Lupus flare and recurrent lupus nephritis following kidney transplantation in patients with lupus nephritis.

BACKGROUND: Clinical manifestations and risk factors associated with systemic lupus erythematosus (SLE) flares, including recurrent lupus nephritis (LN), in patients with LN who undergo kidney transplantation have been unclear. METHODS: Kidney transplant recipients with LN from January 1995 to December 2021 were included in this study. A disease flare was defined as either an increase in the non-renal SLE disease activity index score or the presence of biopsy-proven recurrent LN. RESULTS: Among a total of 93 patients with LN who underwent kidney transplantation, 11 patients (11.8%) experienced SLE flares during a median follow-up period of 76.9 months (IQR, 43.0-122.4). The most common clinical manifestations of SLE flares were recurrent LN (4/11, 36.4%) and hematologic manifestations (4/11, 36.4%). Patients who had flares had significantly higher anti-double-stranded DNA (anti-dsDNA) antibody titers both before and after transplantation. Furthermore, an increased anti-dsDNA antibody level before transplantation was associated with a high risk of an SLE flare (HR, 1.030; p = .008). Conversely, preemptive transplantation was associated with a lower risk of a flare (HR, 0.617; p = .026). The rate of patient death-censored graft survival was found to be considerably lower in patients with recurrent LN than in those without LN. CONCLUSIONS: Approximately 10% of patients with LN experienced an SLE flare after transplantation, with recurrent LN being the most frequent manifestation. Anti-dsDNA antibody titers before transplantation were significantly related to the risk of an SLE flare. Notably, preemptive transplantation was associated with a reduced risk of flares following transplantation.

Demethylzeylasteral ameliorates podocyte damage in murine lupus by inhibiting inflammation and enhancing autophagy.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with multiorgan and tissue involvement. Lupus nephritis (LN), an inflammatory condition of the kidneys associated with SLE, represents a significant cause of morbidity and mortality in SLE patients. Current immunosuppressive therapies for LN have limited efficacy and can lead to significant side effects. Demethylzeylasteral (DML) has shown promise in the treatment of LN, but its precise mechanism of action remains unclear. PURPOSE: To assess the therapeutic effects and potential molecular mechanisms of DML in LN METHODS: The study evaluated the renal protective effects of DML in MRL/lpr mice through assessments of immune complex levels, renal function, and pathological changes. Network pharmacology and transcriptomics approaches were used to elucidate the underlying mechanisms. Molecular docking, biacore assay, monoclonal antibody blocking experiments, and in vitro studies were conducted to verify the mechanisms of action. RESULTS: DML treatment reduced levels of anti-Sm and anti-dsDNA IgG antibodies, as well as serum creatinine and blood urea nitrogen levels. DML also mitigated glomerular damage and fibrosis. Mechanistically, DML alleviated podocyte damage by suppressing inflammation and enhancing autophagy through inhibition of the IL-17A/JAK2-STAT3 pathways. Additionally, DML exhibited high binding affinity with IL17A, JAK2, and STAT3. CONCLUSION: These findings provide strong evidence for the beneficial effects of DML in LN, suggesting its potential as a novel therapeutic strategy for improving renal function in autoimmune kidney diseases.

Severe lupus nephritis in a young adult with PTEN hamartoma tumour syndrome.

On chromosome 10q23 is found the PTEN gene, which encodes a phosphate and tension homologue. The protein dephosphorylates phosphatidylinositol-(3,4,5)-trisphosphate at the plasma membrane to produce inorganic phosphatidylinositol-(4,5)-bisphosphate. This enzymatic activity inhibits the phosphatidylinositol-3-kinase, protein kinase B and mammalian target of the rapamycin signalling cascade. Consequently, essential cellular functions, including metabolic regulation, cellular growth, proliferation and viability, are affected. A mutation in this gene gives rise to hamartoma tumour syndrome, which exhibits a range of phenotypes, including Bannayan-Riley-Ruvalcaba syndrome, Cowden syndrome and proteus-like disease. A man in his late 20s with a PTEN tumour-like arteriovenous malformation in the right thigh was recently diagnosed with lupus nephritis. The patient's nephritic symptoms, pleural effusion, dyslipidaemia and splenomegaly demonstrate systemic lupus erythematosus (SLE) multisystem involvement. The case report identifies an association between a PTEN mutation and a new diagnosis of SLE that might have been triggered by PTEN-associated immune dysregulation.

