Treatment Of Membranous Nephropathy Research Articles

Fumarate modulates phospholipase A2 receptor autoimmunity-induced podocyte injury in membranous nephropathy

Downstream mechanisms that lead to podocyte injury following phospholipase A2 receptor (PLA2R) autoimmunity remain elusive. To help define this we compared urinary metabolomic profiles of patients with PLA2R-associated membranous nephropathy (MN) at the time of kidney biopsy with those of patients with minimal change disease (MCD) and to healthy individuals. Among the metabolites differentially expressed in patients with PLA2R-associated MN compared to healthy individuals, fumarate was the only significant differentially expressed metabolite in PLA2R-associated MN compared to MCD [fold-difference vs. healthy controls and vs. MCD: 1.76 and 1.60, respectively]. High urinary fumarate levels could predict the composite outcome of PLA2R-associated MN. Fumarate hydratase, which hydrolyzes fumarate, colocalized with podocalyxin, and its expression was lower in glomerular sections from patients with PLA2R-associated MN than in those from healthy individuals, patients with non-PLA2R-associated MN or MCD. Podocytes stimulated with IgG purified from serum with a high anti-PLA2R titer (MN-IgG) decreased expression of fumarate hydratase and increased fumarate levels. These changes were coupled to alterations in the expression of molecules involved in the phenotypic profile of podocytes (WT1, ZO-1, Snail, and fibronectin), an increase in albumin flux across the podocyte layer and the production of reactive oxygen species in podocytes. However, overexpression of fumarate hydratase ameliorated these alterations. Furthermore, knockdown of fumarate hydratase exhibited synergistic effects with MN-IgG treatment. Thus, fumarate may promote changes in the phenotypic profiles of podocytes after the development of PLA2R autoimmunity. These findings suggest that fumarate could serve as a potential target for the treatment of PLA2R-associated MN.

Tacrolimus Prevents TWEAK-Induced PLA2R Expression in Cultured Human Podocytes.

Primary membranous nephropathy is usually caused by antibodies against the podocyte antigen membrane M-type phospholipase A2 receptor (PLA2R). The treatment of membranous nephropathy is not fully satisfactory. The calcineurin inhibitor tacrolimus is used to treat membranous nephropathy, but recurrence upon drug withdrawal is common. TNF superfamily members are key mediators of kidney injury. We have now identified key TNF receptor superfamily members in podocytes and explored the regulation of PLA2R expression and the impact of tacrolimus. Data mining of single cell transcriptomics and glomerular transcriptomics data identified TNFRSF12a/Fn14 as the highest expressed TNF receptor superfamily gene in human membranous nephropathy, and this was confirmed by immunohistochemistry that also identified NFκB activation in membranous nephropathy podocytes. Additionally, glomerular transcriptomics identified PLA2R1 expression as being increased in membranous nephropathy in the parenteral administration of the Fn14 ligand TWEAK increased podocyte PLA2R expression in mice. Furthermore, in cultured human podocytes, TWEAK increased the expression of PLA2R as well as the expression of other genes recently identified by GWAS as linked to membranous nephropathy: NFKB1 and IRF4. Interestingly, IRF4 encodes the FK506-binding protein 52 (FKBP52), a protein associated with tacrolimus. Tacrolimus prevented the increased expression of PLA2R, NFKB1 and IRF4 induced by TWEAK in cultured podocytes. In conclusion, TWEAK upregulates the expression of PLA2R and of other genes linked to membranous nephropathy in podocytes, and this is prevented by tacrolimus. An impact of tacrolimus on the expression of PLA2R and other genes in podocytes may underlie its efficacy in treating the disease as well as the frequent recurrence of nephrotic syndrome upon tacrolimus withdrawal.

