iMN Patients Research Articles

A dynamic online nomogram for predicting renal outcomes of idiopathic membranous nephropathy

BackgroundBecause spontaneous remission is common in IMN, and there are adverse effects of immunosuppressive therapy, it is important to assess the risk of progressive loss of renal function before deciding whether and when to initiate immunosuppressive therapy. Therefore, this study aimed to establish a risk prediction model to predict patient prognosis and treatment response to help clinicians evaluate patient prognosis and decide on the best treatment regimen.MethodsFrom September 2019 to December 2020, a total of 232 newly diagnosed IMN patients from three hospitals in Liaoning Province were enrolled. Logistic regression analysis selected the risk factors affecting the prognosis, and a dynamic online nomogram prognostic model was constructed based on extreme gradient boost, random forest, logistic regression machine learning algorithms. Receiver operating characteristic and calibration curves and decision curve analysis were utilized to assess the performance and clinical utility of the developed model.ResultsA total of 130 patients were in the training cohort and 102 patients in the validation cohort. Logistic regression analysis identified four risk factors: course ≥ 6 months, UTP, D-dimer and sPLA2R-Ab. The random forest algorithm showed the best performance with the highest AUROC (0.869). The nomogram had excellent discrimination ability, calibration ability and clinical practicability in both the training cohort and the validation cohort.ConclusionsThe dynamic online nomogram model can effectively assess the prognosis and treatment response of IMN patients. This will help clinicians assess the patient’s prognosis more accurately, communicate with the patient in advance, and jointly select the most appropriate treatment plan.

#2086 Understanding B cell memory autoreactivity in idiopathic membranous nephropathy for tailored therapy

Abstract Background and Aims Idiopathic membranous nephropathy (iMN) is an autoantibody-mediated glomerular disease, and one of the leading causes of nephrotic syndrome in adults. iMN is caused by the formation of immune complexes composed by IgG autoantibodies and target antigens expressed on podocytes. The main autoantigen is the phospholipase A2 receptor1 (PLA2R1) and the antibodies are mainly belonging to the IgG4 isotype. Those immune complexes are responsible for profound changes in the structure and function of the podocytes and disruption of the glomerular barrier. Nevertheless, despite complement components at the site of glomerular injury have been found in biopsies from patients with MN, many factors involved in the pathogenesis are still unclear. We overall aim at characterizing both the serological and the memory cellular component in iMN patients, with identification of dominant B cell epitopes recognized by circulating autoantibodies and autoreactive memory B cells, which could be potentially used to deplete PLA2R1 specific memory B cells and plasma blasts. Method We analyzed the serum from a cohort of 159 iMN patients collected at diagnosis without any previous or concomitant treatment as well as a similar number of healthy controls’ samples. An ELISA-based quantification method has been used to estimate the concentration of circulating anti-PLA2R1 antibodies. Furthermore, we processed 27 additional blood samples from independent iMN patients as well as age and gender matched healthy controls to extract and analyze peripheral blood mononuclear cells by flow cytometry (BD FACS Fortessa) and identify the major B and T cell populations via multi-color staining. In order to identify and clone human anti-PLA2R1 antibodies from primary memory B cells we reproduced the experimental workflow exactly as described in Lindner J.M. et al. Immunity 2019. The isolated antibodies were then characterized with analytical methods (affinity, binding, epitope determination and complement activation ability) and used in competition assays. Results A deep analysis of the serum reactivity has been performed and iMN patients showed a high prevalence of autoantibodies against PLA2R1, mostly of high affine IgG4 subclass with a broad concentration range (1-20ug/ml). A concomitant IgG1 response versus PLA2R1 has been also detected in the serum in different proportion with IgG4. An extended immunophenotyping of circulating peripheral blood mononuclear cells revealed an altered B and T cell compartment in iMN patients. In particular, we described an expansion of circulating CD27neg IgG4 memory B cells, IgG4 plasma blasts, CD4+ T follicular helper cells and CX3CR1+ T peripheral helper cells. Moreover, we isolated and cloned five very specific, highly affine, and somatically hypermutated patient's derived anti-PLA2R1 antibodies. Competition experiments between patient sera and patients’ derived monoclonal antibodies showed a strong inhibitory effect, indicating the presence of a shared epitope recognized on the surface of the CysR domain of PLA2R1. The identified epitope has also shown an important role in complement activation, despite a component patient-specific seems to be involved as well. Conclusion Overall, we performed a comprehensive characterization of the autoreactive B cell memory compartment in iMN, shedding lights on the complexity of the autoantibody repertoire. Indeed, the investigation of the granularity of the anti-PLA2R1 response in term of IgG1 versus IgG4 isotypes provided a potential new way to stratify the patients’ population and potentially tailored the therapy or follow the disease progression. Moreover, the isolation of patient's derived anti-PLA2R1 antibodies opened the possibility of using them the as tools to establish new models directly from the in vivo-selected specificities. Finally, the identification of an immunodominant epitope within PLA2R1 shared among the patients is crucial to develop molecules aimed at depletion of PLA2R1 specific memory B cells and plasma blasts in the patients.

