高リン血症治療薬クエン酸第二鉄の新規生理学的機序の解明

• Material Type: 博士論文
• Title: 高リン血症治療薬クエン酸第二鉄の新規生理学的機序の解明
• Author/Editor: 飯田, 聡夫
• Publication Date: 2020-03-23
• Publication Date (W3CDTF): 2020-03-23
• Degree grantor/type: 新潟大学
• Date Granted: 2020-03-23
• Date Granted (W3CDTF): 2020-03-23
• Dissertation Number: 甲第4774号
• Degree Type: 博士(農学)
• Conferring No. (Dissertation): 甲第4774号
• Text Language Code: jpn
• Note (General): Anemia is present in about a third of the world’s population, and has been a serious and global public health problem that affects maternal and child mortality, and physical performance. About half of the cases are due to iron deficiency. Thus, iron deficiency anemia (IDA) is the most common, and fortunately also the most treatable of all anemias. There is an evolving understanding that iron deficiency can lead to symptoms independent of anemia and can be associated with a variety of diseases. For example, iron deficiency and iron deficiency anemia (IDA) are important signs of gastrointestinal hemorrhage. Two main mechanisms are known to exist in induction of iron deficiency. One involves absolute deficiency, and the other pertains to functional deficiency. Absolute iron deficiency means that total body iron stores are low or exhausted, and functional iron deficiency is a status of functional failure in iron supply. Functional iron deficiency can be induced in several chronic inflammatory diseases, including chronic kidney disease (CKD). Patients with CKD frequently develop many complications, including hyperphosphatemia, ectopic calcification, secondary hyperparathyroidism, and anemia. Among them, CKD mineral bone disorders (CKD-MBD), including hyperphosphatemia, are associated with an increased risk of fracture, cardiovascular disease, and death. Therefore, CKD patients with hyperphosphatemia require treatment with phosphate binders to restore phosphate balance, in addition to treatment for anemia. In such a treatment environment for CKD, iron-containing phosphate binders are used for hyperphosphatemia. Among them, ferric citrate is an iron-based compound with distinctive chemical characteristics and a mechanism of action that render it dually effective as a therapy in patients with CKD; it has been approved as a phosphate binder for the control of serum phosphate levels in adult CKD patients treated with dialysis and as an iron replacement product for the treatment of IDA in adult CKD patients not treated with dialysis. It has been reported that ferric citrate improved hyperphosphatemia, and increased in hemoglobin, transferrin saturation (TSAT), and ferritin. Based on the clinical results of studies in patients with nondialysis-dependent CKD, ferric citrate could be a safe and efficacious treatment for IDA. From these clinical results, there is a possibility that ferric citrate could exert not only phosphate reducing effect, but also hematopoietic effect in advanced CKD patients. It is expected that, in theory, successful treatment of hyperphosphatemia and anemia in patients with CKD could help avoid adverse clinical outcomes; however, with the exception of renal replacement, no interventions have yet been proven to improve outcomes. As mentioned above, IDA is common not only in CKD patients, but also in patients with other diseases. In such IDA patients with normal renal function, although it is possible that treatment with ferric citrate could improve iron deficiency anemia, ferric citrate might also reduce serum phosphorus level by inhibiting phosphorus absorption. However, actual clinical usage of ferric citrate for IDA patients has not been reported yet. Therefore, whether ferric citrate can improve iron deficiency anemia without affecting phosphorus metabolism in IDA patients with normal renal function remains unknown. On the other hand, from the viewpoint of iron repletion, it is possible that ferric citrate might induce oxidative stress via excess absorption of iron. In general, it is thought that administration of iron agents can result in excessive iron existing in the body as unstable iron that does not bind to transferrin, etc., leading to oxidative stress and organ damage. In addition, administration of intravenous iron has also been reported to increase oxidative stress markers. Thus, the overall effects of ferric citrate on oxidative stress also remain unclear. To further understand the potential of ferric citrate as treatment for iron deficiency anemia, we examined the effects on anemia- and phosphorus metabolismrelated parameters and oxidative stress in non-treated and iron-insufficient rats. [Non-treated rat study] In this study, we examined the effects of ferric citrate on both anemia-related parameters and phosphorus metabolism-related parameters in non-treated rats. Nontreated rats were fed a diet containing 0.3 or 3% ferric citrate for 11 days. The effects of ferric citrate on iron status- and phosphorus metabolism-related parameters were evaluated using blood and urine samples. Regarding anemia-related parameters, serum iron concentration and TSAT were increased by 3% ferric citrate treatment, although no changes were seen in hemoglobin or red blood cell (RBC) levels. Therefore, it was considered that a portion