今日の臨床サポート

慢性腎臓病(CKD)

著者: 山縣邦弘 筑波大学 医学医療系 腎臓内科学

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:2020/05/21
患者向け説明資料

概要・推奨   

  1. 健診での蛋白尿などの腎障害の存在が疑われる場合、血清クレアチニンをもとに推算されるGFRが60未満と推定される場合、無症候であってもCKDの存在を疑い、再検査を含めた評価を行う(推奨度1)。
  1. GFR低下がある場合、尿検査(蛋白尿、血尿、円柱尿の有無)を実施し、その原因検索を行う。
  1. CKDの定義に従い検尿異常などの腎障害、腎機能低下が3カ月以上持続する場合CKDと診断する。
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  1. 以下のような場合、腎生検の施行を考慮する必要がある(推奨度2、フローチャート1)[1]
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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:
山縣邦弘 : 講演料(アステラス製薬,アストラゼネカ,協和キリン,第一三共,田辺三菱製薬),奨学(奨励)寄付など(中外製薬,帝人ファーマ,アステラス製薬,協和キリン)[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. 腎臓を専門としない医師、一般医向けのCKD診療ガイドラインとして「エビデンスに基づくCKD診療ガイドライン 2018」が作成され、腎専門医向けには「腎障害進展予防と腎代替療法へのスムーズな移行 CKDステージG3b~5診療ガイドライン2017」、さらに腎臓疾患の生活習慣の改善を含めた集学的「腎臓リハビリテーションガイドライン」が相次いで発刊されたため、これらを踏まえ改訂を行った。

病態・疫学・診察

疾患情報  
ポイント:
  1. 慢性腎臓病(CKD)の定義:2002年にK/DOQIが定めた定義が使われている[2]
  1. NKF‒K/DOQI により2002年に提唱されたCKDの重症度分類は、2002、2009、2011年の見直しを経て、現在、日本人用に改変された定義が用いられている。なお、この定義に厳密に従うと米国で人口の8.4%が、日本では人口の12.9%がCKDに該当することになる。したがって、CKDは、頻度の高い状態で、早期発見と病気の進行の予防を主眼にした管理が必要となる。
  1. CKDの頻度は高齢者ほど高い。56万人の特定健診のデータからは、40歳代11%、50歳代14%、60歳代19%、70歳代25%ということが示されている。また、CKDにおけるA1(蛋白尿陰性)の頻度も、40歳代54%、50歳代66%、60歳代73%、70歳代74%であった。すなわち、CKDは高齢者で頻度が高く、その多くは腎硬化症(腎内小動脈や細動脈の硬化性病変による腎障害)が主体と思われる[3]
  1. なお、GFR 45mL/分/1.73m2未満の患者では、全死亡、心血管死亡、末期腎不全への進行および急性腎障害の罹患率が急激に増加することも知られている。末期腎不全、心血管疾患(CVD)の発症の危険は糸球体濾過量(GFR)が低下するほど高くなり、尿蛋白(尿アルブミン)が増加しても高くなる。そのため、CKDの重症度はGFRと尿蛋白(尿アルブミン)によって定義づけられている。
 
CKDの重症度分類

GFRと尿蛋白(アルブミン)量でCKDの重症度(末期腎不全と心血管疾患のリスク)を色分けして表している。日本では尿中アルブミンは糖尿病腎症のみ保険適用があるため、糖尿病以外では尿蛋白を使うように表に追加している。赤のところは緑のところに比べて、心血管疾患の発症は数倍から10倍程度であるが、末期腎不全の発症は、数百倍から千倍にもなる。

問診・診察のポイント  
  1. CKDは血清クレアチニン測定と尿検査で、簡便に診断できる。それゆえ、このような概念が提唱された。診断後の治療・管理を適正に行うためには以下の3ステップに沿って評価を行うことが必須である。

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11月30日(火)までにお申込みいただくと、
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文献 

著者: National Kidney Foundation
雑誌名: Am J Kidney Dis. 2002 Feb;39(2 Suppl 1):S1-266.
Abstract/Text
PMID 11904577  Am J Kidney Dis. 2002 Feb;39(2 Suppl 1):S1-266.
著者: Seiichi Matsuo, Enyu Imai, Masaru Horio, Yoshinari Yasuda, Kimio Tomita, Kosaku Nitta, Kunihiro Yamagata, Yasuhiko Tomino, Hitoshi Yokoyama, Akira Hishida, Collaborators developing the Japanese equation for estimated GFR
雑誌名: Am J Kidney Dis. 2009 Jun;53(6):982-92. doi: 10.1053/j.ajkd.2008.12.034. Epub 2009 Apr 1.
Abstract/Text BACKGROUND: Estimation of glomerular filtration rate (GFR) is limited by differences in creatinine generation among ethnicities. Our previously reported GFR-estimating equations for Japanese had limitations because all participants had a GFR less than 90 mL/min/1.73 m2 and serum creatinine was assayed in different laboratories.
STUDY DESIGN: Diagnostic test study using a prospective cross-sectional design. New equations were developed in 413 participants and validated in 350 participants. All samples were assayed in a central laboratory.
SETTING & PARTICIPANTS: Hospitalized Japanese patients in 80 medical centers. Patients had not participated in the previous study.
REFERENCE TEST: Measured GFR (mGFR) computed from inulin clearance.
INDEX TEST: Estimated GFR (eGFR) by using the modified isotope dilution mass spectrometry (IDMS)-traceable 4-variable Modification of Diet in Renal Disease (MDRD) Study equation using the previous Japanese Society of Nephrology Chronic Kidney Disease Initiative (JSN-CKDI) coefficient of 0.741 (equation 1), the previous JSN-CKDI equation (equation 2), and new equations derived in the development data set: modified MDRD Study using a new Japanese coefficient (equation 3), and a 3-variable Japanese equation (equation 4).
MEASUREMENTS: Performance of equations was assessed by means of bias (eGFR - mGFR), accuracy (percentage of estimates within 15% or 30% of mGFR), root mean squared error, and correlation coefficient.
RESULTS: In the development data set, the new Japanese coefficient was 0.808 (95% confidence interval, 0.728 to 0.829) for the IDMS-MDRD Study equation (equation 3), and the 3-variable Japanese equation (equation 4) was eGFR (mL/min/1.73 m2) = 194 x Serum creatinine(-1.094) x Age(-0.287) x 0.739 (if female). In the validation data set, bias was -1.3 +/- 19.4 versus -5.9 +/- 19.0 mL/min/1.73 m2 (P = 0.002), and accuracy within 30% of mGFR was 73% versus 72% (P = 0.6) for equation 3 versus equation 1 and -2.1 +/- 19.0 versus -7.9 +/- 18.7 mL/min/1.73 m(2) (P < 0.001) and 75% versus 73% (P = 0.06) for equation 4 versus equation 2 (P = 0.06), respectively.
LIMITATION: Most study participants had chronic kidney disease, and some may have had changing GFRs.
CONCLUSION: The new Japanese coefficient for the modified IDMS-MDRD Study equation and the new Japanese equation are more accurate for the Japanese population than the previously reported equations.

PMID 19339088  Am J Kidney Dis. 2009 Jun;53(6):982-92. doi: 10.1053/j.・・・
著者: Yoshihiro Tani, Masaaki Nakayama, Hiroyuki Terawaki, Kunitoshi Iseki, Tsuyoshi Watanabe
雑誌名: Clin Nephrol. 2015 Nov;84(5):270-3. doi: 10.5414/CN108332.
Abstract/Text BACKGROUND: Albuminuria is thought to reflect generalized endothelial dysfunction. In hypertensive patients, albuminuria is related to the risk for cardiovascular disease (CVD) events. Thus, screening for albuminuria is critical for risk stratification in hypertensive patients. However, the actual state of albuminuria in Japanese patients without diabetes remains unclear due to insurance coverage.
METHODS: The CLINITEK microalb creatinine test® is a urine test paper that can assess albumin excretion corrected for urine creatinine levels in only 60 seconds without any special equipment. The semi-quantitative albuminuria test and urine proteinuria test were performed on 8,181 Japanese hypertensive patients, and the clinical significance of the test was evaluated by comparison with the urine test strip method.
RESULTS: Albumin creatinine ratio (ACR) < 30 mg/g creatinine, ACR 30 - 299 mg/g creatinine, and ACR ≥ 300 mg/g creatinine on the albuminuria test were present in 70.0%, 25.7%, and 4.3%, respectively, of patients with a negative urine protein test strip result. Furthermore, in patients with a negative urine protein test strip result, ACR ≥ 30 mg/g creatinine was independently associated with previous CVD (odds ratio: 1.25, 95% confidence interval: 1.00 - 1.57, p < 0.05) after adjustment for estimated glomerular filtration rate, age, sex, BMI, smoking, dyslipidemia, diabetes, and blood pressure categories on multivariate logistic regression analysis.
CONCLUSIONS: We considered that urine test strip was inadequate test to evaluate albuminuria. Easy and quick albuminuria test on the CLINITEK MICROALB CREATININE TEST might be useful test to risk stratification of hypertensive patients compared to urine test strip.

PMID 26445001  Clin Nephrol. 2015 Nov;84(5):270-3. doi: 10.5414/CN1083・・・
著者: H Köhler, E Wandel, B Brunck
雑誌名: Kidney Int. 1991 Jul;40(1):115-20.
Abstract/Text Erythrocyte morphology by phase contrast microscopic examination (PCM) of the urine is widely employed in distinguishing glomerular from nonglomerular bleeding. The proposed percentages of dysmorphic red cells are significant for glomerular bleeding in the range of 10 to 80% in the literature, because there is no clear cut definition of "dysmorphism." In the present study midstream urine samples of 351 patients with hematuria (greater than 8 erythrocytes/microliters) and of 33 healthy controls were examined. The various dysmorphic red cells were analyzed by PCM according to a detailed hematological classification. Most of the dysmorphic red cells, such as echinocytes, anulocytes, ghost cells, schizocytes, stomatocytes, codocytes and knizocytes, occurred in glomerular or nonglomerular disease as well, and proved to be uncharacteristic for glomerular bleeding. In contrast, a unique red cell deformity, a ringform with vesicle-shaped protrusions (acanthocyte) closely correlated to glomerular disease. In biopsy proven glomerulonephritis acanthocytes comprised 12.4% of all excreted red cells, whereas in nonglomerular diseases or in healthy subjects acanthocytes were seen very rarely (less than 2%) or not at all. Acanthocyturia greater than or equal to 5% (of excreted red cells) was seen in 75 out of 143 patients with proven glomerulonephritis (sensitivity 52%) and in four out of 187 patients with nonglomerular disease (specificity 98%). To improve the diagnostic value of erythrocyte morphology the diagnostic workup should focus on acanthocyturia, which is also indicative in very low erythrocyte counts.

PMID 1921146  Kidney Int. 1991 Jul;40(1):115-20.
著者: G Fuiano, G Mazza, N Comi, A Caglioti, L De Nicola, C Iodice, M Andreucci, V E Andreucci
雑誌名: Am J Kidney Dis. 2000 Mar;35(3):448-57.
Abstract/Text Indications for renal biopsy are still ill defined. We recently sent a detailed questionnaire to 360 nephrologists in different areas of the world with the aim of providing information on this critical issue by evaluating the replies. The questionnaire was organized in four sections that included questions on renal biopsy indications in patients with normal renal function, renal insufficiency, and a transplanted kidney. In addition, the questions included methods applied to each renal biopsy procedure and to specimen processing. We received 166 replies; North Europe (50 replies), South Europe (47 replies), North America (31 replies), Australia and New Zealand (24 replies), and other countries (14 replies). In patients with normal renal function, primary indications for renal biopsy were microhematuria associated with proteinuria, particularly greater than 1 g/d of protein. In chronic renal insufficiency, kidney dimension was the major parameter considered before renal biopsy, whereas the presence of diabetes or serological abnormalities was not considered critical. In the course of acute renal failure (ARF) of unknown origin, 20% of the respondents would perform renal biopsy in the early stages, 26% after 1 week of nonrecovery, and 40% after 4 weeks. In a transplanted kidney, the majority of nephrologists would perform a renal biopsy in the case of graft failure after surgery, ARF after initial good function, slow progressive deterioration of renal function, and onset of nephrotic proteinuria. The last section provided comprehensive information on the technical aspects of renal biopsy. This survey represents the first attempt to provide a reliable consensus that can be used in developing guidelines on the use of kidney biopsy.

PMID 10692270  Am J Kidney Dis. 2000 Mar;35(3):448-57.
著者: A E Parrish
雑誌名: Clin Nephrol. 1992 Sep;38(3):135-41.
Abstract/Text Over a period of 37 years we performed renal biopsies 1812 times in 1638 subjects. Tissue adequate for interpretation was obtained in 1593 subjects (88%). Complications occurred in 7% of the total biopsies performed, consisting of gross hematuria lasting for more than 12 hours (3%), pain lasting for more than 12 hours (4%), a palpable hematoma (1%), infection (0.2%), and death (0.2%). Complications were higher when the biopsy yielded unsatisfactory samples (9.5%), although there were no deaths. Complications were not related to age but an elevated BUN appeared to be associated with a higher rate of complications, although this was not statistically significant. Deaths appeared to occur at unpredictable intervals and in retrospect could not have been foreseen.