#1305 Analysis of clinicopathological characteristics of membranous nephropathy with concomitant malignancy and literature review

Abstract Background and Aims In recent years, the incidence of membranous nephropathy (MN) with malignancy has gradually increased, but the clinical and pathological characteristics of these patients are still unclear. Method Patients diagnosed with renal biopsy-proven MN and comorbid malignancy detected within 5 years before and after MN diagnosis were included. The control group were diagnosed with renal biopsy-proven IMN with no malignancy and no other clear secondary cause for MN. We present a comprehensive analysis of MN with concomitant malignancy in our cohort and literature review. Results A total of 19 MN patients with concomitant malignancy were evaluated at our center; among them, 13 (68.4%) were male, and the median age was 57.0 (45.0, 69.0) years. Malignancy occurred after the onset of renal disease in 61.1% of patients, with digestive system malignancy (36.8%) ranking as the predominant type. 8 (8/11) patients achieved either PR or CR during the follow-up period. Most patients had pathology typical of IMN. IF showed strong positivity for IgG (100%), whereas only 13 (68.4%) patients were positive for C3. IEM showed electron-dense deposits predominantly located in subepithelial. Specific MN antigen staining of renal tissues from 19 patients showed that the highest percentage was 68.4% (13/19) for PLA2R-only positivity followed by 15.8% (3/19) for THSD7A-only positivity. Specific MN antigen staining of malignant tissue was performed in 5 patients whose tumor samples were available. Only 2 patients expressed the same antigen on kidney and tumor. Screening 17 articles encompassing a total of 21 patients in whom MN-specific antigen staining was performed on both renal and tumor tissues simultaneously. Among these patients, 71.4% (15/21) were male, with a median age of 61.0 years (56.3, 72.8). In this cohort, malignancy was diagnosed before or simultaneously with MN in 15 patients (75.0%), with digestive system malignancy constituting the most prevalent comorbid malignancy, at 33.3%. Notably, THSD7A accounted for the highest proportion of MN antigens, at 66.7% (14/21); among these patients, 78.6% (11/14) also exhibited positive tumor THSD7A staining. Of the 21 patients, 72.2% (13/18) achieved CR or PR. No significant difference between the baseline characteristics was observed between the 19 patients from our center and 21 patients documented in the literature. Therefore, the clinicopathological data of these 40 patients were pooled and compared with 101 IMN patients without malignancy at our center. Compared to patients without malignancy, MN patients with malignancy were older at the time of renal biopsy (P = 0.017), had a lower eGFR (P = 0.035) and demonstrated a lower rate of CR or PR after treatment (P < 0.001). The rate of PLA2R positivity in the glomeruli of MN patients with concomitant malignancy was significantly lower (40.0% vs. 92.1%, P < 0.001), while the rate of THSD7A positivity was significantly higher (42.5% vs. 2.0%, P < 0.001). Renal tissue IgG subclass staining showed that the rate of IgG4 positivity was significantly decreased compared with that in IMN patients (59.3% vs. 90.1%, P < 0.001), and the rate of IgG2 positivity was significantly increased (36.0% vs. 16.5%, P = 0.033). Conclusion To conclude, malignancy screening should be more actively performed for MN patients presenting with the above characteristics.

Containing anti-PLA2R IgG antibody induces podocyte injury in idiopathic membranous nephropathy

Background Idiopathic membranous nephropathy is widely recognized as an autoimmune kidney disease that is accompanied by the discovery of several autoantibodies, and the antibody subclass in the circulation of patients with iMN is mainly IgG. However, the direct pathogenic effect of the containing anti-PLA2R IgG antibody on podocytes is not clear. Method A protein G affinity chromatography column was used to purify serum IgG antibodies. Containing anti-PLA2R IgG antibodies from iMN patients and IgG from healthy controls were also obtained. Based on the established in vitro podocyte culture system, purified IgG antibodies from the two groups were used to stimulate podocytes, and the expression of essential podocyte proteins (podocin), the levels of inflammatory cytokines in the cell supernatant, cytoskeletal disorders, and podocyte apoptosis were analyzed. Results Compared with that in the normal IgG group, the expression of podocin and podocin mRNA was reduced (p = 0.016 and p = 0.005, respectively), the fluorescence intensity of podocin on the surface of podocytes was reduced, the cytoskeleton of podocytes was disordered and reorganized, and the ratio of podocyte apoptosis was increased in the iMN group (p = 0.008). Conclusion The containing anti-PLA2R IgG antibody might have a direct damaging effect on podocytes in idiopathic membranous nephropathy.

