Progression Of IgA Nephropathy Research Articles

#1425 Anemia in patients with IgA nephropathy: an impact on the prognosis of IgA nephropathy

Abstract Background and Aims Immunoglobulin A Nephropathy (IgAN) has several well-known predictors of renal outcomes, including persistent proteinuria, hypertension, and baseline eGFR at the time of diagnosis. However, the effect of hemoglobin (Hb) levels on the progression of IgAN is rarely reported. This study aims to evaluate the impact of Hb levels on the prognosis of IgAN and to identify risk factors for anemia in patients with IgAN. Method A retrospective analysis of the data of 855 patients diagnosed with IgAN at Kyungpook National University Hospital between January 2002 and December 2021 was performed. We obtained the data on clinical parameters and pathological findings according to the Oxford classification at the time of the kidney biopsy. Univariate and multivariate logistic regression analyses were used to evaluate the risk factors for anemia, and a Cox proportional hazard model was used to estimate the effects of anemia on the development of end-stage kidney disease (ESKD). Results Lower serum albumin, lower eGFR, severe interstitial fibrosis, and tubular atrophy were associated with anemia in patients with IgAN. The Kaplan-Meier survival curve revealed that patients with anemia had worse renal survival than those without anemia. The multivariable Cox analysis showed that anemia was an independent risk for the progression to ESKD (HR 2.86, confidence interval 1.58–5.17, p = 0.001). In a sex-specific analysis, only the female sex showed a significant and higher risk for ESKD (hazard ratio 4.07, confidence interval 1.53–10.8, p = 0.005). Conclusion A low Hb level at the time of biopsy, even if subclinical, was an independent risk factor for the development of ESKD in patients with IgAN. Therefore, it is necessary to monitor Hb levels at the time of diagnosis and take proactive measures to reduce the risk of disease progression.

#2954 A comparative view of IgA nephropathy care across four global regions

Abstract Background and Aims IgA nephropathy (IgAN) is a chronic, rare, and slow progressing glomerular disease. IgAN treatment currently consists of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), sodium-glucose co-transporter 2 (SGLT2) inhibitors, corticosteroids, and recently approved Nefecon and sparsentan in select markets. This research compares approaches to IgAN treatment in four regions of the world. Method Data was collected in partnership with 730 nephrologists submitting chart data from 1,570 of their most recently seen IgAN patients to create a representative sample across the US, EU5 (UK, Germany, Italy, France, and Spain), Japan, and China via parallel online surveys in 2023. Results Regardless of their geographic location, audited patient charts revealed that hypertension, hyperlipidemia, obesity, and diabetes were the leading comorbid conditions among IgAN patients. Across the four regions evaluated, Japanese patients were the healthiest (44% have no comorbid conditions vs. 28% EU5, 25% China, 18% US) and Japanese nephrologists perceived 79% of their IgAN patients to be in “excellent” overall health. Comparatively, patients in the US had the highest calculated body mass index (28.2) and the most comorbid conditions reported. Audited records also revealed that patients in Japan and China were referred to nephrology care earlier in their CKD progression as measured by eGFR levels, with over 50% of patients referred to their current nephrologist in CKD Stages 1 or 2, compared to approximately 35% of patients in the US and EU5. Chinese nephrologists (59%) and those in the US (53%) were most likely to agree that it is easy to identify IgAN patients who are likely to have rapid progression (vs. 43% EU5 and 40% Japan). When treating their IgAN patients, Japanese nephrologists ordered labs on a more frequent basis compared to those in the US, EU5, and China and on average, Japanese patients had blood work and urinalysis labs conducted six times within the past twelve months (versus four in the other countries.) Most audited patients had a calculated annual eGFR decline of 1 ml/year or more. Chinese patients (77%) were most notable for their IgAN progression, while those in Japan were least likely to be progressing in their disease (41%). Due to its chronic nature, most IgAN patients will eventually need dialysis, and while still representative of the majority of their audited patients, US nephrologists projected the lowest percentage of IgAN patients to eventually progress to end stage renal disease (66% vs. 73% Japan, 75% EU5, and 85% China). Most participating nephrologists reported that they closely adhere to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines when treating their IgAN patients. Nearly all audited IgAN patients were on baseline therapy of ACE inhibitors or ARBs, while the uptake of SGLT2 inhibitors has been notable in China (44%), the US (43%), and EU5 (43%), with Japan (33%) trailing in current treatment rates. Meanwhile, the use of corticosteroid was also higher in patients in Japan (65%) and China (59%) compared to those in the EU5 (51%) and US (43%). Of note, tonsillectomies are frequently used as a treatment approach for IgAN patients in Japan, with 45% of patients having received the procedure, whereas this approach is used much less often in the other regions. Following a tonsillectomy, nearly all Japanese patients received a pulse of steroids, leading to higher overall corticosteroid use compared to other regions. At the time of fielding, Nefecon was available to prescribe in the US and Germany with 9% and 7% of patients currently on treatment, respectfully; however, sparsentan had not been approved in any regions. Conclusion The comparison of patient chart data across various regions reveals differences in perspectives and IgAN treatment approaches among nephrologists. Prognostic and predictive tools are available and utilized globally, but the reliability and correlation between results, lab values, and disease progression calls for better education and alignment of global treatment guidelines.

