Search Results (255)

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease characterized by tissue damage in multiple organs caused by autoantibodies and the resulting immune complexes. One possible way for complement system contribution to onset of autoimmune disorder could be realized by the impairment of C1q-mediated apoptotic clearance as part of human homeostasis. The capacity of C1q to bind early apoptotic cells could be decreased or even lost in the presence of anti-C1q antibodies. A monoclonal anti-idiotypic single-chain (scFv) antibody was selected from the phage library Griffin1” to recognize anti-C1q autoantibodies, purified from sera of lupus nephritis patients. Lupus-prone MRL/lpr mice were injected weekly with scFv A1 fragment-binding anti-C1q antibodies. The number of in vitro and ex vivo studies with collected cells, sera, and organs from the treated animals was performed. scFv treatment changed the percentage of different B-, T-, and NK-cell subpopulations as well as plasma cells and plasmablasts in the spleen and bone marrow. An increase in the levels of splenocyte proliferation, anti-C1q antibodies, and the number of plasma cells producing anti-dsDNA and anti-C1q antibodies were also observed in scFv-treated animals. High levels of proteinuria and hematuria combined with unstable levels of IL10 and IFNγ promote the development of severe lupus and shorten the survival of treated MRL/lpr mice. Therapy with the scFv A1 antibody resulted in BCR recognition on the surface of anti-C1q-specific B-cells and had a disease progression effect, enhancing lupus symptoms in the MRL/lpr mouse model of SLE. Full article

Fc gamma receptors (FcγRs) control humoral and cellular immune responses and maintain the immune system balance. Functional polymorphisms of FcγRs, whose prevalence was dependent on ethnic origin, were found to be associated with systemic lupus erythematosus (SLE) or kidney injuries in several ethnic groups. We aimed at investigating the association between the functional single-nucleotide polymorphisms (SNPs) of FcγRIIa-H131R (rs1801274), FcγRIIb-I232T (rs1050501), FcγRIIIa-V158F (rs396991) and FcγRIIIb variants (NA1 and NA2) and lupus erythematosus systemic in an indigenous African Caribbean population. We compared the frequencies of the functional SNPs of FCGR2A (FcγRIIa-H131R, rs1801274), FCGR2B (FcγRIIb-I232T, rs1050501), FCGR3A (FcγRIIIa-V158F, rs396991) and FCGR3B variants (FcγRIIIb NA1 and NA2) between lupus and healthy controls in an indigenous African Caribbean population. We highlighted an association between the FCGR3B-NA1/NA1 and FCGR3A-158F alleles and systemic lupus erythematosus, in addition to an association between FCGR2A-131R and lupus nephritis. Furthermore, an increase in the 131R-158V haplotype in lupus nephritis (30.4%) vs. lupus non-nephritis (15.8%) was noticed. Surprisingly, in spite of the high frequency of the FCGR2B-232T allele in our population, our study did not highlight any association of this allele either with SLE or lupus nephritis (a severe and frequent form of SLE). CD72-Hap1, which has been shown to confer resistance to SLE against T232 allele, was not enhanced in the control group. Our results emphasize an association between FCGR2A-131R and lupus nephritis with a distinctive FCGR polymorphism distribution in an indigenous African Caribbean population, confirming the important variation in the FCGR locus depending on ethnic origin. Full article

Complement system inhibitors are emerging as promising therapies in nephrology, particularly for diseases where complement dysregulation is central to pathogenesis. This review summarizes the role of complement activation in kidney diseases and current evidence supporting complement-targeted treatments. As the complement system can be involved in the pathogenesis of different diseases to varying degrees, several research works have been conducted. These research efforts aim, firstly, to understand the mechanisms and role of complement cascade components in the most prevalent nephrological diseases and, secondly, to explore the potential of complement system inhibitors in these conditions and their possible clinical applications. Clinical trials demonstrate that complement inhibitors are most effective in conditions with significant complement involvement, such as C3 glomerulopathy (C3G), atypical hemolytic uremic syndrome (aHUS), and immune complex membranoproliferative glomerulonephritis (IC-MPGN). These agents show variable benefits in diseases with partial complement activation, including lupus nephritis and ANCA-associated vasculitis, while their role in disorders like diabetic nephropathy and focal–segmental glomerulosclerosis remains limited. Complement inhibition offers a targeted strategy to prevent disease progression and improve outcomes in selected nephrological disorders. Full article