Oxidative stress and inflammation are mediated via aryl hydrocarbon receptor signalling in idiopathic membranous nephropathy

Membranous nephropathy (MN) patients are diagnosed by the presence of phospholipase A2 receptor (PLA2R) before they progress to renal failure. However, the subepithelium-like immunocomplex deposit-mediated downstream molecular pathways are poorly understood. The aryl hydrocarbon receptor (AHR), NF-ƙB and Nrf2 pathways play central roles in the pathogenesis and progression of chronic kidney disease. However, their mutual effects on MN require further examination. Thus, we investigated the effect of AHR signalling on the NF-ƙB and Nrf2 pathways in IMN patients, cationic bovine serum albumin (CBSA)-injected rats and zymosan activation serum (ZAS)-treated podocytes. IMN patients show significantly decreased serum total protein and albumin levels, increased urine protein levels and intrarenal IgG4 and PLA2R protein expression in glomeruli compared with controls. IMN patients exhibited increased mRNA expression of intrarenal AHR and its target genes, including CYP1A1, CYP1A2, CYP1B1 and COX-2. This increase was accompanied by significantly upregulated protein expression of CD3, NF-ƙB p65 and COX-2 and significantly downregulated Nrf2 and HO-1 expression. Similarly, CBSA-induced rats showed severe proteinuria and activated intrarenal AHR signalling. This was accompanied by significantly upregulated protein expression of intrarenal p-IκBα, NF-κB p65 and its gene products, including COX-2, MCP-1, iNOS, 12-LOX, p47phox and p67phox, and significantly downregulated protein expression of Nrf2 and its gene products, including HO-1, catalase, GCLC, GCLM, MnSOD and NQO1. These results were further verified in ZAS-induced podocytes. Treatment with the AHR antagonist CH223191 and AHRsiRNA significantly preserved podocyte-specific protein expression and improved the NF-ƙB and Nrf2 pathways in ZAS-induced podocytes. In contrast, similar results were obtained in ZAS-induced podocytes treated with the NF-ƙB inhibitor BAY 11–7082 and NF-κBp65 siRNA. However, neither method had a significant effect on AHR signalling. Collectively, these results indicate that the NF-ƙB pathway is a downstream target of AHR signalling. Our findings suggest that blocking AHR signalling inhibits oxidative stress and inflammation, thereby improving proteinuria and renal injury.

Serum metabolomics analysis reveals metabolite profile and key biomarkers of idiopathic membranous nephropathy.

Idiopathic membranous nephropathy (IMN) is an organ-specific autoimmune disease with multiple and complex pathogenic mechanisms. Currently, renal biopsy is considered the gold standard for diagnosing membranous nephropathy. However, there were limitations to the renal puncture biopsy, such as the relatively high cost, longer time consuming, and the risk of invasive procedures. We investigated the profile of serum metabolites in IMN patients based on the UHPLC-QE-MS metabolomics technique for exploring the potential disease biomarkers and clinical implementation. In our research, we collected serum samples from healthy control (n = 15) and IMN patients (n = 25) to perform metabolomics analysis based on the UHPLC-QE-MS technique. We identified 215 differentially expressed metabolites (DEMs) between the IMN and healthy control (HC) groups. Furthermore, these DEMs were significantly identified in histidine metabolism, arginine and proline metabolism, pyrimidine metabolism, purine metabolism, and steroid hormone biosynthesis. Several key DEMs were significantly correlated with the level of clinical parameters, such as serum albumin, IgG, UTP, and cholesterol. Among them, dehydroepiandrosterone sulfate (DHEAS) was considered the reliable diagnostic biomarker in the IMN group. There was an increased abundance of actinobacteria, phylum proteobacteria, and class gammaproteobacterial in IMN patients for host-microbiome origin analysis. Our study revealed the profiles of DEMs from the IMN and HC groups. The result demonstrated that there were disorders of amino acids, nucleotides, and steroids hormones metabolism in IMN patients. The down-regulation of DHEAS may be associated with the imbalance of the immune environment in IMN patients. In host-microbiome origin analysis, the gut microbiota and metabolite disturbances were present in IMN patients.

APC ameliorates idiopathic membranous nephropathy by affecting podocyte apoptosis through the ERK1/2/YB-1/PLA2R1 axis

Idiopathic membranous nephropathy (IMN) belongs to an important pathogenic category of adult nephrotic syndrome. PLA2R1 exposure is critical for triggering the pathogenesis of PLA2R1-related IMN. However, the pathogenesis of IMN and the molecular mechanism of treatment remain to be further clarified. The expression changes of activated protein C (APC) and PLA2R1 in IMN patients were quantified by qPCR. A zymosan activated serum (ZAS)-induced IMN podocyte model was established in vitro. Podocyte apoptosis was detected via flow cytometry and caspase‑3 assay. The expression levels of APC, p-ERK1/2, ERK1/2, YB-1 and PLA2R1 were detected by western blotting. The regulation relationship between YB-1 and PLA2R1 was detected by dual fluorescent reporter system. In IMN patients, the expression level of PLA2R1 was increased, whereas the expression level of APC was decreased. When APC was added to podocytes in vitro, the phosphorylation of ERK1/2 was increased, which could promote the translocation of YB-1 to the nucleus that reduces the expression of PLA2R1 at the cellular transcriptional level, thereby inhibiting podocyte apoptosis. Our study is the first to report that APC can improve membranous nephropathy by affecting podocyte apoptosis through the ERK1/2/YB-1/PLA2R1 axis. This study will provide a new targeted therapy for IMN patients with high PLA2R1 expression.

The Clinical Profile and Long-Term Outcome of Children with Membranous Nephropathy, and the Evaluation of Anti-Phospholipase A2 Receptor Antibody Immunohistochemistry in Kidney Biopsy.

