Response In Lupus Nephritis Research Articles

Immunosuppressives discontinuation after renal response in lupus nephritis: predictors of flares, time to withdrawal and long-term outcomes.

The optimal duration of immunosuppressive (IS) treatment for lupus nephritis (LN) remains uncertain. We assessed the prevalence and predictors of IS tapering and discontinuation (D/C) in LN patients. Data from 137 inception cohort LN patients were analyzed. We examined determinants of flares during tapering and after IS D/C, D/C achievement and time to D/C, and adverse long-term outcomes applying logistic and linear regression models. IS tapering was attempted in 111 (81%) patients, and D/C was achieved in 67.5%. Longer time to achieve complete renal response (CR) (OR : 1.07, p= 0.046) and higher SLEDAI-2K at tapering initiation (OR : 2.57, p= 0.008) were correlated with higher risk of renal flares during tapering. Persistent hydroxychloroquine use (≥2/3 of follow-up) (OR : 0.28, p= 0.08) and lower SLEDAI-2K 12 months before IS D/C (OR : 1.70, p= 0.013) decreased the risk of post-D/C flares. Adverse outcomes (>30% eGFR decline, chronic kidney disease, end-stage renal disease, death) at the end of follow-up (median124 months) were more frequent in patients with flares during IS tapering (53% vs 16%, p< 0.0038) but did not differ between IS D/C achievers and non-achievers. In proliferative LN, differences mirrored those in entire cohort, except for time to D/C, which occurred 20 months earlier in membranous vs proliferative LN (β-coef=-19.8, p= 0.014). Earlier CR achievement and lower SLEDAI-2K at tapering initiation prevent flares during IS tapering, while persistent hydroxychloroquine use and lower SLEDAI-2K 12 months before IS D/C prevent post-D/C flares. Flares during tapering increase the risk of unfavorable long-term outcomes. Earlier IS D/C is feasible in membranous LN.

P060 Multi-targeted therapy better in achieving a complete response in Lupus Nephritis: A systematic review and meta-analysis

Abstract Background/Aims Overall management of SLE and Lupus Nephritis (LN) has significantly improved over the last four decades. Recently great therapeutic strides have been made in management of LN using newer agents alone or combination of older therapies. With the availability of increased number of options choosing the optimal treatment regimen for LN has become challenging. Identifying the treatment regimen most effective in achieving complete response while minimizing adverse events is crucial for improving patient outcomes. We performed a systematic review and meta-analysis of clinical trials to explore optimal treatment regimen for LN. Methods The systematic review and meta-analysis were performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The literature search was conducted using public databases, such as the Cochrane Library, Web of Science and PubMed. Only randomized controlled clinical trials with either active comparator or placebo arms were included. Studies were excluded if they were retrospective, with no comparative drug arm, or less than 20 subjects per treatment response arm. Due to lack of agreed upon outcome measures, complete response (CR) and partial response (PR) criteria were determined as per the definition used by individual studies. Severe adverse reaction (SAE) frequencies were determined for each study for safety evaluation. Publication bias was detected by using funnel plots. Forest plots were used to summarize data, generate frequencies, odds ratio (OR), relative risks (RR) and corresponding 95% confidence intervals (CI) for each subgroup. Heterogeneity was evaluated using the I2 statistic, and labelled as low (25%), moderate (50%) and high (75%). All analyses were performed using R Statistical Software meta package (v4.2.1; R Core Team 2022). Results 31 eligible studies comprising 5495 SLE patients were included in analyses, the study characteristic features are shown in Table 1. Overall significant OR for achieving CR was reported by 10 studies (Figure 1). The highest effect was reported from study by Bao et.al using a combination of tacrolimus(TAC) and mycophenolate mofetil (MMF) compared to cyclophosphamide (CYC) (OR = 10.5, 95% CI 2.27; 48.76), another study using TAC+MMF combo reported OR = 2.49, 95% CI 1.59;3.88. The study by Ginzler et.al reported OR = 5.06 (95% CI 1.6:16.02) in favor of using MMF. Studies using CYC, voclosporin + MMF, and belimumab also reported significant OR for achieving CR. Data for the frequency of SAE were available in 22 studies. The frequency of SAE was not significantly different between treatments arms (OR: 1.07, 95%CI: 0.93-1.23, p &amp;gt; 0.05) Conclusion Our meta-analysis suggests multi-target treatment strategies, by adding calcineurin inhibitors to MMF may be better for achieving complete response in LN. Furthermore, using this combination treatment did not seem to increase the risk of side effects. Heterogenous treatment response criteria and variable comparator arms were major limiting factors of this study. Disclosure O. Pamuk: None. B. Shaikh: None. S. Khan: None. S. Abi Doumeth: None. S. Hasni: None.