Identification of amino acids metabolomic profiling in human plasma distinguishes lupus nephritis from systemic lupus erythematosus.

Lupus nephritis (LN) is an immunoinflammatory glomerulonephritis associated with renal involvement in systemic lupus erythematosus (SLE). Given the close relationship between plasma amino acids (AAs) and renal function, this study aimed to elucidate the plasma AA profiles in LN patients and identify key AAs and diagnostic patterns that distinguish LN patients from those with SLE and healthy controls. Participants were categorized into three groups: normal controls (NC), SLE, and LN. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was employed to quantify AA levels in human plasma. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were utilized to identify key AAs. The diagnostic capacity of the models was assessed using receiver operating characteristic (ROC) curve analysis and area under the ROC curve (AUC) values. Significant alterations in plasma AA profiles were observed in LN patients compared to the SLE and NC groups. The OPLS-DA model effectively separated LN patients from the SLE and NC groups. A joint model using histidine (His), lysine (Lys), and tryptophan (Trp) demonstrated exceptional diagnostic performance, achieving an AUC of 1.0 with 100% sensitivity, specificity, and accuracy in predicting LN. Another joint model comprising arginine (Arg), valine (Val), and Trp also exhibited robust predictive performance, with an AUC of 0.998, sensitivity of 93.80%, specificity of 100%, and accuracy of 95.78% in distinguishing between SLE and LN. The joint forecasting models showed excellent predictive capabilities in identifying LN and categorizing lupus disease status. This approach provides a novel perspective for the early identification, prevention, treatment, and management of LN based on variations in plasma AA levels.

Use of belimumab in treating patients with systemic lupus erythematosus: a single-center, real-world retrospective study.

OBJECTIVE: To investigate the efficacy and safety of belimumab in the treatment of systemic lupus erythematosus (SLE) in a real-world setting and provide a valuable reference for clinical treatment. METHODS: In this retrospective study, 101 patients with SLE who came to our hospital from March 2020 to September 2022, 56 of whom with lupus nephritis (LN), were selected. All patients received belimumab in combination with standard of care(SoC)therapy regimen for more than 52 weeks and their clinical/laboratory data, assessment of disease activity, glucocorticoids dosage and occurrence of adverse events were recorded. Lupus Low Disease Activity State (LLDAS) and DORIS remission as a primary goal in the treatment of SLE. The groups were classified according to the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2 K): SLEDAI-2 K < 6 was categorized as the mild group (mild activity) and SLEDAI-2 K ≥ 6 was categorized as the active group (moderate-severe activity). The disease of the two groups mentioned above were assessed using the SELENA-SLEDAI Flare Index (SFI) and the SLE Responder Index-4 (SRI-4), respectively. Furthermore, we used complete remission (CR) and partial remission (PR) in the kidney as the standard for efficacy evaluation for LN patients. RESULTS: After 52 weeks of treatment with belimumab, patients' complement levels increased significantly (p < 0.05); Other indicators such as 24-hour urine protein quantification and daily glucocorticoids dose decreased compared to pretreatment (p < 0.05). At 52 weeks, (i) after evaluation, the whole group of patients showed significant improvement in their condition; (ii) 55.4% of patients achieved LLDAS and 23.8% achieved DORIS remission; (iii) 73.2% of patients with LN achieved CR, 16.1% achieved PR. Adverse reactions were observed in 15 patients (14.9%), all of which normalized after symptomatic treatment. CONCLUSIONS: In general, during treatment with belimumab, immunological and biochemical indices improved in SLE patients, urinary protein levels were reduced in LN patients, and the rate of renal function remission was effectively increased; At the same time, the use of belimumab is associated with a low frequency of side effects, good overall tolerability and a favorable safety profile.

MME and PTPRC: key renal biomarkers in lupus nephritis.