Background: Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE) and is difficult to cure. Lang Chuang Wan (LCW) has been widely used in clinical practice as a treatment for SLE and LN, but its active ingredients and mechanism of action have not been elucidated. To address this, we aim to analyze LCW’s chemical components and clarify its mechanisms in treating LN. Methods: We utilized ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) to analyze the components of LCW and assessed its effects on MRL/lpr mice through ELISA, H&E staining, Masson’s trichrome staining, and IgG immunofluorescence. Then, we further explored the mechanisms of action through network pharmacology, transcriptomics, and metabolomics, and validated with Western blot. Results: LCW contained 1303 chemical components, primarily flavonoids and terpenoids. It significantly improved kidney pathology and normalized levels of serum ANA, anti-dsDNA, anti-Sm, C3, C4, Cr, BUN, IL-6, IL-10, IL-17, TNF-α, and urinary protein (UP) in MRL/lpr mice. Network pharmacology, transcriptomics, and metabolomics indicated that LCW’s therapeutic effect on LN involved the PI3K/AKT pathway, confirmed by Western blot showing LCW’s suppression of the PI3K/AKT/mTOR pathway. Conclusions: LCW alleviates pathological symptoms in MRL/lpr mice by inhibiting the PI3K/AKT/mTOR signaling pathway, providing insights into its therapeutic mechanisms for lupus nephritis. Full article

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease that affects various organs, including the kidneys. Despite recent advancements, effective treatment options for renal involvement in SLE remain limited. Rebamipide, originally developed as a gastroprotective agent, has been reported to exert immunomodulatory effects in rheumatic diseases. Here, we aimed to evaluate the therapeutic potential of rebamipide in SLE using an animal model and to elucidate its mechanisms of action. We administered rebamipide or vehicle control to lupus-prone MRL/lpr mice and evaluated its efficacy on lupus-like phenotypes, including renal manifestations and immune cell profiles. Additionally, we investigated potential therapeutic mechanisms through in vitro treatment of murine immune cells and podocytes with rebamipide. Oral administration of rebamipide in lupus-prone mice significantly reduced kidney size, weight, and histopathological inflammation. Among circulating immune cell subsets, only regulatory T cells were significantly increased by rebamipide. In vivo treatment with rebamipide enhanced the expression of podocyte structural proteins, such as Synaptopodin, in kidney tissues, accompanied by the recovery of antioxidative factors, including nuclear factor erythroid 2-related factor 2 (Nrf2). Similarly, in vitro treatment of murine immune cells and podocytes with rebamipide replicated its immunoregulatory and antioxidative effects. Rebamipide is proposed as a potential therapeutic candidate for managing renal involvement in SLE through its antioxidative effects on podocytes. Full article

Glomerular diseases are a major cause of chronic kidney disease worldwide, yet epidemiological data from Eastern Europe, and Romania in particular, remain scarce. This study aimed to characterize the spectrum of biopsy-proven glomerulopathies in Romania through a multicenter national registry over a 10-year period. We retrospectively analyzed 4047 native kidney biopsies performed between 2014 and 2023 across four national nephrology reference centers. Patient demographics, clinical presentation, and histopathological diagnoses were collected and categorized into primary and secondary glomerular diseases, glomerulosclerosis, tubulointerstitial nephropathies, hereditary nephropathies, and vascular nephropathies. The mean patient age was 48 years, 54.8% were male, and 51.4% presented with nephrotic-range proteinuria. The most common primary glomerulopathies were membranous nephropathy (16.7%), immunoglobulin A nephropathy (15.6%), focal segmental glomerulosclerosis (8.8%), and membranoproliferative glomerulonephritis (10%). Among secondary glomerular diseases, lupus nephritis (9.3%), diabetic nephropathy (8.5%), and vasculitis (7.7%) were most frequent. Marked inter-center variability was observed, with a notably high prevalence of membranous nephropathy in Iași (31.1%). Over the study period, the incidence of focal segmental glomerulosclerosis increased while immunoglobulin A nephropathy declined. This study provides the first nationwide epidemiological assessment of biopsy-proven glomerular disease in Romania, revealing both similarities and distinctive differences compared to patterns reported in other European countries. Full article

