Lupus Nephritis Group Research Articles

Downregulation of ferroptosis-related ATF3 alleviates lupus nephritis progression

BackgroundThe role of ferroptosis in lupus nephritis (LN) is unclear. This study aimed to explore the effects of ferroptosis-related genes in LN through bioinformatics prediction and experimental validation. MethodsSample data were collected from the GEO dataset and divided into glomeruli and tubulointerstitium. We collected 382 ferroptosis-related genes. The intersection of ferroptosis-related genes with glomeruli and tubulointerstitium data, respectively, was performed. Machine learning methods (including unsupervised cluster typing and random forests) were operated to identify ferroptosis subtyping and ferroptosis important genes in LN. Immune infiltration and functional analysis were performed. The expression of ferroptosis important gene ATF3 was validated in vivo and in vitro. Results6 ferroptosis important genes common to glomeruli and tubulointerstitium were screened, including ATF3, CD44, CYBB, JUN, NCF2, and NNMT. ATF3 decreased in the LN group compared to the Control. Silencing ATF3 mitigated LPS/erastin-induced ferroptosis. Functional analysis showed that ATF3 was markedly enriched in the interferon-gamma-mediated signaling pathway, ECM-receptor interaction, and cell adhesion. In glomeruli, T cells regulatory (Tregs) infiltration decreased and Macrophages M1 levels increased with elevated ATF3 expression. Levels of immune cell infiltration were altered in different ferroptosis subtypes of LN glomeruli and tubulointerstitium. ConclusionsFerroptosis-related ATF3 levels decreased in LN. Inhibition of ATF3 might alleviate LN development by affecting the macrophage M1 and Treg cell infiltration. These implied that ATF3 might be a potential target for developing LN therapeutic strategies.

Clinical Features and Survival Analysis of Lupus Nephritis among Patients with Systemic Lupus Erythematosus: A Three-Decade-Long Retrospective Cohort Study.

Background/Objectives: Lupus nephritis (LN) is one of the most severe organ manifestations of systemic lupus erythematosus (SLE). The aim of our retrospective cohort study was to compare the clinical characteristics, therapy, survival, causes of death, and prognostic factors of LN and non-LN lupus patients. Moreover, we compared a wide spectrum of clinical data of LN patients diagnosed before and since 2005 to determine any changes in disease course and outcomes. Methods: We assessed the clinical and laboratory data of 384 SLE patients, out of whom, 127 patients were diagnosed with LN between 1990 and 2020. Results: Based on our observations, discoid LE, subacute cutaneous LE, antiphospholipid syndrome, Sjögren's syndrome, and rheumatoid arthritis were more common in non-LN patients, while anemia and anti-RNP positivity were more frequent in LN patients. Development of LN did not affect survival rates; male sex and presence of APS were negative prognostic parameters in the non-LN group while achieving remission was a positive prognostic factor in both groups. Death caused by sepsis was more prevalent in the LN group. Serositis and neurological manifestations occurred less frequently in LN patients diagnosed after 2005. The use of mycophenolate mofetil became more common, and the cumulative corticosteroid dose decreased. The SLICC Damage Index score also decreased. Conclusions: Our study demonstrated that the disease course has changed in recent years, and the main therapeutic goal in both SLE and lupus nephritis should be to achieve remission because this significantly improves long-term prognosis and patient survival.

Serum ceramide levels in systemic lupus erythematosus patients: A novel biomarker for renal impairment

Background In between 30 and 80% of SLE patients, lupus nephritis (LN) develops. Thus, we aimed to evaluate the accuracy of serum ceramide (Cer.) in predicting LN in patients with SLE. Patients and methods Forty five patients with SLE with or without renal impairment were diagnosed as SLE according to SLICC classification criteria 2012, besides 20 healthy control subjects. Patients were divided into two groups: group (1); 20 SLE without renal impairment, and group (2); 25 patients confirmed to have LN by renal biopsy before starting treatment and follow-up after 3 cycles of treatment. Those Patients received IV methylprednisolone for 3 days and IV 0.5 gram of cyclophosphamide monthly, for 3 consecutive months. Baseline laboratory data and total serum Cer. levels were assessed by ELISA kit at base line to all studied groups and after 3 consecutive months for SLE patients with LN. Results Total Serum Cer. was significantly higher among patients with LN in comparison to SLE without LN group (60.11 ± 14.14 vs. 40.47 ± 12.34 (ng/ml); P=0.04) and control group (60.11 ± 14.14 vs. 31.14 ± 5.98 (ng/ml); P<0.001). SLE without LN patients group had significantly higher Cer. in comparison to controls (40.47 ± 12.34 vs. 31.14 ± 5.98 (ng/ml); P=0.03). Interestingly we found a significant reduction in serum Cer. levels with the follow-up after three cycles of therapy. Conclusion Serum Cer. is a novel promising biomarker for early detection of LN in patients with SLE. Future studies are warranted to confirm these findings.

