POS-380 A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF ATRASENTAN IN PATIENTS WITH IGA NEPHROPATHY (THE ALIGN STUDY)

Background and Aims IgA nephropathy (IgAN) is the most common primary glomerulonephritis globally and an important cause of chronic kidney disease (CKD). Up to 40% of IgAN patients are at risk of progressing to end-stage kidney disease (ESKD) and proteinuria is the strongest predictor of progression. There are no approved therapies for IgAN, leaving an important need for new strategies to lower proteinuria and preserve kidney function in high-risk patients. Endothelin A (ETA) receptor activation drives proteinuria, along with kidney inflammation and fibrosis. Atrasentan, a potent and selective ETA antagonist, has been studied extensively in >5,000 patients with type 2 diabetes and kidney disease (DKD), demonstrating clinically significant and sustained reductions in proteinuria when administered on top of a maximum tolerated dose of RAS inhibitor (RASi). In a global Phase 3 outcome study in DKD (SONAR), atrasentan demonstrated a 35% reduced risk of the primary composite outcome of doubling of serum creatinine or end stage kidney disease (95% CI: 0.49, 0.88; P = 0.005). The most common adverse event was fluid retention. Selective ETA blockade represents a promising approach to reduce proteinuria and preserve kidney function in high risk IgAN patients. This is a presentation of a global, phase 3, double-blind, placebo-controlled trial to determine the effect of atrasentan in IgAN patients at high risk of kidney function loss. Method Approximately 320 patients across North America, South America, Europe, and Asia-Pacific with biopsy-proven IgAN will be randomized to receive 0.75 mg atrasentan or placebo daily for 132 weeks. Patients will continue receiving a maximally tolerated and stable dose of a RAS inhibitor as standard of care. The study will also include patients that are unable to tolerate RAS inhibitor therapy. Additional eligibility criteria include urine protein creatinine ratio (UPCR) ≥1 g/g and eGFR ≥30 mL/min/1.73 m2. Participants will have study assessments over two and a half years with options for remote study visits using telemedicine and home health visits. The primary objective is to evaluate the effect of atrasentan versus placebo on proteinuria at Week 24. Secondary objectives include evaluating the change from baseline in eGFR, safety, and tolerability, and quality of life. Results N/A Conclusion N/A

BACKGROUND AND AIMS An abundance of inflammatory cells has been found in duodena of IgA nephropathy (IgAN) patients [1, 2]. The degree of intestinal inflammation was shown to correlate with the amount of proteinuria and haematuria in IgAN [3]. Serum intestinal fatty-acid-binding protein (I-FABP) has shown to correlate with the degree of enterocyte damage in untreated coeliac disease (CD) patients [4]. The median level of I-FABP in untreated CD patients was 785 pg/mL and 173 pg/mL in healthy controls [5]. We conducted this study hypothesizing that I-FABP would be elevated in IgAN as a potential biomarker for the presence of subclinical enterocyte damage and intestinal inflammation. CD was excluded with coeliac autoantibody tests. METHOD This study was carried out at the Tampere University Hospital and Tampere University, Finland. Altogether 85 IgAN patients participated (median age 55 years, 54% males). None of the patients had progressed to end-stage kidney disease, nor had they a diagnosed enteropathy. Fifteen healthy controls (median age 57 years, 47% males) were participants from our previous CD studies. Coeliac autoantibodies were determined from the serum samples by measuring IgA class endomysial antibodies (EmA) and transglutaminase antibodies (tTGAb). EmA was determined by an in-house indirect immunofluorescence method using human umbilical cord as substrate. A serum dilution of 1: ≥ 5 was considered positive. tTGAb levels were determined with EliA Celikey assay (ThermoFisher Scientific, Waltham, MA, USA, cut-off for positivity 7.0 U/mL). The serum levels of I-FABP were determined with a commercially available ELISA kit (Hycult Biotech, Uden, The Netherlands, detection limit 47 pg/mL). Current kidney function was available in 68 IgAN patients (80%), and eGFR >60 mL/min/1.73 m2 was regarded as preserved kidney function. RESULTS I-FABP levels among IgAN patients (median 830 pg/mL, IQR 475–1378) were higher (P < .001) compared with healthy controls (289 pg/mL, IQR 199–568). A total of 57% of the IgAN patients from whom the data on current kidney function were available had preserved kidney function. Also, I-FABP levels in IgAN patients with preserved kidney function (650 pg/mL, IQR 419–880) were higher compared with healthy controls (P .006). tTGAb levels in IgAN patients (1.3, 0.8–1.9 U/mL) were higher (P <.001) compared with healthy controls (0.6, 0.3–0.7 U/mL). One IgAN patient had a borderline elevated tTGAb of 7.1 U/mL. No one had an elevated EmA test result. I-FABP and tTGAb levels had no correlation (rS 0.182, P = .051). CONCLUSION The clear difference in the levels of I-FABP in IgAN patients with preserved kidney function compared with healthy controls was of utmost interest. Elevated I-FABP may represent enterocyte injury and intestinal inflammation present in IgAN. Even though CD was excluded serologically, also the tTGAb levels were higher among IgAN patients. These findings spur us in search for an intestinal process in the pathophysiology of IgAN.

