今日の臨床サポート

微小変化型ネフローゼ症候群

著者: 今井圓裕 中山寺いまいクリニック

監修: 岡田浩一 埼玉医科大学 腎臓内科

著者校正/監修レビュー済:2021/04/07
参考ガイドライン:
  1. 厚生労働科学研究費補助金難治性疾患等政策研究事業(難治性疾患政策研究事業)難治性腎障害に関する調査研究班:エビデンスに基づくネフローゼ症候群診療ガイドライン 2020
患者向け説明資料

概要・推奨   

  1. ステロイドの連日投与と隔日投与では、反応性に差はなかった。投与はいずれの方法でもよい(推奨度3)。
  1. 初回再発の患者に、プレドニゾロンにシクロスポリンを併用することによって、プレドニゾロン単独よりも早く寛解導入ができる。したがって、ステロイドを用いて反応が得られない患者では、追加で免疫抑制薬を投与することが勧められる(推奨度2)。
  1. シクロスポリンとシクロホスファミドでは寛解導入率に差はない(推奨度3)。
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲
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  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となりま
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要とな
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧
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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:
今井圓裕 : 講演料(第一三共,ベーリンガーインゲルハイム,日本イーライリリー,バイエル,田辺三菱),研究費・助成金など(田辺三菱,キッセイ,大日本住友,アストラゼネカ)[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. エビデンスに基づくネフローゼ症候群診療ガイドライン2020 に基づき、治療アルゴリズムの改訂を行った。

病態、疫学、診察

疾患情報(疫学・病態)  
疾患のポイント:
  1. 微小変化型ネフローゼ症候群(minimal change nephritic syndrome、MCNS)とは、光学顕微鏡で正常もしくは軽微なメサンギウムの変化を伴うネフローゼ症候群である。
  1. 成人の一次性ネフローゼ症候群の約40%を占める。
  1. 10歳以下の子どものネフローゼ症候群のうち約90%を占める。非ステロイド抗炎症薬(NSAIDs)に関連するものや、傍腫瘍症候群、特にホジキン病に伴って起こることがある(ネフローゼ症候群の診断基準: >詳細情報 )。
  1. 特徴は、比較的急激な発症、小児~青年期に頻度が高い、ステロイド薬が著効することである。
  1. 腎前性の急性腎障害を合併することがある。
  1. 慢性腎不全に至ることは少ないが、急性腎障害が遷延した場合には腎機能障害を残すこともある。
  1. 微小変化型ネフローゼ症候群を含む、一次性ネフローゼ症候群は、指定難病であり、その一部は申請し認定されると保険料の自己負担分の一部が公費負担として助成される。(平成27年7月施行
  1. 難病法に基づく医療費助成制度
問診・診察のポイント  
  1. 急激な発症であることを確認する。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

著者: Hitoshi Yokoyama, Takashi Taguchi, Hitoshi Sugiyama, Hiroshi Sato, Committee for the Standardization of Renal Pathological Diagnosis and for Renal Biopsy and Disease Registry in the Japanese Society of Nephrology
雑誌名: Clin Exp Nephrol. 2012 Aug;16(4):557-63. doi: 10.1007/s10157-012-0593-7. Epub 2012 Feb 23.
Abstract/Text Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults. The J-RBR/J-KDR registry developed by the Japanese Society of Nephrology provides nationwide cohort data for epidemiological studies of MN. MN was present in 36.8% of 1,203 primary nephrotic syndrome patients in Japan. In addition, 633 (77.9%) out of 813 MN patients were referred to as "idiopathic," whereas 22.1% were classified as "secondary" and involved conditions such as systemic lupus erythematosus, drug exposure, infections, cancer, and various collagen diseases. The mean age of the MN patients was 62.2 (2-88) years old, their mean eGFR was 76.7 (7.6-154.6) ml/min/1.73 m(2), and 63.3% had hypertension at the time of renal biopsy. On the basis of these findings, half of Japanese idiopathic MN patients have risk factors (age >60, male, or lower eGFR) for end-stage renal failure, and 10% belong to the high-risk group (daily proteinuria of over 8.0 g). Further studies with high-grade evidence should resolve the natural history and therapeutic problems of idiopathic MN in elderly Japanese.

PMID 22358611  Clin Exp Nephrol. 2012 Aug;16(4):557-63. doi: 10.1007/s・・・
著者: Hitoshi Yokoyama, Hitoshi Sugiyama, Hiroshi Sato, Takashi Taguchi, Michio Nagata, Seiichi Matsuo, Hirofumi Makino, Tsuyoshi Watanabe, Takao Saito, Yutaka Kiyohara, Shinichi Nishi, Hiroyuki Iida, Kunio Morozumi, Atsushi Fukatsu, Tamaki Sasaki, Kazuhiko Tsuruya, Yukimasa Kohda, Makoto Higuchi, Hideyasu Kiyomoto, Shin Goto, Motoshi Hattori, Hiroshi Hataya, Shoji Kagami, Norishige Yoshikawa, Yuichiro Fukasawa, Yoshihiko Ueda, Hiroshi Kitamura, Akira Shimizu, Kazumasa Oka, Naoki Nakagawa, Takafumi Ito, Shunya Uchida, Kengo Furuichi, Izaya Nakaya, Satoshi Umemura, Keiju Hiromura, Mitsuhiro Yoshimura, Nobuhito Hirawa, Takashi Shigematsu, Masafumi Fukagawa, Makoto Hiramatsu, Yoshio Terada, Osamu Uemura, Tetsuya Kawata, Akira Matsunaga, Aki Kuroki, Yasukiyo Mori, Koji Mitsuiki, Haruyoshi Yoshida, Committee for the Standardization of Renal Pathological Diagnosis and for Renal Biopsy and Disease Registry of the Japanese Society of Nephrology, and the Progressive Renal Disease Research of the Ministry of Health, Labour and Welfare of Japan
雑誌名: Clin Exp Nephrol. 2012 Dec;16(6):903-20. doi: 10.1007/s10157-012-0673-8. Epub 2012 Oct 11.
Abstract/Text BACKGROUND AND OBJECTIVES: Data regarding renal disease in the elderly (age ≥65 years old) and very elderly (age ≥80 years old) Japanese are extremely limited. The aim of this study was to examine the causes of renal disease and their clinical presentations in elderly patients who underwent renal biopsy.
DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: From July 2007 to November 2011, all of the elderly native renal biopsy patients who had been registered in the Japan Renal Biopsy Registry (J-RBR; 2802 including 1596 males and 1206 females) were identified. Their data were compared with a control group of 7416 patients who ranged in age from 20 to 64 years old and were registered on the J-RBR over the same period. In addition, the clinical and pathological classifications of 276 very elderly patients were also analyzed.
RESULTS: The indications for biopsy were nephrotic syndrome (NS) in 36.2 and 50.7 % of the elderly and the very elderly patients, chronic nephritic syndrome in 31.8 and 17.4 %, and acute kidney injury including rapidly progressive glomerulonephritis in 18.6 and 22.5 %, respectively. Primary glomerular disease was the most frequent diagnosis, followed by MPO-ANCA-positive nephritis, IgA nephropathy (IgAN), and diabetic nephropathy. In primary GN including IgAN, membranous nephropathy (MN) was the most frequent histological type, followed by IgAN and minor glomerular abnormalities. A comparison with the control group showed that MN, MPO-ANCA-positive nephritis, and amyloid nephropathy were more common in the elderly (P < 0.001), and IgAN was less common (P < 0.001). As for nephrotic syndrome in the elderly, MN was the most common histological type, followed by minimal change NS, diabetic nephropathy, amyloid nephropathy, and focal segmental glomerulosclerosis. There was a significant discrepancy between the urinary protein/creatinine ratio and daily proteinuria after the 7th decade of life.
CONCLUSIONS: Renal biopsy is a valuable diagnostic tool, even in elderly and very elderly Japanese patients. In the future, modified clinical guidelines for elderly renal disease should be developed.

PMID 23053590  Clin Exp Nephrol. 2012 Dec;16(6):903-20. doi: 10.1007/s・・・
著者: Takashi Takei, Minako Koike, Koichi Suzuki, Satsuki Shirota, Mitsuyo Itabashi, Shigeru Ohtsubo, Hidekazu Sugiura, Keiko Suzuki, Chiari Kojima, Masaki Takahashi, Jun Ino, Tetsuya Ogawa, Keiko Uchida, Ken Tsuchiya, Wako Yumura, Kosaku Nitta
雑誌名: Clin Exp Nephrol. 2007 Sep;11(3):214-7. doi: 10.1007/s10157-007-0484-5. Epub 2007 Sep 28.
Abstract/Text BACKGROUND: Although minimal-change nephrotic syndrome (MCNS) is highly steroid-responsive, the frequency of relapses in some patients is high, necessitating the administration of repeated courses of prednisolone in high doses. It is, therefore, necessary to identify factors that can predict this increased risk of relapse in some patients in order to establish useful treatment methods to reduce the risk.
METHODS: To clarify the factors that might increase the risk of relapses, the data of 82 Japanese adult patients with MCNS receiving treatment at our department were analyzed retrospectively. Of the total, 55 patients (67.1%) experienced relapse after showing an initial response. We divided the patients into two groups; namely, the nonrelapse group (n = 27) and the relapse group (n = 55), and compared the clinico-pathophysiological characteristics between the two groups.
RESULTS: Significantly increased serum immunoglobulin E (IgE) levels (P = 0.0002) and increased frequency of steroid side effects were observed in the relapse group as compared to the nonrelapse group.
CONCLUSIONS: To develop effective therapeutic modalities, it is important to have a thorough understanding of the clinico-pathophysiological characteristics of MCNS patients showing relapse.

