Association of Intrarenal B-Cell Infiltrates with Clinical Outcome in Lupus Nephritis: A Study of 192 Cases

Background. Lupus nephritis (LN) remains a major cause of morbidity and end-stage renal disease. Dysfunction of B lymphocytes is thought to be important in the pathogenesis of SLE/LN. Intrarenal B cells have been found in several forms of inflammatory kidney diseases although their role in LN renal is not well defined.Methods. Intrarenal B cells were analyzed in 192 renal biopsies from patients diagnosed with lupus nephritis. Immunohistochemical staining of serial sections was performed for each LN patient using CD20, CD3, and CD21 antibodies.Results. Intrarenal B cells were more likely to be associated with class IV LN and were mainly distributed in the renal interstitium, with very few in the glomerulus. The systemic lupus erythematosus disease activity index (SLEDAI), blood urea nitrogen, and serum creatinine levels were all significantly greater in the LN-B cell groups (allP<0.05). LN renal activity and chronicity indices correlated with B-cells infiltrates (allP<0.0001). Renal biopsies were classified into four distinct categories according to the organizational grade of inflammatory cell infiltrates. Germinal center- (GC-) like structures were not identified in any LN biopsies.Conclusion. It is hypothesized that intrarenal B cells enhance immunological responses and exaggerate the local immune response to persisting autoimmune damage in the tubulointerstitium.

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Cytoplasmic FOXO1 identifies a novel disease-activity associated B cell phenotype in SLE

Lupus Science & Medicine ◽

10.1136/lupus-2018-000296 ◽

2018 ◽

Vol 5 (1) ◽

pp. e000296 ◽

Cited By ~ 4

Author(s):

Molly K Hritzo Ahye ◽

Amit Golding

Keyword(s):

B Cells ◽

Disease Activity ◽

B Cell ◽

Lupus Erythematosus ◽

Cell Activation ◽

Activity Index ◽

Human Lymphocytes ◽

Disease Activity Index ◽

Memory B Cells ◽

Cell Phenotype

Systemic lupus erythematosus (SLE) is a manifestation of hyperactivated lymphocytes and results, in part, from the loss of normal tolerance checkpoints. FOXO1 is a transcription factor involved at critical early and late B cell development checkpoints; however, its role in regulating peripheral B cell tolerance is not fully understood. We have applied our published approach for using imaging flow cytometry to study native FOXO1 localisation in human lymphocytes to peripheral blood samples from healthy individuals versus patients with SLE. We report, here, on dramatic cytoplasmic localisation of FOXO1 in two peripheral B cell SLE subsets: IgD-CD27+ (class-switched memory) B cells and IgD-CD27- (atypical memory) B cells. The latter, so-called ‘Double Negative’ (DN) B cells have previously been shown to be increased in SLE and enriched in autoreactive clones. Cytoplasmic-predominant FOXO1 (CytoFOX) B cells are significantly increased in patients with SLE as compared to healthy controls, and the levels of CytoFoOX DN B cells correlate directly with SLE disease activity. The highest abundance of CytoFox DN B cells was observed in African American females with SLE Disease Activity Index (SLEDAI)≥6. The phenotype of CytoFOX DN B cells in SLE includes uniquely low CD20 expression and high granularity/side scatter. As FOXO1 phosphorylation downstream of B cell receptor-dependent signalling is required for nuclear exclusion, CytoFOX B cells likely represent a high state of B cell activation with excess signalling and/or loss of phosphatase activity. We hypothesise that CytoFOX B cells in lupus represent a novel biomarker for the expansion of pathological, autoreactive B cells which may provide new insights into the pathophysiology of SLE.

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Tacrolimus versus cyclophosphamide as treatment for diffuse proliferative or membranous lupus nephritis: a non-randomized prospective cohort study

Lupus ◽

10.1177/0961203312448105 ◽

2012 ◽

Vol 21 (9) ◽

pp. 1025-1035 ◽

Cited By ~ 32

Author(s):

S Wang ◽

X Li ◽

L Qu ◽

R Wang ◽

Y Chen ◽

...

