scholarly journals Novel Effects of Combination Therapy Through Inhibition of Caspase-1/Gasdermin D Induced-Pyroptosis in Lupus Nephritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Heng Cao ◽  
Junyu Liang ◽  
Jing Liu ◽  
Ye He ◽  
Yini Ke ◽  
...  
Keyword(s):  
Complete Remission ◽  
Lupus Nephritis ◽  
Combination Therapy ◽  
Disease Progression ◽  
Lupus Erythematosus ◽  
Peripheral Blood ◽  
Activity Index ◽  
Kidney Tissue ◽  
Cell Numbers ◽  
Caspase 1

ObjectivesCombination therapy with mycophenolate mofetil, tacrolimus and steroids are effective in achieving complete remission in lupus nephritis (LN). Combination therapy uniquely downregulated caspase-1 compared with monotherapies, which can cleave gasdermin D (GSDMD) and was recently identified as the pyroptosis executioner. We therefore investigated whether combination therapy enabled the suppression of caspase-1/GSDMD-mediated pyroptosis in LN.MethodsExpression and activation of GSDMD were detected in kidney specimens of the human and mouse with LN using immunohistochemical staining and immunoblotting. Primary podocytes isolated from MRL/lpr mice were incubated with LPS+ATP, and pretreated with monotherapy or combination therapy. Inhibition of caspase-1/GSDMD-induced pyroptosis by combination therapy were assessed in MRL/lpr mice and human specimens. Pyroptosis was examined using a FAM caspase-1 kit and flow cytometry. The correlation between pyroptosis in peripheral blood and the systemic lupus erythematosus disease activity index (SLEDAI) was analyzed.ResultsKidney tissue specimens from LN patients and mice exhibited greatly increased expression levels and cleavage of GSDMD. In cultured podocytes, combination treatment significantly suppressed the activation of NLRP3 and caspase-1 and reduced GSDMD N-terminal levels. Combination therapy repressed disease progression through inhibition of caspase-1/GSDMD-mediated pyroptosis in both humans and MRL/lpr mice. Caspase-1/PI positive cell numbers in peripheral blood were positively correlated with SLE-DAI. LN patients with complete remission and partial remission had remarkably reduced caspase-1/PI positive cell numbers compared to baseline. Ac-FLTD-CMK, a GSDMD-derived inhibitor, prevented the development of LN.ConclusionCombination therapy suppressed caspase-1/GSDMD-mediated pyroptosis in vitro and in vivo and reduced disease progression.

scholarly journals Rituximab treatment for lupus nephritis: A systematic review

2020 ◽  
Vol 43 (2) ◽  
pp. E47-54
Author(s):  
Zijie Yuan ◽  
Qifang Xie ◽  
Xiaochuan Wu ◽  
Boyu Tan ◽  
Xianhua Zhang
Keyword(s):  
Systematic Review ◽  
Mycophenolate Mofetil ◽  
Complete Remission ◽  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Activity Index ◽  
Remission Rate ◽  
Complete Remission Rate ◽  
Significant Difference ◽  
Total Remission

Purpose: We used the Cochrane systematic review to analyze the effectiveness and safety of rituximab for lupus nephritis. Methods: Systematic search was performed among Cochrane clinical controlled trials database, MEDLINE, MEDLINE-IN-Process and Other Non-Indexed Citations, EMBASE, EBSCO CINAHL, CNKI, VIP and Wanfang database from the establishment of the database to February 2016. The effectiveness and safety were evaluated in terms of the complete remission rate, total remission rate, urinary protein, Systemic Lupus Erythematosus Disease Activity Index changes and adverse events rate. Data were analyzed by the Review Manager Software version 5.3. Results: Five RCTs that met the inclusion criteria, including a total of 238 patients, were enrolled in our study. The results showed that the complete remission rate in rituximab group was a significantly higher than that of cyclophosphamide group. The difference between the two groups was statistically significant (OR=2.80, 95%CI(1.08,7.26), P=0.03). But there was no significant difference between the two groups in partial and total remission rate. The complete remission rate, partial remission rate and total remission rate in rituximab treatment group was similar compared with mycophenolate mofetil group and rituximab combined with cyclophosphamide group. The adverse reaction rate was also similar among the groups. Conclusion: The study systematically analyzed the effectiveness and safety of rituximab for lupus nephritis, which suggested that the complete remission rate of rituximab in the treatment of lupus nephritis was a significantly higher than that of cyclophosphamide group, while the effectiveness and safety was of no difference compared with cyclophosphamide and mycophenolate mofetil.

