Search Results (225)

Introduction: IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world. In addition to genetic and immunological factors, visceral obesity and metabolic syndrome (MetS) are the main determinants of disease progression. This review aims to critically assess the role of visceral obesity and metabolic syndrome in driving the progression of IgA nephropathy (IgAN), with an emphasis on their underlying pathophysiological mechanisms and clinical implications. Methods: A systematic review was carried out in accordance with PRISMA guidelines. PubMed was searched (2015–2025) using terms related to IgA nephropathy, obesity, metabolic syndrome, and immunometabolic pathways. Only English-language observational and clinical studies in adults, excluding pediatric and animal studies, were included in the review. Additional sources were consulted to give context to the mechanistic aspects of obesity-related IgAN progression. Results: Visceral obesity and MetS accelerate IgAN progression through endocrine, inflammatory, and immune pathways, including cytokines derived from visceral adipose tissue, adipokines, intestinal dysbiosis, and BAFF/APRIL-mediated immune activation. MetS patients had higher proteinuria, a faster decrease in eGFR, and a higher risk of end-stage renal failure (23/65 vs. 15/60 endpoints, p < 0.001). Nutritional and metabolic interventions—including weight reduction, GLP-1 receptor agonists, dual GLP-1/GIP agonists, and bariatric/metabolic surgery—demonstrate renoprotective effects in obesity-related kidney disease and may have implications for IgAN. Conclusions: Obesity should be considered a chronic disease and a modifiable risk factor for IgAN. Nutrition-focused interventions targeting visceral obesity and metabolic dysfunction can slow the progression of the disease and should be included in renal guidelines. This review expands current knowledge by demonstrating that when sequential steps of IgAN pathophysiology are mapped with respect to endocrine and immunological effects of visceral adipose tissue, they converge on the same proinflammatory and immune pathways. This convergence suggests a bidirectional amplification loop in which obesity accelerates IgAN progression and increases the burden of complications. Full article

IgA nephropathy (IgAN) is the most prevalent type of primary glomerulonephritis, with heterogeneous clinical outcomes. Conventional prognostic factors, such as proteinuria, eGFR, and Oxford histologic classification, have poor sensitivity and specificity. Recently, transcriptomic profiling has been employed to provide insights into the molecular definition of IgAN and facilitate patient stratification in those at risk of disease progression. In this review, we summarize our current understanding of IgAN derived from bulk RNA sequencing, single-cell transcriptomics, spatial transcriptomics, and gene expression profiling to elucidate the molecular characteristics of IgAN. Bulk transcriptomics of glomerular and tubulointerstitial compartments highlighted consistently upregulated genes (e.g., CCL2, CXCL10, LCN2, HAVCR1, COL1A1) and altered pathways (e.g., NF-κB, TGF-β, JAK/STAT, and complement) that are associated with clinical decline. Single-cell and single-nucleus RNA-sequencing has also identified the value of pathogenic cell types and regulatory networks in mesangial cells, tubular epithelium, and immune infiltrates. Furthermore, noninvasive transcriptomic signatures developed from urine and blood may represent useful real-time surrogates of tissue activity. With the advent of integrated analyses and machine learning approaches, personalized risk models that outperform traditional metrics are now available. While challenges remain, particularly related to standardization, cohort size, and clinical deployment, transcriptomics is likely to revolutionize IgAN by providing early risk predictions and precision therapeutics. Unlike prior reviews, our work provides an integrative synthesis across bulk, single-cell, spatial, and noninvasive transcriptomics, linking molecular signatures directly to clinical translation in risk stratification and precision therapeutics. Full article

Smoking cigarettes affects the human body on many levels—not only are the lungs and heart targeted, but also other organs, directly and through derived alterations. We decided to parallel the impacts most often described in the literature in the hope of better future targeting regarding treatment for smoke-induced renal injury. As a result of our research, it is clear that damage is mostly localized directly in vessels and glomeruli. We perceive it as a connected web, where oxidative stress leads to local inflammation, general inflammation in the form of obesity, or inflammation due to nasopharyngeal infection. It later affects other types of tissues: podocytes, epithelium in both glomeruli, renal tubules, and vessels. We mention major molecules proven to participate in kidney damage that tend to be similar in all disease entities depicted in this study: IgA nephropathy, membranous nephropathy, and minimal change disease. Moreover, as nicotine is a major component of both classic cigarettes and electronic cigarettes, we decided to approximate and summarize the information on its impact on primary glomerulopathies. Full article