PMID 1395165  Clin Nephrol. 1992 Sep;38(3):135-41.
著者: Raymond Vanholder, Rita De Smet, Griet Glorieux, Angel Argilés, Ulrich Baurmeister, Philippe Brunet, William Clark, Gerald Cohen, Peter Paul De Deyn, Reinhold Deppisch, Beatrice Descamps-Latscha, Thomas Henle, Achim Jörres, Horst Dieter Lemke, Ziad A Massy, Jutta Passlick-Deetjen, Mariano Rodriguez, Bernd Stegmayr, Peter Stenvinkel, Ciro Tetta, Christoph Wanner, Walter Zidek, European Uremic Toxin Work Group (EUTox)
雑誌名: Kidney Int. 2003 May;63(5):1934-43. doi: 10.1046/j.1523-1755.2003.00924.x.
Abstract/Text BACKGROUND: The choice of the correct concentration of potential uremic toxins for in vitro, ex vivo, and in vivo experiments remains a major area of concern; errors at this level might result in incorrect decisions regarding therpeutic correction of uremia and related clinical complications.
METHODS: An encyclopedic list of uremic retention solutes was composed, containing their mean normal concentration (CN), their highest mean/median uremic concentration (CU), their highest concentration ever reported in uremia (CMAX), and their molecular weight. A literature search of 857 publications on uremic toxicity resulted in the selection of data reported in 55 publications on 90 compounds, published between 1968 and 2002.
RESULTS: For all compounds, CU and/or CMAX exceeded CN. Molecular weight was lower than 500 D for 68 compounds; of the remaining 22 middle molecules, 12 exceeded 12,000 D. CU ranged from 32.0 ng/L (methionine-enkephalin) up to 2.3 g/L (urea). CU in the ng/L range was found especially for the middle molecules (10/22; 45.5%), compared with 2/68 (2.9%) for a molecular weight <500 D (P < 0.002). Twenty-five solutes (27.8%) were protein bound. Most of them had a molecular weight <500 D except for leptin and retinol-binding protein. The ratio CU/CN, an index of the concentration range over which toxicity is exerted, exceeded 15 in the case of 20 compounds. The highest values were registered for several guanidines, protein-bound compounds, and middle molecules, to a large extent compounds with known toxicity. A ratio of CMAX/CU <4, pointing to a Gaussian distribution, was found for the majority of the compounds (74/90; 82%). For some compounds, however, this ratio largely exceeded 4 [e.g., for leptin (6.81) or indole-3-acetic acid (10.37)], pointing to other influencing factors than renal function, such as gender, genetic predisposition, proteolytic breakdown, posttranslation modification, general condition, or nutritional status.
CONCLUSION: Concentrations of retention solutes in uremia vary over a broad range, from nanograms per liter to grams per liter. Low concentrations are found especially for the middle molecules. A substantial number of molecules are protein bound and/or middle molecules, and many of these exert toxicity and are characterized by a high range of toxic over normal concentration (CU/CN ratio). Hence, uremic retention is a complex problem that concerns many more solutes than the current markers of urea and creatinine alone. This list provides a basis for systematic analytic approaches to map the relative importance of the enlisted families of toxins.

PMID 12675874  Kidney Int. 2003 May;63(5):1934-43. doi: 10.1046/j.1523・・・
著者: F Gejyo, N Homma, Y Suzuki, M Arakawa
雑誌名: N Engl J Med. 1986 Feb 27;314(9):585-6. doi: 10.1056/NEJM198602273140920.
Abstract/Text
PMID 3080684  N Engl J Med. 1986 Feb 27;314(9):585-6. doi: 10.1056/NE・・・
著者: Raymond Vanholder, Eva Schepers, Anneleen Pletinck, Evi V Nagler, Griet Glorieux
雑誌名: J Am Soc Nephrol. 2014 Sep;25(9):1897-907. doi: 10.1681/ASN.2013101062. Epub 2014 May 8.
Abstract/Text A growing number of publications supports a biologic effect of the protein-bound uremic retention solutes indoxyl sulfate and p-cresyl sulfate. However, the use of unrealistically high free concentrations of these compounds and/or inappropriately low albumin concentrations may blur the interpretation of these results. Here, we performed a systematic review, selecting only studies in which, depending on the albumin concentration, real or extrapolated free concentrations of indoxyl sulfate and p-cresyl sulfate remained in the uremic range. The 27 studies retrieved comprised in vitro and animal studies. A quality score was developed, giving 1 point for each of the following criteria: six or more experiments, confirmation by more than one experimental approach, neutralization of the biologic effect by counteractive reagents or antibodies, use of a real-life model, and use of dose-response analyses in vitro and/or animal studies. The overall average score was 3 of 5 points, with five studies scoring 5 of 5 points and six studies scoring 4 of 5 points, highlighting the superior quality of a substantial number of the retrieved studies. In the 11 highest scoring studies, most functional deteriorations were related to uremic cardiovascular disease and kidney damage. We conclude that our systematic approach allowed the retrieval of methodologically correct studies unbiased by erroneous conditions related to albumin binding. Our data seem to confirm the toxicity of indoxyl sulfate and p-cresyl sulfate and support their roles in vascular and renal disease progression.

Copyright © 2014 by the American Society of Nephrology.
PMID 24812165  J Am Soc Nephrol. 2014 Sep;25(9):1897-907. doi: 10.1681・・・
著者: Andrew S Levey, Paul E de Jong, Josef Coresh, Meguid El Nahas, Brad C Astor, Kunihiro Matsushita, Ron T Gansevoort, Bertram L Kasiske, Kai-Uwe Eckardt
雑誌名: Kidney Int. 2011 Jul;80(1):17-28. doi: 10.1038/ki.2010.483. Epub 2010 Dec 8.
Abstract/Text The definition and classification for chronic kidney disease was proposed by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) in 2002 and endorsed by the Kidney Disease: Improving Global Outcomes (KDIGO) in 2004. This framework promoted increased attention to chronic kidney disease in clinical practice, research and public health, but has also generated debate. It was the position of KDIGO and KDOQI that the definition and classification should reflect patient prognosis and that an analysis of outcomes would answer key questions underlying the debate. KDIGO initiated a collaborative meta-analysis and sponsored a Controversies Conference in October 2009 to examine the relationship of estimated glomerular filtration rate (GFR) and albuminuria to mortality and kidney outcomes. On the basis of analyses in 45 cohorts that included 1,555,332 participants from general, high-risk, and kidney disease populations, conference attendees agreed to retain the current definition for chronic kidney disease of a GFR <60 ml/min per 1.73 m(2) or a urinary albumin-to-creatinine ratio >30 mg/g, and to modify the classification by adding albuminuria stage, subdivision of stage 3, and emphasizing clinical diagnosis. Prognosis could then be assigned based on the clinical diagnosis, stage, and other key factors relevant to specific outcomes. KDIGO has now convened a workgroup to develop a global clinical practice guideline for the definition, classification, and prognosis of chronic kidney disease.

PMID 21150873  Kidney Int. 2011 Jul;80(1):17-28. doi: 10.1038/ki.2010.・・・
著者: Jicheng Lv, Parya Ehteshami, Mark J Sarnak, Hocine Tighiouart, Min Jun, Toshiharu Ninomiya, Celine Foote, Anthony Rodgers, Hong Zhang, Haiyan Wang, Giovanni F M Strippoli, Vlado Perkovic
雑誌名: CMAJ. 2013 Aug 6;185(11):949-57. doi: 10.1503/cmaj.121468. Epub 2013 Jun 24.
Abstract/Text BACKGROUND: Recent guidelines suggest lowering the target blood pressure for patients with chronic kidney disease, although the strength of evidence for this suggestion has been uncertain. We sought to assess the renal and cardiovascular effects of intensive blood pressure lowering in people with chronic kidney disease.
METHODS: We performed a systematic review and meta-analysis of all relevant reports published between 1950 and July 2011 identified in a search of MEDLINE, Embase and the Cochrane Library. We included randomized trials that assigned patients with chronic kidney disease to different target blood pressure levels and reported kidney failure or cardiovascular events. Two reviewers independently identified relevant articles and extracted data.
RESULTS: We identified 11 trials providing information on 9287 patients with chronic kidney disease and 1264 kidney failure events (defined as either a composite of doubling of serum creatinine level and 50% decline in glomerular filtration rate, or end-stage kidney disease). Compared with standard regimens, a more intensive blood pressure-lowering strategy reduced the risk of the composite outcome (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.68-0.98) and end-stage kidney disease (HR 0.79, 95% CI 0.67-0.93). Subgroup analysis showed effect modification by baseline proteinuria (p = 0.006) and markers of trial quality. Intensive blood pressure lowering reduced the risk of kidney failure (HR 0.73, 95% CI 0.62-0.86), but not in patients without proteinuria at baseline (HR 1.12, 95% CI 0.67-1.87). There was no clear effect on the risk of cardiovascular events or death.
INTERPRETATION: Intensive blood pressure lowering appears to provide protection against kidney failure events in patients with chronic kidney disease, particularly among those with proteinuria. More data are required to determine the effects of such a strategy among patients without proteinuria.

PMID 23798459  CMAJ. 2013 Aug 6;185(11):949-57. doi: 10.1503/cmaj.1214・・・
著者: Hirofumi Makino, Masakazu Haneda, Tetsuya Babazono, Tatsumi Moriya, Sadayoshi Ito, Yasuhiko Iwamoto, Ryuzo Kawamori, Masahiro Takeuchi, Shigehiro Katayama, INNOVATION Study Group
雑誌名: Diabetes Care. 2007 Jun;30(6):1577-8. doi: 10.2337/dc06-1998. Epub 2007 Mar 26.
Abstract/Text
PMID 17389334  Diabetes Care. 2007 Jun;30(6):1577-8. doi: 10.2337/dc06・・・
著者: Suetonia C Palmer, Sankar D Navaneethan, Jonathan C Craig, David W Johnson, Vlado Perkovic, Jorgen Hegbrant, Giovanni F M Strippoli
雑誌名: Cochrane Database Syst Rev. 2014 May 31;5:CD007784. doi: 10.1002/14651858.CD007784.pub2. Epub 2014 May 31.
Abstract/Text BACKGROUND: Cardiovascular disease (CVD) is the most frequent cause of death in people with early stages of chronic kidney disease (CKD), for whom the absolute risk of cardiovascular events is similar to people who have existing coronary artery disease. This is an update of a review published in 2009, and includes evidence from 27 new studies (25,068 participants) in addition to the 26 studies (20,324 participants) assessed previously; and excludes three previously included studies (107 participants). This updated review includes 50 studies (45,285 participants); of these 38 (37,274 participants) were meta-analysed.
OBJECTIVES: To evaluate the benefits (such as reductions in all-cause and cardiovascular mortality, major cardiovascular events, MI and stroke; and slow progression of CKD to end-stage kidney disease (ESKD)) and harms (muscle and liver dysfunction, withdrawal, and cancer) of statins compared with placebo, no treatment, standard care or another statin in adults with CKD who were not on dialysis.
SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register to 5 June 2012 through contact with the Trials' Search Co-ordinator using search terms relevant to this review.
SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs that compared the effects of statins with placebo, no treatment, standard care, or other statins, on mortality, cardiovascular events, kidney function, toxicity, and lipid levels in adults with CKD not on dialysis were the focus of our literature searches.
DATA COLLECTION AND ANALYSIS: Two or more authors independently extracted data and assessed study risk of bias. Treatment effects were expressed as mean difference (MD) for continuous outcomes (lipids, creatinine clearance and proteinuria) and risk ratio (RR) for dichotomous outcomes (major cardiovascular events, all-cause mortality, cardiovascular mortality, fatal or non-fatal myocardial infarction (MI), fatal or non-fatal stroke, ESKD, elevated liver enzymes, rhabdomyolysis, cancer and withdrawal rates) with 95% confidence intervals (CI).
MAIN RESULTS: We included 50 studies (45,285 participants): 47 studies (39,820 participants) compared statins with placebo or no treatment and three studies (5547 participants) compared two different statin regimens in adults with CKD who were not yet on dialysis. We were able to meta-analyse 38 studies (37,274 participants).The risk of bias in the included studies was high. Seven studies comparing statins with placebo or no treatment had lower risk of bias overall; and were conducted according to published protocols, outcomes were adjudicated by a committee, specified outcomes were reported, and analyses were conducted using intention-to-treat methods. In placebo or no treatment controlled studies, adverse events were reported in 32 studies (68%) and systematically evaluated in 16 studies (34%).Compared with placebo, statin therapy consistently prevented major cardiovascular events (13 studies, 36,033 participants; RR 0.72, 95% CI 0.66 to 0.79), all-cause mortality (10 studies, 28,276 participants; RR 0.79, 95% CI 0.69 to 0.91), cardiovascular death (7 studies, 19,059 participants; RR 0.77, 95% CI 0.69 to 0.87) and MI (8 studies, 9018 participants; RR 0.55, 95% CI 0.42 to 0.72). Statins had uncertain effects on stroke (5 studies, 8658 participants; RR 0.62, 95% CI 0.35 to 1.12).Potential harms from statin therapy were limited by lack of systematic reporting and were uncertain in analyses that had few events: elevated creatine kinase (7 studies, 4514 participants; RR 0.84, 95% CI 0.20 to 3.48), liver function abnormalities (7 studies, RR 0.76, 95% CI 0.39 to 1.50), withdrawal due to adverse events (13 studies, 4219 participants; RR 1.16, 95% CI 0.84 to 1.60), and cancer (2 studies, 5581 participants; RR 1.03, 95% CI 0.82 to 130).Statins had uncertain effects on progression of CKD. Data for relative effects of intensive cholesterol lowering in people with early stages of kidney disease were sparse. Statins clearly reduced risks of death, major cardiovascular events, and MI in people with CKD who did not have CVD at baseline (primary prevention).
AUTHORS' CONCLUSIONS: Statins consistently lower death and major cardiovascular events by 20% in people with CKD not requiring dialysis. Statin-related effects on stroke and kidney function were found to be uncertain and adverse effects of treatment are incompletely understood. Statins have an important role in primary prevention of cardiovascular events and mortality in people who have CKD.

PMID 24880031  Cochrane Database Syst Rev. 2014 May 31;5:CD007784. doi・・・
著者: Kunitoshi Iseki, Yoshiharu Ikemiya, Taku Inoue, Chiho Iseki, Kozen Kinjo, Shuichi Takishita
雑誌名: Am J Kidney Dis. 2004 Oct;44(4):642-50.
Abstract/Text BACKGROUND: Uric acid may be a true mediator of renal disease and progression. However, epidemiological evidence for the significance of serum uric acid levels on the risk for developing end-stage renal disease (ESRD) is scarce in a setting of community-based screening.
METHODS: Participants in a 1993 mass screening conducted by the Okinawa General Health Maintenance Association in Okinawa, Japan, were investigated: 48,177 screenees (22,949 men, 25,228 women) older than 20 years for whom serum uric acid data were available were studied. All dialysis patients treated in Okinawa were independently registered in the Okinawa Dialysis Study registry. Participants in the 1993 screening who later entered a dialysis program were identified by using 2 computer registries. The cumulative incidence of ESRD was calculated according to quartiles of baseline serum uric acid levels for each sex. The significance of hyperuricemia (serum uric acid level > or = 7.0 mg/dL [> or =416 micromol/L] in men and > or = 6.0 mg/dL [> or =357 micromol/L] in women) for the risk for developing ESRD was evaluated by means of the Cox model after adjusting for age, blood pressure, body mass index, proteinuria, hematocrit, and total cholesterol, triglyceride, fasting blood glucose, and serum creatinine levels.
RESULTS: Mean serum uric acid level was 6.4 +/- 1.4 (SD) mg/dL (381 micromol/L) in men and 4.8 +/- 1.1 mg/dL (286 micromol/L) in women. Prevalences of hyperuricemia were 31.9% in men and 13.6% in women. By the end of 2000, a total of 103 screenees (53 men, 50 women) entered dialysis programs. Calculated incidences of ESRD per 1,000 screenees were 1.22 for men without hyperuricemia and 4.64 for men with hyperuricemia and 0.87 for women without hyperuricemia and 9.03 for women with hyperuricemia. Adjusted hazard ratios for hyperuricemia were 2.004 (95% confidence interval, 0.904 to 4.444; P = not significant) in men and 5.770 (95% confidence interval, 2.309 to 14.421; P = 0.0002) in women.
CONCLUSION: Screenees with hyperuricemia were associated with a greater incidence of ESRD. Hyperuricemia (serum uric acid > or = 6.0 mg/dL [> or =357 micromol/L]) was an independent predictor of ESRD in women. Strategies to control serum uric acid levels in the normal range may reduce the population burden of ESRD.