Modern view on treatment of membranous nephropathy

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults. Since the moment of animal model creation and the recognition of podocytes damage as a key mechanism of MN development, the identification of antigens, first of all the phospholipase A2 receptor (PLA2R), and the development of methods of PLA2R autoantibodies detection and its monitoring opened a new era in the idiopathic MN (iMN) diagnosis, treatment and prognosis evaluation. MN continues to be actively studied in the new millennium, since a number of aspects of its pathogenesis still need to be clarified, and there is still no clear opinion on the iMN treatment optimal approach. Comprehensive clinical and serological assessment of patients with iMN can be the key to individual choice of treatment protocols. In patients with aPLA2R-positive iMN, the predictor of disease remission is the aPLA2R titer decrease or aPLA2R disappearance in the blood serum, and disease relapse is associated with the aPLA2R appearance ore increase of aPLA2R titer in the circulation. Studies which were conducted by today (GEMRITUX, MENTOR, STARMEN, NICE, etc.) confirmed the acceptable safety profile and effectiveness of iMN therapy by anti-CD20 monoclonal antibodies (rituximab): more than half of of iMN patients had remission of nephrotic syndrome or proteinuria decrease, remissions in anti-CD20 monoclonal antibodies treated patients were longer compared to traditional therapy. The obtained data allows us to consider rituximab and anti-CD20 antibody therapy of a new generation not only as an alternative to the more toxic treatment with cyclophosphane and calcineurin inhibitors, but as an independent promising direction of therapy for patients with IMN, which completely changes the paradigm of treatment of this glomerulopathy.

How Does Herbal Medicine Treat Idiopathic Membranous Nephropathy?

Idiopathic membranous nephropathy (IMN) has made increasing progress in mechanism and treatment research. Herbal medicine is gradually being accepted as an alternative therapy in treating IMN. However, the intervention mechanism of herbal medicine in the treatment of membranous nephropathy is still unclear. In this review, we summarize some achievements of herb medicine in treating IMN and discuss the research direction of herb in IMN. Finally, we propose the dilemma about the study on the treatment of IMN with herb medicine. We hope that this article can bring some thoughts for clinical and scientific researchers on the treatment of IMN with herb medicine.

The matrix of SDS integrated with linear hydrophilic polymer for resolution of high- and low-molecular weight hyaluronic acids in MEKC

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults, when not effectively treated. The aim of this study was to discover new targets for the diagnosis and treatment of MN. A reliable mouse model of MN was used by the administration of cationic bovine serum albumin (cBSA). Mice with MN exhibited proteinuria, histopathological changes, and accumulation of immune complexes in the glomerular basement membrane. Label-free proteomics analysis was performed to identify changes in protein expression, and the overexpressed proteins were evaluated. There were 273 proteins that showed significantly different expression in mice with MN, as compared to the controls. String analysis showed that functions related to cellular catabolic processes were downregulated in MN. Among the differentially expressed proteins, prohibitin 1 (PHB1) and prohibitin 2 (PHB2) were upregulated in the kidneys of mice with MN, as demonstrated by immunohistochemistry (IHC), and this upregulation was observed in both the tubular cells and glomeruli. Both shRNA-mediated knockdown of PHB1 or PHB2 inhibited tumor suppressor p53 expression and significantly promoted podocyte proliferation. In addition, both PHB1 and PHB2 were responsible for cBSA-induced cytotoxicity. Microarray analysis further revealed that the upregulation of PHB1 and PHB2 may be due to a blockage of proteasome activity. These data demonstrate that the upregulation of PHB2 is involved in cBSA-mediated podocyte cytotoxicity, which may lead to MN development. © 2019

Efficacy of low or standard rituximab-based protocols and comparison to Ponticelli's regimen in membranous nephropathy.

Patients (pts) with primary Membranous nephropathy (MN) have an autoimmune disease caused by autoantibodies against podocyte antigens and 60-80% of them have antibodies directed against the M-type phospholipase A2 receptor (PLA2R). Immunosuppressive treatment is recommended in high-medium risk pts. Recently the use of rituximab (RTX), has emerged as an important therapeutic option in pts with primary MN. The appropriate cumulative dose of RTX in PMN pts is still uncertain, and favorable outcomes even with low-dose of RTX has been described. We compared efficacy and safety of 3 different treatment regimens: low-dose RTX (Protocol 1, one dose of RTX 375mg/m2), standard RTX protocol (Protocol 2, four weekly doses of rituximab 375mg/m2) and Ponticelli's regimen. 42 pts with primary MN and nephrotic syndrome were assigned to Protocol 1 (14 pts) or Protocol 2 (14 pts). All patients were followed for 24months after RTX. Fourteen pts, matched for age and baseline serum creatinine (sCr) and proteinuria, treated with Ponticelli's regimen were examined as controls. At 24months, a significant improvement in proteinuria levels was observed in pts treated with Protocol 1 (7.5 ± 4.8 at T0; 0.21 ± 0.15 at T24, p < 0.01), Protocol 2 (5.1 ± 1.41g/24 at T0; 0.35 ± 0.39 at T24 p < 0.01) and controls (8.27 ± 4.78 T0; 2.2 ± 1.9g/24h at T24, p < 0.01). No differences in clinical response (p = 0.53) was observed comparing the 3 groups. Our data suggest that the RTX is a promising alternative to Ponticelli's regimen even at low-doses. This makes RTX a cost-effective treatment of primary MN in the short and medium terms.

