, Mar 18;2018:9394060 doi: 10.1155/2018/9394060 eCollection 2018 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.564-572 119 Journal of military pharmaco-medicine n09-2018 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.141-9 Krishnan A et al Anaemia of chronic kidney disease: What We Know Now 2017, Vol 1, p.11 Landray M.J et al Inflammation, endothelial dysfunction, and platelet activation 120 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, Suppl 1, pp.S4-S8 ... 0.001 Min 7 .3 2.1 Max 31 .4 41.6 Median 198. 45 (68. 05 - 255 .22) 4 03. 73 (211 .36 - 54 8.42) Min 16 .5 31 Max 38 3.4 1070.1 Iron (µmoL/L) Ferritin (ng/mL) < 0.001 The concentrations of serum iron in study... requirement [9] Therefore, we conducted this research in order: To find the relationship between serum iron, ferritin concentrations and stage of CKD, serum creatinine and hs-CRP level SUBJECTS AND METHODS... However, serum iron concentrations were not significantly related with the stages of CKD (p > 0. 05) Table 4: Correlation between serum iron, ferritin concentrations and serum creatinine (n = 124) Indexes