PMID 15384015  Am J Kidney Dis. 2004 Oct;44(4):642-50.
著者: Yui-Pong Siu, Kay-Tai Leung, Matthew Ka-Hang Tong, Tze-Hoi Kwan
雑誌名: Am J Kidney Dis. 2006 Jan;47(1):51-9. doi: 10.1053/j.ajkd.2005.10.006.
Abstract/Text BACKGROUND: Hyperuricemia is associated strongly with the development of hypertension, renal disease, and progression. Allopurinol decreases serum uric acid levels by inhibiting the enzyme xanthine oxidase. We hypothesized that administrating allopurinol to decrease serum uric acid levels to the normal range in hyperuricemic patients with chronic kidney disease may be of benefit in decreasing blood pressure and slowing the rate of renal disease progression in these patients.
METHODS: We conducted a prospective, randomized, controlled trial of 54 hyperuricemic patients with chronic kidney disease. Patients were randomly assigned to treatment with allopurinol, 100 to 300 mg/d, or to continue the usual therapy for 12 months. Clinical, hematologic, and biochemical parameters were measured at baseline and 3, 6, and 12 months of treatment. We define our study end points as: (1) stable kidney function with less than 40% increase in serum creatinine level, (2) impaired renal function with creatinine level increase greater than 40% of baseline value, (3) initiation of dialysis therapy, and (4) death.
RESULTS: One patient in the treatment group dropped out because of skin allergy to allopurinol. Serum uric acid levels were significantly decreased in subjects treated with allopurinol, from 9.75 +/- 1.18 mg/dL (0.58 +/- 0.07 mmol/L) to 5.88 +/- 1.01 mg/dL (0.35 +/- 0.06 mmol/L; P < 0.001). There were no significant differences in systolic or diastolic blood pressure at the end of the study comparing the 2 groups. There was a trend toward a lower serum creatinine level in the treatment group compared with controls after 12 months of therapy, although it did not reach statistical significance (P = 0.08). Overall, 4 of 25 patients (16%) in the allopurinol group reached the combined end points of significant deterioration in renal function and dialysis dependence compared with 12 of 26 patients (46.1%) in the control group (P = 0.015).
CONCLUSION: Allopurinol therapy significantly decreases serum uric acid levels in hyperuricemic patients with mild to moderate chronic kidney disease. Its use is safe and helps preserve kidney function during 12 months of therapy compared with controls. Results of this study need to be confirmed with an additional prospective trial involving a larger cohort of patients to determine the long-term efficacy of allopurinol therapy and in specific chronic kidney disease subpopulations.

PMID 16377385  Am J Kidney Dis. 2006 Jan;47(1):51-9. doi: 10.1053/j.aj・・・
著者: Marian Goicoechea, Soledad García de Vinuesa, Ursula Verdalles, Caridad Ruiz-Caro, Jara Ampuero, Abraham Rincón, David Arroyo, José Luño
雑誌名: Clin J Am Soc Nephrol. 2010 Aug;5(8):1388-93. doi: 10.2215/CJN.01580210. Epub 2010 Jun 10.
Abstract/Text BACKGROUND AND OBJECTIVES: Hyperuricemia is associated with hypertension, inflammation, renal disease progression, and cardiovascular disease. However, no data are available regarding the effect of allopurinol in patients with chronic kidney disease.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a prospective, randomized trial of 113 patients with estimated GFR (eGFR) <60 ml/min. Patients were randomly assigned to treatment with allopurinol 100 mg/d (n = 57) or to continue the usual therapy (n = 56). Clinical, biochemical, and inflammatory parameters were measured at baseline and at 6, 12, and 24 months of treatment. The objectives of study were: (1) renal disease progression; (2) cardiovascular events; and (3) hospitalizations of any causes.
RESULTS: Serum uric acid and C-reactive protein levels were significantly decreased in subjects treated with allopurinol. In the control group, eGFR decreased 3.3 +/- 1.2 ml/min per 1.73 m(2), and in the allopurinol group, eGFR increased 1.3 +/- 1.3 ml/min per 1.73 m(2) after 24 months. Allopurinol treatment slowed down renal disease progression independently of age, gender, diabetes, C-reactive protein, albuminuria, and renin-angiotensin system blockers use. After a mean follow-up time of 23.4 +/- 7.8 months, 22 patients suffered a cardiovascular event. Diabetes mellitus, previous coronary heart disease, and C-reactive protein levels increased cardiovascular risk. Allopurinol treatment reduces risk of cardiovascular events in 71% compared with standard therapy.
CONCLUSIONS: Allopurinol decreases C-reactive protein and slows down the progression of renal disease in patients with chronic kidney disease. In addition, allopurinol reduces cardiovascular and hospitalization risk in these subjects.

PMID 20538833  Clin J Am Soc Nephrol. 2010 Aug;5(8):1388-93. doi: 10.2・・・
著者: Mehmet Kanbay, Adem Ozkara, Yusuf Selcoki, Bunyamin Isik, Faruk Turgut, Nuket Bavbek, Ebru Uz, Ali Akcay, Ramazan Yigitoglu, Adrian Covic
雑誌名: Int Urol Nephrol. 2007;39(4):1227-33. doi: 10.1007/s11255-007-9253-3. Epub 2007 Aug 15.
Abstract/Text BACKGROUND: Hyperuricemia has been associated with the development of hypertension, cardiovascular, and renal disease. However, there is no data about the effect of lowering uric acid level on hypertension, renal function, and proteinuria in patients with glomerular filtration rate (GFR) >60 ml/min. We therefore conducted a prospective study to investigate the benefits of allopurinol treatment in hyperuricemic patients with normal renal function.
MATERIALS AND METHODS: Forty-eight hyperuricemic and 21 normouricemic patients were included in the study. Hyperuricemic patients received 300 mg/day allopurinol for three months. All patients' serum creatinine level, 24-h urine protein level, glomerular filtration rate, and blood pressure levels were measured at baseline and after three months of treatment.
RESULTS: A total of 59 patients completed the three-month follow-up period of observation. In the allopurinol group, serum uric acid levels, GFR, systolic and diastolic blood pressure, and C-reactive protein (CRP) levels significantly improved (P < 0.05). However, urine protein excretion remained unchanged (P > 0.05). No correlation was observed between changes in GFR and changes in CRP, or blood pressure in the allopurinol group. No significant changes were observed in the control group (P > 0.05).
CONCLUSION: We bring indirect evidence that hyperuricemia increases blood pressure, and decreases GFR. Hence, management of hyperuricemia may prevent the progression of renal disease, even in patients with normal renal function, suggesting that early treatment with allopurinol should be an important part of the management of chronic kidney disease (CKD) patients. Long-term follow-up studies are warranted to identify the benefits of uric acid management on renal function and hypertension.

PMID 17701281  Int Urol Nephrol. 2007;39(4):1227-33. doi: 10.1007/s112・・・
著者: Bhadran Bose, Sunil V Badve, Swapnil S Hiremath, Neil Boudville, Fiona G Brown, Alan Cass, Janak R de Zoysa, Robert G Fassett, Randall Faull, David C Harris, Carmel M Hawley, John Kanellis, Suetonia C Palmer, Vlado Perkovic, Elaine M Pascoe, Gopala K Rangan, Robert J Walker, Giles Walters, David W Johnson
雑誌名: Nephrol Dial Transplant. 2014 Feb;29(2):406-13. doi: 10.1093/ndt/gft378. Epub 2013 Sep 15.
Abstract/Text BACKGROUND: Non-randomized studies suggest an association between serum uric acid levels and progression of chronic kidney disease (CKD). The aim of this systematic review is to summarize evidence from randomized controlled trials (RCTs) concerning the benefits and risks of uric acid-lowering therapy on renal outcomes.
METHODS: Medline, Excerpta Medical Database and Cochrane Central Register of Controlled Trials were searched with English language restriction for RCTs comparing the effect of uric acid-lowering therapy with placebo/no treatment on renal outcomes. Treatment effects were summarized using random-effects meta-analysis.
RESULTS: Eight trials (476 participants) evaluating allopurinol treatment were eligible for inclusion. There was substantial heterogeneity in baseline kidney function, cause of CKD and duration of follow-up across these studies. In five trials, there was no significant difference in change in glomerular filtration rate from baseline between the allopurinol and control arms [mean difference (MD) 3.1 mL/min/1.73 m2, 95% confidence intervals (CI) -0.9, 7.1; heterogeneity χ2=1.9, I2=0%, P=0.75]. In three trials, allopurinol treatment abrogated increases in serum creatinine from baseline (MD -0.4 mg/dL, 95% CI -0.8, -0.0 mg/dL; heterogeneity χ2=3, I2=34%, P=0.22). Allopurinol had no effect on proteinuria and blood pressure. Data for effects of allopurinol therapy on progression to end-stage kidney disease and death were scant. Allopurinol had uncertain effects on the risks of adverse events.
CONCLUSIONS: Uric acid-lowering therapy with allopurinol may retard the progression of CKD. However, adequately powered randomized trials are required to evaluate the benefits and risks of uric acid-lowering therapy in CKD.

PMID 24042021  Nephrol Dial Transplant. 2014 Feb;29(2):406-13. doi: 10・・・
著者: Kenjiro Kimura, Tatsuo Hosoya, Shunya Uchida, Masaaki Inaba, Hirofumi Makino, Shoichi Maruyama, Sadayoshi Ito, Tetsuya Yamamoto, Yasuhiko Tomino, Iwao Ohno, Yugo Shibagaki, Satoshi Iimuro, Naohiko Imai, Masanari Kuwabara, Hiroshi Hayakawa, Hiroshi Ohtsu, Yasuo Ohashi, FEATHER Study Investigators
雑誌名: Am J Kidney Dis. 2018 Dec;72(6):798-810. doi: 10.1053/j.ajkd.2018.06.028. Epub 2018 Sep 1.
Abstract/Text RATIONALE & OBJECTIVE: Epidemiologic and clinical studies have suggested that urate-lowering therapy may slow the progression of chronic kidney disease (CKD). However, definitive evidence is lacking.
STUDY DESIGN: Randomized, double-blind, placebo-controlled trial.
SETTING & PARTICIPANTS: 467 patients with stage 3 CKD and asymptomatic hyperuricemia at 55 medical institutions in Japan.
INTERVENTION: Participants were randomly assigned in a 1:1 ratio to receive febuxostat or placebo for 108 weeks.
OUTCOMES: The primary end point was the slope (in mL/min/1.73m2 per year) of estimated glomerular filtration rate (eGFR). Secondary end points included changes in eGFRs and serum uric acid levels at 24, 48, 72, and 108 weeks of follow-up and the event of doubling of serum creatinine level or initiation of dialysis therapy.
RESULTS: Of 443 patients who were randomly assigned, 219 and 222 assigned to febuxostat and placebo, respectively, were included in the analysis. There was no significant difference in mean eGFR slope between the febuxostat (0.23±5.26mL/min/1.73m2 per year) and placebo (-0.47±4.48mL/min/1.73m2 per year) groups (difference, 0.70; 95% CI, -0.21 to 1.62; P=0.1). Subgroup analysis demonstrated a significant benefit from febuxostat in patients without proteinuria (P=0.005) and for whom serum creatinine concentration was lower than the median (P=0.009). The incidence of gouty arthritis was significantly lower (P=0.007) in the febuxostat group (0.91%) than in the placebo group (5.86%). Adverse events specific to febuxostat were not observed.
LIMITATIONS: GFR was estimated rather than measured, and patients with stages 4 and 5 CKD were excluded.
CONCLUSIONS: Compared to placebo, febuxostat did not mitigate the decline in kidney function among patients with stage 3 CKD and asymptomatic hyperuricemia.
FUNDING: Funded by Teijin Pharma Limited.
TRIAL REGISTRATION: Registered at the UMIN (University Hospital Medical Information Network) Clinical Trials Registry with study number UMIN000008343.

Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
PMID 30177485  Am J Kidney Dis. 2018 Dec;72(6):798-810. doi: 10.1053/j・・・
著者: Sorot Phisitkul, Apurv Khanna, Jan Simoni, Kristine Broglio, Simon Sheather, M Hasan Rajab, Donald E Wesson
雑誌名: Kidney Int. 2010 Apr;77(7):617-23. doi: 10.1038/ki.2009.519. Epub 2010 Jan 13.
Abstract/Text Metabolic acidosis often accompanies low glomerular filtration rate and induces secretion of endothelin, which in turn might mediate kidney injury. Here we tested whether treatment of metabolic acidosis in patients with low glomerular filtration rate reduced the progression of kidney disease. Fifty-nine patients with hypertensive nephropathy and metabolic acidosis had their blood pressure reduced with regimens that included angiotensin-converting enzyme inhibition. Thirty patients were then prescribed sodium citrate, and the remaining 29, unable or unwilling to take sodium citrate, served as controls. All were followed for 24 months with maintenance of their blood pressure reduction. Urine endothelin-1 excretion, a surrogate of kidney endothelin production, and N-acetyl-beta-D-glucosaminidase, a marker of kidney tubulointerstitial injury, were each significantly lower, while the rate of estimated glomerular filtration rate decline was significantly slower. The estimated glomerular filtration rate was statistically higher after 24 months of sodium citrate treatment compared to the control group. Hence it appears that sodium citrate is an effective kidney-protective adjunct to blood pressure reduction and angiotensin-converting enzyme inhibition.

