今日の臨床サポート

慢性腎臓病(CKD)

薬価収載情報:2022年3月28日 ケレンディア 錠10mg、20mg(フィネレノン 非ステロイド型選択的ミネラルコルチコイド受容体拮抗薬)

概要・推奨   

  1. 慢性腎臓病(chronic kidney diseaseCKDは慢性的に腎臓の異常のある疾患のすべてを包含する疾患概念である。
  1. CKDの重症化により末期慢性腎不全への進行とともに、心血管疾患(cardiovascular disease、CVD)発症のリスクも上昇する。
  1. CKDには腎に異常を来す一次性あるいは二次性の原腎疾患があり、診療においては原腎疾患の管理が優先される。
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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。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※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、実際の保険適応の査定において保険適応及び保険適応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応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(アストラゼネカ,大塚製薬,バイエル,協和キリン,田辺三菱,持田製薬),研究費・助成金など(協和キリン,田辺三菱),奨学(奨励)寄付など(協和キリン,帝人ファーマ,中外製薬)[2022年]
監修:岡田浩一 : 講演料(アストラゼネカ,協和キリン,第一三共,田辺三菱製薬,鳥居薬品),研究費・助成金など(協和キリン),奨学(奨励)寄付など(中外製薬,協和キリン,小野薬品工業,バイエル薬品)[2022年]

改訂のポイント:
  1. 最近の注目されるエビデンスの追加を行う。

病態・疫学・診察

疾患情報  
ポイント:
  1. 慢性腎臓病(chronic kidney disease、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。2015年のわが国のCKD患者数は1480万人と推計され[3]、2005年からの増加の主因は高齢者人口の増加である。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][4]
  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(cardiovascular disease、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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文献 

Kei Nagai, Koichi Asahi, Kunitoshi Iseki, Kunihiro Yamagata
Estimating the prevalence of definitive chronic kidney disease in the Japanese general population.
Clin Exp Nephrol. 2021 Aug;25(8):885-892. doi: 10.1007/s10157-021-02049-0. Epub 2021 Apr 10.
Abstract/Text BACKGROUND: Most data on chronic kidney disease (CKD) prevalence has been based on single measurements of renal function and proteinuria. The aim was to determine the prevalence of CKD diagnosed by chronic proteinuria and/or reduced eGFR in a recent year in Japan.
METHODS: In the main study, using a population-based cohort in Japan, the overall prevalence of CKD, defined as persistent positive proteinuria and/or eGFR < 60 ml/min/1.73 m2, was determined. Of 2,849,557 persons, 763,104 had data for eGFR and proteinuria in both 2014 and 2015. For estimating number of CKD cases in Japanese adults, a regional cohort data with age ranging 22-87 years (N = 22,037) was further applied to the analysis.
RESULTS: Definitive CKD was present in 2.3-23.0% of men and 1.7-17.1% of women age from 40 to 74 years in the main cohort. The estimated prevalence of reduced eGFR and/or proteinuria in the baseline year alone was 15.7% in men and 13.6% in women; the prevalence of definitive CKD was 10.9% in men and 9.2% in women. The number of CKD cases based on a single-year test in Japanese adults over 20 years of age increased from 13.3 million to 14.8 million between 2005 and 2015.
CONCLUSIONS: Recent changes in prevalence of CKD seem to be mainly caused by an increase in Japan's elderly population. Although past reports may lead to overdiagnosis of CKD by a single-year test, the estimated number of definitive CKD was 10.2 million in 2015.

