今日の臨床サポート

腎性貧血

著者: 西 慎一 神戸大学大学院医学研究科腎臓内科/腎・血液浄化センター

監修: 岡田浩一 埼玉医科大学 腎臓内科

著者校正/監修レビュー済:2021/01/20
参考ガイドライン:
  1. 日本透析医学会:2015年版 日本透析医学会 慢性腎臓病患者における腎性貧血治療のガイドライン
患者向け説明資料

概要・推奨   

  1. 腎性貧血の診断には、血中エリスロポエチン濃度測定は有用でないという意見もある。しかし、腎機能が軽度低下例でもエリスロポエチン産生が低下する症例もあり、腎性貧血の診断に血中エリスロポエチン濃度は参考となる(推奨度2)。
  1. 日本人血液透析患者のHb値目標値を10~12g/dlに維持することは、生命予後を良好に保つために推奨される(推奨度2)。
  1. 腎生貧血の治療は、QOLの改善の中でもvitalityを改善するので推奨される(推奨度2)。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
西 慎一 : 講演料(協和キリン,中外製薬),奨学(奨励)寄付など(協和キリン,中外製薬)[2021年]
監修:岡田浩一 : 講演料(協和キリン,中外製薬,田辺三菱,第一三共),研究費・助成金など(協和キリン),奨学(奨励)寄付など(協和キリン,中外製薬,田辺三菱,第一三共,アステラス,MSD,武田薬品,鳥居薬品,ファイザー,ノバルティス,日本ベーリンガーインゲルハイム,大塚製薬,塩野義,大日本住友)[2021年]

改訂のポイント:
  1. 定期レビューを行った。また、2019年度末に新たな腎性貧血治療薬、HIF-PH阻害薬(HIF-PH inhibitor)の市場への登場があり、本剤の使用法について追加記載した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 腎性貧血は、腎障害に伴い出現する貧血であり、その主たる原因は腎臓から産生される赤血球産生刺激因子であるエリスロポエチンの低下である。
  1. しかし、それのみが原因ではなく、腎障害に伴い発生する尿毒症、酸化ストレス、慢性炎症などによる赤血球産生の抑制、あるいは赤血球寿命の短縮なども原因として関与している。
  1. 腎性貧血は、腎機能低下を指標としてみた場合は、慢性腎臓病ステージでいえば、ステージG3以降に認められることがほとんどである。そして、腎機能が低下するにつれ腎性貧血は増加する。
  1. ほとんどの腎性貧血症例では、血中エリスロポエチンレベルは正常上限をやや超えた約50国際単位(IU)/ml未満にとどまる。
問診・診察のポイント  
  1. 腎性貧血の問診症状としては、貧血疾患に共通してみられる全身倦怠感、労作時息切れ、動悸などが聴取される。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

著者: Ferruh Artunc, Teut Risler
雑誌名: Nephrol Dial Transplant. 2007 Oct;22(10):2900-8. doi: 10.1093/ndt/gfm316. Epub 2007 Jun 7.
Abstract/Text BACKGROUND: Renal anaemia is caused by a relative erythropoietin (EPO) deficiency. Due to difficult interpretation of serum EPO concentrations adapted to anaemia and renal function, the diagnostic value of measuring serum EPO concentrations is limited.
METHODS: We retrospectively analysed the relationship between haemoglobin and serum EPO concentrations routinely measured in in- and out-patients of our university hospital from 2001-04. Patients under EPO substitution or those with acute renal failure, polycystic kidney disease, renal carcinoma or polycythaemia due to pulmonary disease were excluded. The study population (n = 500) was then stratified according to the presence or absence of chronic kidney disease (CKD) and to the stage if CKD was present. EPO concentrations were expressed in percentiles corrected for the severity of anaemia and based on the EPO response in patients without CKD.
RESULTS: In patients without CKD (n = 167) there was a strong parametric correlation between severity of anaemia and increase in EPO (r = -0.81). Linear regression of the log-transformed EPO values revealed the equation log EPO (mIU/ml) = -0.135 x Hb (g/dl) + 2.821 (r(2) = 0.65). With increasing stages of CKD the correlation between haemoglobin and EPO concentrations was gradually attenuated and was completely lost in CKD stage four and five. In anaemic patients with Hb < 11 g/dl, relative EPO deficiency defined as EPO concentrations below the 25th percentile was present in 38%, 67%, 93% and 100% of the patients with CKD stages 1-5, respectively.
CONCLUSIONS: Expression of EPO concentrations in percentiles improves the diagnostic value of measuring EPO concentrations for diagnosing relative EPO deficiency and renal anaemia.

PMID 17556407  Nephrol Dial Transplant. 2007 Oct;22(10):2900-8. doi: 1・・・
著者: Yoshiharu Tsubakihara, Shinichi Nishi, Takashi Akiba, Hideki Hirakata, Kunitoshi Iseki, Minoru Kubota, Satoru Kuriyama, Yasuhiro Komatsu, Masashi Suzuki, Shigeru Nakai, Motoshi Hattori, Tetsuya Babazono, Makoto Hiramatsu, Hiroyasu Yamamoto, Masami Bessho, Tadao Akizawa
雑誌名: Ther Apher Dial. 2010 Jun;14(3):240-75. doi: 10.1111/j.1744-9987.2010.00836.x.
Abstract/Text The Japanese Society for Dialysis Therapy (JSDT) guideline committee, chaired by Dr Y. Tsubakihara, presents the Japanese guidelines entitled "Guidelines for Renal Anemia in Chronic Kidney Disease." These guidelines replace the "2004 JSDT Guidelines for Renal Anemia in Chronic Hemodialysis Patients," and contain new, additional guidelines for peritoneal dialysis (PD), non-dialysis (ND), and pediatric chronic kidney disease (CKD) patients. Chapter 1 presents reference values for diagnosing anemia that are based on the most recent epidemiological data from the general Japanese population. In both men and women, hemoglobin (Hb) levels decrease along with an increase in age and the level for diagnosing anemia has been set at <13.5 g/dL in males and <11.5 g/dL in females. However, the guidelines explicitly state that the target Hb level in erythropoiesis stimulating agent (ESA) therapy is different to the anemia reference level. In addition, in defining renal anemia, the guidelines emphasize that the reduced production of erythropoietin (EPO) that is associated with renal disorders is the primary cause of renal anemia, and that renal anemia refers to a condition in which there is no increased production of EPO and serum EPO levels remain within the reference range for healthy individuals without anemia, irrespective of the glomerular filtration rate (GFR). In other words, renal anemia is clearly identified as an "endocrine disease." It is believed that defining renal anemia in this way will be extremely beneficial for ND patients exhibiting renal anemia despite having a high GFR. We have also emphasized that renal anemia may be treated not only with ESA therapy but also with appropriate iron supplementation and the improvement of anemia associated with chronic disease, which is associated with inflammation, and inadequate dialysis, another major cause of renal anemia. In Chapter 2, which discusses the target Hb levels in ESA therapy, the guidelines establish different target levels for hemodialysis (HD) patients than for PD and ND patients, for two reasons: (i) In Japanese HD patients, Hb levels following hemodialysis rise considerably above their previous levels because of ultrafiltration-induced hemoconcentration; and (ii) as noted in the 2004 guidelines, although 10 to 11 g/dL was optimal for long-term prognosis if the Hb level prior to the hemodialysis session in an HD patient had been established at the target level, it has been reported that, based on data accumulated on Japanese PD and ND patients, in patients without serious cardiovascular disease, higher levels have a cardiac or renal function protective effect, without any safety issues. Accordingly, the guidelines establish a target Hb level in PD and ND patients of 11 g/dL or more, and recommend 13 g/dL as the criterion for dose reduction/withdrawal. However, with the results of, for example, the CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) study in mind, the guidelines establish an upper limit of 12 g/dL for patients with serious cardiovascular disease or patients for whom the attending physician determines high Hb levels would not be appropriate. Chapter 3 discusses the criteria for iron supplementation. The guidelines establish reference levels for iron supplementation in Japan that are lower than those established in the Western guidelines. This is because of concerns about long-term toxicity if the results of short-term studies conducted by Western manufacturers, in which an ESA cost-savings effect has been positioned as a primary endpoint, are too readily accepted. In other words, if the serum ferritin is <100 ng/mL and the transferrin saturation rate (TSAT) is <20%, then the criteria for iron supplementation will be met; if only one of these criteria is met, then iron supplementation should be considered unnecessary. Although there is a dearth of supporting evidence for these criteria, there are patients that have been surviving on hemodialysis in Japan for more than 40 years, and since there are approximately 20 000 patients who have been receiving hemodialysis for more than 20 years, which is a situation that is different from that in many other countries. As there are concerns about adverse reactions due to the overuse of iron preparations as well, we therefore adopted the expert opinion that evidence obtained from studies in which an ESA cost-savings effect had been positioned as the primary endpoint should not be accepted unquestioningly. In Chapter 4, which discusses ESA dosing regimens, and Chapter 5, which discusses poor response to ESAs, we gave priority to the usual doses that are listed in the package inserts of the ESAs that can be used in Japan. However, if the maximum dose of darbepoetin alfa that can currently be used in HD and PD patients were to be used, then the majority of poor responders would be rescued. Blood transfusions are discussed in Chapter 6. Blood transfusions are attributed to the difficulty of managing renal anemia not only in HD patients, but also in end-stage ND patients who respond poorly to ESAs. It is believed that the number of patients requiring transfusions could be reduced further if there were novel long-acting ESAs that could be used for ND patients. Chapter 7 discusses adverse reactions to ESA therapy. Of particular concern is the emergence and exacerbation of hypertension associated with rapid hematopoiesis due to ESA therapy. The treatment of renal anemia in pediatric CKD patients is discussed in Chapter 8; it is fundamentally the same as that in adults.