PMID 20072112  Kidney Int. 2010 Apr;77(7):617-23. doi: 10.1038/ki.2009・・・
著者: Sinee Disthabanchong, Akarapong Treeruttanawanich
雑誌名: Am J Nephrol. 2010;32(6):549-56. doi: 10.1159/000321461. Epub 2010 Nov 2.
Abstract/Text BACKGROUND/AIMS: metabolic acidosis (MA) in chronic kidney disease (CKD) associates with protein energy malnutrition, osteoporosis, abnormal endocrine function and increased mortality. Oral sodium bicarbonate has been shown to improve nutritional status and preserve renal function in CKD. Depressed thyroid function has been described in CKD and was believed to be related to MA. This is a prospective randomized study that examined the effect of oral sodium bicarbonate on thyroid function in predialysis CKD with MA.
METHODS: predialysis CKD patients with serum total CO(2) ≤ 22 mM were randomized into two groups. The treatment group received increasing dose of oral sodium bicarbonate until serum total CO(2) was ≥ 24 mM. Control patients were kept on the same medications. Thyroid function tests were measured at baseline and again after 8-12 weeks.
RESULTS: all patients had a glomerular filtration rate <35 ml/min/1.73 m(2). Serum total CO(2) increased significantly in the treatment group and was unchanged in the control group. At baseline, over half of the patients had T3 below the lower limit of normal. At study completion, free T3 declined further in the control group, whereas free T3, total T3, free T4 and TSH rose significantly in the treatment group. Percentage changes of total CO(2) from baseline were strongly associated with the changes of T3 parameters. Glomerular filtration rate was maintained in the treatment group but declined significantly in the control group.
CONCLUSION: oral sodium bicarbonate, through correction of MA, improved thyroid function in predialysis CKD.

2010 S. Karger AG, Basel.
PMID 21042013  Am J Nephrol. 2010;32(6):549-56. doi: 10.1159/000321461・・・
著者: Nan Chen, Chuanming Hao, Xiaomei Peng, Hongli Lin, Aiping Yin, Li Hao, Ye Tao, Xinling Liang, Zhengrong Liu, Changying Xing, Jianghua Chen, Laimin Luo, Li Zuo, Yunhua Liao, Bi-Cheng Liu, Robert Leong, Chunrong Wang, Cameron Liu, Thomas Neff, Lynda Szczech, Kin-Hung P Yu
雑誌名: N Engl J Med. 2019 Sep 12;381(11):1001-1010. doi: 10.1056/NEJMoa1813599. Epub 2019 Jul 24.
Abstract/Text BACKGROUND: Roxadustat (FG-4592) is an oral inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase that stimulates erythropoiesis and regulates iron metabolism. In phase 2 studies involving patients with chronic kidney disease, roxadustat increased levels of endogenous erythropoietin to within or near the physiologic range, along with increasing hemoglobin levels and improving iron homeostasis. Additional data are needed regarding the efficacy and safety of roxadustat for the treatment of anemia in patients with chronic kidney disease who are not undergoing dialysis.
METHODS: In this phase 3 trial conducted at 29 sites in China, we randomly assigned 154 patients with chronic kidney disease in a 2:1 ratio to receive roxadustat or placebo three times a week for 8 weeks in a double-blind manner. All the patients had a hemoglobin level of 7.0 to 10.0 g per deciliter at baseline. The randomized phase of the trial was followed by an 18-week open-label period in which all the patients received roxadustat; parenteral iron was withheld. The primary end point was the mean change from baseline in the hemoglobin level, averaged over weeks 7 through 9.
RESULTS: During the primary-analysis period, the mean (±SD) change from baseline in the hemoglobin level was an increase of 1.9±1.2 g per deciliter in the roxadustat group and a decrease of 0.4±0.8 g per deciliter in the placebo group (P<0.001). The mean reduction from baseline in the hepcidin level (associated with greater iron availability) was 56.14±63.40 ng per milliliter in the roxadustat group and 15.10±48.06 ng per milliliter in the placebo group. The reduction from baseline in the total cholesterol level was 40.6 mg per deciliter in the roxadustat group and 7.7 mg per deciliter in the placebo group. Hyperkalemia and metabolic acidosis occurred more frequently in the roxadustat group than in the placebo group. The efficacy of roxadustat in hemoglobin correction and maintenance was maintained during the 18-week open-label period.
CONCLUSIONS: In Chinese patients with chronic kidney disease who were not undergoing dialysis, those in the roxadustat group had a higher mean hemoglobin level than those in the placebo group after 8 weeks. During the 18-week open-label phase of the trial, roxadustat was associated with continued efficacy. (Funded by FibroGen and FibroGen [China] Medical Technology Development; ClinicalTrials.gov number, NCT02652819.).

Copyright © 2019 Massachusetts Medical Society.
PMID 31340089  N Engl J Med. 2019 Sep 12;381(11):1001-1010. doi: 10.10・・・
著者: Anupama Mohanram, Zhongxin Zhang, Shahnaz Shahinfar, William F Keane, Barry M Brenner, Robert D Toto
雑誌名: Kidney Int. 2004 Sep;66(3):1131-8. doi: 10.1111/j.1523-1755.2004.00863.x.
Abstract/Text BACKGROUND: Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD). Anemia is common in diabetics with nephropathy; however, the impact of anemia on progression to ESRD has not been carefully examined.
METHODS: We studied the relationship between baseline hemoglobin concentration (Hb) and progression of diabetic nephropathy to ESRD in 1513 participants enrolled in Reduction in Endpoints in NIDDM with the Angiotensin II Antagonist Losartan study and followed for an average of 3.4 years. Multivariate Cox proportional hazards models were used to analyze the relationship between Hb and ESRD, after adjusting for predictors for ESRD. Analyses were performed with Hb stratified by quartile: first quartile <11.3 g/dL, second quartile 11.3 to 12.5 g/dL, third quartile 12.6 to 13.8 g/dL, and fourth quartile >/=13.8 g/dL (reference) and as a continuous variable.
RESULTS: Baseline hemoglobin concentration was correlated with subsequent development of ESRD. After adjustment for predictors of ESRD, the hazard ratios for the first, second, and third Hb quartiles were 1.99 (95% CI, 1.34-2.95), 1.61 (95% CI 1.08-2.41), and 1.87 (95% CI 1.25-2.80). With hemoglobin as a continuous variable, the adjusted hazard ratio was 0.90 (95% CI 0.84-0.96, P= 0.0013). The average increase in adjusted relative risk was 11% for each 1 g/dL decrease in hemoglobin concentration.
CONCLUSION: Our data suggest that even mild anemia, Hb <13.8 g/dL increases risk for progression to ESRD. Hemoglobin is an independent risk factor for progression of nephropathy to ESRD in type 2 diabetes.

PMID 15327408  Kidney Int. 2004 Sep;66(3):1131-8. doi: 10.1111/j.1523-・・・
著者: Tilman B Drüeke, Francesco Locatelli, Naomi Clyne, Kai-Uwe Eckardt, Iain C Macdougall, Dimitrios Tsakiris, Hans-Ulrich Burger, Armin Scherhag, CREATE Investigators
雑誌名: N Engl J Med. 2006 Nov 16;355(20):2071-84. doi: 10.1056/NEJMoa062276.
Abstract/Text BACKGROUND: Whether correction of anemia in patients with stage 3 or 4 chronic kidney disease improves cardiovascular outcomes is not established.
METHODS: We randomly assigned 603 patients with an estimated glomerular filtration rate (GFR) of 15.0 to 35.0 ml per minute per 1.73 m2 of body-surface area and mild-to-moderate anemia (hemoglobin level, 11.0 to 12.5 g per deciliter) to a target hemoglobin value in the normal range (13.0 to 15.0 g per deciliter, group 1) or the subnormal range (10.5 to 11.5 g per deciliter, group 2). Subcutaneous erythropoietin (epoetin beta) was initiated at randomization (group 1) or only after the hemoglobin level fell below 10.5 g per deciliter (group 2). The primary end point was a composite of eight cardiovascular events; secondary end points included left ventricular mass index, quality-of-life scores, and the progression of chronic kidney disease.
RESULTS: During the 3-year study, complete correction of anemia did not affect the likelihood of a first cardiovascular event (58 events in group 1 vs. 47 events in group 2; hazard ratio, 0.78; 95% confidence interval, 0.53 to 1.14; P=0.20). Left ventricular mass index remained stable in both groups. The mean estimated GFR was 24.9 ml per minute in group 1 and 24.2 ml per minute in group 2 at baseline and decreased by 3.6 and 3.1 ml per minute per year, respectively (P=0.40). Dialysis was required in more patients in group 1 than in group 2 (127 vs. 111, P=0.03). General health and physical function improved significantly (P=0.003 and P<0.001, respectively, in group 1, as compared with group 2). There was no significant difference in the combined incidence of adverse events between the two groups, but hypertensive episodes and headaches were more prevalent in group 1.
CONCLUSIONS: In patients with chronic kidney disease, early complete correction of anemia does not reduce the risk of cardiovascular events. (ClinicalTrials.gov number, NCT00321919 [ClinicalTrials.gov].).

Copyright 2006 Massachusetts Medical Society.
PMID 17108342  N Engl J Med. 2006 Nov 16;355(20):2071-84. doi: 10.1056・・・
著者: Ajay K Singh, Lynda Szczech, Kezhen L Tang, Huiman Barnhart, Shelly Sapp, Marsha Wolfson, Donal Reddan, CHOIR Investigators
雑誌名: N Engl J Med. 2006 Nov 16;355(20):2085-98. doi: 10.1056/NEJMoa065485.
Abstract/Text BACKGROUND: Anemia, a common complication of chronic kidney disease, usually develops as a consequence of erythropoietin deficiency. Recombinant human erythropoietin (epoetin alfa) is indicated for the correction of anemia associated with this condition. However, the optimal level of hemoglobin correction is not defined.
METHODS: In this open-label trial, we studied 1432 patients with chronic kidney disease, 715 of whom were randomly assigned to receive a dose of epoetin alfa targeted to achieve a hemoglobin level of 13.5 g per deciliter and 717 of whom were assigned to receive a dose targeted to achieve a level of 11.3 g per deciliter. The median study duration was 16 months. The primary end point was a composite of death, myocardial infarction, hospitalization for congestive heart failure (without renal replacement therapy), and stroke.
RESULTS: A total of 222 composite events occurred: 125 events in the high-hemoglobin group, as compared with 97 events in the low-hemoglobin group (hazard ratio, 1.34; 95% confidence interval, 1.03 to 1.74; P=0.03). There were 65 deaths (29.3%), 101 hospitalizations for congestive heart failure (45.5%), 25 myocardial infarctions (11.3%), and 23 strokes (10.4%). Seven patients (3.2%) were hospitalized for congestive heart failure and myocardial infarction combined, and one patient (0.5%) died after having a stroke. Improvements in the quality of life were similar in the two groups. More patients in the high-hemoglobin group had at least one serious adverse event.
CONCLUSIONS: The use of a target hemoglobin level of 13.5 g per deciliter (as compared with 11.3 g per deciliter) was associated with increased risk and no incremental improvement in the quality of life. (ClinicalTrials.gov number, NCT00211120 [ClinicalTrials.gov].).

Copyright 2006 Massachusetts Medical Society.
PMID 17108343  N Engl J Med. 2006 Nov 16;355(20):2085-98. doi: 10.1056・・・
著者: K Yamagata, K Ishida, T Sairenchi, H Takahashi, S Ohba, T Shiigai, M Narita, A Koyama
雑誌名: Kidney Int. 2007 Jan;71(2):159-66. doi: 10.1038/sj.ki.5002017. Epub 2006 Nov 22.
Abstract/Text The purpose of this study was to explore risk factors affecting the incidence of chronic kidney disease (CKD) in general population. We conducted a 10-year follow-up study with 123 764 (male: 41 012, female: 82 752) adults aged 40 years and over who received community-based annual examinations. The primary outcome for the analysis was the development of CKD during the follow-up period. Predictors for the development of CKD were obtained by the significant hazard ratios (HR) in Cox regression model by sex. During the follow-up period, 4307 subjects (male: 2048, female: 2259) developed CKD stage I or II, and 19 411 subjects (male: 4257, female: 15 154) developed CKD stage III or higher. The baseline-adjusted predictor of developing CKD included age, glomerular filtration rate, hematuria, hypertension, diabetes, serum lipids, obesity, smoking status, and consumption of alcohol. Treated diabetes in male subjects, and treated hypertension, systolic blood pressure >160 mm Hg and/or diastolic blood pressure >100 mm Hg, diabetes, and treated diabetes in female subjects were associated with more than a doubling of the HR. For the development of CKD stage III or higher, proteinuria of >or= + +, and proteinuria and hematuria were associated with more than a doubling of the HR in male subjects. The prevalence of newly developed CKD over 10 years was 23 718 subjects (19.2%) in adults. This study suggested that not only hypertension and diabetes but also several metabolic abnormalities were independent risk factors for developing CKD.

PMID 17136030  Kidney Int. 2007 Jan;71(2):159-66. doi: 10.1038/sj.ki.5・・・
著者: Bénédicte Stengel, Michelle E Tarver-Carr, Neil R Powe, Mark S Eberhardt, Frederick L Brancati
雑誌名: Epidemiology. 2003 Jul;14(4):479-87. doi: 10.1097/01.EDE.0000071413.55296.c4.
Abstract/Text BACKGROUND: Some lifestyle behaviors and obesity are risk factors for vascular disease, but their relation to kidney disease is uncertain.
METHODS: To determine whether physical inactivity, smoking, alcohol drinking and obesity are associated with the risk of chronic kidney disease, we examined data from a nonconcurrent cohort study of 9,082 U.S. adults, aged 30-74 years, who participated in the second National Health and Nutrition Examination Survey (NHANES II) from 1976 through 1980. By linking the NHANES II Mortality Study with the Medicare end-stage kidney disease registry, we identified 189 incident cases of either treated end-stage kidney disease or chronic kidney disease-related death through 1992.
RESULTS: The risk of chronic kidney disease was related to physical inactivity both with and without adjustment for age, sex, race and body-mass index. The adjusted relative risk (RR) of moderately active versus very active persons was 1.2 (95% confidence interval = 0.7-1.8), and of inactive versus very active was 2.2 (1.3-3.8). Risk was also related to smoking; the RR in smokers of 1-20 cigarettes a day versus never smokers was 1.2 (0.7-2.3), and in smokers of more than 20 cigarettes a day, the RR was 2.3 (1.3-4.2). The RR in morbidly obese (body-mass index >/= 35 kg/m2) compared with normal weight persons was 2.3 (1.1-4.9), but risk was not increased for those classified as overweight or obese. Obesity risk appeared largely mediated by diabetes and hypertension, whereas physical inactivity risk was only partly explained by these factors, and smoking risk was independent of them. Alcohol consumption was not related to chronic kidney disease.
CONCLUSIONS: These data suggest that physical inactivity, smoking and morbid obesity contribute to the risk of chronic kidney disease.