PMID 33839966
Revised equations for estimated GFR from serum creatinine in Japan.
Am J Kidney Dis. 2009 Jun;53(6):982-92. doi: 10.1053/j.ajkd.2008.12.034. Epub 2009 Apr 1.
Abstract/Text
PMID 19339088
Masahiro Naruse, Masashi Mukoyama, Jun Morinaga, Masanobu Miyazaki, Kunitoshi Iseki, Kunihiro Yamagata
Usefulness of the quantitative measurement of urine protein at a community-based health checkup: a cross-sectional study.
Clin Exp Nephrol. 2020 Jan;24(1):45-52. doi: 10.1007/s10157-019-01789-4. Epub 2019 Sep 20.
Abstract/Text BACKGROUND: The dipstick urinalysis for proteinuria has been used for chronic kidney disease (CKD) screening at community-based health checkups; however, it has major drawbacks in that the result is only semi-quantitative and is influenced by urine concentration.
METHODS: We conducted urine protein/creatinine ratio (UPCR) measurements of 590 participants who showed a result of more than trace proteinuria on a dipstick analysis and evaluated the usefulness of UPCR measurements in community-based health checkups.
RESULTS: The UPCR values increased in accordance with the severity of the dipstick test findings, but statistical significance was only obtained between (±) and (1+), between (±) and (2+), and between (±) and (3+) groups. When the participants with (±) proteinuria were subjected to CGA classification (a classification of CKD by cause, glomerular filtration rate category, and albuminuria category) according to their UPCR data, a significant proportion of subjects (277, 77.0%) moved from the A2 category into A1, which is a less severe category. Conversely, 21 subjects (5.8%) were reclassified into a more severe category (A3). Thus, a dipstick test may produce a non-negligible number of false negatives as well as a large number of false positives. Similarly, the classifications of more than half of the subjects with (1+) or more severe proteinuria were changed based on their UPCR results.
CONCLUSION: The dipstick urinalysis for proteinuria appears less reliable than expected, suggesting that the quantitative measurement of urine protein should be performed even during mass health checkups to ensure the early detection and prevention of CKD.

PMID 31541337
Yoshihiro Tani, Masaaki Nakayama, Hiroyuki Terawaki, Kunitoshi Iseki, Tsuyoshi Watanabe
Comparison of albuminuria test and urine test strip in Japanese hypertensive patients: AVA-E study.
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
Abstract/Text
PMID 1921146
Abstract/Text
PMID 1395165
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)
Review on uremic toxins: classification, concentration, and interindividual variability.
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
F Gejyo, N Homma, Y Suzuki, M Arakawa
Serum levels of beta 2-microglobulin as a new form of amyloid protein in patients undergoing long-term hemodialysis.
N Engl J Med. 1986 Feb 27;314(9):585-6. doi: 10.1056/NEJM198602273140920.
Abstract/Text
PMID 3080684
Raymond Vanholder, Eva Schepers, Anneleen Pletinck, Evi V Nagler, Griet Glorieux
The uremic toxicity of indoxyl sulfate and p-cresyl sulfate: a systematic review.
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
The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report.
Kidney Int. 2011 Jul;80(1):17-28. doi: 10.1038/ki.2010.483. Epub 2010 Dec 8.
Abstract/Text
PMID 21150873
Kunihiro Yamagata, Hirofumi Makino, Kunitoshi Iseki, Sadayoshi Ito, Kenjiro Kimura, Eiji Kusano, Takanori Shibata, Kimio Tomita, Ichiei Narita, Tomoya Nishino, Yoshihide Fujigaki, Tetsuya Mitarai, Tsuyoshi Watanabe, Takashi Wada, Teiji Nakamura, Seiichi Matsuo, Study Group for Frontier of Renal Outcome Modifications in Japan (FROM-J)
Effect of Behavior Modification on Outcome in Early- to Moderate-Stage Chronic Kidney Disease: A Cluster-Randomized Trial.
PLoS One. 2016;11(3):e0151422. doi: 10.1371/journal.pone.0151422. Epub 2016 Mar 21.
Abstract/Text OBJECTIVES: Owing to recent changes in our understanding of the underlying cause of chronic kidney disease (CKD), the importance of lifestyle modification for preventing the progression of kidney dysfunction and complications has become obvious. In addition, effective cooperation between general physicians (GPs) and nephrologists is essential to ensure a better care system for CKD treatment. In this cluster-randomized study, we studied the effect of behavior modification on the outcome of early- to moderate-stage CKD.
DESIGN: Stratified open cluster-randomized trial.
SETTING: A total of 489 GPs belonging to 49 local medical associations (clusters) in Japan.
PARTICIPANTS: A total of 2,379 patients (1,195 in group A (standard intervention) and 1,184 in group B (advanced intervention)) aged between 40 and 74 years, who had CKD and were under consultation with GPs.
INTERVENTION: All patients were managed in accordance with the current CKD guidelines. The group B clusters received three additional interventions: patients received both educational intervention for lifestyle modification and a CKD status letter, attempting to prevent their withdrawal from treatment, and the group B GPs received data sheets to facilitate reducing the gap between target and practice.
MAIN OUTCOME MEASURE: The primary outcome measures were 1) the non-adherence rate of accepting continuous medical follow-up of the patients, 2) the collaboration rate between GPs and nephrologists, and 3) the progression of CKD.
RESULTS: The rate of discontinuous clinical visits was significantly lower in group B (16.2% in group A vs. 11.5% in group B, p = 0.01). Significantly higher referral and co-treatment rates were observed in group B (p<0.01). The average eGFR deterioration rate tended to be lower in group B (group A: 2.6±5.8 ml/min/1.73 m2/year, group B: 2.4±5.1 ml/min/1.73 m2/year, p = 0.07). A significant difference in eGFR deterioration rate was observed in subjects with Stage 3 CKD (group A: 2.4±5.9 ml/min/1.73 m2/year, group B: 1.9±4.4 ml/min/1.73 m2/year, p = 0.03).
CONCLUSION: Our care system achieved behavior modification of CKD patients, namely, significantly lower discontinuous clinical visits, and behavior modification of both GPs and nephrologists, namely significantly higher referral and co-treatment rates, resulting in the retardation of CKD progression, especially in patients with proteinuric Stage 3 CKD.
TRIAL REGISTRATION: The University Hospital Medical Information Network clinical trials registry UMIN000001159.