Chronic kidney disease (CKD) affects as many as 10% of the population, which translates to about 850 million globally. Even though genetics, diabetes, and hypertension contribute to CKD, the underlying pathologic processes remain poorly understood. Mast cells (MCs) are unique tissue immune cells capable of secreting numerous biologically active molecules. MCs have been associated with kidney diseases and poor CKD outcomes, but they have received limited attention in CKD research. MCs are typically located perivascularly and are identified through kidney biopsies, which limits their diagnostic utility. MC-specific biomarkers such as histamine and the proteases chymase and tryptase show potential, but signature biomarker profiles are needed. While MC biomarkers have been studied in non-renal diseases, their clinical relevance in kidney disease remains underexplored. This review aims to clarify the role of MCs in kidney diseases, such as diabetic nephropathy, IgA nephropathy, hypertensive nephropathy, pruritus, parathyroidism, renal amyloidosis, and lupus nephritis, as well as in conditions such as kidney fibrosis, inflammation, and kidney transplant rejection. Evidence indicates an increased number of MCs, as judged by increased urine levels of histamine, chymase, IL-33, metalloproteinase-9 (MMP-9), and tryptase. In conclusion, MCs are involved in the pathogenesis of CKD and may represent new targets for early diagnosis, prevention, and treatment. Full article

Introduction: Primary glomerulopathies are immune-driven kidney diseases. IgA nephropathy (IgAN) and membranoproliferative glomerulonephritis (MPGN) are prevalent entities with a risk of chronic progression. Immune checkpoints, such as PD-1/PD-L1, CTLA-4/CD86, and CD200R/CD200, regulate activation and tolerance in T, B, and NK cells, and also exist in soluble forms, reflecting systemic immune balance. Objective: To compare immune checkpoint profiles in IgAN and MPGN versus healthy volunteers (HV) through surface expression, soluble serum levels, and PBMC transcripts, with attention to sex-related differences and diagnostic value assessed by ROC curves. Materials and Methods: Ninety age-matched subjects were studied: IgAN (n = 30), MPGN (n = 30), HV (n = 30). Flow cytometry evaluated checkpoint expression on CD4+/CD8+ T cells, CD19+ B cells, and NK cells. ELISA quantified sPD-1, sPD-L1, sCTLA-4, sCD86, sCD200, sCD200R; PBMC transcript levels were assessed. Group comparisons, sex stratification, and ROC analyses were performed. Results: Lymphocyte distributions were preserved, but IgAN patients showed anemia and impaired renal function, while MPGN patients had greater proteinuria and dyslipidemia. GN patients displayed increased PD-1/PD-L1 and CD200R/CD200, with reduced CTLA-4/CD86, compared to HV. Serum analysis revealed elevated sPD-1, sPD-L1, sCD200, sCD200R and decreased sCTLA-4, sCD86. PBMC transcripts paralleled these trends, with PD-1/PD-L1 mainly increased in MPGN. Sex had minimal impact. ROC analyses showed strong GN vs. HV discrimination by CD19⁺CTLA-4⁺, PD-1/PD-L1, and CD200/CD200R, but limited ability to separate IgAN from MPGN. Conclusions: IgAN and MPGN share a sex-independent checkpoint signature: PD-1/PD-L1 and CD200R/CD200 upregulation with CTLA-4/CD86 downregulation. CD19⁺, CTLA-4⁺, and soluble PD-1/PD-L1/CD200(R) emerge as promising biomarkers requiring further validation. Full article

(1) Background: IgA nephropathy (IgAN) is a leading cause of chronic kidney disease worldwide. Despite its prevalence, the molecular mechanisms of IgAN remain poorly understood, partly due to limited research scale. Identifying key genes involved in IgAN’s pathogenesis is critical for novel diagnostic and therapeutic strategies. (2) Methods: We identified differentially expressed genes (DEGs) by analyzing public datasets from the Gene Expression Omnibus. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to elucidate the biological roles of DEGs. Hub genes were screened using weighted gene co-expression network analysis combined with machine learning algorithms. Immune infiltration analysis was conducted to explore associations between hub genes and immune cell profiles. The hub genes were validated using receiver operating characteristic curves and area under the curve. (3) Results: We identified 165 DEGs associated with IgAN and revealed pathways such as IL-17 signaling and complement and coagulation cascades, and biological processes including response to xenobiotic stimuli. Four hub genes were screened: three downregulated (FOSB, SLC19A2, PER1) and one upregulated (SOX17). The AUC values for identifying IgAN in the training and testing set ranged from 0.956 to 0.995. Immune infiltration analysis indicated that hub gene expression correlated with immune cell abundance, suggesting their involvement in IgAN’s immune pathogenesis. (4) Conclusion: This study identifies FOSB, SLC19A2, PER1, and SOX17 as novel hub genes with high diagnostic accuracy for IgAN. These genes, linked to immune-related pathways such as IL-17 signaling and complement activation, offer promising targets for diagnostic development and therapeutic intervention, enhancing our understanding of IgAN’s molecular and immune mechanisms. Full article

