Introduction: Podocyte injury is central to the pathogenesis of most glomerulonephritides (GN) and causes segmental glomerulosclerotic lesions that predict progression in IgA Nephropathy (IgAN). Recent advances in high-resolution microscopy and AI-assisted image analysis have enabled detailed quantification of podocyte foot process (FP) morphology. However, whether nanoscale podocyte morphometrics can predict disease progression or treatment response in GN has not been investigated. Aim: To evaluate whether nanoscale podocyte morphometric parameters predict clinical characteristics, disease progression, and treatment response in GN, with a focus on IgAN. Method: Podocyte morphometrics were analyzed in kidney biopsies from patients with GN using high-resolution microscopy and the deep learning-based tool Automatic Morphometric Analysis of Podocytes (AMAP). Four morphometric parameters were quantified: slit diaphragm length (SDL), FP area, FP circularity and FP perimeter. These parameters were correlated with clinical characteristics, conventional electron microscopy (EM) findings and longitudinal follow-up data. Results: The study included 37 patients with GN from Danderyd University Hospital (Stockholm, Sweden), with IgAN representing the largest diagnostic subgroup (n = 19). The median follow-up for the cohort was 3.0 years. SDL correlated significantly with urine albumin-to-creatinine ratio (uACR; p = 0.021), whereas conventional EM measurements did not (p = 0.22). Within the IgAN subgroup, lower SDL was associated with a steeper decline in eGFR, higher FP area with increased long-term proteinuria, and higher FP circularity with improvement in uACR during the first year. The association between lower SDL and eGFR decline remained as a trend in IgAN patients not treated with corticosteroids (p = 0.068) but was absent in the treatment group (p = 0.59). Conclusion: In this proof-of-concept study, nanoscale podocyte morphometrics demonstrated greater sensitivity than conventional EM in quantifying podocyte injury and predicting progression in IgAN. These findings suggest that high-resolution morphometrics may improve risk stratification in IgAN but require validation in larger, independent cohorts before clinical implementation. ### Competing Interest Statement The authors RE, AF, KB, LB, TB, HB & DUJ declare that they are co-founders and shareholders of Magnephy AB with RE, TB & DUJ also being board members. All other authors declare no conflict of interest. ### Funding Statement We acknowledge microscopy support from the Advanced Light Microscopy (ALM) Facility, Royal Institute of Technology (KTH), SciLifeLab Solna, Sweden and the National Microscopy Infrastructure, NMI (VR-RFI 2023-00163). The work was supported by grants to HB from the Clinical Technology Development Project at SciLifeLab. RE and DUJ were funded by the Torsten Söderbergs Stiftelse, Stockholm, Sweden. RE were also funded by Stiftelsen Stig och Gunborg Westman for research on kidney disease, transplantation and organ donation. RE was supported through funding and clinical fellowship with AIDA, Analytic Imaging Diagnostics Areana, Linköping, Sweden. DUJ was supported by funding from University of Cologne, Germany. TB is supported by the German Research Foundation, TRR/CRU 422, project A1. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval for the BIONEF DS project has been received by the Swedish Ethical Review Authority with Dnr 2018/803-31 with approved amendments Dnr 2023-01265-02, Dnr 2024-01876-02, and and Dnr 2025-05680-02 pertaining to the present study. Written informed consent was obtained from all subjects at recruitment. The study was conducted in accordance with the Declaration of Helsinki. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Due to privacy laws and ethical restrictions concerning pseudonymized patient data under the EU General Data Protection Regulation (GDPR) and Swedish law, the clinical data and images underlying this study cannot be made publicly available. Data may be shared with qualified researchers upon reasonable request to the corresponding author after establishment of a formal data transfer agreement and approval from the Swedish Ethical Review Authority.

