Membranous lupus nephritis secondary to secukinumab therapy: A case report and literature review.

The interleukin (IL)-17 axis is involved in many inflammatory and autoimmune diseases. Secukinumab, an IL-17 inhibitor, has been approved for psoriasis treatment. There are accumulating cases of lupus erythematosus induced by IL-17 inhibition. Lupus nephritis after IL-17 inhibition has not been reported. We report the case of a 57-year-old man who developed membranous lupus nephritis after secukinumab treatment for psoriasis. Anti-SSA and PM-Scl antibodies were positive. dsDNA, anti-Smith, and anti-histone antibodies were negative, and serum complement was low. Secukinumab was discontinued, while tacrolimus was initiated, subsequently switched to cyclosporin, belimumab, glucocorticosteroid, and hydroxychloroquine with a good response. The relationship between lupus erythematosus and IL-17 inhibition requires further research.

Herpes zoster in lupus nephritis: experience on 292 patients followed up for 15 years.

Objectives: To evaluate the prevalence, incidence, and predictors of herpes zoster (HZ) development in lupus nephritis (LN). Methods: This retrospective study included 292 LN patients to determine HZ incidence during the last decades and its correlation with LN activity. LN patients with HZ were matched with LN patients without HZ in a 1:2 ratio based on sex, age, year of LN diagnosis, and LN histological class at kidney biopsy to assess HZ risk factors. Statistical tests included t-test, U-test, and Fisher's test. Univariate and multivariate logistic regression analyses were conducted to identify potential risk factors. Results: HZ occurred after LN diagnosis in 66 patients (prevalence 22.6%) with an average of 8.7 years (range 0.2-28.4 years). Although with the potential limitations of the retrospective nature and the extensive duration of the study, the incidence of HZ was 15.6/1,000 person-years, increasing from 6.9 before 1980 to 16.0 in the 1990s and 43.9 after 2010. HZ onset was unrelated to LN activity. LN was active in 43% of cases and quiescent in the other 57% of cases at HZ diagnosis. The percentage of patients who developed lupus flares during the year after HZ (18.9%) was not different from that which occurred during the year before HZ (17.2%, p = 0.804). After excluding confounding factors through matching, the univariate analysis suggested that cyclosporin during induction therapy (p = 0.011) and higher cumulative doses of glucocorticoids (GCs; >50 g, p = 0.004), cyclophosphamide (CYC; >5 g, p = 0.001), and mycophenolate mofetil (MMF > 1,000 g, p = 0.007) predisposed patients to HZ. Univariate and multivariate analyses revealed a protective role of azathioprine (p = 0.008) and methylprednisolone pulses (p = 0.010) during induction therapy. Conclusions: HZ occurs unpredictably throughout the course of LN, underscoring the importance of continuous monitoring for these patients. In addition, the incidence of HZ seems to have increased in recent decades. Induction therapy with azathioprine and methylprednisolone pulses appears to provide protection, while higher cumulative doses of GCs, CYC, and MMF increase susceptibility.

Efficacy and safety of immunosuppressive agents for adults with lupus nephritis: a systematic review and network meta-analysis.

Introduction: Various immunosuppressive regimens have been developed for the treatment of lupus nephritis (LN). This study aimed to compare the efficacy and safety of immunosuppressive regimens in adults with LN. Methods: We systematically searched the PubMed, Embase, and Cochrane Central Register of Controlled Trials databases, including conference proceedings, trial registries, and reference lists, from inception until July 10, 2022. The effects of treatment were compared and ranked using the surface under the cumulative ranking curve (SUCRA). The primary endpoint was total remission. The secondary endpoints were complete remission, systemic lupus erythematosus disease activity index (SLEDAI), relapse, all-cause mortality, end-stage renal disease (ESRD), infection, herpes zoster, ovarian failure, myelosuppression, and cancer. Results: Sixty-two trials reported in 172 studies involving 6,936 patients were included in the network meta-analysis. The combination of tacrolimus (TAC), mycophenolate mofetil (MMF), and glucocorticoid (GC) provided the best result for the total remission rate (SUCRA, 86.63%) and SLEDAI (SUCRA, 91.00%), while the combination of voclosporin (VCS) , MMF and GC gave the best improvement in the complete remission rate (SUCRA, 90.71%). The combination of cyclophosphamide (CYC), MMF and GC was associated with the lowest risk of relapse (SUCRA, 85.57%) and cancer (SUCRA, 85.14%), while the combination of obinutuzumab (OTB), MMF and GC was associated with the lowest risk of all-cause mortality (SUCRA, 84.07%). Rituximab (RTX) plus MMF plus GC was associated with the lowest risk of ESRD (SUCRA, 83.11%), while the risk of infection was lowest in patients treated with azathioprine (AZA) plus CYC plus GC (SUCRA, 68.59%). TAC plus GC was associated with the lowest risk of herpes zoster (SUCRA, 87.67%) and ovarian failure (SUCRA, 73.60%). Cyclosporine (CsA) plus GC was associated with the lowest risk of myelosuppression (SUCRA, 79.50%), while AZA plus GC was associated with the highest risk of myelosuppression (SUCRA, 16.25%). Discussion: This study showed that a combination of TAC, MMF and GC was the best regimen for improving the total remission rate. The optimal regimen for specific outcomes should be highlighted for high-risk patients.