The Landscape and Prognosis Potential of the T-Cell Repertoire in Membranous Nephropathy.

Membranous nephropathy (MN), a common pathological type of adult nephrotic syndrome, is an antibody-mediated kidney disease. It is widely accepted now that MN is an immune-related disease that involves the whole immune system. In this study, we analyzed the T-cell receptor beta chain (TCRβ) repertoire of the circulating T lymphocytes of MN patients and healthy controls using high-throughput sequencing. We compared multiple aspects of the TCRβ repertoire, including diversity and the Vβ and Jβ genes between MN patients and healthy controls, and we found that the diversities within the VJ cassette combination in the peripheral blood of MN patients were lower than in the healthy controls. We also found the TCRβ repertoire similarity between pre- and post-therapy could reflect the clinical outcome, and two Vβ genes in pre-therapy had the potential to predict the therapeutic effect. These findings indicated the potential of the TCRβ repertoire as non-invasive biomarkers for the prognosis prediction of MN. The characteristics of circulating T-lymphocyte repertoires shed light on MN detection, treatment, and surveillance.

Membranous nephropathy: diagnosis, treatment, and monitoring in the post-PLA2R era.

Membranous nephropathy (MN) is an immune complex-mediated cause of the nephrotic syndrome that can occur in all age groups, from infants to the very elderly. However, nephrotic syndrome in children is more frequently caused by conditions such as minimal change disease or focal segmental glomerulosclerosis, and much less commonly by MN. While systemic conditions such as lupus or infections such as hepatitis B may more commonly be associated as secondary causes with MN in the younger population, primary or "idiopathic" MN has generally been considered a disease of adults. Autoantibodies both to the M-type phospholipase A2 receptor (PLA2R) and to thrombospondin type-1 domain-containing 7A (THSD7A), initially described in adult MN, have now been identified in children and adolescents with MN and serve as a useful diagnostic and monitoring tool in this younger population as well. Whereas definitive therapy for secondary forms of MN should be targeted at the underlying cause, immunosuppressive therapy is often necessary for primary disease. Rituximab has been successfully used in the treatment of MN, and is likely effective in children with MN as well, although dosing in the pediatric population is not well established. This review highlights the new findings in adult and pediatric MN since last reviewed in this journal.

Management of anticoagulation and antiplatelet therapy in patients with primary membranous nephropathy

BackgroundIt has been recognized that primary membranous nephropathy (MN) is related to an increased risk for thromboembolic complications. However, the current evidence supporting prophylactic and therapeutic anticoagulation is too weak to better meet the clinical needs of this patient population. The present review provides some suggestions to guide the decision on anticoagulant management in primary MN patients with a high risk of thrombosis or with thromboembolic complication.Materials and methodsWe extracted relevant studies by searching the published literature using the Cochrane Library, Medline, PubMed and Web of Science from March 1968 to March 2018. Eligible publications included guidelines, reviews, case reports, and clinical trial studies that concerned the rational management of anticoagulation therapy in the primary MN population. The evidence was thematically synthesized to contextualize implementation issues.ResultsIt was helpful for clinicians to make a decision for personalized prophylactic aspirin or warfarin in primary MN patients when serum albumin was < 3.2 g/dl to prevent arterial and venous thromboembolic events (VTEs). The treatment regimen for thromboembolic complications (VTEs, acute coronary syndrome and ischemic stroke) in primary MN was almost similar to that for the general population with thromboembolic events. It is noteworthy that patients should continue the previous primary MN treatment protocol during the entire treatment period until they achieve remission, the protocol is complete and the underlying diseases resolve.ConclusionThe utility of prophylactic aspirin or warfarin may have clinical benefits for the primary prevention of thromboembolic events in primary MN with hypoalbuminemia. It is necessary to perform large randomized controlled trials and to formulate relevant guidelines to support the present review.