Risk factors of disease activity and renal damage in patients with systemic lupus erythematosus.

To evaluate the clinical features of patients with Systemic Lupus Erythematosus (SLE) and explore the risk factors of disease activity and renal damage. A retrospective study involving 194 patients were performed. Patients were divided into lupus nephritis (LN) group (63.40%) and non-LN group (36.60%), different disease activity group, and different renal function group according to the clinical data. Multivariate logistic regression analysis showed that albumin (ALB), uric acid (UC), total cholesterol (TC), and anti-dsDNA antibodies were the influencing factors of LN in patients with SLE (P < 0.05); ALB, UC, and complement 3(C3) were the influencing factors of lupus disease activity (P < 0.05); UC, C3, and hemoglobin (HB) were the influencing factors of abnormal renal function in SLE patients. The results of the ROC curve showed that ALB, UA, and TC had certain predictive value for combined LN in patients with SLE, and the predictive value of ALB was greater than that of TC (P < 0.05); ALB, UA, and C3 being predictors of the activity of patients with SLE; BUN, UA, and HB all had certain predictive value for the abnormal renal function in patients with LN. SLE patients have the high incidence of renal impairment. The results of this study suggest that patients with SLE should regularly monitor the levels of ALB, UA, TC, C3, and HB, as well as pay attention to the intervention of hyperlipidemia and hyperuricemia in patients with SLE to better control disease progression.

Integrative analysis of COL6A3 in lupus nephritis: insights from single-cell transcriptomics and proteomics.

Lupus nephritis (LN), a severe complication of systemic lupus erythematosus (SLE), presents significant challenges in patient management and treatment outcomes. The identification of novel LN-related biomarkers and therapeutic targets is critical to enhancing treatment outcomes and prognosis for patients. In this study, we analyzed single-cell expression data from LN (n=21) and healthy controls (n=3). A total of 143 differentially expressed genes were identified between the LN and control groups. Then, proteomics analysis of LN patients (n=9) and control (SLE patients without LN, n=11) revealed 55 differentially expressed genes among patients with LN and control group. We further utilizes protein-protein interaction network and functional enrichment analyses to elucidate the pivotal role of COL6A3 in key signaling pathways. Its diagnostic value is evaluate through its correlation with disease progression and renal function metrics, as well as Receiver Operating Characteristic Curve (ROC) analysis. Additionally, immunohistochemistry and qPCR experiments were performed to validate the expression of COL6A3 in LN. By comparison of single-cell and proteomics data, we discovered that COL6A3 is significantly upregulated, highlighting it as a critical biomarker of LN. Our findings emphasize the substantial involvement of COL6A3 in the pathogenesis of LN, particularly noting its expression in mesangial cells. Through comprehensive protein-protein interaction network and functional enrichment analyses, we uncovered the pivotal role of COL6A3 in key signaling pathways including integrin-mediated signaling pathways, collagen-activated signaling pathways, and ECM-receptor interaction, suggesting potential therapeutic targets. The diagnostic utility is confirmed by its correlation with disease progression and renal function metrics of the glomerular filtration rate. ROC analysis further validates the diagnostic value of COL6A3, with the area under the ROC values of 0.879 in the in-house cohort, and 0.802 and 0.915 in tubular and glomerular external cohort samples, respectively. Furthermore, immunohistochemistry and qPCR experiments were consistent with those obtained from the single-cell RNA sequencing and proteomics studies. These results proved that COL6A3 is a promising biomarker and therapeutic target, advancing personalized medicine strategies for LN.

#401 Cardiovascular risk evaluation in lupus nephritis and ANCA-associated vasculitis

Abstract Background and Aims Individuals with lupus nephritis (LN) and renal ANCA-associated vasculitis (AAV) have amplified cardiovascular risks. Early recognition and intervention for metabolic disease may mitigate cardiovascular risk. We aimed to evaluate the prevalence of cardiovascular metabolic risk evaluation among adults with kidney disease due to LN and AAV treated with immunosuppressants. Method Retrospective cohort study of 219 patients with kidney LN (n = 175) and AAV (n = 44) diagnosed between November 2015 and December 2022. The outcomes were the prevalence of cardiovascular metabolic risk evaluation (HbA1c, fasting glucose and lipid) during the first two years of treatment. Results The median age was 48.6 (33.3, 60.9) years. Table 1 showed that the AAV group had lower eGFR and higher prevalence of diabetes mellitus, hypertension, and hyperlipidemia. Glycemic evaluation was more frequent during the first year than the second year (81.0% versus 61.2%, p &amp;lt; 0.001) for the cohort, as well as the LN (79.2% versus 61.7%, p &amp;lt; 0.001) and AAV groups (88.4% versus 58.8%, p = 0.003). Lipid evaluation was more frequent during the first year than the second year for the cohort (60.5% versus 50.3%, p = 0.04) and for AAV (81.4% versus 47.1%, p = 0004), but not the LN group (55.1% versus 51.0%, p = 0.52). Conclusion Cardiovascular metabolic risk evaluation during lupus nephritis (LN) and ANCA-associated vasculitis (AAV) long-term follow-up should be optimized.