Background and Aims Rare proteinuric kidney diseases are associated with clinical and economic burden, however, the humanistic burden associated with these conditions has not been directly evaluated. HONUS is a multi-national, cross-sectional survey study designed to evaluate the humanistic burden associated with two rare kidney diseases, immunoglobulin A nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS), from the patient and caregiver perspectives in the United States and Europe. The current analysis presents preliminary results from adults with IgAN or FSGS and their care-partners in Spain, Germany, France, or the United Kingdom. Method The study recruited adult patients (≥ 18 years old) with IgAN or FSGS and their adult care-partners. Participants completed an online survey including demographic and clinical characteristics, health-related quality of life (HRQoL) (i.e., Kidney Disease Quality of Life Instrument [KDQoL] including 12-Item Short Form Survey [SF-12]), anxiety and depression (i.e., Generalized Anxiety Disorder Assessment [GAD-7], Patient Health Questionnaire [PHQ-9]), and disease impact on work productivity (i.e., Work Productivity and Activity Impairment [WPAI]). Descriptive analyses were conducted. Results From Europe, 26 IgAN patients, 9 FSGS patients, and their care-partners (4 IgAN and 2 FSGS patients did not report having a care-partner) participated in the survey before November 2023. Mean age for IgAN and FSGS patients was 42.2 years and 51.4 years, with 61.5% and 44.4% being female, respectively. Over two-fifths of both IgAN (42.3%) and FSGS patients (44.4%) were in chronic kidney disease (CKD) stage 3, 4 or 5 (on dialysis), while over one-quarter had received a kidney transplant (IgAN: 26.9%; FSGS: 44.4%). Most patients had worse CKD status since diagnosis (IgAN: 61.5%; FSGS: 77.8%). Hypertension and anemia were the most common comorbidities in both groups. In terms of HRQoL, mean (SD) SF-12 physical and mental component scores (PCS, MCS) indicated IgAN patients were more impacted on the mental component (PCS: 47.3 [11.6], MCS: 43.2 [10.9]), with FSGS patients more impacted on the physical component (PCS: 40.6 [6.0], MCS: 43.8 [9.1]), reflecting generally worse HRQoL (lower scores) than previously published European general population scores (50.0 for PCS and MCS). Moderate to severe anxiety was reported by 30.8% of IgAN and 33.3% of FSGS patients, and moderate to severe depression by 30.8% of IgAN and 44.4% of FSGS patients. Among employed IgAN patients (69.2%), mean percent absenteeism (work time missed) was reported at 13.3%, presenteeism (impairment while working) at 17.7%, and overall work productivity loss at 17.7% due to IgAN-related reasons (only 3 FSGS patients [33.3%] were employed; outcomes not shown). Mean percent activity impairment was reported at 27.3% in IgAN and 43.3% in FSGS patients. Most paired care-partners were partners of patients (IgAN: 81.8%, FSGS: 71.4%), with a mean age of 46.6 years (IgAN) and 50.1 years (FSGS). Mean (SD) SF-12 PCS and MCS of IgAN care-partners were 53.3 (8.8) and 47.9 (10.8), respectively (FSGS: 47.0 [10.6], 49.4 [9.5]). Mild to moderate anxiety was reported in 31.8% (IgAN) and 42.9% (FSGS) of care-partners, with one IgAN care-partner (4.6%) reporting severe anxiety. Mild to moderate depression was reported in 27.3% (IgAN) and 71.4% (FSGS) of care-partners, with two IgAN care-partners (9.1%) reporting moderately severe or severe depression. Among employed IgAN care-partners (86.4%), mean percent absenteeism was reported at 14.2%, presenteeism at 9.3%, and overall work productivity loss at 9.9% due to IgAN-related reasons. Mean percent activity impairment was reported at 18.6% in IgAN and 17.1% in FSGS care-partners. Conclusion Patients with IgAN and FSGS in Europe experience impaired HRQoL compared to previously published European population estimates, as well as anxiety, depression, and impaired productivity. Care-partners of these patients also experience impaired HRQoL, in terms of mental components, and reduced overall productivity.