#2983 Correlation of microRNA expression with IgA nephropathy progression: preliminary results

Abstract Background and Aims IgA nephropathy (IgAN) is the most common cause of glomerulonephritis worldwide. IgAN is diagnosed based on the result of histopathological examination. The risk factors for disease progression primarily include the level of impairment of renal function at the time of diagnosis (GFR < 60 ml/min/1.73 m2), the presence of hypertension, daily administration of more than 1.0 g, and the occurrence of hematuria. MicroRNAs (miRNAs) are important regulators of gene expression. Their role has a significant impact on the proper functioning of the body, and disorders related to their expression can lead to the development of many pathological processes in the body. The study aimed to assess the dependence of microRNA expression on the stage of the disease in patients with IgA nephropathy. Method A study was conducted involving patients newly diagnosed with IgA nephropathy based on histopathological examination results. The expression of microRNA molecules (miR-146a, miR-155, miR-200b, miR-429) was determined in urine sediment and blood. The analysis focused on examining the relationship between microRNA expression and the stage of disease progression (proteinuria, renal parameters). Blood and urine tests were performed before the start of immunosuppressive treatment with glucocorticosteroids according to the Pozzi regimen. Results Twenty-seven patients were included in the study group- 14 women (51.9%) and 13 men (48.1%). Nephrotic-range proteinuria (>3000 mg/24 h) was observed in 5 patients (18.5%), while subnephrotic proteinuria was present in 22 patients (77.8%). Reserved kidney function (eGFR > 90) was found in 17 patients (63%). The exact distribution of results according to the stage of renal failure is given in the Table 1. Statistically significant positive correlation was found between serum creatinine concentration and miR-200b expression in urine (R = 0,398, p = 0,049). Initially, no statistically significant correlation was found between the expression of selected miRNA molecules and the degree of 24-hour proteinuria. Conclusion MiRNA molecules may be promising, non-invasive biomarkers widely used in clinical practice. Determining the viability of clinical use of microRNA molecules will require a panel of miRNAs or miRNAs used in combination with other biomarkers and clinical outcomes to improve diagnostic utility.

#388 IONIS-FB-LRx, an antisense oligonucleotide to complement factor B for treatment of IgA nephropathy

Abstract Background and Aims Pathogenesis of IgA nephropathy (IgAN) is known to be dependent upon multiple factors, one being the complement system. Since overactivity of the complement Alternative Pathway (AP) has been proposed to contribute to pathogenesis of IgAN, it has been hypothesized that a reduction of AP activity would improve proteinuria. IONIS-FB-LRx, (ISIS696844, RO7434656), is an investigational antisense oligonucleotide targeting complement factor B (CFB) mRNA and reduces CFB production in the liver. We have previously demonstrated that administration of IONIS-FB-LRx lowered the production of CFB, a required component of the AP, and led to reduction of AP and reduction in proteinuria in IgAN patients (2023 ASN Abstract#SA-PO926, N = 13 patients). Current abstract provides an update to our previous report extending results to 19 patients treated with IONIS-FB-LRx. Method An exploratory, single-arm, multi-national open-label Ph2 study (NCT04014335) recruited patients with biopsy-confirmed IgAN, proteinuria >1.5 g/d, eGFR >40 mL/min/1.73 m2, and hematuria despite maximum tolerated RAAS blockade and/or stable dose of SGLT-2 inhibitor for a minimum of 6 months. Study drug was administered at Weeks 1, 3, and 5, and then every 4 weeks through Week 25 (Cohort A) and at Week 1 and then every 4 weeks through Week 25 (Cohort B). Primary outcome was change in 24-hr proteinuria at Week 29 (4 weeks after last dose) compared to baseline (BL). Results 19 patients have completed study to date (13Nov2023), 25-62 yr, 42% Female, 11 Asian, and 8 White. Median 24-hr UPCR at BL was 1.56 g/g (IQR 1.23, 2.33 g/g). At Week 29, a 45% geometric mean ratio reduction was observed. There was little change in eGFR at Week 29 compared to BL (mean ± SD; BL 72 ± 22; Week 29 74.6 ± 20 mL/min/1.73 m2). The drug demonstrated an acceptable safety profile with no Treatment Emergent SAEs; the only clinically meaningful laboratory finding was reversible and transient ALT elevation without a change in bilirubin. All patients completed the study and one patient discontinued study drug after 4 months to initiate SGLT-2 inhibitors. That patient experienced a 38% reduction in 24-hr UPCR collected 3 weeks (Week 27) after the last dose of IONIS-FB-LRx, but prior to use of SGLT-2 inhibitors. Conclusion This Ph2 open-label study provides continuing clinical evidence that IONIS-FB-LRx reduces complement levels and proteinuria in patients with IgAN, supporting Ph3 development (NCT05797610) to determine the potential of IONIS-FB-LRx to reduce the progression of IgAN.

