Nonimmunosuppressive therapy of membranous nephropathy

Idiopathic membranous nephropathy (MN) has a variable rate of progression to end-stage renal failure, with a significant number of patients going into spontaneous remission without therapy. For those who have persistent nephrotic proteinuria or manifest deterioration of renal function, steroids and immunosuppressive drugs are used. However, their long-term efficacy is challenged by a meta-analysis presented here. A different approach to reduction of proteinuria, a recognized progression promoter, is based on the notion that angiotensin II inhibition controls proteinuria and slows progression. Further, a more complex approach is required than simple administration of an angiotensin-converting enzyme (ACE) inhibitor: a multidrug approach to remission of nephrotic syndrome therefore is described here.     

Mycophenolate therapy of SLE membranous nephropathy

BACKGROUND: The immunosuppressant mycophenolic acid (MMF) has been used successfully to manage proliferative forms of systemic lupus erythematosus (SLE) glomerulonephritis (GN) World Health Organization (WHO) Classes III and IV. Less is known about MMF treatment of membranous SLE GN (WHO Class V, SLE MN). METHODS: We report our experience with MMF therapy in 13 consecutive SLE MN patients participating in a prospective study of risk factors for SLE flare. RESULTS: Baseline characteristics were: mean age 33 +/- 14 SD years, female/male ratio 11/2, Caucasians 7, African Americans 5, Oriental 1, serum creatinine 1.02 +/- 0.41, and mean 24-hour urine protein (P)/creatinine (C), ratio 5.1 +/- 4.1. Initial therapy was prednisone mean dose 31 +/- 17 mg/day, and MMF mean dose 1173 +/- 746 mg/day. Therapy also featured interventions to achieve renoprotection and proteinuria reduction. At 6 months of therapy, complete or partial remission was achieved in 10 of 13 patients. At most recent follow-up visit (mean follow-up 16 +/- 8 months), 9 of 13 patients were in complete remission, and in 11 of 13 patients, urine P/C ratio was < 0.8. During follow-up, serum creatinine either stabilized or was improved. The only serious complication during 208 patient months of follow-up was histoplasma pneumonia in 1 patient. CONCLUSION: These promising results suggest that moderate dose MMF in combination with renoprotective/antiproteinuria therapy warrants further study in the management of SLE MN.     

Effects of steroid therapy on membranous nephropathy

BACKGROUND: Although membranous nephropathy is a common cause of nephrotic syndrome in adults, its treatment remains under debate. METHODS: To clarify the effects of steroid therapy, the data of 51 Japanese adult patients with idiopathic membranous nephropathy who received treatment at our department were analyzed retrospectively. We divided the patients with nephrotic syndrome and a serum creatinine level <1.7 mg/dL, into two groups: the steroid therapy group (n=20) and the non-steroid therapy group (n=7), and compared the clinical characteristics between the two groups. RESULTS: Significantly decreased proteinuria levels (p<0.05) after 2 and 5 years were observed in the steroid therapy group as compared to the non-steroid therapy group. There was no significant difference in the serum creatinine levels after 2 and 5 years between the steroid therapy group and the non-steroid therapy group. CONCLUSION: Steroid therapy in idiopathic membranous nephropathy showed good efficacy in patients with nephrotic syndrome.     

A pilot study of low-dose fludarabine in membranous nephropathy refractory to therapy.

BACKGROUND: Lymphocytes are believed to play a role in the induction and perpetuation of membranous nephropathy. Fludarabine is a purine nucleoside analog with selective activity against both dividing and resting lymphocytes. We evaluated the tolerance, toxicity, pharmacokinetics, immunologic, and clinical effects of fludarabine in patients with membranous nephropathy in an single arm pilot study. PATIENTS AND METHODS: Eight patients with idiopathic (n = 7) or lupus (n = 1) membranous nephropathy who had failed high-dose prednisone (n = 8) and/or alkylating agents (n = 2), or cyclosporine (n = 1) were treated with 6-monthly cycles of fludarabine (cycles 1-2, 20 mg/m2/day x 2 days, cycles 3-6, 20 mg/m2/day x 3 days). Mean proteinuria was 9 g/day with a mean duration of disease of 25 months (range 12-48). Proteinuria, GFR and effective renal plasma flow were compared before and after completing the treatment. RESULTS: Seven patients completed the protocol. CD3, CD4, CD8 and B cell counts decreased by 53%, 46%, 61% and 84%, respectively, at the end of treatment and remained at lower than pretreatment levels 6 months after completing the trial. Despite lymphopenia, serum immunoglobulin levels remained unchanged. Both naive (CD45RA+) and memory CD4+ T cells (CD45RO+) were reduced (naive > memory). Proteinuria decreased by > or = 50% in 5 out of 7 patients (p = 0.11). Filtration fraction improved in all patients with decreased filtration fraction at baseline. The only side-effect observed was one episode of acute bacterial sinusitis that responded promptly to antibiotic therapy. CONCLUSION: We conclude that low-dose fludarabine treatment in patients with membranous nephropathy is well tolerated and results in significant lymphopenia involving B more than T cells. In this pilot study improvement in proteinuria and filtration rate were observed. Additional studies are required to determine the optimal dose and clinical efficacy of fludarabine.     