#2051 Long-term follow-up of Israeli patients with lupus nephritis

Abstract Background and Aims Systemic lupus erythematosus (SLE) often affects the kidneys, and is associated with morbidity and mortality. Ethnic variations in clinical response to treatment and outcomes have been described. Information on real-life, long-term cohorts of the Middle Eastern Israeli population is lacking. We aimed to characterize the prevalence and long-term outcomes of kidney involvement in SLE patients in Israel and to identify variables associated with lupus nephritis (LN) and end-stage kidney disease (ESKD). Method This retrospective study, conducted between 2014-2023, included adult patients with SLE diagnosed for at least 12 months. Kidney involvement was based on a diagnosis of LN on a kidney biopsy. SLE patients without LN served as controls. Associated variables were collected including socio-demographics, disease-related characteristics, kidney-related factors, comorbidities, and all-cause mortality. Results A total of 182 adult patients with SLE were included. Of them, 54 (29.6%) had LN. Mean follow-up since diagnosis was 16.2 ± 13.8 years. Compared to the control group, patients with LN were diagnosed with SLE at younger ages (26.8 ± 12.9 vs. 35.5 ± 15.4 years, p &amp;lt; 0.01). Patients with LN and controls had similar proportions of females/males and Jewish/Arab patients (Table 1), and had comparable baseline eGFR before LN diagnosis (110 ± 48 vs. 107 ± 39 ml/min/m2, p = 0.66). The LN group had lower complement C3 levels at diagnosis and higher dsDNA titers (p = 0.001, 0.023 respectively; Table 1). Patients with LN had more hospitalization for SLE exacerbations [38.4% vs. 24.5%, odds ratio (OR) 1.9, 95% confidence interval (CI) 1-3.9, p = 0.06]. Of 54 patients with LN, 45 had available treatment information. All patients were treated with hydroxychloroquine, 19 patients (42.2%) were treated with cyclophosphamide, and 36 (80%) were treated with mycophenolate mofetil or mycophenolic acid. During follow-up of the LN patients, 5 patients (9.3%) were diagnosed with diabetes, 21 patients (38.9%) were diagnosed with hypertension, 5 patients (9.3%) had a stroke and 6 patients (11.1%) had an acute coronary syndrome. Eight of the LN patients (14.8%) developed ESKD as compared with one patient (0.8%) of the controls (OR 22.1, 95% CI 2.7-181.5, p &amp;lt; 0.001). On univariate analysis, ESKD was significantly associated with LN, hypertension, heart failure, and non-employment status. No difference in the rate of ESKD was found between Jewish and Arab patients. On multivariate regression analysis, LN and hypertension were the most important predictors for developing ESKD. Mortality among patients with ESKD was 22% vs. 4.6% among non-ESKD patients (p = 0.02) )Fig. 1). Conclusion This long-term study on Israeli SLE patients reveals that despite advances in SLE treatments, LN is associated with significant morbidity and mortality. The elevated risk of ESKD, particularly associated with LN and hypertension, underscores the imperative for targeted interventions to improve outcomes.

#2682 Evaluation of clinical, pathological findings and treatment outcomes of patients diagnosed with lupus nephritis: a single center experience