PMID 17891348  Clin Exp Nephrol. 2007 Sep;11(3):214-7. doi: 10.1007/s1・・・
著者: Masaru Nakayama, Ritsuko Katafuchi, Tetsuro Yanase, Kiyoshi Ikeda, Hiroshi Tanaka, Satoru Fujimi
雑誌名: Am J Kidney Dis. 2002 Mar;39(3):503-12. doi: 10.1053/ajkd.2002.31400.
Abstract/Text To clarify factors influencing the response to corticosteroids and subsequent relapses, 62 Japanese adult patients with minimal change nephrotic syndrome were analyzed retrospectively. Five patients experienced remission spontaneously. Fifty-three patients entered complete remission, 3 patients entered partial remission, and 1 patient showed no response to corticosteroids. Fifty-three patients with complete remission were divided into two groups: 38 early responders who experienced remission completely within 8 weeks after starting treatment and 15 late responders who experienced remission after 8 weeks. Blood urea nitrogen and serum creatinine levels and proteinuria selectivity index at presentation were significantly worse in late than early responders. Relative interstitial volume determined by the point-counting method was significantly greater in late than early responders. Relative interstitial volume showed significant correlations with blood urea nitrogen, serum creatinine, and proteinuria selectivity index values. Thirty-three patients experienced a relapse; 13 patients experienced multiple relapses. Fifty-three patients with remission were divided into three groups: 16 patients who experienced relapse within 6 months after the initial response (early relapsers), 17 patients who experienced relapse after 6 months (late relapsers), and 20 patients who did not experience relapse (nonrelapsers). Mean age at onset was younger in early relapsers than late or nonrelapsers. Age at onset correlated inversely with relapse rate in 53 patients with remission and correlated positively with timing of the first relapse in 33 relapsers. It thus was suggested that impaired renal function and poor selectivity of proteinuria, which might be related to interstitial edema, were factors influencing a slower response to corticosteroids. Younger patients had a greater incidence of relapse and were prone to experience relapse earlier.

Copyright 2002 by the National Kidney Foundation, Inc.
PMID 11877569  Am J Kidney Dis. 2002 Mar;39(3):503-12. doi: 10.1053/aj・・・
著者: Bryce A Kerlin, Rose Ayoob, William E Smoyer
雑誌名: Clin J Am Soc Nephrol. 2012 Mar;7(3):513-20. doi: 10.2215/CJN.10131011. Epub 2012 Feb 16.
Abstract/Text After infections, thromboembolism is considered by many experts to be the most significant life-threatening complication of nephrotic syndrome. The purpose of this review is to summarize the epidemiology, clinical and molecular pathophysiology, and management of this complication. Children (2.8%) are less likely than adults (26.7%) with nephrotic syndrome to develop thromboembolism. However, infants and children aged >12 years are at much greater risk. Membranous histologic changes increase thromboembolic risk at all ages; in particular, adults with membranous nephropathy have the highest reported risk (37.0%) and children with membranous histology have a rate (25%) that approaches the overall adult rate. There are striking, but variable, pathologic alterations of molecular hemostasis associated with nephrotic syndrome. No clear molecular therapeutic targets have been identified, but most studies show that the major pathologic changes involve antithrombin, fibrinogen, and factors V and VIII. There is inadequate evidence to support routine prophylactic therapy. Therapy includes anticoagulation in all cases, with thrombolysis reserved for those with the most severe thromboembolic disease. Future hemostatic research in nephrotic syndrome should focus on identifying cohorts at highest risk for thrombosis through the use of clinical markers and biomarkers as well as searching for molecular targets to correct the prothrombotic pathophysiology of this disease.

PMID 22344511  Clin J Am Soc Nephrol. 2012 Mar;7(3):513-20. doi: 10.22・・・
著者: Rajni Singhal, K Scott Brimble
雑誌名: Thromb Res. 2006;118(3):397-407. doi: 10.1016/j.thromres.2005.03.030. Epub 2005 Jun 28.
Abstract/Text Patients with the nephrotic syndrome are at increased risk of developing venous and arterial thromboembolism, the most common of which is renal vein thrombosis. There are several unanswered or controversial issues relating to the nephrotic syndrome and thromboembolism, which include the mechanism of thromboembolism, and optimal diagnostic and anticoagulant management strategies. This review will discuss several of these issues: the epidemiology and clinical spectrum of thromboembolic disease occurring in patients with the nephrotic syndrome; the pathophysiology of the hypercoagulable state associated with the nephrotic syndrome; the diagnosis of renal vein thrombosis in the nephrotic syndrome; and the evidence for prophylactic and therapeutic anticoagulation strategies in such patients.

PMID 15990160  Thromb Res. 2006;118(3):397-407. doi: 10.1016/j.thromre・・・
著者: S Fujimoto, Y Yamamoto, S Hisanaga, S Morita, T Eto, K Tanaka
雑誌名: Am J Kidney Dis. 1991 Jun;17(6):687-92.
Abstract/Text Rate of response to a corticosteroid and frequency of relapse were studied in 33 patients with adult-onset minimal change nephrotic syndrome (MCNS). Of these, 28 patients were treated with oral prednisolone (PSL) at 1 mg/kg/d for from 4 to 8 weeks depending on their response, followed by PSL, at gradually tapering doses for 1 year. Five severely nephrotic patients received 1 g of methylprednisolone intravenously (IV) for 3 days, followed by 40 mg/d oral PSL for 4 to 8 weeks and finally PSL in gradually reduced doses. Sixteen patients (48%) were free of proteinuria within 4 weeks, and 25 (76%) within 8 weeks. Two patients required cyclophosphamide for induction of remission. Age at presentation was not significantly correlated with response time to corticosteroid therapy. Thirty-two (97%) went into remission, and relapse occurred in 11 (34%) of these. As assessed by the life-table method, 84% of patients were still in remission at 6 months after induction of remission, 75% after 1 year, and 63% during the follow-up period (mean, 47.1 +/- 29.1 months; range, 6 to 123 months). Incidence of relapse was not correlated with remission induction time, ie, earlier (less than or equal to 4 weeks) or later (greater than 4 weeks), but was greater in younger (less than 30 years of age) patients than older (greater than or equal to 30 years) patients (P less than 0.03). At the last follow-up, 31 patients (94%) were in complete remission and had normal renal function.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID 2042651  Am J Kidney Dis. 1991 Jun;17(6):687-92.
著者: Meryl Waldman, R John Crew, Anthony Valeri, Joshua Busch, Barry Stokes, Glen Markowitz, Vivette D'Agati, Gerald Appel
雑誌名: Clin J Am Soc Nephrol. 2007 May;2(3):445-53. doi: 10.2215/CJN.03531006. Epub 2007 Apr 11.
Abstract/Text Minimal-change disease (MCD) counts for 10 to 15% of cases of primary nephrotic syndrome in adults. Few series have examined this disease in adults. A retrospective review was performed of 95 adults who had MCD and were seen at a single referral center. Examined were presenting features, response to daily versus alternate-day steroids, response to second-line agents, relapse patterns, complications of the disease and therapy, presence of acute renal failure (ARF), and outcome data. Sixty-five patients received daily and 23 received alternate-day steroids initially. There were no differences in remissions, time to remission, relapse rate, or time to relapse between daily- and alternate-day-treated patients. More than one quarter of patients were steroid resistant. At least one relapse occurred in 73% of patients; 28% were frequently relapsing. A significant proportion of frequently relapsing patients became steroid dependent. Second-line agents were used for steroid dependence, steroid resistance, or frequent relapses. No single agent proved superior. There were more remissions with second-line agents in steroid-dependent patients compared with steroid-resistant patients, and remissions were more likely to be complete in steroid-dependent patients. ARF occurred in 24 patients; they tended to be older and hypertensive with lower serum albumin and more proteinuria than those without ARF. At follow up, patients with an episode of ARF had higher serum creatinine than those without ARF. Four patients progressed to ESRD. These patients were less likely to have responded to steroids and more likely to have FSGS on repeat renal biopsy. In this referral MCD population, response to daily and alternate-day steroids is similar. Second-line agents give greater response in patients who are steroid dependent. ARF occurs in a significant number of adult MCD patients and may leave residual renal dysfunction. Few patients progress to ESRD.