Enhanced medullary and extramedullary granulopoiesis sustain the inflammatory response in lupus nephritis

ObjectivesIn SLE, deregulation of haematopoiesis is characterised by inflammatory priming and myeloid skewing of haematopoietic stem and progenitor cells (HSPCs). We sought to investigate the role of extramedullary haematopoiesis (EMH)...

Prediction of treatment response in lupus nephritis using density of tubulointerstitial macrophage infiltration.

Lupus nephritis (LN) is a common disease with diverse clinical and pathological manifestations. A major challenge in the management of LN is the inability to predict its treatment response at an early stage. The objective of this study was to determine whether the density of tubulointerstitial macrophage infiltration can be used to predict treatment response in LN and whether its addition to clinicopathological data at the time of biopsy would improve risk prediction. In this retrospective cohort study, 430 patients with LN in our hospitalfrom January 2010 to December 2017 were included. We used immunohistochemistry to show macrophage and lymphocyte infiltration in their biopsy specimens, followed by quantification of the infiltration density. The outcome was the treatment response, defined as complete or partial remission at 12 months of immunosuppression. The infiltration of CD68+ macrophages in the interstitium increased in patients with LN. High levels of CD68+ macrophage infiltration in the interstitium were associated with a low probability of treatment response in the adjusted analysis, and verse vice. The density of CD68+ macrophage infiltration in the interstitium alone predicted the response to immunosuppression (area under the curve [AUC], 0.70; 95% CI, 0.63 to 0.76). The addition of CD68+cells/interstitial field to the pathological and clinical data at biopsy in the prediction model resulted in an increased AUC of 0.78 (95% CI, 0.73 to 0.84). The density of tubulointerstitial macrophage infiltration is an independent predictor for treatment response in LN. Adding tubulointerstitial macrophage infiltration density to clinicopathological data at the time of biopsy significantly improves risk prediction of treatment response in LN patients.

Granulin in renal tubular epithelia is associated with interstitial inflammation and activates the TLR9-IFN-α pathway in lupus nephritis.

This study aimed to investigate the possible role of granulin (GRN) in activating the TLR9-IFN-α pathway in renal tubular epithelial cells (RTECs) and explore clues that RTECs regulate the micro-environment of inflammatory response in lupus nephritis (LN). Renal sections from 57 LN patients and 30 non-LN patients were sampled for histological study, and GRN overexpression RTECs were applied for cytological study. In the histological study, GRN is highly expressed in LN RTECs with tubulointerstitial inflammation (TII) and well co-localized with TLR9. ROC analysis suggested a potential relationship between GRN expression in RTECs and therapeutic response. Moreover, IFN-α also highly expressed in LN RTECs with TII, and the intensity of IFN-α is positively correlated with the co-localization intensity of GRN and TLR9. In the cytological study, LN serum, especially serum from LN with TII, activates the expression of TLR9 in RTECs, and GRN engages the interaction of TLR9 to activate the expression of IFN-α in RTECs. While TLR9 inhibitors can suppress the expression of IFN-α in RTECs, the degree of inhibition is dose-dependent. The expression of GRN in RTECs is associated with interstitial inflammation and therapeutic response. GRN may mediate the activation of the TLR9-IFN-α pathway in RTECs and involve in the micro-environment of inflammatory response in LN.

Urine proteomic signatures of histological class, activity, chronicity, and treatment response in lupus nephritis.