Repeat kidney biopsy findings of lupus nephritis patients in clinical remission treated with Mycophenolate associated with Belimumab or Mycophenolate plus standard of care therapy. A "post-hoc" analysis of participants in the BLISS-LN and open label extension study belonging to a single center.

BACKGROUND: Lupus nephritis affects 40 to 70% of Systemic Lupus Erythematous(SLE) patients increasing their morbi-mortality; therefore, successful treatments are required to improve outcomes. RESEARCH DESIGN AND STUDY SAMPLE: In this paper 20 patients who participated in the BLISS LN trial at a single center (OMI) in Argentina were studied. All the patients continued Mycophenolate (MMF) treatment when the trial was finished and until a second biopsy was performed to determine the withdrawal of the immunosuppression according to the achieved clinical and histological response. Ten patients treated with MMF + Placebo versus 10 receiving MMF + Belimumab, were compared evaluating the complete clinical (CCR) and complete histological response (CHR) and the flares in each group. RESULTS: All the patients in the Belimumab group showed a CCR and 7 in the Placebo one; CHR was found in 9 and 5 patients of the Belimumab and Placebo group, respectively. None of the patients in the Belimumab group flared meanwhile two of the Placebo one did it. CONCLUSIONS: Although the number of patients is insufficient to be able to draw unquestionable conclusions, adding Belimumab to the standard of care treatment with MMF would seem to increase the possibility of achieving a CCR, CHR, and a lower rate of relapses during treatment and long follow-up.

Overlapping drug-induced vasculitis, ANCA-associated vasculitis, and lupus nephritis caused by low-dose hydralazine.

INTRODUCTION: We present a case of drug-induced vasculitis secondary to low-dose hydralazine with overlapping features of antineutrophil cytoplasmic antibody-associated vasculitis and drug-induced lupus nephritis. CASE PRESENTATION: A 52-year-old Hispanic woman with a medical history of resistant hypertension treated with hydralazine 10 mg twice daily for 1 year presented with generalized weakness, dizziness, nausea, vomiting, and gross hematuria. There was fever, tachycardia, leukocytosis, lactic acidosis, hyperkalemia, renal failure, and anemia. Chest computed tomography and bronchoscopy revealed a left lower lobe infiltrate and diffuse alveolar hemorrhage. Serologic testing was positive for anti-double-stranded DNA, anti-Smith, lupus anticoagulant, anti-histone, anti-cardiolipin IgM antibodies, and antineutrophil cytoplasmic antibodies (myeloperoxidase and proteinase 3). A kidney biopsy revealed crescentic glomerulonephritis with an overlapping finding of membranous nephropathy. Broad-spectrum antibiotics, immunosuppressants, corticosteroids, and plasmapheresis were initiated. The patient survived but required continuous hemodialysis. CONCLUSIONS: Although a few cases of simultaneous antibody-associated vasculitis and drug-induced lupus nephritis secondary to hydralazine use have been reported, this case is singular. Similar findings were previously reported with doses of 50-100 mg two to three times daily over 1-5 years. In our patient, a dose of only 10 mg twice daily for a year caused a severe disease presentation. This brings to light the combination of different vasculitides that can coexist and the potentially life-threatening adverse effects of low-dose hydralazine that should be kept in mind.