PMID 17699450  Clin J Am Soc Nephrol. 2007 May;2(3):445-53. doi: 10.22・・・
著者: E Imbasciati, R Gusmano, A Edefonti, P Zucchelli, C Pozzi, C Grassi, M Della Volpe, F Perfumo, P Petrone, M Picca
雑誌名: Br Med J (Clin Res Ed). 1985 Nov 9;291(6505):1305-8.
Abstract/Text In a multicentre, randomised, prospective trial 89 patients (67 children and 22 adults) with the minimal change nephrotic syndrome were treated with three intravenous pulses of methylprednisolone followed by low dose oral prednisone for six months (group given methylprednisolone) or with high dose oral prednisone for four weeks followed by low dose oral prednisone for five months (control group). Five patients in the group given methylprednisolone and one in the control group did not respond initially. The time to response was shorter in children treated with methylprednisolone. No significant differences between the two groups were observed in the number of patients who relapsed or number of relapses per patient per year. Patients given methylprednisolone tended to relapse earlier than patients in the control group. Side effects related to treatment were significantly fewer in the group given methylprednisolone than in the control group. These data suggest that a short course of methylprednisolone pulses followed by low dose oral prednisone is only marginally less effective than a regimen of high dose oral steroids but can improve the ratio of risk to benefit associated with treatment of the minimal change nephrotic syndrome.

PMID 3933645  Br Med J (Clin Res Ed). 1985 Nov 9;291(6505):1305-8.
著者: Maki Shinzawa, Ryohei Yamamoto, Yasuyuki Nagasawa, Susumu Oseto, Daisuke Mori, Kodo Tomida, Terumasa Hayashi, Masaaki Izumi, Megumu Fukunaga, Atsushi Yamauchi, Yoshiharu Tsubakihara, Yoshitaka Isaka
雑誌名: Clin J Am Soc Nephrol. 2014 Jun 6;9(6):1040-8. doi: 10.2215/CJN.12331213. Epub 2014 Apr 10.
Abstract/Text BACKGROUND AND OBJECTIVES: Previous studies suggested that intravenous methylprednisolone possibly accelerates remission of proteinuria in adult-onset minimal change disease; its impact on relapse of proteinuria is unknown.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This multicenter retrospective cohort study included 125 adult-onset minimal change disease patients diagnosed by kidney biopsy between 2000 and 2009 and treated initially with corticosteroid in five nephrology centers in Japan participating in the Study of Outcomes and Practice Patterns of Minimal Change Disease. Times to first remission and first relapse of proteinuria after initiating the first immunosuppressive therapy were compared between 65 patients with initial use of intravenous methylprednisolone followed by prednisolone and 60 patients with initial use of prednisolone alone using multivariate Cox proportional hazards models. After calculating the probability of receiving methylprednisolone and prednisolone using a logistic regression model (propensity score), the results were ascertained using propensity score-matched and -stratified models.
RESULTS: During the median 3.6 years of observation (interquartile range=2.0-6.9), all 65 patients in the methylprednisolone and prednisolone group achieved remission within 11 (8-20) days of the corticosteroid initiation, whereas in the prednisolone group, 58 of 60 patients (96.7%) achieved remission within 19 (12-37) days (P<0.001). After achieving first remission, 32 (49.2%) patients in the methylprednisolone and prednisolone group and 43 (74.1%) patients in the prednisolone group developed at least one relapse. Multivariate Cox proportional hazards models revealed that methylprednisolone and prednisolone use was significantly associated with early remission (multivariate-adjusted hazard ratio, 1.56; 95% confidence interval, 1.06 to 2.30) and lower incidence of relapse (0.50; 95% confidence interval, 0.29 to 0.85) compared with prednisolone use alone. These results were ascertained in propensity score-based models. No significant difference was observed in incidence of adverse events, including infection, aseptic osteonecrosis, cataract, diabetes, and gastrointestinal bleeding.
CONCLUSIONS: Initial use of methylprednisolone was associated with earlier remission and lower incidence of relapse in adult-onset minimal change disease patients. Efficacy of methylprednisolone should be evaluated in randomized controlled trials.

Copyright © 2014 by the American Society of Nephrology.
PMID 24721890  Clin J Am Soc Nephrol. 2014 Jun 6;9(6):1040-8. doi: 10.・・・
著者: J E Homik, A Cranney, B Shea, P Tugwell, G Wells, J D Adachi, M E Suarez-Almazor
雑誌名: J Rheumatol. 1999 May;26(5):1148-57.
Abstract/Text OBJECTIVE: To conduct a metaanalysis on the use of bisphosphonates in corticosteroid induced osteoporosis.
METHODS: A Cochrane systematic review including electronic database searching (MEDLINE and EMBASE), and selected hand searching of reference lists and scientific abstracts was conducted. Metaanalysis using random and fixed effects modeling was used on the selected trials to calculate summary effect measures. All controlled clinical trials dealing with prevention or treatment of corticosteroid induced osteoporosis with bisphosphonates of any type and reporting the outcome of interest were assessed. Trials had to involve adults only, and subjects had to be taking a mean steroid dose of 7.5 mg/day or more. Outcomes of interest were change in bone mineral density (BMD) at the lumbar spine and femoral neck at 6 and 12 months. If present, data on number of new fractures and adverse effects were also extracted. The extraction was performed by 2 independent reviewers.
RESULTS: Results are reported as a weighted mean difference in the percentage change in BMD between the treatment and placebo groups, with trials being weighted by the inverse of their variance. At the lumbar spine the weighted mean difference between the treatment and placebo groups was 4.0% (95% CI 2.5, 5.5). At the femoral neck the weighted mean difference was 2.1% (95% CI 0.2, 4.0). Although there was a 24% reduction in spinal fractures, this result did not reach statistical significance.
CONCLUSION: Bisphosphonates are effective at preventing and treating corticosteroid induced bone loss at the lumbar spine. Efficacy regarding fracture prevention cannot be concluded from this analysis, although bone density changes are correlated with fracture risk. Bisphosphonates are less efficacious at preventing or treating corticosteroid induced osteoporosis at the femoral neck.

PMID 10332982  J Rheumatol. 1999 May;26(5):1148-57.
著者: U Kuhlmann, J Steurer, A Bollinger, G Pouliadis, J Briner, W Siegenthaler
雑誌名: Schweiz Med Wochenschr. 1981 Jul 7;111(27-28):1034-40.
Abstract/Text Chest X-ray, pulmonary isotopic photoscanning. Doppler sonography of iliac and femoral veins, inferior venacavagram and phlebography of the renal veins have been performed in 26 patients with nephrotic syndrome in order to determine the frequency and localization of thromboses and thromboembolic complications in these patients. 7 of 26 patients (26.9%) exhibited thromboses or thromboembolic complications (2 left sided renal vein thromboses, 1 right sided ileofemoral thrombosis and 1 bilateral ileofemoral thrombosis with occlusion of the vena cava inferior). In one patient renal vein thrombosis caused pulmonary embolism. In 3 other cases with life-threatening severe episodes of pulmonary embolism, the origin of the emboli could not be detected. Serum albumin level was found to be an appropriate parameter to assess the risk of thrombosis development in these patients. In 7 patients with thromboses or thromboembolic complications the serum albumin level was below 2 g/dl, whereas in 19 patients without these complications the serum albumin level was, with one exception, higher than 2 g/dl (1.5 +/- 0.3 g/dl vs. 2.6 +/- 0.5 g/dl; p less than 0.001). The possible pathophysiologic mechanisms for this observation are discussed. Our results help to identify the population of nephrotic patients who are most likely to experience thromboembolic disease. It therefore would be justifiable to carry out a prospective controlled study examining the question, whether this group of patients with benefit from prophylactic anticoagulation.

PMID 7268357  Schweiz Med Wochenschr. 1981 Jul 7;111(27-28):1034-40.
著者: Aya Eguchi, Takashi Takei, Takumi Yoshida, Ken Tsuchiya, Kosaku Nitta
雑誌名: Nephrol Dial Transplant. 2010 Jan;25(1):124-9. doi: 10.1093/ndt/gfp422. Epub 2009 Sep 9.
Abstract/Text BACKGROUND: Although minimal-change nephrotic syndrome (MCNS) is highly steroid-responsive, some patients show frequent relapses, necessitating administration of repeated courses of prednisolone (PSL) at high doses. The adverse effects of long-term PSL treatment include osteoporosis, infection, diabetes, cataract, etc., most of which are serious. It is therefore necessary to establish useful strategies to reduce the PSL dose.
METHODS: Patients with the first relapse of MCNS were randomly assigned to two groups, namely, the CyA (AUC 1700-2000 ng/ml) + PSL (0.8 mg/kg/day) group (n = 26) and the PSL alone (PSL) (1.0 mg/kg/day) group (n = 26), and the clinical characteristics were compared between the two groups. All patients used C2 for CyA monitoring.
RESULTS: A significant decrease of the urinary protein excretion (P = 0.02) and serum total cholesterol (P = 0.003) was observed at 2 weeks from the first relapse in the CyA + PSL group. The increase in the serum total protein (P = 0.03) and serum albumin (P = 0.007) as compared with that in the PSL group was also observed in the CyA + PSL group at this time-point. The time to remission in the CyA + PSL group was shorter than that in the PSL group (P = 0.006).
CONCLUSION: It was possible to obtain early remission and reduce the PSL dose with combined CyA and PSL therapy in patients with MCNS.