Keyword(s):

Lupus Nephritis ◽

Renal Disease ◽

Lupus Erythematosus ◽

Activity Index ◽

Disease Activity Index ◽

Severe Adverse Effect ◽

Open Label ◽

Severe Renal Disease ◽

Stage Renal Disease ◽

End Stage

Treatment of lupus nephritis (LN) with cyclophosphamide (CYC) is effective but retains a certain severe adverse effect. Tacrolimus (TAC) may be a suitable treatment for LN. Forty patients with diffuse proliferative or membranous LN were recruited for this non-randomized open-label study — 67.5% (27/40) had nephrotic proteinuria (>3.5 g/day) and 50.0% (20/40) had low estimated glomerular filtration rate (eGFR) (<60 mL/min/1.73m2). We compared the efficacy and adverse effects of TAC (0.04–0.08 mg/kg/d)/prednisone for 12 months (TAC group, n = 20) with intravenous CYC (750 mg/m2 per month)/prednisone for six months followed by azathioprine (Aza) (100 mg/day)/prednisone for six months (CYC group, n = 20). The TAC target concentration was 6–8 ng/mL or 4–6 ng/mL, respectively, when induction or maintenance therapy was required and 4.0 ng/mL for patient with renal insufficiency. In the TAC group, mean urinary protein excretion decreased significantly from 5.00 ± 1.91 g/day at baseline to 2.54 ± 1.68 g/day after two weeks of therapy ( P < 0.001), compared with the CYC group (4.9 ± 19.4 g/day), P = 0.001, and 65.0% (13/20) achieved partial remission at one month, compared with the CYC group (0/20), P < 0.001. The incidence of complete remission (CR) was significantly higher in the TAC group than in the CYC group (55.0% vs.15.0% by five months, P = 0.008, and 75.0% vs.40.0% by 12 months, P = 0.025, respectively). The significant improvement in serum anti-dsDNA and systemic lupus erythematosus (SLE) disease activity index (DAI) was in the TAC group relative to the CYC group at 12 months ( P = 0.031, P = 0.003, respectively). The eGFR improved in the TAC group from 59.90 ± 23.64 mL/min/1.73m2 at baseline to 93.75 ± 28.52 mL/min/1.73m2 after 12 months, P = 0.001. In the CYC group, two patients developed end-stage renal disease (ESRD), three patients experienced serious pneumonia, and one patient died. Our preliminary study showed TAC is a safe and effective treatment for LN with severe renal disease, and with less-severe adverse events compared with CYC followed Aza therapy. Further larger sample studies are needed to confirm our conclusion.

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

Journal of Clinical Medicine ◽

10.3390/jcm10204654 ◽

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.

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Therapeutic potential of allogeneic mesenchymal stromal cells transplantation for lupus nephritis

Lupus ◽

10.1177/0961203318804922 ◽

2018 ◽

Vol 27 (13) ◽

pp. 2161-2165 ◽

Cited By ~ 13

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.

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Expression of XBP1s in B lymphocytes is critical for pristane-induced lupus nephritis in mice

AJP Renal Physiology ◽

10.1152/ajprenal.00472.2019 ◽

2020 ◽

Vol 318 (5) ◽

pp. F1258-F1270 ◽

Cited By ~ 1

Author(s):

Li Xiang ◽

An Liu ◽

Guoshuang Xu

Keyword(s):