scholarly journals The ISN/RPS 2016 classification predicts renal prognosis in patients with first-onset class III/IV lupus nephritis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Asaka Hachiya ◽  
Munetoshi Karasawa ◽  
Takahiro Imaizumi ◽  
Noritoshi Kato ◽  
Takayuki Katsuno ◽  
...  
Keyword(s):  
Complete Remission ◽  
Lupus Nephritis ◽  
Clinical Outcomes ◽  
Lupus Erythematosus ◽  
Cox Regression ◽  
Interstitial Fibrosis ◽  
Activity Index ◽  
Class Iii ◽  
Cox Regression Analysis ◽  
First Onset

AbstractLupus nephritis (LN) is a life-threatening complication of systemic lupus erythematosus. The 2003 pathological classification of LN was revised in 2016; it quantitatively evaluates the interstitium in addition to the glomeruli. We performed a retrospective multi-centre cohort study and investigated the utility of the 2016 classification—including the activity index (AI), chronicity index (CI), and each pathological component to predict complete remission or renal function decline, defined as 1.5-fold increase in serum creatinine levels—and compare with that of the 2003 classification. Ninety-one consecutive adult patients with first-onset class III/IV LN who were newly prescribed any immunosuppressants were enrolled and followed up for a median of 51 months from January 2004. Cox regression analysis demonstrated the subclasses based on the 2003 classification, which mainly evaluate glomerular lesions, were not associated with clinical outcomes. After adjustments for estimated glomerular filtration rate and urinary protein levels, higher CI and higher interstitial fibrosis and lower hyaline deposit scores were associated with renal functional decline. Similarly, higher CI and interstitial inflammation scores were associated with failure to achieve complete remission. Therefore, the 2016 classification can predict the clinical outcomes more precisely than the 2003 classification.

Correlation Between Serological Makers and Immunofluorescence Deposits i n Kidney Tissue of Patients with Lupus Nephritis

2019 ◽  
Vol 9 (02) ◽  
Author(s):  
Haider S Al-Hadad ◽  
Aqeel Abbas Matrood ◽  
Maha Abdalrasool Almukhtar ◽  
Haider Jabur Kehiosh ◽  
Riyadh Muhi Al-Saegh
Keyword(s):  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Kidney Biopsy ◽  
Pearson Correlation ◽  
Standard Procedure ◽  
Kidney Tissue ◽  
P Value ◽  
American College Of Rheumatology ◽  
Immune Deposits ◽  
Number Of Patients