Using GFR, Albuminuria, and Their Changes in Clinical Trials and Clinical Care

Background and Aims IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, with up to 50% of patients progressing to ESKD or death within 20 years. The cytokines B-cell Activating Factor (BAFF) and A Proliferation-Inducing Ligand (APRIL) play key roles in IgAN pathophysiology by binding to the TACI receptor on B cells and fueling production of galactose-deficient IgA1 (Gd-IgA1) and anti-Gd-IgA1 autoantibodies. Gd-IgA1 is recognized as an autoantigen by anti-Gd-IgA1 autoantibodies, forming the immune complexes which drive kidney pathology and clinical disease. Atacicept is a fully humanized TACI-Fc fusion protein that inhibits both BAFF and APRIL with nanomolar binding affinity, interrupting the immunopathogenesis of IgAN. Atacicept is self-administered at home by subcutaneous injection once weekly (QW). The ORIGIN 2b study evaluated the safety and efficacy of atacicept in IgAN and met the primary endpoint with a statistically significant and clinically meaningful UPCR reduction at 24 wk, with deepening efficacy through 36 wk as compared to placebo. In the open-label extension (OLE), atacicept demonstrated further Gd-IgA1 reductions, hematuria improvements, and UPCR reductions with eGFR stabilization at a rate of decline similar to the general population without kidney disease through 96 wk, suggesting atacicept offers a potentially safe, long-term, disease-modifying treatment for IgAN. Herein, we report the changes in Gd-IgA1 and eGFR during the 26-wk follow-up period after atacicept discontinuation. Method The randomized, double-blind, placebo-controlled Phase 2b ORIGIN study included 116 participants with biopsy-proven IgAN, 24 h urine protein >0.75 g/day or UPCR >0.75 g/g, and eGFR ≥30 mL/min/1.73 m2 despite optimized renin–angiotensin system blockade. Participants were randomized to atacicept or placebo QW for up to 36 wk. The double-blind, randomized treatment period was followed by an OLE in which participants received atacicept 150 mg QW for up to 60 wk, for a total of up to 96 wk of treatment. Participants were subsequently followed for a 26-wk follow-up period after completing atacicept treatment, with evaluations at 12 and 26 wk post-treatment. During this follow-up period, routine hematology, chemistry, and Gd-IgA1 levels were collected and analyzed; no urine samples were collected. This analysis includes participants treated with atacicept who had a last on-treatment Gd-IgA1 or eGFR value in the study wk 96 analysis window and ≥1 measure in the follow-up period, with the study wk 96 values reset as the new baseline and analyzed along with the follow-up 12 and 26 wk data. Gd-IgA1 and eGFR changes were analyzed using a MMRM model. Results There were 103 participants who received ≥1 atacicept dose for ≥60 wk and remained in the follow-up study period. Following completion of atacicept treatment, increases in serum Gd-IgA1 were observed at wk 12 and 26 of +90% and +117% respectively. In addition, changes in eGFR at wk 12 and 26 were −1.6 and −3.9 ml/min/1.73 m2, respectively. (Fig. 1) Conclusion IgAN is a chronic and progressive disease of B-cell origin, in which cytokines BAFF and APRIL are sustaining factors in its pathophysiology. Treatment with atacicept, a precision B-cell modulator inhibiting both BAFF and APRIL, demonstrated significant and sustained reductions in Gd-IgA1, improvements in hematuria, and reductions in UPCR, along with stabilization of eGFR over 96 wk. Following discontinuation of atacicept, an increase in Gd-IgA1 and decline in eGFR were observed, consistent with the typical clinical progression of IgAN in high-risk patients despite standard-of-care treatments. In light of these findings, participants may enroll in a new OLE study (ORIGIN Extend), which will provide insights into the effects of atacicept treatment reinitiation. The rapid impact on key markers of kidney function decline and disease progression after atacicept discontinuation underscores the potential therapeutic benefit of atacicept and supports the paradigm of sustained treatment with atacicept in IgAN patients.

