今日の臨床サポート

膜性腎症

著者: 岡田浩一 埼玉医科大学 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:2022/08/31
患者向け説明資料

概要・推奨   

  1. 予後不良因子(男性、60歳以上、ネフローゼ症候群の遷延・特に蛋白尿8~10g/日以上、血清クレアチニン上昇(>1.5mg/dL)、糸球体硬化病変、尿細管間質病変(>20%))を有する患者には、寛解導入を目指した免疫抑制療法が推奨される(推奨度2)
  1. 一次性膜性腎症の寛解導入を目指した初回の免役抑制療法には、シクロホスファミド、ミゾリビン、タクロリムスのいずれかとステロイドの併用療法、もしくはACTHによる治療が推奨される(推奨度2)。またステロイド単独療法もしくはシクロスポリンとステロイドの併用療法を考慮してもよい(推奨度なし)
  1. ステロイド単独療法に抵抗性の膜性腎症患者には、免疫抑制薬とステロイドの併用療法が寛解導入に優れ、第2選択の免役抑制療法として推奨される(推奨度2)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
岡田浩一 : 講演料(アストラゼネカ,協和キリン,第一三共,田辺三菱製薬,鳥居薬品),研究費・助成金など(協和キリン),奨学(奨励)寄付など(中外製薬,協和キリン,小野薬品工業,バイエル薬品)[2022年]
監修:岡田浩一 : 講演料(アストラゼネカ,協和キリン,第一三共,田辺三菱製薬,鳥居薬品),研究費・助成金など(協和キリン),奨学(奨励)寄付など(中外製薬,協和キリン,小野薬品工業,バイエル薬品)[2022年]

改訂のポイント:
  1. 定期レビューを行い、内容をガイドラインに沿ってアップデートした。

病態・疫学・診察

疾患(疫学・病態)  
  1. 一次性膜性腎症とは、臨床的には、中高年で発症するネフローゼ症候群の中で、最も頻度が高い原疾患である。病理的には、糸球体上皮細胞の足突起下の標的抗原に対する抗体が免疫複合体を形成することにより、上皮細胞の機能障害を起こし、蛋白尿を発症させる疾患である。
  1. 膜性腎症の約8割はネフローゼ症候群を呈し、残りの2割は非ネフローゼレベルの蛋白尿を来す。近年、原因抗原としてM-type phospholipase A2 receptor(PLA2R)が発見され日本人発症例の約半数で同抗原への抗体が認められている。
  1. 一次性膜性腎症を含む一次性ネフローゼ症候群は、指定難病であり、一定の重症度基準を満たした場合などでは、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。(222 一次性ネフローゼ症候群 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. 蛋白尿・ネフローゼ症候群の緩徐な発症を確認する。

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文献 

Aki Kuroki, Masayuki Iyoda, Takanori Shibata, Tetsuzo Sugisaki
Th2 cytokines increase and stimulate B cells to produce IgG4 in idiopathic membranous nephropathy.
Kidney Int. 2005 Jul;68(1):302-10. doi: 10.1111/j.1523-1755.2005.00415.x.
Abstract/Text BACKGROUND: The predominant deposition of IgG4 in idiopathic membranous nephropathy indicates that its presence characterizes the systemic immune response of the disease.
METHODS: We analyzed the expressions of CD3, CD19, CD4, and CD8 on peripheral blood mononuclear cells (PBMCs) by flow cytometry, and the levels of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), interferon (IFN)-gamma, interleukin (IL)-4, IL-10, and IL-13 mRNAs in PBMCs using real-time reverse transcription-polymerase chain reaction (RT-PCR) in 14 patients with idiopathic membranous nephropathy and 14 normal control donors. The levels of IgG subclasses in the B-cell culture supernatant in the presence or absence of cytokines were quantified by enzyme-linked immunosorbent assay (ELISA).
RESULTS: Idiopathic membranous nephropathy patients showed an increased CD4(+)/CD8(+) ratio, although the numbers of peripheral T and B cells were comparable to those of the normal control group. IL-10 and IL-13 mRNA expression levels increased in the idiopathic membranous nephropathy group. The levels of spontaneous production of each IgG subclass by B cells were identical in the two groups. In the presence of Th2 cytokines, B cells from several individuals of the idiopathic membranous nephropathy group augmented the production of IgG4. When the individual levels of each IgG subclass in the presence of cytokines were compared with those in the absence of cytokines in each sample, a significant increase in the production of IgG4 in the presence of IL-4 was observed in the idiopathic membranous nephropathy group.
CONCLUSION: These results indicate that the altered functions of T cells to produce Th2 cytokines and the increased production of IgG4 by B cells in response to these cytokines characterize the immune response in idiopathic membranous nephropathy.

PMID 15954921
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
Membranous nephropathy in Japan: analysis of the Japan Renal Biopsy Registry (J-RBR).
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
Cai-Hong Zeng, Hui-mei Chen, Rui-Shi Wang, Yan Chen, Su-Hua Zhang, Li Liu, Lei-Shi Li, Zhi-Hong Liu
Etiology and clinical characteristics of membranous nephropathy in Chinese patients.
Am J Kidney Dis. 2008 Oct;52(4):691-8. doi: 10.1053/j.ajkd.2008.06.006.
Abstract/Text BACKGROUND: Membranous nephropathy (MN) is a common cause of proteinuria and can be subdivided into idiopathic and secondary classifications. Most patients with MN present with associated systemic diseases that need to be identified before appropriately diagnosing idiopathic MN. However, the cause and clinical characteristics of MN in Chinese patients have not been investigated.
STUDY DESIGN: Case series.
SETTING & PARTICIPANTS: Patients with biopsy-proven MN at the Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
OUTCOME: The diagnosis of idiopathic and secondary MN was based on clinical, initial laboratory, and histological findings.
RESULTS: 390 patients with MN were identified from 1985 to 2005. Of 390 patients with MN, 124 (31.8%) had idiopathic MN and 266 had secondary MN (68.2%). Of patients with idiopathic MN, 75 (60.5%) were men and 49 (39.5%) were women. Mean age was 43.9 +/- 13.2 years (range, 14 to 78 years). Common presentations of idiopathic MN were 60.5% with proteinuria (39.5% of whom presented with nephrotic syndrome), 29.8% with hypertension, 17.7% with hematuria, and 0.8% with decreased kidney function. In patients with secondary MN, causes were autoimmune diseases (73.3%), infections (17.7%), tumors (4.5%), and drugs or toxins (4.5%). Systemic lupus erythematosus was the most common autoimmune disease (predominately in younger women). Hepatitis B predominated in younger men. Greater levels of proteinuria were found in patients who presented with drugs or toxins compared with patients with other secondary MNs (P < 0.05).
LIMITATIONS: Not all patients underwent all tests, particularly serum tumor markers, hepatitis C virus antibody, and hepatitis C virus RNA tests.
CONCLUSION: Proteinuria was a common presentation in patients with idiopathic MN, which was predominately found in middle-aged to elderly men. Secondary MN was more common than idiopathic MN, and most secondary MN diagnoses were secondary to systemic lupus erythematosus and hepatitis B infection.

