Cases Of IgA Nephropathy Research Articles

De Novo Biopsy-Proven Glomerular Disease Following COVID-19 Vaccination.

Background: There is still no consensus about the coronavirus disease 2019 (COVID-19) vaccine-associated glomerular disease (CVAGD). Given the large number of vaccinations administered and the variations in glomerulopathy observed across different countries and regional environments, CVAGD remains an important area of concern. Aim of study: We aimed to elucidate the findings of CVAGD within a Taiwanese cohort using biopsy data. Additionally, we endeavored to clarify the presentation of CVAGD. Methods: We collected data from patients who underwent renal biopsy from June 2021 to October 2022 at Taichung Veterans General Hospital. Two independent nephrologists meticulously reviewed the charts to exclude cases unrelated to vaccination. Results: Initially, a total of 286 patients underwent renal biopsy at our institute. Ultimately, we identified 14 patients with highly suspected CVAGD. All 14 patients exhibited proteinuria and hematuria. The urinary protein-to-creatinine ratio was elevated (median of 2012.1 mg/g; interquartile range (IQR) 25%-IQR 75%: 941.85-3884.1 mg/g) with a median serum creatinine level of 1.71 mg/dL (0.79-5.35). The majority of CVAGD cases were diagnosed as immunoglobulin A (IgA) nephropathy (n = 5, 35.7%), followed by antineutrophil cytoplasmic antibody (ANCA)-related rapidly progressive glomerulonephritis (RPGN) (n = 4, 28.6%). There were only three cases of minimal change disease each: one case of focal segmental glomerulosclerosis, one of membranous glomerulonephritis, and one of lupus nephritis. The culprit of COVID-19 vaccinations was 35.7% (n = 5) of Oxford-AstraZeneca (ChAdOx1-S), 42.9% (n = 6) of Moderna, and 21.4% (n = 3) of BNT162b2. Most patients experienced improvements in renal function. Only two cases of P-ANCA RPGN and one case of IgA nephropathy did not recover. Eighty percent of IgA nephropathy cases had favorable outcomes, but none of the patients with P-ANCA RPGN achieved full recovery. Conclusions: IgA nephropathy and ANCA-related RPGN were the most common CVAGD, and all types of COVID-19 vaccines posed a risk for CVAGD. However, further studies are required to confirm causality.

Predictors of glomerular IgA immunostaining patterns and disease progression in IgA nephropathy patients; a 13-year study of clinical and morphological features of renal biopsies

Introduction: IgA nephropathy (IgAN) is a common primary glomerulonephritis with highly heterogeneous clinical and histopathological features. The MEST-C scoring system has been developed to improve prognostic assessment but lacks elements related to immunostaining study. Objectives: This study aimed to investigate the association between the immunofluorescence (IF) deposits’ patterns of IgA (mesangiocapillary versus pure mesangial) with demographic, clinical, biochemical, and morphological parameters of MEST-C classification in IgAN patients. Patients and Methods: This retrospective, cross-sectional study was conducted on 268 biopsy-proven cases of IgAN from July 2009 to July 2022 at a single laboratory in Isfahan in Iran. The demographic, clinical, and laboratory data including age, gender, serum creatinine, and proteinuria were collected from the biopsy request forms. The morphological parameters of MEST-C classification and IF study patterns were collected from the biopsy reports. Results: The average age of all patients was 37.7 ± 13.47 years, with 67% being males. The mean serum creatinine and proteinuria levels were 1.43 mg/dL and 1730.94 mg/day, respectively. MEST-C score analysis revealed that 171 patients (63.8%) had mesangial expansion (M1), while 105 patients (39.2%) exhibited endocapillary hypercellularity (E1). Additionally, segmental glomerulosclerosis (S1) and tubular atrophy/interstitial fibrosis (T1 and T2) was observed in 160 biopsy samples (59.7%). Moreover, crescent (C) formation was noted in 76 (28.4%) of biopsies. Data analysis using univariate logistic regression demonstrated that E, T, and C on morphology, complement C3, IgG, IgM deposits on IF, and the total MEST score were all associated with an increased risk for mesangiocapillary deposits of IgA. However, using the multivariate method, the results indicated that only the total MEST score (OR: 2.4), presence of crescent (OR: 3.22), presence of endocapillary hypercellularity (OR: 4.86), tubular atrophy/interstitial fibrosis grade II (OR: 34.4), and IgG deposition (OR: 3.37) were independent risk factors for mesangiocapillary deposits of IgA. Conclusion: The total MEST score is significantly higher in mesangiocapillary patterns. Furthermore, the presence of E1, T2, and C1-2 morphological parameters of the updated Oxford classification in renal biopsies are independent risk factors for IgA mesangiocapillary deposits. Hyperactivation of immunoglobulins and the complement system appears to contribute to mesangial-capillary proliferation.

