今日の臨床サポート

巣状分節性糸球体硬化症

著者: 丸山彰一 名古屋大学腎臓内科

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:2021/07/14
参考ガイドライン:
  1. 厚生労働省研究班報告: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. 初期治療としてステロイドを投与することが強く推奨される(推奨度1)。
  1. ステロイド療法に抵抗性の場合は、免疫抑制薬の併用が強く推奨される(推奨度1)。
  1. 薬剤治療抵抗例に対してはLDLアフェレシス療法を試みることが推奨される(推奨度2)。
  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
閲覧にはご契
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:
丸山彰一 : 講演料(アステラス製薬株式会社,田辺三菱製薬株式会社,中外製薬株式会社),研究費・助成金など(小野薬品工業株式会社,中外製薬株式会社,ロート製薬株式会社,公益社団法人三菱財団),奨学(奨励)寄付など(アステラス製薬株式会社,大塚製薬株式会社,協和キリン株式会社,サノフィ株式会社,大日本住友製薬株式会社,中外製薬株式会社,帝人ファーマ株式会社,鳥居薬品株式会社)[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. ガイドライン改訂に従い、見直しを行った。 

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 巣状分節性糸球体硬化症は、腎生検標本上、一部の糸球体(巣状)の一部分(分節性)に認められる硬化病変(<図表>)をもって定義される病理形態的診断名であるが、同時に難治性ネフローゼ症候群の経過をとりながら最終的に末期腎不全にも至るような臨床的特徴を有する。巣状糸球体硬化症とも呼ばれる。
  1. 臨床的には、微小変化型ネフローゼ症候群と同じように急性発症のネフローゼ症候群を呈する場合が多いが、緩徐な経過で発症し、健康診断時の検尿などが発見の契機になる場合もある。
  1. 微小変化型ネフローゼ症候群と異なり、ステロイド治療にしばしば抵抗性の経過をとる。
  1. 初期には硬化病変がしばしば傍髄部領域に限られるが、経過とともに皮質全層にまで広がっていく。
  1. 典型的なネフローゼ症候群を呈する原発性(一次性)巣状分節性糸球体硬化症のほかに、肥満関連腎症あるいは逆流性腎症のような続発性(二次性)巣状分節性糸球体硬化症も存在する。本コンテンツでは、原発性(一次性)について解説する。
  1. 遺伝子変異により発症する家族性巣状分節性糸球体硬化症の存在が知られている。
  1. 巣状分節性糸球体硬化症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. 浮腫の有無・程度を確認する(特に前𦙾骨部浮腫)。

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。

最新のエビデンスに基づいた二次文献データベース「今日の臨床サポート」。
常時アップデートされており、最新のエビデンスを各分野のエキスパートが豊富な図表や処方・検査例を交えて分かりやすく解説。日常臨床で遭遇するほぼ全ての症状・疾患から薬剤・検査情報まで瞬時に検索可能です。

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文献 

著者: Misha Witz, Zeev Korzets
雑誌名: Isr Med Assoc J. 2007 May;9(5):402-5.
Abstract/Text Renal vein occlusion in adults is usually a result of vein thrombosis, which is frequently associated with the nephrotic syndrome. The anatomy of renal vascularization is of primary importance for understanding its pathophysiological responses and the clinical and diagnostic presentation of patients with this condition. The reaction of the kidney to its vein occlusion is determined by the balance between the acuteness of the disease, extent of the development of collateral circulation, involvement of one or both kidneys and the origin of the underlying disease. Renal vein occlusion is generally a complication of some other condition, but it may also occur as a primary event. The main goals of therapy should be to conserve renal parenchyma in order to maintain renal function and prevent thromboembolic phenomena.

PMID 17591386  Isr Med Assoc J. 2007 May;9(5):402-5.
著者: M Ogi, H Yokoyama, N Tomosugi, Y Hisada, S Ohta, M Takaeda, T Wada, T Naito, K Ikeda, S Goshima
雑誌名: Am J Kidney Dis. 1994 Sep;24(3):427-36.
Abstract/Text Infection has been recognized as an important cause of morbidity and mortality in children with nephrotic syndrome. However, the incidence and severity of infection and the mechanisms responsible for the increased susceptibility to infection are still unclear in adults. We studied 86 consecutive adult patients with nephrotic syndrome but no diabetic nephropathy. Risk factors for infection were evaluated by logistic regression analysis. Infections were found in 16 patients (19%), of whom six died of infection and two developed end-stage renal failure associated with infection. The relative risk for bacterial infection among patients with serum immunoglobulin G (IgG) levels below 600 mg/dL was 6.74 compared with that for patients with serum IgG levels over 600 mg/dL (95% confidence interval, 1.22 to 36.32; P = 0.029). In patients with serum creatinine levels over 2.0 mg/dL, the relative risk of bacterial infection was 5.31 compared with patients with serum creatinine levels below 2.0 mg/dL (95% confidence interval, 1.08 to 26.09; P = 0.040). Intravenous immunoglobulin (10 to 15 g) was administered prospectively every 4 weeks to 18 patients with serum IgG levels below 600 mg/dL until serum IgG levels increased to over 600 mg/dL. Administration of immunoglobulin resulted in a decreased rate of bacterial infections to a level equal to that in patients with endogenous levels over 600 mg/dL. These data indicate that hypogammaglobulinemia and renal insufficiency are independent risk factors for bacterial infection in adult patients with nephrotic syndrome. The effects of intravenous immunoglobulin suggest that maintenance of serum IgG levels over 600 mg/dL may reduce the risk of infection.

PMID 8079968  Am J Kidney Dis. 1994 Sep;24(3):427-36.
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: S C Cherng, W S Huang, Y F Wang, S P Yang, Y F Lin
雑誌名: Clin Nucl Med. 2000 Mar;25(3):167-72.
Abstract/Text PURPOSE: Patients with nephrotic syndrome (NS) have an increased tendency to develop thrombosis and even to progress to pulmonary embolism (PE). This study was performed to determine the incidence of PE in NS with severe hypoalbuminemia and to investigate the possible role of ventilation-perfusion (V/Q) lung scans to evaluate these patients.
METHODS: Eighty-nine patients with NS (serum albumin concentration < 2 g/dl) and risk factors for PE were studied. In all patients, the probability that PE would develop was assessed based on the results of V/Q lung scans (Xe-133 for ventilation and Tc-99m MAA for perfusion imaging). The lung scans were judged using the modified Prospective Investigation of Pulmonary Embolism Diagnosis criteria. In 25 (28%) patients whose lung scans showed an intermediate or low probability, but for whom there was a strong clinical indication of PE, pulmonary angiography was performed. The patients' clinical symptoms and signs on initial examination were observed. Additional examinations included electrocardiograms, chest radiography, and hematochemical tests such as albumin, blood urea nitrogen, creatinine, cholesterol, triglycerides, fibrinogen, antithrombin III, prothrombin time, and activated partial thromboplastin time.
RESULTS: Based on the findings of lung scans, 19 (21%) of the patients were categorized as having a high probability of PE. However, pulmonary angiography found that 10 (11%) other patients had PE despite having lung scan findings categorized as intermediate or low probability of PE. Except for plasma fibrinogen and antithrombin III levels, neither the clinical symptoms and signs, electrocardiogram findings, chest radiograph results, nor values of hematochemical testing were consistent with the occurrence of PE in these 29 patients.
CONCLUSION: The results of this study suggest that PE is not a rare complication in patients with NS, and is usually clinically silent. In this series, the occurrence of PE did not appear to be always correlated with the clinical or hematochemical severity of NS, except for the association with elevated levels of fibrinogen and antithrombin III. When treating the clinical symptoms of patients with NS, physicians should be alert to the possible complication of PE. Serial V/Q lung scans may provide valuable clues in the evaluation of these patients.

PMID 10698409  Clin Nucl Med. 2000 Mar;25(3):167-72.
著者: N Dodhia, R A Rodby, S C Jensik, S M Korbet
雑誌名: Am J Kidney Dis. 1991 May;17(5):532-6.
Abstract/Text Of 136 patients who received a renal transplant between January 1984 and August 1988, there were six cases (4.4%) of allograft arterial thrombosis (AAT) occurring a mean of 23 days after transplantation. All were maintained on cyclosporine A(CsA) in addition to prednisone and azathioprine. All transplants were performed by the same transplant surgeon. Five of the six episodes (83%) were in allografts that had multiple renal arteries (MRA), giving an incidence of AAT in that group of 36%. Only one of 122 (0.8%) allografts with a single renal artery experienced thrombosis. CsA was started a mean of 9 days after transplantation (range, 16 to 33 days). There was no correlation of AAT to CsA levels. AAT appears to be an early complication of allografts with MRA in patients maintained on CsA.