PMID 18805348
Bryce A Kerlin, Rose Ayoob, William E Smoyer
Epidemiology and pathophysiology of nephrotic syndrome-associated thromboembolic disease.
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
T J Rabelink, J J Zwaginga, H A Koomans, J J Sixma
Thrombosis and hemostasis in renal disease.
Kidney Int. 1994 Aug;46(2):287-96.
Abstract/Text
PMID 7967339
Misha Witz, Zeev Korzets
Renal vein occlusion: diagnosis and treatment.
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
M Ogi, H Yokoyama, N Tomosugi, Y Hisada, S Ohta, M Takaeda, T Wada, T Naito, K Ikeda, S Goshima
Risk factors for infection and immunoglobulin replacement therapy in adult nephrotic syndrome.
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
S C Cherng, W S Huang, Y F Wang, S P Yang, Y F Lin
The role of lung scintigraphy in the diagnosis of nephrotic syndrome with pulmonary embolism.
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
C Bazzi, C Petrini, V Rizza, G Arrigo, G D'Amico
A modern approach to selectivity of proteinuria and tubulointerstitial damage in nephrotic syndrome.
Kidney Int. 2000 Oct;58(4):1732-41. doi: 10.1046/j.1523-1755.2000.00334.x.
Abstract/Text BACKGROUND: The selectivity of proteinuria, introduced in clinical nephrology in 1960 and useful in predicting steroid responsiveness in nephrotic syndrome, found little place in clinical practice in subsequent decades, since its assessment did not appear to help predict histologic diagnosis or determine prognosis. The amount of proteinuria and the degree of tubulointerstitial damage appeared to be better predictors of functional outcome. A correlation between them has been found, referred to some toxicity of proteinuria on tubular cells, but so far no single feature or component of proteinuria has been identified as being responsible for this toxicity.
METHODS: We evaluated 89 patients with nephrotic syndrome [9 with minimal change disease (MCD), 29 with primary focal segmental glomerulosclerosis (FSGS), and 51 with idiopathic membranous glomerulonephritis (MGN)] to determine if the selectivity of proteinuria was associated with tubulointerstitial damage. A semiquantitative grading of histologic lesions and qualitative evaluation of the "tubular" component of proteinuria expressed as a pattern of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and as fractional excretion of the low molecular weight (LMW) protein alpha1-microglobulin (FE alpha1m) were used. A second aim of the study was to assess the predictive value on functional outcome [remission or progression to chronic renal failure (CRF)] and response to therapy of the selectivity of proteinuria, considered alone and in combination with FE alpha1m.
RESULTS: Proteinuria was classified as highly selective [selectivity index (SI) < or = 0.10, N = 15], moderately selective (SI > or = 0.11 < or = 0.20, N = 34), or nonselective (SI > or = 0.21, N = 40). A significant relationship was found between the SI and the histologic degree of tubulointerstitial damage (score 0 to 1 vs. score > or =2, P = 0.000), severity of the tubular component of proteinuria (mixed SDS-PAGE pattern with LMW proteins not lower than 23 kD vs. mixed pattern with LMW proteins up to 20 to 10 kD, P = 0.000), and FE alpha1m (values below vs. above a defined cut-off, P = 0.000). The functional outcome was evaluated in 60 patients with baseline normal renal function (serum creatinine 0.97 +/- 0.19 mg/dL). The patients with high, moderate, or nonselective proteinuria had 100, 50, and 29% of complete or partial remission (P = 0.0001) and 0, 25, and 35% of progression to CRF, respectively (P = 0.050). In 45 patients with moderately selective (N = 28) and nonselective (N = 17) proteinuria, according to some arbitrary cutoffs for FE alpha1m (MGN, < or = vs. > 0. 240% of creatinine clearance; FSGS and MCD, < or = vs. > 0.350%), the remission rate was 62 versus 6% in patients with FE alpha1m below or above the cutoffs (P = 0.0001), and progression to CRF was 7 and 69%, respectively (P = 0.0001). The response to therapy (complete or partial remission at the last observation), evaluated retrospectively in 40 patients, was 100, 67, and 33% in high, moderate, and nonselective proteinuria (P = 0.0002); in 30 patients with moderate and nonselective proteinuria, according to an FE alpha1m value that was < or = or > the cutoffs, the response rate was 75 versus 10% (P = 0.001).
CONCLUSIONS: There is a significant relationship between selectivity of proteinuria and tubulointerstitial damage. Moreover, the selectivity of proteinuria has a predictive value on functional outcome. When proteinuria is highly selective, the tubulointerstitial damage is rather infrequent, and 100% of patients develop clinical remission. When proteinuria is moderately selective or nonselective, increasing numbers of patients develop tubulointerstitial damage; in these patients, the functional outcome and response to therapy is partly dependent on tubulointerstitial involvement, and the best predictor of functional outcome is the combination of SI and FE alpha1m.

PMID 11012907
A Schieppati, L Mosconi, A Perna, G Mecca, T Bertani, S Garattini, G Remuzzi
Prognosis of untreated patients with idiopathic membranous nephropathy.
N Engl J Med. 1993 Jul 8;329(2):85-9. doi: 10.1056/NEJM199307083290203.
Abstract/Text BACKGROUND: Defining the most appropriate treatment for patients with idiopathic membranous nephropathy is a matter of controversy. The course of the disorder is often benign, and the immunosuppressive regimens used in some patients have uncertain benefits and substantial risks. We studied the natural history of idiopathic membranous nephropathy in patients who received only symptomatic therapy.
METHODS: We prospectively studied 100 consecutive patients (68 men and 32 women; mean [+/- SD] age, 51 +/- 17 years) with biopsy-proved idiopathic membranous nephropathy. The patients received diuretic or antihypertensive drugs as needed, but no glucocorticoid or immunosuppressive drugs. We examined the patients and measured their urinary protein excretion and serum creatinine concentrations every 6 months for a mean of 52 months.
RESULTS: Twenty-four (65 percent) of the 37 patients followed for at least five years had complete or partial remission of proteinuria; in 6 others (16 percent), end-stage renal disease developed, and they required dialysis. As calculated by the Kaplan-Meier method, the estimated probability (+/- the standard error of the estimate) of retaining adequate kidney function was 88 +/- 5 percent after five years and 73 +/- 7 percent after eight years. The prognosis was poorer in men and in patients over 50 years of age, but not in patients with the nephrotic syndrome, hypertension, or hypercholesterolemia.
CONCLUSIONS: Most untreated patients with idiopathic membranous nephropathy maintain renal function for prolonged periods and are likely to have spontaneous remission. These results do not support the use of glucocorticoids and immunosuppressive drugs in patients with idiopathic membranous nephropathy.

PMID 8510707
Hideo Shiiki, Takao Saito, Yoshiharu Nishitani, Tetsuya Mitarai, Noriaki Yorioka, Ashio Yoshimura, Hitoshi Yokoyama, Shinichi Nishi, Yasuhiko Tomino, Kiyoshi Kurokawa, Hideto Sakai, Research Group on Progressive Renal Diseases in Japan
Prognosis and risk factors for idiopathic membranous nephropathy with nephrotic syndrome in Japan.
Kidney Int. 2004 Apr;65(4):1400-7. doi: 10.1111/j.1523-1755.2004.00518.x.
Abstract/Text BACKGROUND: Idiopathic membranous nephropathy (IMN) is a representative form of refractory nephrotic syndrome in Japan. Although IMN is thought to run a more benign course in Japanese than in the Caucasian population, risk factors and appropriate treatment are controversial issues.
METHODS: The research group supported by a grant for "Progressive Renal Disease" from the Ministry of Health, Labor and Welfare, Japan, carried out a national survey of patients with IMN and nephrotic syndrome. Of 1066 nephrotic patients with histopathologically proven IMN registered from 1975 to 1993 in 85 institutions, 949 patients were studied.
RESULTS: The overall renal survival rates were 95.8%, 90.3%, 81.1%, and 60.5% at 5, 10, 15, and 20 years after diagnosis, respectively. When clinical and histopathologic features at onset of nephrotic syndrome were evaluated by multivariate analysis, male gender, old age (> or =60 years), high serum creatinine concentration (> or =1.5 mg/dL), and the development of tubulointerstitial lesions (> or =20% of the biopsy sample area) were significant predictors of progression to end-stage renal disease (ESRD). The renal survival rate in patients on steroid therapy was significantly higher than in patients on supportive therapy alone. Patients achieving a remission showed a significant reduction of risk for progression.
CONCLUSION: IMN is a disease with a comparatively good prognosis in Japan even when it is associated with nephrotic syndrome. Steroid therapy, which has not been recommended for IMN in most review articles, seems to be useful at least for Japanese patients. In particular, a remission from heavy proteinuria likely results in a favorable outcome.