PMID 12843775  Epidemiology. 2003 Jul;14(4):479-87. doi: 10.1097/01.ED・・・
著者: Tadao Akizawa, Yasushi Asano, Satoshi Morita, Takafumi Wakita, Yoshihiro Onishi, Shunichi Fukuhara, Fumitake Gejyo, Seiichi Matsuo, Noriaki Yorioka, Kiyoshi Kurokawa, CAP-KD Study Group
雑誌名: Am J Kidney Dis. 2009 Sep;54(3):459-67. doi: 10.1053/j.ajkd.2009.05.011. Epub 2009 Jul 17.
Abstract/Text BACKGROUND: The carbonaceous oral adsorbent AST-120 slows the deterioration of kidney function in patients with advanced chronic kidney disease (CKD). However, information about AST-120 in patients with less severe stages of CKD is lacking.
STUDY DESIGN: Randomized controlled trial.
SETTING & PARTICIPANTS: 75 medical facilities, 460 patients with CKD with serum creatinine (sCr) concentrations less than 5.0 mg/dL (not undergoing dialysis).
INTERVENTION: Random assignment to either a low-protein diet and antihypertensive medication in the control group or that treatment combined with AST-120 (6 g/d).
OUTCOMES & MEASUREMENTS: Composite primary end point: doubling of sCr level, increase in sCr level to 6.0 mg/dL or more, need for dialysis or transplantation, or death.
SECONDARY OUTCOMES: adverse events and changes in estimated creatinine clearance (CCr) rate, proteinuria (protein in milligrams per day), and quality of life.
RESULTS: Mean sCr level was 2.66 mg/dL and estimated CCr was 22.4 mL/min in both groups. During 56 weeks, numbers of primary end-point events (43 for control versus 42 for AST-120) and event-free survival (P = 0.9) did not differ between groups. Gastrointestinal adverse events were less common in the control group than the AST-120 group (2 versus 32 events). Estimated CCr decreased more in the control group than in the AST-120 group (-15% per year versus -12% per year, relative to the baseline value; [corrected] P = 0.001). Median proteinuria changed from protein of 1,162 to 1,167 mg/d in the control group versus 1,102 to 906 mg/d in the AST-120 group (P = 0.2).
LIMITATION: Infrequent primary end-point events.
CONCLUSION: AST-120 did not substantially slow the progression of kidney disease in patients with moderate to severe CKD during 1 year.

PMID 19615804  Am J Kidney Dis. 2009 Sep;54(3):459-67. doi: 10.1053/j.・・・
著者: Gerald Schulman, Rajiv Agarwal, Muralidhar Acharya, Tomas Berl, Samuel Blumenthal, Nelson Kopyt
雑誌名: Am J Kidney Dis. 2006 Apr;47(4):565-77. doi: 10.1053/j.ajkd.2005.12.036.
Abstract/Text BACKGROUND: AST-120 (Kremezin; Kureha Chemical Industry Co Ltd, Tokyo, Japan) is an orally administered adsorbent showing adsorption ability superior to activated charcoal for certain organic compounds known to be precursors of substances that accumulate in patients with chronic kidney disease (CKD) and that are believed to accelerate the decline in kidney function. AST-120 is approved in Japan for prolonging time to hemodialysis therapy and improving uremic symptoms in patients with CKD.
METHODS: A multicenter, randomized, double-blind, placebo-controlled, dose-ranging study was designed to examine the nephroprotective effects of 3 doses of AST-120 versus placebo in adult patients with moderate to severe CKD and elevated serum indoxyl sulfate levels while following an adequate protein-intake diet. Eligible patients were randomly assigned to 1 of 3 doses of AST-120 (0.9, 2.1, or 3.0 g) or placebo 3 times daily for 12 weeks.
RESULTS: AST-120 decreased serum indoxyl sulfate levels in a dose-dependent fashion. During the 12-week treatment period, AST-120 did not affect serum creatinine levels or 24-hour urine creatinine appearance. Significant improvements in malaise were observed in a dose-dependent fashion. All doses of AST-120 were well tolerated and did not adversely affect the general health status of patients.
CONCLUSION: Results suggest that the dose of 3 g 3 times daily is an optimal dose for the US population, and it may be useful in the treatment of patients with CKD. Because AST-120 did not directly affect serum creatinine levels or 24-hour urine creatinine appearance, the composite end point of doubling of serum creatinine level, transplantation, and dialysis therapy would be appropriate for a confirmatory phase III therapeutic outcome study.

PMID 16564934  Am J Kidney Dis. 2006 Apr;47(4):565-77. doi: 10.1053/j.・・・
著者: Yasuaki Hayashino, Shunichi Fukuhara, Tadao Akizawa, Yasushi Asano, Takafumi Wakita, Yoshihiro Onishi, Kiyoshi Kurokawa, CAP-KD study group
雑誌名: Diabetes Res Clin Pract. 2010 Nov;90(2):154-9. doi: 10.1016/j.diabres.2010.07.007. Epub 2010 Aug 13.
Abstract/Text AIMS: AST-120, an oral adsorbent currently on-label only in Asian countries with phase III trials ongoing in the US, slows renal disease progression in patients with diabetes and advanced-stage chronic kidney disease (CKD). The objective of this study is to evaluate the cost-effectiveness of using AST-120 to treat patients with type 2 diabetes and advanced-stage CKD.
METHODS: We used Markov model simulating the progression of diabetic nephropathy. Data were obtained from randomized trials estimating the progression of diabetic nephropathy with and without AST-120, and published literature. The base population was patients 60 years of age with type 2 diabetes and Stages 3 and 4 CKD.
RESULTS: Treating patients with diabetes and advanced-stage CKD was found to be a dominant strategy, and quality of life improved further and more money was saved (0.22 quality-adjusted life years [QALYs] and $15,019 per patient) using AST-120 than the control strategy. Sensitivity analysis results were robust with regard to cost, adherence, and quality of life associated with AST-120 therapy, as well as age at diagnosis. The model was relatively sensitive to the effectiveness of AST-120.
CONCLUSIONS: Treating patients with type 2 diabetes and advanced-stage CKD with AST-120 appears to extend life and reduce costs.

Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
PMID 20708813  Diabetes Res Clin Pract. 2010 Nov;90(2):154-9. doi: 10.・・・
著者: Lisa M Einhorn, Min Zhan, Van Doren Hsu, Lori D Walker, Maureen F Moen, Stephen L Seliger, Matthew R Weir, Jeffrey C Fink
雑誌名: Arch Intern Med. 2009 Jun 22;169(12):1156-62. doi: 10.1001/archinternmed.2009.132.
Abstract/Text BACKGROUND: Hyperkalemia is a potential threat to patient safety in chronic kidney disease (CKD). This study determined the incidence of hyperkalemia in CKD and whether it is associated with excess mortality.
METHODS: This retrospective analysis of a national cohort comprised 2 103 422 records from 245 808 veterans with at least 1 hospitalization and at least 1 inpatient or outpatient serum potassium record during the fiscal year 2005. Chronic kidney disease and treatment with angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers (blockers of the renin-angiotensin-aldosterone system [RAAS]) were the key predictors of hyperkalemia. Death within 1 day of a hyperkalemic event was the principal outcome.
RESULTS: Of the 66 259 hyperkalemic events (3.2% of records), more occurred as inpatient events (n = 34 937 [52.7%]) than as outpatient events (n = 31 322 [47.3%]). The adjusted rate of hyperkalemia was higher in patients with CKD than in those without CKD among individuals treated with RAAS blockers (7.67 vs 2.30 per 100 patient-months; P < .001) and those without RAAS blocker treatment (8.22 vs 1.77 per 100 patient-months; P < .001). The adjusted odds ratio (OR) of death with a moderate (potassium, >or=5.5 and <6.0 mEq/L [to convert to mmol/L, multiply by 1.0]) and severe (potassium, >or=6.0 mEq/L) hyperkalemic event was highest with no CKD (OR, 10.32 and 31.64, respectively) vs stage 3 (OR, 5.35 and 19.52, respectively), stage 4 (OR, 5.73 and 11.56, respectively), or stage 5 (OR, 2.31 and 8.02, respectively) CKD, with all P < .001 vs normokalemia and no CKD.
CONCLUSIONS: The risk of hyperkalemia is increased with CKD, and its occurrence increases the odds of mortality within 1 day of the event. These findings underscore the importance of this metabolic disturbance as a threat to patient safety in CKD.

PMID 19546417  Arch Intern Med. 2009 Jun 22;169(12):1156-62. doi: 10.1・・・
著者: C Barrett Bowling, Bertram Pitt, Mustafa I Ahmed, Inmaculada B Aban, Paul W Sanders, Marjan Mujib, Ruth C Campbell, Thomas E Love, Wilbert S Aronow, Richard M Allman, George L Bakris, Ali Ahmed
雑誌名: Circ Heart Fail. 2010 Mar;3(2):253-60. doi: 10.1161/CIRCHEARTFAILURE.109.899526. Epub 2010 Jan 26.
Abstract/Text BACKGROUND: Little is known about the effects of hypokalemia on outcomes in patients with chronic heart failure (HF) and chronic kidney disease.
METHODS AND RESULTS: Of the 7788 patients with chronic HF in the Digitalis Investigation Group trial, 2793 had chronic kidney disease, defined as estimated glomerular filtration rate <60 mL/min per 1.73 m(2). Of these, 527 had hypokalemia (serum potassium <4 mEq/L; mild) and 2266 had normokalemia (4 to 4.9 mEq/L). Propensity scores for hypokalemia were used to assemble a balanced cohort of 522 pairs of patients with hypokalemia and normokalemia. All-cause mortality occurred in 48% and 36% of patients with hypokalemia and normokalemia, respectively, during 57 months of follow-up (matched hazard ratio when hypokalemia was compared with normokalemia, 1.56; 95% CI, 1.25 to 1.95; P<0.0001). Matched hazard ratios (95% CIs) for cardiovascular and HF mortalities and all-cause, cardiovascular, and HF hospitalizations were 1.65 (1.29 to 2.11; P<0.0001), 1.82 (1.28 to 2.57; P<0.0001), 1.16 (1.00 to 1.35; P=0.036), 1.27 (1.08 to 1.50; P=0.004), and 1.29 (1.05 to 1.58; P=0.014), respectively. Among 453 pairs of balanced patients with HF and chronic kidney disease, all-cause mortality occurred in 47% and 38% of patients with mild hypokalemia (3.5 to 3.9 mEq/L) and normokalemia, respectively (matched hazard ratio, 1.31; 95% CI, 1.03 to 1.66; P=0.027). Among 169 pairs of balanced patients with estimated glomerular filtration rate <45 mL/min per 1.73 m(2), all-cause mortality occurred in 57% and 47% of patients with hypokalemia (<4 mEq/L; mild) and normokalemia, respectively (matched hazard ratio, 1.53; 95% CI, 1.07 to 2.19; P=0.020).
CONCLUSIONS: In patients with HF and chronic kidney disease, hypokalemia (serum potassium <4 mEq/L) is common and associated with increased mortality and hospitalization.

PMID 20103777  Circ Heart Fail. 2010 Mar;3(2):253-60. doi: 10.1161/CIR・・・
著者: Sonal Korgaonkar, Anca Tilea, Brenda W Gillespie, Margaret Kiser, George Eisele, Fredric Finkelstein, Peter Kotanko, Bertram Pitt, Rajiv Saran
雑誌名: Clin J Am Soc Nephrol. 2010 May;5(5):762-9. doi: 10.2215/CJN.05850809. Epub 2010 Mar 4.
Abstract/Text BACKGROUND AND OBJECTIVES: The relationship between serum potassium (S(K)) and mortality in chronic kidney disease (CKD) has not been systematically investigated.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We examined the predictors and mortality association of S(K) in the Renal Research Institute CKD Study cohort, wherein 820 patients with CKD were prospectively followed at four US centers for an average of 2.6 years. Predictors of S(K) were investigated using linear and repeated measures regression models. Associations between S(K) and mortality, the outcomes of ESRD, and cardiovascular events in time-dependent Cox models were examined.
RESULTS: The mean age was 60.5 years, 80% were white, 90% had hypertension, 36% had diabetes, the average estimated GFR was 25.4 ml/min per 1.73 m(2), and mean baseline S(K) was 4.6 mmol/L. Higher S(K) was associated with male gender, lower estimated GFR and serum bicarbonate, absence of diuretic and calcium channel blocker use, diabetes, and use of angiotensin-converting enzyme inhibitors and/or statins. A U-shaped relationship between S(K) and mortality was observed, with mortality risk significantly greater at S(K) < or = 4.0 mmol/L compared with 4.0 to 5.5 mmol/L. Risk for ESRD was elevated at S(K) < or = 4 mmol/L in S(K) categorical models. Only the composite of cardiovascular events or death as an outcome was associated with higher S(K) (> or = 5.5).
CONCLUSIONS: Although clinical practice usually emphasizes greater attention to elevated S(K) in the setting of CKD, our results suggest that patients who have CKD and low or even low-normal S(K) are at higher risk for dying than those with mild to moderate hyperkalemia.

PMID 20203167  Clin J Am Soc Nephrol. 2010 May;5(5):762-9. doi: 10.221・・・
著者: D Fouque, M Laville, J P Boissel
雑誌名: Cochrane Database Syst Rev. 2006 Apr 19;(2):CD001892. doi: 10.1002/14651858.CD001892.pub2. Epub 2006 Apr 19.
Abstract/Text BACKGROUND: For more than fifty years, low protein diets have been proposed to patients with kidney failure. However, the effects of these diets in preventing severe renal failure and the need for maintenance dialysis have not been resolved.
OBJECTIVES: To determine the efficacy of low protein diets in delaying the need to start maintenance dialysis.
SEARCH STRATEGY: Cochrane Renal Group trials register, the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE. Congress abstracts (American Society of Nephrology since 1990, European Dialysis Transplant Association since 1985, International Society of Nephrology since 1987). Direct contacts with investigators. Date of most recent search: December 2004.
SELECTION CRITERIA: Randomised trials comparing two different levels of protein intake in adult patients suffering from moderate to severe renal failure, followed for at least one year.
DATA COLLECTION AND ANALYSIS: Two reviewers independently selected studies and extracted data. Statistical analyses were performed using the random effects model and the results expressed as relative risk (RR) for dichotomous outcomes with 95% confidence intervals (CI). Collection of the number of "renal deaths" defined as the need for starting dialysis, the death of a patient or a kidney transplant during the trial.
MAIN RESULTS: Eight trials were identified from over 40 studies. A total of 1524 patients were analysed, 763 had received reduced protein intake and 761 a higher protein intake. Two hundred and fifty one renal deaths were recorded, 103 in the low protein diet and 148 in the higher protein diet group (RR 0.69, 95% CI 0.56 to 0.86, P = 0.0007). To avoid one renal death, 2 to 56 patients need to be treated with a low protein diet during one year.
AUTHORS' CONCLUSIONS: Reducing protein intake in patients with chronic kidney disease reduces the occurrence of renal death by 31% as compared with higher or unrestricted protein intake. The optimal level of protein intake cannot be confirmed from these studies.