Lupus nephritis (LN) is a pathologically heterogenous autoimmune disease linked to end-stage kidney disease and mortality. Better therapeutic strategies are needed as only 30%-40% of patients completely respond to treatment. Noninvasive biomarkers of intrarenal inflammation may guide more precise approaches. Because urine collects the byproducts of kidney inflammation, we studied the urine proteomic profiles of 225 patients with LN (573 samples) in the longitudinal Accelerating Medicines Partnership in RA/SLE cohort. Urinary biomarkers of monocyte/neutrophil degranulation (i.e., PR3, S100A8, azurocidin, catalase, cathepsins, MMP8), macrophage activation (i.e., CD163, CD206, galectin-1), wound healing/matrix degradation (i.e., nidogen-1, decorin), and IL-16 characterized the aggressive proliferative LN classes and significantly correlated with histological activity. A decline of these biomarkers after 3 months of treatment predicted the 1-year response more robustly than proteinuria, the standard of care (AUC: CD206 0.91, EGFR 0.9, CD163 0.89, proteinuria 0.8). Candidate biomarkers were validated and provide potentially treatable targets. We propose these biomarkers of intrarenal immunological activity as noninvasive tools to diagnose LN and guide treatment and as surrogate endpoints for clinical trials. These findings provide insights into the processes involved in LN activity. This data set is a public resource to generate and test hypotheses and validate biomarkers.

STING upregulation mediates ferroptosis and inflammatory response in lupus nephritis by upregulating TBK1 and activating NF-κB signal pathway

STING upregulation mediates ferroptosis and inflammatory response in lupus nephritis by upregulating TBK1 and activating NF-κB signal pathway

Urine L-selectin reflects clinical and histological renal disease activity and treatment response in lupus nephritis across multi-ethnicity.

There is an urgent need for novel biomarkers in lupus nephritis (LN). We report a non-invasive urinary biomarker, L-selectin, in two independent multi-ethnic cohorts. uL-selectin was tested cross-sectionally in a Chinese cohort (n=255) and a US cohort (n=219) of SLE patients and controls using ELISA. A longitudinal cohort includes 20 active Chinese LN patients. uL-selectin was significantly increased in active LN patients compared to active non-renal SLE, inactive LN, inactive non-renal SLE, chronic kidney disease patients, and healthy controls. uL-selectin positively correlated with global and renal disease activities as well as histological activity index and chronicity index (CI). Low uL-selectin was an independent predictor for high CI. During follow-up, uL-selectin levels decreased significantly in the complete renal remission group. uL-selectin is a novel biomarker of disease activity and renal histopathology in LN across multiple ethnicities. It also reflects treatment response in LN patients during follow up.

Incorporating knowledge of disease-defining hub genes and regulatory network into a machine learning-based model for predicting treatment response in lupus nephritis after the first renal flare

BackgroundIdentifying candidates responsive to treatment is important in lupus nephritis (LN) at the renal flare (RF) because an effective treatment can lower the risk of progression to end-stage kidney disease. However, machine learning (ML)-based models that address this issue are lacking.MethodsTranscriptomic profiles based on DNA microarray data were extracted from the GSE32591 and GSE112943 datasets. Comprehensive bioinformatics analyses were performed to identify disease-defining genes (DDGs). Peripheral blood samples (GSE81622, GSE99967, and GSE72326) were used to evaluate the effect of DDGs. Single-sample gene set enrichment analysis (ssGSEA) scores of the DDGs were calculated and correlated with specific immunology genes listed in the nCounter panel. GSE60681 and GSE69438 were used to examine the ability of the DDGs to discriminate LN from other renal diseases. K-means clustering was used to obtain the separate gene sets. The clustering results were extended to data derived using the nCounter technique. The least absolute shrinkage and selection operator (LASSO) algorithm was used to identify genes with high predictive value for treatment response after the first RF in each cluster. LASSO models with tenfold validation were built in GSE200306 and assessed by receiver operating characteristic (ROC) analysis with area under curve (AUC). The models were validated by using an independent dataset (GSE113342).ResultsForty-five hub genes specific to LN were identified. Eight optimal disease-defining clusters (DDCs) were identified in this study. Th1 and Th2 cell differentiation pathway was significantly enriched in DDC-6. LCK in DDC-6, whose expression positively correlated with various subsets of T cell infiltrations, was found to be differentially expressed between responders and non-responders and was ranked high in regulatory network analysis. Based on DDC-6, the prediction model had the best performance (AUC: 0.75; 95% confidence interval: 0.44–1 in the testing set) and high precision (0.83), recall (0.71), and F1 score (0.77) in the validation dataset.ConclusionsOur study demonstrates that incorporating knowledge of biological phenotypes into the ML model is feasible for evaluating treatment response after the first RF in LN. This knowledge-based incorporation improves the model's transparency and performance. In addition, LCK may serve as a biomarker for T-cell infiltration and a therapeutic target in LN.