PMID 20609178  Ther Apher Dial. 2010 Jun;14(3):240-75. doi: 10.1111/j.・・・
著者: Masaaki Inaba, Yasuaki Hayashino, Tetsuo Shoji, Takashi Akiba, Tadao Akizawa, Akira Saito, Kiyoshi Kurokawa, Shunichi Fukuhara
雑誌名: Nephron Clin Pract. 2012;120(2):c91-c100. doi: 10.1159/000335979. Epub 2012 Feb 22.
Abstract/Text We previously demonstrated that anemia was not associated with mortality in hemodialysis patients with cardiovascular disease (CVD). Since diabetes mellitus (DM) accelerates CVD, the influence of DM on the relationship between anemia and mortality was examined using the data obtained from 1,385 DM patients and 2,583 non-DM hemodialysis patients recruited into the Dialysis Outcomes Practice Pattern Study in Japan (J-DOPPS). When all patients were stratified into four groups on their hematocrit levels, mortality rate was significantly and steadily lower in the subgroups with the higher levels of hematocrit by the Kaplan-Meier method (p = 0.0003 by log-rank test). When DM and non-DM patients were analyzed separately, a significant association of lower hematocrit levels with higher mortality disappeared in DM patients (p = 0.6280), in contrast with its retention in non-DM counterparts (p < 0.0001). Multivariable-adjusted Cox proportional hazards models demonstrated a significant association between hematocrit with all-cause mortality in non-DM patients after adjustment for age, gender, BMI, hemodialysis duration, SBP, DBP, albumin, total cholesterol, calcium, phosphorus, and intact PTH (p = 0.046), whereas this association disappeared in DM patients in the same model (p = 0.583). In conclusion, these results suggested that the association between anemia and higher mortality disappeared in DM hemodialysis patients, in contrast with non-DM counterparts.

Copyright © 2012 S. Karger AG, Basel.
PMID 22377677  Nephron Clin Pract. 2012;120(2):c91-c100. doi: 10.1159/・・・
著者: Tadao Akizawa, Akira Saito, Fumitake Gejyo, Masashi Suzuki, Yoshiki Nishizawa, Yasuhiko Tomino, Yoshiharu Tsubakihara, Takashi Akiba, Hideki Hirakata, Yuzo Watanabe, Hideki Kawanishi, Masami Bessho, Yukio Udagawa, Kotonari Aoki, Yukari Uemura, Yasuo Ohashi, JET Study Group
雑誌名: Ther Apher Dial. 2014 Oct;18(5):404-13. doi: 10.1111/1744-9987.12155. Epub 2014 Feb 25.
Abstract/Text Although erythropoiesis-stimulating agents (ESAs) are effective at treating anemia, the association between hemoglobin (Hb) levels and survival is still unclear, especially for the incident Japanese hemodialysis (HD) population. The Japan Erythropoietin Treatment (JET) Study is an open multi-center, prospective, observational study designed to evaluate the relationship between the maintenance of Hb levels and new HD patient prognosis after the first administration of epoetin beta. Landmark analyses were performed to examine the relationship between Hb levels at 6 months and survival. Among a total of 10,310 patients, 6631 completed the initial 6 months of epoetin beta treatment (induction phase) and were followed up for a further 2.5 years (maintenance phase). Three-year survival rate of patients with <9 g/dL Hb levels after 6 months was 74.1%, which was significantly lower than 89.3% for patients with Hb levels 10 to 11 g/dL; the adjusted hazard ratio (HR) was 2.08 (95% CI, 1.57-2.77; P < 0.0001). Moreover, the 3-year survival rate for poor responders defined by Hb levels <10 g/dL and weekly epoetin beta doses ≥ 9000 IU during the induction phase was 71.6%, which was significantly lower than 89.4% for the group, which had Hb levels 10 to 11 g/dL excluding poor responders and those with excursion; the HR was 1.71 (95% CI, 1.13-2.60; P = 0.0118). Adverse events related to the treatment were reported in 71 of 10,310 patients (0.69%). These findings suggest that the achieved low Hb levels and poor response to ESA therapy are significantly associated with high mortality.