Perspectives on Mycophenolate Mofetil in the Management of Autoimmunity.

Before becoming a cornerstone in the treatment of numerous immune-mediated diseases, mycophenolate mofetil (MMF) was first introduced as an immunosuppressive agent in transplant immunology and later received the attention of rheumatologists and clinicians involved in the management of autoimmune diseases. MMF is now a widespread immunosuppressive drug for the treatment of several conditions, including lupus nephritis, interstitial lung disease associated with systemic sclerosis, and anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis while being efficacious also as rescue therapy in various orphan diseases, including dermatomyositis and IgA-associated nephropathy. Similarly, case reports or series support a possible use of MMF in other rare autoimmune diseases. Beyond modulating lymphocyte activation, MMF acts on other immune and non-immune cells and these effects may explain the therapeutic profile of this medication. The effects of MMF are broadly characterized by the impact on the immune system and the antiproliferative and antifibrotic changes induced. In this latter case, mechanistic data on fibroblasts may in the future allow to reevaluate the use of MMF in selected patients with inflammatory arthritis or systemic sclerosis. Attention must be paid towards the possible occurrence of adverse events, such as gastrointestinal complaints and teratogenicity, while the risk of infections and cancer related to MMF needs to be further investigated.

Systemic lupus erythematosus following human papillomavirus vaccination: A case-based review.

Systemic lupus erythematosus (SLE) is a heterogeneous systemic autoimmune diseases (AIDs) with many pathogenic factors, ranging from genetic to epigenetic to environmental. The human papillomavirus (HPV), a viral infectious agent, is a common contributor to the onset and exacerbation of SLE. HPV infections are more prevalent among SLE patients than healthy individuals, bringing about a substantial need for treatment. While HPV recombinant gene vaccines are accepted as a universal method for infection prevention, they pose a risk for adverse events such as fever, joint pain, and rashes. In rare cases, they might even trigger AIDs such as SLE, especially in patients with a personal or family history of such diseases. In this article, we provide a report of a case of SLE onset following HPV vaccination and a review of 11 similar cases. An analysis of 12 patients revealed that 7 cases of SLE developed between 3 weeks and 2 months post-vaccination. Symptoms of SLE generally manifest as fatigue, fever, joint pain, and myalgia. Two patients had lupus nephritis, 2 showed central nervous system involvement, including abnormal behavior and epileptic seizures, and 1 had intestinal pseudo-obstruction. All patients showed rapid remission with glucocorticoid and immunosuppressive therapy and remained stable during several months of follow-up.

Cost-effectiveness of cyclophosphamide and non-cyclophosphamide in the induction therapy of Malaysian lupus nephritis patients.

BACKGROUND: There is a paradigm shift in the induction therapy for proliferative lupus nephritis (LN). Apart from cyclophosphamide (CYC), mycophenolate mofetil and calcineurin inhibitors have emerged as an alternative option of treatment. OBJECTIVE: We aimed to compare the cost-effectiveness analysis (CEA) per year, adverse events and renal damage at 24 months between CYC and non-CYC agents (calcineurin inhibitors or mycophenolate) as induction treatment among proliferative lupus nephritis (LN) patients. METHODS: This was a retrospective and non-controlled study involving biopsy-proven proliferative LN patients (class III or IV with or without V) in the clinic registry from 2017 to 2019. Their medical records were reviewed to determine the date and type of induction, treatment effectiveness, adverse events and renal damage at 24 months. The total cost of treatment included capital cost (building, furniture and equipment) and recurrent cost (emolument, supply/drug, lab investigations, administrative cost and utilities). Treatment effectiveness was defined as renal remission (partial or complete) at 6 months without relapse up to 24 months. The cost-effectiveness analysis (CEA) was expressed as cost per remission per year in Malaysian Ringgit (MYR). RESULTS: There were a total of 95 inductions with CYC and 27 with non-CYC in 94 LN patients. There was no significant difference in the total mean cost per patient/year between CYC (MYR 18460.26 ± 6500.76) compared to non-CYC (MYR 19302.10 ± 6778.22), p = 0.569. The CEA for CYC was MYR 20,632.06 (GBP 3,538.78) while non-CYC was MYR 20,846.27 (GBP 3,575.52) and mean difference MYR 214.21 (GBP 37.44). There was significantly higher capital cost, consumables, utility, maintenance, administration (p < 0.001) and lab investigations (p = 0.046) in the CYC arm. There was a trend of a higher infection requiring outpatient antibiotic treatment in CYC group (p = 0.05), but similar renal damage outcome with the non-CYC group.Conclusion: For treatment of proliferative LN, there was no significant difference in the CEA and renal damage between CYC and non-CYC induction treatment. There was a trend of a higher rate of infections in the CYC group. Hence, the decision to treat patient with CYC or MMF should be tailored to individual patients, by considering the risk of infection in a particular patient.