Distinct pathogenic roles for resident and monocyte-derived macrophages in lupus nephritis.

Lupus nephritis is a serious complication of systemic lupus erythematosus, mediated by IgG immune complex (IC) deposition in kidneys, with limited treatment options. Kidney macrophages are critical tissue sentinels that express IgG-binding Fcγ receptors (FcγRs), with previous studies identifying prenatally seeded resident macrophages as major IC responders. Using single-cell transcriptomic and spatial analyses in murine and human lupus nephritis, we sought to understand macrophage heterogeneity and subset-specific contributions in disease. In lupus nephritis, the cell fate trajectories of tissue-resident (TrMac) and monocyte-derived (MoMac) kidney macrophages were perturbed, with disease-associated transcriptional states indicating distinct pathogenic roles for TrMac and MoMac subsets. Lupus nephritis-associated MoMac subsets showed marked induction of FcγR response genes, avidly internalized circulating ICs, and presented IC-opsonized antigen. In contrast, lupus nephritis-associated TrMac subsets demonstrated limited IC uptake, but expressed monocyte chemoattractants, and their depletion attenuated monocyte recruitment to the kidney. TrMacs also produced B cell tissue niche factors, suggesting a role in supporting autoantibody-producing lymphoid aggregates. Extensive similarities were observed with human kidney macrophages, revealing cross-species transcriptional disruption in lupus nephritis. Overall, our study suggests a division of labor in the kidney macrophage response in lupus nephritis, with treatment implications - TrMacs orchestrate leukocyte recruitment while MoMacs take up and present IC antigen.

U-KIM-1 as a predictor of treatment response in lupus nephritis.

Biomarkers of disease activity in lupus nephritis (LN) are in demand. This is because they may be useful in patients who are unable to undergo invasive kidney biopsy, as predictors of renal function, and for early detection of LN recurrence. The focus is on the measurement of urinary chemokines and cytokines, especially in urinary biomarkers, which are non-invasive and simple. In our previous report, we reported that kidney injury molecule-1 (KIM-1) is expressed in injured tubules and that the number of tubular-KIM-expressing positive cells correlates with renal pathology findings and also with urinary (u)-KIM-1 levels. However, there have been no reports examining the effect of u-KIM-1 levels on response to therapy, correlation with renal pathology, and usefulness as a predictor of renal function. U-KIM-1 levels were measured by ELISA in 61 SLE patients. In 38 active LN who underwent renal biopsy, we also examined whether u-KIM-1 levels affected LN disease activity, renal histological findings, and predictors of renal function. In SLE patients, proteinuria and u-KIM-1 levels were elevated in active LN compared to inactive LN. U-KIM-1 and proteinuria decreased with intensified treatment. U-KIM-1 levels also correlated with the percentage of glomerular crescent formation in renal pathology. In addition, patients with higher baseline u-KIM-1 levels had significantly higher eGFR and lower LN disease activity at 12months after treatment intensification. These data suggest that u-KIM-1 levels correlate with LN disease activity and renal histopathology findings and may be used as a predictor of treatment response.

Determining treatment response in lupus nephritis.

Determining treatment response in lupus nephritis.

Predictive Factors for Renal Response in Lupus Nephritis: A Single-center Prospective Cohort Study.