#1968 IgA nephropathy and impact of proteinuria and kidney function decline on healthcare resource utilisation among adults in the United Kingdom

Abstract Background and Aims Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis and can result in kidney failure, especially if left untreated. Proteinuria ≥1.0 g/day is a major risk factor for IgAN progression and rapid kidney function decline. This study describes the characteristics of patients with IgAN in the United Kingdom (UK) and the impact of proteinuria and chronic kidney disease (CKD) stage on healthcare resource utilisation (HRU) and costs. Method In this retrospective, descriptive analysis, eligible patients had at least one code among ICD-9 583.9, ICD-10 N02.8, and ICD-10 N02.9 between 1 October 2015 and 1 October 2022. They were stratified by CKD stage and proteinuria level. CKD stage was defined by ICD-10 N18 code and estimated glomerular filtration rate. Proteinuria level was grouped as low or high by protein excretion rate (<1 g/day vs ≥1 g/day), protein/creatinine ratio (<0.88 g/g vs ≥0.88 g/g), or albumin/creatinine ratio (<100 mg/mmol vs ≥100 mg/mmol). HRU data for 1 year from the index date were obtained from electronic medical records, and costs were obtained from the National Schedule of the National Health Service 2021/22. Weighted average costs were calculated for inpatient, outpatient, and emergency visits. Results We identified 6 940 patients with IgAN. The mean age was 62 years, and most patients (n = 3 980; 57%) were male. For all visit types, HRU (Fig.) and costs (Table) increased with advancing CKD. For all visit types combined, the mean total cost per patient was >23 times higher for CKD stage 5 than stage 1 (£60 259 vs £2 609). Of 2 080 patients with proteinuria data, 560 (27%) had high proteinuria. Annual costs per patient (Table) and the numbers of all visit types (Figure) were higher for patients with a protein excretion rate ≥1 g/day than those with a rate <1 g/day (£12 622 vs £2 822). Conclusion In patients with IgAN in the UK, elevated proteinuria and advanced CKD stage were associated with higher HRU and costs across visit types. Treatments that reduce proteinuria can slow disease progression and prevent rapid decline in kidney function while potentially reducing IgAN-related resource utilisation and costs.

#1339 The characteristic of memory B-cell subsets in patients with IgA-nephropathy

Abstract Background and Aims Impaired B-cell development has been postulated to play an important role in the maintaining of autoimmune inflammation what makes memory B-cells a perspective target for a new therapeutic strategy in IgA-nephropathy (IgAN). However, to date there are few and controversial data about the precise role of circulating memory B-cell subsets in clinical progression of IgAN. The aim was to estimate the immunological profile of memory B-cell subpopulations in the peripheral blood of IgAN patients. Method The peripheral blood was obtained from 20 IgAN patients (aged of 32.0 (27.0-36.0) y.o., male/female ratio as 13/7) and 15 donors (aged of 38.0 (30.0-46.0) y.o., male/female ratio as 10/5). The diagnosis was confirmed by morphological examination of the biopsy material. The phenotype of B-cells subsets was determined by a panel of CD38-PE/CD19-ECD/CD27-PC5/IgD-APC antibodies; γδT-lymphocytes—by a panel of TCRγδ-FITC/TCRαβ-PE/HLA-DR-ECD/TCRVδ1-PC7/CD3-APC-A750/TCRVδ2-PB/ CD45-KRO antibodies using flow cytometry method (Cytoflex, Beckman Coulter, USA). The concentration of B-cell activating factor (BAFF) was measured using enzyme-linked immunosorbent assay. Statistical data processing was done in Statistica 10.0 program. Results Based on cell surface markers expression the following B-cells subsets were identified in the peripheral blood: naïve B-cells (CD19+CD27−IgD+), pre-switched B-cells (CD19+CD27+IgD+), switched B-cells (CD19+CD27+IgD−), plasmablasts (CD19+CD27+CD38+) and long-lived plasma cells (CD27hiCD38hi) (Fig. 1). The altered balance in B-cells maturation characterizing by a significant lower percent of pre-switched B-cells and plasmablasts (p < 0.05) as well as a higher trend (>55%) in the naive B-cells (p < 0.01) was established in IgAN patients as compared to healthy donors reflecting the exhaustion of peripheral blood plasmablasts due to constant generation of antibody-producing plasma cells. Moreover, the lower pre-switched B-cells percentage was detected in the blood, the more BAFF production was observed in serum of IgAN patients (R = 0.50; p < 0.05) and the higher proteinuria level was detected (R = 0.47; p < 0.05). The increased total number of γδТ-cells up to 9.42 (6.25-12.44)% in IgAN patients as compared to donors (p = 0.03) was correlated with total memory CD19+CD27+B-cells numbers (R = 0.54; p < 0.05) as well as pre-switched B-cells (R = 0.45; p < 0.05), plasmablasts (R = 0.57; p < 0.01) and long-lived plasma cells (R = 0.51; p < 0.05). A detailed subsets analysis revealed an elevated level of tissue-resident mucosa-associated cells (Vδ1+ and Vδ3+T-lymphocytes) as well as enhanced HLA-DR expression on them (p < 0.05) in combination with decreased normally circulating Vδ2+T-cells numbers (p < 0.01) as compared to healthy donors what characterized Vδ1+ and Vδ3+T-cells subsets as professional antigen presenting cells and indicated their possible role in the priming of antigen specific B-cells. Conclusion Suggesting that most peripheral B-lymphocytes are naïve, the obtained data may reflect a γδT-cells role in migration of pre-switched B-cells from the circulation to mucosa sites for possible further maturation and class-switching what allows us to consider these two parameters as potential useful biomarkers of IgAN disease prognosis in clinical practice.