Background: Lupus nephritis (LN) is an autoimmune-related kidney disease with a poor prognosis, however the potential pathogenic mechanism remains unclear and there is a lack of precise biomarkers. Therefore, a thorough screening and identification of renal markers in LN are immensely beneficial to the research on its pathogenic mechanisms and treatment strategies. Methods: We utilized bioinformatics to analyze the differentially expressed genes (DEGs) at the transcriptome level of three clusters: total renal, glomeruli, and renal tubulointerstitium in the GEO database to discover potential renal biomarkers of LN. We utilized NephroSeq datasets and measured mRNA and protein levels in the kidneys of MRL/lpr mice to confirm the expression of key DEGs. Results: Seven significantly differential genes (EGR1, MME, PTPRC, RORC, MX1, ZBTB16, FKBP5) were revealed from the transcriptome database of GSE200306, which were mostly enriched in the pathway of the hematopoietic cell lineage and T cell differentiation respectively by KEGG and GO analysis. The seven hot differential genes were verified to have consistent change trends using three datasets from NephroSeq database. The receiver operating characteristic (ROC) curve indicated that five DEGs (PTPRC, MX1, EGR1, MME and RORC) exhibited a higher diagnostic ROC value in both the glomerulus and tubulointerstitium group. Validation of core genes using MRL/lpr mice showed that MME and PTPRC exhibit significantly differential mRNA and protein expression patterns in mouse kidneys like the datasets. Conclusions: This study identified seven key renal biomarkers through bioinformatics analysis using the GEO and NephroSeq databases. It was identified that MME and PTPRC may have a high predictive value as renal biomarkers in the pathogenesis of LN, as confirmed by animal validation.

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OBJECTIVES: To study the risk factors and prognostic characteristics of pediatric silent lupus nephritis (SLN) with class Ⅲ to V. METHODS: A retrospective study was conducted to collect clinical data from 30 children diagnosed with SLN at the Department of Pediatrics, Second Xiangya Hospital, Central South University, from May 2007 to April 2023. Based on renal pathological classification, the patients were divided into a class Ⅱ group (12 cases) and a class Ⅲ to Ⅴ group (18 cases). The risk factors for the occurrence of class Ⅲ to Ⅴ SLN were analyzed, and the prognostic characteristics were summarized. RESULTS: Among the 30 SLN patients, the median follow-up time was 61.50 months. There were no statistically significant differences in the proportions of patients who discontinued glucocorticoids or achieved low disease activity status, nor in the annual decline rate of estimated glomerular filtration rate (eGFR) between the class Ⅱ and class Ⅲ to V groups (P>0.05). However, three patients in the class Ⅱ group progressed to stage 1 chronic kidney disease (CKD), while eight patients in the class III to V group reached stage 1 CKD, and four patients reached stage 2 CKD. Among the 26 female SLN patients, serum complement C3 levels in the class III to V group were lower than those in the class Ⅱ group (P<0.05). Serum C3 levels in SLN patients, as well as in female SLN patients, were negatively correlated with the fluorescence intensity of IgA, IgG, and C3 immune complexes in the kidneys (P<0.05). Additionally, serum C3 levels in female SLN patients were negatively correlated with the renal pathological activity index (P<0.05). Binary logistic regression analysis indicated that being female and having low serum complement C3 levels were risk factors for the occurrence of class Ⅲ to V SLN in children (P<0.05). CONCLUSIONS: Class Ⅲ to V SLN is not uncommon among SLN children, and there remains a risk of long-term renal function progression. Being female and having low serum complement C3 levels are identified as risk factors for class Ⅲ to V SLN in children.

Clinical outcomes in lupus nephritis patients treated with belimumab in real-life setting: a retrospective comparative study in China.