PMID 15086481
H Kida, T Asamoto, H Yokoyama, N Tomosugi, N Hattori
Long-term prognosis of membranous nephropathy.
Clin Nephrol. 1986 Feb;25(2):64-9.
Abstract/Text One hundred and four consecutive patients with idiopathic membranous nephropathy have been followed for 24 years. The actuarial survival rates in 5, 10 and 15 years were 94.6, 90.0 and 80.3%, respectively. Within the first 5 years clinical status improved gradually, but thereafter entered into an equilibrated state, when approximately 70% of the patients were in remission of absent (40%) or less than 1.0 g/24 hour urinary protein. As for renal function, within the initial 5 years around 80% of the patients revealed a glomerular filtration rate (GFR) greater than 80 ml/min. This percentage reduced approximately to 70 and 50% over periods of 10 and 15 years, whereas a mean reduction rate of GFR was only 15 ml/min over a period of 8 years. The clinical status at the 5th year correlated well with its outcome (rs = 0.676, p less than 0.001) and GFR estimated around the 5th year with the final estimate (r = 0.796, p less than 0.001). These data suggest that membranous nephropathy follows a fairly good clinical course, and that the 5th year clinical status and renal function are valuable prognostic indices of the disease.

PMID 3698348
Vivekanand Jha, Anirban Ganguli, Tarun K Saha, Harbir S Kohli, Kamal Sud, Krishan L Gupta, Kusum Joshi, Vinay Sakhuja
A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy.
J Am Soc Nephrol. 2007 Jun;18(6):1899-904. doi: 10.1681/ASN.2007020166. Epub 2007 May 9.
Abstract/Text Idiopathic membranous nephropathy (IMN) is the most common cause of nephrotic syndrome in adults. Universal consensus regarding the need for and the modality of therapy has not been formed because of a lack of controlled trials of sufficient size, quality, and duration. This study compared the effect of a 6-mo course of alternating prednisolone and cyclophosphamide with supportive treatment in adults with nephrotic syndrome caused by IMN on doubling of serum creatinine, development of ESRD, and quality of life in a randomized, controlled trial. Patients were followed up for 10 yr. Data were analyzed on an intention-to-treat basis. A total of 93 patients completed the study. Of the 47 patients who received the experimental protocol, 34 achieved remission (15 complete and 19 partial), compared with 16 (five complete, 11 partial) of 46 in the control group (P < 0.0001). The 10-yr dialysis-free survival was 89 and 65% (P = 0.016), and the likelihood of survival without death, dialysis, and doubling of serum creatinine were 79 and 44% (P = 0.0006) in the two groups. Treated patients exhibited significantly lower prevalence of edema, hypertension, hypoalbuminemia, hyperlipidemia that required therapy, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use, and better quality of life on follow-up. The incidence of infections was similar in the two groups. In conclusion, untreated IMN with nephrotic syndrome is associated with a high risk for deterioration of renal function. A 6-mo regimen of cyclophosphamide and steroids induces remissions in a high proportion, arrests progression of renal insufficiency, and improves quality of life.

PMID 17494881
Ryohei Yamamoto, Enyu Imai, Shoichi Maruyama, Hitoshi Yokoyama, Hitoshi Sugiyama, Kosaku Nitta, Tatsuo Tsukamoto, Shunya Uchida, Asami Takeda, Toshinobu Sato, Takashi Wada, Hiroki Hayashi, Yasuhiro Akai, Megumu Fukunaga, Kazuhiko Tsuruya, Kosuke Masutani, Tsuneo Konta, Tatsuya Shoji, Takeyuki Hiramatsu, Shunsuke Goto, Hirofumi Tamai, Saori Nishio, Arimasa Shirasaki, Kojiro Nagai, Kunihiro Yamagata, Hajime Hasegawa, Hideo Yasuda, Shizunori Ichida, Tomohiko Naruse, Tomoya Nishino, Hiroshi Sobajima, Satoshi Tanaka, Toshiyuki Akahori, Takafumi Ito, Yoshio Terada, Ritsuko Katafuchi, Shouichi Fujimoto, Hirokazu Okada, Eiji Ishimura, Junichiro J Kazama, Keiju Hiromura, Tetsushi Mimura, Satoshi Suzuki, Yosuke Saka, Tadashi Sofue, Yusuke Suzuki, Yugo Shibagaki, Kiyoki Kitagawa, Kunio Morozumi, Yoshiro Fujita, Makoto Mizutani, Takashi Shigematsu, Naoki Kashihara, Hiroshi Sato, Seiichi Matsuo, Ichiei Narita, Yoshitaka Isaka
Incidence of remission and relapse of proteinuria, end-stage kidney disease, mortality, and major outcomes in primary nephrotic syndrome: the Japan Nephrotic Syndrome Cohort Study (JNSCS).
Clin Exp Nephrol. 2020 Jun;24(6):526-540. doi: 10.1007/s10157-020-01864-1. Epub 2020 Mar 7.
Abstract/Text BACKGROUND: Despite recent advances in immunosuppressive therapy for patients with primary nephrotic syndrome, its effectiveness and safety have not been fully studied in recent nationwide real-world clinical data in Japan.
METHODS: A 5-year cohort study, the Japan Nephrotic Syndrome Cohort Study, enrolled 374 patients with primary nephrotic syndrome in 55 hospitals in Japan, including 155, 148, 38, and 33 patients with minimal change disease (MCD), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), and other glomerulonephritides, respectively. The incidence rates of remission and relapse of proteinuria, 50% and 100% increases in serum creatinine, end-stage kidney disease (ESKD), all-cause mortality, and other major adverse outcomes were compared among glomerulonephritides using the Log-rank test. Incidence of hospitalization for infection, the most common cause of mortality, was compared using a multivariable-adjusted Cox proportional hazard model.
RESULTS: Immunosuppressive therapy was administered in 339 (90.6%) patients. The cumulative probabilities of complete remission within 3 years of the baseline visit was ≥ 0.75 in patients with MCD, MN, and FSGS (0.95, 0.77, and 0.79, respectively). Diabetes was the most common adverse events associated with immunosuppressive therapy (incidence rate, 71.0 per 1000 person-years). All-cause mortality (15.6 per 1000 person-years), mainly infection-related mortality (47.8%), was more common than ESKD (8.9 per 1000 person-years), especially in patients with MCD and MN. MCD was significantly associated with hospitalization for infection than MN.
CONCLUSIONS: Patients with MCD and MN had a higher mortality, especially infection-related mortality, than ESKD. Nephrologists should pay more attention to infections in patients with primary nephrotic syndrome.