Macrophage activation syndrome (MAS) is a complex, life-threatening, hyperinflammatory condition occurring as a form of hemophagocytic lymphohistiocytosis (HLH), commonly associated with several autoimmune and autoinflammatory diseases, and certain infections such as Parvovirus B19 (P19V). The onset of systemic lupus erythematosus (SLE) presenting as MAS during pregnancy is uncommon, posing significant diagnostic and therapeutic challenges. We present a case of a 30-year-old woman at the 12th gestational week with fever, arthralgia, rash, cervical lymphadenopathy, cytopenia, and elevated liver enzyme. Bone marrow biopsy revealing hemophagocytosis, elevated ferritin and triglycerides, high interleukin-2, fever and cytopenia, confirmed the diagnosis of HLH. Further evaluation revealed the diagnosis of SLE. Treatment was initiated with intravenous immunoglobulin and corticosteroids. Given the deterioration in the patient’s clinical condition, a decision was made to terminate the pregnancy. She continued in the following months to receive SLE treatment with corticosteroids, cyclophosphamide, hydroxychloroquine, and later with mycophenolate mofetil due to the development of Class IV of lupus nephritis. P19V IgM antibodies were initially positive, later seroconverted to IgG, indicating that infection may have acted as a trigger for the onset of SLE and MAS development during pregnancy. The overlapping clinical features of P19V infection, SLE, and MAS pose significant diagnostic and therapeutic challenges. Early recognition and comprehensive diagnostic evaluation are crucial for the management of these conditions, especially during pregnancy, where both maternal outcomes are at risk. Full article

Background/Objectives: A case-control study was conducted to determine the association of the −238 G>A and −308 G>A TNF-alpha (TNFA) promoter polymorphisms with mRNA and protein expression in 180 Systemic Lupus Erythematosus (SLE) patients and 186 control subjects (CS) from western Mexico. Methods: Genotyping was performed using the PCR-RFLP method. TNFA mRNA expression was assessed by real-time quantitative PCR, and soluble TNF-α (sTNF-α) levels were quantified by ELISA. For comparison groups, Chi-square, Mann–Whitney U, or Kruskal–Wallis tests were used. Spearman’s rank correlation coefficient determined the correlation between variables. The Area Under the Curve was used to determine the diagnosing performance of sTNF-α. Results: No differences were found in the genotype distribution of −238 G>A and −308 G>A TNFA polymorphisms between SLE patients and CS. However, the −238A allele was associated with increased SLE susceptibility (OR 1.18 CI 95% 1.02–3.50, p = 0.037). Also, logistic regression analysis showed that LN risk was significantly higher in carriers of the −308A allele (OR 3.11 IC95% 1.15–6.43; p = 0.002). On the other hand, the TNFA mRNA expression was 3.3-fold higher in SLE compared to CS. SLE patients with −308 GG genotype showed higher TNFA mRNA expression compared to GA+AA genotype carriers (p < 0.01). Regarding sTNFa levels, SLE patients showed higher concentration than CS, mainly in lupus nephritis (LN), with a weak negative correlation with estimated Glomerular Filtration Rate and an acceptable accuracy for diagnosing SLE and LN, with areas under the curve of 0.61 and 0.65, respectively. Conclusions: The −238 A allele and −308 A allele of the TNFA gene are linked to a higher risk of susceptibility to SLE and LN in the western Mexican population. Additionally, SLE patients exhibited increased TNF-alpha gene expression and sTNF-α, particularly in LN, demonstrating acceptable diagnostic performance. Full article

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, initially developed for glycaemic control in type 2 diabetes, have demonstrated substantial renal and cardiovascular protective effects across various chronic kidney diseases (CKD), including glomerulonephritis. Beyond their established haemodynamic and metabolic benefits, recent evidence points to additional mechanisms of action potentially relevant to immune-mediated kidney diseases, such as the modulation of inflammation, immunometabolism, and oxidative stress. Randomised clinical trials (DAPA-CKD and EMPA-KIDNEY) and real-world observational studies consistently show that SGLT2 inhibitors reduce proteinuria and slow estimated glomerular filtration rate (eGFR) decline in patients with glomerulonephritis, including IgA nephropathy and focal segmental glomerulosclerosis. These benefits may extend to patients with stable immunosuppression. Further data are needed in this subgroup. Importantly, SGLT2 inhibitors display a favourable safety profile, even among those with immunosuppressed status. Again, further evidence is awaited in this respect. Despite these promising findings, unanswered questions remain regarding their efficacy in nephrotic syndrome, early-stage disease, and in comparison or combination with other supportive therapies. Overall, the evolving evidence supports the inclusion of SGLT2 inhibitors as a key component of supportive therapy in glomerulonephritis, with potential benefits extending beyond proteinuria reduction. Full article