#2663 Assessment of in situ alternative and classical convertases as indicators of ongoing glomerular complement activation in IgA nephropathy

Abstract Background and Aims Complement activation is involved in IgA nephropathy (IgAN), opening up new avenues for complement-targeting therapies. However, precise patient selection and optimal timing for these therapies are essential. Current diagnostic methods of complement activation in IgAN, based on immunostaining, lack precision in identifying specific pathway(s) involved and distinguishing ongoing from past complement activation. Method Complement deposition analysis was conducted on kidney biopsy samples from 53 patients with primary IgAN at diagnosis (NCT05234463). Glomerular complement deposition was assessed through immunohistochemistry for C4d and C5b-9 and immunofluorescence for C3b/iC3b and C1q. In situ detection of C3/C5 convertases complexes from complement classical/lectin (C4b2b) and alternative pathways (C3bBb) was performed on paraffin-embedded kidney biopsies from 33 patients using a proximity ligation assay (Duolink®, Sigma). Kidney biopsies from patients with lupus nephritis (LN) and C3 glomerulopathy (C3G) were used as positive controls for classical/lectin and alternative convertases staining, respectively. The signals corresponding to the convertases were quantified using QuPath® Software and correlated with clinical parameters, MEST-C score and C5b-9 staining. Results At diagnosis, all 53 IgAN patients (100%) exhibited C3 mesangial deposition. Additionally, 51.2% were positive for C4d, 16.5% had C1q deposition and 62.7% had C5b-9 deposition. In situ analysis of C3/C5 convertases revealed the presence of glomerular C3bBb convertases in 20/33 (60.6%) patients, with a median positive area of 14.9 [2.5-26.5]%o of glomerular surface. C4b2b convertases were detected in 21/33 patients (63.6%), with a median glomerular positive area of 8.1 [3.4-12.1]%o. Both C3bBb and C4b2b convertases were detected in 13/33 (39.4%) patients (Fig. 1). By contrast, no convertases were detected in 5/33 (15.2%) patients despite positive C3b/iC3b deposition. The intensity of C3bBb staining positively correlated with terminal pathway C5b-9 glomerular deposits (p = 0.0011, r2 0.29). Patients with MEST-C score S1 lesions and/or interstitial fibrosis/tubular atrophy (T1-2) exhibited a more pronounced intensity of C3bBb at diagnosis (p = 0.0093). Conclusion Our study, for the first time, presents evidence of ongoing complement activation at the tissue level in IgA nephropathy (IgAN), showing variable intensities among patients. The visualization of in situ C3/C5 convertases could enhance the functional aspect of pathological examination, helping identify patients with ongoing complement activation, making them potential candidates for complement inhibitors. Further research is necessary to investigate the kinetics of this staining over the natural course of IgAN and its implications for IgAN progression.

Cross-species single-cell analysis uncovers the immunopathological mechanisms associated with IgA nephropathy progression.

IgA nephropathy (IgAN) represents the main cause of renal failure, while the precise pathogenetic mechanisms have not been fully determined. Herein, we conducted a cross-species single-cell survey on human IgAN and mouse and rat IgAN models to explore the pathogenic programs. Cross-species single-cell RNA sequencing (scRNA-Seq) revealed that the IgAN mesangial cells (MCs) expressed high levels of inflammatory signatures CXCL12, CCL2, CSF1, and IL-34 and specifically interacted with IgAN macrophages via the CXCL12/CXCR4, CSF1/IL-34/CSF1 receptor, and integrin subunit alpha X/integrin subunit alpha M/complement C3 (C3) axes. IgAN macrophages expressed high levels of CXCR4, PDGFB, triggering receptor expressed on myeloid cells 2, TNF, and C3, and the trajectory analysis suggested that these cells derived from the differentiation of infiltrating blood monocytes. Additionally, protein profiling of 21 progression and 28 nonprogression IgAN samples revealed that proteins CXCL12, C3, mannose receptor C-type 1, and CD163 were negatively correlated with estimated glomerular filtration rate (eGFR) value and poor prognosis (30% eGFR as composite end point). Last, a functional experiment revealed that specific blockade of the Cxcl12/Cxcr4 pathway substantially attenuated the glomerulus and tubule inflammatory injury, fibrosis, and renal function decline in the mouse IgAN model. This study provides insights into IgAN progression and may aid in the refinement of IgAN diagnosis and the optimization of treatment strategies.