Clinical pharmacology considerations for the approval of belimumab for the treatment of adult patients with active lupus nephritis: A regulatory perspective.

On 16 December 2020, FDA approved Benlysta® (belimumab) for both the intravenous (IV) and subcutaneous (SC) administration routes for the treatment of adult patients with active lupus nephritis (LN) who are receiving standard therapy. This approval represents the first FDA approved treatment of patients with active LN.The approved IV dosing regimen (10 mg/kg dose Q2W for three doses, then 10 mg/kg Q4W thereafter) was based on a randomized double-blind placebo controlled clinical trial in adult patients with LN. For the approval of the SC dosing regimen (400 mg dose QW for four doses, then 200 mg QW thereafter), efficacy was supported solely by pharmacokinetics (PK) modeling and simulation which estimated a matched steady state average concentration and higher trough concentrations for the SC administration route, for bridging to the efficacy of IV belimumab in adults with LN. The safety and immunogenicity profile of the SC administration route has been assessed in the SLE studies.In a population PK analysis, higher proteinuria was associated with greater belimumab clearance and lower belimumab exposure. In an exposure response analysis, the efficacy of belimumab as evaluated by renal response was mainly driven by patients with lower proteinuria at baseline regardless of other baseline characteristics (e.g. baseline renal function, renal biopsy classification), induction therapies, or belimumab exposure levels (within 10 mg/kg dosing regimen), etc. However, post hoc analyses showed that belimumab had activity in LN patients with higher proteinuria at baseline. There is no adequate information to suggest that a higher dose would provide additional benefit for patients with lower exposure (e.g. higher proteinuria).

5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivative attenuates lupus nephritis with less effect to thymocyte development.

Retinoic­acid­receptor­related orphan nuclear hormone receptor gamma t (RORγt), a critical transcriptional factor of Th17 cells, is a potential therapeutic target for Th17-mediated autoimmune diseases. In addition, RORγt is essential for thymocyte survival and lymph node development, and RORγt inhibition or deficiency causes abnormal thymocyte development, thymus lymphoma, and lymph node defect. Recent study demonstrated that specific regulation of Th17 differentiation related to the hinge region of RORγt. In this research, we investigated the effect of RORγt inhibitor, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivative (TTP), in the therapy of lupus nephritis and its safety on thymocyte development. We demonstrated that TTP repressed the development of Th17 cells and ameliorated the autoimmune disease manifestation in the pristane-induced lupus nephritis mice model. The treatment of TTP in the mice did not interfere with thymocyte development, including total thymocyte number and proportion of CD4+CD8+ double-positive populations in the thymus, and had no substantial effects on the pathogenesis of thymoma. The TTP had a stronger affinity with full-length RORγt protein compared with the truncated RORγt LBD region via surface plasmon resonance, which indicated TTP binding to RORγt beyond LBD region. Molecular docking computation showed that the best binding pocket of TTP to RORγt is located in the hinge region of RORγt. In summary, as a RORγt inhibitor, TTP had a potential to develop the clinical medicine for treating Th17-mediated autoimmune diseases with low safety risk for thymocyte development.

"Protenuria in SLE: Is it always lupus?"

Proteinuria is one of the most typical manifestations of kidney involvement in Systemic Lupus Erythematosus (SLE). We report the case of a 23-year-old woman with a 6-year-long history of SLE presenting with proteinuria after a three-year remission on hydroxychloroquine. Kidney histological examination showed alterations inconsistent with lupus nephritis and suggestive of hydroxychloroquine toxicity or Fabry disease. The latter was confirmed by genetic assay.