Objective Glucoraphanin, a precursor of sulforaphane (SFN), is found in high concentrations in broccoli sprout extract (BSE) and has been shown to have antioxidant effects and to improve glucose control in type 2 diabetes (T2D). This randomized controlled trial (RCT) aimed to investigate whether BSE could improve glucose control in patients with chronic kidney disease (CKD) and T2D. Design and methods This multicentre double-blind placebo-controlled RCT included adult patients with T2D and CKD stages 3b-4. Participants were randomized to receive an incremental dose of BSE (maximum 150 μmol/day BSE (750 μmol SFN)) or placebo. The use BSE or placebo lasted 12 weeks (week 1 to 13) plus 8 weeks (week 14 to 21) with no intervention. The main outcome was improvement in glycemic control. Results 99 patients were included, and 91 completed the study. Mean age was 74±7 years, 69% men and mean estimated glomerular filtration rate (eGFR) 28±7 mL/min/1.73 m2. There were no significant differences in baseline characteristics between the groups. In an intention-to-treat analysis, there were no statistically significant differences between groups in fasting glucose, insulin or HbA1c levels after 13 weeks or at 21 weeks of follow-up (end of study). Similarly, no statistically significant differences were observed between both groups in these variables in a per protocol analysis. Conclusion In patients with T2D and moderate CKD, 12 weeks of treatment with BSE with progressing dose (50 to 150 μmol/day BSE) did not result in statistically significant changes in measures related with glycemic control.

Elevated galactose deficient IgA1 (Gd-IgA1) is known to be associated with IgA nephropathy (IgAN) and is often regarded as the first of four steps in the four hit hypothesis to explain disease pathogenesis. However, while the proposed downstream hits have support from unbiased genetic association studies, similar genetic evidence to support a causal role for Gd-IgA1 in the disease is lacking. Multiple previous genome-wide association studies have shown that common variation in the gene C1GALT1 is strongly associated with Gd-IgA1 levels. We used this established relationship first to calculate power to detect an association of C1GALT1 alleles with IgAN risk and second to conduct association and Mendelian randomisation analyses to detect and quantify evidence for a causal role of Gd-IgA1 in IgA nephropathy. Despite adequate power, we did not observe significant genetic evidence for a causal role of Gd-IgA1 in IgAN that would explain the well-established observational association, and infer that this may not be explained by causation. This raises the possibility that Gd-IgA1 might better be regarded as a biomarker than a cause of IgA nephropathy and suggests that caution is needed when inferring clinical efficacy of treatments based on their effects on Gd-IgA1 levels. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: We accessed the summary statistics of the following study: Kiryluk K, Sanchez-Rodriguez E, Zhou XJ, et al. Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy. Nat Genet. 2023 Jul;55(7):1091-1105. doi: 10.1038/s41588-023-01422-x Gale DP, Molyneux K, Wimbury D, et al. Galactosylation of IgA1 Is Associated with Common Variation in C1GALT1. J Am Soc Nephrol. 2017 Jul;28(7):2158-2166. doi: 10.1681/ASN.2016091043 Kiryluk K, Li Y, Moldoveanu Z, et al. GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway. PLoS Genet. 2017 Feb 10;13(2):e1006609. doi: 10.1371/journal.pgen.1006609 Wang YN, Zhou XJ, Chen P, et al. Interaction between GALNT12 and C1GALT1 Associates with Galactose-Deficient IgA1 and IgA Nephropathy. J Am Soc Nephrol. 2021 Mar;32(3):545-552. doi: 10.1681/ASN.2020060823 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All the data are presented in full in the manuscript and the summary statistics are downloaded from their respective papers (See data availability links).