Background: Anti-PAR 1 (protease-activated receptor 1) and anti-ACE 2 (angiotensin 2-converting enzyme 2) antibodies are a kind of non-HLA (human leukocyte antigens) antibodies postulated to be of significance in autoimmunological diseases and organ transplantation. Methods: We assessed anti-PAR 1 and anti-ACE 2 antibody levels in patients with membranous nephropathy n= 18, focal and segmental glomerulosclerosis (FSGS) n = 25, lupus nephritis (LN) n = 17, IgA nephropathy n = 14, mesangial proliferative (non-IgA) glomerulonephritis n = 6, c-ANCA (cytoplasmic anti-neutrophil cytoplasmic antibodies) vasculitis n = 40, p (perinuclear)-ANCA vasculitis n = 16, and compared them with a healthy control group n = 22. Next, we observed the clinical course of the patients (creatinine, total protein, and albumin) up to 2 years and correlated the results with the level of antibodies. Results: The anti-PAR 1 antibody level was lower in membranous nephropathy and FSGS compared to the control group. Anti-PAR 1 antibody levels were higher in secondary compared to primary glomerulonephritis. Both anti-PAR 1 and anti-ACE 2 antibody levels correlated positively (in focal and segmental glomerulosclerosis) or negatively (in lupus nephritis) with total protein and albumin at different time points of observation. Anti-PAR 1 and anti-ACE 2 antibody levels correlated also with creatinine level at one time point of observation in IgA nephropathy. Anti-PAR 1 and anti-ACE 2 antibodies correlated with each other in membranous nephropathy, FSGS, and p- and c-ANCA vasculitis (p < 0.05). Conclusions: The anti-PAR 1 antibody level was lower in membranous nephropathy and focal and segmental glomerulosclerosis compared to the control group. Anti-PAR 1 antibody levels tend to be higher in secondary compared to primary glomerulonephritis. Full article

Background: Lymphopenia is associated with disease activity in adult patients with systemic lupus erythematosus (SLE), but no similar studies exist among children. Furthermore, lymphopenia has only been used as a parameter of disease activity in the SLE disease activity index (SLEDAI), but not as an independent marker. Objectives: This study aimed to ascertain lymphopenia as an independent marker related to disease activity in children with SLE. Methods: This was a retrospective cohort study on patients newly diagnosed with SLE. The data were collected from January 2009 to March 2017, including clinical manifestations, complete blood counts, anti-dsDNA, and Mexican-SLEDAI (MEX-SLEDAI) scores. Statistical analysis was performed using the Chi-square test, Student’s t-test, and ROC curve analysis. Results: A total of 103 patients, aged from 12 to 18 years, participated in the study. Of these, 58 patients (56.3%) exhibited lymphopenia. The most commonly observed clinical manifestations in the lymphopenia group included nephritis (72.4%), hypertension (24.1%), and leukopenia (36.2%), with p < 0.05. Furthermore, neuropsychiatric SLE was found exclusively in the lymphopenia group. A negative correlation was observed between lymphocyte counts and anti-dsDNA levels (r = −0.24), as well as between lymphocyte counts and the MEX-SLEDAI score (r = −0.63, with p < 0.05). The receiver operating characteristic (ROC) curve indicated that a lymphocyte count with a cut-off point of ≤1738/mm³ is significant for predicting anti-dsDNA reactivity. Conclusions: Lymphopenia is significantly correlated with higher anti-dsDNA levels and increased disease activity, potentially serving as an independent marker of disease activity in children with SLE. However, further research is needed. Full article

Kidney transplantation is the most effective replacement therapy for kidney failure, providing the best outcomes in terms of patient survival and offering a better quality of life. However, despite the progressive improvement in kidney survival, the recurrence of original disease remains one of the most important causes of graft loss and a major challenge that requires clinical vigilance throughout the transplant’s duration. Additionally, the type and severity of recurrence affect both treatment options and graft survival. This is especially true for the recurrence of systemic diseases. In this narrative review, we will discuss the timing, frequency, severity, and treatment of post-transplant recurrence in three systemic diseases: lupus nephritis (LN), Antineutrophil Cytoplasmic Antibodies (ANCA)-associated glomerulonephritis (ANCA-GN), and Henoch–Schönlein purpura (HSP). The recurrence of lupus nephritis is less common than that of primary focal segmental glomerulosclerosis or C3 glomerulopathy. Its severity can range from mild mesangial to diffuse proliferative forms, with varying prognoses and treatment options, much like the original disease. In some patients with LN, as well as in those with ANCA-GN or HSP, the reactivation of the primary disease can affect other organs besides the kidneys, potentially leading to life-threatening conditions. These cases may require a multidisciplinary approach, making these transplants clinically more challenging. Extrarenal flare-ups often necessitate an increase in immunosuppression, which in turn raises the risk of infections. In these autoimmune diseases, the role of immunological tests in determining the timing of kidney transplants remains a topic of ongoing debate. However, elevated levels of certain immunological markers, such as anti-dsDNA antibodies, ANCA titers, or serum immunoglobulin A may indicate a reactivation of the disease, suggesting the need for more intensive patient monitoring. Full article