PMID 2024654  Am J Kidney Dis. 1991 May;17(5):532-6.
著者: G Banfi, M Moriggi, E Sabadini, G Fellin, G D'Amico, C Ponticelli
雑誌名: Clin Nephrol. 1991 Aug;36(2):53-9.
Abstract/Text In this retrospective study we report the outcome of 59 adults with idiopathic focal-segmental glomerulosclerosis (FSGS) and nephrotic syndrome (NS) treated with corticosteroids and/or immunosuppressive drugs. Twenty-seven patients were initially treated with corticosteroids alone for 9.3 +/- 8 months; nineteen patients received corticosteroids and immunosuppressive agents associated or every other month for 5.5 +/- 4 months; thirteen patients received either azathioprine or cyclophosphamide alone for 25 +/- 27 months. At the end of a mean follow-up of 75 +/- 51 months, 35 patients (60%) were in complete (CR) or partial (PR) remission, 6 (10%) were stable and 18 (30%) had either chronic renal failure (CRF) or end-stage renal failure (ESRF). Out of 36 patients (61%) initially responsive to therapy, 30 (83%) obtained CR, 4 (11%) PR, one (2.7%) developed CRF and one (2.7%) ESRF. Only 10 of the responders (28%) attained remission within 8 weeks of treatment. Out of the 23 (39%) patients originally resistant to therapy, only one (4%) had CR, 6 (26%) remained unchanged, 6 (26%) developed CRF and 10 (43%) ESRF. The presence at initial renal biopsy of interstitial fibrosis was the only feature which could predict a poor renal outcome. These data show that prolonged treatment of FSGS can obtain sustained remission of the disease and improved renal survival in a consistent proportion of adult patients which would be considered refractory to a two-month course with corticosteroids.

PMID 1934660  Clin Nephrol. 1991 Aug;36(2):53-9.
著者: D C Cattran, P Rao
雑誌名: Am J Kidney Dis. 1998 Jul;32(1):72-9.
Abstract/Text A retrospective study was conducted in 93 patients (55 adults and 38 children) with classical focal segmental glomerulosclerosis drawn from the Toronto Glomerulonephritis Registry. The average follow-up period was 11 years, with a cumulative experience of 1,053 patient-years. Both adults and children were similar in profile at the time of entry, except that the nephrotic syndrome was more common in children (55% of adults v 76% of children; P < 0.05). During evolution of the disease, however, the percentages became very similar with 82% of adults and 89% of children developing nephrotic-range proteinuria. At the last observation point, the outcome of patients (adults v children) was complete remission, 22% versus 42%; end-stage renal disease, 42% versus 34%; chronic renal insufficiency, 13% versus 11%; and persisting abnormality, 24% versus 13%. Although there were more children than adults in complete remission, the rate was equal in the treated adults compared with the treated children (44% v 47%). Although optimal duration of steroid therapy cannot be determined by this review, treatment beyond 6 months does not appear to be beneficial. The best guide to prognosis remains complete remission, since long-term renal survival in both age groups with this event was 100%. Those without a complete remission generally progress, although even at 10 years the survival rate is 62% in adults and 58% in children.

PMID 9669427  Am J Kidney Dis. 1998 Jul;32(1):72-9.
著者: J J Rydel, S M Korbet, R Z Borok, M M Schwartz
雑誌名: Am J Kidney Dis. 1995 Apr;25(4):534-42.
Abstract/Text The authors performed a retrospective clinicopathologic study in 81 patients with primary focal segmental glomerular sclerosis (FSGS) to determine whether they could identify clinical or histologic features at presentation that could be predictive of outcome and response to therapy. Males constituted 58% of patients, and 53% were black. At biopsy the patients were 40 +/- 17 years old; 74% were nephrotic, and renal insufficiency was present in 62%. The average time from presentation to biopsy was 16 months, and the average total follow-up was 62 months. Nephrotic patients had a significantly poorer prognosis as compared with nonnephrotic patients (5- and 10-year survivals of 76% and 57% v 92% and 92%; P < 0.05). A multivariate analysis was done on histologic and clinical features at biopsy, assessing for risk factors leading to end-stage renal disease, showing only the serum creatinine and the degree of interstitial fibrosis to have a significant correlation. Thirty nephrotic patients received prednisone, with a treatment time of 5.5 +/- 4 months and a total dose of 5.9 +/- 2.9 g per course of treatment. Fifteen of these patients (50%) achieved a remission by 3.7 +/- 2 months (10 complete remission and 5 partial remissions), with all patients responding within 9 months. Only two patients had spontaneous remissions (both partial). The 5- and 10-year survival for patients in remission were both 100% as compared with 66% and 41% (P < 0.01), respectively, for nephrotic patients not in remission. No clinical feature at presentation of biopsy was predictive of response to therapy when a multivariate analysis was performed.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID 7702047  Am J Kidney Dis. 1995 Apr;25(4):534-42.
著者: S K Agarwal, S C Dash, S C Tiwari, U N Bhuyan
雑誌名: Nephron. 1993;63(2):168-71.
Abstract/Text A total of 65 adult cases (53 males, 12 females) with biopsy-proven focal segmental glomerulosclerosis (FSGS) were studied. Hypertension, ascites and haematuria were seen in 13, 12 and 24 cases, respectively. Decreased creatinine clearance at presentation was found in 9 cases. Mean proteinuria per day, serum cholesterol and total protein were 7.5 +/- 4.3 g, 388.95 +/- 213.4 mg% (10.11 +/- 5.55 mmol/l) and 5.27 +/- 1.1 g% (0.527 +/- 0.11 milligram), respectively. Mesangial proliferation was seen in 13 cases and hilar sclerosis in 5. Fifty percent showed positive immunofluorescence; IgM in 10, C3 in 8, and IgG in 2. Forty-two cases could be followed (mean 32 months), out of which 38 had nephrotic syndrome and were treated with prednisolone; 58% showed response (31% complete remission and 27% partial remission). One patient in each group of responders and nonresponders had renal failure at the end of follow-up. Hypertension, degree of proteinuria, mesangial proliferation, degree of tubular atrophy and immunofluorescence findings did not significantly affect the response to steroids. We conclude that a group of patients with idiopathic adult FSGS has a favourable response to steroids, which cannot be predicted clinically.

PMID 8450907  Nephron. 1993;63(2):168-71.
著者: C Ponticelli, M Villa, G Banfi, B Cesana, C Pozzi, A Pani, P Passerini, M Farina, C Grassi, A Baroli
雑誌名: Am J Kidney Dis. 1999 Oct;34(4):618-25. doi: 10.1016/S0272-6386(99)70384-7.
Abstract/Text Eighty nephrotic adults with focal segmental glomerulosclerosis (FSGS) and plasma creatinine lower than 3 mg/dL were given corticosteroids (53 patients) or immunosuppressive agents (27 patients) for a median of 16 and 75 weeks, respectively. Forty-two patients responded with complete remission (29 patients, 36%) or partial remission (13 patients, 16%). Twenty-six patients who did not respond were treated again. Two patients obtained complete remission and 13 partial remission. The probability of remission was associated with treatment with corticosteroids (P = 0.0001; RR, 3. 93; 95% CI, 2.00 to 7.72), absence of arterial hypertension (P = 0. 0023; RR, 2.59; 95% CI, 1.41 to 4.79), and a percentage of hyaline glomeruli lower than 5% (P = 0.0152; RR, 2.04; 95% CI, 1.15 to 3.64). The probability of being alive at 110 months without doubling of plasma creatinine was 69%. The risk of renal insufficiency was correlated with mesangial proliferation (P = 0.0025; RR, 5.50; 95% CI, 1.82 to 16.60) and with interstitial fibrosis (P = 0.0231; RR, 4. 44; 95% CI, 1.23 to 16.08) at initial biopsy. Considering partial or complete remission as a time-dependent variable, only the lack of remission (P = 0.0027; RR, 7.23; 95% CI, 1.98 to 26.33) and mesangial proliferation (P = 0.0069; RR, 4.59; 95% CI, 1.52 to 13. 88) were correlated with renal failure. Major side effects were observed in 11 patients (5 infections, 1 peptic ulcer, 2 diabetes, 3 neoplasias). This study shows that 70% of nephrotic adults with FSGS may obtain complete or partial remission and maintain stable renal function for about 10 years when given a prolonged therapy with corticosteroids or immunosuppressive drugs.

PMID 10516340  Am J Kidney Dis. 1999 Oct;34(4):618-25. doi: 10.1016/S0・・・
著者: A Matalon, A Valeri, G B Appel
雑誌名: Semin Nephrol. 2000 May;20(3):309-17.
Abstract/Text Focal segmental glomerulosclerosis (FSGS) has been increasing in incidence over the past 2 decades and may currently be the most common form of primary nephrotic syndrome in the United States. Nephrotic patients with FSGS who do not achieve a remission in proteinuria usually advance to end-stage renal disease within 5 to 10 years. Although initially felt to be a steroid-resistant disease, especially in adults, studies show significant responsiveness to more prolonged courses of steroids. For patients with steroid-resistant or steroid-dependent FSGS, cyclosporine A and cytotoxic agents have shown efficacy in clinical trials. Other agents used include pulse methylprednisolone, azathioprine, tacrolimus, mycophenolate mofetil, and combination therapy. For recurrent FSGS after renal transplantation, plasmapheresis is often used but appears not to be as efficacious in adults as in the pediatric population.