A membranous nephropathy associated with adult polycystic kidney disease.

A 53-year-old woman with adult polycystic kidney disease (PKD) developed a nephrotic syndrome. Evaluation of the renal biopsy specimens showed typical findings of membranous nephropathy (MN). There are few reports of nephrotic syndrome associated with PKD and only one proved to be MN. The possible mechanism of the association of PKD with MN was evaluated. Autoantibodies against the brush border were not detected in this patient's serum by indirect immunofluorescence. Three monoclonal antibodies against the tubular brush border and epithelial cell of distal tubulus did not react with subepithelial deposits in the biopsy specimen. Therefore tubular brush border antigen which was reported to induce membranous nephropathy was not detected in the immune complexes deposited in the glomeruli. So we could not determine any direct relationship between PKD and MN. The reaction of antibodies against basement membrane components (type IV collagen, laminin, fibronectin, heparansulfate proteoglycan) with the basement membranes of the cysts was evaluated by indirect immunofluorescence. The reaction with anti-heparansulfate proteoglycan antibody was decreased compared with normal tubular basement membrane. The reactivity to anti-fibronectin antibody was remarkably increased in the cystic walls, tubules, and interstitium. Changes of tubular basement membrane antigens was observed in PKD.     

Long-term outcomes of initial therapy for idiopathic membranous nephropathy

Background

The objective of this study is to determine whether initial steroid therapy is actually effective for the treatment of iMN, and we examined a 40% reduction in estimated glomerular filtration rate (eGFR) and remission rates.

Methods

This was a retrospective study between 1993 and 2013. First, we divided patients with iMN having a urinary protein level of ≥1 g/gCre into two groups: those who had received steroid therapy (Group S₁; n = 52) within 6 months of diagnosis and those who had received supportive therapy (Group H₁; n = 31). Second, we compared 20 cases using propensity score matching (Group S₂, Group H₂). Third, we compared patients with a urinary protein level of 1–3.5 g/gCre (Group S₃, n = 18; Group H₃, n = 19) and those with a urinary protein level ≥3.5 g/gCre (Group S₄, n = 34; Group H₄, n = 12). The primary endpoint was a 40% reduction in eGFR, and the secondary endpoint was the achievement of complete remission (CR).

Results

In Group S₁ and Group H₁, a 40% reduction in the eGFR was observed at the end of 5 years in 18 and 17% of the patients, respectively (P = 0.93); at the end of 10 years, these rates had increased to 43% and 50%, respectively (P = 0.88). The CR rates at the end of 5 years were 58% and 32%, respectively (P = 0.02), while the rates at 10 years were 65 and 39%, respectively (P = 0.02). No difference in renal outcomes was observed between Group S₁ and Group H₁. No significant differences were observed between Group S₂ and Group H₂, between Group S₃ and Group H₃, or between Group S₄ and Group H₄.

Conclusion

Initial steroid therapy is not superior to supportive care within the first 6 months after diagnosis in terms of a 40% reduction in eGFR.

     

Effect of mizoribine pulse therapy in adult membranous nephropathy

International Urology and Nephrology - Membraneous nephropathy (MN) is one of the complicated kidney diseases associated with proteinuria. Mizoribine (MZR) is an emerging treatment option for...     

Castleman病并发膜性肾病一例

患者,女,67岁,1个月前无明显诱因出现右上腹及剑突下隐痛,伴而部及双下肢水肿.当地医院查尿蛋白3+,24 h尿蛋白量3.4 g,血白蛋白25 g/L,Scr 48 μmol/L,CT示胰腺领前上方有可疑结节,于2010年10月5日入我院肾科.既往有高血压病史10年.慢性胆囊炎及胆囊结石病史8年.入院查体:血压140/88 mm Hg,面部水肿,肝肋下 1.5 cm,莫菲征阳性,双下肢水肿,余无异常.     