Preclinical Testing of Viral Therapeutic Efficacy in Pristane-Induced Lupus Nephritis and Diffuse Alveolar Hemorrhage Mouse Models.

Systemic lupus erythematosus (SLE) is a multifactorial and heterogeneous autoimmune disease involving multiple organ systems and tissues. Lupus nephritis occurs in approximately 60% of patients with SLE and is the leading cause of morbidity. Diffuse alveolar hemorrhage (DAH) is a rare but very serious complication of SLE with a greater than 50% associated mortality. The etiology of SLE is unclear but has proposed genetic, hormonal, and environmental aspects. Pristane is a saturated terpenoid alkane and has become the most popular laboratory model for inducing lupus in mice. The pristane model of SLE has the capacity to reproduce many components of the human presentation of the disease. Previous studies have demonstrated that virus-derived immune-modulating proteins have the potential to control inflammatory and autoimmune disorders. Serp-1, a 55 kDa secreted and highly glycosylated immune modulator derived from myxoma virus (MYXV), has potent immunomodulatory activity in models of vasculitis, viral sepsis, collagen-induced arthritis, and transplant rejection. This chapter describes the mouse preclinical pristane lupus model as a method to examine virus-derived protein efficacy for treating autoimmune diseases and specifically lupus nephritis and DAH.

Lupus nephritis in a transgender woman on cross-sex hormone therapy: a case for the role of oestrogen in systemic lupus erythematosus.

We present the case of a 22-year-old African American transgender women (male to female), who was admitted for fatigue, abdominal pain and lower extremity edema and was diagnosed with systemic lupus erythematosus (SLE) and lupus nephritis. Treatment with high-dose steroids and mycophenolate mofetil helped resolve her symptoms. She has remained off oestrogen therapy since admission and has not experienced any major complications. It is important to consider therapy outcomes in this specific patient population. A review of four other cases of transgender women on cross-sex hormone therapy who were diagnosed with lupus is also presented.

Low-dose 17α-ethinyl estradiol (EE) exposure exacerbates lupus renal disease and modulates immune responses to TLR7/9 agonists in genetically autoimmune-prone mice.

Estrogens have been shown to regulate the immune system and modulate multiple autoimmune diseases. 17α-ethinyl estradiol (EE), a synthetic analog of 17ß-estradiol, is prescribed commonly and found in oral contraceptives and hormone replacement therapies. Surprisingly, few studies have investigated the immunoregulatory effects of exposure to EE, especially in autoimmunity. In this study, we exposed autoimmune-prone female MRL/lpr mice to a human-relevant dose of EE through the oral route of exposure. Since lupus patients are prone to infections, groups of mice were injected with viral (Imiquimod, a TLR7 agonist) or bacterial (ODN 2395, a TLR9 agonist) surrogates. We then evaluated autoimmune disease parameters, kidney disease, and response to in vivo TLR7/9 pathogenic signals. EE-exposed mice had increased proteinuria as early as 7 weeks of age. Proteinuria, blood urea nitrogen, and glomerular immune complex deposition were also exacerbated when compared to controls. Production of cytokines by splenic leukocytes were altered in EE-exposed mice. Our study shows that oral exposure to EE, even at a very low dose, can exacerbate azotemia, increase clinical markers of renal disease, enhance glomerular immune complex deposition, and modulate TLR7/9 cytokine production in female MRL/lpr mice. This study may have implications for EE-exposure risk for genetically lupus-prone individuals.

α-mangostin attenuates pristane-induced lupus nephritis by regulating Th17 differentiation.