To identify the predictive factors for renal response in patients with lupus nephritis (LN). Patients and data were extracted from a prospective systemic lupus erythematosus cohort in Korea, in which clinical data were collected at 0, 3, 6, and 12 months after induction therapy. Treatment response of LN were evaluated as a complete response (CR), partial response (PR), or non-response (NR) at 3, 6, and 12 months, respectively. Predictive factors for CR at 6 months were evaluated using multivariable Poisson regression analysis. A total of 75 patients with LN who underwent biopsy was enrolled. The mean age at diagnosis of LN was 28.9±9.7 years, and 68 (90.7%) were female. The frequencies of classes III, IV, III+V, IV+V, and V were 20.0%, 44.0%, 16.0%, 12.0%, and 8.0%, respectively. Compared to relapsed LN, new-onset LN showed a lower percentage of glomerulosclerosis (45.5% vs. 76.2%, p=0.013). The overall proportions of CR, PR, and NR at 6 and 12 months were 52.0%, 26.7%, 21.3% and 50.7%, 24.0%, 25.3%, respectively. In multivariate analysis, age at enrollment (odds ratio [OR]=1.02, p=0.022), relapsed LN (OR=0.71, p=0.037), anti-Ro antibody (OR=0.67, p=0.014), and class III LN (OR=1.48, p=0.001) were associated with CR at 6 months. In our prospective cohort, class III LN was a good predictive factor for CR at 6 months in patients with LN, whereas younger age, relapsed LN, and anti-Ro antibody were poor predictive factors.

One-third of patients with lupus nephritis classified as complete responders continue to accrue progressive renal damage despite resolution of proteinuria

ObjectiveTreatment response in lupus nephritis (LN) is defined based on proteinuria, yet protocol kidney biopsy studies have shown that patients with lupus can have active nephritis in the absence of...

Predicting treatment response and clinicopathological findings in lupus nephritis with urine epidermal growth factor, monocyte chemoattractant protein-1 or their ratios.

IntroductionThere is a need for sensitive and specific biomarkers to predict kidney damage and therapeutic response in lupus nephritis (LN). Monocyte chemoattractant protein-1 (MCP-1) and epidermal growth factor (EGF) are cytokines with divergent roles. EGF or EGF/MCP1 ratio have been shown to correlate with prognosis in primary glomerulonephritis, but there is limited information in lupus nephritis (LN). This study evaluated the roles of MCP-1, EGF or their ratio as biomarkers of histopathology and response to treatment in LN.MethodsThis was a cross-sectional and observational study. Baseline urine MCP-1 and EGF levels in systemic lupus erythematosus (SLE) patients and controls (total n = 101) were compared, and levels were correlated with clinicopathological findings and subsequent response to treatment.ResultsMCP-1 was higher in active LN (n = 69) compared to other SLE groups and controls, whereas EGF was not different. MCP-1 correlated with disease activity (proteinuria, renal SLEDAI, classes III/IV/V, and high activity index.) By contrast, EGF correlated with eGFR, but not with proteinuria, activity index, or class III/IV/V. MCP-1 was higher, and EGF was lower in high chronicity index. EGF/MCP-1 decreased with greater clinicopathological severity. In a subgroup with proliferative LN who completed six months of induction therapy (n = 41), EGF at baseline was lower in non-responders compared to responders, whereas MCP-1 was similar. By multivariable analysis, baseline EGF was independently associated with subsequent treatment response. Area under the curve for EGF to predict response was 0.80 (0.66–0.95). EGF ≥ 65.6 ng/ mgCr demonstrated 85% sensitivity and 71% specificity for response. EGF/MCP-1 did not improve the prediction for response compared to EGF alone.ConclusionMCP-1 increased with disease activity, whereas EGF decreased with low GFR and chronic damage. Urine EGF may be a promising biomarker to predict therapeutic response in LN. EGF/MCP-1 did not improve the prediction of response.