© 2014 The Authors. Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis.
PMID 24571446  Ther Apher Dial. 2014 Oct;18(5):404-13. doi: 10.1111/17・・・
著者: Tadao Akizawa, Mai Ueno, Takanori Shiga, Michael Reusch
雑誌名: Ther Apher Dial. 2019 Dec 31;. doi: 10.1111/1744-9987.13468. Epub 2019 Dec 31.
Abstract/Text Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor approved in China for anemia of dialysis-dependent chronic kidney disease (CKD). Japanese hemodialysis patients with anemia of CKD previously naïve to, or converted from, erythropoiesis-stimulating agents (ESAs) were enrolled in two open-label, noncomparative studies of titrated oral roxadustat administered three times weekly. ESA-naïve patients (n = 75) were randomized to roxadustat (initial dose, 50 or 70 mg) for 24 weeks; ESA-converted patients (n = 164) were assigned to roxadustat (initial dose, 70 or 100 mg based on prior ESA dose) for 52 weeks. Efficacy outcomes included average hemoglobin (Hb, weeks 18-24 or 46-52), change of Hb from baseline to weeks 18 to 24 (ΔHb18-24 ) or weeks 46 to 52 (ΔHb46-52 ), and maintenance rate (proportion of patients who achieved average Hb of 10.0-12.0 g/dL for weeks 18-24 or weeks 46-52). Treatment-emergent adverse events (TEAEs) were monitored. Mean (SD) Hb was 10.93 (0.79) g/dL (weeks 18-24) (ESA-Naïve Study), and 10.93 (0.69; weeks 18-24) g/dL and 11.11 (0.67; weeks 46-52) g/dL (ESA-Converted Study). Mean (SD) ΔHb18-24 was 2.26 (1.02) g/dL (ESA-Naïve Study) and -0.03 (0.90) g/dL (ESA-Converted Study); mean (SD) ΔHb46-52 was 0.12 (0.83) g/dL (ESA-Converted Study). The overall maintenance rate was 73.0% (54/74) (ESA-Naïve Study) (weeks 18-24), and 79.1% (129/163; weeks 18-24) and 71.2% (116/163; weeks 46-52) (ESA-Converted Study). Nasopharyngitis was the most common TEAE. Two deaths, considered unrelated to roxadustat, occurred in the ESA-Converted Study. Roxadustat effectively corrected and maintained Hb, regardless of previous ESA treatment, in Japanese anemic CKD patients on hemodialysis.

© 2019 The Authors. Therapeutic Apheresis and Dialysis published by John Wiley & Sons Australia, Ltd on behalf of International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.
PMID 31891449  Ther Apher Dial. 2019 Dec 31;. doi: 10.1111/1744-9987.1・・・
著者: Yves Vanrenterghem, Peter Bárány, Johannes F E Mann, Peter G Kerr, Janet Wilson, Nigel F Baker, Stephen J Gray, European/Australian NESP 970200 Study Group
雑誌名: Kidney Int. 2002 Dec;62(6):2167-75. doi: 10.1046/j.1523-1755.2002.00657.x.
Abstract/Text BACKGROUND: Darbepoetin alfa is a glycoprotein with a three-fold longer terminal half-life than recombinant human erythropoietin (rHuEPO). We aimed to determine whether darbepoetin alfa is as effective and well tolerated as rHuEPO for treating renal anemia in dialysis patients when administered at a reduced dose frequency.
METHODS: A total of 522 European and Australian hemodialysis and peritoneal dialysis patients receiving stable rHuEPO therapy by either the intravenous (IV) or subcutaneous (SC) route were randomized, open-label in a 1:2 ratio to continue rHuEPO or to receive an equivalent dose of darbepoetin alfa at a reduced dose frequency. Patients receiving rHuEPO once weekly changed to once every other week darbepoetin alfa, and those receiving rHuEPO two or three times weekly changed to once-weekly darbepoetin alfa. The doses of rHuEPO and darbepoetin alfa were titrated to maintain hemoglobin close to the patient's baseline level for up to 52 weeks. The primary endpoint was the change in hemoglobin between baseline and the evaluation period at weeks 25 to 32 of treatment.
RESULTS: The mean change in hemoglobin from baseline to the evaluation period was similar in the darbepoetin alfa (-0.03 g/dL; SE 0.11) and rHuEPO (-0.06 g/dL; SE 0.13) groups, and the difference between the two treatments was 0.03 g/dL (95% CI -0.16, 0.21). This was not a statistically significant or clinically relevant difference, despite the reduced frequency of darbepoetin alfa administration. At the end of the evaluation period, >/=95% of patients had their hemoglobin successfully maintained on their assigned dose frequency for darbepoetin alfa (once weekly and once every other week) and rHuEPO (once, twice and three times weekly). The safety profiles of darbepoetin alfa and rHuEPO were similar, and no antibodies to either treatment were detected.
CONCLUSIONS: Darbepoetin alfa maintains hemoglobin as effectively as rHuEPO, but with a reduced dose frequency.

PMID 12427142  Kidney Int. 2002 Dec;62(6):2167-75. doi: 10.1046/j.1523・・・
著者: Hiromichi Suzuki, Tsutomu Inoue, Yusuke Watanabe, Tomohiro Kikuta, Takahiko Sato, Masahiro Tsuda, Kousuke Uchida
雑誌名: Adv Perit Dial. 2011;27:60-4.
Abstract/Text The newly developed erythropoiesis agent darbepoetin alpha (DA) allows for once-monthly dosing in the treatment of anemia in patients on dialysis. This dosing schedule has prompted some studies to examine the efficacy of DA in patients on continuous ambulatory peritoneal dialysis (CAPD). In the present study, we assessed whether intravenous (IV) administration of DA once monthly is effective for maintaining hemoglobin levels near 10.5 g/dL in patients on CAPD. This single-center prospective cohort study included 52 clinically stable patients (25 men, 27 women; mean age: 59 +/- 10 years). All patients had been on a stable weekly or twice monthly regimen of recombinant human erythropoietin (rHuEPO) before initiation of the study. To determine the monthly dose of DA, the previously used mean weekly dose of rHuEPO was divided by 200 to determine the equivalent weekly dose of DA in micrograms; that number was then multiplied by 4 to generate the monthly dose requirement. For example, if 3000 IUrHuEPO was being administered weekly, then the monthly dose of DA was calculated to be 60 microg (3000/200 x 4). All patients received a monthly dose of DA the first month, and hemoglobin and other routine laboratory tests were performed monthly for 24 consecutive weeks. In 26 patients, the calculated monthly DA dose remained stable. The monthly dose was increased by 25% in 22 patients and by 50% in 4 patients. With regard to iron stores and iron availability for erythropoiesis, no significant differences were observed in the patients on various doses of DA. Nonsignificant differences in weekly creatinine clearance as determined using the PD Adequest software (Baxter Healthcare, Tokyo, Japan) were observed between the groups. No clinically meaningful differences in other laboratory values between the groups were observed. Once-monthly administration of DA is not always sufficient to maintain hemoglobin levels in patients on CAPD when adequate dialysis therapy is not achieved.