Idiopathic membranous nephropathy (iMN) is a rare cause of nephrotic syndrome in children (1%-7%). Anti-phospholipase A2 receptor (PLA2R) antibody positivity in kidney biopsy is observed in 52%-78% of adults and 45% of children with iMN. The objectives of the study are to analyze the clinical profile and outcome of membranous nephropathy in children, to assess the prevalence of anti-PLA2R immunohistochemistry (IHC) in kidney biopsy, and to correlate their presence with disease characteristics. We are reporting a single-center retrospective study conducted in pediatric nephrology division. Clinical data and outcome parameters of children with membranous nephropathy were analyzed. PLA2R IHC was performed in kidney biopsy specimens retrospectively. We analyzed 43 children with membranous nephropathy (MN) from a single center. 18 (42%) had idiopathic MN (iMN). PLA2R IHC was performed in kidney biopsy specimens in 14/18 (78%) patients with iMN and 7/9 (78%) non-lupus secondary membranous nephropathy (SMN) patients. The most common cause of SMN was lupus nephritis in 16 patients (64%). The mean estimated glomerular filtration rate (eGFR) at onset was 156 ± 81 ml/min/1.73m2. The sensitivity and specificity of PLA2R IHC in diagnosing pediatric MN was 50% and 57%, respectively; positive and negative predictive values were 70% and 36%, respectively. At the final follow-up, chronic kidney disease stage 5 (CKD 5) developed in 2/14 (14.3%) iMN patients. IHC PLA2R staining of glomerular tissue is a useful diagnostic marker of IMN. Though PLA2R prevalence is lower in children, its role in guiding treatment needs further exploration.

Urinary exosomal hsa_circ_0001250 as a novel diagnostic biomarker of idiopathic membranous nephropathy

AimsIdiopathic membranous nephropathy (IMN) is a common cause of adult nephrotic syndrome. Currently, the diagnosis of IMN mainly depends on renal biopsy, which is invasive. What’s more, markers already known for the clinical diagnosis of IMN are not sensitive enough. The present study aims to investigate the profiling of urinary exosomal circular RNAs (circRNAs) of IMN, and to look for a potential biomarker for diagnosis of IMN.MethodsUrine exosomes were collected from patients with IMN and idiopathic nephrotic syndrome (INS), as well as healthy controls (HCs) by ultracentrifuge. A pairwise comparison between 5 IMN and 5 HC was performed by high-throughput sequencing. Enrichment analysis were performed to explore the potential functions of differentially expressed circRNAs in IMN. Among three differentially expressed circRNAs which may be involved in signaling pathways of pathogenesis of IMN and matched conserved mouse circRNAs, hsa_circ_0001250 was selected as the target circRNA after quantitative polymerase chain reaction among 23 IMN, 19 INS and 23HC. Sanger sequencing and RNase R digestion assay were performed to validated the ring-structure and sequence of hsa_circ_0001250. ROC (Receiver Operating Characteristic) curve correlation analysis was used to further validate the potential utility of hsa_circ_0001250 as a diagnostic biomarker of IMN. A circRNA-miRNA-mRNA network was constructed to reflect the relationship between hsa_circ_0001250 and its target miRNAs and mRNAs.Results766 up-regulated and 283 down-regulated circRNAs were identified in IMN patients. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed signaling pathways of pathogenesis of IMN which the different expressed circRNAs may participate in. The ring-structure and the sequence of hsa_circ_0001250 were confirmed, the expression of hsa_circ_0001250 was validated significantly increased in IMN, relevant with high level of proteinuria. A circRNA-miRNA-mRNA network reflected that hsa_circ_0001250 may play a role in the pathogenesis of IMN by target hsa-miR-639 and hsa-miR-4449.ConclusionWe revealed the expression and functional profile of differentially expressed urinary exosomal circRNAs of IMN patients. Urinary exosomal hsa_circ_0001250 was tested as a potential biomarker of IMN and a predicted circRNA-miRNA-mRNA network was constructed.

Anti-phospholipase A2 receptor antibody levels at diagnosis predicts outcome of TAC-based treatment for idiopathic membranous nephropathy patients

BackgroundIdiopathic membranous nephropathy (iMN) is recognized as an organ-specific autoimmune disease, mainly caused by anti-PLA2R antibody. This study aimed to study between anti-PLA2R antibody level at diagnosis and the response to tacrolimus (TAC)-based treatment in iMN patients.MethodsThis was a retrospective cohort study including 94 kidney biopsy-proven MN patients with positive anti-PLA2R antibody at diagnosis from May 2017 to September 2021 in our center. All iMN patients received the TAC regimen as the initial immunosuppressive therapy. All patients were divided into two groups according to anti-PLA2R antibody titer at diagnosis: high-level group (> 150 RU/ml; n = 42) and low-level group (≤ 150 RU/ml; n = 52). The association between anti-PLA2R antibody levels and clinical outcomes was assessed using the Kaplan–Meier method.ResultsThe low density lipoprotein in the high-level group was significantly higher than low-level group at diagnosis, otherwise, serum albumin was significantly lower than low-level group; however, there was no significant difference in creatinine levels between two groups. The remission rates were significantly higher in the low-level group than high-level group after treatment with TAC for 12, 18, or 24 months (all P < 0.05). After 12 months of treatment with TAC, 82.7% of the patients in the low-level group achieved complete remission (CR) or partial remission (PR) (mean, 6.52 ± 0.53 months). However, 38.1% of the patients in high-level group achieved CR or PR (mean, 9.86 ± 0.51 months). Moreover, CR rate at 12 months in the high-level group was only 4.7% (mean, 11.88 ± 0.63 months). The infection frequency in the high-level group (35.6%) was higher than the low-level group (20%) during the TAC treatment, although there was no significant difference (P = 0.065). There were 19% patients who had end-stage kidney disease (ESKD), and 7.1% of patients died of ESKD in the high-level group during the follow-up period.ConclusionAnti-PLA2R antibody level above 150 RU/ml at diagnosis can predict a poor treatment response and outcome of TAC treatment in iMN patients, who may not benefit from TAC or other calcineurin inhibitor regimens as the initial treatment.