PMID 16625550  Cochrane Database Syst Rev. 2006 Apr 19;(2):CD001892. d・・・
著者: F M Sacks, L P Svetkey, W M Vollmer, L J Appel, G A Bray, D Harsha, E Obarzanek, P R Conlin, E R Miller, D G Simons-Morton, N Karanja, P H Lin, DASH-Sodium Collaborative Research Group
雑誌名: N Engl J Med. 2001 Jan 4;344(1):3-10. doi: 10.1056/NEJM200101043440101.
Abstract/Text BACKGROUND: The effect of dietary composition on blood pressure is a subject of public health importance. We studied the effect of different levels of dietary sodium, in conjunction with the Dietary Approaches to Stop Hypertension (DASH) diet, which is rich in vegetables, fruits, and low-fat dairy products, in persons with and in those without hypertension.
METHODS: A total of 412 participants were randomly assigned to eat either a control diet typical of intake in the United States or the DASH diet. Within the assigned diet, participants ate foods with high, intermediate, and low levels of sodium for 30 consecutive days each, in random order.
RESULTS: Reducing the sodium intake from the high to the intermediate level reduced the systolic blood pressure by 2.1 mm Hg (P<0.001) during the control diet and by 1.3 mm Hg (P=0.03) during the DASH diet. Reducing the sodium intake from the intermediate to the low level caused additional reductions of 4.6 mm Hg during the control diet (P<0.001) and 1.7 mm Hg during the DASH diet (P<0.01). The effects of sodium were observed in participants with and in those without hypertension, blacks and those of other races, and women and men. The DASH diet was associated with a significantly lower systolic blood pressure at each sodium level; and the difference was greater with high sodium levels than with low ones. As compared with the control diet with a high sodium level, the DASH diet with a low sodium level led to a mean systolic blood pressure that was 7.1 mm Hg lower in participants without hypertension, and 11.5 mm Hg lower in participants with hypertension.
CONCLUSIONS: The reduction of sodium intake to levels below the current recommendation of 100 mmol per day and the DASH diet both lower blood pressure substantially, with greater effects in combination than singly. Long-term health benefits will depend on the ability of people to make long-lasting dietary changes and the increased availability of lower-sodium foods.

PMID 11136953  N Engl J Med. 2001 Jan 4;344(1):3-10. doi: 10.1056/NEJM・・・
著者: H Buter, M H Hemmelder, G Navis, P E de Jong, D de Zeeuw
雑誌名: Nephrol Dial Transplant. 1998 Jul;13(7):1682-5.
Abstract/Text BACKGROUND: Dietary sodium restriction enhances the antiproteinuric and blood pressure lowering effect of ACE inhibition. In clinical practice, however, long-term compliance to a low-sodium diet may be difficult to obtain. We therefore investigated whether the blunting of the antiproteinuric and blood pressure lowering efficacy of ACE inhibition by high sodium intake can be restored by the addition of a diuretic.
PATIENTS AND METHODS: Seven proteinuric patients with non-diabetic renal disease on chronic ACE inhibition were studied during three consecutive 4-week periods: low sodium (50 mmol/day), high sodium (200 mmol/day) and high sodium plus hydrochlorothiazide (50 mg o.i.d.).
RESULTS: During low sodium intake proteinuria was 3.1 (0.7-5.2) g/day, during high sodium intake proteinuria increased to 4.5 (1.6-9.2) g/day (P < 0.05). Interestingly, addition of hydrochlorothiazide again reduced proteinuria to 2.8 (0.6-5.8) g/day (P < 0.05). Mean arterial blood pressure was 89 (84-96), 98 (91-104) and 89 (83-94) mmHg (P < 0.05) during the three periods, respectively.
CONCLUSION: Addition of hydrochlorothiazide can overcome the blunting of the therapeutic efficacy of ACE inhibition on proteinuria and blood pressure by a high sodium intake.

PMID 9681711  Nephrol Dial Transplant. 1998 Jul;13(7):1682-5.
著者: Nimrit Goraya, Jan Simoni, Chanhee Jo, Donald E Wesson
雑誌名: Kidney Int. 2012 Jan;81(1):86-93. doi: 10.1038/ki.2011.313. Epub 2011 Aug 31.
Abstract/Text The neutralization of dietary acid with sodium bicarbonate decreases kidney injury and slows the decline of the glomerular filtration rate (GFR) in animals and patients with chronic kidney disease. The sodium intake, however, could be problematic in patients with reduced GFR. As alkali-induced dietary protein decreased kidney injury in animals, we compared the efficacy of alkali-inducing fruits and vegetables with oral sodium bicarbonate to diminish kidney injury in patients with hypertensive nephropathy at stage 1 or 2 estimated GFR. All patients were evaluated 30 days after no intervention; daily oral sodium bicarbonate; or fruits and vegetables in amounts calculated to reduce dietary acid by half. All patients had 6 months of antihypertensive control by angiotensin-converting enzyme inhibition before and during these studies, and otherwise ate ad lib. Indices of kidney injury were not changed in the stage 1 group. By contrast, each treatment of stage 2 patients decreased urinary albumin, N-acetyl β-D-glucosaminidase, and transforming growth factor β from the controls to a similar extent. Thus, a reduction in dietary acid decreased kidney injury in patients with moderately reduced eGFR due to hypertensive nephropathy and that with fruits and vegetables was comparable to sodium bicarbonate. Fruits and vegetables appear to be an effective kidney protective adjunct to blood pressure reduction and angiotensin-converting enzyme inhibition in hypertensive and possibly other nephropathies.

PMID 21881553  Kidney Int. 2012 Jan;81(1):86-93. doi: 10.1038/ki.2011.・・・
著者: Mark G Spigt, J A Knottnerus, Klaas R Westerterp, Marcel G M Olde Rikkert, C P Schayck
雑誌名: J Am Geriatr Soc. 2006 Mar;54(3):438-43. doi: 10.1111/j.1532-5415.2005.00606.x.
Abstract/Text OBJECTIVES: To study whether there are any negative or positive effects of 6 months of increased fluid intake in reasonably healthy elderly men.
DESIGN: Randomized trial.
SETTING: Community-based.
PARTICIPANTS: One hundred forty-one healthy participants aged 55 to 75.
INTERVENTION: One group was given the advice to increase their daily fluid intake by 1.5 L of water; the other group was given placebo medication (8 mL inactive syrup per day).
MEASUREMENTS: At 6 months blood sodium, glomerular filtration rate (GFR), blood pressure, and quality of life (QOL) were measured. The changes in water turnover were measured using deuterium.
RESULTS: Most subjects did not manage to increase their fluid intake by 1.5 L. The average increase in the intervention group was approximately 1 L. Twenty-four-hour water turnover in the water group was 359 mL (95% confidence interval=171-548) higher than that of the control group at 6-month follow-up. Blood pressure, sodium level, GFR, and QOL did not change significantly in either group during the intervention period. In addition, the cases reporting a worsening on the effect measures were equally distributed over the two study groups.
CONCLUSION: The advice to increase fluid intake by 1.5 L had no negative effects in reasonably healthy men aged 55 to 75.

PMID 16551310  J Am Geriatr Soc. 2006 Mar;54(3):438-43. doi: 10.1111/j・・・
著者: Diego Viasus, Carolina Garcia-Vidal, Josep M Cruzado, Jordi Adamuz, Ricard Verdaguer, Frederic Manresa, Jordi Dorca, Francesc Gudiol, Jordi Carratalà
雑誌名: Nephrol Dial Transplant. 2011 Sep;26(9):2899-906. doi: 10.1093/ndt/gfq798. Epub 2011 Jan 27.
Abstract/Text BACKGROUND: Although infection remains among the most common causes of morbidity and mortality in patients with chronic kidney disease (CKD), data on epidemiology, clinical features and outcomes of pneumonia in this population are scarce.
METHODS: Observational analysis of a prospective cohort of hospitalized adults with pneumonia, between 13 February 1995 and 30 April 2010, in a tertiary teaching hospital. CKD patients, defined as patients with a baseline glomerular filtration rate <60 mL/min/1.73 m(2), were compared with non-CKD patients.
RESULTS: During the study period, 3800 patients with pneumonia required hospitalization. Two-hundred and three (5.3%) patients had CKD, of whom 46 were on dialysis therapy. Patients with CKD were older (77 versus 70 years; P < 0.001), were more likely to have comorbidities (82.3 versus 63.3%; P < 0.001) and more commonly classified into high-risk pneumonia severity index classes (89.6 versus 57%; P < 0.001) than were the remaining patients. Streptococcus pneumoniae was the most frequent pathogen (28.1 versus 34.7%; P = 0.05). Mortality was higher in patients with CKD (15.8 versus 8.3%; P < 0.001). Among CKD patients, age [+1 year increase; adjusted odds ratio, 1.25; 95% confidence interval (CI) 1.07-1.46] and cardiac complications during hospitalization (adjusted odds ratio, 9.23; 95% CI 1.39-61.1) were found to be independent risk factors for mortality, whereas prior pneumococcal vaccination (adjusted odds ratio, 0.05; 95% CI 0.005-0.69) and leukocytosis at hospital admission (adjusted odds ratio, 0.10; 95% CI 0.01-0.64) were protective factors.
CONCLUSIONS: Pneumonia is a serious complication in CKD patients. Independent factors for mortality are older age and cardiac complications, whereas prior pneumococcal vaccination and leucokytosis at hospital admission are protective factors. These findings should encourage physicians to increase pneumococcal vaccine coverage among CKD patients.

PMID 21273232  Nephrol Dial Transplant. 2011 Sep;26(9):2899-906. doi: ・・・
著者: A Fuchshuber, O Kühnemund, B Keuth, R Lütticken, D Michalk, U Querfeld
雑誌名: Nephrol Dial Transplant. 1996 Mar;11(3):468-73.
Abstract/Text BACKGROUND: Pneumococcal vaccination has been recommended for immunocompromised children over 2 years including patients with chronic renal disease. However, the effect of vaccination and revaccination is variable and the indication for immunization is a subject of controversy.
METHODS: Forty children and young adults with chronic renal diseases (including the idiopathic nephrotic syndrome, chronic renal failure, patients undergoing dialysis and after transplantation) were vaccinated with a 23-valent pneumococcal vaccine. The efficacy of the vaccine was evaluated by measuring antibody titres before and 4 weeks, 6 months, and 12 months after vaccination. Twenty-two patients were submitted to a revaccination 1 year after the first vaccination.
RESULTS: A sufficient immune response, defined as an at least fourfold increase of postvaccinal antibody titres and an antibody titre > 200, was observed in 83% of the patients 4 weeks after vaccination, but only in 68% after 6 months, and in 48% after 1 year. Revaccination produced a significant immune response in 11/22 patients (50%) followed by a rapid decline of antibody levels within 6 months. Both vaccinations were well tolerated.
CONCLUSIONS: The currently available vaccine is without major side-effects and effective in producing a significant immune response. Antibody levels should be monitored in vaccinated patients with chronic renal diseases considering the rapid decline as early as 6 months after vaccination. Evaluation of the efficacy of revaccination in these patients requires further investigations.

PMID 8671817  Nephrol Dial Transplant. 1996 Mar;11(3):468-73.
著者: Dick de Zeeuw, Giuseppe Remuzzi, Hans-Henrik Parving, William F Keane, Zhongxin Zhang, Shahnaz Shahinfar, Steve Snapinn, Mark E Cooper, William E Mitch, Barry M Brenner
雑誌名: Circulation. 2004 Aug 24;110(8):921-7. doi: 10.1161/01.CIR.0000139860.33974.28. Epub 2004 Aug 9.
Abstract/Text BACKGROUND: Albuminuria is an established risk marker for both cardiovascular and renal outcomes. Albuminuria can be reduced with drugs that block the renin-angiotensin system (RAS). We questioned whether the short-term drug-induced change in albuminuria would predict the long-term cardioprotective efficacy of RAS intervention.
METHODS AND RESULTS: We analyzed data from Reduction in Endpoints in Non-insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL), a double-blind, randomized trial in 1513 type 2 diabetic patients with nephropathy, focusing on the relationship between the prespecified cardiovascular end point (composite) or hospitalization for heart failure and baseline or reduction in albuminuria. Patients with high baseline albuminuria (> or =3 g/g creatinine) had a 1.92-fold (95% CI, 1.54 to 2.38) higher risk for the cardiovascular end point and a 2.70-fold (95% CI, 1.94 to 3.75) higher risk for heart failure compared with patients with low albuminuria (<1.5 g/g). Among all available baseline risk markers, albuminuria was the strongest predictor of cardiovascular outcome. The association between albuminuria and cardiovascular outcome was driven by those patients who also had a renal event. Modeling of the initial 6-month change in risk parameters showed that albuminuria reduction was the only predictor for cardiovascular outcome: 18% reduction in cardiovascular risk for every 50% reduction in albuminuria and a 27% reduction in heart failure risk for every 50% reduction in albuminuria.
CONCLUSIONS: Albuminuria is an important factor predicting cardiovascular risk in patients with type 2 diabetic nephropathy. Reducing albuminuria in the first 6 months appears to afford cardiovascular protection in these patients.