Abstract Background and Aim Renal involvement of systemic lupus erythematosus (SLE) is known as lupus nephritis (LN). The prognosis of lupus patients with LN is worse than those without kidney involvement. Renal survival can be improved in patients with lupus nephritis with appropriate and timely treatment. The aim of our study is to compare the clinical and pathological findings of patients diagnosed with LN in our clinic by renal biopsy, the results of the treatment applied in our center, and renal survival with the literature. Method The local ethical committee approved the study design (date: 04/10/2021; reference number: 121/07) and all procedures were conducted in accordance with the Declaration of Helsinki. Forty-four patients diagnosed with lupus nephritis between January 2012 and January 2021 in the Nephrology Department of Ankara Dıskapı Yıldırım Beyazıt Education and Research Hospital were enrolled in this study. Patient data were analyzed retrospectively. Exclusion criteria were as follows: 1) Patients under 18 years of age, 2) patients with follow-up of period less than 6 months and who did not attend regular follow-ups, 3) patients with connective tissue diseases other than SLE. Results The mean age of the study population was 36.0 ± 10.8, and the majority were female. All patients had proteinuria at diagnosis. Class IV LN was the most common (36.4%). Majority of the patients were in the proliferative LN group (65.9%). A significant difference was found between patients diagnosed with proliferative LN (n = 29) and non-proliferative LN (n = 15) in terms of high serum creatinine levels, low serum complement, presence of anti-dsDNA antibodies and active urinary sediment with proliferative LN (p = 0.021, p = 0.024, p = 0.008, p = 0.008). Treatment responses at 6 and 12 months are shown in Table 1. A significant difference was found between the patients who were in complete remission (n = 16) at 12 months and those who were not in remission (n = 27) in terms of low systolic blood pressure and the estimated glomerular filtration rate (eGFR) at the time of diagnosis (p = 0.008, p = 0.016). It was observed that most of the patients who were not in complete remission at 12 months were in the proliferative LN group (p = 0.024). There was no significant difference in the partial and complete remission rates at 6 and 12 months between the group receiving steroids + cyclophosphamide (n = 14) and the group receiving steroid + mycophenolate mofetil (MMF) (n = 15) in the initial treatment of proliferative LN (p&amp;gt;0.05). In the group taking MMF treatment (n = 15) had a shorter time to reach complete remission than the group taking cyclophosphamide treatment, and it was statistically significant (Table 2) (p = 0.048). It was found that end-stage renal disease (ESRD) developed in 9% of the patients and 2 patients died during followed up period. Recurrence was detected in 8 patients, and it was observed that more than half of the patients with relapse could not achieve complete remission at 12 months. Patients with relapse had higher systolic blood pressure and serum total cholesterol level at the time of diagnosis compared to patients without recurrence (p = 0.013, p = 0.045). In addition, patients with relapse were found to have a higher level of proteinuria at the time of diagnosis (p = 0.036). Conclusion Lupus nephritis remains an important source of morbidity and mortality for SLE patients. SLE patients should be regularly examined for renal involvement. About 10-20% of patients diagnosed with lupus nephritis develop ESRD. Early diagnosis of LN and initiating appropriate treatment when diagnosed without delay is important for renal and patient survival. Although there were some different results, most of the statistically significant data in our study were found to be compatible with the existing literature. However, these data need to be confirmed by studies with high patient participation.

Platelet-to-lymphocyte ratio as a biomarker of systemic inflammation in systemic lupus erythematosus: A meta-analysis and systematic review.

The objective of this study was to evaluate the relationship between the platelet-to-lymphocyte ratio (PLR) and systemic lupus erythematosus (SLE). Additionally, the study aimed to establish an association between PLR and SLE disease activity, specifically lupus nephritis (LN). We conducted a comprehensive search across Medline, Embase, and Cochrane databases to identify relevant articles. Subsequently, we performed meta-analyses to compare PLR between SLE patients and controls, as well as active and inactive SLE cases, along with LN and non-LN groups. Furthermore, a meta-analysis was conducted on correlation coefficients between PLR and various parameters in SLE patients, including the SLE Disease Activity Index (SLEDAI), C3, C4, anti-dsDNA, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). In total, fifteen studies comprising 1,522 SLE patients and 1,424 controls were eligible for inclusion. The meta-analysis demonstrated a significant elevation of PLR in the SLE group compared to the control group (Standardized Mean Difference [SMD] = 0.604, 95% Confidence Interval [CI] = 0.299-0.909, p < 0.001). Upon stratification by ethnicity, an elevated PLR was observed in the SLE group among both Asian and Arab populations. Subgroup analysis based on sample size revealed consistently higher PLR in both small (n < 200) and large sample (n ≥ 200) SLE groups. Moreover, when considering disease activity, there was a noteworthy trend of increased PLR in the active disease group compared to the inactive group (SMD = 0.553, 95% CI = 0.000-1.106, p = 0.050). However, the meta-analysis did not demonstrate a significant distinction in PLR between the LN and non-LN groups. Notably, a positive association was established between PLR and SLEDAI (correlation coefficient = 0.325, 95% CI = 0.176-0.459, p < 0.001). Furthermore, PLR exhibited positive correlations with ESR, CRP, proteinuria, C3, and anti-dsDNA antibody levels. The outcomes of this meta-analysis underscored the elevated PLR in SLE patients, suggesting its potential as a biomarker for gauging systemic inflammation in SLE. Additionally, PLR exhibited correlations with SLEDAI, as well as with key indicators such as ESR, CRP, proteinuria, C3, and anti-dsDNA antibody levels.

Imbalance of programmed cell death patterns mediated by dendritic cell subsets in systemic lupus erythematosus and lupus nephritis.