Chronic Tonsillitis and IgA Nephropathy: Findings From a Nationwide Japanese Cohort Study

Rationale & ObjectiveLittle is known regarding the association between chronic tonsillitis and the onset of IgA nephropathy (IgAN). In the present study, we examined the potential relationship between chronic tonsillitis and a subsequent risk of developing IgAN. Study DesignObservational cohort study. Setting& Participants: 4,311,393 individuals without a history of IgAN identified between January 2005 to May 2022 within a Japanese nationwide epidemiological database, the JMDC Claims Database, representing health claims to over 60 insurers. ExposureComorbid chronic tonsillitis based on diagnosis codes. OutcomeIgAN occurrence. Analytical ApproachCause-specific Cox proportional hazards analysis adjusting for potential confounding factors were employed to estimate hazard ratios (HRs). ResultsComorbid chronic tonsillitis was identified in 12,842 individuals, constituting 0.3% of the cohort. The cohort had a median age of 44 years (interquartile range: 36-53), and males accounted for 57.9%, with a follow-up of 1,089 days (interquartile range: 532-1,797), during which 2,653 cases of IgAN developed. Cumulative incidence curve showed a higher cumulative incidence of IgAN in individuals with chronic tonsillitis compared to their counterparts without this condition. Multivariable cause-specific analysis further demonstrated that individuals with chronic tonsillitis had an elevated risk of developing IgAN, with a HR of 2.72 (95% confidence interval: 1.79-4.14). LimitationsPotential residual confounders, and lack of consideration for ethnic distinctions. ConclusionsUsing a largescale epidemiological dataset, these findings suggest a relationship between chronic tonsillitis and an elevated risk of IgAN development in the general Japanese population.

#1039 Characteristics and outcome of IgA nephropathy in Switzerland – a single center perspective

Abstract Background and Aims IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide leading to end-stage kidney disease (ESKD) in roughly 40% of affected patients by ten years. Geographic differences in clinical course and response to treatment may partly result from different disease entities. The purpose of this retrospective cohort analysis was to study all cases of IgAN from a single tertiary center with respect to clinical and histological characteristics, treatment practices and outcome. Method This retrospective cohort analysis identified 158 cases of adult biopsy-proven IgAN by chart review diagnosed between 1980 and 2017. Detailed phenotypisation including clinical, paraclinical, histological, treatment and outcome parameters was performed. Remission status was defined as described previously (Reich 2007). Statistical analysis was performed using Excel and SPSS software and included standard descriptive methods and included standard descriptive methods and student's t-test on a significance level of 0.05. Results Subjects were majorly male and of Caucasian descent. Mean estimated glomerular filtration rate (eGFR) according to Chronic Kidney Disease Epidemiology Collaboration formula at diagnosis was 55.3 ml/min/1.73 m2, mean proteinuria was 3.2 g/d. 70.3% of patients were hypertensive at presentation. Clinical presentation varied according to age. Thus, younger patients (18-39 years) presented more frequently with macrohematuria, asymptomatic urine abnormalities and by trend acute kidney injury whereas nephrotic syndrome and extrarenal symptoms were recorded in similar proportions of patients (Fig. 1). 28.5% of initial biopsies showed moderate to severe tubular atrophy and interstitial fibrosis (IFTA), 38% included crescents, 1.9% > 50% crescents. 86.1% of the patients were treated by renin-angiotensin-aldosterone-system inhibitors, 46.8% received immunosuppressive therapy including steroids in 46.2% and other immunosuppressive medications in 19.6% the most common being azathioprine (Fig. 2). There were 33.5% complete and 13.3% partial remissions. Progression to ESKD was noted in 42.1%. 51.4% of patients treated with immunosuppressive therapy experienced remission. Recurrence rate after transplantation was 18.4%. Patients treated by immunosuppressants had higher levels of baseline proteinuria (3.2 ± 2.3 vs. 1.6 ± 1.6 g/d, p < 0.00001), lower baseline eGFR (50 ± 31 vs. 61 ± 30 ml/min/1.73 m2, p = 0.04), higher number of crescents (9.4 ± 15.0 vs 2.3 ± 8.5%, p = 0.001), higher IFTA scores (1.7 ± 0.8 vs. 1.3 ± 0.6, p = 0.007) and higher fluorescence intensity scores for C3 (2.0 ± 0.9 vs. 1.6 ± 0.9, p = 0.02) on initial biopsy as compared to patients treated conservatively. Patients progressing to ESKD presented with higher blood pressure (146 ± 26 vs. 135 ± 18 mmHg systolic, p = 0.005; 89 ± 14 vs. 82 ± 14 mmHg diastolic, p = 0.006), lower eGFR (41 ± 29 vs. 64 ± 28 ml/min/1.73 m2, p = 0.00001), higher levels of proteinuria (3.4 ± 2.0 vs. 1.8 ± 1.9 g/d, p = 0.0001), higher number of crescents (9 ± 17 vs. 4 ± 9%, p = 0.03) and higher IFTA scores (1.8 ± 0.8 vs. 1.3 ± 0.6, p = 0.00001) as compared to patients without ESKD at last follow up. Baseline blood pressure (134 ± 18 vs. 147 ± 26 mmHg systolic, p = 0.004; 82 ± 14 vs. 89 ± 15 mmHg diastolic, p = 0.01), eGFR (60 ± 29 vs. 41 ± 27 mmHg, p = 0.0007), proteinuria (2.3 ± 1.9 vs. 3.2 ± 2.3 g/d, p = 0.03) and severity of IFTA (1.4 ± 0.6 vs. 1.8 ± 0.9, p = 0.003) differed significantly between patients who experienced any remission vs. those who did not achieve remission respectively. Conclusion This analysis gives insight into the characteristics and treatment practices of a Swiss single center cohort of IgAN patients from 1980-2017.