390 Chronic kidney disease (CKD) stage progression in IgA nephropathy (IgAN): A retrospective linked electronic medical record (EMR) and claims analysis

390 Chronic kidney disease (CKD) stage progression in IgA nephropathy (IgAN): A retrospective linked electronic medical record (EMR) and claims analysis

Efficacy and safety of biologic agents for IgA nephropathy: A protocol for systematic review and meta-analysis.

IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis worldwide and a leading cause of chronic kidney failure. There are currently no definitive therapeutic regimens to treat or prevent the progression of IgAN. However, biologic agents offer novel therapeutic approaches that target immunological mechanisms to slow or halt disease progression. The objective of this study is to evaluate the efficacy and safety of biologic agents in patients with IgA nephropathy. We will systematically search PubMed, EMbase, Web of Science, Cochrane Library, and www.clinicaltrials.gov for randomized controlled trials of biologic agents for the treatment of IgA nephropathy. The search period will span from the establishment of each database until October 2023. The quality assessment of included studies will be performed individually using the revised Cochrane risk-of-bias tool for randomized trials (RoB 2), and meta-analysis will be conducted using Revman 5.4.1 software. The results of this study will provide evidence-based medical evidence for the clinical application of biologic agents in patients with IgA nephropathy. CRD42023400450.

Circulating soluble CD30 is associated with renal tertiary lymphoid structures and the progression of IgA nephropathy

BackgroundRenal tertiary lymphoid structures (TLSs) are involved in renal pathology and prognosis of IgA nephropathy (IgAN). CD30 and its ligands participate in the formation of renal TLSs. However, the relationship between circulating CD30 and renal prognosis is unclear. The objective of this study was to evaluate the relationship between circulating CD30 and prognosis in patients with IgAN. MethodsWe conducted a retrospective study including 351 patients with biopsy proved IgAN. We collected clinical and pathologic features at the time of biopsy and recorded renal follow-up outcomes. Circulating CD30 levels in IgAN patients at the time of biopsy were measured via enzyme-linked immunosorbent assay (ELISA). The association between elevated CD30 levels and the composite endpoint (defined as a ≥ 50 % decline in eGFR from baseline, end-stage renal disease, or death) was investigated using Cox regression analysis. ResultsDuring a median follow-up period of 5.12 years, 44 (12.5 %) patients in the cohort reached the composite endpoint. Kaplan-Meier survival curve analysis revealed a significant association between higher circulating CD30 levels and a poorer renal prognosis (log-rank P < 0.001). Cox regression analysis showed that high CD30 was an independent factor for the composite endpoints in multivariable-adjusted models (HR 3.397, 95 % CI: 1.230–9.384, P = 0.018). These associations were also observed in a subgroup of patients with concomitant renal TLSs formation (10.443, 95 % CI: 1.680–65.545, P = 0.012), proteinuria > 1 g/d (HR 12.287, 95 % CI: 1.499–100.711, P = 0.019), and female patients (HR 22.372, 95 % CI: 1.797–278.520, P = 0.016). ConclusionElevated level of circulating CD30 is an independent risk factor for renal disease progression in patients with IgAN.

