Course Of Idiopathic Membranous Nephropathy Research Articles

Comprehensive RNA-Sequencing Analysis in Peripheral Blood Cells Reveals Differential Expression Signatures with Biomarker Potential for Idiopathic Membranous Nephropathy.

To date, the clinical course of idiopathic membranous nephropathy (iMN) remains unclear and lacks direct and effective diagnostic methods. To better understand the host gene expression changes involved in the iMN process and identify the potential signatures for clinical diagnosis, we performed a whole genome-wide transcriptome profile of peripheral blood cells (PBC) from patients with iMN and healthy controls (HCs). A total of 188 differentially expressed genes (DEGs) were detected in patients with iMN versus HCs. Gene ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that these DEGs were mainly correlated with protein targeting, ion homeostasis GO terms, and ribosome and phagosome pathways. The top 10 differentially expressed protein-coding genes with >2-fold changes and high expression levels were validated using quantitative real-time PCR, and showed high consistency with the high-throughput sequencing results. HLA-C, S100A8, and FTH1 genes were selected for further validation and showed the most significant difference between the iMN and HC group, indicating that they could be used as potential clinical diagnostic biomarkers. Our results provide novel potential diagnostic signatures for iMN and have important implications for better understanding the pathogenesis of iMN.

Anti-phospholipase A2 receptor antibody and spontaneous remission in membranous nephropathy.

Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in native kidney biopsies from adults. In 2009, antibodies to the M-type receptor of phospholipase A2 (anti-PLA2R) were identified in idiopathic MN patients, both within the kidney and in the circulation. The clinical course of idiopathic MN is variable and ranges from spontaneous remission to end-stage renal disease. Clinical variables such as proteinuria levels, patient sex, age and renal function at diagnosis have been associated with renal MN progression. In this editorial, we update the importance of anti-PLA2R levels as a prognostic marker in idiopathic MN at the diagnosis of the disease.

Urinary N-acetyl-β-glucosaminidase and estimated Glomerular filtration rate may identify patients to be treated with immuno-suppression at diagnosis in idiopathic membranous nephropathy.

The clinical course of idiopathic membranous nephropathy (IMN) varies from spontaneous remission of nephrotic syndrome (NS) to end-stage renal disease (ESRD). The aim of the study was baseline identification of patients with high risk of progression for which immunosuppressive therapy is mandatory. Eighty-six IMN subjects were followed for a median of 69months (range 6-253). Receiver operating characteristic curve and Cox proportional hazards model were used to evaluate prognostic factors for progression, defined as ESRD or estimated glomerular filtration rate (eGFR) reduction ≥50% of baseline. Among all, 24 subjects had progression. Area under the ROC curve of N-acetyl-β-glucosaminidase/creatinine ratio (NAG/C) were significantly higher than proteinuria/24h (0.770 and 0.637 respectively, P = 0.018). In Cox proportional hazards regression analysis, NAG/C and eGFR were independent predictors of progression. Compared to lowest tertile of NAG/C (<9.4 UI/gC) or highest tertile of eGFR (≥88mL/min per 1.73m2 ), the multivariable-adjusted hazard ratio of highest tertile of NAG/C (≥19.2) was 18.97 (95%CI, 1.70-211.86) and lowest tertile of eGFR (<59) was 11.58 (95%CI, 2.02-66.29). Subjects with high NAG/C or low eGFR (high-risk, n=43) had greater progression rate compared to moderate to low NAG/C and high eGFR (low-risk, n=43) with or without NS at baseline (Log-rank test P = 0.001 and 0.006, respectively). In NS subjects (n=65), high-risk group progression rate was significantly higher (91% vs. 29%, P = 0.003) and remission rate significantly lower (0% vs. 42%, p<0.001) in non-immunosuppressed compared to steroids and cyclophosphamide treated patients; no significant differences were observed in low-risk group. Idiopathic membranous nephropathy subjects with high NAG/C and low eGFR have greater risk of progression, and immunosuppressive treatment is suggested at diagnosis.