Involvement of prohibitin 1 and prohibitin 2 upregulation in cBSA-induced podocyte cytotoxicity

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults, when not effectively treated. The aim of this study was to discover new targets for the diagnosis and treatment of MN. A reliable mouse model of MN was used by the administration of cationic bovine serum albumin (cBSA). Mice with MN exhibited proteinuria, histopathological changes, and accumulation of immune complexes in the glomerular basement membrane. Label-free proteomics analysis was performed to identify changes in protein expression, and the overexpressed proteins were evaluated. There were 273 proteins that showed significantly different expression in mice with MN, as compared to the controls. String analysis showed that functions related to cellular catabolic processes were downregulated in MN. Among the differentially expressed proteins, prohibitin 1 (PHB1) and prohibitin 2 (PHB2) were upregulated in the kidneys of mice with MN, as demonstrated by immunohistochemistry (IHC), and this upregulation was observed in both the tubular cells and glomeruli. Both shRNA-mediated knockdown of PHB1 or PHB2 inhibited tumor suppressor p53 expression and significantly promoted podocyte proliferation. In addition, both PHB1 and PHB2 were responsible for cBSA-induced cytotoxicity. Microarray analysis further revealed that the upregulation of PHB1 and PHB2 may be due to a blockage of proteasome activity. These data demonstrate that the upregulation of PHB2 is involved in cBSA-mediated podocyte cytotoxicity, which may lead to MN development.

Immunological Pathogenesis of Membranous Nephropathy: Focus on PLA2R1 and Its Role.

Membranous nephropathy (MN) is the major cause of nephrotic syndrome with special pathological features, caused by the formation of immune complexes in the space between podocytes and the glomerular basement membrane. In idiopathic membranous nephropathy (IMN) the immune complexes are formed by circulating antibodies binding mainly to one of two naturally-expressed podocyte antigens: the M-type receptor for secretory phospholipase A2 (PLA2R1) and the Thrombospondin type-1 domain-containing 7A (THSD7A). Formation of antibodies against PLA2R1 is much more common, accounting for 70–80% of IMN. However, the mechanism of anti-podocyte antibody production in IMN is still unclear. In this review, we emphasize that the exposure of PLA2R1 is critical for triggering the pathogenesis of PLA2R1-associated MN, and propose the potential association between inflammation, pollution and PLA2R1. Our review aims to clarify the current research of these precipitating factors in a way that may suggest future directions for discovering the pathogenesis of MN, leading to additional therapeutic targets and strategies for the prevention and early treatment of MN.

Successful management of visceral disseminated varicella zoster virus infection during treatment of membranous nephropathy: a case report

BackgroundVisceral disseminated varicella zoster virus (VDVZV) infection is a rare disease with a high mortality rate (55%) in immunocompromised patients, but it is not yet widely recognized in the field of nephrology. We report a case of VDVZV contracted during immunosuppressive therapy for membranous nephropathy.Case presentationA 36-year-old woman was diagnosed with membranous nephropathy and was being treated with immunosuppressive therapy consisting of 60 mg/day prednisolone, 150 mg/day mizoribine, and 150 mg/day cyclosporine. Nephrosis eased; therefore, the prednisolone dosage was reduced. However, 50 days after starting immunosuppressive therapy, the patient suddenly developed strong and spontaneous abdominal pain, predominantly in the epigastric area, without muscular guarding or rebound tenderness. Blood data indicated neutrophil-dominant elevated white blood cell count, reduced platelet count, elevated transaminase and lactate dehydrogenase, slightly increased C-reactive protein, and enhanced coagulability. Abdominal computed tomography revealed a mildly increased enhancement around the root of the superior mesenteric artery with no perforation, intestinal obstruction, or thrombosis. The cause of the abdominal pain was unknown, so the patient was carefully monitored and antibiotic agents and opioid analgesics administered. The following day, blisters appeared on the patient’s skin, which were diagnosed as varicella. There was a marked increase in the blood concentration of VZV-DNA; therefore, the cause of the abdominal pain was diagnosed as VDVZV. Treatment with acyclovir and immunoglobulin was immediately started, and the immunosuppressive therapy dose reduced. The abdominal pain resolved rapidly, and the patient was discharged 1 week after symptom onset.Discussions and conclusionsThis patient was VZV-IgG positive, but developed VDVZV due to reinfection. Abdominal pain due to VDVZV precedes the skin rash, which makes it difficult to diagnose before the appearance of the rash, but measuring the VZV-DNA concentration in the blood may be effective. Saving the patient’s life requires urgent administration of sufficient doses of acyclovir and reduced immunosuppressive therapy.

Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy

BackgroundB-cell anomalies play a role in the pathogenesis of membranous nephropathy. B-cell depletion with rituximab may therefore be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria in patients with this condition.MethodsWe randomly assigned patients who had membranous nephropathy, proteinuria of at least 5 g per 24 hours, and a quantified creatinine clearance of at least 40 ml per minute per 1.73 m2 of body-surface area and had been receiving angiotensin-system blockade for at least 3 months to receive intravenous rituximab (two infusions, 1000 mg each, administered 14 days apart; repeated at 6 months in case of partial response) or oral cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed for 24 months. The primary outcome was a composite of complete or partial remission of proteinuria at 24 months. Laboratory variables and safety were also assessed.ResultsA total of 130 patients underwent randomization. At 12 months, 39 of 65 patients (60%) in the rituximab group and 34 of 65 (52%) in the cyclosporine group had a complete or partial remission (risk difference, 8 percentage points; 95% confidence interval [CI], −9 to 25; P=0.004 for noninferiority). At 24 months, 39 patients (60%) in the rituximab group and 13 (20%) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95% CI, 25 to 55; P<0.001 for both noninferiority and superiority). Among patients in remission who tested positive for anti–phospholipase A2 receptor (PLA2R) antibodies, the decline in autoantibodies to anti-PLA2R was faster and of greater magnitude and duration in the rituximab group than in the cyclosporine group. Serious adverse events occurred in 11 patients (17%) in the rituximab group and in 20 (31%) in the cyclosporine group (P=0.06).ConclusionsRituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months. (Funded by Genentech and the Fulk Family Foundation; MENTOR ClinicalTrials.gov number, NCT01180036.)

SAT-009 Exploring novel biomarkers in Membranous Nephropathy using protein array platform

Membranous nephropathy (MN) is the leading cause of adult-onset nephrotic syndrome. Autoantibody biomarkers for MN include the landmark discovery of Anti-PLA2R antibody against phospholipase A2 receptor (PLA2R) with a prevalence of 50-70% followed by Thrombospondin Type-1 Domain-Containing 7A (THSD7A), with a prevalence of 2-3%. It is believed that yet undiscovered autoantibodies might be involved in the remaining 20-25% of MN patients. In this pilot study, we sought to identify a panel of candidate protein biomarkers in MN using the Sengenics™ Immunome protein array Single-center cohort study of 10 patients with biopsy proven MN (cases) and 10 individuals with biopsy proven minor glomerular abnormalities (controls), recruited at the Department of Renal Medicine of the Singapore General Hospital (SGH) between 1st January 2016 and 31st March 2017. Scientific Methods: After hybridizing the 20 serum samples on the Sengenics Immunome™ protein microarray slides, signals were detected using a microarray laser scanner at a 10μm resolution. The penetrance-based fold change (pFC) analysis method was implemented for the identification of antibodies against the proteins in each case sample, thus eliminating false positive signals from the data by setting a protein-specific threshold which was calculated on a per-protein basis via the mean +2 standard deviation intensity of the signal for each specific protein measured for the matched healthy control samples. Bioinformatics analyses were performed to identify and rank the biomarkers based on their sensitivity and specificity. Cases were 50% male, with 20% diabetic and 60% hypertensive, median age of 52.5years (IQR 48.5, 68.5), 90% Chinese, with median eGFR 76.5 (IQR 61.2, 111.7) and median proteinuria 5.61g (IQR 4.0, 7.4). Controls were race and gender matched with 50% male, 90% Chinese, with 40% diabetic and 80% hypertensive, median age of 53.5years (IQR 45.8, 59.8), median eGFR 74.3 (IQR 44.5, 100.8), median proteinuria 1.67g (IQR 0.6, 4.1). Both groups were comparable except for median proteinuria (p=0.035). A total of 328 biomarkers were identified and the top 15 are listed in Table 1. The top 5 biomarkers in our study show high differential expression in MN serum when compared to controls (see table 1). Mx1, a GTPase commonly involved downstream of the type I IFN pathway and associated with antiviral activity, has been found to be upregulated in lupus nephritis and its association with MN warrants further investigation. The presence of EEF1G in MN patients correlate to MN murine mice model studies that have shown differential expression of EEF1G, specifically subunit alpha, in MN kidney tissue when compared with normal kidneys. GSK3B, which has been found to be associated with diabetic nephropathy through microRNA and haplotype association studies, was prominently elevated in MN patients with diabetes versus diabetes alone and may be useful in the stratification between membranous nephropathy and diabetic nephropathy. From this pilot study, we have found a panel of potential candidate proteins that can be further studied in a larger scale protein profiling study which can eventually lead to the discovery of more specific biomarkers which can act as a management adjunct by accurately diagnosing, prognosticating and aid in treatment of MN.