PMID 26999730
Abstract/Text
PMID 17136030
Keiichi Sumida, Miklos Z Molnar, Praveen K Potukuchi, Fridtjof Thomas, Jun Ling Lu, Kunihiro Matsushita, Kunihiro Yamagata, Kamyar Kalantar-Zadeh, Csaba P Kovesdy
Constipation and Incident CKD.
J Am Soc Nephrol. 2017 Apr;28(4):1248-1258. doi: 10.1681/ASN.2016060656. Epub 2016 Nov 10.
Abstract/Text Constipation is one of the most prevalent conditions in primary care settings and increases the risk of cardiovascular disease, potentially through processes mediated by altered gut microbiota. However, little is known about the association of constipation with CKD. In a nationwide cohort of 3,504,732 United States veterans with an eGFR ≥60 ml/min per 1.73 m2, we examined the association of constipation status and severity (absent, mild, or moderate/severe), defined using diagnostic codes and laxative use, with incident CKD, incident ESRD, and change in eGFR in Cox models (for time-to-event analyses) and multinomial logistic regression models (for change in eGFR). Among patients, the mean (SD) age was 60.0 (14.1) years old; 93.2% of patients were men, and 24.7% were diabetic. After multivariable adjustments, compared with patients without constipation, patients with constipation had higher incidence rates of CKD (hazard ratio, 1.13; 95% confidence interval [95% CI], 1.11 to 1.14) and ESRD (hazard ratio, 1.09; 95% CI, 1.01 to 1.18) and faster eGFR decline (multinomial odds ratios for eGFR slope <-10, -10 to <-5, and -5 to <-1 versus -1 to <0 ml/min per 1.73 m2 per year, 1.17; 95% CI, 1.14 to 1.20; 1.07; 95% CI, 1.04 to 1.09; and 1.01; 95% CI, 1.00 to 1.03, respectively). More severe constipation associated with an incrementally higher risk for each renal outcome. In conclusion, constipation status and severity associate with higher risk of incident CKD and ESRD and with progressive eGFR decline, independent of known risk factors. Further studies should elucidate the underlying mechanisms.

