IgA nephropathy (IgAN) is characterised by the production of galactose-deficient IgA1 (GdIgA1) antibodies. As the source of pathogenic antibodies, B cells are central to IgAN pathogenesis, but the B cell activation pathways as well as the potential B cell source of dysregulated IgA-secretion remain unknown. We carried out flow cytometry analysis of peripheral blood B cells in patients with IgA nephropathy and control subjects with a focus on IgA-expressing B cells to uncover the pathways of B cell activation in IgAN and how these could give rise to pathogenic GdIgA1 antibodies. In addition to global changes in the B cell landscape – expansion of naive and reduction in memory B cells – IgAN patients present with an increased frequency of IgA-expressing B cells that lack the classical memory marker CD27, but are CD21^pos. IgAN patients further have an expanded population of IgA^pos antibody-secreting cells, which correlate with serum IgA levels. Both IgA^pos plasmabalsts and CD27^neg B cells co-express GdIgA1. Implicating dysregulation at mucosal surfaces as the driver of such B cell differentiation, we found a correlation between lipopolysaccharide (LPS) in the serum and IgA^posCD27^neg B cell frequency. We propose that dysregulated immunity in the mucosa may drive de novo B cell activation within germinal centres, giving rise to IgA^posCD27^neg B cells and subsequently IgA-producing plasmablasts. These data integrate B cells into the paradigm of IgAN pathogenesis and allow to further investigate this pathway to uncover biomarkers and develop therapeutic interventions.

Peritonitis caused by Staphylococcusaureus is of major importance in peritoneal dialysis (PD) patients due to its great virulence profile and biofilm formation ability. Bacteriophages are a potential tool to treat peritonitis resulting from biofilm-associated infections. We screened S. aureus colonization in 71 PD patients from the nasal cavity, groin, and PD exit-site regions and analyzed clinical outcomes in these patients. We performed biofilm-formation testing of different strains and compared the isolates of one patient to detect phenotypic differences in S. aureus. Phage cocktails were used to detect S. aureus in vitro susceptibility. An adaptation procedure was performed in cases of bacterial resistance. Around 30% of PD patients (n = 21) were found to be S. aureus carriers; from these, a total of 34 S. aureus strains were isolated, of which 61.8% (n = 21) produced a strong biofilm. Phenotypic differences in strain biofilm production were detected in eight patients out of ten. All strains were sensitive to commonly used antibiotics. Broadly positive phage lytic activity (100%) was observed in six cocktails out of seven, and bacterial resistance towards phages was overcome using adaptation. Overall phages showed a promising in vitro effect in biofilm-forming S. aureus strains.

Kidney transplantation is the treatment of choice for most patients with end-stage renal disease. To improve patient and transplant survival, non-invasive diagnostic methods for different pathologies are important. Leucine-rich alpha-2-glycoprotein (LRG-1) is an innovative biomarker that is elevated in cases of angiogenesis, inflammation, and kidney injury. However, there are limited data about the diagnostic role of LRG-1 in kidney transplant recipients. The aim of this study was to evaluate the association between serum LRG-1, urine LRG-1, and kidney transplant function and injury. We enrolled 35 kidney transplant recipients in the study. LRG-1 in the serum and urine was detected using ELISA. We evaluated the correlation of serum and urine LRG-1 with traditional serum and urine kidney injury markers. A higher level of serum LRG-1 correlates with a higher level of urine LRG-1. Serum LRG-1 has a positive correlation with transplant age, serum urea, serum creatinine, serum cystatin C, proteinuria, and fractional excretion of sodium (FENa) and a negative correlation with hemoglobin and estimated glomerular filtration rate (eGFR). Urine LRG-1 has a positive correlation with serum cystatin C, proteinuria, and urine neutrophil gelatinase-associated lipocalin (NGAL). Higher levels of serum and urine LRG-1 are associated with kidney transplant injury and functional deterioration. Thus, LRG-1 might be also as a biomarker for tubular dysfunction in patients after kidney transplantation.