#162 Single-nucleus RNA-seq of biopsy-confirmed IgA nephropathy reveals cell-specific transcriptomic alteration

Abstract Background and Aims Single-nucleus RNA-seq (SnRNA-seq) is a valuable method for identifying cell-specific transcriptomic alterations in kidney cells. Our objective was to investigate SnRNA-seq data from biopsy-confirmed IgA nephropathy (IgAN) cases and identify cell-specific alterations in the transcriptome. Method We collected snap-frozen kidney biopsy tissues from 6 cases of IgA nephropathy (IgAN) and 7 nephrectomy control cases. The disease control group included 3 cases of diabetic kidney disease, 6 cases of minimal change disease, and 6 PLA2R-Ab positive membranous nephropathy cases. SnRNA-seq was performed on the kidney tissues, and kidney cells were identified in the dataset through UMAP clustering. We investigated differences in the proportion of kidney cell types and identified differentially expressed genes (DEGs). Additionally, we searched for representative gene loci previously reported in a multiethnic genome-wide association study (GWAS). Results We successfully collected transcriptomic profiles of >50 000 cells from IgAN, with a considerable enrichment of intraglomerular cells. The DEG analysis revealed a high number of DEGs in mesangial cells, fibroblasts, and vascular smooth muscle cells in the IgAN transcriptome compared to the nephrectomy and disease control cases. In the gene set enrichment analysis, the epithelial-mesenchymal transition pathway was enriched in the glomerular cells of IgAN. Furthermore, among various GWAS loci, ETS1 was the gene significantly highly expressed in the mesangial cells of IgAN, consistent across the compared control groups. Conclusion This investigation represents the largest SnRNA-Seq profiling of IgAN kidney cells to date. We identified notable enriched cell-specific pathways in IgAN. ETS1 may be a kidney-indwelling causal factor for IgAN pathophysiology, considering its notable significance in both previous GWAS results and the current SnRNA-Seq data.

#161 Single-Nucleus RNA-Seq of Human Kidney Biopsy Tissue Reveals Microstructure-Specific Similarities and Differences in Various Glomerulonephritis

Abstract Background and Aims Transcriptomic alterations in kidney diseases may lead to the discovery of novel biomarkers. Single-nucleus RNA-seq (SnSeq) is a valuable method for profiling the transcriptome of kidney-residing cells. Additional SnRNA-seq data is necessary, including cases of human biopsy-confirmed glomerulonephritis. Method We collected snap-frozen kidney biopsy tissues from 6 cases of IgA nephropathy (IgAN), 6 cases of minimal change disease, 6 cases of PLA2R-Ab positive membranous nephropathy, 3 cases of diabetic kidney disease, and 7 nephrectomy control cases. SnSeq was performed on the kidney tissues, and kidney cells were identified in the dataset through UMAP clustering. The proportions of each cell subcluster were compared between the study groups. Differentially expressed genes (DEGs) were identified. K-means clustering and Weighted Gene Co-expression Network Analysis (WGCNA) were performed. Results We successfully collected transcriptomic profiles of 55 615 cells from IgAN, 53 370 from minimal change disease, 53 495 from membranous nephropathy, 34 343 from diabetic kidney disease, and 66 161 from control cases. The SnSeq data successfully identified major kidney cell clusters, including a considerable number of glomerular cells such as podocytes, mesangial cells, endothelial cells, and others. DEGs were largely identified in podocytes and proximal tubule cells, as well as in other glomerular cells. K-means clustering identified diverse similarities and differences between the study groups for each cell type. We identified diverse cell type-specific but disease-common DEGs, particularly in the downregulated genes, suggesting that the studied diseases share similar destruction in kidney microstructure. In comparison, cell type-common but disease-specific DEGs were also identified, considering a common pathophysiologic mechanism may occur in total kidney cortex. Diseases that can feature nephrotic syndrome showed high expression of AVP receptors, suggesting the association with edema, or highly expressed renin-angiotensin-aldosterone pathway was noted in IgAN or diabetic kidney disease, which was not evident in minimal change disease or membranous nephropathy patients. The studied disease shared certain types of inflammatory pathways (e.g. interferon-alpha or TGF-beta) but some pathways were differently enriched according to the disease types. WGCNA analysis revealed gene modules that were highly correlated with age, proteinuria, and estimated GFR, regardless of the diagnosis subtype. Conclusion The current SnSeq data is, to date, the largest one, including biopsy-confirmed human kidney glomerulonephritis cases. The results identified disease-specific changes in specific cell types. Additionally, common transcriptomic alterations occurring following changes in estimated GFR, age, and proteinuria were investigated. The data may be a valuable resource for future research on glomerulonephritis biomarker development.