PMID 32146646
Daniel Cattran
Management of membranous nephropathy: when and what for treatment.
J Am Soc Nephrol. 2005 May;16(5):1188-94. doi: 10.1681/ASN.2005010028. Epub 2005 Mar 30.
Abstract/Text
PMID 15800117
D C Cattran, G B Appel, L A Hebert, L G Hunsicker, M A Pohl, W E Hoy, D R Maxwell, C L Kunis
A randomized trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis. North America Nephrotic Syndrome Study Group.
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
Meryl Waldman, Howard A Austin
Controversies in the treatment of idiopathic membranous nephropathy.
Nat Rev Nephrol. 2009 Aug;5(8):469-79. doi: 10.1038/nrneph.2009.101. Epub 2009 Jul 7.
Abstract/Text Optimum treatment of idiopathic membranous nephropathy is both controversial and challenging. The most extensively studied and frequently used immunosuppressive regimens for this disease comprise alkylating agents plus corticosteroids or ciclosporin. All of these treatment options have inherent problems: they are not effective in all patients, partial-rather than complete-remissions are common, adverse effects are worrisome, and relapses after treatment cessation remain problematic. Alternative immunosuppressive agents have been tested in an effort to overcome these unresolved issues. This paper reviews the available evidence regarding both established and new agents for the treatment of patients with idiopathic membranous nephropathy, with an emphasis on the results of the most recent clinical trials.

PMID 19581908
Nosratola D Vaziri
Molecular mechanisms of lipid disorders in nephrotic syndrome.
Kidney Int. 2003 May;63(5):1964-76. doi: 10.1046/j.1523-1755.2003.00941.x.
Abstract/Text
PMID 12675893
Stéphan Troyanov, Catherine A Wall, Judith A Miller, James W Scholey, Daniel C Cattran, Toronto Glomerulonephritis Registry Group
Idiopathic membranous nephropathy: definition and relevance of a partial remission.
Kidney Int. 2004 Sep;66(3):1199-205. doi: 10.1111/j.1523-1755.2004.00873.x.
Abstract/Text BACKGROUND: Membranous nephropathy (MGN) remains the most common cause of adult onset nephrotic syndrome, and within the primary glomerulonephritis group is a leading cause of renal failure. A complete remission (CR) confers an excellent long-term prognosis, but the quantitative benefits of partial remissions (PR) have not been defined.
METHODS: This study evaluated the rate of renal function decline (slope), relapse, and renal survival in nephrotic MGN patients with CR, PR, or no remission (NR). Multivariate analysis included clinical and laboratory data at presentation and over follow-up, blood pressure control and agents employed, and immunosuppressive therapy.
RESULTS: The study cohort consisted of 348 nephrotic MGN patients with a minimum of 12 months follow-up identified from the Toronto Glomerulonephritis Registry. Over a median follow-up of 60 months, 102 experienced a CR, 136 had a PR, and 110 had no remission. A PR was independently predictive of slope and survival from renal failure by multivariate analysis (hazard ratio 0.08, 95% CI 0.03-0.19, P < 0.001). Benefit from immunosuppression could only be shown in a subset of high-risk patients. Treatment-related PR had the same long-term implication as spontaneous ones. Relapses from PR were high (47%) but often reversible.
CONCLUSION: A partial remission is an important therapeutic target with implications for both progression rate and renal survival.

PMID 15327418
Natalia Polanco, Elena Gutiérrez, Adelardo Covarsí, Francisco Ariza, Agustín Carreño, Ana Vigil, José Baltar, Gema Fernández-Fresnedo, Carmen Martín, Salvador Pons, Dolores Lorenzo, Carmen Bernis, Pilar Arrizabalaga, Gema Fernández-Juárez, Vicente Barrio, Milagros Sierra, Ines Castellanos, Mario Espinosa, Francisco Rivera, Aniana Oliet, Francisco Fernández-Vega, Manuel Praga, Grupo de Estudio de las Enfermedades Glomerulares de la Sociedad Española de Nefrología
Spontaneous remission of nephrotic syndrome in idiopathic membranous nephropathy.
J Am Soc Nephrol. 2010 Apr;21(4):697-704. doi: 10.1681/ASN.2009080861. Epub 2010 Jan 28.
Abstract/Text Spontaneous remission is a well known characteristic of idiopathic membranous nephropathy, but contemporary studies describing predictors of remission and long-term outcomes are lacking. We conducted a retrospective, multicenter cohort study of 328 patients with nephrotic syndrome resulting from idiopathic membranous nephropathy that initially received conservative therapy. Spontaneous remission occurred in 104 (32%) patients: proteinuria progressively declined after diagnosis until remission of disease at 14.7 +/- 11.4 months. Although spontaneous remission was more frequent with lower levels of baseline proteinuria, it also frequently occurred in patients with massive proteinuria: 26% among those with baseline proteinuria 8 to 12 g/24 h and 22% among those with proteinuria >12 g/24 h. Baseline serum creatinine and proteinuria, treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists, and a >50% decline of proteinuria from baseline during the first year of follow-up were significant independent predictors for spontaneous remission. Only six patients (5.7%) experienced a relapse of nephrotic syndrome. The incidence of death and ESRD were significantly lower among patients with spontaneous remission. In conclusion, spontaneous remission is common among patients with nephrotic syndrome resulting from membranous nephropathy and carries a favorable long-term outcome with a low incidence of relapse. A decrease in proteinuria >50% from baseline during the first year predicts spontaneous remission.

PMID 20110379
A Schieppati, A Perna, J Zamora, G A Giuliano, N Braun, G Remuzzi
Immunosuppressive treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome.
Cochrane Database Syst Rev. 2004 Oct 18;(4):CD004293. doi: 10.1002/14651858.CD004293.pub2. Epub 2004 Oct 18.
Abstract/Text BACKGROUND: Idiopathic membranous nephropathy (IMN) is the most common form of nephrotic syndrome in adults. The disease shows a benign or indolent course in the majority of patients, with a rate of spontaneous complete or partial remission of nephrotic syndrome as high as 30% or more. Despite this, 30-40% of patients progress toward end-stage renal failure (ESRF) within 5-15 years.
OBJECTIVES: To assess the benefits and harms of immunosuppressive treatment for IMN in adults.
SEARCH STRATEGY: We searched the Cochrane Renal Group Specialised Register (December 2003), The Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library Issue 4, 2003), MEDLINE and Pre-MEDLINE (1966 - December 2003), EMBASE (1980 - December 2003), reference lists of nephrology textbooks, review articles, prospective trial registers, relevant trials and abstracts from nephrology scientific meetings and the internet without language restriction. We also contacted principal investigators of controlled studies.
SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing any immunosuppressive interventions for the treatment of IMN in adults.
DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed and extracted information. Information was collected on method, participants, interventions and outcomes (death, ESRF, proteinuria, serum creatinine, GRF, remission, adverse events).
MAIN RESULTS: A total of 18 trials with 1025 patients were included. No differences were found when we combined data of all treatment categories as a group and compared them with placebo or no treatment. Oral glucocorticoids. No beneficial effect on any of the end points chosen for efficacy was observed. Alkylating agents showed a significant beneficial effect on complete remission (RR 2.37, 95%CI 1.32 to 4.25, P = 0.004) but not on partial remission (RR 1.22, 95%CI 0.63 to 2.35, P = 0.56) or complete or partial remission (RR 1.55, 95%CI 0.72 to 3.34, P = 0.27). Cyclophosphamide treatment resulted in significantly lower rate of discontinuations due to adverse events as compared to chlorambucil (RR 2.34, 95%CI 1.25 to 4.39, P = 0.008). There was no evidence of clinically relevant differences in favour of cyclosporin and there was insufficient data on anti-proliferative agents.
REVIEWERS' CONCLUSIONS: This review failed to show any long-term effect of immunosuppressive treatment on patient and/or renal survival. There was an increased number of discontinuations due to adverse events in immunosuppressive treatment groups. Within the class of alkylating agents there is weak evidence supporting the efficacy of cyclophosphamide as compared to chlorambucil. On the other hand, cyclophosphamide had fewer side effects leading to patient withdrawal than chlorambucil.