Immunoglobulin A nephropathy (IgAN) is the most common chronic glomerulopathy with variable clinical manifestations. IgAN diagnostics became possible in Latvia in 2013. The study aim was to describe IgAN manifestations in the Latvian population by analysing epidemiological, clinical, histological data, and reveal factors that might determine the course of the disease. The retrospective, one-centre study included biopsy-proven IgAN patients over a five-year period in the Nephrology Centre at Pauls Stradiņš Clinical University Hospital. Data from inpatient and outpatient medical records were collected. The study included 69 patients with histologically confirmed IgAN (23% of all renal biopsies): 52% men with mean age of 37. More than a half of them had hypertension, changes in urinalysis and kidney structure, and GFR < ml/min before the biopsy. Pathology data stratified by MEST-C score were: M1 (93%), E1 (5%), S1 (81%), T1 and T2 (24%), C1 (18%). 20% started renal replacement therapy (RRT). Proteinuria, obesity, hyperuricemia, high total MEST-C score, and low serum C3 were associated with a worse prognosis. As a significant part of patients start RRT in the five-year period after the biopsy, the disease course is not benign. IgAN in the study population was diagnosed with clinical and histological signs of advanced disease.

Background: IgA nephropathy (IgAN) is characterised by the production of galactose-deficient IgA1 (Gd-IgA1) antibodies. As the source of pathogenic antibodies, B cells are central to IgAN pathogenesis, but the B cell activation pathways as well as the potential B cell source of dysregulated IgA-secretion remain unknown. Methods: We carried out flow cytometry analysis of peripheral blood B cells in patients with IgA nephropathy and control subjects with a focus on IgA-expressing B cells to uncover the pathways of B cell activation in IgAN and how these could give rise to pathogenic GdIgA1 antibodies. Results: In addition to global changes in the B cell landscape – expansion of naive and reduction in memory B cells – IgAN patients present with an increased frequency of IgA-expressing B cells that lack the classical memory marker CD27, but are CD21 ^pos . IgAN patients further have an expanded population of IgA ^pos antibody-secreting cells, which correlate with serum IgA levels. Both IgA ^pos plasmabalsts and CD27 ^neg B cells co-express GdIgA1. Implicating dysregulation at mucosal surfaces as the driver of such B cell differentiation, we found a correlation between lipopolysaccharide (LPS) in the serum and IgA ^pos CD27 ^neg B cell frequency. Conclusion: We propose that dysregulated immunity in the mucosa may drive de novo B cell activation within germinal centres, giving rise to IgA ^pos CD27 ^neg B cells and subsequently IgA-producing plasmablasts. These data integrate B cells into the paradigm of IgAN pathogenesis and allow to further investigate this pathway to uncover biomarkers and develop therapeutic interventions. Key learning points: What was known: Patients with IgA nephropathy (IgAN) have aberrant production of galactose-deficient IgA1 (Gd-IgA1) and antibodies against it, which together form immune complexes that are deposited in the renal mesangium and lead to kidney damage; this is known as the multi-hit model of IgAN pathogenesis. The multi-hit model centrally implicates B cells as they produce both Gd-IgA1 and antibodies against it, yet B cell activation pathways that lead to aberrant antibody production are absent from the model. Only isolated reports exist describing specific features of B cells that are altered in patients with IgAN, including a reduction in regulatory B cells, increase in toll-like receptor 7 expression in total peripheral blood B cells and elevated frequency of circulating CCR9 ⁺ IgA ⁺ B cells. This study adds: In addition to changes in the overall circulating B cell landscape, differentiation of IgA ⁺ plasmablasts is enhanced in patients with IgAN and their levels correlate with serum IgA. IgA-expressing plasmablast frequency correlates with that of IgA ⁺ CD21 ⁺ B cells, that lack the classical memory B cell marker CD27. Both IgA ⁺ plasmablasts and IgA-expressing CD27 ^- B cells co-express GdIgA1 receptors. IgA ⁺ CD27 ^- CD21 ⁺ B cell frequency correlates with serum lipopolysaccharide (LPS) levels, implicating mucosa in their activation. Potential impact: We uncover the previously unknown B cell activation pathway that appears to be associated with pathogenic IgA secretion in IgAN and integrate this into the multi-hit model of IgAN pathogenesis. This pathway holds potential for further investigation to identify biomarkers and therapeutic targets in IgAN.