PMID 10855941  Semin Nephrol. 2000 May;20(3):309-17.
著者: S M Korbet
雑誌名: Ren Fail. 2000 Nov;22(6):685-96.
Abstract/Text Nephrotic patients with primary focal segmental glomerulosclerosis (FSGS) have a poor prognosis with 50% progressing to end stage renal disease (ESRD) over 3 to 8 years. The achievement of a remission in proteinuria has been associated with a significantly improved renal survival as compared to those patients not attaining a remission. Unfortunately, spontaneous remissions are rare in FSGS, and the response to therapy has historically been poor. Recent experience with more aggressive immunosuppressive therapy has lead to an increase in the remission rate for FSGS patients and given rise to optimism in the treatment of this glomerulopathy.

PMID 11104158  Ren Fail. 2000 Nov;22(6):685-96.
著者: Stephen M Korbet
雑誌名: Kidney Int. 2002 Dec;62(6):2301-10. doi: 10.1046/j.1523-1755.2002.00674.x.
Abstract/Text
PMID 12427162  Kidney Int. 2002 Dec;62(6):2301-10. doi: 10.1046/j.1523・・・
著者: P Hari, A Bagga, N Jindal, R N Srivastava
雑誌名: Pediatr Nephrol. 2001 Nov;16(11):901-5.
Abstract/Text Patients with steroid-resistant nephrotic syndrome often have an unsatisfactory long-term outcome and are at risk of developing chronic renal failure. We prospectively treated 65 children with idiopathic steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis (FSGS) with intravenous pulses of corticosteroids and oral cyclophosphamide. Dexamethasone (5 mg/kg) or methylprednisolone (30 mg/kg) was administered intravenously, initially 6 pulses on alternate days, followed by 4 fortnightly and 8 monthly pulses. Oral cyclophosphamide therapy was given for 12 weeks and tapering doses of prednisolone were administered for 52 weeks. The mean age at treatment was 85.7+/- 44.9 months. Five patients developed serious infections during administration of initial alternate-day pulses and were excluded. Of 59 patients who completed initial alternate-day therapy, 17 had complete and 8 partial remission; 34 (57.6%) patients did not respond to treatment. The median urine protein to creatinine ratio decreased from 10.0 to 0.75 (P<0.005) and serum albumin increased from 1.9 g/dl to 2.4 g/dl (P<0.01). The median duration of follow-up after stopping pulse therapy was 25.6 months. Thirty-four patients were followed for more than 3 years (median 4.5 years). Of these, 22 (64.7%) patients had a favorable outcome; persistent complete remission was seen in 15 patients and steroid-responsive relapses in 7. Seven patients had non- nephrotic-range proteinuria, 2 had nephrotic-range proteinuria, and 3 (8.8%) were in chronic renal failure. There was no significant difference in the short- and long-term outcome of patients with initial (n=28) and late resistance (n=31). The outcome in patients receiving intravenous dexamethasone (n=48) or methylprednisolone (n=11) was also similar. The chief side effects included worsening of height standard deviation score (47.4%), transient hypertension (42.5%), and serious infections (18.5%). We conclude that prolonged treatment with intravenous corticosteroids and oral cyclophosphamide is beneficial in patients with steroid-resistant FSGS. Expensive protocols can be successfully modified and used, depending upon the availability of health resources.

PMID 11685598  Pediatr Nephrol. 2001 Nov;16(11):901-5.
著者: Rashmi Kirpekar, Peter D Yorgin, Bruce M Tune, Mi-Kyung Kim, Richard K Sibley
雑誌名: Am J Kidney Dis. 2002 Jun;39(6):1143-52. doi: 10.1053/ajkd.2002.33382.
Abstract/Text Although pulse methylprednisolone therapy (PMT) has been used successfully in the management of children with steroid-resistant nephrotic syndrome (SRNS), the relationship between initial presenting findings and renal histological characteristics to the subsequent clinical response to PMT is unknown. A retrospective analysis was conducted in a study cohort of 42 children (30 boys, 12 girls; mean age, 7.4 +/- 4.7 years) with SRNS administered PMT between June 1976 and July 1994 at Stanford University (Stanford, CA). Four diagnostic categories were created: group I, minimal change disease with or without mesangial hypercellularity (n = 10); group II, mesangial proliferation (n = 7); group III, focal segmental glomerulosclerosis (FSGS) with or without mesangial hypercellularity (n = 10); and group IV, FSGS plus mesangial proliferation (n = 15). Primary variables analyzed were remission in response to PMT with or without alkylating agent therapy and end-stage renal disease (ESRD). Remission rates were best in group I (90%) and worst in group IV (46%). With the exception of hematuria, presenting clinical features did not correlate with outcome. Segmental sclerosis, glomerular adhesion to Bowman's capsule, epithelial sloughing, corona (segmental scar surrounded by visceral epithelial cells), subepithelial deposits, inflammatory cells, and percentage of interstitium, immunoglobulin M (IgM), IgG, and C3 deposition univariately correlated with ESRD in univariate analysis. In a multivariate logistic regression model, only segmental sclerosis (P = 0.008) correlated with ESRD. Histological analysis is important because it identifies features, including segmental sclerosis, that portend a poor prognosis in children with SRNS.

Copyright 2002 by the National Kidney Foundation, Inc.
PMID 12046024  Am J Kidney Dis. 2002 Jun;39(6):1143-52. doi: 10.1053/a・・・
著者: Stéphan Troyanov, Catherine A Wall, Judith A Miller, James W Scholey, Daniel C Cattran, Toronto Glomerulonephritis Registry Group
雑誌名: J Am Soc Nephrol. 2005 Apr;16(4):1061-8. doi: 10.1681/ASN.2004070593. Epub 2005 Feb 16.
Abstract/Text Focal and segmental glomerulosclerosis (FSGS) is one of the most common primary glomerular diseases to terminate in ESRD. A complete remission (CR) confers an excellent long-term prognosis, but the quantitative benefits of partial remissions (PR) have not been defined. This study evaluated the rate of renal function decline (slope of creatinine clearance) and renal survival in nephrotic FSGS patients with CR, PR, or no remission. It also examined relapse rate from remission and its impact on outcome. Multivariate analysis included clinical and laboratory data at presentation and over follow-up, BP control, the agents used, and immunosuppressive therapy. The study cohort was 281 nephrotic FSGS patients who had a minimum of 12 mo of observation and were identified from the Toronto Glomerulonephritis Registry. Over a median follow-up of 65 mo, 55 experienced a CR, 117 had a PR, and 109 had no remission. A PR was independently predictive of slope and survival from renal failure by multivariate analysis (adjusted time-dependent hazard ratio, 0.48; 95% confidence interval, 0.24 to 0.96; P = 0.04). Immunosuppression with high-dose prednisone was associated with a higher rate of PR and CR. Relapse from PR was frequent (56%) and associated with a more rapid rate of renal function decline and worse renal survival compared with relapse-free partial remitters. Only female gender and the nadir of proteinuria during remission were associated with a sustained remission. A PR in proteinuria and its maintenance are important therapeutic targets in FSGS, with implications for both slowing progression rate and improving renal survival.