B Cells ◽

Lupus Nephritis ◽

Mouse Model ◽

B Cell ◽

Lupus Erythematosus ◽

Cell Activation ◽

B Lymphocyte ◽

B Cell Activation ◽

Protein Levels ◽

Almost All

B lymphocyte hyperactivity plays a pathogenic role in systemic lupus erythematosus (SLE), and spliced X box-binding protein 1 (XBP1s) has been implicated in B cell maturation and differentiation. We hypothesized that blockade of the XBP1s pathway inhibits the B cell hyperactivity underlying SLE and lupus nephritis (LN) development. In the present study, we systematically evaluated the changes in B cell activation induced by the Xbp1 splicing inhibitor STF083010 in a pristane-induced lupus mouse model. The lupus mouse model was successfully established, as indicated by the presence of LN with markedly increased urine protein levels, renal deposition of Ig, and mesangial cell proliferation. In lupus mice, B cell hyperactivity was confirmed by increased CD40 and B cell-activating factor levels. B cell activation and plasma cell overproduction were determined by increases in CD40-positive and CD138-positive cells in the spleens of lupus mice by flow cytometry and further confirmed by CD45R and Ig light chain staining in the splenic tissues of lupus mice. mRNA and protein expression of XBP1s in B cells was assessed by real-time PCR, Western blot analysis, and immunofluorescence analysis and was increased in lupus mice. In addition, almost all changes were reversed by STF083010 treatment. However, the expression of XBP1s in the kidneys did not change when mice were exposed to pristane and STF083010. Taken together, these findings suggest that expression of XBP1s in B cells plays key roles in SLE and LN development. Blockade of the XBP1s pathway may be a potential strategy for SLE and LN treatment.

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Clinical And Morphological Improvement Of Lupus Nephritis Treated With Rituximab

Folia Medica ◽

10.1515/folmed-2015-0003 ◽

2014 ◽

Vol 56 (4) ◽

pp. 245-252 ◽

Cited By ~ 2

Author(s):

Maria E. Tsanyan ◽

Sergey K. Soloviev ◽

Stefka G. Radenska-Lopovok ◽

Anna V. Torgashina ◽

Ekaterina V. Nikolaeva ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Nephritis ◽

Cell Therapy ◽

Disease Activity ◽

B Cell ◽

Renal Biopsy ◽

Lupus Erythematosus ◽

Systemic Lupus ◽

Renal Biopsies

Abstract Aim: TO assess the effects of rituximab (RTM) therapy on clinical and morphologic activity of lupus nephritis (LN). Material and methods: The study included 45 patients with confirmed diagnosis of systemic lupus erythematosus (SLE), unaffected by previously received standard therapy with glucocorticoids (GCs) and cytostatics. The disease activity was assessed using Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K); to assess the LN activity we used the SLICC RA/RE index. Forty-five patients with LN were given puncture renal biopsy prior to prescribing RTM; 16 patients had repeated renal biopsy 1 year and more after beginning the anti-B-cell therapy. LN was graded histologically in accordance with the WHO classification (2003) with indices of activity (AI) and chronicity (CI). Results: The predominant number of patients had class III - IV of LN. The repeated renal biopsies demonstrated that LN had undergone a transition into a more favourable morphologic class, which was associated, in most of these cases, with a positive therapeutic effect. The follow-up dynamics showed a statistically significant reduction of AI (p=0.006), and no statistically significant changes in the CI (p = 0.14). Conclusion: The long-term follow-up in the study has showed that repeated courses of anti-B-cell therapy with RTM have a positive effect both on SLE activity and generally on the renal process. The reduction of the morphologic class of LN as assessed in the repeated renal biopsies is a convincing proof for this. Eleven out of 16 patients experienced transition of the morphologic class into a more favourable type, which in most cases was combined with lower AI (p = 0.006). We found no evidence of increase in the CI (p = 0.14).

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Urinary Neutrophil Gelatinase-Associated Lipocalin to Monitor Lupus Nephritis Disease Activity

Biomarker Insights ◽

10.4137/bmi.s27625 ◽

2015 ◽

Vol 10 ◽

pp. BMI.S27625 ◽

Cited By ~ 1

Author(s):

Hani Susianti ◽

Jullyanny W. Wijaya ◽

Ati Rastini ◽

Kusworini Handono ◽

Atma Gunawan ◽

...