"Immunoglobulin A nephropathy (IgAN) is the most prevalent primary glomerular disease in numerous countries and continues to be a significant contributor to chronic kidney disease and end-stage kidney disease (ESKD). The clinical course can vary, but on average 30–40 % of patients reach ESKD within 20–30 years of diagnosis, and the disease may recur in the kidney graft. As the prognosis of this disease varies depending on its clinical presentation, the International IgAN Prediction Tool (IIgANPT) was developed in 2019 to integrate clinicopathological prognostic factors at the time of diagnosis and generate an individualised risk of disease progression. According to existing evidence, IgAN is believed to result from a combination of various pathogenic factors rather than a singular cause. This study was conducted to evaluate the risk of disease progression in IgAN patients and to analyse B-cell differentiation and the gut microbiome as potential factors in the pathogenesis of the disease. During a median follow-up of 18 months, 14.7 % of IgAN patients progressed to ESKD, corresponding to an incidence rate of 0.11 episodes per patient-year. Gender, MEST-T score and increased diastolic blood pressure were identified as significant risk factors for reduced kidney survival. We carried out flow cytometry analysis of peripheral blood B cells in IgAN patients and healthy controls (HC) to investigate how B cells are activated to produce pathogenic IgA. Expansion of naïve and reduction in memory B cells was seen in IgAN patients with an increased frequency of IgA-expressing B cells that lacked the classical memory marker CD27, but were CD21+. IgAN patients furthermore had an expanded population of IgA+ antibody-secreting cells, which correlated with serum IgA levels. Both IgA+ plasmabalsts and CD27− B cells co-expressed galactose-deficient IgA1 (Gd-IgA1). Implicating dysregulation at mucosal surfaces as the driver of such B cell differentiation, we found a correlation between lipopolysaccharide in the serum and IgA+CD27− B cell frequency. Metagenomic analysis and functional profiling of the gut microbiome were performed in IgAN patients categorised either as progressors (defined by an estimated glomerular filtration rate decline > 5 ml/min/1.73 m²/year), or non-progressors, and HC. Compared to HC, IgAN patients showed a reduced abundance of butyrate-producing bacteria. In addition, pathways related to nucleotide and nucleoside biosynthesis were more pronounced in IgAN patients, suggesting underlying immune activation and inflammation. Variations in these metabolic pathways were, in part, explained by Gd-IgA1 levels. Notably, the progressor group exhibited functional microbial changes linked to the stabilisation of bacterial cell membranes. The Doctoral Thesis was developed at Rīga Stradiņš University, Pauls Stradins Clinical University Hospital, Latvia. Defence of the Doctoral Thesis will take place at the public session of the Promotion Council of Clinical Medicine on 2 February 2026 at 11.00 in in the Boris Teterev Auditorium, 26A Anniņmuižas Boulevard, Rīga Stradiņš University Medical Education Technology Centre. This Doctoral Thesis was supported by RSU PhD grant and by the Fundamental and Applied Research Project No lzp-2019/1-0139 “Dissecting the interplay between intestinal dysbiosis and B cell function in the pathogenesis of immunoglobulin A nephropathy”. 3.2. Clinical Medicine; Sub-Sector – Internal Medicine. Kewords: Immunoglobulin A nephropathy; kidney survival; B cell differentiation; microbiome characteristics. "