Abnormal programmed cell death in immune cells is associated with autoimmune diseases, but the patterns of programmed cell death in systemic lupus erythematosus (SLE) and especially lupus nephritis (LN) remain unclear. This study aims to explore the association between SLE, LN, and immune cell death patterns. Bulk RNA sequencing (bulk RNA-seq) and single-cell RNA sequencing (scRNA-seq) data were downloaded from the Gene Expression Omnibus (GEO) database. Bioinformatic analysis was conducted to explore the expression levels of genes related to 3 cell death patterns in peripheral blood mononuclear cells of SLE patients. Key cell subsets involved in the imbalance of cell death patterns were identified through scRNA-seq. Immunofluorescence was used to detect the expression levels of receptor interacting serine/threonine kinase 3 (RIPK3), mixed-lineage kinase domain-like protein (MLKL), phosphorylated MLKL (pMLKL), caspase 1 (CASP1), CD1c molecule (CD1C), C-type lectin domain containing 9A (CLEC9A), and X-C motif chemokine receptor 1 (XCR1) in dendritic cells (DC). scRNA-seq was performed on kidney tissues collected from LN patients and healthy controls (HC) at the Third Xiangya Hospital of Central South University, followed by bioinformatic analysis to identify key cell subsets involved in the imbalance of cell death patterns. Pseudotime analysis and ligand-receptor analysis were used to explore the differentiation direction and cell communication of different DC subsets. Transient transfection was used to transfect RAW264.7 cells with empty plasmid, empty plasmid+dsDNA (HSV-DNA), empty plasmid+200 μmol/L tert-butyl hydroperoxide (TBHP), stimulator of interferon genes (STING) shRNA plasmid, STING shRNA plasmid+dsDNA (HSV-DNA), and STING shRNA plasmid+200 μmol/L TBHP. Annexin V-mCherry and SYTOX Green staining were used to detect cell death in each group. Western blotting was used to detect the activation of CASP1, gasdermin D (GSDMD), RIPK3, and MLKL in each group. Bioinformatic analysis showed an imbalance in 3 cell death patterns in SLE and LN patients: Pro-inflammatory pyroptosis and necroptosis were activated, while anti-inflammatory apoptosis was inhibited. The key cell subsets involved were DC subsets, particularly focusing on CLEC9A+cDC1. Immunofluorescence results showed that the expression levels of RIPK3, MLKL, and CASP1 in DCs were higher in the SLE group compared to the HC group. pMLKL and CASP1 expression levels in renal cDC1 marked by CLEC9A and XCR1 were higher in the LN group than in the HC group. Pseudotime analysis and ligand-receptor analysis suggested that the CLEC9A+cDC1 subset in LN kidney tissues originated from peripheral circulation. Annexin V-mCherry and SYTOX Green staining results showed that the number of dead cells decreased in the STING shRNA transfection group compared to the empty plasmid group in RAW264.7 cells. Western blotting results showed that the activation of CASP1, GSDMD, RIPK3, and MLKL was decreased in the STING shRNA transfection group compared to the empty plasmid group. This study provides novel insights into the role of CLEC9A+cDC1 in the imbalance of cell death patterns in SLE and LN.

Comprehensive analysis of lactate-related gene profiles and immune characteristics in lupus nephritis.

The most frequent cause of kidney damage in systemic lupus erythematosus (SLE) is lupus nephritis (LN), which is also a significant risk factor for morbidity and mortality. Lactate metabolism and protein lactylation might be related to the development of LN. However, there is still a lack of relative research to prove the hypothesis. Hence, this study was conducted to screen the lactate-related biomarkers for LN and analyze the underlying mechanism. To identify differentially expressed genes (DEGs) in the training set (GSE32591, GSE127797), we conducted a differential expression analysis (LN samples versus normal samples). Then, module genes were mined using WGCNA concerning LN. The overlapping of DEGs, critical module genes, and lactate-related genes (LRGs) was used to create the lactate-related differentially expressed genes (LR-DEGs). By using a machine-learning algorithm, ROC, and expression levels, biomarkers were discovered. We also carried out an immune infiltration study based on biomarkers and GSEA. A sum of 1259 DEGs was obtained between LN and normal groups. Then, 3800 module genes in reference to LN were procured. 19 LR-DEGs were screened out by the intersection of DEGs, key module genes, and LRGs. Moreover, 8 pivotal genes were acquired via two machine-learning algorithms. Subsequently, 3 biomarkers related to lactate metabolism were obtained, including COQ2, COQ4, and NDUFV1. And these three biomarkers were enriched in pathways 'antigen processing and presentation' and 'NOD-like receptor signaling pathway'. We found that Macrophages M0 and T cells regulatory (Tregs) were associated with these three biomarkers as well. Overall, the results indicated that lactate-related biomarkers COQ2, COQ4, and NDUFV1 were associated with LN, which laid a theoretical foundation for the diagnosis and treatment of LN.

Uncovering lupus nephritis-specific genes and the potential of TNFRSF17-targeted immunotherapy: a high-throughput sequencing study.

Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE). This study aimed to identify LN specific-genes and potential therapeutic targets. We performed high-throughput transcriptome sequencing on peripheral blood mononuclear cells (PBMCs) from LN patients. Healthy individuals and SLE patients without LN were used as controls. To validate the sequencing results, qRT-PCR was performed for 5 upregulated and 5 downregulated genes. Furthermore, the effect of the TNFRSF17-targeting drug IBI379 on patient plasma cells and B cells was evaluated by flow cytometry. Our analysis identified 1493 and 205 differential genes in the LN group compared to the control and SLE without LN groups respectively, with 70 genes common to both sets, marking them as LN-specific. These LN-specific genes were significantly enriched in the 'regulation of biological quality' GO term and the cell cycle pathway. Notably, several genes including TNFRSF17 were significantly overexpressed in the kidneys of both LN patients and NZB/W mice. TNFRSF17 levels correlated positively with urinary protein levels, and negatively with complement C3 and C4 levels in LN patients. The TNFRSF17-targeting drug IBI379 effectively induced apoptosis in patient plasma cells without significantly affecting B cells. Our findings suggest that TNFRSF17 could serve as a potential therapeutic target for LN. Moreover, IBI379 is presented as a promising treatment option for LN.

Renal arterial resistive index as a prognostic marker in lupus nephritis patients

IntroductionLupus nephritis (LN) is known to be one of the most serious complications of SLE and it is a major predictor of poor prognosis. Despite the improvement in understanding the pathophysiology of lupus nephritis and greater improvement in diagnostic approaches, lupus nephritis patients have poorer outcomes. ObjectivesStudy the relation between renal resistive index (RRI) and renal function and histopathological parameters in lupus nephritis (LN) patients. Also to investigate the usefulness of RRI in predicting response to treatment. Patients and methodsThis study included 126 patients who were split into two groups (group 1: 101 LN patients and group 2: 25 SLE patients without renal affection); and 100 healthy controls (group 3). The RRI was measured for all participants through a colored Doppler ultrasound examination. LN patients underwent renal biopsy and received their therapy and were followed up for 6 months. ResultsThe RRI was significantly greater in the LN group (mean±SD; 0.64±0.07) than in SLE patients without nephritis (0.5884±0.04) (P<0.0001). The RRI was greater in LN class IV (P<0.0001). RRI significantly correlated with the chronicity index (r=0.704, P<0.0001), activity index (r=0.310, P=0.002), and serum creatinine (r=0.607, P<0.0001) and negatively correlated with eGFR (r=−0.719, P<0.0001). Almost eighty-five percent (84.8%) of LN patients responded to induction therapy. RRI was significantly greater in the nonresponder group (mean±SD, 0.73±0.02) than that in the responder group (0.63±.07) (P<0.0001). All non-responders to induction therapy while only 29.8% of responders had an RRI of ˃0.7. RRI, according to regression analysis was a significant predictor of response to treatment in LN patients. ConclusionRRI was significantly greater in the LN group and significantly correlated with kidney function and histopathological parameters. RRI can predict response to induction therapy in LN patients.

Influence of Podocyte Injury on the Development of Class IV Lupus Nephritis.

In the kidneys, Systemic Lupus Erythematosus leads to Lupus Nephritis (LN), a form of glomerulonephritis. There is evidence that patients with LN may present activation of specific pathways for podocyte injury. This injury can occur through different mechanisms such as loss of podocyte adhesion to the glomerular basement membrane, cell death or dedifferentiation. Podocyturia with consequent podocytopenia has been described in some nephropathies such as LN, highlighting the importance of studying podocyte injuries in this condition. Evaluating in situ morphological characteristics of podocytes becomes relevant for a better understanding of the processes involved in their pathogenesis. This study investigated podocytes in different classes of LN in renal biopsies performed by the Kidney Research Center at the Federal University of Triângulo Mineiro. Twenty control cases and 29 biopsy cases diagnosed with LN were selected, divided according to the histopathological classes of the disease. Podocyte density was assessed through immunohistochemistry for Wilms tumor 1 protein and the evaluation of foot process effacement was performed by transmission electron microscopy. Podocyte density was lower in the LN and this reduction was observed in all analyzed classes when compared to the control group. More foot process effacement was observed in the LN group, with more effacement in classes I/II and class IV compared to the control group. The class IV group showed more foot process effacement than the class III group and presented higher proteinuria levels compared to the classes I/II group. A strong, positive, and significant correlation was observed between the activity index and foot process effacement in the class IV group. Podocytes play an important role in the development of LN, and possibly, injuries to these cells are more closely related to the inflammatory/diffuse proliferative cellular process developed in class IV LN.