Glomerular IgG deposition predicts kidney disease progression in IgA nephropathy

ObjectiveWe aimed to explore the relationship between the presence and intensity of glomerular IgG deposition and the occurrence of kidney progression events in IgA nephropathy (IgAN). MethodsThis retrospective study encompassed a total of 1207 patients with IgAN spanning the period from 2010 to 2022, and complete follow-up data were accessible for 736 patients. The IgG intensity was categorized as follows: low-level, defined as IgG (±) and IgG (+), and high-level, defined as IgG (++) and IgG (+++). ResultsWe found that the IgG-positive deposited group (N = 113, 9.36%) had significantly higher levels of ESR, TC, LDL, uric acid, proteinuria, and blood glucose, and lower serum albumin level compared to the IgG-negative deposited group (N = 1094, 90.64%). In terms of pathology, the IgG-positive deposited group had a significantly higher percentage of T2 score compared to the IgG-negative deposited group (p = 0.002). At the end of the follow-up period, the IgG-positive deposited group had a higher eGFR decline (−5.7 ± 4.37 ml/year) compared to the IgG-negative deposited group (−4 ± 2.52 ml/year), however, there was not a statistically significant difference between the two groups (p = 0.096). We observed that the high-IgG group had significantly higher level of TG compared to the low-IgG group (p = 0.042). Further analysis revealed that the group of patients with high level of IgG deposition in the kidney experienced a higher incidence of composite kidney outcomes compared to the group with low level of IgG deposition (p = 0.009). Logistic regression analyses showed that high level IgG deposition was an independent risk factor for kidney progression of IgAN (HR 13.419; 95% CI 2.690–66.943, P = 0.029). Further analyses for a solid conclusion using Cox regression that we found high level IgG deposition (HR 115.277; 95% CI 2.299–5.779E3, P = 0.017), eGFR (HR 0.932; 95% CI 0.870–0.999, P = 0.047), and urine protein excretion (HR 1.001; 95% CI 1.000–1.002, P = 0.015) were independent risk factor for kidney progression of IgAN. ConclusionsThe intensity of IgG deposition has been found to be associated with the progression of IgAN. Future prospective studies should provide more robust evidence on the impact of IgG deposition on kidney outcomes in patients with IgAN.

Urinary C4d and progression of kidney disease in IgA vasculitis.

IgA vasculitis nephritis is the most common secondary IgA nephropathy. Urinary C4d have been identified associated with the development and progression in primary IgA nephropathy. However, its role in kidney disease progression of IgA vasculitis nephritis is still unclear. This study enrolled 139 patients with IgA vasculitis nephritis (IgAVN), 18 healthy subjects, 23 Focal segmental glomerulosclerosis patients and 38 IgA nephropathy (IgAN) patients. Urinary C4d levels at kidney biopsy were measured using enzyme-linked immunosorbent assay. The association between urinary C4d/creatinine and kidney disease progression event, defined as 40% eGFR decline or ESKD, was assessed using Cox proportional hazards models and restricted cubic splines. The levels of urinary C4d/creatinine in IgAVN and IgAN patients were higher than in healthy controls. Higher levels of urinary C4d/creatinine were associated with higher proteinuria and severe Oxford C lesions and glomerular C4d deposition. After a median follow-up of 52.79 months, 18 (12.95%) participants reached composite kidney disease progression event. The risk of kidney disease progression event was higher with higher levels of ln (urinary C4d/creatinine). After adjustment for clinical data, higher levels of urinary C4d/creatinine were associated with kidney disease progression in IgA vasculitis nephritis (per ln transformed urinary C4d/creatinine, hazard ratio (HR) =1.573, 95% confidence interval (CI) 1.101-2.245; P=0.013). Compared to the lower C4d/creatinine group, hazard ratio was 5.539(95%CI, 1.135-27.035; P=0.034) for the higher levels group. Higher levels of urinary C4d/creatinine were associated with kidney disease progression event in patients IgAVN.

Urinary miR-185-5p is a biomarker of renal tubulointerstitial fibrosis in IgA nephropathy.

For IgA nephropathy (IgAN), tubular atrophy/interstitial fibrosis is the most important prognostic pathological indicator in the mesangial and endocapillary hypercellularity, segmental sclerosis, interstitial fibrosis/tubular atrophy, and presence of crescents (MEST-C) score. The identification of non-invasive biomarkers for tubular atrophy/interstitial fibrosis would aid clinical monitoring of IgAN progression and improve patient prognosis. The study included 188 patients with primary IgAN in separate confirmation and validation cohorts. The associations of miR-92a-3p, miR-425-5p, and miR-185-5p with renal histopathological lesions and prognosis were explored using Spearman correlation analysis and Kaplan-Meier survival curves. Bioinformatics analysis and dual luciferase experiments were used to identify hub genes for miR-185-5p. The fibrotic phenotypes of tubular epithelial cells were evaluated in vivo and in HK-2 cells. miRNA sequencing and cohort validation revealed that the expression levels of miR-92a-3p, miR-425-5p, and miR-185-5p in urine were significantly increased among patients with IgAN; these levels could predict the extent of tubular atrophy/interstitial fibrosis in such patients. The combination of the three biomarkers resulted in an area under the receiver operating characteristic curve of 0.742. The renal prognosis was significantly worse in the miR-185-5p high expression group than in the low expression group (P=0.003). Renal tissue in situ hybridization, bioinformatics analysis, and dual luciferase experiments confirmed that miR-185-5p affects prognosis in patients with IgAN mainly by influencing expression of the target gene tight junction protein 1 (TJP1) in renal tubular epithelial cells. In vitro experiment revealed that an miR-185-5p mimic could reduce TJP1 expression in HK-2 cells, while increasing the levels of α-smooth muscle actin, fibronectin, collagen I, and collagen III; these changes promoted the transformation of renal tubular epithelial cells to a fibrotic phenotype. An miR-185-5p inhibitor can reverse the fibrotic phenotype in renal tubular epithelial cells. In a unilateral ureteral obstruction model, the inhibition of miR-185-5p expression alleviated tubular atrophy/interstitial fibrosis. Urinary miR-185-5p, a non-invasive biomarker of tubular atrophy/interstitial fibrosis in IgAN, may promote the transformation of renal tubular epithelial cells to a fibrotic phenotype via TJP1.