Lupus nephritis (LN), a significant complication of systemic lupus erythematosus (SLE), represents a challenging manifestation of the disease. One of the prominent pathophysiologic mechanisms targeting the renal parenchyma is fibrosis, a terminal process resulting in irreversible tissue damage that eventually leads to a decline in renal function and/or end-stage kidney disease (ESKD). Both glomerulosclerosis and interstitial fibrosis emerge as reliable prognostic indicators of renal outcomes. This article reviews the hallmarks of renal fibrosis in lupus nephritis, including the known and putative drivers of fibrogenesis. A better understanding of the cellular and molecular processes driving fibrosis in LN may help inform the development of therapeutic strategies for this disease, as well as the identification of individuals at higher risk of developing ESKD. Full article

Background: Tubulointerstitial hypoxia is a key factor for lupus nephritis progression to end-stage renal disease. Numerous aquaporins (AQPs) are expressed by renal tubules and are essential for their proper functioning. The aim of this study is to characterize the tubular expression of AQP1, AQP2 and AQP3, which could provide a better understanding of tubulointerstitial stress during lupus nephritis. Methods: This retrospective monocentric study was conducted at Erasme-HUB Hospital. We included 37 lupus nephritis samples and 9 healthy samples collected between 2000 and 2020, obtained from the pathology department. Immunohistochemistry was performed to target AQP1, AQP2 and AQP3 and followed by digital analysis. Results: No difference in AQP1, AQP2 and AQP3 staining location was found between healthy and lupus nephritis samples. However, we observed significant differences between these two groups, with a decrease in AQP1 expression in the renal cortex and in AQP3 expression in the cortex and medulla. In the subgroup of proliferative glomerulonephritis (class III/IV), this decrease in AQPs expression was more pronounced, particularly for AQP3. In addition, within this subgroup, we detected lower AQP2 expression in patients with higher interstitial inflammation score and lower AQP3 expression when higher interstitial fibrosis and tubular atrophy were present. Conclusions: We identified significant differences in the expression of aquaporins 1, 2, and 3 in patients with lupus nephritis. These findings strongly suggest that decreased AQP expression could serve as an indicator of tubular injury. Further research is warranted to evaluate AQP1, AQP2, and AQP3 as prognostic markers in both urinary and histological assessments of lupus nephritis. Full article

The role of gut microbiota (GM) and intestinal dysbiosis in triggering the onset and/or modulating the severity and progression of lupus nephritis (LN) has been the object of intense research over the last few years. Some alterations at the phyla level, such as the abundance of Proteobacteria and reduction in Firmicutes/Bacteroidetes (F/B) ratio and in α-diversity have been consistently reported in systemic lupus erythematosus (SLE), whereas a more specific role has been ascribed to some species (Bacteroides thetaiotaomicron and Ruminococcus gnavus) in LN. Underlying mechanisms include microbial translocation through a “leaky gut” and subsequent molecular mimicry, immune dysregulation (alteration of IFNγ levels and of balance between Treg and Th17 subsets), and epigenetic interactions. Levels of bacterial metabolites, such as butyrate and other short-chain fatty acids (SCFAs), appear to play a key role in modulating LN. Beyond bacterial components of GM, virome and mycobiome are also increasingly recognized as important players in the modulation of an immune response. On the other hand, microbiota-based therapy appears promising and includes diet, prebiotics, probiotics, symbiotics, and fecal microbiota transplantation (FMT). The modulation of microbiota could correct critical alterations, such as F/B ratio and Treg/Th17 imbalance, and blunt production of autoantibodies and renal damage. Despite current limits, GM is emerging as a powerful environmental factor that could be harnessed to interfere with key mechanisms leading to SLE, preventing flares and organ damage, including LN. The aim of this review is to provide a state-of-the-art analysis of the role of GM in triggering and modulating SLE and LN on the one hand, while exploring possible therapeutic manipulation of GM to control the disease on the other hand. Full article