PMID 19740915  Nephrol Dial Transplant. 2010 Jan;25(1):124-9. doi: 10.・・・
著者: A Meyrier, L H Noël, P Auriche, P Callard
雑誌名: Kidney Int. 1994 May;45(5):1446-56.
Abstract/Text Repeat renal biopsies and serial serum creatinine measurements were done in 36 adults who were treated for steroid-dependent or -resistant idiopathic nephrotic syndrome with 5.54 +/- 0.81 mg/kg/day of cyclosporin A (CsA). Pre-CsA renal biopsy (RB1) had been carried out 11.6 +/- 12.2 months prior to CsA treatment. It showed minimal glomerular changes (MCD) in 22, and 1 to 16 glomeruli with lesions of focal segmental glomerulosclerosis (FSGS) per biopsy in 14. Pretreatment serum creatinine levels were (mumol/liter) 97.6 +/- 39.4 and were higher in FSGS (117.1 +/- 48.3) than in MCD (85.2 +/- 26.9; P < 0.04). Repeat biopsy (RB2) was done after 19.6 +/- 15.2 months (6 to 78) of CsA treatment. At this time, in 15 patients the minimal glomerular lesions observed on RB1 were unchanged, whereas in 7 patients lesions of FSGS were now visible. In patients with FSGS on RB1 and RB2, serum creatinine at the end of CsA treatment was 130.6 +/- 60.1 mumol/liter, significantly greater (P = 0.022) than the corresponding levels in the subset with MCD (87.3 +/- 24.8). The contrast between the remarkable stability of renal function in the patients with MCD and the worsening of renal function in the subgroup with FSGS was explained in the latter by an aggravation of renal histologic lesions, with a greater number of glomeruli with FSGS, of obsolescent glomeruli, and of interstitial fibrosis/infiltrates. This aggravation of the primary renal disease was observed in some cases where CsA had obtained partial or even complete remission. Few of the tubular lesions and of vascular changes were typical of CsA toxicity but rather suggested development of the primary renal disease. In contrast, although some increase in the degree of tubulointerstitial lesions was observed on RB2, the rating of such lesions was much less severe in patients whose renal biopsy showed persistently normal glomeruli after exposure to CsA. Overall, the most severe interstitial/vascular lesions were observed in patients treated with the highest CsA dosages, and the "cut-off" of dosage safety appeared to be 5.5 mg/kg/day. Two patients died during the study period. Long-term surveillance of the extant 34 patients showed that 8, all of whom had FSGS, evolved to end-stage renal failure due to progression of their primary renal disease after ending CsA treatment. Four patients were failures of CsA and returned to conventional therapy. CsA treatment was continued for 12 to 60 months in fourteen patients who achieved remission.(ABSTRACT TRUNCATED AT 400 WORDS)

PMID 8072258  Kidney Int. 1994 May;45(5):1446-56.
著者: C Ponticelli, A Edefonti, L Ghio, G Rizzoni, S Rinaldi, R Gusmano, G Lama, G Zacchello, R Confalonieri, P Altieri
雑誌名: Nephrol Dial Transplant. 1993;8(12):1326-32.
Abstract/Text OBJECTIVE: To compare the efficacy (maintenance of remission), safety and tolerability of cyclosporin (CsA) with those of cyclophosphamide in patients with steroid-dependent or frequently relapsing nephrotic syndrome (NS).
DESIGN: Open, prospective, randomized, multicentre, controlled study for parallel groups, stratified for adults and children. The setting was in nephrological departments in Italy.
SUBJECTS AND INTERVENTIONS: Seventy-three patients with steroid-sensitive idiopathic NS admitted to the study were randomly assigned to cyclophosphamide (2.5 mg/kg/day) for 8 weeks or CsA (5 mg/kg/day in adults, 6 mg/kg/day in children) for 9 months, tapered off by 25% every month until complete discontinuation at month 12. Seven patients lost to follow up were not considered in the analysis. The remaining 66 patients were followed up for 3-24 months after randomization.
MAIN OUTCOME MEASURES: Relapse-free survival; number of N.S. relapses/patient/year; cumulative dose of prednisone/patient; laboratory investigations (kidney and liver functions, haematological parameters); incidence of adverse events.
RESULTS: At month 9, 26 of 35 CsA-treated patients were still in complete remission and a further five patients were in partial remission; 18 of 28 cyclophosphamide-treated patients were in complete remission, and one in partial remission (P = NS). No difference between adults and children was seen with either treatment. The risk of relapse was similar between frequent relapsers (19 of 22) and steroid-dependent patients (8 of 14) given CsA, and those given cyclophosphamide (5 of 15 and 6 of 15). The mean number of relapses per year and the mean dose of prednisone per year were significantly less (P < 0.001) in both groups for the experimental year than for the year before randomization. At 2 years, 25% of the patients given CsA (50% adults and 20% children) and 63% of those given cyclophosphamide (40% adults and 68% children) had not had any relapse of NS. Tolerance to the two drugs was generally good. The CsA-related side-effects were mild and disappeared after drug discontinuation.
CONCLUSIONS: This study shows that both treatments are effective and well tolerated; more patients given cyclophosphamide had stable remissions.

PMID 8159300  Nephrol Dial Transplant. 1993;8(12):1326-32.
著者: Swati Choudhry, Arvind Bagga, Pankaj Hari, Sonika Sharma, Mani Kalaivani, Amit Dinda
雑誌名: Am J Kidney Dis. 2009 May;53(5):760-9. doi: 10.1053/j.ajkd.2008.11.033. Epub 2009 Mar 5.
Abstract/Text BACKGROUND: To examine whether tacrolimus is more effective and safe than cyclosporine (CsA) in inducing remission in patients with steroid-resistant nephrotic syndrome (SRNS).
STUDY DESIGN: Randomized controlled trial, nonblind, parallel group.
SETTINGS & PARTICIPANTS: Tertiary-care hospital; 41 consecutive patients with idiopathic SRNS, estimated glomerular filtration rate greater than 60 mL/min/1.73 m(2), and histological characteristics showing minimal change disease, focal segmental glomerulosclerosis, or mesangioproliferative glomerulonephritis were randomly assigned to treatment with tacrolimus (n = 21) or CsA (n = 20).
INTERVENTION: Tacrolimus (0.1 to 0.2 mg/kg/d) or CsA (5 to 6 mg/kg/d) for 1 year; cotreatment with alternate-day prednisolone and enalapril.
OUTCOMES: Patients achieving complete remission (urinary protein-creatinine ratio < 0.2 g/g and serum albumin > or = 2.5 g/dL) or partial remission (urinary protein-creatinine ratio, 0.2 to 2 g/g, and serum albumin > or =2.5 g/dL) at 6 and 12 months; time to remission; proportion with relapses; side effects.
RESULTS: No patient was lost to follow-up. After 6 months of therapy, remission occurred in 18 (85.7%) and 16 patients (80%) treated with tacrolimus and CsA, respectively (relative risk [RR], 1.07; 95% confidence interval [CI], 0.81 to 1.41). Rates of remission at 12 months were also similar (RR, 1.14; 95% CI, 0.84 to 1.55). The proportion of patients who experienced relapse was significantly greater in those receiving CsA compared with tacrolimus (RR, 4.5; 95% CI, 1.1 to 18.2; P = 0.01). The decrease in blood cholesterol levels was greater with tacrolimus compared with CsA (difference in mean values, 45.1 mg/dL; 95% CI, 19.1 to 71.2). Persistent nephrotoxicity necessitating stoppage of medicine was seen in 4.7% and 10% patients, respectively. Cosmetic side effects (hypertrichosis and gum hypertrophy) were significantly more frequent in CsA-treated patients (P < 0.001).
LIMITATIONS: Single-center study, small sample size, and short duration of follow-up.
CONCLUSIONS: Tacrolimus or CsA in combination with low-dose steroids show similar efficacy in inducing remission in patients with SRNS. Therapy with tacrolimus is a promising alternative to CsA in view of the lower risk of relapses and lack of cosmetic side effects.