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease. Few biomarkers for SLE have been validated and widely accepted for the laboratory follow-up of inflammatory activity. In SLE patients, with lupus nephritis (LN), complement activation leads to fluctuation of serum C3 and C4 that are frequently used as clinicalm biomarker of disease activity in SLE. Patients and Methods: In this study the number of patients were 37, seven patients were excluded for incomplete data collection, 28 were females ,2 were males. The duration of the study is two years from 2015 to 2017. Patients were considered to have SLE and LN according to American College of Rheumatology (ACR) criteria, and International Society of Nephrology/ Renal Pathology Society (ISN/RPS). All patients were evaluated withm clinical presentation, laboratory investigations. Our patients underwent kidney biopsy according to standard procedure by Kerstin Amann, and their tissue specimens were studied in the laboratory with light microscope (LM) and immunofluorescence microscope reagents. The relationship between the serological markers and immunofluorescence deposits in kidney biopsy of all patients were studied using the statistical analysis of Pearson correlation and single table student's T test. A P value 0.05 was considered statistically significant. Results: The granular pattern of IF deposits was present in all LN patients, and in more than two third of patients these IF deposits presented in glomerular, tubular, and mesangium sites. While less than one third of patients had IF deposits in the mesangium only. There was no statistically significant correlation between serum ANA, anti-dsDNA, and IF deposits of different types. There was significant correlation between serum C3 and C4 hypocomplementemia and IgG immune deposits in kidney biopsy, and there was significant relationship between serum C3 hypocomplementemia and full house immunofluorescence (FHIF) deposits inm kidney biopsy.Conclusions:Immunofluorescence deposits is mainly granular pattern in LN patients. There was no significant association between serum ANA, anti-dsDNA, and immune deposits in kidney tissue. Immunofluorescence deposits of IgG type correlates significantly with serum C3 and C4 hypocomplemetemia, and these immune deposits in association with low complement levels correlates with LN flare. There was significant correlation between C3 hypocomplementemia and FHIF.

THE CLINICAL, LABORATORY MANIFESTATIONS AND HISTOPATHOLOGY IN NEPHROTIC PATIENTS WITH LUPUS NEPHRITIS

2018 ◽  
pp. 52-58
Author(s):  
Le Thuan Nguyen ◽  
Bui Bao Hoang
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Clinical Laboratory ◽  
Activity Index ◽  
Clinical Manifestations ◽  
Systemic Lupus ◽  
Cross Sectional ◽  
Organ Systems ◽  
Tubulointerstitial Lesions

Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disease involving multiple organ systems. The kidney appears to be the most commonly affected organ, especially nephrotic is a serious kidney injury. The clinical, laboratory manifestations and histopathology are very useful for diagnosis, provide the means of predicting prognosis and guiding therapy in nephrotic patients with lupus nephritis. Methods: Descriptive cross-sectional study of nephrotic patients with lupus treated in the Department of Nephrology Trung Vuong Hospital and Cho Ray Hospital between May/2014 and May/2017. Renal histopathological lesions were classified according to International Society of Nephrology/Renal Pathology Society - ISN/RPS ’s 2003. The clinical, laboratory manifestations and histopathological features were described. Results: Of 32 LN with nephritic range proteinuria cases studied, 93.7% were women. The 3 most common clinical manifestations were edema (93.8%), hypertension (96.8%) and pallor (68.9%), musculoskeletal manifestions (46.9%), malar rash (40.6%). There was significant rise in laboratory and immunological manifestions with hematuria (78.1%), Hb < 12g/dL (93.5%), increased Cholesterol (100%), and Triglycerid (87.5%), Creatinine > 1.4 mg/dL (87.5%), increased BUN 71.9%, ANA (+) 93.8%, Anti Ds DNA(+) 96.9%, low C3: 96.9%, low C4: 84.4%. The most various and severe features were noted in class IV with active tubulointerstitial lesions and high activity index. Conclusion: Lupus nephritis with nephrotic range proteinuria has the more severity of histopathological feature and the more severity of the more systemic organ involvements and laboratory disorders were noted. Key words: Systemic lupus, erythematosus (SLE) lupus nepphritis, clinical

A Comparative Study on the Incidence, Aggravation, and Remission of Lupus Nephritis Based on iTRAQ Technology

2020 ◽  
Vol 23 (7) ◽  
pp. 649-657
Author(s):  
Dong-Jiang Liao ◽  
Xi-Ping Cheng ◽  
Nan Li ◽  
Kang-Li Liang ◽  
Hui Fan ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Kidney Tissue ◽  
Quantitative Information ◽  
Enzyme Linked Immunosorbent Assay ◽  
Absolute Quantitation ◽  
Western Blot Method ◽  
Close Relationship ◽  
Polymerase Chain ◽  
Isobaric Tags