Association of serum mannose-binding lectin, anti-phospholipase A2 receptor antibody and renal outcomes in idiopathic membranous nephropathy and atypical membranous nephropathy: a single center retrospective cohort study

Objectives Idiopathic membranous nephropathy (iMN) is a major cause of nephrotic syndrome. Atypical membranous nephropathy (aMN) is a new type of nephropathy in China, characterized by a ‘full-house’ on immunofluorescent examination, that is IgG, IgA, IgM, C3, C1q positive, but without clinical evidence of a secondary cause. Phospholipase A2 receptor (PLA2R) was the major target antigens in iMN patients. Activation of the mannose-binding lectin (MBL) pathway plays a vital role in the development of MN. Our objective was to investigate the role of PLA2R and MBL in the pathogenesis of iMN and aMN. Methods We conducted a retrospective observational study using propensity score matching by age, gender, and eGFR. All clinical, laboratory data, and follow-up data of the patients were collected. Serum levels of anti-PLA2R antibodies and MBL were tested. Results Finally, 30 iMN patients and 30 aMN patients were included, and 20 healthy controls were retrospectively collected in this study. The 24 h proteinuria level was higher and serum albumin was lower in anti-PLA2R (+) patients than in anti-PLA2R (−) patients in both iMN and aMN groups. In aMN patients, MBL levels were significantly higher in anti-PLA2R (+) patients than in anti-PLA2R (−) patients (p = .045). The serum level of anti-PLA2R positively correlated with no-remission in both iMN and aMN groups. Conclusions The complement lectin pathway has an association with the development of MN, especially in patients with positive anti-PLA2R antibodies. Serum MBL cannot differentiate between the two diseases. Serum MBL levels are not associated with clinical manifestations, nor with prognosis.

Urinary peptidomics reveals proteases involved in idiopathic membranous nephropathy

BackgroundIdiopathic membranous nephropathy (IMN) is a cause of nephrotic syndrome that is increasing in incidence but has unclear pathogenesis. Urinary peptidomics is a promising technology for elucidating molecular mechanisms underlying diseases. Dysregulation of the proteolytic system is implicated in various diseases. Here, we aimed to conduct urinary peptidomics to identify IMN-related proteases.ResultsPeptide fingerprints indicated differences in naturally produced urinary peptide components among 20 healthy individuals, 22 patients with IMN, and 15 patients with other kidney diseases. In total, 1,080 peptide-matched proteins were identified, 279 proteins differentially expressed in the urine of IMN patients were screened, and 32 proteases were predicted; 55 of the matched proteins were also differentially expressed in the kidney tissues of IMN patients, and these were mainly involved in the regulation of proteasome-, lysosome-, and actin cytoskeleton-related signaling pathways. The 32 predicted proteases showed abnormal expression in the glomeruli of IMN patients based on Gene Expression Omnibus databases. Western blot revealed abnormal expression of calpain, matrix metalloproteinase 14, and cathepsin S in kidney tissues of patients with IMN.ConclusionsThis work shown the calpain/matrix metalloproteinase/cathepsin axis might be dysregulated in IMN. Our study is the first to systematically explore the role of proteases in IMN by urinary peptidomics, which are expected to facilitate discovery of better biomarkers for IMN.

Serum complement factor B is associated with disease activity and progression of idiopathic membranous nephropathy concomitant with IgA nephropathy.

Few studies have reported the roles of the complement system in concomitant idiopathic membranous nephropathy and IgA nephropathy (IMN-IgAN). Complement factor B (CFB) is a crucial factor that involved in the alternative complement pathway. We aimed to evaluate the association between disease activity (eGFR, anti-PLA2R antibody levels and 24h urinary protein excretion), progression and serum CFB levels of IMN-IgAN patients. In total, 39 IMN-IgAN patients (median follow-up, 46.6months), 99 IMN patients and 92 IgAN patients participated in this study. The disease progression event was defined as end-stage renal disease (ESRD) or a 30% decline in estimated glomerular filtration rate (eGFR). The serum CFB concentration was measured by enzyme-linked immunosorbent assay. Serum CFB levels were lower in IMN-IgAN patients than in patients with IgAN only (P < .001). Serum CFB levels correlated positively with serum creatinine levels, anti-PLA2R antibody levels and 24h urinary protein excretion (P < .05). Kaplan-Meier analysis revealed that IMN-IgAN patients with high serum CFB levels had a significantly lower cumulative renal survival rate than patients with low levels (log-rank test, P = .009). Multivariate Cox regression analysis showed that high baseline serum CFB levels were significantly associated with poor renal outcome in patients with IMN-IgAN (HR: 2.727, 95% CI 1.076-6.913, P = .034). High serum CFB levels correlated with increased serum creatinine, anti-PLA2R antibody and urinary protein excretion as well as poor renal prognosis in patients with IMN-IgAN, indicating that serum CFB may be a marker of disease activity and progression.