PMID 15716334  J Am Soc Nephrol. 2005 Apr;16(4):1061-8. doi: 10.1681/A・・・
著者: B M Tune, S A Mendoza
雑誌名: J Am Soc Nephrol. 1997 May;8(5):824-32.
Abstract/Text This review compares the biopsy patterns, complications, responses to therapy, and long-term outcomes of idiopathic NS in children and adults. On first examination, distinctions between the pediatric and adult diseases seem more quantitative than absolute. However, underlying determinants of outcome, including immunocompetence, growth, maturity, and senescence, can present very different challenges for pediatricians and internists. The major biopsy patterns in pediatric NS include MCD, FSGS, and DMP. MCD is overwhelmingly the most frequent and most steroid-responsive of the three but commonly presents problems of massive edema, serious bacterial infections, and multiple relapses. Because of the prompt response of pediatric MCD to corticosteroids, steroid resistance in children has generally been defined as persistence of proteinuria after 1 month of daily followed by 1 month of intermittent prednisone administration. By this criterion, nephrotic FSGS is usually steroid-resistant and, if not controlled by more aggressive therapy, typically progresses to ESRD. DMP is commonly steroid-resistant but may slowly resolve. It is not clear to what extent remissions of DMP represent a delayed response to steroids or would have occurred without treatment. Biopsies showing a few globally obsolescent glomeruli or mild mesangial hypercellularity may be associated with greater difficulty in management but have been included in the broad category of MCD. Moreover, evolution of patterns in serial biopsies, variable steroid-responsiveness of FSGS and DMP, and progression of some cases of MCD to ESRD suggest common features in the three major categories. Among adults with idiopathic NS, FSGS is the most frequent biopsy pattern, followed by MN (which is rare in children) and then by MCD. In contrast to its pediatric counterpart, MCD in adults is less regularly and more slowly responsive to corticosteroids and in the elderly is more commonly associated with hypertension and renal failure. MCD in adults is less likely to relapse once remission is achieved. Adults with FSGS present less commonly with severe edema than do children with this lesion. Although children and adults with FSGS present similar challenges of resistance to therapy and loss of renal function, the more aggressive oral steroid regimens used by internists preclude strict comparisons between pediatric and adult series. There is insufficient information to support a systematic analysis of DMP in adults. Cytotoxic agents and cyclosporine have been used with varying success in children and adults with difficult cases of NS. In MCD, an alkylating agent can increase the likelihood and duration of remission. Cyclosporine can also improve control in MCD, but continued treatment is often needed to maintain remission. Significant control of steroid-resistant FSGS has not been achieved with limited courses of an alkylating agent or cyclosporine. Longer courses of either of these immunosuppressants, especially when combined with intermittent steroid administration, can produce more complete and/or more sustained remissions. However, cyclosporine nephrotoxicity is more severe in FSGS than in MCD and in steroid-resistant than in steroid-dependent NS, regardless of biopsy pattern. A protocol combining iv M-P pulses, alternate-day prednisone, and an alkylating agent in steroid-resistant pediatric FSGS has produced the highest percentage of sustained remissions with normal renal function, of all reported regimens. Controlled trials of this and other combined drug protocols are needed in children and adults.

PMID 9176855  J Am Soc Nephrol. 1997 May;8(5):824-32.
著者: Jei-Wen Chang, Ling-Yu Yang, Hsin-Hui Wang
雑誌名: Pediatr Int. 2007 Jun;49(3):349-54. doi: 10.1111/j.1442-200X.2007.02373.x.
Abstract/Text BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a primary glomerular disease that usually progresses to renal failure. Although high-dose pulse methylprednisolone therapy (PMT) has been shown to be effective in the treatment of steroid-resistant FSGS, adverse effects have caused parents to hesitate in approving the treatment. The aim of this study is to investigate whether low-dose PMT based protocol for treatment of young children with steroid resistant FSGS would effectively induce remission of proteinuria and prevent the progression of renal insufficiency.
METHODS: This is a retrospective study. The authors treated eight children with steroid-resistant FSGS with intravenous methylprednisolone pulse 10 mg/kg per day for three consecutive days weekly for 8 weeks. Partial responders were treated with the addition of chlorambucil or cyclosporine (CsA) and four fortnightly and eight monthly pulses of high-dose PMT (30 mg/kg per day).
RESULTS: Of the eight patients, six attained complete remission initially. The median urinary protein excretion in 24 h decreased from 4.25 to 0.39 g following 8 weeks of low dose (P = 0.012). Marked decrease in urinary protein-creatinine ratio was noted soon after treatment (P = 0.012). There was a significant increase in serum albumin level after treatment compared to the pretreatment condition (median, 3.35 vs 4.1 mg/dL, P = 0.018). Five of the eight patients remained in complete remission, and one of the eight patients relapsed during follow up. Relapse responded to repeated treatments of PMT and cyclosporine. The two patients with partial remission initially progressed to renal insufficiency in one patient and end-stage renal disease in the other patient.
CONCLUSIONS: Low-dose PMT caused a significant decrease in the proteinuria of Chinese children with steroid-resistant FSGS with a low frequency of intolerance.

PMID 17532834  Pediatr Int. 2007 Jun;49(3):349-54. doi: 10.1111/j.1442・・・
著者: Antonia Peña, Juan Bravo, Marta Melgosa, Carlota Fernandez, Carmen Meseguer, Laura Espinosa, Angel Alonso, M Luz Picazo, Mercedes Navarro
雑誌名: Pediatr Nephrol. 2007 Nov;22(11):1875-80. doi: 10.1007/s00467-007-0567-2. Epub 2007 Sep 18.
Abstract/Text We present a retrospective study of 30 children of mean age 3.02 +/- 1.81 years with steroid-resistant nephrotic syndrome (SRNS) treated with intravenous injection of methylprednisolone plus orally administered prednisone; 24 children also received cyclophosphamide (CP). Sixteen were resistant to steroids from the beginning, and 14 after a mean of 11.26 +/- 16.61 months. The initial histological diagnosis was: 18 minimal change disease (MCD), 11 focal segmental glomerulosclerosis (FSGS) and one diffuse mesangial proliferative glomerulonephritis (DMPG). Total remission was achieved in 22 patients (73.3%), partial response in three (10%) and no response in five (16.6%), two of whom were brothers carrying an NPHS2 gene double mutation. There was no difference in response between the MCD and FSGS patients; the only patient with DMPG did not respond. Only initial resistance was a sign of bad prognosis. At follow-up (6.4 +/- 3.6 years from last pulse), 21/22 were still in remission, 14/21 were without treatment. Six patients required cyclosporine or mycophenolate mofetil because of steroid dependence. Two non-responders developed end-stage renal failure (ESRF); the remaining patients maintained normal glomerular filtration. The treatment was well tolerated. In conclusion, most of the patients treated with sequential therapy consisting of methylprednisolone (MP) (100%) and CP (80%) showed remission and preserved renal function, but 20% developed steroid dependence.

PMID 17876609  Pediatr Nephrol. 2007 Nov;22(11):1875-80. doi: 10.1007/・・・
著者: Yuko Hamasaki, Norishige Yoshikawa, Shinzaburo Hattori, Satoshi Sasaki, Kazumoto Iijima, Koichi Nakanishi, Takeshi Matsuyama, Kenji Ishikura, Nahoko Yata, Tetsuji Kaneko, Masataka Honda, Japanese Study Group of Renal Disease
雑誌名: Pediatr Nephrol. 2009 Nov;24(11):2177-85. doi: 10.1007/s00467-009-1264-0.
Abstract/Text We conducted a prospective, multicenter trial to evaluate the efficacy and safety of a 12-month course of cyclosporine in children with steroid-resistant nephrotic syndrome (SRNS). Thirty-five patients were enrolled, of whom 28 had minimal change or diffuse mesangial proliferation (MC/DMP), and seven had focal segmental glomerulosclerosis (FSGS). All patients received cyclosporine and prednisolone; patients with FSGS additionally received methylprednisolone pulse therapy (MPT). The dose of cyclosporine was adjusted to maintain a trough level of 120-150 ng/ml during the initial 3 months of treatment, followed by 80-100 ng/ml during months 4-12. The primary end point was the remission rate at month 12. Remission was achieved in 23 of 28 (82.1%) patients in the MC/DMP group and in six of the seven (85.7%) patients in the FSGS group. Follow-up renal biopsies were performed in 26 patients (nine at month 12, 17 at month 24), and cyclosporine-related nephrotoxicity was detected in one (3.8%). Major adverse events comprised severe bacterial infections (two patients) and posterior reversible encephalopathy syndrome (one patient). In conclusion, a high remission rate was achieved in our patient cohort using a combined cyclosporine/ prednisolone treatment regimen in children with SRNS who had MC/DMP and a combined cyclosporine/prednisolone plus MPT regimen in children who had FSGS.

PMID 19714370  Pediatr Nephrol. 2009 Nov;24(11):2177-85. doi: 10.1007/・・・
著者: Mohan Shenoy, Nicholas D Plant, Malcolm A Lewis, Mark G Bradbury, Rachel Lennon, Nicholas J A Webb
雑誌名: Pediatr Nephrol. 2010 May;25(5):899-903. doi: 10.1007/s00467-009-1417-1. Epub 2010 Jan 27.
Abstract/Text The aim of our study was to determine the clinical course of children with idiopathic childhood nephrotic syndrome (ICNS) who received intravenous methylprednisolone (ivMP) following failure to achieve remission with standard oral prednisolone therapy. This study was designed as a retrospective case record review from 1993 to 2007. Sixteen children received ivMP over the 15-year study period, of whom ten responded, achieving clinical remission. The remaining six children with steroid resistant nephrotic syndrome (SRNS) underwent biopsy [four focal segmental glomerulosclerosis (FSGS), two minimal change disease (MCD)]. Three responders developed late secondary steroid resistance (two FSGS, one MCD). At the latest follow-up (mean 6.7 years), three of the ten ivMP responders and none (0/6) of the children with SRNS had heavy proteinuria and chronic kidney disease (CKD) stage 3-5. The remaining 13 children demonstrated significant steroid dependency but had achieved stable remission following cyclophosphamide and/or ciclosporin therapy. The majority of children with ICNS who do not respond to 4 weeks of daily prednisolone therapy will enter remission following three to five doses of ivMP, thus avoiding a renal biopsy at initial presentation. These children are likely to develop steroid dependency, and the majority will require treatment with alkylating agents and/or ciclosporin to maintain remission. The requirement for ivMP in this setting appears to be associated with a risk of developing CKD in the longer term.