#1450 Polygenic risk score of native IgA nephropathy predicts risk of post-transplant disease recurrence

Abstract Background and Aims IgA nephropathy (IgAN) is a polygenic immune-mediated progressive glomerular disease. Recent GWAS reported that high genome-wide polygenic risk score (IgAN GPS), including 1 249 077 variants mapping to systemic immune pathways, was associated with risk of end stage kidney disease (ESKD). Post transplant (KTx) IgAN recurrence occurs in 30% of cases and it is a major cause of graft loss. Pathogenesis and predictors of IgAN recurrence are still not well defined. Herein, we studied the role of native IgAN GPS and clinical factors in predicting post-KTx IgAN recurrence and graft failure in a large cohort of KTx recipients. Method Four thousand one hundred eighty six KTx recipients from 6 sites were genome wide genotyped and imputed against multi-ancestry reference panels, retrieving >10 million variants. In each recipient, native IgAN GPS was computed and standard-normalized (i.e. expressed in units of standard deviations from the mean distribution in matched controls). Native kidney disease diagnosis, clinical parameters, and post-KTx outcome data were retrieved retrospectively from clinical charts. The IgAN GPS was tested as predictor of native IgAN in the entire KTx cohort in a logistic regression model adjusted for sex, age, recruitment site, and first 5 PCs. IgAN GPS was tested as predictor of age at transplantation (proxy for age at ESKD) among KTx recipients with native IgAN in a linear regression model adjusted for sex, recruitment site, and first 5 PCs. In recipients with native IgAN, recipient and donor parameters were individually tested as predictors for time to IgAN recurrence and time to graft failure in Cox proportional hazards models adjusted for recruitment site and first 5 PCs. Predictors with P-value < .1 were included in the multivariable models. Recipient IgAN GPS was added to the clinical models and tested for prediction of time-to IgAN recurrence, and, among KTx recipients with IgAN recurrence, of time-to subsequent graft failure. Results Three hundred sixty nine KTx recipients were affected by native IgAN, 271 were of male sex, median age at transplantation was 45 years, and 149 received a living donor KTx. Over a median follow-up time of 46 months, 96 IgAN recurrence events occurred, and, among KTx recipients with recurrent IgAN, 27 subsequent graft failure events occurred after 100 months post KTx. IgAN GPS significantly predicted native IgAN cases among all KTx recipients (OR [95% CI]: 1.95 [1.76,2.16], p = 5.60E-07, AUROC 0.73), and lower age at transplantation among recipients with native IgAN (beta [s.e.]: −1.11[0.55], p = 0.04). Clinical model for IgAN recurrence included age, sex, year of transplant, HLA mismatch, recruitment site, and first 5 PCs; clinical model for graft failure included age, sex, year of transplant, HLA mismatch, type of donation, donor age, sex, rejection events, recruitment site, and first 5 PCs. At the multivariable analysis, IgAN GPS, lower age at transplantation, lower HLA mismatch, and higher year of transplant were independently associated with time to IgAN recurrence (Fig. 1a). Among KTx recipients with recurrent IgAN, higher IgAN GPS predicted time-to graft failure independently from clinical factors (Fig. 1b), but not in non-recurrent cases. Conclusion In the KTx setting, IgAN GPS was an independent predictor of IgAN recurrence, suggesting shared genetic susceptibility between native and recurrent IgAN. In addition, associations of IgAN GPS with lower age at transplantation, and with graft failure among recurrent IgAN cases, suggest that IgAN GPS may be predictive of a more aggressive native as well as recurrent disease. Associations with lower HLA mismatch advocate donor-recipient genetic similarities as potential additional predictors of IgAN recurrence. These data, which need external validation, may provide potential new insights into the pathobiology and prediction of recurrent IgAN.

Correlation of Serum Galactose-Deficient IgA1 and Oxford Class in Cases of IgA Nephropathy.

Galactose-deficient immunoglobulin A1 (Gd-IgA1) deposition in the renal mesangium plays a role in the pathogenesis of IgA nephropathy. To assess the serum Gd-IgA1 level in biopsy-proven IgA nephropathy cases on diagnosis and 3 months post treatment and its relation with histologic Oxford classification. In this hospital-based prospective cohort study, 40 cases and 20 controls were enrolled. Serum samples of biopsy-proven IgA nephropathy cases collected on the day of biopsy and 3 months post treatment were evaluated. Solid-phase ELISA (enzyme-linked immunosorbent assay) was performed for assessment of Gd-IgA1 level. All renal biopsies were scored by using Oxford Classification (C-MEST score). The association of serum Gd-IgA1 levels with other established prognostic parameters was assessed. To estimate the prognostic value of markers, logistic regression analysis and Kruskal-Wallis ANOVA (analysis of variance) were used. Significant difference was observed in the serum Gd-IgA1 level values in the IgA nephropathy cases and healthy controls (P = .001) at baseline. However, no significant correlation between serum Gd-IgA1 levels at baseline and 3 months of follow-up (P = .31) or between baseline levels and age, proteinuria, hematuria, or estimated glomerular filtration rate was noted. There was no significant correlation between C-MEST score and serum Gd-IgA1 levels at baseline (P > .05); however, the distribution of Gd-IgA1 at 3 months was found to differ significantly between different grades of S score (P = .008). Serum Gd-IgA1 levels may be of utility in predicting disease progression in IgA nephropathy cases. Measurement of serum Gd-IgA1 levels for the diagnosis and prognosis of IgA nephropathy may preclude the need for invasive renal biopsies.