Particulate matter (PM) exposure is linked to chronic kidney disease; however, its effect on immunoglobulin A (IgA) nephropathy (IgAN) remains unclear. We investigated whether PM exposure exacerbates IgAN in a mouse model. HIGA mice (IgAN model) and BALB/c controls were exposed to PM in a sealed chamber for 13 weeks. Lung Toll-like receptor 9 (TLR9) expression, serum aberrantly glycosylated IgA, A proliferation-inducing ligand (APRIL) levels, mesangial IgA deposition, and kidney pathology were assessed. RNA sequencing of splenic B cells was performed to evaluate immune-related gene expression. PM exposure increased lung TLR9 expression in both strains, particularly around pigment-laden macrophages. HIGA mice showed elevated aberrant IgA and APRIL levels, with aggravated mesangial expansion and IgA deposition. Transcriptomic analysis revealed immune dysregulation in splenic B cells of PM-exposed HIGA mice. Our findings provide experimental evidence that PM exposure aggravates IgAN via TLR9-mediated mucosal immune activation, leading to aberrant IgA glycosylation and mesangial deposition. These findings emphasize that reducing PM exposure may benefit patients with IgAN. Full article

Recurrence of the original glomerular disease (GN) poses a significant threat to kidney transplant function and longevity. The probability and severity of this recurrence vary, with C3 glomerulopathy and certain forms of FSGS exhibiting particularly high rates. Kidney transplant GN recurrence risk hinges on the characteristics of the initial GN, recipient/donor genetics, recipient age, donor type, end-stage kidney disease (ESRD) progression rate, and proteinuria levels. Standard immunosuppression has limited efficacy in preventing primary disease recurrence; however, agent selection and induction therapy can influence the risk for specific GNs. Diagnosing recurrent GN involves a comprehensive approach, including clinical evaluation, laboratory tests (such as proteinuria, hematuria, and specific biomarkers like anti-PLA2R for membranous nephropathy or complement for C3G), and, critically, an allograft biopsy analyzed with light, immunofluorescence, and electron microscopy. Treatment strategies are evolving towards targeted therapies, such as rituximab for antibody-mediated GN and complement inhibitors for C3G, moving away from broad immunosuppression. This narrative literature review provides practical monitoring algorithms for post-transplant settings, synthesizing information on the incidence, predictors, diagnostic strategies, and therapeutic options for various glomerular disease subtypes. The methodology involved searching MEDLINE, Embase, and Cochrane databases from 1996 to 2025, prioritizing systematic reviews, cohort studies, registries, and interventional reports. Eligibility criteria included adult transplant recipients and English-language reports on recurrent glomerular disease outcomes, excluding most single-patient case reports. Limitations include potential selection bias, omission of relevant studies, and the absence of a formal risk-of-bias assessment or meta-analysis. The evidence base is heterogeneous, with inconsistent outcome reporting and scarce randomized controlled trials. Future efforts should focus on developing predictive biomarkers, standardizing diagnostic and response criteria, conducting multicenter prospective cohorts and pragmatic trials, and creating shared registries with harmonized data. Full article

Exosomes are nanosized vesicles that carry intracellular mediators and their abundance in urine opens new and intriguing possibilities in nephrology since they provide a non-invasive insight into kidney diseases. The aim of this review is to examine the main applications of urinary exosomes in nephropathies. Urinary exosomes are isolated through ultrafiltration, ultracentrifugation, precipitation, and immunoaffinity chromatography. After isolation they are characterized through Western blotting, flow cytometry, and, more recently, with mass spectrometry. Through the analysis of urinary exosomes, it has been possible to distinguish patients with IgA nephropathy from healthy controls. Different profiles of expression have been identified between patients with MCD and FSGS. A distinct exosomal composition has been discovered in patients with lupus nephropathy when compared to those without renal involvement. Significant findings have been reported also in patients with monoclonal gammopathy of renal significance, allowing a differential diagnosis between LCDD and amyloidosis. Among kidney transplant recipients, the analysis of urinary exosomes highlighted differences between antibody-mediated rejection and cell-mediated rejection. Urinary exosomes are new non-invasive, promising biomarkers and potential therapeutic options that have already shown interesting results in the nephrological field. Further studies are needed to harness their potential and diffusion. Full article

