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The pathogenesis, diagnosis and treatment of lupus nephritis.

ABSTRACT: Renal involvement is a major cause of morbidity and mortality in systemic lupus erythematosus. In this review, we provide an update on recent discoveries in the pathogenesis, diagnosis, and treatment of lupus nephritis.Localized long-lived plasma cells have been identified as playing an important role in lupus nephritis. In addition, the roles of aberrant expression of microRNAs and proinflammatory cytokines have been explored. Early diagnosis is important for effective treatment and multiple biomarkers have been identified; however, none has been yet validated for clinical use. Biomarker panels may turn out to be more accurate than each individual component. Biologic agents for the treatment of lupus nephritis are being studied, including belimumab which was recently approved for nonrenal systemic lupus erythematosus. Rituximab has not proven itself in large, placebo-controlled trials, although it is still being used in refractory cases of lupus nephritis.Lupus nephritis is a potentially devastating complication of systemic lupus erythematosus. Immune cells, cytokines, and epigenetic factors have all been recently implicated in lupus nephritis pathogenesis. These recent discoveries may enable a paradigm shift in the treatment of this complex disease, allowing the tailoring of treatment to target specific pathogenic mediators at specific points in time in the progression of disease.

SUBMITTER: Schwartz N

PROVIDER: S-EPMC4221732 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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CD11b Activity Modulates Pathogenesis of Lupus Nephritis.

Project description:Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE) with unclear etiology and limited treatment options. Immune cell infiltration into the kidneys, a hallmark of LN, triggers tissue damage and proteinuria. CD11b, the α-chain of integrin receptor CD11b/CD18 (also known as αMβ2, Mac-1, and CR3), is highly expressed on the surface of innate immune cells, including macrophages and neutrophils. Genetic variants in the human ITGAM gene, which encodes for CD11b, are strongly associated with susceptibility to SLE, LN, and other complications of SLE. CD11b modulates several key biological functions in innate immune cells, including cell adhesion, migration, and phagocytosis. CD11b also modulates other signaling pathways in these cells, such as the Toll-like receptor signaling pathways, that mediate generation of type I interferons, a key proinflammatory cytokine and circulating biomarker in SLE and LN patients. However, how variants in ITGAM gene contribute to disease pathogenesis has not been completely established. Here, we provide an overview of CD11b modulated mechanisms and the functional consequences of the genetic variants that can drive disease pathogenesis. We also present recent insights from studies after pharmacological activation of CD11b. These studies offer novel mechanisms for development of therapeutics for LN, SLE and other autoimmune diseases.

| S-EPMC5862812 | biostudies-literature

The treatment of lupus nephritis.

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Advances in Lupus Nephritis Pathogenesis: From Bench to Bedside.

Project description:Systemic lupus erythematosus (SLE) is the prototype of autoimmune disorders caused by a loss of tolerance to endogenous nuclear antigens triggering an aberrant autoimmune response targeting various tissues. Lupus nephritis (LN), a major cause of morbidity and mortality in patients with SLE, affects up to 60% of patients. The recent insights into the genetic and molecular basis of SLE and LN paved the way for newer therapies to be developed for these patients. Apart from the traditional B-cell-centered view of this disease pathogenesis, acknowledging that multiple extrarenal and intrarenal pathways contribute to kidney-specific autoimmunity and injury may help refine the individual therapeutic and prognostic characterization of such patients. Accordingly, the formerly induction-maintenance treatment strategy was recently challenged with the exciting results obtained from the trials that evaluated add-on therapy with voclosporin, belimumab, or Obinutuzumab. The scope of this review is to provide an insight into the current knowledge of LN pathogenesis and future therapeutic strategies.

| S-EPMC8038540 | biostudies-literature

Gender differences in the pathogenesis and outcome of lupus and of lupus nephritis.

Project description:Systemic Lupus Erythematosus (SLE) typically affects females at far greater rates than males; however male SLE patients often have more severe disease than females. The gender disparities have been reported in clinical manifestations and in serological and hematological indices as well. In particular, SLE complicated with nephritis is more frequent in men than women, and several groups identified male gender as a risk factor for progression to renal failure. The specific differences in pathogenesis amongst genders have yet to be conclusively defined, though genetic, hormonal, and immune responses have been analyzed thus far. Further research is warranted to further elucidate these differences and permit the development of gender-tailored treatment regimens.

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Lupus nephritis or not? A simple and clinically friendly machine learning pipeline to help diagnosis of lupus nephritis.

Project description:ObjectiveDiagnosis of lupus nephritis (LN) is a complex process, which usually requires renal biopsy. We aim to establish a machine learning pipeline to help diagnosis of LN.MethodsA cohort of 681 systemic lupus erythematosus (SLE) patients without LN and 786 SLE patients with LN was established, and a total of 95 clinical, laboratory data and 17 meteorological indicators were collected. After tenfold cross-validation, the patients were divided into training set and test set. The features selected by collective feature selection method of mutual information (MI) and multisurf were used to construct the models of logistic regression, decision tree, random forest, naive Bayes, support vector machine (SVM), light gradient boosting (LGB), extreme gradient boosting (XGB), and artificial neural network (ANN), the models were compared and verified in post-analysis.ResultsCollective feature selection method screens out antistreptolysin (ASO), retinol binding protein (RBP), lupus anticoagulant 1 (LA1), LA2, proteinuria and other features, and the hyperparameter optimized XGB (ROC: AUC = 0.995; PRC: AUC = 1.000, APS = 1.000; balance accuracy: 0.990) has the best performance, followed by LGB (ROC: AUC = 0.992; PRC: AUC = 0.997, APS = 0.977; balance accuracy: 0.957). The worst performance is naive Bayes model (ROC: AUC = 0.799; PRC: AUC = 0.822, APS = 0.823; balance accuracy: 0.693). In the composite feature importance bar plots, ASO, RF, Up/Ucr, and other features play important roles in LN.ConclusionWe developed and validated a new and simple machine learning pathway for diagnosis of LN, especially the XGB model based on ASO, LA1, LA2, proteinuria, and other features screened out by collective feature selection.

| S-EPMC10257380 | biostudies-literature

Editorial: Systemic lupus erythematosus - predisposition factors, pathogenesis, diagnosis, treatment and disease models.