PMID 22073831  Adv Perit Dial. 2011;27:60-4.
著者: Michèle Kessler, Alberto Martínez-Castelao, Kostas C Siamopoulos, Giuseppe Villa, Bruce Spinowitz, Frank C Dougherty, Ulrich Beyer
雑誌名: Hemodial Int. 2010 Apr;14(2):233-9. doi: 10.1111/j.1542-4758.2009.00421.x. Epub 2009 Nov 3.
Abstract/Text C.E.R.A., a continuous erythropoietin receptor activator is approved for the treatment of anemia in patients with chronic kidney disease (CKD). The ARCTOS (administration of C.E.R.A. in CKD patients to treat anemia with a twice-monthly schedule) phase 3 study demonstrated the efficacy and safety of C.E.R.A. in correcting anemia when administered once every 2 weeks (Q2W) subcutaneously in patients with CKD not on dialysis. We assessed the feasibility and long-term safety of converting patients who responded to treatment with C.E.R.A. Q2W to C.E.R.A. once every 4 weeks (Q4W) during a 24-week extension period. After the core ARCTOS study period (28 weeks), 296 patients entered the 24-week extension period. At week 29, patients who responded to C.E.R.A. Q2W during the core period were rerandomized to receive subcutaneous C.E.R.A. Q2W or Q4W. Patients in the comparator arm could receive darbepoetin alfa once weekly or Q2W. Dosage was adjusted to maintain hemoglobin (Hb) between 11 and 13 g/dL. Mean Hb levels remained stable in all groups, and were comparable at the end of the extension period (mean [standard deviation], C.E.R.A. Q2W, 11.92 [0.90] g/dL; C.E.R.A. Q4W, 11.70 [0.86] g/dL; darbepoetin alfa, 11.89 [0.98] g/dL). Mean within-patient standard deviation values for Hb were also comparable in all groups (0.66, 0.62, and 0.65 g/dL for C.E.R.A. Q2W, C.E.R.A. Q4W and darbepoetin alfa, respectively). All treatments were well tolerated. Subcutaneous C.E.R.A. Q4W is safe and effective in maintaining stable Hb levels in patients with CKD not on dialysis following correction with subcutaneous C.E.R.A. Q2W.

PMID 19888948  Hemodial Int. 2010 Apr;14(2):233-9. doi: 10.1111/j.1542・・・
著者: Marian Klinger, Manual Arias, Vassilis Vargemezis, Anatole Besarab, Wladyslaw Sulowicz, Trevor Gerntholtz, Kazimierz Ciechanowski, Frank C Dougherty, Ulrich Beyer
雑誌名: Am J Kidney Dis. 2007 Dec;50(6):989-1000. doi: 10.1053/j.ajkd.2007.08.013.
Abstract/Text BACKGROUND: C.E.R.A. (methoxy polyethylene glycol-epoetin beta), a continuous erythropoietin receptor activator, was developed to provide stable control of hemoglobin (Hb) levels at extended administration intervals in patients with chronic kidney disease. We examined its efficacy for Hb level correction when administered once every 2 weeks in erythropoiesis-stimulating agent-naive dialysis patients.
STUDY DESIGN: Open-label, multicenter, randomized, parallel-group, phase 3 study.
SETTING & PARTICIPANTS: Dialysis patients (age >or= 18 years).
INTERVENTION: Patients (n = 181) were randomly assigned (3:1) to receive intravenous C.E.R.A. once every 2 weeks or epoetin 3 times weekly.
OUTCOMES & MEASUREMENTS: The primary end point was Hb level response rate (increase in Hb level >or= 1 g/dL [10 g/L] versus baseline and Hb level >or= 11 g/dL [110 g/L] without blood transfusion during the 24-week correction period) in the intent-to-treat population.
RESULTS: Hb response rates (intent-to-treat population) were 93.3% with C.E.R.A. and 91.3% with epoetin. Similar results were found in the per-protocol population. Peak mean Hb levels were 12.28 +/- 1.13 (SD) g/dL (122.8 +/- 11.3 g/L) with C.E.R.A. and 12.19 +/- 1.24 g/dL (121.9 +/- 12.4 g/L) with epoetin. Mean change in Hb levels from baseline to the end of the correction period were 2.70 +/- 1.45 g/dL (27 +/- 14.5 g/L) with C.E.R.A. and 2.56 +/- 1.31 g/dL (25.6 +/- 13.1 g/L) with epoetin. Both treatments were generally well tolerated.
LIMITATIONS: Open-label study design, 3:1 randomization, limited peritoneal dialysis population, descriptive statistics, and lack of formal prespecified comparison to epoetin.
CONCLUSIONS: Intravenous C.E.R.A. once every 2 weeks may be as safe and effective as 3-times-weekly epoetin for correcting anemia in dialysis patients. These results show the utility of intravenous C.E.R.A. administered once every 2 weeks in erythropoiesis-stimulating agent-naive dialysis patients.

PMID 18037099  Am J Kidney Dis. 2007 Dec;50(6):989-1000. doi: 10.1053/・・・
著者: Iain C Macdougall, Rowan Walker, Robert Provenzano, Fernando de Alvaro, Harold R Locay, Paul C Nader, Francesco Locatelli, Frank C Dougherty, Ulrich Beyer, ARCTOS Study Investigators
雑誌名: Clin J Am Soc Nephrol. 2008 Mar;3(2):337-47. doi: 10.2215/CJN.00480107. Epub 2008 Feb 20.
Abstract/Text BACKGROUND AND OBJECTIVES: This study examined the efficacy of C.E.R.A., a continuous erythropoietin receptor activator, for correcting anemia in patients who had chronic kidney disease (CKD) and were not on dialysis.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this open-label, randomized, parallel-group, Phase III study, 324 adult patients with CKD not on dialysis nor receiving treatment with erythropoiesis-stimulating agents (ESAs) were randomly assigned (1:1) to receive subcutaneous C.E.R.A. once every 2 wk or darbepoetin alfa once weekly during an 18-wk correction period and a 10-wk evaluation period. Thereafter, patients receiving C.E.R.A. were randomly assigned to C.E.R.A. once every 2 wk or once monthly, and patients receiving darbepoetin alfa could receive darbepoetin alfa once weekly or once every 2 wk for a 24-wk extension period. Dosage was adjusted to achieve a hemoglobin (Hb) response and to maintain Hb +/-1 g/dl of the response level and 11 to 13 g/dl. Primary end points were Hb response rate during correction and evaluation and change in Hb concentration between baseline and evaluation.
RESULTS: Hb response rates were 97.5% for C.E.R.A. and 96.3% for darbepoetin alfa. Adjusted mean changes in Hb from baseline to evaluation were 2.15 g/dl (C.E.R.A.) and 2.00 g/dl (darbepoetin alfa). Analysis showed that C.E.R.A. once every 2 wk was as effective as darbepoetin alfa once weekly for correcting anemia. Hb levels remained stable in all groups during the extension period. C.E.R.A. and darbepoetin alfa were well tolerated.
CONCLUSIONS: Subcutaneous C.E.R.A. once every 2 wk corrects anemia in ESA-naïve patients who are not on dialysis.