Unveiling a Novel Trend: Belimumab Amplifies Retinal Microvascular Density Decline in Lupus Nephritis Patients Revealed by Optical Coherence Tomography Angiography

Background: In systemic lupus erythematosus (SLE), retinopathy is connected to severe disease and poorer prognosis. This study aimed to investigate changes in retinal vascular density (VD) in SLE and lupus nephritis (LN) patients and to examine the effects of Belimumab and hydroxychloroquine (HCQ) on retinal VD in these patients. Methods: This cross-sectional study enrolled 54 SLE patients (21 with LN and 33 without LN). A comprehensive ophthalmological evaluation using optical coherence tomography angiography (OCTA) was conducted on SLE patients. Rheumatological evaluations were performed through the collection of relevant clinical and laboratory data, as well as the assessment of rheumatological treatment. Results: We found that the mean VD in the superficial capillary plexus (SCP-VD) of most regions showed a significant decrease in the LN group. Further analysis revealed that LN patients using Belimumab exhibited a reduction in SCP-VD and deep capillary plexus VD (DCP-VD) (P&lt;0.05). Furthermore, LN patients who had been using HCQ for more than 5 years exhibited a notable decrease in DCP-VD. Notably, SCP-VD and the cumulative dose of HCQ demonstrated a significant negative correlation. Conclusion: This study provides insights into the changes in retinal vascular density in LN patients and highlights the potential impact of long-term Belimumab and HCQ treatment on retinal microvascular damage. These findings contribute to the development of effective strategies for preventing and managing retinal complications in LN patients.

The gut microbe-derived metabolite trimethylamine N-oxide in patients with systemic lupus erythematosus

Background/Aim: Both human and animal studies suggest that the gut microbe-derived metabolite trimethylamine N-oxide (TMAO) is strongly associated with several autoimmune diseases including systemic lupus erythematosus (SLE) and correlates to disease severity. The study aimed to investigate the diagnostic and prognostic validity of TMAO as a potential biomarker in patients with SLE, particularly focusing on lupus nephritis patients and its relation to disease activity. Methods: A total of 90 patients were included and assigned into either: group I (SLE without nephritis (NN)), group II (lupus nephritis (LN)) and group III (healthy controls). Serum TMAO levels were compared between the study groups and correlated to the clinical, laboratory and histopathological criteria. Results: Unpredictably, TMAO levels were significantly higher in healthy controls compared to the total SLE population (p = 0.003), to LN and NN groups individually (p = 0.01). TMAO levels did not significantly vary be-tween (NN) and (LN) patients and only correlated to anti-dsDNA titres (p = 0.02) and red blood cells count (p = 0.02) among LN patients. Conclusion: Contrary to previous studies, TMAO levels were found to be higher in healthy controls. A possible confounding effect of the dietary pat-tern and ingested drugs on the gut microbiome limits the utility of TMAO as a potential marker in different diseases.

The Neutrophil-to-C3 Ratio: Unveiling Diagnostic Efficacy for Lupus Nephritis and Association with Reduced Retinal Vascular Density in Systemic Lupus Erythematosus

Background: Lupus nephritis (LN) frequently manifests as a significant complication in systemic lupus erythematosus (SLE) patients, with emerging research indicating a plausible correlation between subclinical retinal involvement and renal manifestations. This study aims to investigate the relationship between the neutrophil-to-C3 ratio (NC3R) and both LN as well as retinal microvasculature damage among SLE patients. Methods: In this cross-sectional study, a cohort of 220 participants was recruited, consisting of 78 LN patients and 142 patients without LN. We assessed clinical indicators and organ involvement and conducted correlation analyses between NC3R and markers of lupus activity. Additionally, we analyzed the diagnostic performance of NC3R in diagnosing LN and constructing ROC curves. Logistic regression analysis was performed to investigate the impact of NC3R on LN. We further examined the influence of NC3R on retinal vasculature density based on its cutoff value and conducted correlation analyses accordingly. Results: The LN group exhibited a significant increase in NC3R compared to the group without LN (5.9 vs 4.5, P=0.007). NC3R demonstrated positive correlations with 24-hour proteinuria (R=0.329, P&lt;0.001) and systemic lupus erythematosus disease activity index (SLEDAI) score (R=0.268, P&lt;0.001). Multiple regression analysis revealed NC3R as an independent risk factor for LN (OR: 2.01, P=0.035). NC3R was proven valuable in distinguishing LN patients (AUC: 0.613), with an optimal cutoff value of 6.40 (sensitivity: 48.1%, specificity: 72%). Our results indicated that the lower NC3R group (NC3R&lt;6.40) exhibited reduced vascular density, particularly within the macular region. Furthermore, we observed a positive correlation between NC3R levels and vascular density. Conclusions: NC3R demonstrated promising potential as a reliable indicator for predicting both LN and retinal microvasculature involvement. Consequently, the pre-treatment evaluation of NC3R had the potential to assist clinicians in identifying potential organ involvement among SLE patients.

Clinical Research of Lupus Retinopathy: Quantitative Analysis of Retinal Vessels by Optical Coherence Tomography Angiography in Patients with Systemic Lupus Erythematosus.