Background: The complement system factors’ role in the pathogenesis of autoimmunological diseases is known, but the influence of autoantibodies against complement factors’ receptors on the course of specific glomerular diseases remains unclear. Methods: We measured the levels of anti-C3aR and anti-C5aR antibodies in patients with membranous nephropathy (n = 18), primary 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), and p (perinuclear)-ANCA vasculitis (n = 16). These conditions were compared to a healthy control group (n = 22). Then, for up to two years, we tracked the patients’ clinical progress (in terms of creatinine, total protein, and albumin levels) and compared the outcomes with their antibody levels. Results: The lupus nephritis group had higher levels of anti-C3aR and anti-C5aR antibodies than the other groups. The lupus nephritis group’s anti-C3aR antibody level showed a negative correlation with albumin and total protein at several time points of observation. Additionally, at numerous observational points, the anti-C3aR antibody level showed a positive correlation with both the basic albumin level in the FSGS group and the total protein level. Conclusions: The anti-C3aR and anti-C5aR antibodies are higher in lupus nephritis patients compared to other glomerulonephritis patients and healthy individuals. Albumin and total protein levels appear to be correlated positively with anti-C3aR antibody levels in FSGS and negatively in lupus nephritis. Full article

IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis worldwide, with a heterogeneous clinical course that may progress to end-stage kidney disease (ESKD) in approximately 20% of patients. Despite recent advances, including the U.S. Food and Drug Administration (FDA) approval of three novel agents, optimal therapeutic strategies remain uncertain, and access to new drugs is often limited. This underscores the need to evaluate established and widely available options such as mycophenolate mofetil (MMF). The aim of this review is to critically assess the role of MMF, either as monotherapy or in combination with systemic corticosteroids, in the treatment of IgAN based on evidence cited in the KDIGO 2024 Draft Guidelines. We analyzed seven major clinical studies—five randomized controlled trials and two long-term observational studies—with particular focus on the influence of histological activity on treatment outcomes. The Oxford classification was applied to explore whether specific histological variables correlate with prognosis and predict treatment response. Trials conducted in Chinese cohorts demonstrated significant benefits of MMF, including proteinuria reduction, delayed progression to ESKD, and improved long-term renal outcomes, particularly in patients with recent disease onset and active proliferative lesions such as endocapillary hypercellularity and crescent formation. In contrast, studies from Western populations generally failed to demonstrate comparable benefit possibly due to differences in disease chronicity, histopathological patterns, and genetic background. Overall, MMF appears most effective when initiated early and in patients with histologic evidence of intraglomerular inflammation. It may represent a viable steroid-sparing option in appropriately selected patients, particularly where access to newly approved agents is restricted. These population- and pathology-based differences highlight the need for individualized treatment decisions and further research to refine the therapeutic role of MMF in IgAN. Full article

Oxidative stress (OS), defined as an imbalance between pro-oxidant and antioxidant mechanisms, contributes to DNA and protein oxidation as well as cellular injury, and plays a pivotal role in the pathogenesis of chronic kidney disease (CKD). Peroxiredoxins (PRDXs) are key antioxidant enzymes that regulate intracellular peroxide levels and maintain redox homeostasis. Beyond its renal implications, OS is closely intertwined with hypertension and atherosclerosis, both common comorbidities that accelerate CKD progression. As previously reported, serum concentrations of PRDXs 1-5 may help to differentiate between IgA nephropathy (IgAN), membranous nephropathy (MN), and lupus nephritis (LN). This study aimed to assess the utility of baseline serum PRDX levels in predicting longitudinal changes in kidney function and proteinuria in patients with IgAN, MN, and LN. We analyzed data from 80 patients (IgAN, n = 36; MN, n = 23; LN, n = 21) drawn from an initial cohort of 108 in whom baseline serum concentrations of PRDX 1–5 were measured. Patients were stratified into low, medium, and high PRDX level groups at baseline, and associations between these strata and longitudinal changes in eGFR and proteinuria were assessed over a follow-up period of up to five years. Across all groups, the follow-up eGFR was significantly associated with low baseline serum PRDX 1, 2, 3, and 5 (p = 0.043; p = 0.001; p = 0.036; p = 0.007, respectively). Significant associations were also observed between 24 h follow-up proteinuria and low baseline serum PRDX 2, 3, and 5 (p = 0.025; p = 0.025; p = 0.005, respectively), medium PRDX 4 (p = 0.010), and high PRDX 2 (p = 0.019). No significant associations were found within the study groups; however, these associations were more pronounced in IgAN and MN patients. These findings suggest a potential role for PRDXs in predicting and monitoring CKD progression, especially eGFR decline. Full article