PMID 18287255  Clin J Am Soc Nephrol. 2008 Mar;3(2):337-47. doi: 10.22・・・
著者: Gian P Rossi, Teresa M Seccia, Carmela Maniero, Achille C Pessina
雑誌名: J Hypertens. 2011 Dec;29(12):2295-309. doi: 10.1097/HJH.0b013e32834c465d.
Abstract/Text Several drugs can cause hypertension and/or blunt the effect of antihypertensive treatment. They can exacerbate a previously well controlled hypertension and/or render it resistant to therapy. Accordingly, drugs represent a common cause of resistance of hypertension to treatment. Identification of drug-related hypertension can be achieved with a thorough medical history targeted to ascertain concurrent therapies that are prescribed for conditions other than cardiovascular diseases. This can avoid prescribing a more aggressive antihypertensive treatment and may prevent embarking in costly and sometimes invasive diagnostic procedures. Drugs that commonly raise blood pressure include NSAIDs, steroids, oestroprogestinic agents, immunosuppressants, erythropoietin, inhibitors of angiogenesis, anti-HIV agents, and also some high-density lipoprotein-raising agents. As withdrawal of the offending drug is often impracticable, knowledge of the mechanism(s) by which each drug exerts its pressor effects may help selecting the most effective treatment. Purpose of this review is to examine the most common causes of resistant hypertension that are due to drugs or abuse of substances along with their underlying pathophysiological mechanisms. The strategy for selecting the most appropriate treatment and the reasons for 'a call of action' of research in this area are also examined.

PMID 22002334  J Hypertens. 2011 Dec;29(12):2295-309. doi: 10.1097/HJH・・・
著者: Alex Disney, Peter D E Jersey, Geoff Kirkland, Murty Mantha, John A Charlesworth, Martin Gallagher, David Harris, Hilton Gock, George J Mangos, Jamie Macmillan, Wei Liu, Ajit Viswalingam
雑誌名: Nephrology (Carlton). 2007 Feb;12(1):95-101. doi: 10.1111/j.1440-1797.2006.00757.x.
Abstract/Text AIM: Darbepoetin alfa, an erythropoiesis-stimulating protein, has a longer serum half-life than recombinant human erythropoietin, allowing less-frequent administration. This study aimed to demonstrate that once-monthly (QM) darbepoetin alfa administration would maintain haemoglobin (Hb) concentrations in subjects with chronic kidney disease (CKD) not receiving dialysis who had previously been administered darbepoetin alfa every 2 weeks (Q2W).
METHODS: This was a multicentre study in which subjects with CKD receiving stable Q2W darbepoetin alfa doses and with stable Hb (100-130 g/L) were started on QM darbepoetin alfa dosing. The initial QM darbepoetin alfa dose was equivalent to the cumulative darbepoetin alfa dose administered during the month preceding enrollment. Darbepoetin alfa doses were titrated to maintain Hb concentrations between 100 and 130 g/L. The primary endpoint was the proportion of subjects maintaining mean Hb >or= 100 g/L during the evaluation period (weeks 21-33).
RESULTS: Sixty-six subjects were enrolled in the study and all received at least one dose of darbepoetin alfa; 55 (83%) had mean Hb >or= 100 g/L during evaluation. Mean (SD) Hb concentrations at baseline and during the evaluation period were 119 (8.7) g/L and 114 (9.8) g/L, respectively. The median QM darbepoetin alfa dose at baseline and during the evaluation period was 80 microg. Darbepoetin alfa was considered to be well-tolerated.
CONCLUSION: Patients with CKD not receiving dialysis who are receiving darbepoetin alfa Q2W can be safely and effectively extended to darbepoetin alfa QM. Dosing QM may simplify anaemia management for patients and health-care providers.

PMID 17295668  Nephrology (Carlton). 2007 Feb;12(1):95-101. doi: 10.11・・・
著者: A K Agarwal, M R Silver, J E Reed, R K Dhingra, W Liu, N Varma, C Stehman-Breen
雑誌名: J Intern Med. 2006 Dec;260(6):577-85. doi: 10.1111/j.1365-2796.2006.01723.x.
Abstract/Text OBJECTIVE: To demonstrate the efficacy and safety of once-monthly (QM) darbepoetin alfa administration in maintaining haemoglobin (Hb) 11.0-13.0 g dL(-1) in subjects with chronic kidney disease (CKD) not receiving dialysis and previously treated with darbepoetin alfa every other week (Q2W).
SUBJECTS: This open-label study enrolled subjects > or =18 years of age who had glomerular filtration rate > or =15 and < or =60 mL min(-1)/1.73 m(2), had Hb 11.0-13.0 g dL(-1), and were receiving Q2W darbepoetin alfa.
DESIGN: Subjects were switched to QM darbepoetin alfa therapy for 28 weeks; the QM dose was titrated to maintain Hb levels. Primary end-point: proportion of subjects maintaining Hb > or =11.0 g dL(-1) during the final 8 weeks of the study (evaluation phase). Secondary end-points: Hb concentration during evaluation, darbepoetin alfa dose during the study, adverse events, laboratory parameters, and blood pressure.
RESULTS: The study enrolled 152 subjects (female 52%, white 64%). Mean Hb > or =11.0 g dL(-1) during evaluation was achieved by 76% of the 150 subjects who received at least one dose of darbepoetin alfa [95% confidence interval (CI): 68%, 83%]. Mean (SD) Hb during evaluation was 11.71 (0.92) g dL(-1). Eighty-five per cent of 129 subjects who completed the study (95% CI: 78%, 91%) had Hb > or =11.0 g dL(-1) during evaluation. The dose of darbepoetin alfa over the study period was median (95% CI) 124.4 mug (106.2, 140.0). Darbepoetin alpha administered QM was well tolerated in study subjects.
CONCLUSION: Darbepoetin alpha administered QM maintained Hb in study subjects with CKD not receiving dialysis.

PMID 17116009  J Intern Med. 2006 Dec;260(6):577-85. doi: 10.1111/j.13・・・
著者: Simon D Roger, Francesco Locatelli, Rainer P Woitas, Maurice Laville, Sheldon W Tobe, Robert Provenzano, Thomas A Golper, Prajej Ruangkanchanasetr, Ho Yung Lee, Kwan-Dun Wu, Michal Nowicki, Agnes Ladanyi, Alberto Martínez-Castelao, Ulrich Beyer, Frank C Dougherty
雑誌名: Nephrol Dial Transplant. 2011 Dec;26(12):3980-6. doi: 10.1093/ndt/gfr160. Epub 2011 Apr 19.
Abstract/Text BACKGROUND: No previous randomized controlled studies have been reported examining de novo, once every 4 weeks (Q4W) administration of erythropoiesis-stimulating agents in chronic kidney disease (CKD) patients. We report results from a randomized multinational study that compared continuous erythropoietin receptor activator (C.E.R.A.) Q4W with darbepoetin alfa once weekly (QW) or every 2 weeks (Q2W) for the correction of anaemia in non-dialysis CKD patients.
METHODS: Patients were randomized (1:1) to receive either 1.2 μg/kg C.E.R.A. Q4W or darbepoetin alfa QW/Q2W during a 20-week correction period and an 8-week evaluation period. Two primary end points were assessed: the haemoglobin (Hb) response rate and the change in average Hb concentration between baseline and evaluation.
RESULTS: The Hb response rate for C.E.R.A. was 94.1%, significantly higher than the protocol-specified 60% response rate [95% confidence interval (CI): 89.1, 97.3; P < 0.0001] and comparable with darbepoetin alfa (93.5%; 95% CI: 88.4, 96.8; P < 0.0001). C.E.R.A. Q4W was non-inferior to darbepoetin alfa QW/Q2W, with similar mean Hb changes from baseline of 1.62 g/dL and 1.66 g/dL, respectively. Patients receiving C.E.R.A. showed a steady rise in Hb, with fewer patients above the target range during the first 8 weeks compared with darbepoetin alfa [39 patients (25.8%) versus 72 patients (47.7%); P < 0.0001]. Adverse event rates were comparable between the treatment groups.
CONCLUSION: C.E.R.A. Q4W successfully corrects anaemia and maintains stable Hb levels within the recommended target range in non-dialysis CKD patients.