PMID 19268410  Am J Kidney Dis. 2009 May;53(5):760-9. doi: 10.1053/j.a・・・
著者: Xiayu Li, Heng Li, Jianghua Chen, Qiang He, Rong Lv, Weiqin Lin, Qun Li, Xuelin He, Lihui Qu, Wang Suya
雑誌名: Nephrol Dial Transplant. 2008 Jun;23(6):1919-25. doi: 10.1093/ndt/gfm637. Epub 2007 Oct 1.
Abstract/Text BACKGROUND: Treatment of adults with steroid-dependent minimal change nephrotic syndrome (SD-MCNS) can be a significant challenge. Cyclophosphamide (CYC) and cyclosporin (CYA) are often effective steroid-sparing agents. Tacrolimus (TAC) may be another treatment option.
METHODS: This open, prospective cohort study enrolled Chinese adults with SD-MCNS. At the start of the study, we administered TAC or intravenous CYC together with prednisone (0.5 mg/kg/day), the dose of which was tapered off throughout the study. The TAC cohort received oral TAC (target trough blood level of 4-8 ng/ml) for 24 weeks and the CYC cohort received intravenous CYC (750 mg/m(2) body surface) once every 4 weeks for 24 weeks.
RESULTS: Twenty-six patients met the criteria for enrollment (14 patients in the CYC group and 12 patients in the TAC group). One patient from each group discontinued treatment because of a drug-related side effect. Complete remission (CR) after the 24-week therapeutic period was 76.9% (10/13) in the CYC group and 90.9% (10/11) in the TAC group. The mean time required for CR in the TAC group was significantly less than in the CYC group (P = 0.031). Eight of 13 (61.5%) patients in the CYC group and 8 of 11 (72.7%) patients in the TAC group successfully stopped steroids and changed their status from steroid dependence. Sixty percent (6/10) of the CYC patients and 50% (5/10) of the TAC patients who achieved CR maintained remission during the follow-up period of 23.0 +/- 10.1 months. Four (40%) CYC patients and five (50%) TAC patients experienced relapses, and two CYC patients experienced frequent relapses.
CONCLUSION: A 24-week course of TAC is a favorable steroid-sparing agent for treatment of Chinese adults with SD-MCNS. Therapy with TAC accompanied by a tapering dose of prednisolone appears to yield quicker remission than treatment with CYC together with prednisone.

PMID 17911091  Nephrol Dial Transplant. 2008 Jun;23(6):1919-25. doi: 1・・・
著者: Nicholas Rhys Medjeral-Thomas, Christopher Lawrence, Marie Condon, Bhrigu Sood, Paul Warwicker, Heather Brown, James Pattison, Sunil Bhandari, Jonathan Barratt, Neil Turner, H Terence Cook, Jeremy B Levy, Liz Lightstone, Charles Pusey, Jack Galliford, Thomas D Cairns, Megan Griffith
雑誌名: Clin J Am Soc Nephrol. 2020 Feb 7;15(2):209-218. doi: 10.2215/CJN.06180519. Epub 2020 Jan 17.
Abstract/Text BACKGROUND AND OBJECTIVES: Minimal change disease is an important cause of nephrotic syndrome in adults. Corticosteroids are first-line therapy for minimal change disease, but a prolonged course of treatment is often required and relapse rates are high. Patients with minimal change disease are therefore often exposed to high cumulative corticosteroid doses and are at risk of associated adverse effects. This study investigated whether tacrolimus monotherapy without corticosteroids would be effective for the treatment of de novo minimal change disease.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a multicenter, prospective, open-label, randomized, controlled trial involving six nephrology units across the United Kingdom. Adult patients with first presentation of minimal change disease and nephrotic syndrome were randomized to treatment with either oral tacrolimus at 0.05 mg/kg twice daily, or prednisolone at 1 mg/kg daily up to 60 mg daily. The primary outcome was complete remission of nephrotic syndrome after 8 weeks of therapy. Secondary outcomes included remission of nephrotic syndrome at 16 and 26 weeks, rates of relapse of nephrotic syndrome, and changes from baseline kidney function.
RESULTS: There were no significant differences between the tacrolimus and prednisolone treatment cohorts in the proportion of patients in complete remission at 8 weeks (21 out of 25 [84%] for prednisolone and 17 out of 25 [68%] for tacrolimus cohorts; P=0.32; difference in remission rates was 16%; 95% confidence interval [95% CI], -11% to 40%), 16 weeks (23 out of 25 [92%] for prednisolone and 19 out of 25 [76%] for tacrolimus cohorts; P=0.25; difference in remission rates was 16%; 95% CI, -8% to 38%), or 26 weeks (23 out of 25 [92%] for prednisolone and 22 out of 25 [88%] for tacrolimus cohorts; P=0.99; difference in remission rates was 4%; 95% CI, -17% to 25%). There was no significant difference in relapse rates (17 out of 23 [74%] for prednisolone and 16 out of 22 [73%] for tacrolimus cohorts) for patients in each group who achieved complete remission (P=0.99) or in the time from complete remission to relapse.
CONCLUSIONS: Tacrolimus monotherapy can be effective alternative treatment for patients wishing to avoid steroid therapy for minimal change disease.
PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_01_16_CJN06180519.mp3.

Copyright © 2020 by the American Society of Nephrology.
PMID 31953303  Clin J Am Soc Nephrol. 2020 Feb 7;15(2):209-218. doi: 1・・・
著者: Ho Jun Chin, Dong-Wan Chae, Yong Chul Kim, Won Suk An, ChunGyoo Ihm, Dong-Chan Jin, Sung Gyun Kim, Yong-Lim Kim, Yong-Soo Kim, Yoon-Goo Kim, Ho Seok Koo, Jung Eun Lee, Kang Wook Lee, Jieun Oh, Jung Hwan Park, Hongsi Jiang, Hyuncheol Lee, Sang Koo Lee
雑誌名: J Am Soc Nephrol. 2021 Jan;32(1):199-210. doi: 10.1681/ASN.2019050546. Epub 2020 Nov 9.
Abstract/Text BACKGROUND: Tacrolimus is used as a steroid-sparing immunosuppressant in adults with minimal change nephrotic syndrome. However, combined treatment with tacrolimus and low-dose steroid has not been compared with high-dose steroid for induction of clinical remission in a large-scale randomized study.
METHODS: In this 24-week open-label noninferiority study, we randomized 144 adults with minimal change nephrotic syndrome to receive 0.05 mg/kg twice-daily tacrolimus plus once-daily 0.5 mg/kg prednisolone, or once-daily 1 mg/kg prednisolone alone, for up to 8 weeks or until achieving complete remission. Two weeks after complete remission, we tapered the steroid to a maintenance dose of 5-7.5 mg/d in both groups until 24 weeks after study drug initiation. The primary end point was complete remission within 8 weeks (urine protein: creatinine ratio <0.2 g/g). Secondary end points included time until remission and relapse rates (proteinuria and urine protein: creatinine ratio >3.0 g/g) after complete remission to within 24 weeks of study drug initiation.
RESULTS: Complete remission within 8 weeks occurred in 53 of 67 patients (79.1%) receiving tacrolimus and low-dose steroid and 53 of 69 patients (76.8%) receiving high-dose steroid; this difference demonstrated noninferiority, with an upper confidence limit below the predefined threshold (20%) in both intent-to-treat (11.6%) and per-protocol (17.0%) analyses. Groups did not significantly differ in time until remission. Significantly fewer patients relapsed on maintenance tacrolimus (3-8 ng/ml) plus tapered steroid versus tapered steroid alone (5.7% versus 22.6%, respectively; P=0.01). There were no clinically relevant safety differences.
CONCLUSIONS: Combined tacrolimus and low-dose steroid was noninferior to high-dose steroid for complete remission induction in adults with minimal change nephrotic syndrome. Relapse rates were significantly lower with maintenance tacrolimus and steroid compared with steroid alone. No clinically-relevant differences in safety findings were observed.

Copyright © 2021 by the American Society of Nephrology.
PMID 33168602  J Am Soc Nephrol. 2021 Jan;32(1):199-210. doi: 10.1681/・・・
著者: Kazumoto Iijima, Mayumi Sako, Kandai Nozu, Rintaro Mori, Nao Tuchida, Koichi Kamei, Kenichiro Miura, Kunihiko Aya, Koichi Nakanishi, Yoshiyuki Ohtomo, Shori Takahashi, Ryojiro Tanaka, Hiroshi Kaito, Hidefumi Nakamura, Kenji Ishikura, Shuichi Ito, Yasuo Ohashi, Rituximab for Childhood-onset Refractory Nephrotic Syndrome (RCRNS) Study Group
雑誌名: Lancet. 2014 Oct 4;384(9950):1273-81. doi: 10.1016/S0140-6736(14)60541-9. Epub 2014 Jun 22.
Abstract/Text BACKGROUND: Rituximab could be an effective treatment for childhood-onset, complicated, frequently relapsing nephrotic syndrome (FRNS) and steroid-dependent nephrotic syndrome (SDNS). We investigated the efficacy and safety of rituximab in patients with high disease activity.
METHODS: We did a multicentre, double-blind, randomised, placebo-controlled trial at nine centres in Japan. We screened patients aged 2 years or older experiencing a relapse of FRNS or SDNS, which had originally been diagnosed as nephrotic syndrome when aged 1-18 years. Patients with complicated FRNS or SDNS who met all other criteria were eligible for inclusion after remission of the relapse at screening. We used a computer-generated sequence to randomly assign patients (1:1) to receive rituximab (375 mg/m(2)) or placebo once weekly for 4 weeks, with age, institution, treatment history, and the intervals between the previous three relapses as adjustment factors. Patients, guardians, caregivers, physicians, and individuals assessing outcomes were masked to assignments. All patients received standard steroid treatment for the relapse at screening and stopped taking immunosuppressive agents by 169 days after randomisation. Patients were followed up for 1 year. The primary endpoint was the relapse-free period. Safety endpoints were frequency and severity of adverse events. Patients who received their assigned intervention were included in analyses. This trial is registered with the University Hospital Medical Information Network clinical trials registry, number UMIN000001405.
FINDINGS: Patients were centrally registered between Nov 13, 2008, and May 19, 2010. Of 52 patients who underwent randomisation, 48 received the assigned intervention (24 were given rituximab and 24 placebo). The median relapse-free period was significantly longer in the rituximab group (267 days, 95% CI 223-374) than in the placebo group (101 days, 70-155; hazard ratio: 0·27, 0·14-0·53; p<0·0001). Ten patients (42%) in the rituximab group and six (25%) in the placebo group had at least one serious adverse event (p=0·36).
INTERPRETATION: Rituximab is an effective and safe treatment for childhood-onset, complicated FRNS and SDNS.
FUNDING: Japanese Ministry of Health, Labour and Welfare.