Project description: Not available

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MicroRNAs in Lupus Nephritis-Role in Disease Pathogenesis and Clinical Applications.

Project description:MicroRNAs (miRs) are non-coding small RNAs that act as epigenetic modulators to regulate the protein levels of target mRNAs without modifying the genetic sequences. The role of miRs in the pathogenesis of lupus nephritis (LN) is increasingly recognized and highly complex. Altered levels of different miRs are observed in the blood, urine and kidney tissues of murine LN models and LN patients. Accumulating evidence suggests that these miRs can modulate immune cells and various key inflammatory pathways, and their perturbations contribute to the aberrant immune response in LN. The dysregulation of miRs in different resident renal cells and urinary exosomes can also lead to abnormal renal cell proliferation, inflammation and kidney fibrosis in LN. While miRs may hold promise in various clinical applications in LN patients, there are still many potential limitations and safety concerns for their use. Further studies are worthwhile to examine the clinical utility of miRs in the diagnosis, disease activity monitoring, prognostication and treatment of LN.

| S-EPMC8509214 | biostudies-literature

Pathogenesis of lupus nephritis: RIP3 dependent necroptosis and NLRP3 inflammasome activation.

Project description:RIP3 activation leads to activation of necroptosis and the NLRP3 inflammasome pathways. The activation of RIP3 in lupus nephritis (LN) has not been investigated. In this study, RIP3 and necroptosis pathway activations were demonstrated in podocytes in renal biopsies from patients with class IV LN and in the diseased kidneys from lupus-prone NZM2328 and MRL/lpr mice. RIP3 activation was accompanied with the activation of MLKL, the effector molecule of the necroptosis pathway, and activation of caspase-1, the effector of the NLRP3 inflammasome pathway. Podocyte activation of RIP3 was detected readily with the development of LN in NZM2328 mice, suggesting this activation may play a significant role in the pathogenesis of LN. GSK872, a RIP3 specific inhibitor, inhibited the development of LN in MRL/lpr mice with down-regulation of RIP3 activation in podocytes, decreased the splenic sizes and weights and anti-dsDNA antibody titers. IgG from pooled sera of diseased NZM2328 mice succumbing to LN induced both the necroptosis pathway and NLRP3 inflammasome activation in a podocyte cell line and this activation was specifically blocked by GSK872. These results indicate that the necroptosis pathway and the RIP3 dependent NLRP3 inflammasome pathway are activated in podocytes during LN. Inhibition of RIP3 kinase may be a novel therapeutic approach to treat LN and systemic lupus erythematosus (SLE).

| S-EPMC6708470 | biostudies-literature

Intertwined pathways of complement activation command the pathogenesis of lupus nephritis.

Project description:The complement system is involved in the origin of autoimmunity and systemic lupus erythematosus. Both genetic deficiency of complement components and excessive activation are involved in primary and secondary renal diseases, including lupus nephritis. Among the pathways, the classical pathway has long been accepted as the main pathway of complement activation in systemic lupus erythematosus. However, more recent studies have shown the contribution of factors B and D which implies the involvement of the alternative pathway. While there is evidence on the role of the lectin pathway in systemic lupus erythematosus, it is yet to be demonstrated whether this pathway is protective or harmful in lupus nephritis. Complement is being explored for the development of disease biomarkers and therapeutic targeting. In the current review we discuss the involvement of complement in lupus nephritis.

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De novo lupus nephritis during treatment with belimumab.

Project description:ObjectiveIn light of reports of de novo LN during belimumab (BLM) treatment, we sought to determine its frequency and contributing or protective factors in a real-life setting.MethodsPatients with SLE who received BLM between 2011 and 2017 at five European academic practices were enrolled (n = 95) and followed longitudinally for a median time of 13.1 months [interquartile range (IQR): 6.0-34.7]; 52.6% were anti-dsDNA positive, 60.0% had low complement levels, and 69.5% had no renal involvement prior to/at BLM initiation [mean disease duration at baseline: 11.4 (9.3) years]. Age- and sex-matched patients with non-renal SLE who had similar serological profiles, but were not exposed to BLM, served as controls (median follow-up: 132.0 months; IQR: 98.3-151.2).ResultsWe observed 6/66 cases (9.1%) of biopsy-proven de novo LN (4/6 proliferative) among the non-renal BLM-treated SLE cases after a follow-up of 7.4 months (IQR: 2.7-22.2). Among controls, 2/66 cases (3.0%) of de novo LN (both proliferative) were observed after 21 and 50 months. BLM treatment was associated with an increased frequency and/or shorter time to de novo LN [hazard ratio (HR): 10.7; 95% CI: 1.7, 67.9; P = 0.012], while concomitant use of antimalarial agents along with BLM showed an opposing association (HR: 0.2; 95% CI: 0.03, 0.97; P = 0.046).ConclusionAddition of BLM to standard-of-care did not prevent LN in patients with active non-renal SLE, but a favourable effect of concomitant use of antimalarials was implicated. Studies of whether effects of B-cell activating factor inhibition on lymphocyte subsets contribute to LN susceptibility are warranted.

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