Renal outcomes of idiopathic and atypical membranous nephropathy in adult Chinese patients: a single center retrospective cohort study

BackgroundMembranous nephropathy (MN) is mainly classified into idiopathic MN (iMN) and secondary MN in etiology. In recent years, a new kind of membranous nephropathy, atypical membranous nephropathy (aMN) which shows “full house” in immunofluorescence but without definite etiology was paid more attention. In a single center cohort, the renal outcomes of iMN and aMN were compared.MethodsiMN and aMN patients were selected from renal pathology databank from January 2006 to December 2015. Patients’ demographics, laboratory values, induction regimens and patients’ responses were recorded. Specially, creatinine, eGFR, albumin and 24 h urinary protein excretion were recorded at 6th month after the induction of immunosuppressive (IS) treatment and at the end of follow up. Complete proteinuria remission was defined as urinary protein < 0.3 g/d, partial proteinuria remission was defined as urinary protein between 0.3 g/d ~ 3.5 g/d and decreased > 50 % from the baseline. The primary outcome was worsening renal function, defined as a 30 % or more decrease in eGFR or end-stage renal disease (eGFR < 15ml/min/1.73m2). COX proportional hazard models were used to test if aMN was a risk factor of worsening renal function compared with iMN.ResultsThere were 298 patients diagnosed with MN and followed in our center for 1 year or more, including 145 iMN patients with an average follow-up time of 4.5 ± 2.6 years, and 153 aMN patients with 4.1 ± 2.0 years (p = 0.109). The average age of iMN patients was older than aMN patients (56.1 ± 12.2 versus 47.2 ± 16.2 years old, p < 0.001). There were 99 iMN patients and 105 aMN patients with nephrotic range proteinuria and without previous immunosuppressive treatment. 93 (93.9 %) and 95 (90.5 %) patients underwent immunosuppressive treatment in iMN and aMN group, and there was no significant difference of the overall proteinuria remission rates at 6th month (59.1 % vs. 52.0 %, p = 0.334) and endpoint (73.7 % vs. 69.5 %, p = 0.505) between the two groups. 25 (25.3 %) patients in iMN group and 21 (20.0 %) patients in aMN group reached primary endpoint (X2 = 0.056, p = 0.812). Multivariate COX regression showed that after demographics, baseline laboratory values and remission status at 6th month were adjusted, aMN group had similar renal outcome compared with iMN group, the HR of primary outcome was 0.735 (95 % CI 0.360 ~ 1.503, p = 0.399).ConclusionsThe proteinuria remission rates and renal outcomes were similar in iMN and aMN patients after covariables were adjusted.

Efficacy and cost of different treatment in patients with idiopathic membranous nephropathy: A network meta-analysis and cost-effectiveness analysis

BackgroundIdiopathic membranous nephropathy (IMN) is the most common pathological type of adult nephrotic syndrome. However, the treatments for IMN patients had not been compared from the perspectives of therapeutic effect and pharmacoeconomics. Therefore, a network meta-analysis and a cost-effectiveness analysis were conducted to find the optimum treatment for IMN patients. MethodsRandomized controlled trials (RCTs) which compared the treatments including cyclophosphamide (CTX), mycophenolate mofetil (MMF), cyclosporine (CsA), tacrolimus (TAC), leflunomide (LEF), chlorambucil (CLB) and rituximab (RTX) for patients with IMN were reviewed. The complete and partial remission rates were extracted and then compared by network meta-analysis. The surface under the cumulative ranking area (SUCRA) was calculated to rank the remission rate for all treatments. Then, the cost-effectiveness analysis was performed to compared the incremental cost-effectiveness ratio (ICER) of different treatments. ResultsA total of 75 articles with 4806 participants were included according to the inclusion and exclusion criteria. Compared with the glucocorticoids (GC) group, CTX + GC (95%RR 1.02,1.76), CsA + GC (95%RR 1.11,2.13) and TAC + GC (95%RR 1.44,2.59) were associated with a significantly higher rate of complete remission. TAC + GC were most likely to be ranked the best (SUCRA of 92.1%). From the perspective of the cost-effectiveness analysis in China, the ICER of LEF + GC to CTX + GC was $30616.336 per unit utility, and that of TAC + GC to CTX + GC was $670475.210 per unit utility. And the ICER of CTX + GC to LEF + GC in the UK was $-65680.879 per unit utility. ConclusionsCTX + GC was the cheapest treatment with obvious curative effect in China, while LEF + GC was a cost-effective alternative to CTX + GC. The remission rate of TAC + GC was highest despite the high single-dose cost.