Copyright © 2014 Elsevier Ltd. All rights reserved.
PMID 24965823  Lancet. 2014 Oct 4;384(9950):1273-81. doi: 10.1016/S014・・・
著者: Pietro Ravani, Roberta Rossi, Alice Bonanni, Robert R Quinn, Felice Sica, Monica Bodria, Andrea Pasini, Giovanni Montini, Alberto Edefonti, Mirco Belingheri, Donatella De Giovanni, Giancarlo Barbano, Ludovica Degl'Innocenti, Francesco Scolari, Luisa Murer, Jochen Reiser, Alessia Fornoni, Gian Marco Ghiggeri
雑誌名: J Am Soc Nephrol. 2015 Sep;26(9):2259-66. doi: 10.1681/ASN.2014080799. Epub 2015 Jan 15.
Abstract/Text Steroid-dependent nephrotic syndrome (SDNS) carries a high risk of toxicity from steroids or steroid-sparing agents. This open-label, noninferiority, randomized controlled trial at four sites in Italy tested whether rituximab is noninferior to steroids in maintaining remission in juvenile SDNS. We enrolled children age 1-16 years who had developed SDNS in the previous 6-12 months and were maintained in remission with high prednisone doses (≥0.7 mg/kg per day). We randomly assigned participants to continue prednisone alone for 1 month (control) or to add a single intravenous infusion of rituximab (375 mg/m(2); intervention). Prednisone was tapered in both groups after 1 month. For noninferiority, rituximab had to permit steroid withdrawal and maintain 3-month proteinuria (mg/m(2) per day) within a prespecified noninferiority margin of three times the levels among controls (primary outcome). We followed participants for ≥1 year to compare risk of relapse (secondary outcome). Fifteen children per group (21 boys; mean age, 7 years [range, 2.6-13.5 years]) were enrolled and followed for ≤60 months (median, 22 months). Three-month proteinuria was 42% lower in the rituximab group (geometric mean ratio, 0.58; 95% confidence interval, 0.18 to 1.95 [i.e., within the noninferiority margin of three times the levels in controls]). All but one child in the control group relapsed within 6 months; median time to relapse in the rituximab group was 18 months (95% confidence interval, 9 to 32 months). In the rituximab group, nausea and skin rash during infusion were common; transient acute arthritis occurred in one child. In conclusion, rituximab was noninferior to steroids for the treatment of juvenile SDNS.

Copyright © 2015 by the American Society of Nephrology.
PMID 25592855  J Am Soc Nephrol. 2015 Sep;26(9):2259-66. doi: 10.1681/・・・
著者: Hiroshi Matsumoto, Toshiyuki Nakao, Tomonari Okada, Yume Nagaoka, Fumihiro Takeguchi, Ryo Tomaru, Hideaki Iwasawa
雑誌名: Intern Med. 2004 Aug;43(8):668-73.
Abstract/Text OBJECTIVE: There have been few studies on cyclosporine (CsA) monotherapy in adult minimal change nephrotic syndrome (MCNS). To delineate CsA therapy as new treatment options for MCNS, we conducted a prospective single-center study.
METHODS: We assessed the efficacy of 3 different regimens in 36 patients, consisting of 26 first attacks or 10 relapses, of adult-onset MCNS. In 12 patients, CsA alone was given orally at a dose of 2-3 mg/kg/d, and in 12 patients, CsA after intravenous pulse methylprednisolone therapy (CsA/PMT) was given at the same dose. CsA was given for 12 months, tapered slowly, then stopped. The other 12 patients were treated with oral prednisolone (PSL, 40-60 mg/d) alone for 4 to 6 weeks, followed by daily PSL, with slowly tapering doses.
RESULTS: Complete remission (CR) was obtained in 75% with CsA alone, 100% with CsA/PMT and 92% with PSL alone (p = 0.0379). The days required for CR were shortest in the CsA/PMT group (40.9 +/- 35.5 days with CsA alone vs. 11.0 +/- 5.6 with CsA/PMT vs. 21.5 +/- 15.8 with PSL alone). The cumulative rates of CR were significantly different among the 3 groups (p < 0.0001). The real numbers of the relapse were smallest in the CsA/PMT group, however, the cumulative rates of sustained remission among the 3 treatment arms were not statistically different. Renal function was well preserved with each treatment period. CsA-associated adverse effects were minimal but one patient developed new-onset hypertension and gingival hyperplasia. However, the adverse effects of PSL alone were serious in 3 cases: bleeding from gastric ulcer, diabetes mellitus, and aseptic necrosis. Many patients with PSL but few with CsA experienced cosmetic problems.
CONCLUSIONS: CsA/PMT may be the most advantageous when the clinical efficacy of each treatment for MCNS is integrated.

PMID 15468963  Intern Med. 2004 Aug;43(8):668-73.
著者: H Y Lee, H S Kim, C M Kang, S G Kim, M J Kim
雑誌名: Clin Nephrol. 1995 Jun;43(6):375-81.
Abstract/Text A multicenter prospective study conducted in four university hospitals in Korea investigated the efficacy and tolerance of cyclosporine A (CyA, Sandimmun) in 30 patients with adult nephrotic syndrome [25 patients with minimal change disease (MCD) and 5 with focal-segmental glomerulosclerosis (FSGS)]. After a 6-week washout period, CyA 5 mg/kg/day and prednisolone 10 mg/day were administered for up to 8 months, depending on responses to CyA. The rate of relapse after withdrawal of CyA was assessed up to 10 months. Of the 30 patients enrolled, 3 withdrew prematurely due to adverse events. Of the 27 patients who completed the study, 22 had MCD and 5 had FSGS. The prior steroid responses of these patients were 19 steroid-dependent (SD), 4 frequent-relapser (FR) and 4 steroid-resistant (SR) type. High rates of complete remission were obtained after CyA treatment in both MCD and FSGS patients, 86.4% (19/22) and 80% (4/5) respectively. Previous steroid responses did not affect the response to CyA; complete remission was obtained in 84.2% (16/19) of SD patients and in 75% (3/4) of SR patients. The mean (+/- SEM) duration of CyA treatment to attain complete remission in SD and SR patients was 3.8 (+/- 0.6) weeks and 10.7 (+/- 2.7) weeks, respectively (not significantly different). Tapering or withdrawal of CyA was followed by release of nephrotic syndrome in many patients, and the cumulative relapse rates at month 10 were 68.4% (13/19) in MCD patients and 50% (2/4) in FSGS patients. When considered according to prior steroid responses, the relapse rate was 73.3% (11/15) in SD patients and 50% (2/4) in SR patients.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID 7554521  Clin Nephrol. 1995 Jun;43(6):375-81.
著者: Shuichiro Fujinaga, Daishi Hirano, Naoto Nishizaki, Tomonosuke Someya, Yoshiyuki Ohtomo, Yoshikazu Ohtsuka, Toshiaki Shimizu, Kazunari Kaneko
雑誌名: Pediatr Nephrol. 2011 Mar;26(3):479-83. doi: 10.1007/s00467-010-1707-7. Epub 2010 Dec 21.
Abstract/Text Although cyclosporine (CsA) therapy is effective in the management of children with steroid-dependent nephrotic syndrome (SDNS), a recent study has revealed that the use of CsA itself was a significant predictor of NS relapse in adulthood. The efficacy of single daily high-dose mizoribine (MZR) therapy was assessed in 10 children with SDNS (mean age, 6.2 years) who had never been treated with CsA previously. MZR was started at 5 mg/kg, administered as a single daily dose after breakfast, and the dose was adjusted to achieve 2-h post-dose MZR levels (C2) of approximately 3 μg/ml. In 9 of the 10 patients, treatment with a single daily dose of MZR (mean dose, 8.4 mg/kg/day) over a period of 22 months (median) resulted in significant reduction of the mean prednisolone dose from 0.39 to 0.15 mg/kg/day and the median 12-month relapse rate from 3.0 to 0.4 episodes/12 months. Although cyclophosphamide was initiated in one patient because of treatment failure, none of the 10 patients required treatment with CsA during the observation period (median, 33 months). These data indicate that single daily high-dose MZR therapy is possibly useful in treating children with SDNS and that it may also eliminate the need for CsA in some patients.