Introduction The activation of the complement system plays an important role in the pathogenesis of IgA nephropathy (IgAN). Our primary aim was to evaluate a range of complement-related proteins, including pentraxin-3 (PTX-3), in blood and urine at diagnosis and their association with disease activity in the kidney biopsy, eGFR, albuminuria, and outcome. Our secondary aim was to compare the same biomarkers between patients with IgAN and IgA vasculitis with renal involvement (IgAVN).Methods In a longitudinal Swedish cohort of 96 patients with IgAN (n = 65) or IgAVN (n = 31), with a median follow-up time of 10.8 years, we analysed mainly lectin-pathway-related proteins and PTX-3 in plasma and urine (u) samples stored at the time of kidney biopsy. Outcome was defined by the GFR slope or by the combined outcome of 50% loss of eGFR or end-stage kidney disease (ESKD).Results Patients with detectable vs undetectable u-PTX-3 and u-mannose-binding lectin (MBL) more frequently had mesangial hypercellularity, endocapillary proliferation, and crescents in their kidney biopsy. u-C4c levels were higher in patients with advanced tubulointerstitial fibrosis, and u-C4c was also an independent predictor of a more severe eGFR slope. There were no differences in the levels of biomarkers between patients with IgAN and IgAVN.Conclusion u-PTX-3 and u-MBL might be biomarkers of an active proliferative stage of the disease, while higher u-C4c levels indicate more chronic lesions in both IgAN and IgAVN. These results must, however, be confirmed in larger and multiethnic cohorts. 10.1093/ckj/sfae395 Video Abstract Watch the video abstract of this contribution sfae395Media1 6367687771112

Abstract Maximal oxygen uptake (VO2max) in healthy subjects is primarily limited by systemic oxygen delivery. In chronic kidney disease (CKD), VO2max is potentially reduced by both central and peripheral factors. We aimed to investigate the effect on VO2peak of adding arm exercise to leg exercise. Ten individuals with CKD stages 3–5 and 10 healthy controls, matched for age, sex, body size, and physical activity level, were included. Subjects performed two maximal exercise tests, one with legs only (L exercise) and one test where arm exercise was added to leg exercise (LA exercise). The increase in VO2peak, when comparing LA exercise with L exercise, was significantly higher in CKD (0.20 ± 0.18 L/min or 2.31 ± 1.78 mL/(kg·min)) than in controls (0.019 ± 0.12 L/min or 0.26 ± 1.62 mL/(kg·min); p = 0.02 and 0.01, respectively). The decrease in peak leg workload, when comparing L exercise with LA exercise, was larger in controls than in CKD, in absolute terms (p = 0.002) and relative to body weight (p = 0.01). VO2max in individuals with CKD is dependent on the active muscle mass, supporting a peripheral limitation to VO2max in CKD. By contrast, the control group appeared to have a more central limitation to VO2max.

Abstract Background and Aims IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide. Dysregulation of the complement system is considered a part of the pathogenesis and can occur both in the circulation and locally in the kidney. Despite this, most studies have focused on complement biomarkers in the blood, rather than in urine. Our aim was to evaluate a wide range of complement-related proteins in blood and urine at diagnosis and their association with disease activity in biopsy findings, proteinuria, and outcome. We added PTX-3, a protein expressed in activated endothelial cells, which can be both produced by and activate mesangial cells in IgAN and has a function in all three complement pathways. Adult-onset IgA vasculitis with renal involvement (IgAVN) shares many similarities with IgAN and cannot currently be distinguished by kidney biopsy or any established biomarker. We therefore also aimed to compare the same biomarkers between these two disorders. Method In a Swedish cohort of 96 patients with IgAN (n = 65) and IgAVN (n = 31), who had been followed prospectively for a median of 10.8 years, we performed the following analysis in plasma and urine in samples stored at the time of kidney biopsy. Analyses in plasma (p-) included C3bc, C4c, C5b-9, MASP2, MASP3, MAP1, FCN 1-3, MBL, CL11 and PTX-3 and in urine (u-) C3bc, C4c, C5b-9, MASP3, FCN2, FCN3, MBL and PTX-3. An in-house developed sandwich ELISA was used for all analyses. Kidney biopsies were classified according to the Oxford MEST-C score, describing (simplified for this small cohort) the presence vs absence (1 vs 0) of mesangial proliferation (M), endocapillary