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.

Hyperhomocysteinemia (HHcy) is widely observed in chronic kidney disease (CKD) patients. In early CKD stages, HHcy is more prevalent in IgA nephropathy (IgAN) patients. Here, we investigated the relationship between HHcy and renal outcomes among patients with IgAN. This study evaluated patients with IgAN who underwent diagnostic renal biopsies in the National Clinical Research Center of Kidney Diseases Jinling Hospital from October 2012 to June 2024. Patients were stratified into two groups based on serum homocysteine (Hcy) levels: an HHcy group and a normal Hcy group. A comprehensive comparison between groups was conducted, assessing clinical and pathological manifestations. The end point was end-stage kidney disease (ESKD). The impact of HHcy on renal outcomes was evaluated using multivariate Cox proportional hazards regression models and Kaplan-Meier survival analysis. This study enrolled 366 patients with biopsy-proven IgAN. The cohort had a median age of 37years, with 60.4% male, and a median serum Hcy level of 13.6μmol/L. HHcy was present at diagnosis in 145 patients (39.6%). IgAN patients with HHcy demonstrated significantly worse renal function and histopathological severity compared to those with normal Hcy levels. These manifestations included lower eGFR, higher proteinuria, more severe global glomerulosclerosis and crescent lesions, a higher incidence of T1/T2 lesions, and more severe acute and chronic tubular injury, ultimately culminating in a higher incidence of ESKD (all P < 0.05). After a median follow-up of 42.5months, 38 patients (10.4%) progressed to end-stage kidney disease (ESKD), 33 of whom were in the HHcy group. On multivariate Cox regression analysis, HHcy was identified as an independent risk factor for ESKD in patients with IgAN (HR = 4.008, 95% CI 1.093-14.691, P = 0.036). Kaplan-Meier survival analysis demonstrated significantly poorer renal survival in the HHcy group (P < 0.001). Our findings suggest that hyperhomocysteinemia is associated with worse renal function and more severe renal pathological manifestations, and serves as an independent risk factor for kidney failure in IgAN.

Effectiveness and safety of tacrolimus treatment for IgA nephropathy: A prospective cohort study

Effectiveness and safety of tacrolimus treatment for IgA nephropathy: A prospective cohort study