Glomerular spatial transcriptomics of IgA nephropathy according to the presence of mesangial proliferation

Mesangial proliferation is a diagnostic feature and a prognostic predictor of immunoglobulin A nephropathy (IgAN). We aimed to investigate the gene expression profiles of IgAN glomerulus according to the presence of mesangial proliferation. We performed spatial-specific transcriptomic profiling on kidney biopsy tissues using the GeoMx Digital Spatial Profiler. Twelve cases with three glomeruli for each case were profiled using direct pathologic classification (4 M1-IgAN, 4 M0-IgAN, and 4 donor controls). The results of enriched glom-specific genes demonstrated that M1-IgAN could be distinguished from controls (77 upregulated and 55 downregulated DEGs), while some DEGs were identified between M1-IgAN and M0-IgAN cases (24 upregulated and 8 downregulated DEGs) or between M0 and controls (1 upregulated and 16 downregulated DEGs). TCF21, an early podocyte damage marker, was the only differentially expressed gene (DEG) consistently upregulated in both M1-IgAN and M0-IgAN patients, whereas ATF3, EGR1, DUSP1, FOS, JUNB, KLF2, NR4A1, RHOB, and ZFP36 were consistently downregulated in IgAN cases. Glomeruli from M1-IgAN cases were significantly enriched for cell surface/adhesion molecules and gene expressions associated with vascular development or the extracellular matrix. Spatial transcriptomic analysis may contribute to dissecting structure-specific pathophysiology and molecular changes in IgAN.

Points of view in nephrology: personalized management of IgA nephropathy, beyond KDIGO.

IgA nephropathyis the most common primary glomerulonephritis worldwide, and an important cause of kidney failure, as 20-40% of patients progress to renal replacement therapy 20-30years after diagnosis. Its clinical presentation ranges from isolated microscopic hematuria to nephrotic syndrome, and even to a rapidly progressive course. Ethnicity and epigenetics play a key role in its clinical aggressiveness. Selection of patients at risk needing immunosuppressive treatment is a challenge for the nephrologist. Some active and chronic kidney lesions detected on kidney biopsy have been demonstrated to have prognostic value according to the Oxford Classification of IgA nephropathy, later validated by numerous studies. However, KDIGO 2021 guidelines still consider persistent proteinuria > 1g/24h to be the most relevant risk factor for the progression of IgA nephropathy and the only one requiring immunosuppressive treatment. KDIGO guidelines have proposed a therapeutic algorithm, but many patients present peculiar characteristics that are not addressed by the current guidelines, pointing to the need for alternative approaches. In these cases, a tailored approach to each patient should be followed in which clinical, histological, laboratory, social and ethical aspects must be considered. In this manuscript we present three cases of IgA nephropathy from different countries, highlighting many of the aspects encountered in clinical practice that illustrate an individualized approach to the treatment of these patients.

Molecular alterations of podocytes in primary focal segmental glomerulosclerosis and IgA nephropathy. (An exploratory study)

An evaluation of podocyte's molecular phenotype alterations in primary focal segmental glomerulosclerosis (pFSGS) and IgA nephropathy (IgAN). The exploratory study included 14 cases of morphologically confirmed pFSGS, 14 cases of IgAN, and 12 negative controls. The negative controls comprised samples of the unaltered renal cortex obtained during laparoscopic nephrectomy in patients with malignant neoplasms of the kidney and bladder and without proteinuria. A quantitative immunomorphological study of Wilms tumour protein (WT1) expression and mesenchymal markers of podocytes (desmin and vimentin) was conducted on all kidney samples. The co-expression of the aforementioned molecules was analysed using confocal microscopy. Cases of pFSGS exhibited nephrotic syndrome with proteinuria of 9.3 (3.1-14) g/24 and typical glomerular alterations in light microscopy and ultrastructural analysis. In the IgAN group, proteinuria was less severe (1.2 (0.7-1.6) g/24). The estimated glomerular filtration rate in pFSGS and IgAN was similar (pFSGS: 85 (53-103) ml/min/1.72 m², IgAN: 76 (52-87) ml/min/1.72 m²; p=0.40). In both pFSGS and IgAN, there was a reduction in WT1 expression in podocytes and an increase in vimentin expression when compared to negative controls. Compared to IgAN and controls, pFSGS exhibited a lower prevalence of glomerular WT1 expression and higher expression of desmin, which was predominantly localised in WT1-negative glomerular areas in confocal microscopy. In pFSGS, decreased nuclear expression of WT1 and increased expression of desmin were observed in the parietal epithelium of the glomerular capsule. Bidirectional alterations in the glomerular expression of WT1 and intermediate filament proteins are apparent in pFSGS and IgAN. These findings are suggestive for the genomic reprogramming of podocytes and the parietal epithelium of the glomerulus as part of the epithelial-mesenchymal transition, determining the structural and functional disorders of these cells, more prominent in pFSGS.