Aim and Objective: Lupus nephritis (LN) is one of the major complications of systemic lupus erythematosus (SLE). The specific mechanisms of pathogenesis, aggravation, and remission processes in LN have not been clarified but is of great need in the clinic. Using isobaric tags for relative and absolute quantitation (iTRAQ) technology to screen the functional proteins of LN in mice. Especially under intervention factors of lipopolysaccharide (LPS) and dexamethasone. Methods: Mrl-lps mice were intervened with LPS, dexamethasone, and normal saline (NS) using intraperitoneal injection, and c57 mice intervened with NS as control. The anti-ANA antibody enzyme-linked immunosorbent assay (ELISA) was used to verify disease severity. Kidney tissue is collected and processed for iTRAQ to screen out functional proteins closely related to the onset and development of LN. Western blot method and rt-PCR (real-time Polymerase Chain Reaction) were used for verification. Results: We identified 136 proteins that marked quantitative information. Among them, Hp, Igkv8-27, Itgb2, Got2, and Pcx proteins showed significant abnormal manifestations. Conclusion: Using iTRAQ methods, the functional proteins Hp, Igkv8-27, Itgb2, Got2, and Pcx were screened out for a close relationship with the pathogenesis and development of LN, which is worth further study.

Characteristics of lupus and lupus nephritis at a tertiary care center in Lebanon

Lupus ◽  
2019 ◽  
Vol 28 (13) ◽  
pp. 1598-1603 ◽  
Author(s):  
S H Koubar ◽  
J Kort ◽  
S Kawtharani ◽  
M Chaaya ◽  
M Makki ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Kidney Disease ◽  
Complete Remission ◽  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Partial Remission ◽  
Care Center ◽  
Tertiary Care ◽  
Tertiary Care Center ◽  
Systemic Lupus

Introduction Systemic lupus erythematosus affects 4.8–78.5 people per 100,000 worldwide, 90% of whom are females. Geography and ethnicity have been shown to significantly affect the prevalence and natural history of the disease. Lupus nephritis affects around half of patients with systemic lupus erythematosus. Data about systemic lupus erythematosus and lupus nephritis in the Middle East are still scarce. In this study, we aimed to describe the characteristics of systemic lupus erythematosus and lupus nephritis at a tertiary care center in Lebanon. Methods This is a retrospective chart review of all biopsy-proven lupus nephritis patients admitted to the American University of Beirut medical center between January 2000 and December 2018. Patients above 12 years of age who had any International Society of Nephrology/Renal Pathology Society (ISN/RPS) class of lupus nephritis on their renal biopsy were included in the study. Results The study included 55 patients with lupus nephritis. Upon presentation of systemic lupus erythematosus, the most common clinical feature was arthritis, seen in 83% of patients, followed by anemia (82%) and malar rash (48%). In total 93% had positive ANA, 89% had positive anti-dsDNA and 98% of patients had proteinuria. The most common ISN/RPS class of lupus nephritis in our series was IV (49%). At the time of the biopsy 15% of patients underwent dialysis. At 6 months, 11/27 had complete remission, 6/27 had partial remission and 10/27 had no remission. At 1 year, 8/23 had complete remission, 4/23 had partial remission and 11/23 had no remission. During the study period, 15 out of 35 patients available for analysis had chronic kidney disease (CKD) and six out of 34 patients developed end-stage kidney disease requiring renal replacement therapy. In comparison to other series in the region, our series had more males affected, higher creatinine at the time of biopsy and greater degree of proteinuria. Conclusion Our study provided insight on the demographics, characteristics, and outcomes of lupus nephritis in Lebanon. Interestingly, male gender was present in a quarter of patients. This warrants further investigation and confirmation. We are hoping to expand this experience into a national prospective registry to further characterize this entity in our region.