Keyword(s):

Lupus Nephritis ◽

Disease Activity ◽

Lupus Erythematosus ◽

Transforming Growth Factor ◽

Activity Index ◽

Disease Activity Index ◽

Transforming Growth Factor Β1 ◽

Sledai Score ◽

Neutrophil Gelatinase Associated Lipocalin ◽

Neutrophil Gelatinase

Background This study was conducted to determine whether there is an association between urinary neutrophil gelatinase-associated lipocalin (uNGAL) and urinary transforming growth factor-β1 (uTGF-β1) with lupus nephritis (LN) disease activity. Methods Urine samples from 18 LN patients were collected every month for six months then examined for uNGAL, uTGF-β1, and renal domain Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score. Results The uNGAL levels were significantly different between active and inactive LN (P < 0.05). uTGF-β1 levels were not different between active and inactive LN (P > 0.05). There was a significant correlation between uNGAL levels and renal domain SLEDAI score (r= 0.417, P < 0.05). There was no correlation between uTGF-β1 levels and renal domain SLEDAI score (r = 0.031, P > 0.05). Conclusion uNGAL is better than uTGF-β1 for differentiation of active and inactive LN. uNGAL can be considered as a biomarker to monitor LN disease activity.

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HLA-DRB1*04 as a Risk Allele to Systemic Lupus Erythematosus and Lupus Nephritis in the Malay Population of Malaysia

Frontiers in Medicine ◽

10.3389/fmed.2020.598665 ◽

2021 ◽

Vol 7 ◽

Author(s):

Malarvili Selvaraja ◽

Voon Kin Chin ◽

Maha Abdullah ◽

Masita Arip ◽

Syafinaz Amin-Nordin

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Nephritis ◽

Lupus Erythematosus ◽

Activity Index ◽

Disease Activity Index ◽

Systemic Lupus ◽

Mortality And Morbidity ◽

Curative Therapy ◽

Multiple Organs ◽

Increased Risk

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease afflicting multiple organs. Lupus nephritis (LN) is a serious complication of SLE and remains a major cause of mortality and morbidity. Curative therapy remains unavailable as etiology from genetic and environmental factors is still unclear. The present study was conducted to elucidate the link between HLA-DRB1 gene polymorphisms with SLE and LN through clinical and laboratory/biological presentations in a population of Malaysian Malay females with SLE. A total of 100 Malay female SLE patients inclusive of 70 SLE patients without LN and 30 patients with LN were included in this study. HLA-DRB1 allele examination in SLE patients was performed using PCR-SSO, and the alleles' frequencies were compared with 951 publicly available datasets representing Malay healthy controls in Malaysia. Cytokines and free radical levels were detected by ELISA and bead-based multiplexed Luminex assays. The association between HLA-DRB1 alleles with clinical and serological manifestations and immune mediators was analyzed using different statistical approaches whenever applicable. Our study showed that HLA-DRB1*0405, HLA-DRB1*1502, and HLA-DRB1*1602 were associated with the increased risk of SLE while HLA-DRB1*1201 and HLADRB1*1202 alleles were associated with a lower risk of SLE development. Furthermore, HLA-DRB1*04 showed significant association to LN and arthritis while HLA-DRB1*15 was significantly associated with oral ulcer in Malay SLE patients. Association analysis of HLA-DRB1*04 with clinical and biological factors revealed that HLA-DRB1*04 was significantly associated with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores, anti-nuclear antibody (ANA), C-reactive protein (CRP) in the blood, and total protein in the urine. SLE carriers with the HLA-DRB1*04 allele were significantly correlated to the increased levels of cytokines (IFN-y, GM-CSF, IL-17F, IL-18, IL-21, and VEGF) and were significantly showing negative correlation to IL-5 and free radicals (LPO and catalase enzyme) levels compared to SLE carriers without HLA-DRB1*04 allele. The results suggested that disease severity in SLE may be determined by HLA-DRB1 alleles. The risk of HLA-DRB1*04 allele with LN was supported by the demonstration of an intense inflammatory response in Malay SLE patients in Malaysia. More studies inclusive of a larger and multiple SLE cohorts in the future are warranted to validate these findings.