PMID 15495098
Yizhi Chen, Arrigo Schieppati, Guangyan Cai, Xiangmei Chen, Javier Zamora, Giovanni A Giuliano, Norbert Braun, Annalisa Perna
Immunosuppression for membranous nephropathy: a systematic review and meta-analysis of 36 clinical trials.
Clin J Am Soc Nephrol. 2013 May;8(5):787-96. doi: 10.2215/CJN.07570712. Epub 2013 Feb 28.
Abstract/Text BACKGROUND AND OBJECTIVES: The efficacy and safety of immunosuppression for idiopathic membranous nephropathy (IMN) with nephrotic syndrome are still controversial. A systematic review and meta-analysis of randomized controlled trials (RCTs) was performed.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Cochrane Library, PUBMED, EMBASE, Chinese Database, and Clinical Trial Registries (June 2012) were searched to identify RCTs investigating the effect of immunosuppression on adults with IMN and nephrotic syndrome.
RESULTS: This review was an update (36 RCTs, 1762 participants) of the 2004 version (18 RCTs, 1025 participants). Immunosuppression significantly reduced all-cause mortality or ESRD (15 RCTs, 791 participants; risk ratio, 0.58 [95% confidence interval, 0.36-0.95]; P=0.03). However, the result was not consistent when prespecified subgroup analyses were undertaken. Immunosuppression increased complete or partial remission (CR + PR) (16 RCTs, 864 participants; 1.31 [1.01-1.70]; P=0.04) but resulted in more withdrawals or hospitalizations (16 RCTs, 880 participants; 5.35 [2.19-13.02]; P=0.002). Corticosteroids combined with alkylating agents significantly reduced all-cause mortality or ESRD (8 RCTs, 448 participants; 0.44 [0.26-0.75]; P=0.002) and increased CR + PR (7 RCTs, 422 participants; 1.46 [1.13-1.89]; P=0.004) but led to more adverse events (4 RCTs, 303 participants; 4.20 [1.15-15.32]; P=0.03). Cyclophosphamide was safer than chlorambucil (3 RCTs, 147 participants; 0.48 [0.26-0.90]; P=0.02). Cyclosporine and mycophenolate mofetil failed to show superiority over alkylating agents. Tacrolimus and adrenocorticotropic hormone significantly reduced proteinuria.
CONCLUSIONS: Alkylating agents plus corticosteroids had long-term and short-term benefits for adult IMN, but resulted in more withdrawals or hospitalizations.

PMID 23449768
Andrew Howman, Tracey L Chapman, Maria M Langdon, Caroline Ferguson, Dwomoa Adu, John Feehally, Gillian J Gaskin, David R W Jayne, Donal O'Donoghue, Michael Boulton-Jones, Peter W Mathieson
Immunosuppression for progressive membranous nephropathy: a UK randomised controlled trial.
Lancet. 2013 Mar 2;381(9868):744-51. doi: 10.1016/S0140-6736(12)61566-9. Epub 2013 Jan 9.
Abstract/Text BACKGROUND: Membranous nephropathy leads to end-stage renal disease in more than 20% of patients. Although immunosuppressive therapy benefits some patients, trial evidence for the subset of patients with declining renal function is not available. We aimed to assess whether immunosuppression preserves renal function in patients with idiopathic membranous nephropathy with declining renal function.
METHODS: This randomised controlled trial was undertaken in 37 renal units across the UK. We recruited patients (18-75 years) with biopsy-proven idiopathic membranous nephropathy, a plasma creatinine concentration of less than 300 μmol/L, and at least a 20% decline in excretory renal function measured in the 2 years before study entry, based on at least three measurements over a period of 3 months or longer. Patients were randomly assigned (1:1:1) by a random number table to receive supportive treatment only, supportive treatment plus 6 months of alternating cycles of prednisolone and chlorambucil, or supportive treatment plus 12 months of ciclosporin. The primary outcome was a further 20% decline in renal function from baseline, analysed by intention to treat. The trial is registered as an International Standard Randomised Controlled Trial, number 99959692.
FINDINGS: We randomly assigned 108 patients, 33 of whom received prednisolone and chlorambucil, 37 ciclosporin, and 38 supportive therapy alone. Two patients (one who received ciclosporin and one who received supportive therapy) were ineligible, so were not included in the intention-to-treat analysis, and 45 patients deviated from protocol before study end, mostly as a result of minor dose adjustments. Follow up was until primary endpoint or for minimum of 3 years if primary endpoint was not reached. Risk of further 20% decline in renal function was significantly lower in the prednisolone and chlorambucil group than in the supportive care group (19 [58%] of 33 patients reached endpoint vs 31 [84%] of 37, hazard ratio [HR] 0·44 [95% CI 0·24-0·78]; p=0·0042); risk did not differ between the ciclosporin (29 [81%] of 36) and supportive treatment only groups (HR 1·17 [0·70-1·95]; p=0·54), but did differ significantly across all three groups (p=0·003). Serious adverse events were frequent in all three groups but were higher in the prednisolone and chlorambucil group than in the supportive care only group (56 events vs 24 events; p=0·048).
INTERPRETATION: For the subset of patients with idiopathic membranous nephropathy and deteriorating excretory renal function, 6 months' therapy with prednisolone and chlorambucil is the treatment approach best supported by our evidence. Ciclosporin should be avoided in this subset.
FUNDING: Medical Research Council, Novartis, Renal Association, Kidney Research UK.

Copyright © 2013 Elsevier Ltd. All rights reserved.
PMID 23312808
Radomir Naumovic, Dijana Jovanovic, Stevan Pavlovic, Milan Stosovic, Jelena Marinkovic, Gordana Basta-Jovanovic
Cyclosporine versus azathioprine therapy in high-risk idiopathic membranous nephropathy patients: A 3-year prospective study.
Biomed Pharmacother. 2011 Mar;65(2):105-10. doi: 10.1016/j.biopha.2010.10.009. Epub 2010 Nov 5.
Abstract/Text There is no consensus regarding the modality of therapy for idiopathic membranous nephropathy (IMN), especially for patients who did not react to treatment with cytotoxic drugs. This study followed prospectively for 3-year IMN patients who did not react to Ponticelli protocol comparing effects of 2-year course of cyclosporine (CsA) with azathioprine (Aza) treatment both with small doses of prednisolone. Twenty-three patients were randomly assigned to receive either cyclosporine at 3mg/kg per day (10 patients) or azathioprine at 1.5 to 2mg/kg (13 patients). Both groups were comparable regarding age, sex and renal function, except for proteinuria, which was significantly greater in CsA group (P=0.003). Similar rate of remission of nephrotic syndrome (NS) have been noted at the end of treatment (80% CsA versus 93% Aza). During last year, follow-up relapses of NS were more frequent in Aza group (5 versus 1). A fall in proteinuria was recorded in both groups during treatment, but it rose significantly in Aza group (1.5g/day versus 3.1g/day, P=0.04) and remained unchanged in CsA group (3.9g/day versus 4.1g/day) after treatment cessation. Renal function deteriorated in Aza group (sCr 120.5 versus 269.8μmol/L; P<0.01) and was stable in CsA group. In conclusion, CsA and steroids may be a very important option in the management of high-risk IMN patients. Long-term treatment is necessary for achievement of full therapeutic effect. Treatment with Aza did not have long-term benefits particularly regarding renal function preservation.