scholarly journals PERIPHERAL BLOOD MITOCHONDRIAL DNA ALTERATION DURING SYSTEMIC LUPUS NEPHRITIS

2021 ◽  
Vol 10 (19) ◽  
pp. 416-421
Author(s):  
Ruchi Upadhyay ◽  
Ratika Srivastava
Keyword(s):  
Mitochondrial Dna ◽  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Peripheral Blood ◽  
Normal Subjects ◽  
Mitochondrial Genes ◽  
Systemic Lupus ◽  
Mt Dna ◽  
Mitochondrial Dna Copy Number ◽  
Genes Encoding

The investigation of mitochondrial DNA (Mt-DNA) alterations could impart light on the involvement of mitochondria in the pathophysiology of Systemic Lupus Erythematosus. The purpose of this study is to examine the peripheral blood mitochondrial DNA copy number variation in Lupus Nephritis patients and also to find out it’s correlation with amount of protein present in urine. The significant correlation could aid in the inspection of mitochondrial involvement, particularly in Lupus Nephritis. Two mitochondrial genes encoding MT-CYT and MT-TL1 were measured quantitatively by qRT-PCR in whole blood of 17 SLE patients and 15 healthy subjects with similar gender (female: male ratio) and age group. The amount of mitochondrial genes MT-CYT and MT-TL1 was 1.69 and 1.26 fold higher respectively in patients. The significantly higher amount of protein detected in lupus nephritis patients (129.4±116.4 mg/dl) in comparison to normal subjects (25.3 ±10.7 mg/dl). No significant correlation was established between Mt-DNA quantity and proteinuria. Alteration in mitochondrial genes reflects the possibilities of altered mitophagy or mitochondrial biosynthesis during SLE. These findings are required to be further validated by studying mitophagy and biogenesis during SLE in details.

scholarly journals Change of Renal Gallium Uptake Correlated with Change of Inflammation Activity in Renal Pathology in Lupus Nephritis Patients

2021 ◽  
Vol 10 (20) ◽  
pp. 4654
Author(s):  
Tsu-Yi Hsieh ◽  
Yi-Ching Lin ◽  
Wei-Ting Hung ◽  
Yi-Ming Chen ◽  
Mei-Chin Wen ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Activity Index ◽  
Left Kidney ◽  
Renal Pathology ◽  
Class Iii ◽  
Stage Renal Disease ◽  
End Stage ◽  
Active Inflammation ◽  
Histological Results

Background: Lupus nephritis (LN) often lead to end-stage renal disease in systemic lupus erythematosus patients. This study aimed to investigate the clinical application of renal gallium-67 scans for determining renal histological parameters in LN patients. Methods: Between 2006 and 2018, 237 biopsy-proven and 35 repeat biopsies LN patients who underwent renal gallium scans before or after biopsy were included for analysis. The classification and scoring of LN were assessed according to the International Society of Nephrology/Renal Pathology Society. A delayed 48-h gallium scan was performed and interpreted by semiquantitative methods using left kidney/spine (K/S) ratio. The renal histological results were compared with gallium uptake. Results: Out of 237 participants, 180 (76%) had proliferative LN. Baseline gallium left K/S ratio was significantly higher in class IV LN as compared to class III (median (interquartile range, IQR): 1.16 (1.0–1.3), 0.95 (0.9–1.1), respectively, p < 0.001). Furthermore, changes in gallium uptake between two biopsies were positively correlated with changes activity index (r = 0.357, p = 0.035), endocapillary hypercellularity (r = 0.385, p = 0.032), and neutrophils infiltration (r = 0.390, p = 0.030) in renal pathology. Conclusions: Renal gallium uptake is associated with active inflammation in LN. Changes in renal gallium uptake positively correlated with changes in activity index in renal pathology.