Urinary exosomal miRNA signature of IgA nephropathy: a case–control study

IgA nephropathy is the most common primary glomerulonephritis worldwide and can progress to end-stage kidney disease (ESKD). The current “gold standard” for diagnosis is kidney biopsy, which is invasive and associated with morbidity. miRNAs are small, non-coding endogenous RNA that may serve as non-invasive biomarkers, and that are found in urinary exosomes. Thus far, there is a paucity of studies of the miRNA profile for the diagnosis of IgA nephropathy. Hence, we aimed to study the urinary exosomal miRNA signature of Indian patients with IgA nephropathy. Fifty biopsy-proven IgA nephropathy patients, 50 healthy controls and 25 patients with ESKD (IgA nephropathy) were recruited over 2 years (2020–2022). Urinary exosomes were isolated from which miRNA was extracted . Analysis of urinary exosomal miRNA was done using the digital multiplexed nCounter® human v3 miRNA Expression Assay which contains 799 unique miRNA barcodes. Candidate miRNAs were identified using Lasso regression and consensus clustering. The mean age of IgA nephropathy patients was 36.32 ± 3.067 years, mean creatinine was 2.26 ± 0.318 mg/dl and mean proteinuria was 2.69 ± 0.64 g/day. Compared to healthy controls, the majority (N = 150) of miRNAs were significantly downregulated. Five candidate miRNAs (hsa.miR.146b.3p, hsa.miR.599, hsa.miR.4532, hsa.miR.664b.5p and hsa.miR.221.5p) were able to differentiate between IgA nephropathy cases and controls (AUC > 0.90); the presence of all 5 was associated with 100% specificity and sensitivity for diagnosing IgA nephropathy cases. This study of Indian patients identified that there was a significant difference in the urinary exosomal miRNA profile between IgA nephropathy cases and healthy controls, suggesting that miRNAs may be valuable in the non-invasive diagnosis of IgA nephropathy.

Colocalization of IgG and IgA Heavy Chains with Kappa and Lambda Light Chains in Glomerular Deposits of IgA Nephropathy Patients Using High-Resolution Confocal Microscopy and Correlation with Oxford MEST-C Scores

Routine immunofluorescence microscopy of glomerular immunodeposits in IgA nephropathy shows IgA, C3, and lambda light chains, and sometimes IgG, IgM, and kappa light chains. However, a previous study using high-resolution confocal microscopy showed IgG in all IgA nephropathy cases, likely representing autoantibodies specific for galactose-deficient IgA1. Here, we used high-resolution confocal microscopy to examine the composition of glomerular immunodeposits and colocalization of kappa and lambda light chains with IgA or IgG heavy chains in kidney-biopsy samples from twenty patients with IgA nephropathy, seventeen without IgG, and nine with no or trace kappa light chains by routine immunofluorescence microscopy. IgG was detected in all biopsies by high-resolution confocal microscopy. Single-optical-plane images showed similar colocalization of IgG heavy chains with kappa and lambda light chains. Colocalization of IgA heavy chains was greater with lambda light chains than with kappa light chains. Colocalization of IgG heavy chain with kappa light chains was higher than with lambda light chains in biopsies with endocapillary hypercellularity and crescents, i.e., biopsies with active lesions. We confirmed the utility of high-resolution confocal microscopy to detect components of glomerular immunodeposits not apparent on routine immunofluorescence microscopy and for colocalization of different components, potentially clarifying the pathogenesis of IgA nephropathy.

Two cases of IgA nephropathy after splenectomy: spleen as a silent culprit in the pathogenesis of IgA nephropathy.

Two cases of IgA nephropathy after splenectomy: spleen as a silent culprit in the pathogenesis of IgA nephropathy.

MTMR3 risk alleles enhance Toll Like Receptor 9-induced IgA immunity in IgA nephropathy

Multiple genome-wide association studies (GWASs) have reproducibly identified the MTMR3/HORMAD2/LIF/OSM locus to be associated with IgA nephropathy (IgAN). However, the causal variant(s), implicated gene(s), and altered mechanisms remain poorly understood. Here, we performed fine-mapping analyses based on GWAS datasets encompassing 2762 IgAN cases and 5803 control individuals, and identified rs4823074 as the candidate causal variant that intersects the MTMR3 promoter in B-lymphoblastoid cells. Mendelian randomization studies suggested the risk allele may modulate disease susceptibility by affecting serum IgA levels through increased MTMR3 expression. Consistently, elevated MTMR3 expression in peripheral blood mononuclear cells was observed in patients with IgAN. Further mechanistic studies invitro demonstrated that MTMR3 increased IgA production dependent upon its phosphatidylinositol 3-phosphate binding domain. Moreover, our study provided the invivo functional evidence that Mtmr3-/- mice exhibited defective Toll Like Receptor 9-induced IgA production, glomerular IgA deposition, as well as mesangial cell proliferation. RNA-seq and pathway analyses showed that MTMR3 deficiency resulted in an impaired intestinal immune network for IgA production. Thus, our results support the role of MTMR3 in IgAN pathogenesis by enhancing Toll Like Receptor 9-induced IgA immunity.

To evaluate the utility of Oxford classification in predicting renal outcome in IgA nephropathy patients.