Membranous Nephropathy (MN) Recurrence After Renal Transplantation.

Primary membranous nephropathy (MN) is a frequent cause of NS in adults. In native kidneys the disease may progress to ESRD in the long term, in some 40–50% of untreated patients. The identification of the pathogenic role of anti-podocyte autoantibodies and the development of new therapeutic options has achieved an amelioration in the prognosis of this disease. MN may also develop in renal allograft as a recurrent or a de novo disease. Since the de novo MN may have some different pathogenetic and morphologic features compared to recurrent MN, in the present paper we will deal only with the recurrent disease. The true incidence of the recurrent form is difficult to assess. This is mainly due to the variable graft biopsy policies in kidney transplantation, among the different transplant centers. Anti-phospholipase A2 receptor (PLA2R) autoantibodies are detected in 70–80% of patients. The knowledge of anti-PLA2R status before transplant is useful in predicting the risk of recurrence. In addition, the serial survey of the anti-PLA2R titers is important to assess the rate of disease progression and the response to treatment. Currently, there are no established guidelines for prevention and treatment of recurrent MN. Symptomatic therapy may help to reduce the signs and symptoms related to the nephrotic syndrome. Anecdotal cases of response to cyclical therapy with steroids and cyclophosphamide have been published. Promising results have been reported with rituximab in both prophylaxis and treatment of recurrence. However, these results are based on observational data, and prospective controlled trials are still missing.

Sanqi oral solution ameliorates renal damage and restores podocyte injury in experimental membranous nephropathy via suppression of NFκB

Membranous nephropathy (MN) is one of the leading causes of nephrotic syndrome in adults. However, the current treatment of MN has been a matter of fierce debate for decades, and the needs for more advanced pharmaceuticals are critical for improving the treatment strategies. Sanqi oral solution (SQ), mainly consisting of Radix Astragali and Radix Notoginseng, is a formulated product to treat chronic kidney disease for over 20 years with good efficiency in clinic, while the role of SQ on MN remains unclear. In this study, by establishing an experimental rat model of membranous nephropathy induced by cationic Bovine Serum Albumin (C-BSA), we tried to investigate the effects of SQ. We found that administration of SQ ameliorated MN by reducing proteinuria, elevating serum albumin, and ameliorating pathological renal damages. SQ also significantly reduced the C3 and IgG depositions, and restored podocin and synaptopodin expressions. Furthermore, SQ inhibited the activation of nuclear factor-kappa B (NF-κB) signaling pathway. Our results provide evidence that SQ exerts a novel therapeutic effect on MN via reducing proteinuria, ameliorating renal damage and restoring podocyte injuries, which are associated with the suppression of NFκB.

Efficacy and safety of rituximab therapy for membranous nephropathy: a meta-analysis.

Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults, but the treatment of MN remains controversial. Rituximab, a possible alternative treatment option, represented a new therapeutic hope for the treatment of membranous nephropathy (MN). We performed a meta-analysis to perform the efficacy and safety of rituximab therapy. Either randomized controlled trials (RCTs), cohort studies or case studies were eligible for review and were performed in Medline, Embase, Web of Science, Cochrane database with the computerized searches. The primary outcome measure was remissions and the endpoint outcomes. We assessed the following studies methodological quality independently by using the Cochrane Collaboration tool for assessing risk of bias scale. The primary meta-analyses were performed using fixed or random effects models due to a1n expected clinical diversity. Five trials with a total of 351 patients were included. We found significant difference between rituximab and the placebo group on complete remissions rate (OR=1.6, 95%; CI=0.96, 2.66; I2 of 0% indicating no heterogeneity) and eGFR (MD=-0.69, 95% CI=-14.53, 0.73). The factors of remission and no remission MN patients who received treatment with rituximab on remission were proteinuria and albumin, which reported different (MD=7.20, 95% CI=-9.07, -5.33) (MD=10.70, 95% CI=7.23, 14.17). But remains high risk of infusion reactions (OR= 81.37, 95% CI=4.89, 1354.41). No evidence of significant risk of bias was reported. Rituximab had a beneficial effect and remissions of proteinuria on MN during follow-up times, but some adverse events were still unknown. Taking consideration of long-term therapeutic side effects and dose of the drug, we suggest that rituximab might replace cyclophosphamide and steroids as first-line immunosuppressive therapy in MN patients.