proliferation (E), segmental sclerosis (S), tubular atrophy/interstitial fibrosis (T) and crescents (C). Severe outcome was defined by a combination of an eGFR slope > 2.5 ml/min/1.73 m2 per year or end stage kidney disease. For statistical analysis, Mann-Whitney U test was performed for comparison between independent groups, Chi squared test and Fisher's test for categorical variables and Spearman's ranks test for correlation analysis. Median values are presented without IQR for this abstract. Results Urine samples were available in 59 patients (IgAN n = 39, IgAVN n = 20). Patients with detectable u-MBL (28.9%) and u-C5b-9 (27.1%) had higher levels of proteinuria than those with undetectable levels (1.5 g/d vs 0.71g/d; p = 0.009 and 2.3 g/d vs 0.7 g/d respectively; p < 0.001). Lower eGFR (71 ml/min/1.73 m2 vs 88 ml/min/1.73 m2; p = 0.034) were observed if u-C5b-9 was measurable. Detectable levels of u-PTX-3 and u-MBL were more often found in the presence of M1 vs M0 (53% vs 20%; p = 0.022 and 47% vs 12.5%; p = 0.011), E1 vs E0 (55% vs 14%; p = 0.001 and 40% vs 11%; p = 0.020) and C1 vs C0 (56% vs 11%; p = 0.003 and 44% vs 11%; p = 0.012). No differences in proteinuria or eGFR were seen in patients with or without detectable u-PTX-3. The degree of proteinuria was positively correlated to the levels of u-C3bc (r = 0.33; p = 0.011) and u-C4c (r = 0.39; p < 0.001). U-C4c levels were higher in patients with M1 vs M0 (54.4 Au/mL vs 23.8 Au/mL; p = 0.037) and T1 vs T0 (53.2 Au/mL vs 23.8 Au/mL; p = 0.034). Concerning the analyses in plasma (n = 95), lower p-MASP3 and p-CL11 levels were correlated with lower eGFR (r = 0.29; p = 0.004 and r = 0.31, p = 0.002). Moreover, lower p-MASP3 levels were detected in patients with E1 vs E0 (2918 ng/mL vs 3404 ng/mL; p = 0.002) and C1 vs C0 (3053 ng/mL vs 3427 ng/mL; p = 0.015). Both p-C5b-9 (13.3 Au/mL vs 8.2 Au/mL; p = 0.001) and p-FCN 1 (395 ng/mL vs 289 ng/mL; p = 0.001) were higher in patients with C1 vs C0. No single complement-related protein was associated with severe outcome, and no statistically significant differences in plasma or urine levels between patients with IgAN and IgAVN were observed. Conclusion Increased urinary levels of MBL and PTX-3 could be potential biomarkers of disease activity in both IgAN and IgAVN, whereas excretion of C5b-9 might be more unspecific and associated with chronic damage. However, these results need to be confirmed in larger and more ethnically diverse cohorts. The impact of treatment on these potential biomarkers for disease activity need to be evaluated in longitudinal studies.

Background and hypothesis. KDIGO recommends proteinuria < 1 g/d as a treatment target in patients with immunoglobulin A nephropathy (IgAN) because of high risk of progression to kidney failure. However, long-term kidney outcomes in patients with lowgrade proteinuria remain insufficiently studied. Methods. We enrolled patients with biopsy-proven primary IgAN from the Swedish Renal Registry and analyzed associations between urine albumin-to-creatinine ratio (uACR, in categories < 0.3, 0.3-0.5, 0.5-1.0, 1.0-1.5, 1.5-2.0, and >= 2.0 g/g) and the occurrence of major adverse kidney events [MAKE, a composite of kidney replacement therapy (KRT) and > 30% decline in estimated glomerular filtration rate (eGFR)]. We also explored the risk of kidney events associated with change in uACR within a year. Results. We included 1269 IgAN patients (74% men, median 53 years, mean eGFR 33 ml/min/1.73 m2, median uACR 0.7 g/g). Over a median follow-up of 5.5 [2.8; 9.2] years, 667 MAKE and 517 KRT events occurred, and 528 patients experienced > 30% eGFR decline. Compared with uACR < 0.3 g/g, any higher uACR category was strongly and incrementally associated with the risk of MAKE [adjusted hazard ratios (HR) ranging from 1.56 (95%CI 1.14-2.14) if uACR 0.3-0.5 g/g to 4.53 (3.36-6.11) if uACR >= 2.0 g/g], KRT (HR ranging from 1.39 to 4.65), and eGFR decline > 30% (HR ranging from 1.76 to 3.47). In 785 patients who had repeated uACR measurements within a year, and compared with stable uACR, the risk of kidney events was lower if uACR decreased by 2-fold (HR ranging from 0.47 to 0.49), and higher if uACR increased by 2-fold (HR from 1.18 to 2.56), irrespective of baseline uACR. Conclusions. There is substantial risk of adverse kidney outcomes among patients with IgAN and uACR between 0.3 and 1.0 g/g, a population currently considered at low risk of CKD progression. Reduction in uACR is associated with better kidney outcomes, irrespective of baseline uACR.