Effectiveness of steroid therapy in different stages of membranous nephropathy

The published studies on histological staging and response to steroid therapy of membranous glomerulonephritis are not consistent. We analysed data from 25 adult patients with stage I (group 1, n = 7) and stage II (group 2, n = 18) disease. The interval between clinical onset and admission was similar in the two groups. At admission all patients had normal creatinine clearance; proteinuria averaged 5.4 +/- 4.0 in group 1 and 9.0 +/- 4.0 in group 2 (g/day per 100 ml GFR). All patients received 6 months steroid therapy (months 1-2, 1 mg/kg b.w. per day; month 3-5: 0.65 mg/kg b.w. e.o.d.; month 6, tapering). After this cycle of steroid therapy, proteinuria declined by 84% in group 1 (five patients being in partial remission, i.e. 0.4-2 g/day, and two patients in complete remission, i.e. less than or equal to 0.3 g/day) and by 47% in group 2 (two patients being in complete remission and six in partial remission). Only 1 patient in group 1 relapsed with nephrotic proteinuria after 36 months, and renal function was still normal in all patients at the most recent follow-up (59 +/- 32 months). In contrast, 14 patients in group 2 had nephrotic syndrome and seven renal insufficiency at the most recent follow-up. We conclude that short-term steroid therapy is effective only in patients with early membranous changes.     

Predictive factors of response to steroids and cyclophosphamide therapy in idiopathic membranous nephropathy

Objectives To investigate demographic and clinical factors which could be predictive of clinical remission or relapse in patients with idiopathic membranous nephropathy treated with oral steroids and iv cyclophosphamide therapy. Methods This was a retrospective cohort study where a total of 83 patients with biopsy-proven IMN who had received oral prednisone and iv cyclophosphamide for at least 6 months were enrolled. Demographic and clinical factors of these patients were analyzed at baseline and three months after the initiation of therapy to evaluate their respective effects upon clinical remission and relapse. Results Median follow-up duration was 20 (12-30) months. At the end of follow-up, 80.7% (67/83) of the patients attained remission and 47.0% (39/83) attained complete remission (CR). The amount of proteinuria at baseline and the reduction rate of proteinuria three months after treatment predicted clinical remission and CR. 54 patients in the remission group were followed up to the endpoint and 14 of them relapsed with nephroticsyndrome. The presence of a PR versus CR significantly predicted relapse (HR: 40.198, 95%CI: 5.023-333.355, P=0.001). Infection was the most common adverse event. Two patients developed malignancies after onset of cyclophosphamide treatment. Conclusions A high rate of good response and a relatively low rate of adverse events were observed in this study. Baseline proteinuria and reduction rate of proteinuria 3 months after onset of cyclophosphamide regimen were independent predictive factors of response. Compared with CR, PR was predictive of a high probability of relapse.     

Corticosteroids,cyclophosphamide, and chlorambucil therapy of membranous nephropathy

Corticosteroids and cytotoxic agents have been studied widely in membranous nephropathy (MN). However, controlled studies with corticosteroids have not shown a clear benefit of these agents on the outcome of the disease. Some controlled trials reported that cytotoxic agents can reduce proteinuria significantly, but it was difficult to assess the efficacy of these drugs in protecting renal function because of the short follow-up period of the studies. Three randomized controlled trials showed that a 6-month treatment regimen based on corticosteroids and a cytotoxic agent, giving each for 1 month at a time in an alternating schedule, could favor remission of the nephrotic syndrome and protect renal function. Taken together, the results of these trials at the end of the follow-up period, 74% of the 174 treated patients were without nephrotic syndrome, 4 patients were on chronic dialysis, and 2 patients died. Good results with cytotoxic drugs, often associated with corticosteroids, also have been reported in progressive membranous nephropathy. However, in patients with renal insufficiency side effects were frequent and severe. Moreover, in most cases renal function improved but did not return to normal.     

Efficacy of a second course of immunosuppressive therapy in patients with membranous nephropathy and persistent or relapsing disease activity.