Acute kidney injury in idiopathic membranous nephropathy with nephrotic syndrome

Background and objectives The impact of acute kidney injury (AKI) on the progression of renal function in idiopathic membranous nephropathy (iMN) with nephrotic syndrome (NS) patients have not yet been reported, we sought to investigate the incidence, clinical features and prognosis of AKI in iMN with NS patients and determine clinical predictors for progression from AKI to advanced chronic kidney disease (CKD) stage. Methods We analyzed clinical and pathological data of iMN with NS patients retrospectively collected from Jan 2012 to Dec 2018. The primary renal endpoint was defined as persistent eGFR <45ml/min per 1.73 m2 more than 3 months. Comparisons of survival without primary renal endpoint were performed by Kaplan-Meier curves and log-rank test. Univariate and multivariate Cox proportional hazard models were constructed to determine independent variables associated with primary renal endpoint . Results 434 iMN with NS patients were enrolled. The incidence of AKI 1 stage, AKI 2 stage and AKI 3 stage was 23.1, 4.8 and 0.7% respectively. 66 (53.2%) patients with AKI had complete renal function recovery and 42 (33.9%) patients with AKI reached primary renal endpoint. Survival without primary renal endpoint was worse in AKI patients than No AKI patients (67.1 ± 5.3 and 43.7 ± 7.3% vs 99.5 ± 0.5 and 92.5 ± 4.2% at 2 and 4 years,p < 0.001). AKI was independently associated with primary renal endpoint, with an adjusted hazard ratio(HR) of 25.1 (95%CI 7.7–82.1, p < 0.001). Conclusions AKI was usually mild and overlooked in iMN patients with NS, but it had a strong association with poor clinical outcomes and was an independent risk factor for CKD progression.

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.

The impact of coexisting diabetes mellitus on clinical outcomes in patients with idiopathic membranous nephropathy: a retrospective observational study

BackgroundIdiopathic membranous nephropathy (IMN) is frequently coexisted with diabetes mellitus (DM). Few researches investigate clinical outcomes in IMN patients coexisting diabetes mellitus (DM), including remission rates, renal survival and complications. Concurrent DM also pose therapeutic challenges to IMN patients due to the influence of glucocorticoids and immunosuppressant on metabolic disorders. We performed this study to investigate the impact of DM on clinical outcomes in IMN and the influence of therapeutic regime on metabolic parameters in diabetic IMN patients.MethodsTwo hundred and six adult hospitalized patients diagnosed with biopsy-proven IMN were retrospectively studied, including 42 patients coexisted with DM. Clinical outcomes including remission rates, renal outcome and complications were compared between groups. Impact of cyclophosphamide and ciclosporin on metabolism and complications were analyzed in IMN patients coexisting DM.ResultsIMN patients coexisted with DM were presented with advanced age, lower level of eGFR and hemoglobin. Patients coexisted with DM experienced worse renal function deterioration and higher incidence of infection. COX regression analysis showed that DM was an independent risk factor for renal function deterioration in IMN patients. There was no significant difference in remission rates and incidence of venous thromboembolism between two groups. Further exploration on the impact of therapeutic regimens on complications and metabolism showed that cyclophosphamide and ciclosporin had no significant difference in incidence of complications including infection and venous thromboembolism, and posed comparable influences on blood glucose, uric acid and blood lipids in IMN patients coexisted with DM.ConclusionCoexisting DM was an independent risk factor for renal function deterioration in IMN patients but did not influence the remission of proteinuria. Glucocorticoids in combination with cyclophosphamide or ciclosporine had similar impact on complications and metabolic index including blood glucose, uric acid and blood lipids in IMN patients coexisted with DM.