Abstract Background and Aims KDIGO recommends proteinuria <1 g/d as a treatment target in patients with immunoglobulin A nephropathy (IgAN) because of high-risk of progression to kidney failure. However, long-term kidney outcomes in patients with low-grade proteinuria remain poorly studied. Method We enrolled patients with biopsy-proven primary IgAN from the Swedish Renal Registry and analyzed associations between first-recorded urinary albumin-to-creatinine ratio (uACR, in categories <0.3, 0.3-0.5, 0.5-1.0, 1.0-1.5, 1.5-2.0 and >2.0 g/g) and the occurrence of major adverse kidney events (MAKE, a composite of kidney replacement therapy [KRT] and >30% decline in eGFR). We also explored the risk of MAKE associated with the fold-change in uACR within a year. Results We enrolled 1269 patients with primary IgAN (74% men, median 53 years, mean eGFR 33 mL/min/1.73 m², median uACR 0.7 g/g). Compared to patients with uACR <0.3 g/g, those with higher uACR levels were younger, more often men, had a higher prevalence of hypertension, diabetes, acute kidney injury, lower eGFR and serum albumin level, and were less often prescribed RASi. Over median follow-up of 5.5 [2.8;9.2] years, 667 MAKE and 517 KRT events occurred, and 528 patients experienced > 30% eGFR decline. In multivariable analyses, and compared with uACR <0.3 g/g, any higher uACR category strongly and incrementally associated with the risk of MAKE (Figure), with Hazard Ratios (HR) ranging from 1.56 [95% CI 1.14-2.14] in patients with uACR 0.3-0.5 g/g to 4.53 [3.36-6.11] in patients with uACR>2g/g. Similar graded relationships were observed for KRT (HR ranging from 1.39 to 4.65), and for >30% decline in eGFR (HR ranging from 1.76 to 3.47). In the 785 patients who had repeated uACR measurements within a year, and compared with stable uACR, the risk of kidney events was lower if uACR decreased by 2-fold (HR ranging from 0.47 to 0.49), and higher if uACR increased by 2-fold (HR from 1.18 to 2.56), irrespective of baseline uACR. Conclusion Our findings show substantial risk of adverse kidney outcomes among patients with IgAN and uACR between 0.3 and 1.0 g/g, a population currently considered at low-risk of CKD progression. Reduction in uACR is associated with better kidney outcomes, irrespective of baseline uACR.

BACKGROUND:Although glomerular diseases are the third most frequent cause of end-stage kidney disease worldwide, little is known about their long-term outcomes. METHODS:In patients with chronic kidney disease (CKD) stage 3-5 enrolled in the Swedish Renal Registry, we compared risks of hospitalization, kidney replacement therapy (KRT), major cardiovascular events (MACE), and death of the four most frequent primary glomerular diseases (IgA nephropathy [IgAN], focal segmental glomerulosclerosis [FSGS], minimal change disease [MCD], and membranous nephropathy [MN]), and patients with CKD due to the most common non-communicable diseases (control-CKD). RESULTS:We identified 2396 patients with glomerular disease (97% biopsy-proven, 69% men, 57 years, eGFR 29 mL/min/1.73 m2, uACR 88 mg/mmol, 1524 with IgAN, 398 FSGS, 94 MCD, and 380 MN) and 37,697 controls (64% men, 74 years, eGFR 25 mL/min/1.73 m2, uACR 23 mg/mmol), mainly with diabetic nephropathy and nephroangiosclerosis. The median follow-up was 6.3 (3.3; 9.9) years. Compared with control-CKD, patients with primary glomerular diseases generally had a lower risk of hospitalization, MACE (adjusted hazard ratios [HRs] ranging from 0.44 to 0.88 depending on the etiology) and death (HRs ranging 0.45-0.76). Patients with IgAN and FSGS had a faster eGFR decline and a higher rate of KRT (HRs 1.26 [95%CI: 1.15-1.37] and 1.34 [1.15-1.57], respectively). Conversely, patients with MN and MCD had a lower KRT rate and slower eGFR decline. CONCLUSION:Despite having a lower relative risk of hospitalization, cardiovascular events and mortality, patients with IgAN and FSGS are at higher risk of CKD progression than the most common etiologies of CKD, emphasizing the need for more stringent treatment strategies in these patients.