PMID 15302780  Circulation. 2004 Aug 24;110(8):921-7. doi: 10.1161/01.・・・
著者: Neil A Smart, Gudrun Dieberg, Maleeka Ladhani, Thomas Titus
雑誌名: Cochrane Database Syst Rev. 2014 Jun 18;6:CD007333. doi: 10.1002/14651858.CD007333.pub2. Epub 2014 Jun 18.
Abstract/Text BACKGROUND: Early referral of patients with chronic kidney disease (CKD) is believed to help with interventions to address risk factors to slow down the rate of progression of kidney failure to end-stage kidney disease (ESKD) and the need for dialysis, hospitalisation and mortality.
OBJECTIVES: We sought to evaluate the benefits (reduced hospitalisation and mortality; increased quality of life) and harms (increased hospitalisations and mortality, decreased quality of life) of early versus late referral to specialist nephrology services in CKD patients who are progressing to ESKD and RRT. In this review, referral is defined as the time period between first nephrology evaluation and initiation of dialysis; early referral is more than one to six months, whereas late referral is less than one to six months prior to starting dialysis. All-cause mortality and hospitalisation and quality of life were measured by the visual analogue scale and SF-36. SF-36 and KDQoL are validated measurement instruments for kidney diseases.
SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2012; Issue 1) which contains the Cochrane Renal Group's Specialised Register; MEDLINE (1966 to February 2012), EMBASE (1980 to February 2012). Search terms were approved by the Trial Search Co-ordinator.
SELECTION CRITERIA: Randomised controlled trials (RCTs), quasi-RCTs, prospective and retrospective longitudinal cohort studies were eligible for inclusion.
DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. Events relating to adverse effects were collected from the studies.
MAIN RESULTS: No RCTs or quasi-RCTs were identified. There were 40 longitudinal cohort studies providing data on 63,887 participants; 43,209 (68%) who were referred early and 20,678 (32%) referred late.Comparative mortality was higher in patients referred to specialist services late versus those referred early. Risk ratios (RR) for mortality reductions in patients referred early were evident at three months (RR 0.61, 95% CI 0.55 to 0.67; I² = 84%) and remained at five years (RR 0.66, 95% CI 0.60 to 0.71; I² = 87%). Initial hospitalisation was 9.12 days shorter with early referral (95% CI -10.92 to -7.32 days; I² = 82%) compared to late referral. Pooled analysis showed patients referred early were more likely than late referrals to initiate RRT with peritoneal dialysis (RR 1.74, 95% CI 1.64 to 1.84; I² = 92%).Patients referred early were less likely to receive temporary vascular access (RR 0.47, 95% CL 0.45 to 0.50; I² = 97%) than those referred late. Patients referred early were more likely to receive permanent vascular access (RR 3.22, 95% CI 2.92 to 3.55; I² = 97%). Systolic blood pressure (BP) was significantly lower in early versus late referrals (MD -3.09 mm Hg, 95% CI -5.23 to -0.95; I² = 85%); diastolic BP was significantly lower in early versus late referrals (MD -1.64 mm Hg, 95% CI -2.77 to -0.51; I² = 82%). EPO use was significantly higher in those referred early (RR 2.92, 95% CI 2.42 to 3.52; I² = 0%). eGFR was higher in early referrals (MD 0.42 mL/min/1.73 m², 95% CI 0.28 to 0.56; I² = 95%). Diabetes prevalence was similar in patients referred early and late (RR 1.05, 95% CI 0.96 to 1.15; I² = 87%) as was ischaemic heart disease (RR 1.05, 95% CI 0.97 to 1.13; I² = 74%), peripheral vascular disease (RR 0.99, 95% CI 0.84 to 1.17; I² = 90%), and congestive heart failure (RR 1.00, 95% CI 0.86 to 1.15; I² = 92%). Inability to walk was less prevalent in early referrals (RR 0.66, 95% CI 0.51 to 0.86). Prevalence of chronic obstructive pulmonary disease was similar in those referred early and late (RR 0.89, 95% CI 0.70 to 1.14; I² = 94%) as was cerebrovascular disease (RR 0.90, 95% CI 0.74 to 1.11; I² = 83%).The quality of the included studies was assessed as being low to moderate based on the Newcastle-Ottawa Scale. Slight differences in the definition of early versus late referral infer some risk of bias. Generally, heterogeneity in most of the analyses was high.
AUTHORS' CONCLUSIONS: Our analysis showed reduced mortality and mortality and hospitalisation, better uptake of peritoneal dialysis and earlier placement of arteriovenous fistulae for patients with chronic kidney disease who were referred early to a nephrologist. Differences in mortality and hospitalisation data between the two groups were not explained by differences in prevalence of comorbid disease or serum phosphate. However, early referral was associated with better preparation and placement of dialysis access.

PMID 24938824  Cochrane Database Syst Rev. 2014 Jun 18;6:CD007333. doi・・・
著者: Szu-Chia Chen, Jer-Ming Chang, Ming-Chin Chou, Ming-Yen Lin, Jui-Hsin Chen, Jia-Hui Sun, Jinn-Yuh Guh, Shang-Jyh Hwang, Hung-Chun Chen
雑誌名: Nephrology (Carlton). 2008 Dec;13(8):730-6. doi: 10.1111/j.1440-1797.2008.01023.x. Epub 2008 Nov 17.
Abstract/Text AIM: Late referral of chronic kidney disease (CKD) patients to nephrologists is associated with increased morbidity and mortality and is still quite common and seldom studied in Taiwan because of unique sociocultural factors. We aimed to study the decline in renal function and factors related to the change in renal function before and after referral.
METHODS: We retrospectively reviewed the changes of estimated glomerular filtration rate (eGFR) in 213 new referrals of patients with CKD stages 3-5 to the nephrology divisions of one medical centre and one regional hospital from 2001-2006. Data on demographics and laboratory investigations were collected for study.
RESULTS: The rates of annual eGFR decline slowed significantly from -7.38 +/- 0.84 before referral to -1.02 +/- 0.45 mL/min per 1.73 m(2)/year after referral (mean +/- standard error of the mean, P < 0.001). The nephrology referral was the most significant factor associated with the slowing of renal function progression, as was younger age and female sex. After nephrology referral, patients with diabetes had an increase in eGFR compared to those without diabetes (P = 0.034). Patients had better control of diastolic blood pressure, sugar and lipid, more frequent use of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and statins, less frequent use of non-steroidal anti-inflammatory drugs, and more serum creatinine measurements after nephrology referral.
CONCLUSION: Slowing renal functional decline in CKD patients after referral addresses the importance of nephrology referral for CKD care, which should be strongly promoted in CKD prevention projects in Taiwan.

PMID 19019170  Nephrology (Carlton). 2008 Dec;13(8):730-6. doi: 10.111・・・
著者: Chris Jones, Paul Roderick, Scott Harris, Mary Rogerson
雑誌名: Nephrol Dial Transplant. 2006 Aug;21(8):2133-43. doi: 10.1093/ndt/gfl198. Epub 2006 Apr 27.
Abstract/Text BACKGROUND: The burden of chronic kidney disease (CKD) is high, but its natural history and the benefit of routine nephrology care is unclear. This study investigated the decline in kidney function prior to and following nephrology referral and its association with mortality.
METHODS: This study provides a retrospective review of the individual rates of glomerular filtration rate (GFR) decline (millilitre per minute per 1.73 m(2)/year) for the 5 years before and after referral in 726 new referrals with stages 3-5 CKD to one renal unit between 1997 and 2003. Blood pressures are averages at referral, 1 and 3 years post referral. Logistic regression and Cox's models tested factors predicting post-referral GFR decline and the impact on mortality.
RESULTS: Mean (SD) age was 72 (14), and 389 (54%) patients had stages 4-5 CKD. GFR decline slowed significantly from -5.4 ml/min/1.73 m(2)/year (-13. to -2) before to -0.35 ml/min/1.73 m(2)/year (-3 to +3) after referral (P < 0.001). Blood pressure also reduced significantly (155/84 to 149/80, P < 0.05) with most changes occurring within 1 year of referral. Factors predicting a non-progressive post-referral decline included a lower systolic blood pressure at referral and 1 year after referral, a CKD diagnosis other than diabetic nephropathy, less baseline proteinuria and a non-progressive pre-referral GFR decline. A non-progressive post-referral GFR decline was independently associated with significantly better survival (hazard ratio 0.55, 95% CI 0.40-0.75, P CONCLUSIONS: Following nephrology referral, GFR decline slowed significantly and was associated with better survival. Earlier detection of patients with progressive CKD and interventions to slow progression may have benefits on both kidney and patient survival.

PMID 16644779  Nephrol Dial Transplant. 2006 Aug;21(8):2133-43. doi: 1・・・
著者: Héctor R Martínez-Ramírez, Basilio Jalomo-Martínez, Laura Cortés-Sanabria, Enrique Rojas-Campos, Graciela Barragán, Gilberto Alfaro, Alfonso M Cueto-Manzano
雑誌名: Am J Kidney Dis. 2006 Jan;47(1):78-87. doi: 10.1053/j.ajkd.2005.09.015.
Abstract/Text BACKGROUND: Early referral of patients with end-stage renal disease to a nephrologist is associated with lower morbidity and mortality after initiating dialysis therapy; earlier referral may have better results. The aim of the study is to prospectively determine the impact of earlier referral to a nephrologist on renal damage progression of patients with type 2 diabetes mellitus (DM2) with early nephropathy.
METHODS: Fifty-two patients (27 patients, early nephropathy [EN]; 25 patients, overt nephropathy [ON]) from a primary health care unit were referred to a nephrologist (study cohort); 65 patients (34 patients, EN; 31 patients, ON) from another health care unit remained treated by only family doctors (control cohort). Both cohorts were followed up for 1 year.
RESULTS: Delta (final-baseline) in serum creatinine levels was maintained better by the nephrologist in the EN (study, 0.02 mg/dL versus control, 0.13 mg/dL [2 versus 11 micromol/L]; P = 0.02) than ON group (study, 0.15 mg/dL versus control, 0.25 mg/dL [13 versus 22 micromol/L]). In concordance, glomerular filtration rate was maintained better by the nephrologist in EN (study, 3.2 mL/min/1.73 m2 versus control, -13.3 mL/min/1.73 m2 [0.05 versus -0.22 mL/s/1.73 m2]; P = 0.01) than ON patients (study, -9.8 mL/min/1.73 m2 versus control, -10.9 mL/min/1.73 m2 [-0.16 versus -0.18 mL/s/1.73 m2]). Albuminuria increased more in patients treated by family doctors in the EN (study, 30 mg/d versus control, 116 mg/d; P < 0.05) and ON groups (study, 160 mg/d versus control, 623 mg/d). The nephrologist controlled systolic blood pressure better in both the EN (study, -3 mm Hg versus control, 2 mm Hg; P < 0.05) and ON groups (study, -19 mm Hg versus control, 5 mm Hg; P < 0.05); diastolic blood pressure had a similar pattern. The nephrologist significantly increased (P < 0.05) the use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and statins and discontinued nonsteroidal anti-inflammatory drugs more than family doctors (study, 42%, 43%, 39%, and -11% versus control, 17%, 4%, -7%, and 27%, respectively). Glycemic and lipid control and stopping smoking were not attained by either the nephrologist or family doctors.
CONCLUSION: Earlier referral of patients with DM2 to a nephrologist was associated with better renal function preservation, which was significantly more evident in the EN than ON group. The nephrologist obtained better blood pressure control, more frequently used angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and statins; and discontinued nonsteroidal anti-inflammatory drugs more than family doctors. However, metabolic control and stopping smoking were not attained by either the nephrologist or family doctors.

PMID 16377388  Am J Kidney Dis. 2006 Jan;47(1):78-87. doi: 10.1053/j.a・・・
著者: P Jungers, Z A Massy, T Nguyen-Khoa, G Choukroun, C Robino, F Fakhouri, M Touam, A T Nguyen, J P Grünfeld
雑誌名: Nephrol Dial Transplant. 2001 Dec;16(12):2357-64.
Abstract/Text BACKGROUND: Late nephrological referral of chronic renal failure patients has been shown to be associated with high morbidity and short-term mortality on dialysis. However, the impact of predialysis nephrological care duration (PNCD) on the long-term survival of dialysis patients had not been evaluated.
METHODS: We studied data from all 1057 consecutive patients who started dialysis treatment at the Necker Hospital from 1989 to 1998 (mean age at start of dialysis 53.8+/-17.2 years (range 18-91 years), excluding from analysis patients who presented with acute renal failure (n=60) or advanced malignancy (n=35). We evaluated the effects of PNCD and clinical risk factors on all-cause mortality after long-term follow-up on dialysis.
RESULTS: Among the 1057 patients analysed (13.2% diabetics), PNCD was <6 months in 258 patients, 6-35 months in 267 patients, 36-71 months in 227 patients and >or=72 months in 307 patients. Cardiovascular (CV) morbidity, namely a history of myocardial or cerebral infarction, peripheral arteriopathy, and/or cardiac failure, before starting dialysis was 39.6% and 37.4%, respectively, in patients followed for <6 months or 6-35 months, compared with 24.4% in those followed for 36-71 months and 19.9% in those followed for >or=72 months (P<0.001). Five-year survival was significantly lower in patients with a PNCD of <6 months (59+/-4.1%) than for 36-71 months or >or=72 months (77.1+/-3.7 and 73.3+/-3.6%, respectively, P<0.001), but similar to those followed for 6-35 months (65.3+/-3.9%, NS). By Cox proportional hazard analysis, PNCD <6 months, age, diabetes and prior CV disease were independent predictive factors of all-cause death on dialysis.
CONCLUSIONS: This study provides suggestive evidence that longer duration of regular nephrological care in the predialysis period, at least for several years prior to the start of dialysis, is associated with a better long-term survival on dialysis. Such data strongly support the argument for early referral and regular nephrological care of chronic renal failure patients.