PMID 21505096  Nephrol Dial Transplant. 2011 Dec;26(12):3980-6. doi: 1・・・
著者: Hideki Hirakata, Yoshiharu Tsubakihara, Fumitake Gejyo, Shinichi Nishi, Yasuhiko Iino, Yuzou Watanabe, Masashi Suzuki, Akira Saito, Takashi Akiba, Daijo Inaguma, Shunichi Fukuhara, Satoshi Morita, Michiaki Hiroe, Yoshiyuki Hada, Makoto Suzuki, Makoto Akaishi, Kazutaka Aonuma, Tadao Akizawa
雑誌名: Clin Exp Nephrol. 2010 Feb;14(1):28-35. doi: 10.1007/s10157-009-0212-4. Epub 2009 Sep 9.
Abstract/Text BACKGROUND: Anemia is common among patients with chronic kidney disease (CKD). The introduction of erythropoietin treatment has changed anemia management, but the therapeutic hemoglobin (Hb) target is still under debate, and clinical evidence for its effect on cardiac functions and QOL is sparse.
METHODS: A 16-week dose-response study and a 32-week follow-Up study were combined. After correcting anemia of less than 10 g/dl in pre-dialysis Japanese CKD patients, a higher Hb target (12-13 g/dl) by darbepoetin alfa (DPO) was compared with the conventional Hb target by epoetin alfa (EPO). Outcomes were anemia correction, management of the left ventricular mass index (LVMI) and QOL scores.
RESULTS: No significant difference was seen in Hb at baseline and week 16, but a significant difference was recorded at week 34 (12.34 +/- 0.93 g/dl for DPO and 10.43 +/- 0.90 g/dl for EPO). In both groups, LVMI decreased similarly until week 16, but the decrease of EPO was retarded, and a significant difference between LVMI was seen only in DPO at week 34 (100.7 +/- 16.6 g/m(2) for DPO and 110.9 +/- 25.2 g/m(2) for EPO). Relationships between Hb and LVMI change at week 34 were examined by stratifying Hb into four groups (Hb <10 g/dl, 10 g/dl < or = Hb <11 g/dl, 11 g/dl < or = Hb <12 g/dl and 12 g/dl < or = Hb), and a decrease of LVMI was prominent in the 12 g/dl < or = Hb group. Correction of anemia to 11 g/dl or more led to improved QOL scores. No safety difference was observed among the treatments.
CONCLUSIONS: Targeting a higher Hb around 12 g/dl was more beneficial than targeting conventional Hb in terms of reduction of LVMI and QOL. Further studies to determine the appropriate Hb target are necessary.

PMID 19763743  Clin Exp Nephrol. 2010 Feb;14(1):28-35. doi: 10.1007/s1・・・
著者: Shunichi Fukuhara, Tadao Akizawa, Satoshi Morita, Shozo Koshikawa, KRN321 A08 Study Group
雑誌名: Ther Apher Dial. 2008 Feb;12(1):72-7. doi: 10.1111/j.1744-9987.2007.00544.x.
Abstract/Text Short-acting hematopoietic agents can improve the quality of life (QOL) of hemodialysis patients, but questions remain regarding the domains of QOL affected, the relative importance of initial and final hemoglobin (Hb) concentrations, and the use of long-acting hematopoietic agents. We measured Hb concentrations and QOL in 487 hemodialysis patients who were switched from treatment with recombinant human erythropoietin to treatment with darbepoetin alfa. QOL was measured with the Japanese-language version of the SF-36, at the start of therapy with darbepoetin alfa and again 7-14 weeks later. We examined changes in QOL over time in the group as a whole, and in subgroups stratified by the change in Hb concentration. We also studied relationships between the final Hb concentration achieved and the magnitude of change in QOL. QOL scores increased significantly in all SF-36 domains except Social Functioning. The greatest increases were in vitality and in the two role-functioning domains. The magnitude of the increase in Hb concentration was related to the magnitude of the increase in QOL for only one subscale: Vitality. Patients with higher final Hb concentrations also had greater increases in Vitality scores. Hematopoiesis induced by darbepoetin alfa is associated with increased vitality and may also be associated with improved role functioning. Vitality increased significantly only in those patients with the greatest increases in Hb concentration and in those with higher final Hb concentrations.

PMID 18257816  Ther Apher Dial. 2008 Feb;12(1):72-7. doi: 10.1111/j.17・・・
著者: Shravanthi R Gandra, Fredric O Finkelstein, Antonia V Bennett, Eldrin F Lewis, Tracy Brazg, Mona L Martin
雑誌名: Am J Kidney Dis. 2010 Mar;55(3):519-34. doi: 10.1053/j.ajkd.2009.09.019. Epub 2009 Dec 23.
Abstract/Text BACKGROUND: Previous analyses report the impact of erythropoiesis-stimulating agents (ESAs) on health-related quality of life across various populations. In this analysis, we review published studies and quantify the effect of ESA therapy on energy/fatigue and physical function in nondialysis patients with chronic kidney disease (CKD) related anemia.
STUDY DESIGN: Systematic literature search to identify articles (1980-2008) that evaluated effects of ESAs on patient-reported energy and physical function.
SETTING & POPULATION: Nondialysis CKD patients with anemia enrolled in prospective trials.
SELECTION CRITERIA FOR STUDIES: Prospective studies measuring energy or physical function with both baseline and follow-up measurement.
INTERVENTION: ESA treatment.
OUTCOMES: Improvements in energy and physical function assessed using effect size, a measure of treatment responsiveness.
RESULTS: 14 studies were identified: 11 measured energy and 14 measured physical function. The 36-Item Short-Form Health Survey (SF-36) was the most common instrument used to report energy and physical function. Of 11 studies measuring energy, 2 were double-blind randomized placebo-controlled trials (RCTs), 5 were open-label RCTs, and 4 were single-arm open-label studies. Eight of 11 studies reported statistically significant improvements in energy. Effect size for energy ranged from small (0.24) to large (1.90) in ESA-treated groups and was moderate in each arm of the low- versus high-hemoglobin target RCTs. Of 14 studies measuring physical function, 2 were double-blind RCTs, 6 were open-label RCTs, and 6 were single-arm open-label studies. Ten of 14 studies reported statistically significant improvements in physical function. Effect size for physical function ranged from small (0.37) to large (2.38) in ESA-treated groups and was negligible to moderate in each arm of low- versus high-hemoglobin target studies.
LIMITATIONS: Findings and conclusions were limited by the available evidence.
CONCLUSION: RCTs and single-arm studies indicate that treatment of anemia with ESAs improves energy and physical function in nondialysis CKD patients.