PMID 20108003  Pediatr Nephrol. 2010 May;25(5):899-903. doi: 10.1007/s・・・
著者: D C Cattran, E Alexopoulos, P Heering, P F Hoyer, A Johnston, A Meyrier, C Ponticelli, T Saito, G Choukroun, P Nachman, M Praga, N Yoshikawa
雑誌名: Kidney Int. 2007 Dec;72(12):1429-47. doi: 10.1038/sj.ki.5002553. Epub 2007 Sep 26.
Abstract/Text Management of idiopathic glomerular disease associated with nephrotic syndrome (INS) remains controversial and one of the most complex areas relates to utilization of the drug cyclosporin. This is despite its demonstrated effectiveness in several histologic types of the INS in randomized controlled trials. Cyclosporin is effective in inducing remission of proteinuria in approximately 80% of steroid-sensitive cases of minimal change disease (MCD). Cyclosporin is also effective in both the induction of remission and long-term preservation of renal function in steroid-dependent/-resistant MCD and steroid-resistant focal segmental glomerulosclerosis (FSGS). The overall response rate in FSGS is lower than in MCD, and long-term therapy (>12 months) may be required to both achieve remission and sustain it. Cyclosporin therapy is also of benefit in reducing proteinuria in 70-80% of patients with steroid-resistant membranous nephropathy (MGN). In MGN, the maximum benefit is often delayed compared to MCD (>12 weeks). Cyclosporin is generally well tolerated and safe. The major concern remains the nephrotoxicity, but with careful monitoring of the patient's renal function; minimizing the maintenance dose and utilizing repeat renal biopsy in those receiving long-term therapy, this risk can be minimized. The algorithms have been developed derived from the best evidence in the literature in each of the histologic types to help provide a guide to the integration of cyclosporin into the management of INS for the practicing nephrologist.

PMID 17898700  Kidney Int. 2007 Dec;72(12):1429-47. doi: 10.1038/sj.ki・・・
著者: D C Cattran, G B Appel, L A Hebert, L G Hunsicker, M A Pohl, W E Hoy, D R Maxwell, C L Kunis
雑誌名: Kidney Int. 1999 Dec;56(6):2220-6. doi: 10.1046/j.1523-1755.1999.00778.x.
Abstract/Text UNLABELLED: A randomized trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis.
BACKGROUND: A clinical trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis (FSGS) was conducted. Despite the fact that it is the most common primary glomerulonephritis to progress to renal failure, treatment trials have been very limited.
METHODS: We conducted a randomized controlled trial in 49 cases of steroid-resistant FSGS comparing 26 weeks of cyclosporine treatment plus low-dose prednisone to placebo plus prednisone. All patients were followed for an average of 200 weeks, and the short- and long-term effects on renal function were assessed.
RESULTS: Seventy percent of the treatment group versus 4% of the placebo group (P < 0. 001) had a partial or complete remission of their proteinuria by 26 weeks. Relapse occurred in 40% of the remitters by 52 weeks and 60% by week 78, but the remainder stayed in remission to the end of the observation period. Renal function was better preserved in the cyclosporine group. There was a decrease of 50% in baseline creatinine clearance in 25% of the treated group compared with 52% of controls (P < 0.05). This was a reduction in risk of 70% (95% CI, 9 to 93) independent of other baseline demographic and laboratory variables.
CONCLUSIONS: These results suggest that cyclosporine is an effective therapeutic agent in the treatment of steroid-resistant cases of FSGS. Although a high relapse rate does occur, a long-term decrease in proteinuria and preservation of filtration function were observed in a significant proportion of treated patients.

PMID 10594798  Kidney Int. 1999 Dec;56(6):2220-6. doi: 10.1046/j.1523-・・・
著者: Norbert Braun, Frank Schmutzler, Catalina Lange, Annalisa Perna, Giuseppe Remuzzi, Teut Risler, Narelle S Willis
雑誌名: Cochrane Database Syst Rev. 2008 Jul 16;(3):CD003233. doi: 10.1002/14651858.CD003233.pub2. Epub 2008 Jul 16.
Abstract/Text BACKGROUND: Corticosteroids remain the mainstay of treatment in idiopathic nephrotic syndrome, including focal and segmental glomerulosclerosis (FSGS). However, only about 20% of patients with FSGS experience a partial or complete remission of nephrotic syndrome despite treatment.
OBJECTIVES: To assess the effects of different immunomodulatory and immunosuppressive regimes in adults with FSGS.
SEARCH STRATEGY: We searched MEDLINE, EMBASE and CENTRAL and handsearched congress reports of the American Society of Nephrology and the European Dialysis and Transplantation Association. Date of search: 31 January 2007.
SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs which examined the effects of different doses, dose strategies and duration of treatment of steroids, alkylating agents, cyclosporin A and antimetabolites in the treatment of FSGS in adults, where included.
DATA COLLECTION AND ANALYSIS: At least two authors independently assessed abstracts and/or full text articles to determine which studies satisfied the inclusion criteria. Information was entered onto a separate data sheet for each identified study. Data relevant to outcomes (complete or partial remission of nephrotic syndrome, doubling of serum creatinine, adverse effects) from identified studies were included. Results were expressed as risk ratios (RR) with 95% confidence intervals (CI).
MAIN RESULTS: Four studies (108 participants) were included. Three studies investigated cyclosporin A (CSA) with or without prednisone versus prednisone or no treatment and one compared chlorambucil plus prednisone versus no treatment. Outcome data was only available for complete or partial remission and doubling of serum creatinine. There was a significant increase in the number of participants who obtained complete or partial remission with CSA plus low dose prednisone versus prednisone alone (one study, 49 participants: RR 8.85, 95% CI 1.22 to 63.92). Pooled analyses were not performed due to the heterogeneity of the data.
AUTHORS' CONCLUSIONS: Adult patients treated with CSA at an initial dose of 3.5-5 mg/kg/d in two divided doses perhaps in combination with oral prednisolone 0.15 mg/kg/d are more likely to achieve a partial remission of the nephrotic syndrome compared with symptomatic treatment or prednisolone alone. However, there is a probability of deterioration of kidney function due to the nephrotoxic effect of CSA in the long term. For CSA, a larger controlled trial with longer follow-up should be performed to prove the benefit of this regimen not only on proteinuria but also on the preservation of kidney function. Present available data do not support the general use of alkylating substances for the treatment of FSGS in adults.

PMID 18646090  Cochrane Database Syst Rev. 2008 Jul 16;(3):CD003233. d・・・
著者: Peter Heering, Norbert Braun, Reinhard Müllejans, Katrin Ivens, Ingeborg Zäuner, Reinhard Fünfstück, Frieder Keller, Bernhard K Krämer, Peter Schollmeyer, Teut Risler, Bernd Grabensee, German Collaborative Glomerulonephritis Study Group
雑誌名: Am J Kidney Dis. 2004 Jan;43(1):10-8.
Abstract/Text BACKGROUND: The therapy of nephrotic syndrome in focal segmental glomerulosclerosis (FSGS) is still a matter of controversy.
METHODS: We performed a prospective randomized study of the treatment of nephrotic syndrome due to FSGS. We compared 2 specific treatment protocols to assess the effect of treatment on proteinuria and renal function. Fifty-seven patients were randomly assigned to 2 groups: group 1 (n = 34) received steroids and cyclosporine, and group 2 (n = 23) received steroids and chlorambucil for 6 months. When treatment was refractory to chlorambucil, the patients in this group were treated with cyclosporine. Creatinine, blood urea nitrogen, proteinuria, lipids, and arterial hypertension were monitored at regular intervals.
RESULTS: Patients showed a mean serum creatinine of 1.5 +/- 0.2 mg/dL (132.6 +/- 17.7 micromol/L) and proteinuria of 4.8 +/- 2.8 g/24 h with no differences between the groups. At the end of the chlorambucil therapy, patients in group 2 had creatinine levels of 1.8 +/- 0.6 mg/dL (159.1 +/- 53 micromol/L) and proteinuria levels of 3.4 +/- 1 g/24 h. All patients in this group were given cyclosporine. After 4 years the mean creatinine level in group 1 was 1.7 +/- 0.4 mg/dL (150.3 +/- 35.4 micromol/L) and the proteinuria level was 2.5 +/- 1 g/24 h. In group 2, the mean creatinine level was 1.9 +/- 0.6 mg/dL (168 +/- 53 micromol/L) (not significant [NS]) and the mean proteinuria level was 2.3 +/- 1.1 g/24 h (NS). Full remission occurred in 23% of the patients in group 1 (n = 8) and 17% of the patients in group 2 (n = 4; NS). Partial remission was observed in 38% of the patients in group 1 (n = 13) and 48% in group 2 (n = 11; NS). The number of patients who developed end-stage renal disease was comparable in both groups: 4 of 34 patients in group 1 after 2.5 +/- 0.8 years, and 5 of 23 patients in group 2 (NS).
CONCLUSION: Additional treatment with chlorambucil was found to be ineffective in FSGS. Patients responded to treatment with steroids or cyclosporine, but additional treatment with chlorambucil did not improve the patient's outcome. Future studies must focus on the long-term prognosis of these patients.