Therapeutic potential of allogeneic mesenchymal stromal cells transplantation for lupus nephritis

Lupus ◽  
2018 ◽  
Vol 27 (13) ◽  
pp. 2161-2165 ◽  
Author(s):  
J Barbado ◽  
S Tabera ◽  
A Sánchez ◽  
J García-Sancho
Keyword(s):  
Lupus Nephritis ◽  
Mesenchymal Stromal Cells ◽  
Lupus Erythematosus ◽  
Stromal Cells ◽  
Therapeutic Potential ◽  
Activity Index ◽  
Disease Activity Index ◽  
Controlled Clinical Trial ◽  
Allogeneic Mscs

Animal and human studies have suggested the potential of mesenchymal stromal cells (MSCs) to treat systemic lupus erythematosus (SLE). Here, we present the results of compassionate MSC treatments for three SLE patients to provide the proof of concept for a randomized and controlled clinical trial. Three patients of different ethnicities who suffer from chronic SLE, and who presented with class IV active proliferative nephritis confirmed by biopsy, were treated with allogeneic MSCs from healthy donors. Ninety million cells were infused intravenously into each patient during high and very high activity disease flare-ups and follow-up was continued for 9 months. Multi-organic affectation was quantified by the SLE disease activity index (SLEDAI), and indicators of lupus nephritis activity, such as proteinuria, as well as lymphocyte and monocyte antigens and anti-HLA antibodies were measured at 1, 3, 6, and 9 months after treatment. Proteinuria levels improved dramatically during the 1st month after treatment and the ameliorations were sustained throughout the follow-up period. SLEDAI scores revealed early, durable, and substantial remissions that were complete for two patients and partial for the third patient and that permitted medication doses to be reduced 50–90%. These favourable outcomes support completion of the randomized and controlled MSC trial for SLE.

The correlation of urinary podocytes and podocalyxin with histological features of lupus nephritis

Lupus ◽  
2017 ◽  
Vol 27 (3) ◽  
pp. 484-493 ◽  
Author(s):  
D Ikuma ◽  
K Hiromura ◽  
H Kajiyama ◽  
J Suwa ◽  
H Ikeuchi ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Activity Index ◽  
Sandwich Elisa ◽  
Characteristic Analysis ◽  
Crescent Formation ◽  
Class V ◽  
Histological Features ◽  
Cellular Crescent ◽  
Class Iv

Objectives The objective of this study was to test the correlation of urinary podocyte number (U-Pod) and urinary podocalyxin levels (U-PCX) with histology of lupus nephritis. Methods This was an observational, cross-sectional study. Sixty-four patients were enrolled: 40 with lupus nephritis and 24 without lupus nephritis (12 lupus nephritis patients in complete remission and 12 systemic lupus erythematosus patients without lupus nephritis). Urine samples were collected before initiating treatment. U-Pod was determined by counting podocalyxin-positive cells, and U-PCX was measured by sandwich ELISA, normalized to urinary creatinine levels (U-Pod/Cr, U-PCX/Cr). Results Lupus nephritis patients showed significantly higher U-Pod/Cr and U-PCX/Cr compared with patients without lupus nephritis. U-Pod/Cr was high in proliferative lupus nephritis (class III±V/IV±V), especially in pure class IV (4.57 (2.02–16.75)), but low in pure class V (0.30 (0.00–0.71)). U-Pod/Cr showed a positive correlation with activity index ( r=0.50, P=0.0012) and was independently associated with cellular crescent formation. In contrast, U-PCX/Cr was high in both proliferative and membranous lupus nephritis. Receiver operating characteristic analysis revealed significant correlation of U-Pod/Cr with pure class IV, class IV±V and cellular crescent formation, and the combined values of U-Pod/Cr and U-PCX/Cr were shown to be associated with pure class V. Conclusions U-Pod/Cr and U-PCX/Cr correlate with histological features of lupus nephritis.

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