Survey on the relationship between serum concentration of iron, ferritin and some characterisitics in patients with stage 3 to 5 chronic predialysis kidney disease – Nguyen Van Hung

Journal of military pharmaco-medicine n 0 9-2018 114 SURVEY ON THE RELATIONSHIP BETWEEN SERUM CONCENTRATION OF IRON, FERRITIN AND SOME CHARACTERISITICS IN PATIENTS WITH STAGE 3 TO 5 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 3 - 5 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 3 - 5 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 successful ly 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, 1. Transport Hospital 2. Bachmai Hospital 3. 103 Military Hospital Corresponding author: Nguyen Van Hung (hunggttw@gmail.com) Date received: 15/09/2018 Date accepted: 12/11/2018 Journal of military pharmaco-medicine n 0 9-2018 115 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 1. Subjects. The study was conducted with a study group of 124 stage 3 - 5 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 3 months prior to study period; taking iron products within last 7 days; did not agree to participate in the study. 2. 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/1.73m2) 1 Kidney damage with normal or increase GFR ≥ 90 2 Kidney damage with mild decrease GFR 60 - 90 3 Moderate decrease GFR 30 - 59 4 Severe decrease GFR 15 - 29 5 Kidney failure < 15 (or dialysis) - Serum hs-CRP > 5 mg/L: diagnosed as increase. * Statistical analysis: Statistical analyses were conducted using SPSS 20.0. Journal of military pharmaco-medicine n 0 9-2018 116 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 Iron (µmoL/L) Max 31.4 41.6 Median 198.45 (68.05 - 255.22) 403.73 (211.36 - 548.42) < 0.001 Min 16.5 31 Ferritin (ng/mL) Max 383.4 1070.1 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) 3 + 4 (n = 25) 10.16 (7 - 14.58) 252.6 (177.89 - 437) 5 (n = 99) 10.7 (6.6 - 15.6) 435.5 (250.49 - 557.68) p > 0.05 < 0.05 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). Creatinine (µmoL/L) Indexes r p Correlation equation 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). Journal of military pharmaco-medicine n 0 9-2018 117 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 Iron (µmoL/L) (median) Ferritin (ng/mL) (median) hs-CRP > 5 mg/L (n = 48) 6.87 (4.35 - 12.34) 431.25 (231.5 - 567.73) hs-CRP ≤ 5 mg/L (n = 64) 11.9 (8.8 - 18.6) 385.2 (193.1 - 544.61) p 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 r p Correlation equation 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). Journal of military pharmaco-medicine n 0 9-2018 118 Chart 2: Correlation between serum iron concentration and hs-CRP. DISCUSSION As the results in table 1, we found that patients with stage 3 - 5 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 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 n 0 9-2018 119 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 4 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 1. 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. 2. 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. 3. 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, 4 (1), pp.57-61. 4. 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. Journal of military pharmaco-medicine n 0 9-2018 120 5. Kalantar-Zadeh K, R.A. Rodriguez, M.H. Humphreys. 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