PMID 14712422  Am J Kidney Dis. 2004 Jan;43(1):10-8.
著者: Alain Y Meyrier
雑誌名: Kidney Int. 2009 Sep;76(5):487-91. doi: 10.1038/ki.2009.204. Epub 2009 Jun 3.
Abstract/Text Nephrotic focal segmental glomerulosclerosis (FSGS) represents a difficult therapeutic challenge. FSGS has long been considered a subset of idiopathic nephrotic syndrome, lumping together FSGS and minimal change disease (MCD). The time-honored 'Shalhoub hypothesis' has led to treating FSGS as a T-cell-driven condition in which a lymphokine, considered without proof as being the 'glomerular permeability factor,' induces proteinuria and podocyte functional and structural derangement. This has led to trying, in addition to steroids, every new drug marketed in the field of organ transplantation, first cyclosporine (CsA) and then other immunophilin modulators. The fact that alkylating agents and mycophenolate mofetil have obtained a poor and inconstant favorable effect, and that rituximab may obtain remissions, although inconstantly, has not led to reconsidering the T-cell hypothesis. This wrong thinking has fostered innumerable, mostly uncontrolled, treatment trials with various immunosuppressive agents. In fact, clinicians have not considered the fact that some but not all immunophilin modulators may be effective as nonspecific antiproteinuric agents, rather than as immunosuppressive drugs, and that treatment success does not exclude a non-immunologic pathophysiology. Recent findings on the mode of action of CsA and FK-506 have lent support to this concept. This review should be considered as a plea to reconsider the pathogenesis of nephrotic FSGS, applying all efforts to the identification of the factor, or factors, responsible for nephrotic FSGS, and to fund treatment to counteract the 'factor,' rather than pursuing costly and non-evidence-based immunosuppressive therapeutic trials.

PMID 19494796  Kidney Int. 2009 Sep;76(5):487-91. doi: 10.1038/ki.2009・・・
著者: Alain Meyrier
雑誌名: Expert Opin Pharmacother. 2009 Mar;10(4):615-28. doi: 10.1517/14656560902754029.
Abstract/Text Focal segmental glomerulosclerosis (FSGS) is not a disease but a lesion initially affecting the podocyte. Various factors may induce 'secondary' FSGS, including defects in molecules that contribute to the podocyte slit diaphragm permselectivity to albumin. They do not represent indications for immunosuppression and require symptomatic treatment only, comprising angiotensin 2 and endothelin antagonists. Primary (idiopathic) FSGS is possibly but not certainly of immunologic origin, owing to an elusive glomerular permeability factor (GPF), explaining relapse on a renal transplant and justifying an immunosuppressive treatment. The best prognostic feature of primary nephrotic FSGS is its response to corticosteroids. Alkylating agents are mostly ineffective in steroid-resistant forms. An association of corticosteroids and cyclosporine A (CsA) remains the mainstay of treatment, with a good tolerability when CsA dosage is low. A definite advantage of tacrolimus on CsA has not yet been established. Sirolimus appears ineffective and potentially harmful. Azathioprine is not indicated. A number of mostly uncontrolled trials indicate that mycophenolate mofetil might find an adjunctive place in the treatment. Plasmapheresis is of no avail outside the special case of relapse in a transplanted kidney. Immunoabsorption of the GPF has not led to practical treatment options. Anecdotal reports on rituximab are as yet too few to determine whether this monoclonal anti-CD20 antibody will find a place in the treatment of primary FSGS.

PMID 19284364  Expert Opin Pharmacother. 2009 Mar;10(4):615-28. doi: 1・・・
著者: Hidekazu Sugiura, Takashi Takei, Mitsuyo Itabashi, Misao Tsukada, Takahito Moriyama, Chiari Kojima, Toshiharu Shiohira, Ari Shimizu, Yuki Tsuruta, Nobuyuki Amemiya, Tetsuya Ogawa, Keiko Uchida, Ken Tsuchiya, Kosaku Nitta
雑誌名: Nephron Clin Pract. 2011;117(2):c98-105. doi: 10.1159/000319656. Epub 2010 Aug 6.
Abstract/Text BACKGROUND: A paradigm shift from such toxic 'nonspecific' therapies to selective immunomodulating regimens is necessary for glomerular diseases. Rituximab, which acts by inhibiting CD20-mediated B cell proliferation and differentiation, could be effective in the treatment of nephrotic syndrome as shown in recent reports.
DESIGN: To assess the effects of rituximab in patients with primary glomerular diseases, including minimal-change disease, immunoglobulin A (IgA) nephropathy, focal segmental glomerulonephritis, membranous nephropathy and membranoproliferative glomerulonephritis, we performed a prospective trial of the effects of single-dose rituximab therapy in 24 patients. We prospectively evaluated the serum and urinary biochemical parameters before and after 6 months of therapy.
RESULTS: In all of the patients studied, depletion of CD19 and CD20 cells was noted, with significant reduction in the degree of proteinuria from 3.7 ± 3.4 g/day at baseline to 1.3 ± 2.0 g/day at 6 months after the drug administration (p = 0.002). However, no significant changes of the serum creatinine, urinary RBC sediment, serum CD4/8 or serum IL-4 levels were observed at 6 months after the drug administration. In subjects with IgA nephropathy, while depletion of CD19 and CD20 cells was noted, no significant change in the severity of proteinuria was observed at 6 months after the drug administration as compared with the level at the baseline.
CONCLUSION: For the treatment of primary glomerular diseases, the use of a single dose of rituximab is demonstrated with no serious adverse events. Further study of the mechanism of action of rituximab in successfully treated patients could encourage new perspectives in the treatment of primary glomerular diseases.

Copyright © 2010 S. Karger AG, Basel.
PMID 20693810  Nephron Clin Pract. 2011;117(2):c98-105. doi: 10.1159/0・・・
著者: Gema Fernandez-Fresnedo, Alfonso Segarra, Ester González, Simona Alexandru, Ramon Delgado, Natalia Ramos, Jesús Egido, Manuel Praga, Trabajo de Enfermedades Glomerulares de la Sociedad Española de Nefrología (GLOSEN)
雑誌名: Clin J Am Soc Nephrol. 2009 Aug;4(8):1317-23. doi: 10.2215/CJN.00570109. Epub 2009 Jul 2.
Abstract/Text BACKGROUND AND OBJECTIVES: Isolated case reports have shown a beneficial effect of rituximab on pediatric patients with primary FSGS, but there is no information about rituximab treatment of FSGS in adults.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: All patients who had biopsy-proven FSGS and were treated with rituximab in Spain were identified, independent of their positive or negative response, among the nephrology departments that belong to the Spanish Group for the Study of Glomerular Diseases (GLOSEN). Their characteristics and outcome after rituximab treatment were studied.
RESULTS: Eight patients were identified. Rituximab failed to improve nephrotic syndrome in five of eight patients, who continued to show massive proteinuria and exhibited a rapidly deteriorating renal function in two cases. Among the remaining three patients, two of them showed an improvement of renal function and a remarkable proteinuria reduction and one experienced a beneficial but transitory effect after rituximab. There were no differences in clinical or laboratory characteristics or in the CD20 B lymphocyte count after rituximab between these three patients and the five who had a negative response. The only difference was in the regimen of rituximab administration: Whereas the five patients with a negative response received only four weekly consecutive infusions of 375 mg/m(2), the three remaining patients received additional doses of rituximab.
CONCLUSIONS: Only a minority (three of eight) of patients in our series of adult patients with FSGS showed a positive influence of rituximab. More studies are necessary to characterize further the optimal dosages and the mechanisms of action of rituximab in FSGS.