Objective: The use of belimumab in treating lupus nephritis (LN) patients in China is still in its early stages. This retrospective comparative study aims to delineate the disease activity, associated therapies, clinical outcomes, and adverse events among LN patients treated with belimumab, reflecting real-world experience in southeastern China. Methods: From May 2020 to December 2023, 54 LN patients treated with belimumab and 42 LN patients treated with conventional therapy were enrolled. All patients had a follow-up period of more than 3 months. The general information, presenting clinical and laboratory data, and outcomes were collected and compared. Results: At 3 months of belimumab treatment, compared to baseline, there was a decrease in proteinuria from 74.1% to 64.8% (p < 0.001), a reduction in hematuria from 59.3% to 37.0% (p = 0.008), and an increase in partial or complete renal response from 53.7% to 75.9% (p < 0.001). The median SLEDAI score decreased from 10 to 5 (p < 0.001), and the proportion of patients achieving low lupus disease activity state (LLDAS) increased from 11.11% to 16.67% (p < 0.001) by the 3-month evaluation. Notably, there were significant reductions in oral corticosteroid dosages, with a median decrease from 30 to 17.5 mg/day (p < 0.001) by 3 months, and the proportion of patients requiring >5 mg/day of steroids decreased from 88.89% at baseline to 79.07% at six months (p < 0.001). Compared to the conventional therapy group, the belimumab group experienced a significant reduction in median steroid dosage and increased the proportion of patients achieving remission or LLDAS. The incidence of treatment-emergent adverse events (TEAEs) was significantly lower in the belimumab group (29.6% vs 52.4%, p = 0.024). Conclusion: These findings support the potential of belimumab to improve renal and serological parameters, reduce disease activity, lessen corticosteroid dependence, and decrease the risk of TEAEs, demonstrating its safety and efficacy as an adjunct therapy in LN management.

Biologicals for the treatment of lupus nephritis: a Bayesian network meta-regression analysis.

Background: Previous studies comparing the efficacy and safety of different treatment regimens for lupus nephritis are scarce. Moreover, confounding factors such as the duration of follow-up were hardly adjusted in those studies, potentially compromising the results and their extents to clinical settings. Objective: To rigorously investigate the efficacy and safety of biologics in patients with lupus nephritis using Bayesian network meta-regression analyses that adjust for the follow-up period, in order to provide more robust evidence for clinicians. Methods: Databases comprising PubMed, Embase, MedlinePlus, Cochrane Library, Google Scholars, and Scopus were retrieved for eligible articles from inception to February 29, 2024. The primary endpoint was the complete response rate, the secondary endpoint was the partial response rate, the tertiary endpoints were the adverse events, and infection-related adverse events. Napierian Logarithm of hazard ratio (lnHR) and the standard error of lnHR (selnHR) were generated for dichotomous variants by STATA 18.0 MP and then put into Rstudio 4.3.2 to conduct Bayesian network meta-analysis as well as network meta-regression analysis to yield hazard ratio (HR) as pairwise effect size. Results: Ten studies involving 2138 patients and 11 treatment regimens were ultimately included. In the original analysis, for the primary endpoint, compared to the control group, obinutuzumab (22.6 months), abatacept-30mg (20.5 months), abatacept-10mg (17.8 months), and belimumab (23.3 months) demonstrated significant superiority (HR ranged from 1.6 to 2.5), more ever, their significance regarding relative efficacy was correlated with follow up period, namely "time window" (shown in parentheses above). For the secondary endpoint, compared to the control group, obinutuzumab and abatacept-30mg showed conspicuous preponderance (HR ranged from 1.6 to 2.4), "time window" was also detected in abatacept-30mg (20.5 months), whereas obinutuzumab remained consistently obviously effective regardless of the follow-up period (shown in parentheses above). For the tertiary endpoint, there were no differences among active regimens and control. Conclusions: Considering the efficacy and safety and "time window" phenomenon, we recommend obinutuzumab as the preferred treatment for LN. Certainly, more rigorous head-to-head clinical trials are warranted to validate those findings.

Attainment of EULAR/ERA-EDTA targets of therapy with current immunosuppressive regimens and adjustments in treatment: a multicentre, real-life observational study.