Clinical Challenges in Diagnosis and Management of Diabetic Kidney Disease

BACKGROUND AND AIMS IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the developed world. Up to 40% of patients with IgAN are at risk of progressing to end-stage kidney disease (ESKD), with proteinuria being a strong predictor of disease progression. Treatments that reduce proteinuria in IgAN are accompanied by eGFR preservation and improved kidney outcomes.[1] Endothelin A (ETA) receptor activation is a key driver of proteinuria, inflammation and fibrosis in patients with glomerular diseases.[2] Therefore, ETA receptor blockade has potential to be of therapeutic benefit for patients with proteinuric glomerular diseases, including IgAN. Atrasentan, a potent and selective ETA receptor antagonist that has demonstrated clinically significant reductions in proteinuria and risk of ESKD in a study of over 5300 patients with diabetic kidney disease (DKD), represents a potential therapy to reduce proteinuria and preserve kidney function in patients with IgAN and other glomerular diseases.[3] AFFINITY is a global, phase 2, open-label basket study to evaluate the efficacy and safety of atrasentan in patients with proteinuric glomerular diseases due to IgAN, Alport syndrome, focal segmental glomerulosclerosis and DKD. Here we present interim results from the first 17 patients enrolled in the IgAN cohort of the AFFINITY study, through week 12 of treatment. METHOD Approximately 20 patients will be enrolled in the IgAN cohort. They must have biopsy proven IgAN, be receiving a maximally tolerated and stable dose of renin angiotensin system inhibitor and have a urine protein creatinine ratio [UPCR] between 0.5 and &amp;lt;1.0 g/g from a first morning void urine sample. Patients are treated orally with 0.75 mg atrasentan daily. The primary endpoint is the change in 24-h UPCR from baseline to Week 12. Key exploratory endpoints include changes in eGFR from baseline to Week 56. RESULTS A total of 17 patients have enrolled in the IgAN cohort as of 4 January 2022. A total of 12 and 8 patients have completed visits through Week 6 and Week 12, respectively. The median age is 47 years and 41% are women. The geometric mean (GM) baseline proteinuria is 1.2 g/day, and median eGFR is 41 mL/min/1.73 m2 (Table 1). The 8 patients on treatment through Week 12 had a GM % reduction from baseline in 24-h UPCR of 43.6% [95% confidence interval (95% CI) 29.0–55.2] (Figure 1). Pharmacokinetic data are currently available for nine patients and showed a mean trough plasma atrasentan concentration in the targeted therapeutic range. Adverse events (AE) were observed in nne patients (53%), all mild or moderate in severity, most of which have resolved. One patient experienced an unrelated serious adverse event of traffic accident without long-term injuries. All patients remain on treatment with study drug except for one patient who discontinued drug due to an unrelated AE at week 13. CONCLUSION Treatment of patients with IgAN with atrasentan in addition to standard of care provided a &amp;gt;43% GM reduction in proteinuria after 12 weeks and was well tolerated, strongly supporting a key role of the endothelin pathway in the pathogenesis of IgAN. The ongoing phase 3 ALIGN study for patients with IgAN and proteinuria ≥1g/day will provide further assessment of the proteinuria lowering effects of atrasentan in this high-risk patient population.

BACKGROUND AND AIMSSeveral models have been proposed to describe the pathogenesis of Immunoglobulin A nephropathy (IgAN) and, among them, the multihit model where the gut-microbiota may play an important role. These models explain the pathogenesis of IgAN caused by the production of aberrant IgA, but it is believed that further predisposing factors are present, including immunological, genetic, environmental or nutritional factors.Recently, the role of IL-6 in IgAN pathogenesis is becoming increasingly important. It is essential for the deposition of glomerular immunoglobulin A and the development of renal disease in Cd37-deficient mice, although the pathogenetic mechanisms that determine its increase are not well known.A possible hypothesis emerges from our recent work on genome-wide DNA methylation screening in patients with IgAN, which identified, among other findings, a hypermethylated region comprising Vault 2–1 RNA (VTRNA2-1), a non-RNA coding also known as a precursor of miR-886 (pre-mi-RNA). Consistently, VTRNA2-1 expression was found downregulated in IgAN patients.Here we studied the involvement of the VTRNA2-1/PKR/CREB/IL-6 pathway in IgAN.METHODTotal RNA were isolated from PBMCs of IgAN patients, transplanted IgAN patients (TP-IgAN), non-IgAN transplanted patients (TP) and healthy subjects (HS). VTRNA2-1, CREB and PKR transcripts were evaluated by RT-PCR. Total and phosphorylated PKR, CREB and Il-6 proteins were evaluated by ELISA. Poly (I: C), a synthetic analogue of dsRNA and Pfizer-BioNTech COVID-19 COMIRNATY vaccine were used to transfect patient PBMCs. PKR inhibitor imoxin (C16) 1 µM was used to stimulate patient PBMCs.RESULTSHere we confirm that VTRNA2-1 transcript was down-regulated in native and transplanted IgAN subjects compared to HS and non IgAN transplanted patients, with a decrease of 30- and 100-folds, respectively (P < 0.05, and P < 0.0001). IgAN patients with downregulated VTRNA2-1 showed a PKR overactivation (fold increase of phosphorilation of 2.6- in IgAN and 2-folds in TP-IgAN patients; P < 0.05), coherently with the role played by VTRNA2-1 that binds to PKR and inhibits its phosphorylation. Then, we found that PKR causes the activation of CREB, a classical cAMP-inducible CRE-binding factor (fold increase of phosphorilation of 3- in IgAN and 2.67-folds in TP-IgAN patients; P < 0.01). CREB, interacting with a region of the IL-6 promoter, led to IL-6 production. Indeed, in IgAN patients we showed a IL-6 mean increase to 120 pg/mL compared to the respective controls (P < 0.05). Moreover, the IL-6 levels correlated with CREB and PKR phosphorylation (r = 0.97; P = 0.0006 and r = 0.89; P = 0.0064, respectively, for IgAN and TP-IgAN patients).Since PKR is normally activated by bacterial and viral RNA, we hypothesized that these microorganisms can further activate the PKR/CREB/IL-6 pathway leading to an excess of IL-6 production. This may explain both the high levels of IL-6, and infection involvement in the disease, and cases of IgAN associated with COVID-19 infection or with COVID-19 RNA-vaccination, and recent data showing microbiota involvement in IgAN. Effectively, we found that IgAN PMBCs stimulated with RNA poly(I: C) or the COVID-19 RNA-vaccine showed a significant increase in IL-6 levels compared to not-stimulated PBMCs (P < 0.05), supporting the pathogentic role played by viral RNA in IgAN pathogenesis and explaining the cases of IgAN patients developing episodes of macrohematuria after a COVID-19 infection or vaccination.Finally, we showed that the IL-6 secretion can be reduced by the PKR inhibitor imoxin (fold decrease of 5-folds in IgAN and TP-IgAN patients; P < 0.05).CONCLUSIONIn conclusion, the discovery of the upregulated VTRNA2-1/PKR/CREB/IL-6 pathway in IgAN patients may provide a new pathogenic mechanism in IgAN and may be useful for the development of novel therapeutic approaches, likely by modulating the VTRNA2-1 methylation level in IgAN patients.