PMID 19578004  Clin J Am Soc Nephrol. 2009 Aug;4(8):1317-23. doi: 10.2・・・
著者: M Usta, A Ersoy, K Dilek, B Ozdemir, M Yavuz, M Güllülü, M Yurtkuran
雑誌名: J Intern Med. 2003 Mar;253(3):329-34.
Abstract/Text OBJECTIVES: Angiotensin II may play an important role in the progression of renal disease. Currently, angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists are commonly used for renoprotection. To our knowledge, there is no study investigating this effect of angiotensin II receptor antagonists in patients with primary focal segmental glomerulosclerosis (FSGS) in the literature. The aim of this study was to evaluate the effects of losartan on proteinuria and renal function in patients with FSGS refractory to immunosuppressive treatment.
DESIGN: Twenty-three normotensive patients with FSGS proven through renal biopsy were included in the study. Thirteen of them, five men and eight women, were given losartan in a dose of 50 mg day(-1) during 12 months, and 10, four men and six women, were in the control group. Mean arterial blood pressure (MAP), 24-h urine protein excretion, serum total protein and albumin levels were determined just before the start of treatment as well as after 1, 6 and 12 months of the study. In addition, serum creatinine, creatinine clearance (CrCl), cholesterol and triglyceride levels were determined at the beginning and end of the study.
RESULTS: Age, gender and baseline levels of proteinuria, serum albumin, total protein, creatinine, CrCl and MAPs were similar in the two groups. Nephrotic range of proteinuria was present in five of 13 patients (38.4%) in the losartan group and in four of 10 patients (40%) in the control group. In the losartan group, 24-h proteinuria had decreased from 3.6 +/- 0.5 g to 2.3 +/- 0.5 g after 1 month, to 2.4 +/- 0.7 g after 6 months and to 1.9 +/- 0.7 g after 12 months. In the control group, a significant increase in proteinuria compared with the baseline value was noticed after 12 months. Proteinuria levels were significantly higher in the control group than in the losartan group after 6 and 12 months. Whilst total protein and albumin levels increased in the losartan group, they did not change significantly in the control group. The total protein levels after 6 and 12 months, and albumin levels after 6 months were significantly higher in the losartan group than in the control group. No significant change was observed between the baseline and the 12-month creatinine and CrCl levels of the groups when intra- and inter-group comparisons were made. Furthermore, serum cholesterol levels of the losartan group were reduced significantly. The changes in MAP values did not reach significant levels in either of the groups. There was no correlation between the percentage changes in MAP and in proteinuria of the losartan group after 12 months.
CONCLUSIONS: Angiotensin II receptor antagonists may be an alternative therapy in FSGS patients who are resistant to immunosuppressive therapy.

PMID 12603500  J Intern Med. 2003 Mar;253(3):329-34.
著者: Tsukasa Nakamura, Eiichi Sato, Nobuharu Fujiwara, Yasuhiro Kawagoe, Yoshihiko Ueda, Tsukasa Suzuki, Seiji Ueda, Kei Fukami, Seiya Okuda, Sho-Ichi Yamagishi
雑誌名: Pharmacol Res. 2010 Jan;61(1):58-61. doi: 10.1016/j.phrs.2009.07.011. Epub 2009 Aug 8.
Abstract/Text Since co-administration of ezetimibe, a specific inhibitor of cholesterol absorption into the intestine, has been shown to augment lipid-lowering effects of statins, ezetimibe plus statins is a novel therapeutic strategy for the treatment of dyslipidemia in high-risk patients. Statins have been shown to ameliorate renal function and reduce proteinuria in patients with chronic kidney disease (CKD). However, effects of co-administration of ezetimibe with statins on renal damage and dysfunction in CKD patients remain unknown. In this study, we examined whether co-administration of ezetimibe with pitavastatin could augment renoprotective properties of pitavastatin in non-diabetic CKD patients with dyslipidemia. Total cholesterol, LDL-cholesterol and triglycerides levels were reduced more by co-administration of ezetimibe (10mg/day) with pitavastatin (2mg/day) (n=10) than by pitavastatin alone (n=10). In addition, ezetimibe plus pitavastatin treatment produced significant incremental reduction in proteinuria related to pitavastatin therapy alone. In univariate analyses, proteinuria was correlated with plasma levels of total cholesterol, LDL-cholesterol, triglycerides, HDL-cholesterol (inversely), asymmetric dimethylarginine, an endogenous nitric oxide synthase inhibitor, and urinary excretion levels of L-fatty acid binding protein (L-FABP), a marker of tubular injury and 8-hydroxydeoxyguanosine (8-OHdG), an oxidative stress marker. Multiple stepwise regression analysis revealed that LDL-cholesterol (p<0.001) and urinary excretion levels of L-FABP (p=0.001) and 8-OHdG (p<0.001) were independently related to proteinuria (R(2)=0.969). Our present study demonstrated for the first time that co-administration of ezetimibe enhanced proteinuria-lowering effects of pitavastatin in non-diabetic CKD patients partly via a cholesterol-independent manner. Ezetimibe may have pleiotropic actions that could contribute to renoprotective properties of this lipid-lowering agent.

Copyright 2009 Elsevier Ltd. All rights reserved.
PMID 19666118  Pharmacol Res. 2010 Jan;61(1):58-61. doi: 10.1016/j.phr・・・
著者: Colin Baigent, Martin J Landray, Christina Reith, Jonathan Emberson, David C Wheeler, Charles Tomson, Christoph Wanner, Vera Krane, Alan Cass, Jonathan Craig, Bruce Neal, Lixin Jiang, Lai Seong Hooi, Adeera Levin, Lawrence Agodoa, Mike Gaziano, Bertram Kasiske, Robert Walker, Ziad A Massy, Bo Feldt-Rasmussen, Udom Krairittichai, Vuddidhej Ophascharoensuk, Bengt Fellström, Hallvard Holdaas, Vladimir Tesar, Andrzej Wiecek, Diederick Grobbee, Dick de Zeeuw, Carola Grönhagen-Riska, Tanaji Dasgupta, David Lewis, William Herrington, Marion Mafham, William Majoni, Karl Wallendszus, Richard Grimm, Terje Pedersen, Jonathan Tobert, Jane Armitage, Alex Baxter, Christopher Bray, Yiping Chen, Zhengming Chen, Michael Hill, Carol Knott, Sarah Parish, David Simpson, Peter Sleight, Alan Young, Rory Collins, SHARP Investigators
雑誌名: Lancet. 2011 Jun 25;377(9784):2181-92. doi: 10.1016/S0140-6736(11)60739-3. Epub 2011 Jun 12.
Abstract/Text BACKGROUND: Lowering LDL cholesterol with statin regimens reduces the risk of myocardial infarction, ischaemic stroke, and the need for coronary revascularisation in people without kidney disease, but its effects in people with moderate-to-severe kidney disease are uncertain. The SHARP trial aimed to assess the efficacy and safety of the combination of simvastatin plus ezetimibe in such patients.
METHODS: This randomised double-blind trial included 9270 patients with chronic kidney disease (3023 on dialysis and 6247 not) with no known history of myocardial infarction or coronary revascularisation. Patients were randomly assigned to simvastatin 20 mg plus ezetimibe 10 mg daily versus matching placebo. The key prespecified outcome was first major atherosclerotic event (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or any arterial revascularisation procedure). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00125593, and ISRCTN54137607.
FINDINGS: 4650 patients were assigned to receive simvastatin plus ezetimibe and 4620 to placebo. Allocation to simvastatin plus ezetimibe yielded an average LDL cholesterol difference of 0·85 mmol/L (SE 0·02; with about two-thirds compliance) during a median follow-up of 4·9 years and produced a 17% proportional reduction in major atherosclerotic events (526 [11·3%] simvastatin plus ezetimibe vs 619 [13·4%] placebo; rate ratio [RR] 0·83, 95% CI 0·74-0·94; log-rank p=0·0021). Non-significantly fewer patients allocated to simvastatin plus ezetimibe had a non-fatal myocardial infarction or died from coronary heart disease (213 [4·6%] vs 230 [5·0%]; RR 0·92, 95% CI 0·76-1·11; p=0·37) and there were significant reductions in non-haemorrhagic stroke (131 [2·8%] vs 174 [3·8%]; RR 0·75, 95% CI 0·60-0·94; p=0·01) and arterial revascularisation procedures (284 [6·1%] vs 352 [7·6%]; RR 0·79, 95% CI 0·68-0·93; p=0·0036). After weighting for subgroup-specific reductions in LDL cholesterol, there was no good evidence that the proportional effects on major atherosclerotic events differed from the summary rate ratio in any subgroup examined, and, in particular, they were similar in patients on dialysis and those who were not. The excess risk of myopathy was only two per 10,000 patients per year of treatment with this combination (9 [0·2%] vs 5 [0·1%]). There was no evidence of excess risks of hepatitis (21 [0·5%] vs 18 [0·4%]), gallstones (106 [2·3%] vs 106 [2·3%]), or cancer (438 [9·4%] vs 439 [9·5%], p=0·89) and there was no significant excess of death from any non-vascular cause (668 [14·4%] vs 612 [13·2%], p=0·13).
INTERPRETATION: Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease.
FUNDING: Merck/Schering-Plough Pharmaceuticals; Australian National Health and Medical Research Council; British Heart Foundation; UK Medical Research Council.