AIM: α-mangostin, a polyphenolic xanthone derivative of mangosteen, has been reported to possess multiple therapeutic properties, such as anti-cancer, anti-allergy and anti-inflammatory activity. However, its anti-inflammatory effects in autoimmune diseases such as lupus nephritis (LN) remain unclear. In this study, we want to investigate the therapeutic effect of α-mangostin in LN. METHODS: First, we elucidated the retinoic acid receptor related orphan receptor gamma t (RORγt) inhibitory activity of α-mangostin in cell-based assay and T helper 17 (Th17) differentiation in vitro assay. Then, we established a pristane-induced LN mouse model and randomly divided these into a normal control group, model control group, α-mangostin group and prednisone acetate group. Finally, anti-double-stranded DNA (anti-dsDNA) level in serum was detected by enzyme-linked immunosorbent assay, interleukin (IL)-17A and interferon (IFN)-γ expression in spleen cells by flow cytometry; histomorphology examination of kidneys was performed by periodic acid-Schiff staining and immunofluorescence analysis with an anti-immunoglobulin G (anti-IgG) and anti-IgM antibodies. RESULTS: We found that α-mangostin inhibited RORγt transcription activity in a cell-based assay and also polarized Th17 cells in an in vitro induction experiment. Our results also showed that α-mangostin could significantly decrease serum anti-dsDNA antibody levels, IL-17A and IFN-γ expression and alleviate renal pathological damage in the α-mangostin-treated group mice than in the model group mice. CONCLUSION: Thus, α-mangostin demonstrated its potential as a candidate therapeutic drug for LN and other Th17-mediated autoimmune diseases by inhibiting the function of Th17.

Accelerated and Severe Lupus Nephritis Benefits From M1, an Active Metabolite of Ginsenoside, by Regulating NLRP3 Inflammasome and T Cell Functions in Mice.

Chinese herbal medicines used in combination have long-term been shown to be mild remedies with "integrated effects." However, our study provides the first demonstration that M1, an active metabolite of ginsenoside, exerted its dramatic therapeutic effects on accelerated and severe lupus nephritis (ASLN) mice, featuring acute renal function impairment, heavy proteinuria, high serum levels of anti-dsDNA, and high-grade, diffuse proliferative renal lesions. In the present study, NZB/WF1 mice were given injections of lipopolysaccharide to induce the ASLN model. M1 (30 mg/kg) was then administered to the mice by gavage daily, and the mice were sacrificed on week 3 and week 5 after the induction of disease. To identify the potential mechanism of action for the pure compound, levels of NLRP3 inflammasome activation in bone marrow-derived dendritic cells (BMDCs), podocytes and macrophages, and antigen-specific T cell activation in BMDCs were determined in addition to mechanistic experiments in vivo. Treatment with M1 dramatically improved renal function, albuminuria and renal lesions and reduced serum levels of anti-dsDNA in the ASLN mice. These beneficial effects with M1 treatment involved the following cellular and molecular mechanistic events: [1] inhibition of NLRP3 inflammasome associated with autophagy induction, [2] modulation of T help cell activation, and [3] induction of regulatory T cell differentiation. M1 improved the ASLN mice by blunting NLRP3 inflammasome activation and differentially regulating T cell functions, and the results support M1 as a new therapeutic candidate for LN patients with a status of abrupt transformation of lower-grade (mesangial) to higher-grade (diffuse proliferative) nephritis.

Vasoactive intestinal peptide ameliorates renal injury in a pristane-induced lupus mouse model by modulating Th17/Treg balance.

BACKGROUND: Lupus nephritis (LN) is an inflammation of the kidneys and is a major cause of mortality in systemic lupus erythaematosus (SLE) patients. In addition, Th17/Treg balance is one of the most important factors that can promote the development of LN. It has been reported that vasoactive intestinal peptide (VIP) is associated with the downregulation of both inflammatory and autoimmune diseases through regulating T lymphocyte balance. Therefore, the aim of this study was to determine the role of VIP in modulating Th17/Treg balance in LN. METHODS: LN was induced in BALB/c female mice by injection pristane. After 3 months, mice were randomly divided into four groups: control, VIP + control, LN and VIP + LN. Autoantibody levels were tested by ELISA. The distribution of Th17/Treg cells in vivo and in vitro was detected by FC. Renal tissues were examined by PASM and DIF for pathology and Foxp3+CD3+. The mRNA and protein expression levels of pro- and anti-inflammatory cytokines were detected by qRT-PCR and western blotting. RESULTS: VIP can improve renal injury by regulating Th17/Treg imbalance in LN mice. Proteinuria, renal function defects and autoantibodies were significantly decreased, and Th17/Treg cell balance was restored in VIP compared with LN mice. In addition, VIP improved renal lesions by promoting the expression of Foxp3+CD3+ in renal tissue. Furthermore, VIP downregulated the mRNA and protein expression of IL-17, IL-6 and upregulated Foxp3, IL-10 expression. CONCLUSIONS: VIP reduced LN proteinuria and renal function defects and restored the Th17/Treg cell balance. Furthermore, VIP also downregulated autoantibody and inflammatory cytokine expression and upregulated Foxp3 and IL-10 expression.