Immunoglobulin A Nephropathy (IgAN) is a heterogeneous disorder. Multiple ethnicities conducted studies to assess the effectiveness of the Oxford classification of IgAN in prognostication. However, there is no study on the Pakistani population. We aim to identify its prognostic effectivity in our patients. We retrospectively reviewed the medical records of 93 biopsy-proven cases of primary IgAN. We collected the clinical and pathological data at baseline and on follow-ups. The median follow-up period was 12months. We defined the renal outcome as a ≥ 50% decline in eGFR or end-stage renal disease (ESRD). Of 93 cases, 67.7% were males with a median age of 29. Glomerulosclerosis was the most prevalent lesion (71%). The median MEST-C was 3. On follow-up, median serum creatinine worsened from 1.92 to 2.2mg/dL, and median proteinuria reduced from 2.3g/g to 1.072g/g. The reported renal outcome was 29%. T and C scores and MEST-C scores above 2 were significantly associated with pre-biopsy eGFR. On Kaplan-Meier analysis, the T and C scores' association was significant with the renal outcome (p-value 0.000 and 0.002). In univariate and multivariate analyses, the association of T-score (p-value 0.000, HR 4.691), total MEST-C score (p-value 0.019), and baseline serum creatinine (p-value 0.036, HR 1.188) were significant with the outcome. We validate the prognostic significance of the Oxford classification. T and C scores, baseline serum creatinine, and total MEST-C score significantly affect the renal outcome. Furthermore, we recommend the inclusion of the total MEST-C score in determining the IgAN prognosis.

Development of angiogenic periglomerular microvessels after acute glomerular lesions in IgA nephropathy.

To clarify the clinicopathological characteristics and role of periglomerular angiogenesis in IgA nephropathy. The renal biopsy specimens of 114 patients with IgA nephropathy were examined. Among them, 46 (40%) showed periglomerular angiogenesis around the glomeruli. CD34 and α-smooth muscle actin (α-SMA) staining in serial sections revealed that these vessels contained CD34+ α-SMA+ microarterioles along with CD34+ α-SMA- capillaries. We termed these "periglomerular microvessels (PGMVs)". Patients with PGMVs (PGMV group) had clinically and histologically more severe disease than those without PGMVs (non-PGMV group) at the time of biopsy. Even after adjusting for age, there were significant differences in the degree of proteinuria and estimated glomerular filtration rate reduction between the PGMV and non-PGMV groups. The PGMV group showed a higher incidence of segmental and global glomerulosclerosis and crescentic lesions than the non-PGMV group (P < 0.01). Here, PGMVs were undetectable in the acute and active inflammation phase, but were observed in the acute to chronic or chronic glomerular remodelling phase. PGMVs mainly developed around glomerular adherent lesions to the Bowman's capsule with small or minimal glomerular sclerotic lesions. Conversely, they were rarely observed in segmental sclerosis areas. The PGMV group is clinically and pathologically more severe than the non-PGMV group; however, they were undetectable in segmental sclerosis with mesangial matrix accumulation. PGMVs might occur after acute/active glomerular lesions, suggesting that PGMVs may inhibit segmental glomerulosclerosis progression and could be a marker for good repair response after acute/active glomerular injury in severe IgA nephropathy cases.

#5921 COMPLEMENT FACTOR H RELATED PROTEINS AND IGA NEPHROPATHY: CLINICAL CORRELATION

Abstract Background and Aims Complement Factor H (FH) function is modulated by their homologous FH related proteins (FHRs), which compete with FH for binding to certain ligands on plasma and on cellular surfaces. Genetic variants in the CFH-CFHRs region (coding for FH and the FHRs) confer susceptibility or protection to complement-mediated renal diseases, such as IgA nephropathy (IgAN). The CFHR3-CFHR1 deletion provides a strong protection against IgAN, while protein levels of FHR-1 and FHR-5 are higher in plasma samples from IgAN patients than in controls. The contribution of other FHR proteins to IgAN is so far unknown. The objective of this study is to determine the role of FH and FHR proteins in the renal progression of IgAN, and to establish whether plasma levels of these proteins could at least partially explain the heterogeneity observed in the patients. Method Plasma levels of FH, FHR-1, FHR-2, FHR-4A and FHR-5 was carried out in patients diagnosed with IgAN by renal biopsy (n = 45), and compared with a control group (n = 45). Protein levels observed in the IgAN patients were subsequently compared according to renal progression. Results Forty-five IgAN patients with a mean age of 46±18 years and 71% male were included. 15% of patients were hypertensive and 4% were diabetic. 90% had antiproteinuric treatment, and 44% immunosuppressive treatment. In renal biopsy according to Oxford classification: M1: 11,4%, E1:8,8%, S1:22%; T1:10,5%. The basal creatinine was 1.3 ± 0.47mg/dl (eFG 67; IQR 16-116 ml/min/1.73m2), and proteinuria (uPCR) 500 mg/g (IQR 30-3220). The patients were followed for a median of 83 months (IQR 0-111 months). Seven patients progressed, defined as a loss of &amp;gt;40% of glomerular filtration rate (GFR). FH and FHR-1 plasma levels were significantly higher in IgAN cases (FH: cases 2400±650 nM vs controls 1980±573 nM, p = 0.002), (FHR-1: cases 497±256 vs controls 379±152 nM; p = 0.011), but the patients had a lowest FH/FHR-1 ratio (FH/FHR-1 cases 5.4±2.58 vs controls 6.3±3.67, p = 0.061). The levels of FHR-2 and FHR-4A were also elevated in IgAN cases (FHR-2: cases 214±127 vs controls 132±71 nM, p&amp;lt;0.0001), (FHR-4A: cases 45±22 vs controls 31±14 nM, p&amp;lt;0.001), while no differences in FHR-5 levels were found (FHR-5: cases 25.7 ± 17 vs controls 27 ± 15, p = 0.7). When the patients who progressed and those who did not progressed were compared, it was observed that, as previously described, FHR-1 levels showed a tendency to be higher in progressing patients (566±333 vs 451±203 nM, p = 0.2), and a lower FH/FHR-1 ratio (4.1±2.4 vs 5.8±2.6, p = 0.1). Moreover, we also observed a similar trend in the other FHR proteins: (FHR-2: 304±106 vs 195 ±118 nM, p = 0.043); (FHR-4A: 53±26 vs 43±21, p = 0.29); (FHR-5: 41±35 vs 23±8.9 nM, p = 0.2). Conclusion We observed increased levels of several FHR proteins and FHRs/FH ratios in our IgAN cohort. We confirm that FHR-1 is implicated in renal progression, and we also show that other proteins of the family (FHR-2, FHR-4, and FHR-5) also contribute, suggesting that dysregulation of the alternative Complement pathway by FHR proteins is involved in IgAN. Genetic studies in the CFH-CFHR region may provide additional evidence to our protein findings.