IgA nephropathy is the most common primary glomerulonephritis, with pathohistological changes described by the Oxford classification, while the Banff classification is used in transplant pathology. This study included 253 patients with IgA nephropathy in native kidneys, divided into the pediatric (n = 105) and adult (n = 148) groups. It aimed to examine clinical, and Oxford and Banff morphological parameters in relation to age, correlations of clinical data with pathohistological parameters, and predictors of the disease outcome. Pediatric patients more frequently presented with macroscopic hematuria, while adults showed higher urea and creatinine levels, and lower eGFR. Examining Oxford classification parameters, chronic glomerular and tubulointerstitial lesions were more common in adults. Banff parameters revealed more frequent chronically active glomerular, inflammatory, chronic tubulointerstitial, and vascular lesions in adults. All inflammatory, chronic tubulointerstitial, and vascular parameters correlated with serum urea levels, eGFR and CKD stage in adults, while less frequent in pediatric patients. Tubulointerstitial Oxford and Banff parameters were strong predictors of CKD and proteinuria progression in children, while such predictors were fewer in adults; segmental glomerulosclerosis predicted hematuria progression in adults. Banff parameters (cg, t, ti, i, i-IFTA, ptc, cv), not in Oxford classification, significantly predict outcomes and are recommended for incorporation into IgA nephropathy reports. Full article

There is rapidly increasing evidence of the role of complement in different forms of kidney disease and this has broadened the field to involve not only atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G), but also a number of other glomerular diseases, mainly ANCA-associated renal vasculitis, immune-complex glomerulonephritis, membranous nephropathy, and IgA nephropathy (IgAN). In parallel, the field of therapeutic agents able to target the three complement pathways at different levels, both proximally and terminally, has grown tremendously in recent years. This has led to the approval of agents targeting complement for ANCA-associated vasculitis, IgA nephropathy, and, very recently, C3 glomerulopathy. The real-world implementation of these agents remains a challenge. This review will attempt, through the presentation of representative clinical vignettes, to provide some practical guidance for the nephrologist in how to navigate these new therapeutic opportunities, focusing on aHUS, C3G, and IgAN. Full article

IgA nephropathy (IgAN) is an inflammatory glomerular disease caused by the production of galactose-deficient IgA1 (Gd-IgA1), which induces the formation of autoantibodies and IgA immune complexes (IgAICs) that are ultimately deposited in the mesangium. This event triggers mesangial cell proliferation, cytokine release and complement activation, and both glomerular and interstitial damage, eventually leading to kidney function decline. Persisting proteinuria is the most relevant marker of disease progression. Systemic corticosteroids (CSs), a powerful anti-inflammatory approach, have shown kidney protective effects in early trials involving patients with IgAN at risk of progression with persistent proteinuria. However, later studies raised concerns regarding severe adverse events associated with high doses of methylprednisolone and questioned the long-term benefits. As a result, the KDIGO 2021 guidelines recommended limiting CS therapy to selected patients who accepted the high risk of adverse events. The treatment landscape shifted when reduced doses of methylprednisolone, combined with Pneumocystis pneumonia prophylaxis, demonstrated similar kidney protection compared to full methylprednisolone doses with fewer adverse events. An innovative approach involves a targeted budesonide formulation acting on Peyer’s patches, the main site of Gd-IgA1 production. This treatment showed benefits comparable to systemic CSs, with valuable limitations of adverse events. Several new drugs targeting key pathogenetic events of IgAN are under investigation, with promising results published in recent months. These new therapies target B cell activation (and subsequent Gd-IgA1 production), the complement cascade triggered by IgAIC deposition and the endothelin system, a key amplifier of kidney damage that contributes to the chronicity of IgAN. Full article