Hydroxychloroquine-induced podocytopathy mimicking Fabry disease.

Hydroxychloroquine (HCQ) is largely prescribed as an immunomodulator to prevent systemic diseases flares in patients with systemic lupus erythematous, rheumatoid arthritis, Sjogren's disease. Among reported side effects, HCQ can accumulate in lysosomes and induced phospholipidosis. Here, we report an HCQ-induced podocytopathy mimicking Fabry disease (FD). They share the same histological lesions: cytoplasmic vacuolisation of the podocytes and zebra bodies on light and electronic microscopy. FD has been ruled out by measuring enzymatic activity and genetic test. The persistence of proteinuria after immunological remission of a systemic disease treated with HCQ could suggest this HCQ-induced podocytopathy.

microRNA-199a may be involved in the pathogenesis of lupus nephritis via modulating the activation of NF-κB by targeting Klotho.

Klotho is considered to have renal protective effect by prohibiting the activation of the nuclear factor (NF)-κB pathway, while the role of microRNA-199a (miR-199a)/Klotho in lupus nephritis (LN) is still unknown. A single dose of pristane (0.5 ml) was intraperitoneally injected into 8 weeks-old female mice to establish the LN model. MiR-199a mimic or miR-199a inhibitor, Klotho plasmid or Klotho siRNA, and miR-199a inhibitor plus si-Klotho were transfected into lipopolysaccharides (LPS) stimulated human embryonic kidney 293 T (HEK293 T) cells. Western Blot was adopted to measure p-P65 expression. Tumor necrosis factor (TNF)-α and interleukin (IL)-1ß in the supernatant were determined by enzyme-linked immunosorbent assay (ELISA). The expression of Klotho was suppressed by miR-199a through direct binding to the three prime untranslated regions (3'-UTR). The high miR-199a level was accompanied by low Klotho expression in the LN kidney. MiR-199a promoted LPS-induced NF-κB activation and improved the secretion of TNF-α and IL-1ß by regulation of Klotho in HEK293 T cells. If miR-199a antagomir was administrated after 48 h of pristane administration, the expression of p-P65 and the secretion of TNF-α and IL-1ß were significantly down-regulated in LN kidney. Although the direct involvement and detailed mechanism of miR-199a in LN still need further investigation, our data show that MiR-199a could regulate the activation of NF-κB by directly targeting Klotho.

Fisetin inhibits pristine-induced systemic lupus erythematosus in a murine model through CXCLs regulation.

Systemic lupus erythematosus (SLE) is associated with an increased risk of vascular complications. Lupus nephritis is a major manifestation of SLE in the clinic. Lupus nephritis is elevated by T helper type 17 (Th17) cells, the major pro­inflammatory T­cell subset, leading to autoimmunity modulation. Therapeutic treatments targeting leukocyte recruitment may be useful in attenuating vascular complications linked to SLE progression. 3,7,3',4'­Tetrahydroxyflavone (fisetin) is a flavonol and a member of the flavonoid polyphenols. It is present in various fruits and vegetables, including persimmons, apples, kiwis, grapes, onions, strawberries and cucumbers. In the present study, the effects of fisetin against SLE induced by pristane (PRI) were evaluated in mice. Fisetin was indicated to reduce PRI­induced anti­double stranded DNA, anti­ small nuclear ribonucleoprotein and the ratio of albumin to creatinine in urine. In addition, the chemokine (C­X­C motif) ligand (CXCL) signaling pathway was activated for PRI treatment, which was reversed by fisetin administration by reducing CXCL­1 and 2, chemokine (C­C motif) ligand 3, as well as CXC receptor 2 expression. In addition, the induction of inflammatory cytokines, including interleukin (IL)­6, tumor necrosis factor­α, IL­1ß, as well as the chemokine interferon­Î³, by PRI were downregulated by fisetin treatment in mice. Furthermore, Th17 cells and their associated cytokines were highly induced by PRI treatment, which was inhibited by fisetin administration. The present results indicated that fisetin may be an effective management for SLE by targeting the CXCL signaling pathway and regulating Th17 differentiation during lupus nephritis development.