PMID 21174219  Pediatr Nephrol. 2011 Mar;26(3):479-83. doi: 10.1007/s0・・・
著者: E Muso, M Mune, Y Fujii, E Imai, N Ueda, K Hatta, A Imada, S Miki, T Kuwahara, Y Takamitsu, T Takemura, Y Tsubakihara
雑誌名: Kidney Int Suppl. 1999 Jul;71:S122-5.
Abstract/Text BACKGROUND: The pathogenic role of hyperlipidemia in long-standing nephrotic syndrome (NS) is known to be responsible for both the progression of glomerulosclerosis and tubulointerstitial injury, especially in focal segmental glomerulosclerosis (FGS).
METHODS: Aggressive lipid lowering treatment by low density lipoprotein (LDL) apheresis (LDL-A) using a dextran sulfate cellulose column to treat patients with steroid-resistant or frequently recurrent severe NS was performed first without fixing the protocol in eight patients with FGS and one with minimal change nephrotic syndrome (MCNS). The period of NS before LDL-A, number and average intervals of LDL-A until the end of the therapy, and the prognosis were investigated. Next, a multicenter study with a fixed protocol of LDL-A treatment was designed in combination with steroid therapy for treatment twice a week for three weeks and weekly for six weeks, and was performed in 17 patients with FGS. The effects on the state of NS in addition to the change of urinary eicosanoid metabolites and remission rates were evaluated.
RESULTS: In the preliminary study, along with a rapid improvement of hyperlipidemia, a high incidence of remission was achieved by LDL-A performed at relatively short intervals. In the multicenter study with a fixed protocol, there was a significant decrease of urinary protein (P < 0.001) and increase of serum albumin (P < 0.02) as well as a decrease of thromboxane B2 (TXB2) excretion (P < 0.05) after the treatment. Urinary excretion of TXB2 was significantly reduced after LDL-A (P < 0.05). The rate of entering into complete or incomplete remission was 71% with a relatively short duration of nephrotic-range proteinuria using the LDL-A therapy in comparison with steroid therapy alone.
CONCLUSION: The rapid improvement of hypercholesterolemia with LDL-A treatment may provide a new approach for a high rate of improvement in the degree of NS in steroid-resistant NS of FGS and MCNS.

PMID 10412754  Kidney Int Suppl. 1999 Jul;71:S122-5.
著者: Norishige Yoshikawa, Koichi Nakanishi, Mayumi Sako, Mari S Oba, Rintaro Mori, Erika Ota, Kenji Ishikura, Hiroshi Hataya, Masataka Honda, Shuichi Ito, Yuko Shima, Hiroshi Kaito, Kandai Nozu, Hidefumi Nakamura, Takashi Igarashi, Yasuo Ohashi, Kazumoto Iijima, Japanese Study Group of Kidney Disease in Children
雑誌名: Kidney Int. 2015 Jan;87(1):225-32. doi: 10.1038/ki.2014.260. Epub 2014 Jul 23.
Abstract/Text In this multicenter, open-label, randomized controlled trial, we determined whether 2-month prednisolone therapy for steroid-sensitive nephrotic syndrome was inferior or not to 6-month therapy despite significantly less steroid exposure. The primary end point was time from start of initial treatment to start of frequently relapsing nephrotic syndrome. The pre-specified non-inferiority margin was a hazard ratio of 1.3 with one-sided significance of 5%. We randomly assigned 255 children with an initial episode of steroid-sensitive nephrotic syndrome to either 2 - or 6-month treatment of which 246 were eligible for final analysis. The total prednisolone exposure counted both initial and relapse prednisolone treatment administered over 24 months. Median follow-up in months was 36.7 in the 2-month and 38.2 in the 6-month treatment group. Time to frequent relaps was similar in both groups; however, the median was reached only in the 6-month group (799 days). The hazard ratio was 0.86 (90% confidence interval, 0.64-1.16) and met the non-inferior margin. Time to first relapse was also similar in both groups: median day 242 (2-month) and 243 (6-month). Frequency and severity of adverse events were similar in both groups. Most adverse events were transient and occurred during initial or relapse therapy. Thus, 2 months of initial prednisolone therapy for steroid-sensitive nephrotic syndrome, despite less prednisolone exposure, is not inferior to 6 months of initial therapy in terms of time to onset of frequently relapsing nephrotic syndrome.

PMID 25054775  Kidney Int. 2015 Jan;87(1):225-32. doi: 10.1038/ki.2014・・・
著者: E M Hodson, N S Willis, J C Craig
雑誌名: Cochrane Database Syst Rev. 2007 Oct 17;(4):CD001533. doi: 10.1002/14651858.CD001533.pub4. Epub 2007 Oct 17.
Abstract/Text BACKGROUND: In nephrotic syndrome (NS) protein leaks from the blood to the urine through the glomeruli resulting in hypoproteinaemia and generalised oedema. While the majority of children with NS respond to corticosteroids, 70% experience a relapsing course. Corticosteroids have reduced the mortality rate to around 3%. However corticosteroids have well recognised potentially serious adverse effects such as obesity, poor growth, hypertension, diabetes mellitus and osteoporosis.
OBJECTIVES: To determine the benefits and harms of corticosteroid regimens in preventing relapse in children with steroid sensitive NS (SSNS).
SEARCH STRATEGY: We searched CENTRAL, Cochrane Renal Group Specialised Register, MEDLINE and EMBASE without language restriction, reference lists of articles and contact with known investigators. Date of last search: December 2006
SELECTION CRITERIA: Randomised controlled trials performed in children (three months to 18 years) in their initial or subsequent episode of SSNS, comparing different durations, total doses or other dose strategies using any corticosteroid agent, with outcome data at six months or more.
DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. Results were expressed as relative risk (RR) with 95% confidence intervals (CI) or mean difference (WMD). Meta-regression was used to explore potential between-study differences due to baseline risk of relapse, study quality and interventions.
MAIN RESULTS: Twenty four trials were identified. Six trials comparing two months of prednisone or prednisolone with three months or more in the first episode showed longer duration significantly reduced the risk of relapse at 12 to 24 months (RR 0.70, 95% CI 0.58 to 0.84). There was an inverse linear relationship between treatment duration and risk of relapse (RR = 1.26 - 0.112 duration; P = 0.03). Four trials showed that six months of prednisone was more effective than three months in reducing the risk for relapse (RR 0.57; 95% CI 0.45 to 0.71). Deflazacort was significantly more effective in maintaining remission than prednisone in children who frequently relapsed in a single study (RR 0.44, 95% CI 0.25 to 0.78). There were no increases in adverse events.
AUTHORS' CONCLUSIONS: Children in their first episode of SSNS should be treated for at least three months with an increase in benefit for up to seven months of treatment. For a baseline risk for relapse following the first episode of 60% with two months of therapy, daily prednisone or prednisolone given for four weeks followed by alternate-day therapy for six months would reduce the number of children relapsing by 33%.

PMID 17943754  Cochrane Database Syst Rev. 2007 Oct 17;(4):CD001533. d・・・
著者: S L Hogan, K E Muller, J C Jennette, R J Falk
雑誌名: Am J Kidney Dis. 1995 Jun;25(6):862-75.
Abstract/Text The treatment of idiopathic membranous glomerulopathy remains an enigma. We have reviewed many of the important clinical trials concerning membranous glomerulopathy using a meta-analysis and a secondary pooled analysis to test the effects of corticosteroid or alkylating, therapy compared with no treatment on renal survival and complete remission of the nephrotic syndrome. A search was performed using MEDLINE (1968 through 1993) for articles on idiopathic membranous glomerulopathy and glomerulonephritis. Bibliographies of articles were reviewed for completeness. Sixty-nine articles were reviewed. Meta-analysis was performed for four trials that evaluated corticosteroids compared with no treatment and for three trials that evaluated alkylating therapy compared with no treatment. Pooled analysis was performed on randomized and prospective studies (10 studies) and then with 22 case series added. All studies evaluated renal biopsy-proven disease. Meta-analysis was performed on the relative chance of being in complete remission for each study. Renal survival could be evaluated by pooled analysis only. For pooled analyses, Cox's proportional hazard and logistic regression models were used to test the effect of therapy on renal survival and the nephrotic syndrome, respectively. Data concerning gender, nephrotic syndrome, and geographic region were used in all statistical models. Evaluation of renal survival revealed no differences by treatment group (P > 0.1). By meta-analysis, the relative chance of complete remission was not improved for corticosteroid-treated patients (1.55; 95% confidence interval, 0.99 to 2.44; P > 0.1), but was improved for patients treated with alkylating agents (4.8; 95% confidence interval, 1.44 to 15.96; P < 0.05) when compared with no treatment. Pooled analysis of randomized and prospective studies, as well pooled analysis with all studies, supported the findings of the meta-analysis. Corticosteroids or alkylating therapy did not improve renal survival in idiopathic membranous glomerulopathy. Complete remission of the nephrotic syndrome was observed more frequently with the use of alkylating agents.