Lupus retinopathy, an ocular manifestation of systemic lupus erythematosus (SLE), is the major pathology attributed to retinal vasculopathy. Our study is to analyze the changes in retinal vessels in patients with SLE by optical coherence tomography angiography. A total of 61 SLE patients without obvious retinal manifestation and 71 healthy people were included. The SLE patients were further divided into a lupus nephritis (LN) group and a non-LN group. The changes in central macular thickness (CMT) and the retinal vessel densities were compared between the two groups, and the correlation between retinal vascular changes and disease activity was analyzed. Compared with healthy control, the CMT and the retinal vascular densities in both superficial and deep retina were decreased significantly in SLE patients. There was no significant difference in retinal vascular densities between LN groups and non-LN groups. The CMT and retinal vessel densities were decreased in SLE patients without clinical manifestations, which might serve as a sensitive biomarker for early changes of lupus retinopathy in SLE patients.

Urinary neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury molecule-1 (uKIM-1) as markers of active lupus nephritis

Background and objectivesDespite much research about lupus nephritis, none of the urinary biomarkers has been proven to be truly reflecting lupus nephritis activity, response to treatment, or prognosis. We aimed to study urinary biomarkers in lupus nephritis and test their relation to kidney damage.Patients and methodsForty patients with systemic lupus erythematosus (SLE) were divided into two graoups: (1) lupus nephritis group with biopsy-proven proliferative lupus nephritis (classes III and IV) and who did not receive immunosuppressive drugs within the preceding 3 months except for glucocorticoids and (2) lupus non-nephritis group with SLE patients without any renal manifestation. We assessed disease activity by the SLE disease activity index. uNGAL, uKim-1, uNGAL to urinary creatinine excretion (mg/dl), and uKim-1 to urinary creatinine excretion were measured in random spot urine samples at the time of renal biopsy and 6 months after the induction therapy.ResultsThe LN group before treatment showed higher levels of uNGAL and uKIM-1 (P-value < 0.001). ROC analysis showed that uNGAL at level of > 59 has a 95 % sensitivity, a 100 % specificity, and an AUC = 0.996 in the ability to diagnose LN. While the uKIM-1 ROC showed that at level of > 1.6, it has an 85 % sensitivity, an 80 % specificity, and an AUC = 0.919. uNGAL and uKIM levels were significantly lower after treatment (P-value < 0.001). No significant correlations were found between urinary markers before and after treatment with other clinical, inflammatory, and serological markers of lupus nephritis.ConclusionuNGAL, uKIM, uNGAL/Creat ratio, and uKIM/Creat ratio can be used as a predictor and a marker of disease activity for lupus nephritis.Key Points• Renal biopsy is the current standard for diagnosis of lupus nephritis and none of the urinary biomarkers has been fully concluded to have a diagnostic power to reflect the activity or the response to treatment.• However, based on the finding of the current study, uNGAL, uKIM, uNGAL/Creat ratio, and uKIM/Creat ratio showed significant diagnostic performance and were powerful indices of renal involvement in systemic lupus patients and as markers of disease activity.

Renal arterial resistive index as a prognostic marker in lupus nephritis patients

IntroductionLupus nephritis (LN) is known to be one of the most serious complications of SLE and it is a major predictor of poor prognosis. Despite the improvement in understanding the pathophysiology of lupus nephritis and greater improvement in diagnostic approaches, lupus nephritis patients have poorer outcomes. ObjectivesStudy the relation between renal resistive index (RRI) and renal function and histopathological parameters in lupus nephritis (LN) patients. Also to investigate the usefulness of RRI in predicting response to treatment. Patients and methodsThis study included 126 patients who were split into two groups (group 1: 101 LN patients and group 2: 25 SLE patients without renal affection); and 100 healthy controls (group 3). The RRI was measured for all participants through a colored Doppler ultrasound examination. LN patients underwent renal biopsy and received their therapy and were followed up for 6 months. ResultsThe RRI was significantly greater in the LN group (mean±SD; 0.64±0.07) than in SLE patients without nephritis (0.5884±0.04) (P<0.0001). The RRI was greater in LN class IV (P<0.0001). RRI significantly correlated with the chronicity index (r=0.704, P<0.0001), activity index (r=0.310, P=0.002), and serum creatinine (r=0.607, P<0.0001) and negatively correlated with eGFR (r=−0.719, P<0.0001). Almost eighty-five percent (84.8%) of LN patients responded to induction therapy. RRI was significantly greater in the nonresponder group (mean±SD, 0.73±0.02) than that in the responder group (0.63±.07) (P<0.0001). All non-responders to induction therapy while only 29.8% of responders had an RRI of ˃0.7. RRI, according to regression analysis was a significant predictor of response to treatment in LN patients. ConclusionRRI was significantly greater in the LN group and significantly correlated with kidney function and histopathological parameters. RRI can predict response to induction therapy in LN patients.