Evaluation of Treatment Response in Lupus Nephritis

Objectives: To evaluate the effectiveness of the treatment reflected by the rate of response to therapy at 6 months and 12 months of follow-up respectively. Methods: We retrospectively analyzed clinical, laboratory data, treatment regimens, the type of response and relapse rate of 51 patients diagnosed with LN between January 2017 and February 2020. Results:47.06% of the patients underwent renal biopsy, classes III and IV being the most common lupus nephritis types (totaling 35.3% of biopsied patients). All induction therapy choices analyzed in the study- CYC, Glucocorticoids (GCs) and MMF- proved effective at reducing the proteinuria of the patients (p=0.001, p=0.012 and p=0,019 respectively. The 12 months evaluation demonstrated an ascending trend of the complete response, starting from 27.45% at 6 months and almost doubling at 1 year (56.86%). Almost half of patients (49.02%) did not relapse, while most of them (27.45%) had only 1 relapse. Analyzing the risk of relapse for each induction drug used, CYC had the highest rate of recurrence (62.07%). The use of MMF as a maintenance drug associated the lowest degree of recurrence. Conclusions: Both CYC and MMF as induction therapy are significantly effective in reducing proteinuria. The complete response was more frequently identified as an endpoint at 12 months of follow-up.

Prediction models of treatment response in lupus nephritis

In order to develop prediction models of one-year treatment response in lupus nephritis, an approach using machine learning to combine traditional clinical data and novel urine biomarkers was undertaken. Contemporary lupus nephritis biomarkers were identified through an unbiased PubMed search. Thirteen novel urine proteins contributed to the top 50% of ranked biomarkers and were selected for measurement at the time of lupus nephritis flare. These novel markers along with traditional clinical data were incorporated into a variety of machine learning algorithms to develop prediction models of one-year proteinuria and estimated glomerular filtration rate (eGFR). Models were trained on 246 individuals from four different sub-cohorts and validated on an independent cohort of 30 patients with lupus nephritis. Seven models were considered for each outcome. Three-quarters of these models demonstrated good predictive value with areas under the receiver operating characteristic curve over 0.7. Overall, prediction performance was the best for models of eGFR response to treatment. Furthermore, the best performing models contained both traditional clinical data and novel urine biomarkers, including cytokines, chemokines, and markers of kidney damage. Thus, our study provides further evidence that a machine learning approach can predict lupus nephritis outcomes at one year using a set of traditional and novel biomarkers. However, further validation of the utility of machine learning as a clinical decision aid to improve outcomes will be necessary before it can be routinely used in clinical practice to guide therapy.

Non-albumin proteinuria in lupus nephritis with tubulointerstitial inflammation and its clinical significance

Abstract Background Tubulointerstitial inflammation (TI) associated with systemic lupus erythematosis is an increasing finding in lupus nephritis. TI severity may have prognostic significance in the renal outcomes of lupus nephritis. Here, we aimed to determine whether non-albumin proteinuria is associated with TI severity and with the renal response in lupus nephritis. Objective To investigate the possible association between non-albumin proteinuria, tubulointerstial inflammation severity and poor renal response after immunosuppressive treatment. Patients and Methods This is a case series study which was conducted on 100 patients with systemic lupus erythematosis recruited from the outpatient clinic of Clinical Immunology at Ain Shams University Hospitals. Subject ages were between 13-53 years old, each one was subjected to detailed history, physical examination, laboratory investigations including serum creatinine before and after treatment, protein/creatinine ratio before and after treatment, albumin/creatinine ratio, ESR, CRP, CBC, C3 C4, anti DNA, eGFR and renal biopsy Results Our results showed that non-albumin proteinuria (uPCR − uACR) was significantly higher in patients with moderate-to-severe TI than in patients with no-tomild TI. Further, higher uPCR − uACR levels at baseline were associated with poor renal response after 6 months of treatment. Conclusion we found that non-albumin proteinuria (uPCR-uACR) is associated with severe tubulointerstitial inflammation (TI) in lupus nephritis.