PMID 11733627  Nephrol Dial Transplant. 2001 Dec;16(12):2357-64.
著者: Hemodialysis Adequacy 2006 Work Group
雑誌名: Am J Kidney Dis. 2006 Jul;48 Suppl 1:S2-90. doi: 10.1053/j.ajkd.2006.03.051.
Abstract/Text
PMID 16813990  Am J Kidney Dis. 2006 Jul;48 Suppl 1:S2-90. doi: 10.105・・・
著者: John Kelly, Melissa Stanley, David Harris, Caring for Australians with Renal Impairment (CARI)
雑誌名: Nephrology (Carlton). 2005 Oct;10 Suppl 4:S46-60. doi: 10.1111/j.1440-1797.2005.00486_1.x.
Abstract/Text
PMID 16221124  Nephrology (Carlton). 2005 Oct;10 Suppl 4:S46-60. doi: ・・・
著者: European Best Practice Guidelines Expert Group on Hemodialysis, European Renal Association
雑誌名: Nephrol Dial Transplant. 2002;17 Suppl 7:7-15.
Abstract/Text
PMID 12386205  Nephrol Dial Transplant. 2002;17 Suppl 7:7-15.
著者: K C Mange, M M Joffe, H I Feldman
雑誌名: N Engl J Med. 2001 Mar 8;344(10):726-31. doi: 10.1056/NEJM200103083441004.
Abstract/Text BACKGROUND: The effect on allograft survival of the transplantation of kidneys from living donors without the previous initiation of long-term dialysis is controversial.
METHODS: Using data from the U.S. Renal Data System, we performed a retrospective cohort study of 8481 patients who were or who were not treated by long-term dialysis before receiving a kidney transplant from a living donor. The relative rate of allograft failure for patients who received a transplant without previously undergoing long-term dialysis, as compared with patients who underwent long-term dialysis before transplantation, was assessed by proportional-hazards analysis, with adjustment for potential confounding variables, including the transplantation center and median household income. The association between the receipt of a kidney transplant from a living donor without previous dialysis ("preemptive transplantation") and the risk of biopsy-confirmed acute rejection within six months after transplantation was evaluated by conditional logistic-regression analysis, with adjustment for the transplantation center.
RESULTS: Transplantation of a kidney from a living donor without previous long-term dialysis was associated with a 52 percent reduction in the risk of allograft failure during the first year after transplantation (rate ratio, 0.48; P=0.002), an 82 percent reduction during the second year (rate ratio, 0.18; P=0.001), and an 86 percent reduction during subsequent years (rate ratio, 0.14; P=0.001), as compared with transplantation after dialysis. The reduction in the rate of allograft failure during the first year was attenuated when adjustment was made for the timing of acute rejection within the first year (rate ratio, 0.69; 95 percent confidence interval, 0.44 to 1.10; P=0.10). Increasing duration of dialysis was associated with increasing odds of rejection within six months after transplantation (P=0.001).
CONCLUSIONS: Preemptive transplantation of kidneys from living donors without the previous initiation of dialysis is associated with longer allograft survival than transplantation performed after the initiation of dialysis.

PMID 11236776  N Engl J Med. 2001 Mar 8;344(10):726-31. doi: 10.1056/N・・・
著者: A N Vats, L Donaldson, R N Fine, B M Chavers
雑誌名: Transplantation. 2000 Apr 15;69(7):1414-9.
Abstract/Text BACKGROUND: There are no large studies of the effect of pretransplant dialysis status on the outcome of renal transplantation (Tx) in children. This study evaluated the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) registry data for the outcome of Tx in pediatric patients who either (1) received their transplants preemptively or (2) were maintained on dialysis before receiving their transplants.
METHODS: We compared graft survival and patient survival rates, incidence of acute tubular necrosis (ATN), acute rejection episodes, and causes of graft failure in peritoneal dialysis (PD) patients with those maintained on hemodialysis (HD) and those undergoing preemptive Tx (PTx).
RESULTS: Primary Tx was performed in 2495 children (59% male; 61% Caucasian; 1090 PD, 780 HD, 625 PTx) between 1/1/1992 and 12/31/1996. The overall graft survival rates of the PD and HD groups were similar, but were less than that of the PTx group (3-year: 82% PD and HD, 89% PTx, overall P = 0.0003). Improved graft survival in the PTx group was present only in recipients of grafts from living donors. There was no difference in the overall patient survival rate at 3 years, or in time to first acute-rejection episodes in the three groups. The incidence of ATN in the first 7 days post-Tx was higher in PD and HD patients than in PTx patients (11% PD and 12% HD vs. 2% PTx, P<0.001; HD vs. PD, P = NS). The major single cause of graft failure in each group was: PD, vascular thrombosis (200%); HD, chronic rejection (27%); PTx, acute and chronic rejection (21% each).
CONCLUSION: NAPRTCS data show that graft survival is improved in patients receiving PTx, compared with those receiving PD and HD. Graft loss resulting from vascular thrombosis is more common in children who receive PD than in those receiving HD.

PMID 10798764  Transplantation. 2000 Apr 15;69(7):1414-9.
著者: Kevin C Mange, Marshall M Joffe, Harold I Feldman
雑誌名: Nephrol Dial Transplant. 2003 Jan;18(1):172-7.
Abstract/Text BACKGROUND: The relationship between transplantation prior to chronic dialysis initiation and the pattern of acute rejection of kidneys from living donors (LDKT) has not been fully explored.
METHODS: Using data provided by the United States Renal Data System, we performed a retrospective cohort study fitting multivariate proportional hazards models to characterize the association of chronic use of dialysis prior to transplantation [non-pre-emptive LDKT (non-PLDKT)] and acute rejection, and to examine if this association varies throughout the first year.
RESULTS: Non-PLDKT was associated with a 2.5-fold higher rate of biopsy-confirmed rejection during the first month [adjusted HR 2.5, 95% confidence interval (1.85-3.33)], compared with no dialysis prior to transplantation. Increasing duration of pre-transplant dialysis was associated with increasing rate of biopsy-confirmed acute rejection during the first month (P = 0.001 for trend). Over the first year, there was a diminishing relationship between non-PLDKT and acute rejection: 2.5-, 2.22-, 2.13- and 1.78-fold elevation in the episodes of biopsy-confirmed acute rejection during the first, second, third through to the sixth and seventh through to the twelfth month post-transplant, respectively (P = 0.05 for trend).
CONCLUSIONS: The waning of the association of non-PLDKT with acute rejection over time supports the hypothesis that dialysis exposure prior to transplantation may modulate the immune system to increase the rates of acute rejection.

PMID 12480977  Nephrol Dial Transplant. 2003 Jan;18(1):172-7.
著者: H U Meier-Kriesche, F K Port, A O Ojo, S M Rudich, J A Hanson, D M Cibrik, A B Leichtman, B Kaplan
雑誌名: Kidney Int. 2000 Sep;58(3):1311-7. doi: 10.1046/j.1523-1755.2000.00287.x.
Abstract/Text BACKGROUND: Numerous factors are known to impact on patient survival after renal transplantation. Recent studies have confirmed a survival advantage for renal transplant patients over those waiting on dialysis. We aimed to investigate the hypothesis that longer waiting times are more deleterious than shorter waiting times, that is, to detect a "dose effect" for waiting time.
METHODS: We analyzed 73,103 primary adult renal transplants registered at the United States Renal Data System Registry from 1988 to 1997 for the primary endpoints of death with functioning graft and death-censored graft failure by Cox proportional hazard models. All models were corrected for donor and recipient demographics and other factors known to affect outcome after kidney transplantation.
RESULTS: A longer waiting time on dialysis is a significant risk factor for death-censored graft survival and patient death with functioning graft after renal transplantation (P < 0.001 each). Relative to preemptive transplants, waiting times of 6 to 12 months, 12 to 24 months, 24 to 36, 36 to 48, and over 48 months confer a 21, 28, 41, 53, and 72% increase in mortality risk after transplantation, respectively. Relative to preemptive transplants, waiting times of 0 to 6 months, 6 to 12 months, 12 to 24 months, and over 24 months confer a 17, 37, 55, and 68% increase in risk for death-censored graft loss after transplantation, respectively.
CONCLUSIONS: Longer waiting times on dialysis negatively impact on post-transplant graft and patient survival. These data strongly support the hypothesis that patients who reach end-stage renal disease should receive a renal transplant as early as possible in order to enhance their chances of long-term survival.

PMID 10972695  Kidney Int. 2000 Sep;58(3):1311-7. doi: 10.1046/j.1523-・・・
著者: Herwig-Ulf Meier-Kriesche, Bruce Kaplan
雑誌名: Transplantation. 2002 Nov 27;74(10):1377-81. doi: 10.1097/01.TP.0000034632.77029.91.
Abstract/Text BACKGROUND: Waiting time on dialysis has been shown to be associated with worse outcomes after living and cadaveric transplantation. To validate and quantify end-stage renal disease (ESRD) time as an independent risk factor for kidney transplantation, we compared the outcome of paired donor kidneys, destined to patients who had ESRD more than 2 years compared to patients who had ESRD less than 6 months.
METHODS: We analyzed data available from the U.S. Renal Data System database between 1988 and 1998 by Kaplan-Meier estimates and Cox proportional hazards models to quantify the effect of ESRD time on paired cadaveric kidneys and on all cadaveric kidneys compared to living-donated kidneys.
RESULTS: Five- and 10-year unadjusted graft survival rates were significantly worse in paired kidney recipients who had undergone more than 24 months of dialysis (58% and 29%, respectively) compared to paired kidney recipients who had undergone less than 6 months of dialysis (78% and 63%, respectively; P<0.001 each). Ten-year overall adjusted graft survival for cadaveric transplants was 69% for preemptive transplants versus 39% for transplants after 24 months on dialysis. For living transplants, 10-year overall adjusted graft survival was 75% for preemptive transplants versus 49% for transplants after 24 month on dialysis.
CONCLUSIONS: ESRD time is arguably the strongest independent modifiable risk factor for renal transplant outcomes. Part of the advantage of living-donor versus cadaveric-donor transplantation may be explained by waiting time. This effect is dominant enough that a cadaveric renal transplant recipient with an ESRD time less than 6 months has the equivalent graft survival of living donor transplant recipients who wait on dialysis for more than 2 years.

PMID 12451234  Transplantation. 2002 Nov 27;74(10):1377-81. doi: 10.10・・・
著者: Bertram L Kasiske, Jon J Snyder, Arthur J Matas, Mary D Ellison, John S Gill, Annamaria T Kausz
雑誌名: J Am Soc Nephrol. 2002 May;13(5):1358-64.
Abstract/Text It remains unclear whether preemptive transplantation is beneficial, and if so, who benefits. A total of 38,836 first, kidney-only transplants between 1995 and 1998 were retrospectively studied. A surprising 39% of preemptive transplants were from cadaver donors, and the proportions of cadaver donor transplants that were preemptive changed little, from 7.3% in 1995 to 7.7% in 1998. Preemptive transplants using cadaver donors were more likely among recipients aged 0 to 17 yr versus 18 to 29 yr (odds ratio [OR], 2.48; 95% confidence interval [CI], 1.94 to 3.17), white versus black (OR, 2.33; 95% CI, 2.03 to 2.68), able to work versus unable to work (OR, 1.42; 95% CI, 1.26 to 1.61), covered by private insurance versus Medicare (OR, 4.77; 95% CI, 4.26 to 5.32), or recipients with a college degree versus no college degree (OR, 1.34; 95% CI, 1.17 to 1.54). Preemptive transplants were less likely for Hispanics versus non-Hispanics (OR, 0.57; 95% CI, 0.50 to 0.67), patients with type 2 versus type 1 diabetes (OR, 0.76; 95% CI, 0.61 to 0.96), and for 2 to 5 HLA mismatches compared with 0 HLA mismatches (OR range, 0.77 to 0.82). In adjusted Cox proportional hazards analysis, the relative risk of graft failure for preemptive transplantation was 0.75 (0.67 to 0.84) among 25,758 cadaver donor transplants and 0.73 (0.64 to 0.83) among 13,078 living donor transplants, compared with patients who received a transplant after already being on dialysis. Preemptive transplantation was associated with a reduced risk of death: 0.84 (0.72 to 0.99) for cadaver donor transplants and 0.69 (0.56 to 0.85) for living donor transplants. Thus, preemptive transplantation, which is associated with improved patient and graft survival, is less common among racial minorities, those who have less education, and those who must rely on Medicare for primary payment. Alterations in the payment system, emphasis on early referral, and changes in cadaver kidney allocation could increase the number of patients who benefit from preemptive transplantation.

PMID 11961024  J Am Soc Nephrol. 2002 May;13(5):1358-64.
著者: Abimereki D Muzaale, Allan B Massie, Mei-Cheng Wang, Robert A Montgomery, Maureen A McBride, Jennifer L Wainright, Dorry L Segev
雑誌名: JAMA. 2014 Feb 12;311(6):579-86. doi: 10.1001/jama.2013.285141.
Abstract/Text IMPORTANCE: Risk of end-stage renal disease (ESRD) in kidney donors has been compared with risk faced by the general population, but the general population represents an unscreened, high-risk comparator. A comparison to similarly screened healthy nondonors would more properly estimate the sequelae of kidney donation.
OBJECTIVES: To compare the risk of ESRD in kidney donors with that of a healthy cohort of nondonors who are at equally low risk of renal disease and free of contraindications to live donation and to stratify these comparisons by patient demographics.
DESIGN, SETTINGS, AND PARTICIPANTS: A cohort of 96,217 kidney donors in the United States between April 1994 and November 2011 and a cohort of 20,024 participants of the Third National Health and Nutrition Examination Survey (NHANES III) were linked to Centers for Medicare & Medicaid Services data to ascertain development of ESRD, which was defined as the initiation of maintenance dialysis, placement on the waiting list, or receipt of a living or deceased donor kidney transplant, whichever was identified first. Maximum follow-up was 15.0 years; median follow-up was 7.6 years (interquartile range [IQR], 3.9-11.5 years) for kidney donors and 15.0 years (IQR, 13.7-15.0 years) for matched healthy nondonors.
MAIN OUTCOMES AND MEASURES: Cumulative incidence and lifetime risk of ESRD.
RESULTS: Among live donors, with median follow-up of 7.6 years (maximum, 15.0), ESRD developed in 99 individuals in a mean (SD) of 8.6 (3.6) years after donation. Among matched healthy nondonors, with median follow-up of 15.0 years (maximum, 15.0), ESRD developed in 36 nondonors in 10.7 (3.2) years, drawn from 17 ESRD events in the unmatched healthy nondonor pool of 9364. Estimated risk of ESRD at 15 years after donation was 30.8 per 10,000 (95% CI, 24.3-38.5) in kidney donors and 3.9 per 10,000 (95% CI, 0.8-8.9) in their matched healthy nondonor counterparts (P < .001). This difference was observed in both black and white individuals, with an estimated risk of 74.7 per 10,000 black donors (95% CI, 47.8-105.8) vs 23.9 per 10,000 black nondonors (95% CI, 1.6-62.4; P < .001) and an estimated risk of 22.7 per 10,000 white donors (95% CI, 15.6-30.1) vs 0.0 white nondonors (P < .001). Estimated lifetime risk of ESRD was 90 per 10,000 donors, 326 per 10,000 unscreened nondonors (general population), and 14 per 10,000 healthy nondonors.
CONCLUSIONS AND RELEVANCE: Compared with matched healthy nondonors, kidney donors had an increased risk of ESRD over a median of 7.6 years; however, the magnitude of the absolute risk increase was small. These findings may help inform discussions with persons considering live kidney donation.

PMID 24519297  JAMA. 2014 Feb 12;311(6):579-86. doi: 10.1001/jama.2013・・・
著者: John S Gill, Marcello Tonelli
雑誌名: JAMA. 2014 Feb 12;311(6):577-9. doi: 10.1001/jama.2013.285142.
Abstract/Text
PMID 24519296  JAMA. 2014 Feb 12;311(6):577-9. doi: 10.1001/jama.2013.・・・

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