Copyright © 2010 Elsevier Masson SAS. All rights reserved.
PMID 21109389
Efstathios Alexopoulos, Aikaterini Papagianni, Mzia Tsamelashvili, Maria Leontsini, Dimitrios Memmos
Induction and long-term treatment with cyclosporine in membranous nephropathy with the nephrotic syndrome.
Nephrol Dial Transplant. 2006 Nov;21(11):3127-32. doi: 10.1093/ndt/gfl360. Epub 2006 Sep 12.
Abstract/Text BACKGROUND: Cyclosporine A (CyA) has been shown to be effective in membranous nephropathy (MN). However, the optimal dose and the duration of treatment remain controversial issues. We evaluated the efficacy of low-dose CyA alone or combined with corticosteroids as induction and long-term treatment for nephrotic patients with MN.
METHODS: In the first part of the study, 51 nephrotic patients with MN were treated either with CyA and prednisolone (n=31) or CyA alone (n=20) for 12 months. Patients who responded with complete remission (CR) or partial remission (PR) were placed on long-term treatment with lower doses of CyA and prednisolone or CyA alone. The mean follow-up of the second part of the study was 26+/-16 months and 18+/-7 months, respectively.
RESULTS: After 12 months of treatment, 26 patients in the combination group and 17 patients in the monotherapy group had a CR or PR of proteinuria (P=NS). Renal function was unchanged in the two groups. During long-term treatment relapses were more frequent in the monotherapy group (47 vs 15%, P<0.05). Daily CyA dose was higher in non-relapsers in both groups (combination 1.4+/-0.5 vs 1.0+/-0.3 mg/kg, P<0.001, monotherapy 1.5+/-0.4 vs 1.1+/-0.2 mg/kg, P<0.003). Relapsers in both groups had lower CyA trough levels (72+/-48 ng/ml) compared with non-relapsers (194+/-80 ng/ml) (P<0.03). Renal function and proteinuria remained stable during the follow-up.
CONCLUSION: This study suggests that 12-month therapy with CyA (+/-prednisolone) is effective in inducing remission in most nephrotic patients with MN and well-preserved renal function. Longer treatment with lower doses is a useful approach to maintain remission. Relapses occur more frequently in the monotherapy group and usually are associated with CyA trough levels<100 ng/ml.

PMID 16968719
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
Cyclosporin in idiopathic glomerular disease associated with the nephrotic syndrome : workshop recommendations.
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
Takao Saito, Masayuki Iwano, Koichi Matsumoto, Tetsuya Mitarai, Hitoshi Yokoyama, Noriaki Yorioka, Shinichi Nishi, Ashio Yoshimura, Hiroshi Sato, Satoru Ogahara, Hideki Shuto, Yasufumi Kataoka, Shiro Ueda, Akio Koyama, Shoichi Maruyama, Masaomi Nangaku, Enyu Imai, Seiichi Matsuo, Yasuhiko Tomino, Refractory Nephrotic Syndrome Study Group
Significance of combined cyclosporine-prednisolone therapy and cyclosporine blood concentration monitoring for idiopathic membranous nephropathy with steroid-resistant nephrotic syndrome: a randomized controlled multicenter trial.
Clin Exp Nephrol. 2014 Oct;18(5):784-94. doi: 10.1007/s10157-013-0925-2. Epub 2013 Dec 23.
Abstract/Text BACKGROUND: Combined treatment with cyclosporine microemulsion preconcentrate (CyA MEPC) and steroids has been widely used for idiopathic membranous nephropathy (IMN) associated with steroid-resistant nephrotic syndrome (SRNS). Recent studies have shown that once-a-day and preprandial administration of CyA MEPC is more advantageous than the conventional twice-a-day administration in achieving the target blood CyA concentration at 2 h post dose (C2). We designed a randomized trial to compare these administrations.
METHODS: IMN patients with SRNS (age 16-75 years) were divided prospectively and randomly into 2 groups. In group 1 (n = 23), 2-3 mg/kg body weight (BW) CyA MEPC was given orally once a day before breakfast. In group 2 (n = 25), 1.5 mg/kg BW CyA MEPC was given twice a day before meals. CyA + prednisolone was continued for 48 weeks.
RESULTS: Group 1 showed a significantly higher cumulative complete remission (CR) rate (p = 0.0282), but not when incomplete remission 1 (ICR1; urine protein 0.3-1.0 g/day) was added (p = 0.314). Because a C2 of 600 ng/mL was determined as the best cut-off point, groups 1 and 2 were further divided into subgroups A (C2 ≥600 ng/mL) and B (C2 <600 ng/mL). Groups 1A and 2A revealed significantly higher cumulative remission (CR + ICR1) (p = 0.0069) and CR-alone (p = 0.0028) rates. On the other hand, 3 patients with high CyA levels (C2 >900 ng/mL) in Group 1A were withdrawn from the study because of complications.
CONCLUSION: CyA + prednisolone treatment is effective for IMN with associated SRNS at a C2 of ≥600 ng/mL. To achieve remission, preprandial once-a-day administration of CyA at 2-3 mg/kg BW may be the most appropriate option. However, we should adjust the dosage of CyA by therapeutic drug monitoring to avoid complications.

PMID 24363128
C Ponticelli, P Altieri, F Scolari, P Passerini, D Roccatello, B Cesana, P Melis, B Valzorio, M Sasdelli, S Pasquali, C Pozzi, G Piccoli, A Lupo, S Segagni, F Antonucci, M Dugo, M Minari, A Scalia, L Pedrini, G Pisano, C Grassi, M Farina, R Bellazzi
A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy.
J Am Soc Nephrol. 1998 Mar;9(3):444-50.
Abstract/Text To assess whether chlorambucil or cyclophosphamide may have a better therapeutic index in patients with idiopathic membranous nephropathy, we compared two regimens based on a 6-mo treatment, alternating every other month methylprednisolone with chlorambucil or methylprednisolone with cyclophosphamide. Patients with biopsy-proven membranous nephropathy and with a nephrotic syndrome were randomized to be given methylprednisolone (1 g intravenously for 3 consecutive days followed by oral methylprednisolone, 0.4 mg/kg per d for 27 d) alternated every other month either with chlorambucil (0.2 mg/kg per d for 30 d) or cyclophosphamide (2.5 mg/kg per d for 30 d). The whole treatment lasted 6 mo; 3 mo with corticosteroids and 3 mo with one cytotoxic drug. Among 87 patients followed for at least 1 yr, 36 of 44 (82%; 95% confidence interval [CI], 67.3 to 91.8%) assigned to methylprednisolone and chlorambucil entered complete or partial remission of the nephrotic syndrome, versus 40 of 43 (93%; 95% CI, 80.9 to 98.5%) assigned to methylprednisolone and cyclophosphamide (P = 0.116). Of patients who attained remission of the nephrotic syndrome, 11 of 36 in the chlorambucil group (30.5%) and 10 of 40 in the cyclophosphamide group (25%) had a relapse of the nephrotic syndrome between 6 and 30 mo. The reciprocal of plasma creatinine improved in the cohort groups followed for 1 yr for both treatment groups (P < 0.01) and remained unchanged when compared with basal values in the cohort groups followed for 2 and 3 yr. Six patients in the chlorambucil group and two in the cyclophosphamide group did not complete the treatment because of side effects. Four patients in the chlorambucil group but none in the cyclophosphamide group suffered from herpes zoster. One patient per group developed cancer. It is concluded that in nephrotic patients with idiopathic membranous nephropathy both treatments may be effective in favoring remission and in preserving renal function for at least 3 yr.