of the administered iron was absorbed into the body, and that 3% ferric citrate treatment could affect iron status. Regarding phosphorus metabolism parameters, serum phosphorus concentration and urinary phosphorus excretion in 3% Ferric citrate group were significantly decreased. As an additional investigation regarding phosphorus metabolism, it was shown that 3% ferric citrate treatment significantly decreased intact fibroblast growth factor 23 (iFGF23) level. These results suggested that 3% ferric citrate treatment exerted phosphorus-reducing effects and supplemented iron into the body. On the other hand, 0.3% ferric citrate treatment did not induce any significant changes in serum iron concentration, TSAT, hemoglobin or RBC level, indicating that little iron would be absorbed due to the homeostasis of iron in this normal condition (Non-treated rat study). Furthermore, 0.3% ferric citrate treatment did not show significant decrease in serum phosphorus level or urinary phosphorus excretion. Taken together, it is possible that 0.3% ferric citrate treatment would not affect phosphorus metabolism in non-treated rats with normal renal function. [Iron deficiency anemia rat study] Next, we examined the effects of 0.3% ferric citrate treatment on iron status and phosphorus metabolism in rats with an iron-insufficient condition. Iron deficiency anemia was induced by feeding iron-depleted diet to rats (Day 1). Seven days after starting the iron-depleted diet (Day 8), 0.3% ferric citrate was administered for 7 days by dietary admixture (~Day 15). Iron status- and phosphorus metabolismrelated parameters were evaluated using blood and urine samples. The results showed that first, iron-depleted diet induced reduction in serum iron concentration, TSAT, and hemoglobin level, leading to anemic condition; next, 0.3% ferric citrate treatment increased parameters related to iron status and improved anemia (serum iron level, TSAT and hemoglobin), but did not show any apparent changes in phosphorus metabolism-related parameters (serum phosphorus level, iFGF23 level, and urinary excretion of phosphorus). It was thus shown that 0.3% ferric citrate treatment could exert hematopoietic effects without inhibiting phosphorus absorption in iron deficiency anemia rats with normal renal function. [Effects on an oxidative stress marker] To examine effects on oxidative stress, rats were given intravenous administration of saccharated ferric oxide or oral administration of ferric citrate, and blood samples were collected via tail vein to measure serum malondialdehyde (MDA) concentration, an oxidative stress marker, as thiobarbituric acid reactive substance (TBARS) concentration. In addition, serum iron concentration and unsaturated iron-binding capacity (UIBC) were measured at each time point. Serum TBARS concentration was significantly increased from 5 minutes to 1 hour after intravenous administration of saccharated ferric oxide (2 mg / kg as iron). On the other hand, no significant change was observed from 5 minutes to 1 hour after oral administration of ferric citrate hydrate (100 mg / kg, 20.3 mg / kg as iron). In addition, serum iron concentration was increased rapidly 5 minutes after administration of saccharated ferric oxide, and it decreased to the level before administration 2 hours later. UIBC was not changed significantly throughout the experimental period. In contrast, when ferric citrate hydrate was administered orally, the serum iron concentration was increased 30 minutes after administration, and decreased to the level before administration 24 hours later. UIBC was decreased from 30 minutes after administration, and recovered to the level before administration after 24 hours. The above results obtained using serum MDA concentration as an index of oxidative stress confirmed that an intravenous iron agent could induce oxidative stress. Most of the serum iron increased by oral administration of ferric citrate hydrate would bind to transferrin and would be stable, whereas most of the serum iron increased by intravenous iron administration would not bind to transferrin, resulting in induction of non transferrin-bound iron (unstable iron). As a result, some unstable iron might cause oxidative stress. In conclusion, ferric citrate could have hematopoietic effects without affecting phosphorus metabolism and oxidative stress, and could be a potential option for the treatment of IDA in patients without CKD.; 新大院博(農)甲第205号; 開始ページ : 1; 終了ページ : 61
• Persistent ID (NDL): info:ndljp/pid/11538596; https://dl.ndl.go.jp/pid/11538596
• Collection: 障害者向け資料
• Collection (Materials For Handicapped People:1): テキストデータ
• Collection (particular): 国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文; https://dl.ndl.go.jp/collections/A00014
• Acquisition Basis: 博士論文（自動収集）
• Date Accepted (W3CDTF): 2020-09-07T06:04:08+09:00
• Date Created (W3CDTF): 2020-08-31
• Format (IMT): application/pdf
• Access Restrictions: 国立国会図書館内限定公開
• Service for the Digitized Contents Transmission Service: 図書館・個人送信対象外
• Availability of remote photoduplication service: 可
• Periodical Title (URI): http://hdl.handle.net/10191/00051785
• Data Provider (Database): 国立国会図書館 : 国立国会図書館デジタルコレクション; https://dl.ndl.go.jp