Copyright 2010 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
PMID 20031287  Am J Kidney Dis. 2010 Mar;55(3):519-34. doi: 10.1053/j.・・・
著者: Tadao Akizawa, Fumitake Gejyo, Shinichi Nishi, Yasuhiko Iino, Yuzou Watanabe, Masashi Suzuki, Akira Saito, Takashi Akiba, Hideki Hirakata, Shunichi Fukuhara, Satoshi Morita, Michiaki Hiroe, Yoshiyuki Hada, Makoto Suzuki, Makoto Akaishi, Manabu Iwasaki, Yoshiharu Tsubakihara, KRN321 STUDY Group
雑誌名: Ther Apher Dial. 2011 Oct;15(5):431-40. doi: 10.1111/j.1744-9987.2011.00931.x. Epub 2011 May 25.
Abstract/Text Correcting anemia in patients with chronic kidney disease (CKD) to higher hemoglobin (Hb) levels may be associated with increased risk. No optimal target for Hb has been established. This controlled study examined 321 patients with CKD who were not on dialysis, had a Hb level of <10g/dL, and a serum creatinine of 2.0 to 6.0mg/dL. They were randomized into two target Hb groups: 161 to high Hb (11.0-13.0g/dL) to receive darbepoetin alfa and low Hb to 160 (9.0-11.0g/dL) to receive recombinant erythropoietin. The study lasted 48weeks. Of 154 and 153 patients with adverse events, cardiovascular adverse events developed in 42 and 51 patients in the high and low Hb groups, respectively, with no significant difference in the incidence. All quality of life scores improved in the high Hb group and vitality improved significantly more with high Hb (P=0.025). The left ventricular mass index (LVMI) remained stable in the low Hb group, but there was a significant decrease in LVMI in the high group (P<0.001). There were no safety concerns with targeting a higher Hb level during the 48weeks of this study. Patients with a higher Hb target had comparatively better outcomes with respect to quality of life and LVMI.

© 2011 The Authors. Therapeutic Apheresis and Dialysis © 2011 International Society for Apheresis.
PMID 21974695  Ther Apher Dial. 2011 Oct;15(5):431-40. doi: 10.1111/j.・・・
著者: A Besarab, W K Bolton, J K Browne, J C Egrie, A R Nissenson, D M Okamoto, S J Schwab, D A Goodkin
雑誌名: N Engl J Med. 1998 Aug 27;339(9):584-90. doi: 10.1056/NEJM199808273390903.
Abstract/Text BACKGROUND: In patients with end-stage renal disease, anemia develops as a result of erythropoietin deficiency, and recombinant human erythropoietin (epoetin) is prescribed to correct the anemia partially. We examined the risks and benefits of normalizing the hematocrit in patients with cardiac disease who were undergoing hemodialysis.
METHODS: We studied 1233 patients with clinical evidence of congestive heart failure or ischemic heart disease who were undergoing hemodialysis: 618 patients were assigned to receive increasing doses of epoetin to achieve and maintain a hematocrit of 42 percent, and 615 were assigned to receive doses of epoetin sufficient to maintain a hematocrit of 30 percent throughout the study. The median duration of treatment was 14 months. The primary end point was the length of time to death or a first nonfatal myocardial infarction.
RESULTS: After 29 months, there were 183 deaths and 19 first nonfatal myocardial infarctions among the patients in the normal-hematocrit group and 150 deaths and 14 nonfatal myocardial infarctions among those in the low-hematocrit group (risk ratio for the normal-hematocrit group as compared with the low-hematocrit group, 1.3; 95 percent confidence interval, 0.9 to 1.9). Although the difference in event-free survival between the two groups did not reach the prespecified statistical stopping boundary, the study was halted. The causes of death in the two groups were similar. The mortality rates decreased with increasing hematocrit values in both groups. The patients in the normal-hematocrit group had a decline in the adequacy of dialysis and received intravenous iron dextran more often than those in the low-hematocrit group.
CONCLUSIONS: In patients with clinically evident congestive heart failure or ischemic heart disease who are receiving hemodialysis, administration of epoetin to raise their hematocrit to 42 percent is not recommended.

PMID 9718377  N Engl J Med. 1998 Aug 27;339(9):584-90. doi: 10.1056/N・・・
著者:
雑誌名: N Engl J Med. 2006 Nov 16;355(20):2071-84.
Abstract/Text
PMID 17108342  N Engl J Med. 2006 Nov 16;355(20):2071-84.
著者:
雑誌名: N Engl J Med. 2006 Nov 16;355(20):2085-98.
Abstract/Text
PMID 17108343  N Engl J Med. 2006 Nov 16;355(20):2085-98.
著者: Marc A Pfeffer, Emmanuel A Burdmann, Chao-Yin Chen, Mark E Cooper, Dick de Zeeuw, Kai-Uwe Eckardt, Jan M Feyzi, Peter Ivanovich, Reshma Kewalramani, Andrew S Levey, Eldrin F Lewis, Janet B McGill, John J V McMurray, Patrick Parfrey, Hans-Henrik Parving, Giuseppe Remuzzi, Ajay K Singh, Scott D Solomon, Robert Toto, TREAT Investigators
雑誌名: N Engl J Med. 2009 Nov 19;361(21):2019-32. doi: 10.1056/NEJMoa0907845. Epub 2009 Oct 30.
Abstract/Text BACKGROUND: Anemia is associated with an increased risk of cardiovascular and renal events among patients with type 2 diabetes and chronic kidney disease. Although darbepoetin alfa can effectively increase hemoglobin levels, its effect on clinical outcomes in these patients has not been adequately tested.
METHODS: In this study involving 4038 patients with diabetes, chronic kidney disease, and anemia, we randomly assigned 2012 patients to darbepoetin alfa to achieve a hemoglobin level of approximately 13 g per deciliter and 2026 patients to placebo, with rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter. The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease.
RESULTS: Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa vs. placebo, 1.05; 95% confidence interval [CI], 0.94 to 1.17; P=0.41). Death or end-stage renal disease occurred in 652 patients assigned to darbepoetin alfa and 618 patients assigned to placebo (hazard ratio, 1.06; 95% CI, 0.95 to 1.19; P=0.29). Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 patients assigned to placebo (hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001). Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa and 496 patients assigned to placebo (P<0.001). There was only a modest improvement in patient-reported fatigue in the darbepoetin alfa group as compared with the placebo group.
CONCLUSIONS: The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke. For many persons involved in clinical decision making, this risk will outweigh the potential benefits. (ClinicalTrials.gov number, NCT00093015.)