26 Cases of Intractable Membranous Nephropathy Glucocorticoid Combined Gilad Amine Clinical Curative Effect Observation

To study the clinical effect of glucocorticoid combined with thalidomide in the treatment of refractory nephrotic syndrome with membranous nephropathy. Methods: the pathological for membranous nephropathy of 26 patients with refractory nephrotic syndrome, glucocorticoid + gilad amine 50 mg 2 times/d, to turn the urine protein application again after 12 weeks after the reduction of 50 mg, l/d, maintain half year outage. The invalid was given a maximum of 24 weeks to stop the drug. The observation time was 24 weeks. Results: 24h urine protein decreased from 9.15 ±3.23 to 1.43±1.91 (P<0.01).Plasma albumin rose from 26.02 ± 6.75 to 35.57 ±4.02 (P<0.01). In most cases, the onset time was between 8 and 16 weeks, with a total relief of 30.77% in 24 weeks and 50.00% in partial relief, with a total effective rate of 80.77%.The main side effects are: rash, lethargy, fatigue, dizziness. No liver and kidney damage, bone marrow suppression. Conclusion: thalidomide combined with glucocorticoid is effective in the treatment of membranous nephropathy, with mild side effects, which provides a new way for the treatment of refractory membranous nephropathy.

Rituximab Exhibits Altered Pharmacokinetics in Patients With Membranous Nephropathy.

Rituximab (RTX) is a chimeric monoclonal anti-CD20 antibody used off-label in the treatment of membranous nephropathy (MN). Unfortunately, limited information is available on the pharmacokinetics of therapeutic proteins such as RTX in patients with glomerular kidney diseases. The current study evaluated RTX pharmacokinetics in patients with MN (n = 20) who received 4 RTX weekly intravenous infusions (375 mg/m2) over a month, with a repeat of the identical treatment at 6 months. Baseline patient characteristics were gender (17 male/3 female), age (49 ± 13 years), and body surface area (2.2 ± 0.24 m2). Compartmental pharmacokinetic analyses were conducted using Phoenix, and comparisons of these parameters were made between the MN patients and published data from 2 reference populations without kidney diseases (follicular lymphoma and autoimmune disorders). Patients with MN exhibited a shorter half-life, reduced volume of central compartment, decreased area under the serum concentration-time curve (exposure), and increased RTX clearance from the central compartment versus previous reports in the reference patient populations. These results suggest that shorter half-life and lower exposures to RTX in patients with MN may necessitate higher doses and/or changes to dosing frequency to optimize the relationships between serum concentrations and therapeutic effects.

Clinical Presentation, Outcomes, and Treatment of Membranous Nephropathy after Transplantation.

There are scarce data about clinical presentation and outcomes of posttransplant membranous nephropathy (MN), and few reports include a large number of patients. This was a retrospective cohort including adult patients with posttransplant MN transplanted between 1983 and 2015 in a single center (n=41). Only patients with histological diagnosis of MN in kidney grafts were included. Clinical and laboratory presentation, histological findings, treatment, and outcomes were detailed. Patients were predominantly male (58.5%), with a mean age of 49.4 ± 13.2 years; 15 were considered as recurrent primary MN; 3 were class V lupus nephritis; 14 were considered as de novo cases, 7 secondary and 7 primary MN; and 9 cases were considered primary but it was not possible to distinguish between de novo MN and recurrence. Main clinical presentations were proteinuria (75.6%) and graft dysfunction (34.1%). Most patients with primary recurrent and de novo primary MN were submitted to changes in maintenance immunosuppressive regimen, but no standard strategy was identified; 31 patients presented partial or complete remission, and glomerulopathy appeared not to impact graft and patient survival.