P0411PREDICTORS OF RENAL AND PATIENT OUTCOME IN PATIENTS WITH IDIOPATHIC MEMBRANOUS NEPHROPATHY: FROM KOGNET DATA

Abstract Background and Aims Idiopathic membranous nephropathy (iMN) is a leading cause of nephrotic syndrome and one of the major causes of end-stage renal disease (ESRD). Various factors can affect renal and patient outcome in patients with iMN. In this study, we analyzed the predictors of renal and patient survival in patients with iMN. Method We analyzed 1,776 patients diagnosed with iMN in Korean GlomeruloNEphritis STudy (KoGNET), a retrospective database of patients with renal biopsy from 1979 to 2018 from 18 centers in Korea. Student t-test for continuous variables and Chi-square test for categorical variables were performed for analyses. Cox proportional hazard regression was used to determine risk factors affecting renal and patient survival. Results The mean age of patients was 53.0 ± 14.7 years old and 1,075 (60.5%) were male. At the time of renal biopsy, 755 (46.0%) and 266 (16.2%) had hypertension and diabetes, respectively. Serum albumin level was 2.7 ± 0.8 g/dL and 871 (49.0%) had nephrotic range of proteinuria. When analyzed by dividing over 65 and under, the hemoglobin and serum albumin level were lower, more patients showed nephrotic ranged proteinuria, and higher prevalence of comorbidities such as hypertension, diabetes, coronary heart disease and cerebrovascular disease in the group over 65 than in the group under 65. Median duration of follow-up was 88.0 (38.0 – 115.1) months. Complete or partial remission rates were 48.5%, 63.8%, and 68.0% at 6 months, 12months after biopsy, and last follow-up, respectively. In Cox proportional hazard regression, high hemoglobin [HR 0.66 (0.47 – 0.93), p=0.017], high serum albumin level [HR 0.41 (0.18 – 0.94), p=0.034], and high estimated GFR by CKD-EPI equation [HR 0.94 (0.91 – 0.96), p&amp;lt;0.001] at biopsy were good predictors for renal outcome, whereas presence of cerebrovascular disease at biopsy [HR 6.45 (1.16 – 35.71), p=0.033] were poor prognostic factors for ESRD. Age 65 and older [HR 3.26 (1.53 – 6.95), p=0.002] and presence of hypertension at biopsy [HR 2.45 (1.09 – 5.54), p=0.031] were significant risk factors for patient survival in multivariate Cox proportional regression analysis. Conclusion High hemoglobin and serum albumin, and good renal function at biopsy were good predictors for renal survival. Older age and hypertension at biopsy were poor prognostic factors for patient survival in iMN patients. Prognostic information of outcomes in this study might be helpful to optimize management in iMN patients.

P0287LONG-TERM CLINICAL OUTCOMES IN IDIOPATHIC MEMBRONOUS NEPHROPATHY TREATED BY CYCLOSPORINE AND PREDNISOLONE

Abstract Background and Aims Membranous nephropathy (MN) is the most common primary glomerular disease diagnosed in older patients. MN in adults is most often idiopathic, and risk factors of clinical findings for progressive idiopathic MN (iMN) seems to be older age at onset, male sex, and nephrotic-range proteinuria persisting for several months. Immunosuppressive therapy should be applied to the patients with iMN who have risk factors for progression, however little is known about the most effective regimen of immunosuppressive therapy. In addition, long-term prognosis of iMN for each immunosuppressive regimen is unclear. Most of the patients with iMN at our center were treated by prednisolone (PSL) and cyclosporine (CYA) combination therapy, and commencement of therapy was around the time of renal biopsy. The objective of this study is to assess medium to long-term outcome of treated iMN patients with CYA at our center. Method Retrospective data were collected from January 2000 to December 2014 on all consecutive 1080 native renal biopsy at our center. 102 cases were diagnosed as MN. Of 102 MN cases, 43 cases were iMN, which was IgG4 dominant or codominant in immunofluorescence of IgG subclass. Secondary MN is diagnosed by clinical history of possible drug use, the presence of malignancy, positive serologic tests for both infection and connective tissue diseases, hepatitis B or hepatitis C virus positive, and full house immunofluorescence. Results Of 43 iMN cases, there were 4 cases who were treated with only nonimmunosuppressive therapies, 5 cases who were treated with PSL, and 34 cases who were treated with CYA combination. Immunosuppressive therapy commenced within one month before and after renal biopsy. Immunosuppressive regimen was determined by each doctor. CYA was administered once-daily, and the area under the concentration-time curve up to 4 hour after administration of CYA (AUC0-4h) was determined in each patient. No infectious complications were found. The duration of CYA use was 194.7±848.9 days (median 786.5 days), and follow-up period of CYA group was 3026.4±1608.0 days. There were no significant differences between PSL group and CYA group in age (53.4±20.6 years vs. 64.1±10.6 years, p=0.162), sex (1 male 4 female vs. 23 male 11 female ,p=0.162), urinary protein (1.37±0.65 g/gCre vs. 5.44±3.64 g/gCre, p=0.0679), serum creatinine at the time of renal biopsy (0.66±0.19 mg/dl vs. 1.09±0.57 mg/dl, p=0.352), a 30% eGFR decline (0 cases vs. 2 cases), cases achieved complete remission (CR) (5 cases vs. 26 cases, p=0.196), and time from commencement of immunosuppressive therapy to CR (748.2±795.5 days vs. 422.2±379.9 days, p=0.242). There were no significant differences between non-remission cases in CYA group (8 cases) and remission cases in CYA group (26 cases) in age, sex, and urinary protein, but serum creatinine was significantly greater in non-remission cases than remission cases in CYA group (1.75±1.01 mg/dL vs. 0.94±0.29mg/dL, p=0.0251). There were no significant differences between non-recurrent cases in CYA group (16 cases) and recurrent cases (10 cases) in CYA group in age, sex, urinary protein, and serum creatinine at the time of renal biopsy. Conclusion Between PSL group and CYA group, there were no significant differences in age, and sex at the time of biopsy, and there was a trend that urinary protein was greater in CYA group than in PSL group (p=0.0679). Due to the tendency that urinary protein at the biopsy was greater in CYA group, no significant differences were seen in the remission rate and the time from commencement of immunosuppressive therapy to remission between PSL group and CYA group. Despite long duration of CYA use, infectious complications and renal function deterioration were not seen, so CYA can use safely by dose adjustment by AUC0-4h. Further study is needed to provide enough evidence of effectiveness of CYA combination therapy.