2009 Massachusetts Medical Society
PMID 19880844  N Engl J Med. 2009 Nov 19;361(21):2019-32. doi: 10.1056・・・
著者: Suetonia C Palmer, Lucia Di Micco, Mona Razavian, Jonathan C Craig, Vlado Perkovic, Fabio Pellegrini, Massimiliano Copetti, Giusi Graziano, Gianni Tognoni, Meg Jardine, Angela Webster, Antonio Nicolucci, Sophia Zoungas, Giovanni F M Strippoli
雑誌名: Ann Intern Med. 2012 Mar 20;156(6):445-59. doi: 10.7326/0003-4819-156-6-201203200-00007.
Abstract/Text BACKGROUND: Antiplatelet agents are used to prevent cardiovascular events; however, treatment effects may differ in persons with chronic kidney disease (CKD) because atherosclerotic disease is less prevalent, whereas bleeding hazards may be increased in this population.
PURPOSE: To summarize the effects of antiplatelet treatment on cardiovascular events, mortality, and bleeding in persons with CKD.
DATA SOURCES: Embase and Cochrane databases through November 2011 without language restriction.
STUDY SELECTION: Randomized trials that included adults with CKD and compared antiplatelet agents with standard care, placebo, or no treatment.
DATA EXTRACTION: Data for populations, interventions, outcomes, and risk for bias were extracted. Quality of evidence for treatment effects on myocardial infarction, death, and bleeding was summarized by using Grading of Recommendations Assessment, Development, and Evaluation guidelines.
DATA SYNTHESIS: Nine trials (all post hoc subgroup analyses for CKD) involving 9969 persons who had acute coronary syndromes or were undergoing percutaneous coronary intervention and 31 trials involving 11,701 persons with stable or no cardiovascular disease were identified. Low-quality evidence has found that in persons with acute coronary syndromes, glycoprotein IIb/IIIa inhibitors or clopidogrel plus standard care compared with standard care alone had little or no effect on all-cause or cardiovascular mortality or on myocardial infarction but increased serious bleeding. Compared with placebo or no treatment in persons with stable or no cardiovascular disease, antiplatelet agents prevented myocardial infarction but had uncertain effects on mortality and increased minor bleeding according to generally low-quality evidence.
LIMITATIONS: Data for antiplatelet agents in persons with CKD are frequently derived from post hoc analyses of trials of broader populations. Definitions for bleeding outcomes and trial duration were heterogeneous.
CONCLUSION: Benefits for antiplatelet therapy among persons with CKD are uncertain and are potentially outweighed by bleeding hazards.
PRIMARY FUNDING SOURCE: None.

PMID 22431677  Ann Intern Med. 2012 Mar 20;156(6):445-59. doi: 10.7326・・・
著者: Andrew F Goddard, Martin W James, Alistair S McIntyre, Brian B Scott, British Society of Gastroenterology
雑誌名: Gut. 2011 Oct;60(10):1309-16. doi: 10.1136/gut.2010.228874. Epub 2011 May 11.
Abstract/Text BACKGROUND: Iron deficiency anaemia (IDA) occurs in 2-5% of adult men and postmenopausal women in the developed world and is a common cause of referral to gastroenterologists. Gastrointestinal (GI) blood loss from colonic cancer or gastric cancer, and malabsorption in coeliac disease are the most important causes that need to be sought. DEFINING IRON DEFICIENCY ANAEMIA: The lower limit of the normal range for the laboratory performing the test should be used to define anaemia (B). Any level of anaemia should be investigated in the presence of iron deficiency (B). The lower the haemoglobin the more likely there is to be serious underlying pathology and the more urgent is the need for investigation (B). Red cell indices provide a sensitive indication of iron deficiency in the absence of chronic disease or haemoglobinopathy (A). Haemoglobin electrophoresis is recommended when microcytosis and hypochromia are present in patients of appropriate ethnic background to prevent unnecessary GI investigation (C). Serum ferritin is the most powerful test for iron deficiency (A).
INVESTIGATIONS: Upper and lower GI investigations should be considered in all postmenopausal female and all male patients where IDA has been confirmed unless there is a history of significant overt non-GI blood loss (A). All patients should be screened for coeliac disease (B). If oesophagogastroduodenoscopy (OGD) is performed as the initial GI investigation, only the presence of advanced gastric cancer or coeliac disease should deter lower GI investigation (B). In patients aged >50 or with marked anaemia or a significant family history of colorectal carcinoma, lower GI investigation should still be considered even if coeliac disease is found (B). Colonoscopy has advantages over CT colography for investigation of the lower GI tract in IDA, but either is acceptable (B). Either is preferable to barium enema, which is useful if they are not available. Further direct visualisation of the small bowel is not necessary unless there are symptoms suggestive of small bowel disease, or if the haemoglobin cannot be restored or maintained with iron therapy (B). In patients with recurrent IDA and normal OGD and colonoscopy results, Helicobacter pylori should be eradicated if present. (C). Faecal occult blood testing is of no benefit in the investigation of IDA (B). All premenopausal women with IDA should be screened for coeliac disease, but other upper and lower GI investigation should be reserved for those aged 50 years or older, those with symptoms suggesting gastrointestinal disease, and those with a strong family history of colorectal cancer (B). Upper and lower GI investigation of IDA in post-gastrectomy patients is recommended in those over 50 years of age (B). In patients with iron deficiency without anaemia, endoscopic investigation rarely detects malignancy. Such investigation should be considered in patients aged >50 after discussing the risk and potential benefit with them (C). Only postmenopausal women and men aged >50 years should have GI investigation of iron deficiency without anaemia (C). Rectal examination is seldom contributory, and, in the absence of symptoms such as rectal bleeding and tenesmus, may be postponed until colonoscopy. Urine testing for blood is important in the examination of patients with IDA (B).
MANAGEMENT: All patients should have iron supplementation both to correct anaemia and replenish body stores (B). Parenteral iron can be used when oral preparations are not tolerated (C). Blood transfusions should be reserved for patients with or at risk of cardiovascular instability due to the degree of their anaemia (C).

PMID 21561874  Gut. 2011 Oct;60(10):1309-16. doi: 10.1136/gut.2010.228・・・
著者: Angelo Karaboyas, Hal Morgenstern, Ronald L Pisoni, Jarcy Zee, Raymond Vanholder, Stefan H Jacobson, Masaaki Inaba, Lisa C Loram, Friedrich K Port, Bruce M Robinson
雑誌名: Nephrol Dial Transplant. 2018 Dec 1;33(12):2234-2244. doi: 10.1093/ndt/gfy190.
Abstract/Text Background: The Kidney Disease: Improving Global Outcomes guidelines have cautioned against administering intravenous (IV) iron to hemodialysis patients with high serum ferritin levels due to safety concerns, but prior research has shown that the association between high ferritin and mortality could be attributed to confounding by malnutrition and inflammation. Our goal was to better understand the ferritin-mortality association and relative influence of IV iron and inflammation in the USA, where ferritin levels have recently increased dramatically, and in Europe and Japan, where ferritin levels are lower and anemia management practices differ.
Methods: Data from 18 261 patients in Phases 4 and 5 (2009-15) of the international Dialysis Outcomes and Practice Patterns Study, a prospective cohort study, were analyzed. Using Cox regression, we modeled the association between baseline ferritin and 1-year mortality with restricted cubic splines and assessed the impact of potential confounders.
Results: Median ferritin levels were 718 ng/mL in the USA, 405 in Europe and 83 in Japan. High ferritin levels were associated with elevated mortality (relative to region-specific medians) in all three regions. The strength of this association was attenuated more by adjustment for malnutrition and inflammation than by IV iron and erythropoiesis-stimulating agent dose in each region.
Conclusion: The utility of high ferritin as a biomarker for clinical risk due to excess iron stores may be limited, although caution regarding IV iron dosing to higher upper ferritin targets remains warranted. Research to resolve biomarker criteria for iron dosing, and whether optimal anemia management strategies differ internationally, is still needed.

PMID 30010940  Nephrol Dial Transplant. 2018 Dec 1;33(12):2234-2244. d・・・

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