Anti-PLA2R Antibodies as a Prognostic Factor in PLA2R-Related Membranous Nephropathy

Background: The natural course of idiopathic membranous nephropathy (MN) varies, as it is known through favorable outcomes in most patients. However, one third of patients with idiopathic MN will slowly progress to end-stage renal disease (ESRD). To prevent disease progression, patients at high risk to develop ESRD are treated with immunosuppressive agents. Therefore, a correct selection of patients who need immunosuppressive treatment is important. Methods: Here, we evaluated the prognostic value of anti-phospholipase A2 receptor 1 antibody (anti-PLA2R) levels regarding clinical outcome in a well-defined cohort of 73 PLA2R-related MN patients with long-term follow-up. At baseline, patients were subdivided into patients with either low or high antibody levels based on ELISA testing. Results: Spontaneous remission rates were highest among patients with low anti-PLA2R levels (79%; hazard ratio 2.72 (95% CI 1.22-6.08), p = 0.02) after a median follow-up of 2.9 (95% CI 0.8-5.0, p < 0.001) years, whereas high anti-PLA2R levels were associated with persistent proteinuria (p = 0.04) and/or the need for immunosuppressive therapy (p < 0.001). Renal survival rates were 97% at 5 years, 93% at 10 years, and 89% at 15 years; however, this was not different between the anti-PLA2R groups. ESRD occurred significantly faster in patients with severe proteinuria as compared to patients with either mild (p = 0.02) or moderate proteinuria (p = 0.05). Conclusions: Low anti-PLA2R levels may predict spontaneous remissions in patients with PLA2R-related MN. Therefore, we suggest that quantification of anti-PLA2R is of value to monitor these patients.

Glomerular diseases: membranous nephropathy--a modern view.

Membranous nephropathy (MN) is an autoimmune disease usually associated with a nephrotic syndrome and it may progress to ESRD in the long term. Its etiology is often unknown (idiopathic MN), whereas other cases have a recognizable etiology (secondary MN). In idiopathic MN, the glomerular lesions are mainly caused by autoantibodies against a podocyte membrane protein, the M-type of phospholipase A2 receptor 1. The natural course of idiopathic MN is quite varied with spontaneous complete or partial remissions a relatively common occurrence. Patients with asymptomatic non-nephrotic proteinuria seldom progress and need only conservative management. Those with persistent full-blown nephrotic syndrome and those with declining renal function are candidates for specific treatment with any of several regimens. Cyclical therapy with alternating monthly intravenous and oral glucocorticoids combined with a cytotoxic agent can induce remission and preserve renal function in the long term. Cyclosporine or tacrolimus can induce remission, but relapses are frequent after the drug withdrawal. Mycophenolate mofetil monotherapy seems to be ineffective, but may be beneficial when administered together with steroids. The experience with adrenocorticotropic hormone, natural or synthetic, is limited to a few studies with short-term follow-up, but high rates of remission can be seen after prolonged treatment. A high rate of remission and good tolerance have also been reported with rituximab. Patients with moderate renal insufficiency may also benefit from treatment, but at a price of frequent and serious side effects. With these limitations in mind, idiopathic MN may be considered a treatable disease in many patients.

Outcome of idiopathic membranous nephropathy using targeted stepwise immunosuppressive treatment strategy