PMID 9513907
Andrew C Currie, Simon R Knight, Peter J Morris
Tuberculosis in renal transplant recipients: the evidence for prophylaxis.
Transplantation. 2010 Oct 15;90(7):695-704. doi: 10.1097/TP.0b013e3181ecea8d.
Abstract/Text BACKGROUND: Tuberculosis (TB) remains a leading cause of death in endemic countries and is 20 to 70 times more common in renal transplant recipients, where it contributes to both increased morbidity and mortality. This review will focus on the epidemiology of TB in renal transplant recipients and critically appraise the published literature on isoniazid prophylaxis in renal transplantation.
METHODS: A literature search for randomized and nonrandomized studies investigating the use of isoniazid prophylaxis in renal transplant recipients was conducted using Ovid MEDLINE, the Cochrane Library, the Transplant Library, and EMBASE. Relative risks (RRs) with 95% confidence intervals (CIs) are reported. Meta-analysis of the randomized controlled trials (RCTs) was performed with a fixed-effects model.
RESULTS: Eleven relevant studies were identified; six nonrandomized and five RCTs. The nonrandomized studies indicate a reduced risk of TB with isoniazid prophylaxis. The RCTs demonstrated conflicting results, with two studies finding a reduction in TB with prophylaxis and two studies finding no difference. Meta-analysis of the 709 patients from the four RCTs demonstrated a reduced risk of TB with isoniazid prophylaxis (RR, 0.31; 95% CI, 0.19-0.51). No significant difference was found in the incidence of hepatitis (RR, 1.22; 95% CI, 0.91-1.65).
CONCLUSION: Both randomized and nonrandomized studies support the value of isoniazid as TB prophylaxis in renal transplant recipients at risk of active infection. Clinicians should consider prophylaxis in renal transplant recipients in endemic areas or in recipients in nonendemic countries who are at risk. However, the evidence for the benefit of isoniazid prophylaxis in renal transplantation is not robust and there is still a need for a large multicenter trial of isoniazid prophylaxis in kidney transplantation in an endemic area.

PMID 20647975
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
Significantly rapid relief from steroid-resistant nephrotic syndrome by LDL apheresis compared with steroid monotherapy.
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
E Muso, M Mune, N Yorioka, Y Nishizawa, T Hirano, M Hattori, S Sugiyama, T Watanabe, K Kimura, H Yokoyama, H Sato, T Saito
Beneficial effect of low-density lipoprotein apheresis (LDL-A) on refractory nephrotic syndrome (NS) due to focal glomerulosclerosis (FGS).
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
Motoshi Hattori, Hiroko Chikamoto, Yuko Akioka, Hyogo Nakakura, Daisuke Ogino, Akira Matsunaga, Akira Fukazawa, Sanpei Miyakawa, Miyuki Khono, Hiroshi Kawaguchi, Katsumi Ito
A combined low-density lipoprotein apheresis and prednisone therapy for steroid-resistant primary focal segmental glomerulosclerosis in children.
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
Sophia Lionaki, Vimal K Derebail, Susan L Hogan, Sean Barbour, Taewoo Lee, Michelle Hladunewich, Allen Greenwald, Yichun Hu, Caroline E Jennette, J Charles Jennette, Ronald J Falk, Daniel C Cattran, Patrick H Nachman, Heather N Reich
Venous thromboembolism in patients with membranous nephropathy.
Clin J Am Soc Nephrol. 2012 Jan;7(1):43-51. doi: 10.2215/CJN.04250511. Epub 2011 Nov 10.
Abstract/Text BACKGROUND AND OBJECTIVES: The aims of this study were to determine the frequency of venous thromboembolic events in a large cohort of patients with idiopathic membranous nephropathy and to identify predisposing risk factors.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We studied patients with biopsy-proven membranous nephropathy from the Glomerular Disease Collaborative Network (n=412) and the Toronto Glomerulonephritis Registry (n=486) inception cohorts. The cohorts were pooled after establishing similar baseline characteristics (total n=898). Clinically apparent and radiologically confirmed venous thromboembolic events were identified. Potential risk factors were evaluated using multivariable logistic regression models.
RESULTS: Sixty-five (7.2%) subjects had at least one venous thromboembolic event, and this rate did not differ significantly between registries. Most venous thromboembolic events occurred within 2 years of first clinical assessment (median time to VTE = 3.8 months). After adjusting for age, sex, proteinuria, and immunosuppressive therapy, hypoalbuminemia at diagnosis was the only independent predictor of a venous thromboembolic event. Each 1.0 g/dl reduction in serum albumin was associated with a 2.13-fold increased risk of VTE. An albumin level <2.8 g/dl was the threshold below which risk for a venous thromboembolic event was greatest.
CONCLUSIONS: We conclude that clinically apparent venous thromboembolic events occur in about 7% of patients with membranous nephropathy. Hypoalbuminemia, particularly <2.8 g/dl, is the most significant independent predictor of venous thrombotic risk.

PMID 22076873
F P Sarasin, J A Schifferli
Prophylactic oral anticoagulation in nephrotic patients with idiopathic membranous nephropathy.
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
Abstract/Text Of 17 patients with idiopathic membranous nephropathy (IMN) and nephrotic syndrome, 9 were allocated to treatment with simvastatin (an HMG CoA-reductase inhibitor) and low cholesterol diet, and 8 to diet alone. At entry, the treatment and control groups did not differ in mean serum creatinines, chromium-labelled EDTA clearances, urinary protein/creatinine ratios, serum albumins, and lipid profiles. The mean follow up period (+/- SEM) in the treated group was 19.3 (+/- 4.4) months compared with 16.6 (+/- 5.9) months in the control group. At the end of the trial the fall in chromium-labelled EDTA clearances was similar (-1.27 versus -1.28 mls/min/months/1.73 m2) in the treatment and control groups respectively. The mean (+/- SEM) total and LDL-cholesterol had gone from 10.5 (+/- 0.94) and 8.02 (+/- 1) mmol/l to 5.2 (+/- 0.49) and 3.47 (+/- 0.44) respectively in the treated patients. Additionally the mean (+/- SEM) albumin and urinary protein/creatinine ratio went from 25.6 (+/- 2.4) gm/l and 0.52 (+/- 0.09) gm/mmol to 45.5 (+/- 2.8) and 0.13 (+/- 0.04) respectively. There was little change in total and LDL-cholesterol; albumin and urinary protein/creatinine ratio in the control group. This study supports the observation that lowering serum cholesterol in the nephrotic syndrome reduces proteinuria and increases serum albumin levels. No difference in the rate of decline in renal function could be demonstrated.

PMID 8905205
G Fuiano, C Esposito, V Sepe, G Colucci, M Bovino, M Rosa, M Balletta, G Bellinghieri, G Conte, B Cianciaruso, A Dal Canton
Effects of hypercholesterolemia of renal hemodynamics: study in patients with nephrotic syndrome.
Nephron. 1996;73(3):430-5.
Abstract/Text Experimental and clinical studies have demonstrated a positive relationship between hyperlipidemia and rate of progression of renal disease, suggesting that lipids can induce or aggravate glomerular injury mainly by interacting with mesangial cells. Nevertheless, recently has been demonstrated that increased cholesterol levels can also induce endothelial cell dysfunction. Thus, since endothelium is known to play a major role in modulating the vascular tone, we have tested the possibility that hypercholesterolemia impairs the renal hemodynamics in patients with active nephrotic syndrome and elevated serum cholesterol levels. In this single-blind, nonrandom study, 12 patients were treated with pravastatin (group T, treated, n = 12) and 8 with placebo (group C, controls, n = 8). The controls were studied after the pravastatin group had been completed. Before starting the treatment the patients underwent basal determinations including routine laboratory investigations and PAH and inulin clearances. The same determinations were repeated after 48 h, and 6 and 12 weeks from the beginning of the treatment. The study at 48 h was performed to see if pravastatin had a direct, cholesterol-independent effect on renal function. The following basal results were reported (mean +/- SEM; group T vs. group C): serum cholesterol (mmol/l) 9.7 +/- 0.4 vs. 9.1 +/- 0.3 (NS); proteinuria (g/24 h): 6.2 +/- 0.2 vs. 7.0 +/- 0.7 (NS); PAH clearance (ml/min): 353 +/- 21 vs. 385 +/- 31 (NS); inulin clearance (ml/min): 62.5 +/- 7.7 vs. 67 +/- 9.3 (NS). After 48 h, no changes were observed in both groups. Subsequently, in group T, the following percentage changes of basal levels were observed: serum cholesterol -21.4 +/- 3.2% at 6 weeks (p < 0.05) and -34.9 +/- 3.2% at 12 weeks (p < 0.01); inulin clearance +3 +/- 3.7% at 6 weeks (NS) and +9.3 +/- 2.9% at 12 weeks (p < 0.05); PAH clearance +7 +/- 3.1% at 6 weeks (p < 0.05) and +21.2 +/- 5.5% at 12 weeks (p < 0.01). By contrast, no significant changes of these parameters occurred in group C at any time, so that the percent changes of baseline values of CPAH were significantly greater in group T (at 6 weeks: p < 0.05; at 12 weeks p < 0.005). These results indicate that the reduction of cholesterol is associated with a significant increase in renal plasma flow, thus, suggesting that hypercholesterolemia may actually impair the renal hemodynamics. We speculate that this effect may contribute to increase the risk of ischemic acute renal failure in nephrotic patients and, along with changes induced in the mesangium by other mechanisms, to contribute to the progression of renal disease.