BACKGROUND: A single course of immunosuppressive treatment improves renal survival in patients with idiopathic membranous nephropathy (iMN) and renal insufficiency. However, not all patients respond and relapses occur within 5 years in 30% of patients. It is unknown if a second course of immunosuppressive therapy is effective in such patients. METHODS: We have prospectively studied and evaluated the clinical course in 15 patients (14 male, one female; age: 52+/-12 years) with iMN who have received a repeated course of immunosuppressive therapy because of deteriorating renal function associated with relapsing or persistent nephrotic syndrome. RESULTS: The first course of immunosuppression was started 8 months (range: 0-143 months) after renal biopsy and consisted of chlorambucil (n = 8) or cyclophosphamide (n = 7); the second course consisted of cyclophosphamide in all patients. The interval between the first and second course was 40 months (range: 7-112 months). Total follow-up was 110 months (range: 46-289 months). Renal function and proteinuria improved at least temporarily in all patients after the second course. During follow-up, an additional course of therapy was given in four patients. Status at the end of follow-up was complete remission (n = 2), partial remission (n = 8), persistent proteinuria (n = 3), end-stage renal disease (n = 1) and death (n = 1, due to cardiovascular disease while nephrotic). Renal survival was 86% at 5 and 10 years of follow-up. The repeated courses of immunosuppression have resulted in a gain of dialysis-free survival time of > or =93 months (range: 43-192 months). CONCLUSIONS: Our results indicate that patients with iMN who do not respond well or relapse after a first course of immunosuppressive therapy and have renal insufficiency should be offered a second course of immunosuppression. Such a strategy maintains renal function in the majority of patients.     

混合性结缔组织病并发继发性膜性肾病一例

混合性结缔组织病(MCTD)是一种具有系统性红斑狼疮、全身性硬皮病、多发性肌炎或皮肌炎等表现的系统性疾病.本病肾脏累及率低且表现轻微,多为镜下血尿或少量蛋门尿.国内该病肾脏病理类型报道甚少,现报道1例并发继发性膜性肾病(MN)如下.     

Treatment of membranous nephropathy in the elderly

MN is relatively common in the elderly and can lead to significant morbidity and mortality as a result of complications of the nephrotic syndrome and end-stage renal disease. Some cases of MN may be missed as asymptomatic urinary abnormalities and progressive renal disease may be attributed incorrectly to vascular disease or normal aging. Urinary abnormalities and changes in renal function should be evaluated in the elderly using the same criteria as applied in younger individuals. When MN is diagnosed in an elderly individual, it has the same risks for progression as in younger individuals; thus, therapy for hypertension, hyperlipidemia, edema, and proteinuria should be instituted. When appropriate, elderly individuals should receive immunosuppressive therapy to induce a remission of the nephrotic syndrome and reduce the risk for progressive loss of renal function using criteria similar to younger patients. Most studies show response rates to be comparable in all age groups examined. The only consistent recommendation is to avoid high-dose corticosteroids when possible. Recognize that drug dosages need to be modified and carefully monitored and that the elderly may be particularly prone to side effects and infectious complications of immunosuppressive therapy. Although treatment of MN in the elderly has unique challenges, reducing the need for renal replacement therapy in this population merits special attention. This is a US government work. There are no restrictions on its use.     

Analysis of clinical manifestations and outcomes of idiopathic membranous nephropathy compared with diabetic nephropathy in patients with type 2 diabetes

Objective To evaluate the predictive factors and renal outcomes of idiopathic membranous nephropathy (IMN) in patients with type 2 diabetes (T2DM). Methods In this retrospective study, clinical data of 101 IMN patients with T2DM and 96 patients with diabetic nephropathy (DN) were consecutively collected. Logistic regression was used to assess potential clinical factors indicating IMN and COX regression was employed to analyze risks of IMN in developing to end-stage renal disease (ESRD), as compared with that of DN, in patients with T2DM. Results In a multivariate model, age≥55 years old, presence of nephrotic syndrome, estimated glomerular filtration rate (eGFR)＞60 ml?min-1?(1.73 m2)-1, duration of diabetes≤5 years and absence of diabetic retinopathy, were associated with IMN, as compared with DN, in patients with T2DM. In T2DM patients presented with nephrotic syndrome, age≥55 years old, eGFR＞60 ml?min-1?(1.73 m2)-1, duration of diabetes≤5 years and absence of diabetic retinopathy, were also associated with IMN, as compared with DN. Receiver operating characteristic curve (ROC) showed eGFR 65.5 ml?min-1?(1.73 m2)-1 was an optimal cutoff in differentiating DN and IMN. DN was associated with 16.8 times as high risk of incident ESRD as compared with IMN in T2DM patients. Conclusions In patients with T2DM, age≥55 years, presence of nephrotic syndrome, early stage of CKD, duration of diabetes≤5 years and absence of retinopathy, may indicate IMN rather than DN. T2DM patients with IMN have much better renal prognosis as compared with DN.