Identification of inflammatory biomarkers in IgA nephropathy using the NanoString technology: a validation study in Caucasians

Objective and designImmunoglobulin A nephropathy (IgAN) is a kidney disease characterized by the accumulation of IgA deposits in the glomeruli of the kidney, leading to inflammation and damage to the kidney. The inflammatory markers involved in IgAN remain to be defined. Gene expression analysis platforms, such as the NanoString nCounter system, are promising screening and diagnostic tools, especially in oncology. Still, their role as a diagnostic and prognostic tool in IgAN remains scarce. In this study, we aimed to validate the use of NanoString technology to identify potential inflammatory biomarkers involved in the progression of IgAN.SubjectsA total of 30 patients with biopsy-proven IgAN and 7 cases of antineutrophil cytoplasmic antibody (ANCA)-associated pauci-immune glomerulonephritis were included for gene expression measurement. For the immunofluorescence validation experiments, a total of 6 IgAN patients and 3 controls were included.MethodsTotal RNA was extracted from formalin-fixed paraffin-embedded kidney biopsy specimens, and a customized 48-plex human gene CodeSet was used to study 29 genes implicated in different biological pathways. Comparisons in gene expression were made between IgAN and ANCA-associated pauci-immune glomerulonephritis patients to delineate an expression profile specific to IgAN. Gene expression was compared between patients with low and moderate risk of progression. Genes for which RNA expression was associated with disease progression were analyzed for protein expression by immunofluorescence and compared with controls.ResultsIgAN patients had a distinct gene expression profile with decreased expression in genes IL-6, INFG, and C1QB compared to ANCA patients. C3 and TNFRSF1B were identified as potential biomarkers for IgAN progression in patients early in their disease course. Protein expression for those 2 candidate genes was upregulated in IgAN patients compared to controls. Expression of genes implicated in fibrosis (PTEN, CASPASE 3, TGM2, TGFB1, IL2, and TNFRSF1B) was more pronounced in IgAN patients with severe fibrosis compared to those with none.ConclusionsOur findings validate our NanoString mRNA profiling by examining protein expression levels of two candidate genes, C3 and TNFRSF1B, in IgAN patients and controls. We also identified several upregulated mRNA transcripts implicated in the development of fibrosis that may be considered fibrotic markers within IgAN patients.

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.

Hepatitis B Virus Status and Clinical Outcomes in IgA Nephropathy

Immunoglobulin A nephropathy (IgAN) has been reported to coexist with hepatitis B virus (HBV) infection. Despite the clinical significance of this association, there is a lack of comprehensive research investigating the impact of various common conditions following HBV infection and the potential influence of anti-HBV therapy on the progression of IgAN. We investigated 3 distinct states of HBV infection, including chronic HBV infection, resolved HBV infection, and the deposition of hepatitis B antigens in renal tissue, in a follow-up database of 1961 patients with IgAN. IgAN progression was defined as a loss of estimated glomerular filtration rate (eGFR) >40%. Multivariable cause-specific hazards models to analyze the relationship between HBV states and IgAN progression. Chronic HBV infection was identified as an independent risk factor for IgAN progression, supported by both prematching analysis (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.06-2.44; P= 0.024) and propensity-score matching analysis (HR, 1.74; 95% CI 1.28-2.37; P< 0.001). Conversely, resolved HBV infection showed no significant association with IgAN progression (HR, 1.01; 95% CI 0.67-1.52; P= 0.969). Moreover, the presence of HBV deposition in the kidneys and the utilization of anti-HBV therapy did not appear to be significant risk factors for renal outcomes (P > 0.05). Chronic HBV infection is an independent risk factor for IgAN progression, whereas resolved HBV infection is not. In patients with IgAN, management of concurrent chronic HBV infection should be enhanced. The presence of HBV deposition in the kidneys and the use of anti-HBV medications do not impact the kidney disease progression in patients with IgAN with concurrent HBV infection.

Association between urinary C4d levels and disease progression in IgA nephropathy.