OBJECTIVE: To estimate real-life European Alliance of Associations for Rheumatology (EULAR)/European Renal Association (ERA)-European Dialysis and Transplantation Association (EDTA) response rates and predictors for no response in patients with lupus nephritis (LN) managed with conventional immunosuppressive therapies. METHODS: Ambidirectional cohort study of patients with new-onset LN (period 2014-to date). Response rates in the first year were calculated, and all treatment modifications were recorded. Univariate and multivariate regression analyses were performed to assess determinants of failure to respond at 12 months. RESULTS: 140 patients were included (81.4% women, median (IQR) age at LN diagnosis 38 (22) years). Among them, 32.1% presented with nephrotic range proteinuria, 28.6% with glomerular filtration rate <60 mL/min, 76.6% had proliferative and 19.7% class V LN. Initial treatment consisted of cyclophosphamide in 51.4% of patients (84.7% high-dose, 15.3% low-dose) and mycophenolate in 32.1%. 120 patients had available data at 12 months. EULAR/ERA-EDTA renal response rates at 3, 6 and 12 months were achieved by 72.6%, 78.5% % and 69.2% of patients, respectively. In multivariate analysis, increased Chronicity Index at baseline was associated with failure to achieve either complete or partial response at 12 months (OR 2.26, 95% CI 1.35 to 3.77). Notably, 20% of patients required treatment modifications due to suboptimal response during the first 12 months, with the addition of or switch to a different immunosuppressive drug in seven and nine patients, respectively. CONCLUSIONS: More than two-thirds of patients with LN attain EULAR/ERA-EDTA response rates by 12 months, but 20% require therapy modifications within this time period. Patients with increased chronicity in baseline biopsy, when combined with histological activity, are at higher risk for a lack of clinical response.

Tubulointerstitial nephropathy is the predominant finding in men in a review of more than 3000 renal biopsies over a 10-year period from Sri Lanka.

BACKGROUND: Chronic kidney disease (CKD) is a significant clinical challenge in Sri Lanka. The present study presents histopathological diagnoses from native renal biopsies in Kandy District, 2011-2020. METHODS: Reports of 5,014 renal biopsies principally performed at Kandy Teaching Hospital over 2011-2020 were reviewed. After exclusions for post-kidney transplant biopsies (1,572) and those without evident pathology (347), 3,095 biopsies were included. The predominant histopathological entities were grouped and categorised according to diagnosis and stratified by age and sex. RESULTS: The main histopathological entities (all biopsies) were tubulointerstitial nephropathy (TIN) 25% (n = 760), glomerulonephritis (GN) 15% (467), lupus nephropathy 14% (429), focal segmental glomerular sclerosis (FSGS) 10% (297), and IgA nephropathy (IgAN) 8% (242). For adult women ≥ 15 years, the main histopathological entities were lupus nephropathy 24% (325), TIN 17% (228), and GN 16% (217). For adult men ≥ 15 years, the main histopathological entities were TIN 34% (449), GN 14% (180), and IgAN 10% (125). The proportion of TIN in the present study was higher than international studies of a similar size. CONCLUSION: This is the largest study of renal biopsies reported from Sri Lanka to date. TIN was the most common diagnosis in adults ≥ 15 years at 25%. Notable sex differences showed TIN was the most common histopathology in men (34%) but not in women (17%). No previously published similar study of this size has found TIN as the predominant diagnosis amongst renal biopsies in men. Further research is required into the possible causes of these observations in Sri Lanka. CLINICAL TRIAL NUMBER: Not applicable.

Applying 12 machine learning algorithms and Non-negative Matrix Factorization for robust prediction of lupus nephritis.

Lupus nephritis (LN) is a challenging condition with limited diagnostic and treatment options. In this study, we applied 12 distinct machine learning algorithms along with Non-negative Matrix Factorization (NMF) to analyze single-cell datasets from kidney biopsies, aiming to provide a comprehensive profile of LN. Through this analysis, we identified various immune cell populations and their roles in LN progression and constructed 102 machine learning-based immune-related gene (IRG) predictive models. The most effective models demonstrated high predictive accuracy, evidenced by Area Under the Curve (AUC) values, and were further validated in external cohorts. These models highlight six hub IRGs (CD14, CYBB, IFNGR1, IL1B, MSR1, and PLAUR) as key diagnostic markers for LN, showing remarkable diagnostic performance in both renal and peripheral blood cohorts, thus offering a novel approach for noninvasive LN diagnosis. Further clinical correlation analysis revealed that expressions of IFNGR1, PLAUR, and CYBB were negatively correlated with the glomerular filtration rate (GFR), while CYBB also positively correlated with proteinuria and serum creatinine levels, highlighting their roles in LN pathophysiology. Additionally, protein-protein interaction (PPI) analysis revealed significant networks involving hub IRGs, emphasizing the importance of the interleukin family and chemokines in LN pathogenesis. This study highlights the potential of integrating advanced genomic tools and machine learning algorithms to improve diagnosis and personalize management of complex autoimmune diseases like LN.

Research progress on miR-124-3p in the field of kidney disease.