Abstract Background and Aims Adult-onset IgA Vasculitis (IgAV) is poorly responsive to glucocorticoids (GC) and conventional immunosuppressive therapies, such as cyclophosphamide. Rituximab has been successfully used in a few cases and may represent a safer and potentially more effective option [1]. Crescentic IgA Nephropathy (cIgAN), a rare entity that shares features of renal vasculitis with IgAV, is also frequently refractory to cyclophosphamide, while response to rituximab is unknown. We investigated outcomes after rituximab in a multicentre European cohort of adult-onset IgAV and cIgAN. Method We screened clinical records of patients followed at 18 European consorted centres who were ≥18 years old at the onset of IgAV and received ≥1 rituximab dose. Furthermore, we identified patients with cIgAN (≥25% crescentic glomeruli and rapidly progressive glomerulonephritis), who were treated with rituximab. Remission was defined as Birmingham Vasculitis Activity Score (BVAS) <3 at month 6 after rituximab and renal response as stable or improved eGFR and ≥50% proteinuria reduction. Relapse was defined as an increase in BVAS requiring a change in immunosuppressive therapy. Outcomes of IgAV with severe nephritis (eGFR <60 mL/min) were compared with those of cIgAN. Results We included 61 patients with IgAV and 15 with cIgAN (Table). Rituximab was administered as initial therapy in 23/61 (38%) patients with IgAV and 13/15 with cIgAN (87%), while the remainder had refractory or relapsing disease. Active skin involvement was present in 49 patients (80%) and nephritis in 55 patients (90%) with IgAV at the time of starting rituximab. This was given alone in 13/61 (21%) or combined with GC in 48 (79%) patients with IgAV and in all those with cIgAN. Furthermore, cyclophosphamide was used in 15% of patients with IgAV and 40% of those with cIgAN. Remission at 6 months was achieved by 52 (85%) patients with IgAV and 12/13 (92%) of those treated with rituximab alone. A renal response was observed among 49/55 (89%) of those with nephritis. Patients with IgAV and severe nephritis had similar eGFR to those with cIgAN at the time of starting rituximab, but the latter had lower rate of remission and a higher frequency of kidney failure. A relapse occurred in 15/52 patients (29%) who achieved remission a median of 13 months (10-15) after rituximab. Eight patients resumed rituximab and achieved again remission. Conclusion Rituximab alone or in combination with GC and immunosuppressants appeared to achieve a high rate of remission in this cohort of adult-onset IgAV. Renal response among those with severe nephritis was also good, while this was worse among patients with cIgAN, suggesting substantial differences among these conditions despite similar histological appearances.

IgA vasculitis (IgAV) is a pediatric disease with skin and systemic manifestations. Here, we conducted genome, transcriptome, and proteome-wide association studies in 2,170 IgAV cases and 5,928 controls, generated IgAV-specific maps of gene expression and splicing from blood of 255 pediatric cases, and reconstructed myeloid-specific regulatory networks to define disease master regulators modulated by the newly identified disease driver genes. We observed significant association at the HLA-DRB1 (OR=1.55, P=1.1×10-25) and fine-mapped specific amino-acid risk substitutions in DRβ1. We discovered two novel non-HLA loci: FCAR (OR=1.51, P=1.0×10-20) encoding a myeloid IgA receptor FcαR, and INPP5D (OR=1.34, P=2.2×10-9) encoding a known inhibitor of FcαR signaling. The FCAR risk locus co-localized with a cis-eQTL increasing FCAR expression; the risk alleles disrupted a PRDM1 binding motif within a myeloid enhancer of FCAR. Another risk locus was associated with a higher genetically predicted levels of plasma IL6R. The IL6R risk haplotype carried a missense variant contributing to accelerated cleavage of IL6R into a soluble form. Using systems biology approaches, we prioritized IgAV master regulators co-modulated by FCAR, INPP5D and IL6R in myeloid cells. We additionally identified 21 shared loci in a cross-phenotype analysis of IgAV with IgA nephropathy, including novel loci PAID4, WLS, and ANKRD55.