Serum complement levels as prognostic marker for monitoring treatment response in lupus nephritis

Background: Lupus nephritis (LN) is one of the most common and serious manifestations of systemic lupus erythematosus (SLE) that causes significant morbidity and mortality. Certain biomarkers for LN are sometimes able to assess treatment response in lupus nephritis. This study aimed to compare serum complement levels (C3 and C4) as markers of treatment response of LN and their relation to the LN class in renal biopsy.&#x0D; Methods: This prospective observational study was conducted in the Department of Nephrology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from July 2018 to August 2019. Twenty seven patients who were diagnosed with LN after kidney biopsy were included in this study. Serum complement levels (C3 and C4), 24 hours urinary total protein (24-hr UTP) and anti-double-stranded DNA (anti-ds DNA) were measured in all patients at baseline, 3 months and 6 months after treatment initiation. These biomarker values before and after treatment were compared between the proliferative and non-proliferative LN patients.&#x0D; Results: Serum C3 levels were significantly different between patients with proliferative LN (Class III and Class IV) and non-proliferative LN (Class V) at baseline (0.47 ± 0.32 g/l versus 0.89 ± 0.43 g/l, p=0.009) and levels changed significantly 6 months after treatment initiation (p&lt;0.001) and likewise for serum C4 levels (0.10 ± 0.06 g/l versus 0.24 ± 0.26 g/l, p=0.040). The values of 24-hr UTP and anti-ds-DNA were significantly different 6 months after treatment with p value &lt;0.05 in both groups but C3 (p&lt;0.001) and renal Systemic Lupus Erythematosus Disease Activity Index (rSLEDAI) (p&lt;0.001) were only significant in the proliferative group. On the other hand, after 6 months treatment, C4 levels became relatively higher but that was not significant in both groups (p&gt;0.05).&#x0D; Conclusion: After 6 months of treatment, serum C3 and C4 levels increased towards normal in both LN groups. Serum C3 and C4 levels in patients with LN correlate with disease activity. Therefore, serum complement (C3 and C4) levels may be utilized as serological biomarkers for treatment response of LN.&#x0D; Birdem Med J 2021; 11(2): 97-102

The role of neuraminidase 1 (NEU1) in cytokine release by primary mouse mesangial cells and disease outcomes in murine lupus nephritis

The importance of altered glycosphingolipid (GSL) metabolism is increasingly gaining attention as a characteristic of multiple chronic kidney diseases. Previously, we reported elevated levels of GSLs and neuraminidase (NEU) enzyme activity/expression in the urine or kidney of lupus patients and lupus-prone mice, and demonstrated NEU activity mediates the production of cytokines by lupus-prone mouse primary mesangial cells. This mediation occurs in part through TLR4 and p38/ERK MAPK signalling in response to lipopolysaccharide (LPS) and lupus serum (LS). However, the precise role of NEU1, the most abundant NEU in the kidney, is incompletely known. In this study, we investigated the effect of genetically reduced Neu1 levels in vitro and in vivo. Mesangial cells from non-autoimmune prone Neu1+/− C57BL/6 mice had significantly reduced NEU activity, cytokine expression and cytokine secretion in response to LS and LPS, thereby suggesting reducing Neu1 expression may reduce the inflammatory response in lupus nephritis. Disease was assessed in female B6.SLE1/2/3 lupus-prone mice with genetically reduced levels (Neu1+/−) or wild-type levels (Neu1+/+) of Neu1 from 28 to 44 weeks of age along with aged-matched C57BL/6 controls. Renal disease was unexpectedly mild in all B6.SLE1/2/3 mice despite evidence of systemic disease. B6.SLE1/2/3 Neu1+/− mice exhibited significantly reduced levels of renal NEU1 expression and changes in renal α-2,6 linked sialylated N-glycans compared to the Neu1+/+ or healthy C57BL/6 mice, but measures of renal and systemic disease were similar between the B6.SLE1/2/3 Neu1+/+ and Neu1+/− mice. We conclude that NEU1 is the NEU largely responsible for mediating cytokine release by mesangial cells, at least in vitro, but may not be involved in modulating renal GSL levels in vivo or impact onset of nephritis in lupus-prone mice. However, the effect of reduced NEU1 levels on disease may not be appreciated in the mild disease expression in our colony of B6.SLE1/2/3 mice. The impact of the altered renal sialylated N-glycan levels and potential role of NEU1 with respect to established nephritis (late disease) in lupus-prone mice bears further investigation.