Copyright © 2017 by the American Society of Nephrology.
PMID 28122944
Reiko Okubo, Masahide Kondo, Shu-Ling Hoshi, Masafumi Okada, Mariko Doi, Hideto Takahashi, Hirayasu Kai, Chie Saito, Kunitoshi Iseki, Chiho Iseki, Tsuyoshi Watanabe, Ichiei Narita, Seiichi Matsuo, Hirofumi Makino, Akira Hishida, Kunihiro Yamagata
Cost-Effectiveness of Behavior Modification Intervention for Patients With Chronic Kidney Disease in the FROM-J Study.
J Ren Nutr. 2021 Sep;31(5):484-493. doi: 10.1053/j.jrn.2020.12.008. Epub 2021 Mar 18.
Abstract/Text OBJECTIVES: Chronic kidney disease (CKD) is a significant public health problem. An advanced, or innovative, CKD care system of clinical practice collaboration among general physicians (GPs), nephrologists, and other healthcare workers achieved behavior modification in patients with Stage 3 CKD in the Frontier of Renal Outcome Modifications in Japan (FROM-J) study. This behavior modification intervention consisted of educational sessions on nutrition and lifestyle, as well as encouragement of patients' regular visits. The intervention contributed to slowing CKD progression. This study aimed to evaluate the cost-effectiveness of the widespread diffusion of the behavior modification intervention proven effective by the FROM-J study.
METHODS: A cost-effectiveness analysis was carried out to compare the behavior modification intervention with the current practice recommended by the latest CKD clinical guidelines for GPs. A Markov model with a societal perspective under Japan's health system was constructed. We assumed that the behavior modification intervention proven effective by the FROM-J study would be initiated by GPs for targeted patient cohorts-patients aged 40-74 years with Stage 3 CKD-as a part of the innovative CKD care system.
RESULTS: The incremental cost-effectiveness ratio for the behavior modification intervention compared with current guideline-based practice was calculated as 145,593 Japanese yen (¥; $1,324 United States dollars [$]) per quality-adjusted life year (QALY).
CONCLUSIONS: Using the suggested value of social willingness to pay for a one-QALY gain in Japan of ¥5 million (US$45,455) as the threshold to judge cost-effectiveness, the behavior modification intervention is cost-effective. Our results suggest that diffusing the behavior modification intervention proven effective by the FROM-J study could be justifiable as an efficient use of finite healthcare resources. GPs could be encouraged to initiate this intervention by revising the National Health Insurance fee schedule and strengthening clinical guidelines regarding behavior modification interventions.

Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
PMID 33744060
Abstract/Text
PMID 23798459
HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis.
Cochrane Database Syst Rev. 2014 May 31;(5):CD007784. doi: 10.1002/14651858.CD007784.pub2.
Abstract/Text
PMID 24880031
Effect of allopurinol in chronic kidney disease progression and cardiovascular risk.
Clin J Am Soc Nephrol. 2010 Aug;5(8):1388-93. doi: 10.2215/CJN.01580210. Epub 2010 Jun 10.
Abstract/Text
PMID 20538833
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
Effects of uric acid-lowering therapy on renal outcomes: a systematic review and meta-analysis.
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
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
Febuxostat Therapy for Patients With Stage 3 CKD and Asymptomatic Hyperuricemia: A Randomized Trial.
Am J Kidney Dis. 2018 Aug 31;. doi: 10.1053/j.ajkd.2018.06.028. Epub 2018 Aug 31.
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
Abstract/Text
PMID 20072112
Oral sodium bicarbonate improves thyroid function in predialysis chronic kidney disease.
Am J Nephrol. 2010;32(6):549-56. doi: 10.1159/000321461. Epub 2010 Nov 2.
Abstract/Text
PMID 21042013
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
Roxadustat for Anemia in Patients with Kidney Disease Not Receiving Dialysis.
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
Abstract/Text
PMID 17108342
Correction of anemia with epoetin alfa in chronic kidney disease.
N Engl J Med. 2006 Nov 16;355(20):2085-98.
Abstract/Text
PMID 17108343
Abstract/Text
PMID 12843775
Tadao Akizawa, Yasushi Asano, Satoshi Morita, Takafumi Wakita, Yoshihiro Onishi, Shunichi Fukuhara, Fumitake Gejyo, Seiichi Matsuo, Noriaki Yorioka, Kiyoshi Kurokawa, CAP-KD Study Group
Effect of a carbonaceous oral adsorbent on the progression of CKD: a multicenter, randomized, controlled trial.
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
Cost-effectiveness of administering oral adsorbent AST-120 to patients with diabetes and advance-stage chronic kidney disease.
Diabetes Res Clin Pract. 2010 Nov;90(2):154-9. doi: 10.1016/j.diabres.2010.07.007. Epub 2010 Aug 13.
Abstract/Text
PMID 20708813
The frequency of hyperkalemia and its significance in chronic kidney disease.
Arch Intern Med. 2009 Jun 22;169(12):1156-62. doi: 10.1001/archinternmed.2009.132.
Abstract/Text
PMID 19546417
Hypokalemia and outcomes in patients with chronic heart failure and chronic kidney disease: findings from propensity-matched studies.
Circ Heart Fail. 2010 Mar;3(2):253-60. doi: 10.1161/CIRCHEARTFAILURE.109.899526. Epub 2010 Jan 26.
Abstract/Text
PMID 20103777
Serum potassium and outcomes in CKD: insights from the RRI-CKD cohort study.
Clin J Am Soc Nephrol. 2010 May;5(5):762-9. doi: 10.2215/CJN.05850809. Epub 2010 Mar 4.
Abstract/Text
PMID 20203167
Hiddo J L Heerspink, Bergur V Stefánsson, Ricardo Correa-Rotter, Glenn M Chertow, Tom Greene, Fan-Fan Hou, Johannes F E Mann, John J V McMurray, Magnus Lindberg, Peter Rossing, C David Sjöström, Roberto D Toto, Anna-Maria Langkilde, David C Wheeler, DAPA-CKD Trial Committees and Investigators
Dapagliflozin in Patients with Chronic Kidney Disease.
N Engl J Med. 2020 Oct 8;383(15):1436-1446. doi: 10.1056/NEJMoa2024816. Epub 2020 Sep 24.
Abstract/Text BACKGROUND: Patients with chronic kidney disease have a high risk of adverse kidney and cardiovascular outcomes. The effect of dapagliflozin in patients with chronic kidney disease, with or without type 2 diabetes, is not known.
METHODS: We randomly assigned 4304 participants with an estimated glomerular filtration rate (GFR) of 25 to 75 ml per minute per 1.73 m2 of body-surface area and a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 200 to 5000 to receive dapagliflozin (10 mg once daily) or placebo. The primary outcome was a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes.
RESULTS: The independent data monitoring committee recommended stopping the trial because of efficacy. Over a median of 2.4 years, a primary outcome event occurred in 197 of 2152 participants (9.2%) in the dapagliflozin group and 312 of 2152 participants (14.5%) in the placebo group (hazard ratio, 0.61; 95% confidence interval [CI], 0.51 to 0.72; P<0.001; number needed to treat to prevent one primary outcome event, 19 [95% CI, 15 to 27]). The hazard ratio for the composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45 to 0.68; P<0.001), and the hazard ratio for the composite of death from cardiovascular causes or hospitalization for heart failure was 0.71 (95% CI, 0.55 to 0.92; P = 0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (hazard ratio, 0.69; 95% CI, 0.53 to 0.88; P = 0.004). The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes. The known safety profile of dapagliflozin was confirmed.
CONCLUSIONS: Among patients with chronic kidney disease, regardless of the presence or absence of diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lower with dapagliflozin than with placebo. (Funded by AstraZeneca; DAPA-CKD ClinicalTrials.gov number, NCT03036150.).