C4d mesangial deposition, a hallmark of lectin pathway activation in IgA nephropathy (IgAN), has been shown to be associated with risk of kidney failure. To date, the relationship between urinary C4d and renal outcome remain unelucidated. A total of 508 patients with biopsy-proven IgAN were enrolled in this study, whose baseline urine samples at the time of biopsy were collected and the levels of urinary C4d were quantified by enzyme-linked immunosorbent assay. The time-averaged C4d (TA-C4d) and the change in proteinuria were measured in sequential urine samples obtained from IgAN patients. The kidney progression event was defined as a 50% estimated glomerular filtration rate (eGFR) decline or end-stage kidney disease (ESKD) or death. After a median follow-up of 36 months, 70 (13.8%) of the participants reached the kidney progression event. Higher levels of urinary C4d/creatinine were found to be associated with decreased eGFR, massive proteinuria, lower serum albumin levels, hypertension, and severe Oxford E and T scores. Upon adjusting for traditional risk factors (including demographics, eGFR, proteinuria, hypertension, Oxford pathologic score, and immunosuppressive therapy), elevated levels of urinary C4d/creatinine were independently associated with an increased risk of CKD progression (adjusted HR per standard deviation increment of log-transformed C4d/creatinine: 1.46; 95% CI: 1.04 to 2.06; P=0.030). In reference to the low C4d group, the risk of poor renal outcome increased for the high C4d group (adjusted HR: 1.93; 95% CI: 1.05 to 3.54; P=0.033). Additionally, a low baseline C4d level was independently assosicated with a favorable proteinuria response to immunosuppressive therapy at three months (adjusted relative risk: 2.20; 95% CI: 1.04-4.63, P=0.038). The urinary C4d, serving as a non-invasive biomarker, is associated with the progression of IgAN and holds the potential to predict proteinuria response in this disease.

Association of time-averaged serum uric acid level with clinicopathological information and long-term outcomes in patients with IgA nephropathy.

Whether serum uric acid (SUA) at baseline could been identiûed as a risk factor for progression in IgA nephropathy (IgAN) patients remains unclear, therefore, long- term SUA control levels must be monitored. We aimed to investigate the relevant factors affecting time-averaged SUA (TA-SUA) and to assess the prognostic value of TA-SUA in IgAN. This retrospective study included 152 patients with IgAN. The relationships between TA-SUA and clinicopathological features and renal outcomes (defined as the doubling of the baseline serum creatinine level or end-stage renal disease) were analyzed in groups divided by quartiles of TA-SUA levels, the presence of hyperuricemia, and sex. Patients with high TA-SUA levels had higher levels of baseline SUA, blood urea nitrogen (BUN), triglycerides, serum C3 and serum C4 and were more likely to be male and have hypertension, proteinuria, poor renal function, and pathological injuries including high grades of tubular atrophy/interstitial fibrosis (T1-T2). These patients had a poorer prognosis compared with patients with low TA-SUA levels. The TA-SUA level was positively correlated with baseline age and BUN, triglycerides, serum C3, and serum C4 levels, and negatively correlated with baseline eGFR. Survival curve analysis indicated that persistent hyperuricemia was associated with significantly poorer renal outcomes than normo-uricemia in both men and women. The TA-SUA level also was an independent predictor of renal outcome in patients with IgAN, with optimal cutoû values of 451.38 µmol/L (area under the curve (AUC) = 0.934) for men and 492.83 µmol/L (AUC = 0.768) for women. The TA-SUA level is associated with triglyceride level, complement component levels, renal function, and pathological severity of IgAN, and it may be a prognostic indicator in male and female patients with IgAN.

Accelerated involution of germinal center in palatine tonsils in IgA nephropathy.

Altered immunological responses in the palatine tonsils may be involved in the pathogenesis of IgA nephropathy (IgAN). The germinal center serves as the site for antigen-specific humoral immune responses in the palatine tonsils. Germinal center involution is frequently observed in the palatine tonsils of IgAN (IgAN tonsils). However, the pathogenic significance of these characteristic changes remains unclear. This study aimed to investigate the morphological changes in secondary lymphoid follicles in IgAN tonsils and to evaluate the correlation between the morphometric results and the clinicopathological severity of IgAN. The tonsils of age-matched patients with recurrent tonsillitis (RT tonsils) were used as controls. The correlation between the degree of lymphoid follicular involution and histopathological severities in clinical or kidney biopsy was evaluated. In total, 87 patients with IgAN were included (48% male, median age 35 years, median estimated glomerular filtration rate: 74 mL/min/1.73 m2). Compared to RT tonsils, IgAN tonsils showed smaller median sizes of lymphoid follicles and germinal centers (P < 0.001). The relative areas of lymphoid follicles (%LFA) and germinal centers (%GCA) in the total tonsillar tissue were smaller in the IgAN tonsils than in the RT tonsils (P < 0.001). In contrast, the median proportion of mantle zones in the total tonsillar tissue was comparable between the groups. A lower %LFA was associated with a longer period from the onset of urinary abnormalities to biopsy diagnosis and higher urinary protein excretion (P = 0.01). %LFA showed significant negative correlations with frequencies of glomeruli with both global and segmental sclerosis. The present study confirmed accelerated germinal center involution in the tonsils of patients with IgAN. This characteristic change in the IgAN tonsil correlates with heavy proteinuria and advanced chronic histopathological changes in the kidneys, thereby suggesting the involvement of repeated tonsillar immunoreactions during IgAN progression.