BackgroundAs an indispensable marker of complement cascades activation, C4d was confirmed of its crucial role in the pathogenesis of both lupus nephritis (LN) and IgA nephropathy (IgAN). While the studies directly comparing the diagnostic value, and outcomes predicting function of C4d between LN and IgAN are still absent.MethodsA cohort of 120 LN patients, 120 IgAN patients who were diagnosed by renal biopsy between January 2015 and December 2017 and 24 healthy age matched controls were prospectively analyzed. The patients were followed till December 2020. The outcomes were adverse disease treatment response (disease relapse) and kidney disease progression event (decline of estimated glomerular filtration rate by more than 20% or end-stage kidney disease). The renal C4d deposition proportion and pattern were compared between IgAN and LN patients. In addition, the relationship between renal C4d deposition and disease subtypes, disease relapse as well as disease progression for LN and IgAN patients were also analyzed.ResultsThe LN, IgAN patients and healthy controls were well matched in ages. The follow-up period was 38.5 (30.3–60.8) months for LN patients and 45.0 (30.5–57.0) months for IgAN patients. 78 patients (65.0%) with LN had renal C4d deposition, compared with only 39 IgAN patients (32.5%) with C4d deposition in renal tissues (P < 0.001). The LN patients shared different renal C4d distribution patterns with IgAN patients. Compared with IgAN patients, the C4d deposition in LN patients was significantly more in renal glomerulus (P < 0.001) and less in renal tubules (P = 0.003). For disease subtypes, renal C4d deposition was especially strong in class V membranous LN and IgAN with tubulointerstitial fibrosis (T1/T2) lesions. Renal C4d deposition was independently correlated with the disease relapse of LN patients (HR = 1.007, P = 0.040), and acted as an independent predictor of disease progression during the follow-up period for IgAN patients (HR = 1.821, P = 0.040).ConclusionsRenal C4d distribution proportion and pattern differed between LN and IgAN patients. The presence of C4d in renal tissue acted as an independent predictor of relapse for LN patients and disease progression for IgAN patients.