Copyright © 2020 Massachusetts Medical Society.
PMID 32970396
Low protein diets for chronic kidney disease in non diabetic adults.
Cochrane Database Syst Rev. 2006 Apr 19;(2):CD001892.
Abstract/Text
PMID 16625550
Epidemiology, clinical features and outcomes of pneumonia in patients with chronic kidney disease.
Nephrol Dial Transplant. 2011 Sep;26(9):2899-906. doi: 10.1093/ndt/gfq798. Epub 2011 Jan 27.
Abstract/Text
PMID 21273232
Abstract/Text
PMID 8671817
Abstract/Text
PMID 15302780
Early referral to specialist nephrology services for preventing the progression to end-stage kidney disease.
Cochrane Database Syst Rev. 2014 Jun 18;(6):CD007333. doi: 10.1002/14651858.CD007333.pub2.
Abstract/Text
PMID 24938824
Slowing renal function decline in chronic kidney disease patients after nephrology referral.
Nephrology (Carlton). 2008 Dec;13(8):730-6. doi: 10.1111/j.1440-1797.2008.01023.x. Epub 2008 Nov 17.
Abstract/Text
PMID 19019170
Clinical practice guidelines for hemodialysis adequacy, update 2006.
Am J Kidney Dis. 2006 Jul;48 Suppl 1:S2-90.
Abstract/Text
PMID 16813990
The CARI guidelines. Acceptance into dialysis guidelines.
Nephrology (Carlton). 2005 Oct;10 Suppl 4:S46-60.
Abstract/Text
PMID 16221124
Abstract/Text
PMID 12386205
Abstract/Text
PMID 12480977
Effect of waiting time on renal transplant outcome.
Kidney Int. 2000 Sep;58(3):1311-7.
Abstract/Text
PMID 10972695
Abstract/Text
PMID 11961024
Risk of end-stage renal disease following live kidney donation.
JAMA. 2014 Feb 12;311(6):579-86. doi: 10.1001/jama.2013.285141.
Abstract/Text
PMID 24519297
Understanding rare adverse outcomes following living kidney donation.
JAMA. 2014 Feb 12;311(6):577-9. doi: 10.1001/jama.2013.285142.
Abstract/Text
PMID 24519296

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