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Multitarget Therapy: An Effective and Safe Therapeutic Regimen for Lupus Nephritis

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/jpps30526 ◽

2019 ◽

Vol 22 ◽

pp. 365-375

Author(s):

Tianbiao Zhou ◽

Xialan Zhang ◽

Wenshan Lin ◽

Shujun Lin

Keyword(s):

Lupus Nephritis ◽

Lupus Erythematosus ◽

Activity Index ◽

Therapy Group ◽

Meta Analysis ◽

Disease Activity Index ◽

Biomedical Literature ◽

Cochrane Library ◽

Negative Rate ◽

Multitarget Therapy

Introduction: We evaluated the effectiveness and safety of various multitarget therapies for inducing remission in lupus nephritis patients. Methods: Randomized controlled trials (RCT) were identified and extracted from the Embase, PubMed, Chinese Biomedical Literature Database (CBM), and the Cochrane Library until Oct 31, 2018, investigations meeting inclusion criteria were extracted, and data were analyzed by meta-analysis. The total remission (TR; complete to partial remission), complete remission (CR), albumin, proteinuria levels, negative rate of anti-double-stranded DNA antibody (ds-DNA), negative rate of anti-nuclear antibody (ANA), and systemic lupus erythematosus disease activity index (SLE-DAI) were calculated using the software of RevMan 5.3. Results: Eleven RCTs were included and analyzed. The multitarget therapy group exhibited a higher value of CR (OR=3.06, 95%CI: 2.35-3.99, P﹤0.00001) as well as TR (OR=3.83, 95%CI: 2.77-5.31, P﹤0.00001) than those in the cyclophosphamide (CYC) group. In addition, multitarget therapies had more albumin (WMD=3.50, 95%CI: 1.04-5.95, P=0.005), greater albumin increases (OR=1.96, 95%CI: 0.63-3.29, P=0.004) and higher negative rates of ds-DNA (OR=2.13, 95%CI: 1.51-3.01, P﹤0.0001) and ANA (OR=2.82, 95%CI: 1.77-4.50, P﹤0.0001) when compared with the CYC group. This group also had less proteinuria levels (WMD=-0.55, 95%CI: -0.79 to -0.30, P﹤0.0001), lower degrees of SLE-DAI (OR=-1.80, 95%CI:-2.78 to -0.81, P=0.0004), and a lower adverse reaction rate. For example, gastrointestinal syndrome, irregular menstruation and leucopenia happened less frequently in the multitarget therapy group. However, hypertension was more prevalent in the multitarget therapy group. Conclusions: Multitarget therapy is an effective and safe intervention for inducing remission in lupus nephritis patients.

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Interleukin-34 as a marker for subclinical proliferative lupus nephritis

Lupus ◽

10.1177/0961203320914976 ◽

2020 ◽

Vol 29 (6) ◽

pp. 607-616

Author(s):

Asmaa SM Abdel-Rehim ◽

Nesrine A Mohamed ◽

Marwa M Shakweer

Keyword(s):

Lupus Nephritis ◽

Lupus Erythematosus ◽

Activity Index ◽

Renal Involvement ◽

Clinical Manifestations ◽

Surrogate Marker ◽

Disease Activity Index ◽

Class Iii ◽

Group I ◽

Dsdna Antibodies

Background Lupus nephritis (LN) is an ominous manifestation of systemic lupus erythematosus (SLE). Clinical renal affection is present in about 70% of lupus patients, and more patients have histological evidence of renal involvement without clinical manifestations. This study aimed to investigate the potential role of serum interleukin-34 (IL-34) as an early marker for the detection of silent LN. Methods Thirty-three lupus patients with silent LN (group I), 37 patients with clinical LN (group II) and 20 controls were included. The SLE Disease Activity Index (SLEDAI), IL-34, anti-dsDNA antibodies and renal biopsy were assessed in all patients. Results Serum IL-34 levels were significantly higher in all lupus patients compared to healthy controls ( p < 0.001) and showed a significant positive correlation with SLEDAI score. SLE patients with positive anti-dsDNA antibodies had more active disease according to SLEDAI and higher levels of IL-34 than those with negative anti-dsDNA antibodies. In both studied groups, serum IL-34 levels were significantly higher in patients with proliferative LN (class III and class IV) than those with non-proliferative lupus (class II and class V) and controls. Yet, in both groups, IL-34 was not useful in differentiating active from chronic renal affection. Conclusion In lupus patients with insignificant proteinuria, serum levels of IL-34 distinguished the different histological classes of subclinical LN. Serum IL-34 may be used as a surrogate marker for early renal affection in silent LN, especially the proliferative type.

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