PMID 7771482  Am J Kidney Dis. 1995 Jun;25(6):862-75.
著者: Tetsuro Kusaba, Yusuke Konno, Shigeo Hatta, Tomoya Fujino, Takashi Yasuda, Hiroshi Miura, Hiroyo Sasaki, Jun Okabayashi, Mei Murao, Tsutomu Sakurada, Goro Imai, Sayuri Shirai, Shingo Kuboshima, Yoshinori Shima, Goichi Ogimoto, Takeo Sato, Keisou Masuhara, Kenjiro Kimura
雑誌名: Pharmacotherapy. 2005 Jan;25(1):52-8. doi: 10.1592/phco.25.1.52.55617.
Abstract/Text STUDY OBJECTIVE: To compare the absorption profile of cyclosporine after preprandial administration with that after postprandial administration, and to determine which administration time resulted in a more stable absorption profile and the timing of the drug concentration that was the most reliable marker for monitoring drug absorption.
DESIGN: Prospective analysis.
SETTING: University teaching hospital in Japan.
PATIENTS: Sixteen patients with refractory nephrotic syndrome.
INTERVENTION: Thirteen patients received cyclosporine after breakfast (postprandial group) and eight received the drug 30 minutes before breakfast (preprandial group).
MEASUREMENTS AND MAIN RESULTS: Blood cyclosporine concentration was measured 5 times serially: before administration (C 0 ) and at 1-hour intervals until 4 hours after administration of cyclosporine (C 1 -C 4 ). Also, area under the concentration-time curve from 0-4 hours (AUC 0-4 ) was calculated. Of the 13 patients in the postprandial group, six (46%) showed fair absorption and exhibited a peak concentration at C 1 or C 2 (high-absorption pattern); seven (54%) showed poor absorption and did not reach the peak concentration within the 4-hour period (low-absorption pattern). Five of the seven patients with the low-absorption pattern were switched from postprandial to preprandial administration. All patients in the preprandial administration group showed a high-absorption pattern and reached the peak cyclosporine concentration at C 1 . The C 2 value showed the best correlation with AUC 0-4 in both groups, and the C 0 parameter did not correlate with AUC 0-4 in either group.
CONCLUSION: Preprandial administration provided a more stable absorption profile of cyclosporine compared with postprandial administration. From the correlation with AUC 0-4 , we concluded that C 2 , and not C 0 , is a reliable marker for monitoring cyclosporine exposure.

PMID 15767220  Pharmacotherapy. 2005 Jan;25(1):52-8. doi: 10.1592/phco・・・
著者: Asami Takeda, Keiji Horike, Hiroshi Onoda, Yasuhiro Ohtsuka, Astuhiro Yoshida, Kazuharu Uchida, Kunio Morozumi
雑誌名: Nephrology (Carlton). 2007 Apr;12(2):197-204. doi: 10.1111/j.1440-1797.2007.00773.x.
Abstract/Text AIM: Cyclosporine is known to improve proteinuria in nephrotic syndrome (NS), but is also associated with drug-related renal impairment. In this case series, therapeutic drug monitoring using the absorption profile was applied to adults with NS to investigate the efficacy and safety of once-daily administration of cyclosporine microemulsion (CSAME).
METHODS: Twenty patients received CSAME starting at 100-175 mg/day (1.4-3.1 mg/kg per day) once daily after breakfast. The area under the concentration-time curve up to 4 h after administration of cyclosporine (AUC(0-4 h)) was determined in each patient within 1 week after the start of CSAME treatment. Thereafter, the dose of CSAME was adjusted according to the absorption profile.
RESULTS: After 6 months, treatment with CSAME improved efficacy test values compared with those prior to treatment, and the severe nephrotic state was eliminated in all patients. No changes in serum creatinine or blood urea nitrogen levels were observed. The dose of CSAME was adjusted so that AUC(0-4 h) and the peak level fell within the range of target values, resulting in a significant decrease in the mean dose of cyclosporine (P = 0.0001). Time of peak level was variable among patients, but when CSAME was administered before breakfast, good absorption was achieved in all patients.
CONCLUSION: By monitoring the absorption profile in patients with NS, a once-daily administration of CSAME was used to achieve both efficacy and a reduction in total exposure to the drug. Preprandial administration provided a more stable absorption profile of cyclosporine. The authors hope this method will become standard procedure during cyclosporine treatment in these patients.

PMID 17371346  Nephrology (Carlton). 2007 Apr;12(2):197-204. doi: 10.1・・・
著者: Toshiaki Shibasaki, Akio Koyama, Akira Hishida, Eri Muso, Gengo Osawa, Hideaki Yamabe, Hideo Shiiki, Hirofumi Makino, Hiroshi Sato, Isao Ishikawa, Kenji Maeda, Kimio Tomita, Masaaki Arakawa, Masashi Ishida, Masashi Sato, Mitsumasa Nagase, Naoki Kashihara, Noriaki Yorioka, Takao Koike, Takao Saito, Takashi Harada, Tetsuya Mitarai, Tetsuzo Sugisaki, Toshihiko Nagasawa, Yasuhiko Tomino, Yoshihisa Nojima, Yutaka Kobayashi, Osamu Sakai
雑誌名: Clin Exp Nephrol. 2004 Jun;8(2):117-26. doi: 10.1007/s10157-004-0276-0.
Abstract/Text BACKGROUND: A previous double-blind 24-week clinical trial of mizoribine (MZ) vs placebo in steroid-resistant primary nephrotic syndrome (SRPNS) showed that MZ was more effective than placebo in reducing the rate of deterioration of renal function. The present study was conducted to evaluate the efficacy and safety of MZ in patients with SRPNS after 2 years' treatment.
METHODS: A multicenter randomized open-label controlled trial in patients with SRPNS was conducted as a 2-year prospective postmarketing study.
RESULTS: There was a significant imbalance in the baseline serum albumin level (s-Alb) between the conventional therapy (CT) and MZ onlay therapy groups. Early dropouts were more frequent in the subset of patients in the CT group having a baseline s-Alb < or =3 g/dl. Therefore, the primary analysis (urinary protein level (UP)-improving effect) was performed using a mixed-effects model, with stratification according to the baseline s-Alb value. The analysis revealed that, in the subset of 34 patients with membranous nephropathy (MN) within the stratum of patients with baseline s-Alb < or =3 g/dl (n = 52), the rate of change (slope of change in the UP level/month), in terms of the log (UP+0.2), was -0.0577 in those allocated to the MZ group and -0.0227 in those allocated to the CT group (P = 0.058). In the stratum of patients with a baseline s-Alb >3 g/dl (n = 97), there were no significant differences in the UP between the two treatment groups. Hence, MZ onlay therapy was not considered to be efficacious in this group of patients. No serious adverse reactions to the drug were observed.
CONCLUSIONS: The present study yielded significant results, in that it suggested the possibility that long-term MZ therapy may afford further reduction of the UP, in addition to that obtained following CT, in particular, in MN patients in a severe nephrotic state.

PMID 15235928  Clin Exp Nephrol. 2004 Jun;8(2):117-26. doi: 10.1007/s1・・・
著者: Y Sawara, M Itabashi, C Kojima, H Tabata, D Kamei, K Kawanishi, T Moriyama, H Sugiura, M Tsukada, T Takei, T Ogawa, T Yoshida, J Arai, K Uchida, K Tsuchiya, K Nitta
雑誌名: Clin Nephrol. 2009 Jul;72(1):69-72.
Abstract/Text Minimal change nephrotic syndrome (MCNS) usually is considered to have a good renal prognosis, but the frequency of relapses is a therapeutic challenge to physicians. The treatment of patients with multiple relapses remains a matter of controversy, because few controlled studies are available. We report the case of a 25-year-old man who experienced relapses of MCNS. Single-dose rituximab therapy (total dose 500 mg) was given during the fourth relapse. Complete remission occurred 10 days later, when no CD19/20-positive B cells were detected in the blood. This the first report of efficacy of single-dose rituximab therapy to treat multi-relapsing MCNS in an adult patient.

PMID 19640390  Clin Nephrol. 2009 Jul;72(1):69-72.
著者: Julia M Hofstra, Jeroen K J Deegens, Jack F M Wetzels
雑誌名: Nephrol Dial Transplant. 2007 Jul;22(7):2100-2. doi: 10.1093/ndt/gfm128. Epub 2007 Mar 26.
Abstract/Text
PMID 17389619  Nephrol Dial Transplant. 2007 Jul;22(7):2100-2. doi: 10・・・

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