Background and Aims Current literature indicates that up to 40% of patients in China with IgAN progressed to end-stage kidney disease (ESKD) within 20 years of diagnosis. Proteinuria has been identified as a predictor of kidney failure in IgAN. In China, real-world evidence on the differences in disease progression across various levels of proteinuria is limited. This study aimed to assess the association of proteinuria with disease progression of IgAN in China. Method A retrospective observational study of adult patients with biopsy-confirmed primary IgAN from Tianjin City, China was conducted using data between 01/01/2015 to 06/30/2023. Patients with secondary IgAN, history of dialysis or eGFR &amp;lt;15 mL/min/1.73 m2 at renal biopsy, or a history of kidney transplantation, were excluded. Index date was the date of the initial biopsy which confirmed IgAN. Patients were followed from index biopsy until clinical outcomes (ESKD, doubling of serum creatinine, 40% decline in eGFR or mortality) and censored for disenrollment, or end of study. Time-to-event analysis was performed for these outcomes. Associations of time-averaged proteinuria with composite renal event were estimated using Cox proportional hazard regression. Results A total of 1,674 patients were included, with 50.4% being female. At renal biopsy, 55.0% of patients were aged &amp;lt;40 years, 60.3% had hypertension, 6.6% had diabetes and 67.3% were in CKD stage I or II. RAAS inhibitors (62.1%), corticosteroids (59.6%) and immunosuppressants (30.3%) were the most frequently used treatments during the follow-up, with a high proportion of concomitant use of traditional Chinese medicine (86.8%). Of 1,357 patients with time-averaged proteinuria during the follow-up, 26.9% had &amp;lt;0.5 g/day, 27.4% had 0.5–&amp;lt;1 g/day, and 45.7% had ≥1 g/day. Over a median (mean) follow-up period of 1.7 (2.2) years, 9.2% of patients experienced composite renal event (6.5% progressed to ESKD, 5.0% experienced 40% decline in eGFR, 3.6% experienced doubling of serum creatinine, 1.3% had mortality). Unadjusted hazard ratios (HRs) of composite renal event occurrence were higher in patients with time-averaged proteinuria ≥0.5 g/day than those with proteinuria &amp;lt;0.5 g/day (HR [95% confidence interval]: 1.5 [0.7, 3.1] for 0.5–&amp;lt;1 g/day, 2.7 [1.4, 5.3] for 1–&amp;lt;2 g/day, 4.8 [2.3, 10.0] for 2–&amp;lt;3 g/day, and 13.7 [7.4, 25.3] for ≥3g/day). Conclusion Results showed that IgAN patients in this Chinese cohort had relatively preserved kidney function but high-risk comorbid conditions. Sustained proteinuria over 1 g/day during the follow-up is a strong predictor of CKD progression. Patients with 0.5–1 g/day proteinuria had an elevated risk of CKD progression; however this was not statistically significant and should be contextualized with other risk factors for rapid progression. Findings support the goal of lowering proteinuria to &amp;lt;0.5 g/day to reduce the risk of renal failure among IgAN patients in China.

Background: The outcomes of pregnancy in immunoglobulin A nephropathy (IgAN) remain controversial. We sought to evaluate the effect of pregnancy on the progression of IgAN as well as the impact of IgAN on pregnancy outcomes. Methods: We systematically searched MEDLINE, Embase for cohort or case-control studies. OR reductions were calculated with a random-effects model, and kidney outcomes and adverse pregnancy events were analyzed. Results: Our literature search returned 652 relevant articles; 4 studies were included, providing data of 376 pregnancies in 273 patients with IgAN and that of 241 IgAN who did not become pregnant. Four hundred sixty seven patients with chronic kidney disease stages 1-2 were included. Pregnancy in patients with IgAN did not increase the risk of adverse renal events including doubling of serum creatinine, 50% decline in glomerular filtration rate (GFR) and end-stage kidney disease (OR 0.97, 95% CI 0.55-1.70; p = 0.90; I² = 0.0%, p = 0.79). There was no significant difference in the change in estimated GFR at the end of follow-up in the pregnant and non-pregnant groups (weighted mean difference 0.1 ml/min/1.73 m² (95% CI -4.85 to 5.04 ml/min/1.73 m²), p = 0.97; I² = 0%, p = 0.95). Women with IgAN had high rates of infant loss (12.2, 7.4-19.4%), preterm delivery (8.5, 5.9-12.1%), low birth weight (9.5, 6.7-13.3%), and preeclampsia/severe preeclampsia (7.3, 4.9-10.6%). Conclusions: Pregnancy in IgAN patients with preserved kidney function did not accelerate deterioration of renal function. But pregnant women with IgAN are at higher risk of pregnancy complications.