The natural course of idiopathic membranous nephropathy (IMN) is variable and the role of immunosuppressive therapy is controversial. In our centre, the strategy has been conservative: the immunomodulating treatment (glucocorticoids and/or cyclosporine A) has been targeted to patients at high risk of developing progressive renal disease and the cytotoxic drugs have been used cautiously. The aim of this retrospective observational study was to evaluate the efficacy of this strategy. We evaluated the clinical course and outcome of IMN patients diagnosed between 1993 and 2003. Risk assessment was done during an observation period of ≥6 months after the initial renal biopsy. Patients were followed up until death, the development of end-stage renal disease (ESRD) or the last clinical visit (before December 2006). Treatments and their side effects were recorded. One hundred and forty-two patients with membranous nephropathy were diagnosed of which 81 were idiopathic. The clinical course of 76 IMN patients (38 high risk and 38 low risk) were followed up [mean duration 66 ± 40 (median 59) months]. Thirty-five patients were treated with immunosuppressive drugs, and at last follow-up, 71% of them were in complete or partial remission. The overall response rate of this therapy was 83%. 11% of the high-risk patients had reached ESRD. For the high-risk patients, 10-year survival (alive with glomerular filtration rate >10 mL/min/1.73 m(2)) was 79%. No major side effects were observed. This study suggests that targeted, stepwise, cytotoxic drug-sparing immunosuppressive treatment in IMN was associated with favourable renal, as well as overall survival among patient at risk of developing ESRD.

Management of idiopathic membranous nephropathy

Importance of the field: Idiopathic membranous nephropathy (IMN) can have a variable natural course. Treatments able to induce remission can improve the long-term prognosis. However, the optimal therapy for IMN remains controversial.Area covered in this review: We reviewed the historical and current literature from 1979 to 2010 regarding the natural course of IMN and the possible treatments giving special emphasis to randomized controlled trials and to more recent approaches.What the reader will gain: The reader will gain a comprehensive review of the available treatments of IMN. A personal therapeutic algorithm for nephrotic patients with IMN is also provided.Take home message: At least five different treatments showed efficacy in many (but not all) patients with IMN.

Idiopathic Membranous Nephropathy

Treatment of idiopathic membranous nephropathy is based on a 'symptomatic' therapy that includes ACE inhibitors or angiotensin II receptor antagonists, and on an 'aetiological' therapy aimed at modulating underlying immunological mechanisms. The role of the latter is still debated given the usually indolent course of disease; furthermore, traditional immunosuppressants would not have an impact on patient and renal survival according to a systematic review of literature. However, up to 40% of untreated patients eventually develop end-stage renal disease and remission of nephrotic syndrome protects patients from related life-threatening complications and is the strongest positive prognostic factor for long-term kidney function. Therefore, immunosuppressive therapy seems to be rational in high-risk patients with nephrotic syndrome or deteriorating renal function. This article outlines a possible role for each 'aetiological' therapy on the basis of available evidence in order to provide some practical recommendations. The first-line therapy is based on a 6-month regimen of alternating corticosteroids and an alkylating agent ('Ponticelli' regimen), whereas oral ciclosporin and intramuscular corticotrophin (adrenocorticotrophic hormone) are alternatives that provide comparable results in terms of remission of proteinuria, with a different adverse effect profile. New drugs are emerging as potential treatments, such as mycophenolate mofetil, tacrolimus, intravenous immunoglobulins and rituximab. Specific settings, such as chronic renal failure or elderly age, require a careful balance between benefits and toxicity of immunosuppression. The tailor-made use of this repertoire of drugs can provide a tool to achieve remission of proteinuria and modify the natural course of idiopathic membranous nephropathy.

Focal segmental glomerulosclerosis is not a sufficient predictor of renal outcome in patients with membranous nephropathy