Copyright © 2011 Elsevier Ltd. All rights reserved.
PMID 21663949  Lancet. 2011 Jun 25;377(9784):2181-92. doi: 10.1016/S01・・・
著者: K Tojo, S Sakai, T Miyahara
雑誌名: Nihon Jinzo Gakkai Shi. 1988 Sep;30(9):1153-60.
Abstract/Text
PMID 3216557  Nihon Jinzo Gakkai Shi. 1988 Sep;30(9):1153-60.
著者: E Muso, M Mune, Y Fujii, E Imai, N Ueda, K Hatta, A Imada, T Takemura, S Miki, T Kuwahara, Y Takamitsu, Y Tsubakihara, Kansai FGS LDL Apheresis Treatment (K-FLAT) Study Group
雑誌名: Nephron. 2001 Dec;89(4):408-15.
Abstract/Text Rapid amelioration of hypercholesterolemia by LDL apheresis (LDL-A) was performed for long-standing nephrotic syndrome (NS) with hyperlipidemia due to focal segmental glomerulosclerosis (FGS) and the clinical data and prognosis were compared between LDL-A-treated and nontreated groups. Seventeen steroid-resistant NS patients treated with LDL-A (LDL-A group) and 10 NS patients treated with steroids only (steroid-monotherapy (SM) group) were compared. Serum cholesterol and phospholipid levels were significantly lowered only in the LDL-A group (p < 0.01, respectively). The LDL-A group showed a significant decrease of urinary protein (UP, p < 0.01) and increase of serum albumin (p < 0.05). Average time needed to achieve a decrease of UP to less than nephrotic range (< 3.5 g/day) was significantly shorter in the LDL-A group than in the SM group (p < 0.01). Although this is not a prospective study, it is highly expected that a rapid improvement of hypercholesterolemia by LDL-A in steroid-resistant NS will provide more rapid relief from NS than steroid therapy alone.

Copyright 2001 S. Karger AG, Basel
PMID 11721158  Nephron. 2001 Dec;89(4):408-15.
著者: Motoshi Hattori, Hiroko Chikamoto, Yuko Akioka, Hyogo Nakakura, Daisuke Ogino, Akira Matsunaga, Akira Fukazawa, Sanpei Miyakawa, Miyuki Khono, Hiroshi Kawaguchi, Katsumi Ito
雑誌名: Am J Kidney Dis. 2003 Dec;42(6):1121-30.
Abstract/Text BACKGROUND: Treatment of steroid-resistant (SR) primary focal segmental glomerulosclerosis (FSGS) remains a major challenge in nephrology. A prospective study was conducted to clarify the therapeutic role of low-density lipoprotein apheresis (LDL-A) in 11 nephrotic children with SR and cyclosporine A (CsA)-resistant primary FSGS.
METHODS: Based on entry criteria, all 11 eligible patients had biopsy-proven primary FSGS presenting with nephrotic syndrome (NS) and were resistant to steroid and conventional-dose CsA therapy. LDL-A was performed twice a week for 3 weeks (first course), then weekly for 6 weeks (second course). Beginning from the second LDL-A course, a dosage of 1 mg/kg/d of prednisone was administered for 6 weeks, then tapered.
RESULTS: Seven patients experienced remission of NS, 5 of whom achieved complete remission within 4 weeks after initiating prednisone therapy with LDL-A. These 5 patients maintained normal renal function during follow-up (median, 4.4 years). Of 2 patients with partial remission, 1 patient maintained stable renal function during follow-up (4.5 years), whereas the other patient showed a gradual decline in renal function and progressed to end-stage renal failure (ESRF) 7.8 years after LDL-A therapy. Four patients who were considered to experience treatment failure had persistent NS and progressed to ESRF in 1.3 years (median) after LDL-A therapy. Complete remission (n = 5) was associated with significantly more highly selective proteinuria compared with treatment failure (n = 4).
CONCLUSION: This study suggests that combined LDL-A and prednisone therapy can be a valuable addition to therapeutic options for treating patients with SR-FSGS. The role of LDL-A in treating these patients deserves to be assessed further in larger randomized controlled trials.

PMID 14655182  Am J Kidney Dis. 2003 Dec;42(6):1121-30.
著者: E Muso, M Mune, N Yorioka, Y Nishizawa, T Hirano, M Hattori, S Sugiyama, T Watanabe, K Kimura, H Yokoyama, H Sato, T Saito
雑誌名: Clin Nephrol. 2007 Jun;67(6):341-4.
Abstract/Text AIMS: Hypercholesterolemia is one of the factors which deteriorate renal function in NS especially due to FGS. LDL-A is a potential option for treating NS due to FGS accompanied by hypercholesterolemia and resistant to conventional drug therapy with steroids and/or cyclosporine A (CsA). As reported by Muso et al. [2001], LDL-A combined with drug therapy yields more rapid relief from NS and better prognosis than drug therapy alone. However, very limited data are available on outcome at several years after treatment. The aim of this study was to clarify long-term outcome of NS patients treated with LDL-A and to evaluate the effectiveness of this treatment.
PATIENTS AND METHODS: To clarify the long-term outcome of LDL-A, we conducted a retrospective survey on outcome up to 5 years. From 36 hospitals in Japan, 41 patients with NS whose short-term outcomes with LDL-A were reported from 1999-2004 were collected and analyzed.
RESULTS: In all, 29 and 15 patients with outcomes determined at 2 and 5 years after treatment, respectively, were obtained. At 2 and 5 years after treatment, 62 and 87% of patients, respectively, were classified into complete or Type 1 incomplete remission. The strength of correlations between outcome and several factors including parameters of renal function measured before and after treatment and treatment condition revealed that early administration of LDL-A after the onset of NS provided a good long-term outcome. The data also suggest that more drastic decrease of LDL favored a better prognosis.
CONCLUSIONS: In NS due to FGS treated with LDL-A, long-term outcome was as good as short-term outcome. Early administration of LDL-A after the onset of NS provided a good long-term outcome. To obtain more precise findings regarding the effects of this treatment, a large-scale prospective study will be needed.

PMID 17598368  Clin Nephrol. 2007 Jun;67(6):341-4.
著者: F Llach, S Papper, S G Massry
雑誌名: Am J Med. 1980 Dec;69(6):819-27.
Abstract/Text The present study is a prospective evaluation of 151 patients with the nephrotic syndrome in regard to the incidence of renal vein thrombosis, modes of clinical presentation, pathogenetic course and response to anticoagulant therapy. Of the 151 nephrotic patients studied, 33 had renal vein thrombosis and membranous nephropathy was present in 20. There were two modes of clinical presentation: (1) a sudden renal vein thrombosis was observed in the young patient with acute flank pain, marked costovertebral angle tenderness and macroscopic hematuria; a characteristic intravenous pyelogram, renal histologic changes and anticoagulant therapy were followed by marked improvement in renal function; (2) long-term renal vein thrombosis was observed in the older patients; they were asymptomatic and intravenous pyelograms disclosed no abnormalities; there were no suggestive renal histologic findings; the incidence of thromboembolic phenomena other than renal vein thrombosis was high, and there was mild progressive deterioration of renal function which was not altered by anticoagulant drugs; treated nephrotic patients with chronic renal vein thrombosis did not experience a new episode of thromboembolism whereas untreated nephrotic patients without renal vein thrombosis did. Finally, the sequence of nephrotic syndrome leading to renal vein thrombosis was clearly established showing the pathogenetic role of the nephrotic syndrome in renal vein thrombosis. Possible mechanisms in the pathogenesis of renal vein thrombosis are also discussed.

PMID 7446547  Am J Med. 1980 Dec;69(6):819-27.
著者: F P Sarasin, J A Schifferli
雑誌名: Kidney Int. 1994 Feb;45(2):578-85.
Abstract/Text Whether the high incidence of thromboembolic events in nephrotic patients with membranous nephropathy justifies prophylactic administration of oral anticoagulants remains controversial. We used a Markov-based decision analysis model, explicitly considering the consequences of recurrent embolic and bleeding events to quantify the risk-benefit trade-offs of: (1) prophylactic therapy, in which oral anticoagulation was started at the time of diagnosis of nephrotic syndrome (before any thromboembolic event); and (2) anticoagulant therapy, in which treatment was started after the first clinical thromboembolic event. We assumed that anticoagulant therapy was discontinued if there was remission of the nephrotic syndrome. The overall number of fatal emboli prevented by prophylactic anticoagulants exceeded the one of fatal bleeding events for all clinically meaningful ranges of the following parameters: nephrotic syndrome duration, incidence of thromboembolic events, likelihood of embolization, and mortality rates of embolic and bleeding events. For a hypothetical 50-year-old patient who remained nephrotic for 2 years, prophylactic anticoagulation yielded a gain representing 2.5 months of quality-adjusted life expectancy. We conclude that for nephrotic patients with membranous nephropathy, the benefits of prophylactic administration or oral anticoagulants outweigh the risks.

PMID 8164448  Kidney Int. 1994 Feb;45(2):578-85.
著者: Kate Bramham, Beverley J Hunt, David Goldsmith
雑誌名: Clin Adv Hematol Oncol. 2009 Jun;7(6):368-72.
Abstract/Text
PMID 19606070  Clin Adv Hematol Oncol. 2009 Jun;7(6):368-72.
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: 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.

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