PMID 8832603
Hong Mei Wu, Jin-Ling Tang, Li Cao, Zhao Hui Sha, Youping Li
Interventions for preventing infection in nephrotic syndrome.
Cochrane Database Syst Rev. 2012 Apr 18;4:CD003964. doi: 10.1002/14651858.CD003964.pub3. Epub 2012 Apr 18.
Abstract/Text BACKGROUND: Infection is one of the most common complications and still remains a significant cause of morbidity and occasionally mortality in patients, especially children with nephrotic syndrome. Many different prophylactic interventions have been used or recommended for reducing the risks of infection in nephrotic syndrome in clinical practice. Whether the existing evidence is scientifically rigorous and which prophylactic intervention can be recommended for routine use based on the current evidence is still unknown.
OBJECTIVES: To assess the benefits and harms of any prophylactic intervention for reducing the risk of infection in children and adults with nephrotic syndrome.
SEARCH METHODS: We searched the Cochrane Renal Group's specialised register, the Cochrane Central Register of Controlled Trials (CENTRAL) (in The Cochrane Library), MEDLINE and Pre-MEDLINE (from 1966), EMBASE (from 1980), China Biological Medicine Database (1979 to December 2009), Chinese Science and Technique Journals Database (to December 2009), China National Infrastructure (to December 2009), WangFang database (to December 2009), reference lists of nephrology textbooks, review articles, relevant studies and abstracts from nephrology meetings without language restriction.Date of last search: 6 February 2012
SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing any prophylactic interventions (pharmacological or non-pharmacological) for preventing any infection in children and adults with nephrotic syndrome.
DATA COLLECTION AND ANALYSIS: Two authors independently assessed and extracted information. Information was collected on methods, participants, interventions and outcomes (appearance of infection, mortality, quality of life and adverse events). Results were expressed as risk ratios (RR) for dichotomous outcomes or as mean differences (MD) for continuous data with 95% confidence intervals (CI).
MAIN RESULTS: Twelve studies conducted in China, including 762 children with nephrotic syndrome were identified. No studies were identified in adults. All studies compared one kind of prophylactic pharmacotherapy (intravenous immunoglobulin (IVIG), thymosin, oral transfer factor, mannan peptide tablet, Bacillus Calmette-Guerin (BCG) vaccine injection, polyvalent bacterial vaccine (Lantigen B) and two kinds of Chinese medicinal herbs: a compound of Chinese medicinal herbs (TIAOJINING) and Huangqi (astragalus) granules) plus baseline treatment with baseline treatment alone. No RCTs were identified comparing antibiotics, non-pharmacological prophylaxis, or pneumococcal vaccination. Four studies showed a significantly beneficial effect of IVIG on preventing nosocomial or unspecified infection in children with nephrotic syndrome (RR 0.47, 95% CI 0.31 to 0.73). Thymosin (RR 0.50, 95% CI 0.26 to 0.97), oral transfer factor (RR 0.51, 95% CI 0.35 to 0.73), BCG vaccine injection (RR 0.68, 95% CI 0.48 to 0.95), Huangqi granules (RR 0.62, 95% CI 0.47 to 0.83) and TIAOJINING (RR 0.59, 95% CI 0.43 to 0.81) were also effective in reducing the risk of infection in children with nephrotic syndrome. However mannan peptide tablet (RR 0.46, 95% CI 0.21 to 1.01) and polyvalent bacterial vaccine (RR 0.24, 95% CI 0.06 to1.00) were not superior to baseline treatment in reducing the risk of infection for nephrotic children. No serious adverse events were reported.
AUTHORS' CONCLUSIONS: IVIG, thymosin, oral transfer factor, BCG vaccine, Huangqi granules and TIAOJINING may have positive effects on the prevention of nosocomial or unspecified infection with no obvious serious adverse events in children with nephrotic syndrome. However the methodological quality of all studies was poor, the sample sizes small, and all studies were from China, and thus there is no strong evidence on the effectiveness of these interventions.

PMID 22513919
S L Hogan, K E Muller, J C Jennette, R J Falk
A review of therapeutic studies of idiopathic membranous glomerulopathy.
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
Asami Takeda, Keiji Horike, Hiroshi Onoda, Yasuhiro Ohtsuka, Astuhiro Yoshida, Kazuharu Uchida, Kunio Morozumi
Benefits of cyclosporine absorption profiling in nephrotic syndrome: preprandial once-daily administration of cyclosporine microemulsion improves slow absorption and can standardize the absorption profile.
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
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
A randomized open-label comparative study of conventional therapy versus mizoribine onlay therapy in patients with steroid-resistant nephrotic syndrome (postmarketing survey).
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
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
Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial.
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
Piero Ruggenenti, Paolo Cravedi, Antonietta Chianca, Annalisa Perna, Barbara Ruggiero, Flavio Gaspari, Alessandro Rambaldi, Maddalena Marasà, Giuseppe Remuzzi
Rituximab in idiopathic membranous nephropathy.
J Am Soc Nephrol. 2012 Aug;23(8):1416-25. doi: 10.1681/ASN.2012020181. Epub 2012 Jul 19.
Abstract/Text Selective depletion of B cells with the mAb rituximab may benefit the autoimmune glomerular disease idiopathic membranous nephropathy (IMN). Here, we describe our experience treating 100 consecutive IMN patients with persistent nephrotic syndrome with rituximab. We defined complete remission as persistent proteinuria <0.3 g/24 h and partial remission as persistent proteinuria <3 g/24 h, each also having >50% reduction in proteinuria from baseline. During a median follow-up of 29 months after rituximab administration, 65 patients achieved complete or partial remission. The median time to remission was 7.1 months. All 24 patients who had at least 4 years of follow-up achieved complete or partial remission. Rates of remission were similar between patients with or without previous immunosuppressive treatment. Four patients died and four progressed to ESRD. Measured GFR increased by a mean 13.2 (SD 19.6) ml/min per 1.73 m(2) among those who achieved complete remission. Serum albumin significantly increased and albumin fractional clearance decreased among those achieving complete or partial remission. Proteinuria at baseline and the follow-up duration each independently predicted the decline of proteinuria. Furthermore, the magnitude of proteinuria reduction significantly correlated with slower GFR decline (P=0.0001). No treatment-related serious adverse events occurred. In summary, rituximab achieved disease remission and stabilized or improved renal function in a large cohort of high-risk patients with IMN.

PMID 22822077

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