The course of idiopathic membranous nephropathy (iMN) is variable in untreated patients. Accurate prediction of renal outcome would allow optimal treatment decisions. We demonstrated that urinary beta2-microglobulin (beta2M) predicted prognosis in iMN with high sensitivity and specificity. It has been suggested that focal segmental glomerulosclerosis (FSGS) is a discriminative parameter with independent prognostic value. We selected patients with iMN biopsied between 1988 and 2002. Biopsies were analysed for the presence of FSGS, interstitial fibrosis and vascular lesions. Serum creatinine, creatinine clearance, proteinuria and blood pressure were recorded at baseline. Outcome variables included remission of proteinuria, renal death (RD) defined as serum creatinine >135 micromol/l or increase of serum creatinine of >50%, or end-stage renal disease (ESRD). In a subgroup of patients, urinary beta2-microglobulin (beta2M) was measured. We included 53 patients (33M, 20F). Mean age was 51 years, serum creatinine 99 micromol/l, and proteinuria 7.0 g/10 mmol creatinine. FSGS was present in 22 patients. These patients were characterized by a higher serum creatinine at time of biopsy (P = 0.035), more severe interstitial fibrosis (P = 0.001) and higher stage of membranous nephropathy (P = 0.001). During follow-up 24 patients developed RD, almost equally distributed between patients with and without FSGS. Renal survival was numerically, but not significantly, lower in patients with FSGS. In Cox proportional hazard analysis, only serum creatinine at the time of biopsy was an independent predictor of RD or ESRD (P < 0.001). In patients with known urinary beta2M, there was no significant correlation with FSGS score (P = 0.174). FSGS is not an accurate prognostic marker in iMN. Histological scoring of FSGS is inferior to measurement of urinary proteins in predicting renal outcome in iMN.

A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy

The natural course of idiopathic membranous nephropathy is variable, with some patients slowly progressing to renal failure while others maintain normal renal function over the entire time. Whether to treat this disease or not is controversial due to the lack of controlled data about the long-term effects of treatment. We updated at 10 years the results of a controlled trial in which 81 patients with idiopathic membraneous nephropathy and nephrotic syndrome were randomly assigned to receive symptomatic therapy (39 patients) or a treatment of six months with methylprednisolone and chlorambucil (42 patients). The probability of surviving without developing end-stage renal disease at 10 years was 92% in patients given methylprednisolone and chlorambucil versus 60% in controls (P = 0.0038). The slope of the reciprocal of plasma creatinine up to 10 years was significantly better in treated patients than in controls (P = 0.035). The probability of having a complete or partial remission of the nephrotic syndrome was significantly higher in treated patients (P = 0.000). Patients assigned to therapy spent significantly longer time without nephrotic syndrome than untreated patients (P = 0.0001). Four patients had to stop treatment because of reversible side-effects. In the long-term one treated patient developed diabetes and another one became obese. In conclusion, a six-month therapy with methylprednisolone and chlorambucil increases the probability of remission of proteinuria and protects from renal function deterioration even in the long-term. This treatment may avoid dialysis or death within 10 years to about one third of nephrotic patients with membranous nephropathy.

Therapy of idiopathic membranous nephropathy.

Whether and how treating idiopathic membranous nephropathy (IMN) is still a matter of debate. While there is general agreement that nonnephrotic patients should be given symptomatic treatment alone, the results of specific therapy addressed to interfere with direct or indirect causes of renal damage are controversial. There is no evidence in favour of therapies based on corticosteroids alone. A few old randomized controlled trials (RCT) reported that alkylating agents, cyclophosphamide and chlorambucil, may increase the probability of remission, but the prolonged use of these agents may cause disquieting adverse effects. RCT showed that a treatment based on alternating corticosteroids and a cytotoxic agent every other month for 6 months may favour remission of the nephrotic syndrome (NS) and may protect renal function in the long-term. More recently, good results have also been reported with synthetic adrenocorticotropic hormone (ACTH), cyclosporine, tacrolimus, mycophenolate mofetil (MMF), and rituximab. Unfortunately, however, most of the therapeutical attempts with these drugs have not been tested in controlled, randomized trials and the follow-up in these studies was generally short-time. Attempts of modifying the natural course of IMN have also been tried in patients with an established renal insufficiency. A number of patients showed improvement of proteinuria and renal function after treatments based on corticosteroids and cytotoxic drugs. However, in most responders the values of creatinine clearance did not return to normal and little information is available about the long-term follow-up of these patients.

Nephrology: An Annotated Bibliography of Recent Literature

Nephrology: An Annotated Bibliography of Recent Literature

The Clinical Course of Idiopathic Membranous Nephropathy.

Excerpt Idiopathic membranous nephropathy, well defined morphologically, is usually associated with the nephrotic syndrome and has a variable disease course. We describe 36 patients with clinically...