MicroRNAs (miRNAs) are 18-25 nucleotides long, single-stranded, non-coding RNA molecules that regulate gene expression. They play a crucial role in maintaining normal cellular functions and homeostasis in organisms. Studies have shown that miR-124-3p is highly expressed in brain tissue and plays a significant role in nervous system development. It is also described as a tumor suppressor, regulating biological processes like cancer cell proliferation, apoptosis, migration, and invasion by controlling multiple downstream target genes. miR-124-3p has been found to be involved in the progression of various kidney diseases, including diabetic kidney disease, calcium oxalate kidney stones, acute kidney injury, lupus nephritis, and renal interstitial fibrosis. It mediates these processes through mechanisms like oxidative stress, inflammation, autophagy, and ferroptosis. To lay the foundation for future therapeutic strategies, this research group reviewed recent studies on the functional roles of miR-124-3p in renal diseases and the regulation of its downstream target genes. Additionally, the feasibility, limitations, and potential application of miR-124-3p as a diagnostic biomarker and therapeutic target were thoroughly investigated.

Angiotensin II Type 2 Receptor Antibodies in Glomerular Diseases.

We evaluated the concentration of AT2R antibodies in 136 patients with primary and secondary glomerular diseases: membranous nephropathy (n = 18), focal and segmental glomerulosclerosis (n = 25), systemic lupus erythematosus (n = 17), immunoglobulin A (IgA) nephropathy (n = 14), mesangial (non-IgA) proliferative nephropathy (n = 6), c-ANCA vasculitis (n = 40), perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) vasculitis (n = 16), and compared it with a healthy control group (22 patients). Serum creatinine levels, proteinuria, serum albumin, and total protein concentrations were prospectively recorded for 2 years. The mean levels of AT2R antibodies in the lupus nephropathy group were significantly higher compared to the control group, 64.12 ± 26.95 units/mL and 9.72 ± 11.88 units/mL, respectively. There was no association between this level and the clinical course of the disease. The AT2R levels in other kinds of glomerular disease were no different from the control group. We found significant correlations between AT1R and AT2R in patients with membranous nephropathy (r = 0.66), IgA nephropathy (r = 0.61), and c-ANCA vasculitis (r = 0.63). Levels of AT2R antibodies in systemic lupus erythematosus are higher compared to other types of glomerulonephritis, vasculitis, and a healthy control group. Levels of AT2R antibodies correlate with AT1R antibodies in the groups of patients with membranous nephropathy, IgA nephropathy, and c-ANCA vasculitis. These kinds of AT2R antibodies have a stimulative effect on AT2R, but we have not found the influence of these antibodies on the clinical course of glomerular diseases.

Development and validation of a predictive model for end-stage renal disease in systemic lupus erythematosus patients.

Systemic lupus erythematosus (SLE) affects many populations. This study aims to develop a predictive model and create a nomogram for assessing the risk of end-stage renal disease (ESRD) in patients diagnosed with SLE. Data from electronic health records of SLE patients treated at the Affiliated Hospital of North Sichuan Medical College between 2013 and 2023 were collected. The dataset underwent thorough cleaning and variable assignment procedures. Subsequently, variables were selected using one-way logistic regression and lasso logistic regression methods, followed by multifactorial logistic regression to construct nomograms. The model's performance was assessed using calibration, receiver operating characteristic (ROC), and decision curve analysis (DCA) curves. Statistical significance was set at P < 0.05. The predictive variables for ESRD development in SLE patients included anti-GP210 antibody presence, urinary occult blood, proteinuria, white blood cell count, complement 4 levels, uric acid, creatinine, total protein, globulin, glomerular filtration rate, pH, specific gravity, very low-density lipoprotein, homocysteine, apolipoprotein B, and absolute counts of cytotoxic T cells. The nomogram exhibited a broad predictive range. The ROC area under the curve (AUC) was 0.886 (0.858-0.913) for the training set and 0.840 (0.783-0.897) for the testing set, indicating good model performance. The model demonstrated both applicability and significant clinical benefits. The developed model presents strong predictive capabilities and considerable clinical utility in estimating the risk of ESRD in patients with SLE.

Lupus Nephritis: Immune Cells and the Kidney Microenvironment.