The role of glomerular lesions in the prognosis of patients with acute kidney injury during hemorrhagic fever with renal syndrome

Objective This study aimed to explore the role of glomerular lesions in patients who suffered from acute kidney injury (AKI) during hemorrhagic fever with renal syndrome (HFRS). Methods The study comprised 66 patients with AKI during HFRS treated at the National Clinical Research Center of Kidney Diseases of China, Jinling Hospital, from January 2014 to December 2018. According to the kidney pathological findings, the 66 patients were divided into two groups: the tubulointerstitial injury group (HFRS-TI group, n = 43) and the tubulointerstitial injury with glomerular lesions group (HFRS-GL group, n = 23). The clinical and pathological characteristics of the 66 patients were analyzed. Results There were 9 cases of IgA nephropathy, 1 case of membranous nephropathy, 2 cases of diabetic nephropathy, and 11 cases of mesangial proliferative glomerulonephritis in the HFRS-GL group. There were more males in the HFRS-GL group than in the HFRS-TI group (92.3% vs. 69.8%, p < .05). A higher proportion of interstitial fibrosis (56.5% vs. 27.9%, p < .05) and more immunoglobulin and complement depositions (p < .001) were observed in the HFRS-GL group than in the HFRS-TI group. Rates of remission of AKI were lower in the HFRS-GL group than in the HFRS-TI group (73.9% vs. 95.3%, p < .05). The presence of glomerular lesions (HR = 5.636, 95% CI = 1.121–28.329, p = .036) and moderate tubulointerstitial injury (HR = 3.598, 95% CI = 1.278–10.125, p = .015) were found to be independent risk factors for kidney prognosis. Conclusions Patients with AKI during HFRS can have glomerular lesions or glomerulonephritis. Patients with AKI during HFRS who have glomerular lesions or moderate renal tubulointerstitial injury proven by kidney biopsy have a relatively poor kidney prognosis. A kidney biopsy can help determine long-term prognosis in patients with AKI during HFRS.

Gender-related differences in IgA nephropathy; an eleven-year experience according to revised Oxford classification

Introduction: IgA nephropathy (IgAN) is a common glomerular disease characterized by dominant or co-dominant granular IgA deposits in the glomerular mesangial areas. Objectives: This study aimed to determine the possible gender-related differences in IgAN at a single center in Iran. Patients and Methods: All renal biopsy-proven cases of IgAN during the last 11 years (2009-2020) were studied. All kidney biopsies had two samples for immunofluorescence and light microscopy. Renal biopsies were reviewed using the recently revised Oxford classification of IgAN. In addition to Oxford-MEST morphologic variables, other data consisting of age, gender, serum creatinine and level of proteinuria within 24 hours at the time of biopsy were collected. The data were analyzed in SPSS version 21.0. Results: This study included 246 biopsy-proven cases of IgAN patients with a mean age of 38.23±13.71 years and a male prevalence of 67.1% (n=161). The mean ± SD values of serum creatinine and 24-hour proteinuria were 1.47±1.06 mg/dL and 1753.63±1049.418 mg/d, respectively. Analysis regarding age, serum creatinine, the quantity of 24-hour proteinuria, the number of sclerotic glomeruli, and the percent of interstitial fibrosis showed only serum creatinine to be significantly higher in males than females (P=0.017). Moreover, 24-hour proteinuria was higher in males than females (P=0.047). Our study showed that males have more segmental sclerosis (P=0.023) and more significant IgM deposits than females (P=0.003). The mean scores of IgA, IgG, and C3 deposited immunological reactants were not substantially different between males and females (P&gt;0.05). Conclusion: Our study showed that serum creatinine and proteinuria were significantly higher in males. Males also had higher segmental sclerosis on biopsies. Larger-scale research is needed to confirm our results.