Lupus nephritis (LN) is the most common major organ manifestation of the autoimmune disease SLE (lupus), with 10% of those afflicted progressing to ESKD. The kidney in LN is characterized by a significant immune infiltrate and proinflammatory cytokine milieu that affects intrinsic renal cells and is, in part, responsible for the tissue damage observed in LN. It is now increasingly appreciated that LN is not due to unidirectional immune cell activation with subsequent kidney damage. Rather, the kidney microenvironment influences the recruitment, survival, differentiation, and activation of immune cells, which, in turn, modify kidney cell function. This review covers how the biochemical environment of the kidney ( i.e ., low oxygen tension and hypertonicity) and unique kidney cell types affect the intrarenal immune cells in LN. The pathways used by intrinsic renal cells to interact with immune cells, such as antigen presentation and cytokine production, are discussed in detail. An understanding of these mechanisms can lead to the design of more kidney-targeted treatments and the avoidance of systemic immunosuppressive effects and may represent the next frontier of LN therapies.

LncRNA XIST/miR-381-3P/STAT1 axis as a potential biomarker for lupus nephritis.

OBJECTIVE: We aim to investigate the potential roles of key genes in the development of lupus nephritis (LN), screen key biomarkers, and construct the lncRNA XIST/miR-381-3P/STAT1 axis by using bioinformatic prediction combined with clinical validation, thereby providing new targets and insights for clinical research. METHODS: Gene expression microarrays GSE157293 and GSE112943 were downloaded from the GEO database to obtain differentially expressed genes (DEGs), followed by enrichment analyses on these DEGs, which were enriched and analyzed to construct a protein-protein interaction (PPI) network to screen core genes. The lncRNA-miRNA-mRNA regulatory network was predicted and constructed based on the miRNA database. 37 female patients with systemic lupus erythematosus (SLE) were recruited to validate the bioinformatics results by exploring the diagnostic value of the target ceRNA axis in LN by dual luciferase and real-time fluorescence quantitative PCR (RT-qPCR) and receiver operating characteristic (ROC). RESULTS: The data represented that a total of 133 differential genes were screened in the GSE157293 dataset and 2869 differential genes in the GSE112943 dataset, yielding a total of 26 differentially co-expressed genes. Six core genes (STAT1, OAS2, OAS3, IFI44, DDX60, and IFI44L) were screened. Biological functional analysis identified key relevant pathways in LN. ROC curve analysis suggested that lncRNA XIST, miR-381-3P, and STAT1 could be used as potential molecular markers to assist in the diagnosis of LN. CONCLUSION: STAT1 is a key gene in the development of LN. In conclusion, lncRNA XIST, miR-381-3P, and STAT1 can be used as new molecular markers to assist in the diagnosis of LN, and the lncRNA XIST/miR-381-3P/STAT1 axis may be a potential therapeutic target for LN.

PM2.5 constituents associated with mortality and kidney failure in childhood-onset lupus nephritis: A 19-year cohort study.

BACKGROUND: Childhood-onset lupus nephritis (cLN) is a severe form of systemic lupus erythematosus (SLE) with high morbidity and mortality. The impact of long-term exposure to fine particulate matter (PM2.5) on adverse outcomes in cLN remains unclear. METHODS: We combined a 19-years cLN cohort from seven provinces in China with high-resolution PM2.5 dataset from 2001 to 2020, investigating the association between long-term exposure to PM2.5 and its constituents (sulfate, nitrate, organic matter, black carbon, ammonium) with the risk of death and kidney failure, analyzed with multiple variables Cox models. We also evaluated the association between 3-year average PM2.5 exposure before study entry and baseline SLE disease activity index (SLEDAI) scores using linear regression models. RESULTS: Each 10 µg/m3 increase in annual average PM2.5 exposure was associated with an increased risk of death and kidney failure (HR = 1.58, 95 % CI: 1.24-2.02). Black carbon showed the strongest association (HR = 2.14, 95 % CI: 1.47-3.12). Higher 3-year average exposures to PM2.5 and its constituents were significantly associated with higher baseline SLEDAI scores. CONCLUSIONS: These findings highlight the significant role of environmental pollutants in cLN progression and emphasize the need for strategies to mitigate exposure to harmful PM2.5 constituents, particularly in vulnerable pediatric populations.