More than 50 years after the description of IgA nephropathy as Berger's disease, 20–40% of affected individuals still progress to end-stage kidney disease within 10–20 years of diagnosis, which negatively affects life expectancy. 1 Jarrick S Lundberg S Welander A et al. Mortality in IgA nephropathy: a nationwide population-based cohort study. J Am Soc Nephrol. 2019; 30: 866-876 Crossref PubMed Scopus (44) Google Scholar Glucocorticoids can halt progression in some patients but rarely prevent the final development of end-stage kidney disease, and side-effects limit the intensity and duration of treatment. 2 Tesar V Troyanov S Bellur S et al. Corticosteroids in IgA nephropathy: a retrospective analysis from the VALIGA Study. J Am Soc Nephrol. 2015; 26: 2248-2258 Crossref PubMed Scopus (154) Google Scholar , 3 Lv J Wong MG Hladunewich MA et al. Effect of oral methylprednisolone on decline in kidney function or kidney failure in patients with IgA nephropathy: the TESTING randomized clinical trial. JAMA. 2022; 327: 1888-1898 Crossref PubMed Scopus (31) Google Scholar A challenge for the assessment of treatment effects in IgA nephropathy is the usual long time-course to traditional outcomes of doubling of serum creatinine, end-stage kidney disease, or death. A breakthrough has been the Kidney Health Initiative (KHI) project that, on the basis of published trials, evaluated and confirmed the predictive value of proteinuria reduction on this combined outcome. This resulted in the KHI recommendation of proteinuria reduction as a surrogate efficacy endpoint for accelerated approval of new therapies for IgA nephropathy by the US Food and Drug Administration (FDA). 4 Thompson A Carroll K A Inker L et al. Proteinuria reduction as a surrogate end point in trials of IgA nephropathy. Clin J Am Soc Nephrol. 2019; 14: 469-481 Crossref PubMed Scopus (77) Google Scholar Since then, an increasing number of new therapies are under investigation for IgA nephropathy. Recently, targeted-release budesonide for a course of 9 months has been approved as the first specific immunosuppressive treatment in IgA nephropathy. 5 Fellström BC Barratt J Cook H et al. Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial. Lancet. 2017; 389: 2117-2127 Summary Full Text Full Text PDF PubMed Scopus (203) Google Scholar Sustained proteinuria reduction is essential for the prognosis of IgA nephropathy, 6 Canney M Barbour SJ Zheng Y et al. Quantifying duration of proteinuria remission and association with clinical outcome in IgA nephropathy. J Am Soc Nephrol. 2021; 32: 436-447 Crossref PubMed Scopus (17) Google Scholar which highlights the need for additional non-toxic treatments that can be given in the long term and at different disease stages. Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trialOnce-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. Full-Text PDF

Background and Aims In advanced stages of chronic kidney disease (CKD) some glucose-lowering agents, such as metformin, cannot be prescribed to patients with type 2 diabetes (T2D) due to the risk of accumulation and adverse events. Foods with bioactive components, “functional food”, can be an alternative to mitigate the metabolic disturbances in these patients. Previous research on experimental animals and patients with T2D has shown that sulforaphane, present in broccoli sprouts, improves insulin sensitivity and glucose control. We hypothesize that sulforaphane ingested as a broccoli sprout extract (BSE) can improve glucose control in patients with T2D and CKD. Method This is an ongoing multicentre randomized double-blinded controlled trial with glucose control as the primary outcome. Glucose control is evaluated by fasting serum glucose, serum insulin in all patients, and oral glucose tolerance test (OGTT) in patients not on insulin treatment. Moreover, as a secondary aim, we investigate the role of BSE in improving other signs of metabolic alterations, including oxidative stress, proteinuria, inflammation and production of uremic toxins from the gut microbiota. Patients: Adult patients with T2D and CKD (eGFR 15- 45 ml/min/1.73m2) are included and randomized 1:1 to receive BSE or placebo. Both groups are followed for 20 weeks. The first 12 weeks, patients receive BSE or placebo and are then followed for 8 weeks. Patients randomized to BSE receive an increasing dose of sulforaphane administered as BSE (Lantmännen®) starting with 50 µmmol/day in week 0 - 4; 100 µmmol/day in week 5 - 8 and 150 µmmol/day in week 9 - 12. The placebo consists of maltodextrin sprayed with copper-chlorophyllin. Blood and urine laboratory measurements and OGTT is performed at week 0, 12 and 20. Randomization is done using a computer-based block randomization algorithm. The protocol is registered at clinicaltrials.gov (NCT04858854). Results 98 patients with T2D and CKD from 12 centers in Sweden were included and the recruiting phase has now been finalized but the follow up phase is still ongoing. We here present baseline characteristics of all study participants (Table 1). Median age is 75 years and a minority are women. Mean eGFR corresponds to CKD stage 4 and there are large variations in albumin/creatinine ratios. Most participants are on a combination of oral glucose-lowering agents and insulin. A history of cardiovascular disease is common, and 21% had a previously had myocardial infarction. Conclusion We are currently conducting a randomized clinical trial testing if BSE can be used as an alternative or add-on to improve glucose control in patients with T2D and CKD stages 3-4 type and to see if this ‘high risk’ patient group could benefit from treatment with BSE.

ABSTRACTIgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. We performed a genome-wide association study involving 10,146 kidney biopsy-diagnosed IgAN cases and 28,751 matched controls across 17 international cohorts. We defined 30 independent genome-wide significant risk loci jointly explaining 11% of disease risk. A total of 16 loci were novel, including TNFSF4, REL, CD28, CXCL8/PF4V1, LY86, LYN, ANXA3, TNFSF8/15, REEP3, ZMIZ1, RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The SNP-based heritability of IgAN was estimated at 23%. We observed a positive genetic correlation between IgAN and total serum IgA levels, allergy, tonsillectomy, and several infections, and a negative correlation with inflammatory bowel disease. All significant non-HLA loci shared with serum IgA levels had a concordant effect on the risk of IgAN. Moreover, IgAN loci were globally enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. The explained heritability was enriched in the regulatory elements of cells from the immune and hematopoietic systems and intestinal mucosa, providing support for the pathogenic role of extra-renal tissues. The polygenic risk of IgAN was associated with early disease onset, increased lifetime risk of kidney failure, as well as hematuria and several other traits in a phenome-wide association study of 590,515 individuals. In the comprehensive functional annotation analysis of candidate causal genes across genome-wide significant loci, we observed the convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.

Abstract Background and Aims In advanced stages of chronic kidney disease (CKD) some glucose-lowering agents, such as metformin, cannot be prescribed to patients with type 2 diabetes (T2D) due to the risk of accumulation and adverse events. Foods with bioactive components, “functional food”, can be an alternative to mitigate the metabolic disturbances in these patients. Previous research on experimental animals and patients with T2D has shown that sulforaphane, present in broccoli sprouts, improves insulin sensitivity and glucose control. We hypothesize that sulforaphane ingested as a broccoli sprout extract (BSE) can improve glucose control in patients with T2D and CKD. Method This is an ongoing multicentre randomized double-blinded controlled trial with glucose control as the primary outcome. Glucose control is evaluated by fasting serum glucose, serum insulin in all patients, and oral glucose tolerance test (OGTT) in patients not on insulin treatment. Moreover, as a secondary aim, we investigate the role of BSE in improving other signs of metabolic alterations, including oxidative stress, proteinuria, inflammation and production of uremic toxins from the gut microbiota. Patients: Adult patients with T2D and CKD (eGFR 15- 45 ml/min/1.73m2) are included and randomized 1:1 to receive BSE or placebo. Both groups are followed for 20 weeks. The first 12 weeks, patients receive BSE or placebo and are then followed for 8 weeks. Patients randomized to BSE receive an increasing dose of sulforaphane administered as BSE (Lantmännen®) starting with 50 µmmol/day in week 0 - 4; 100 µmmol/day in week 5 - 8 and 150 µmmol/day in week 9 - 12. The placebo consists of maltodextrin sprayed with copper-chlorophyllin. Blood and urine laboratory measurements and OGTT is performed at week 0, 12 and 20. Randomization is done using a computer-based block randomization algorithm. The protocol is registered at clinicaltrials.gov (NCT04858854). Results 98 patients with T2D and CKD from 12 centers in Sweden were included and the recruiting phase has now been finalized but the follow up phase is still ongoing. We here present baseline characteristics of all study participants (Table 1). Median age is 75 years and a minority are women. Mean eGFR corresponds to CKD stage 4 and there are large variations in albumin/creatinine ratios. Most participants are on a combination of oral glucose-lowering agents and insulin. A history of cardiovascular disease is common, and 21% had a previously had myocardial infarction. Conclusion We are currently conducting a randomized clinical trial testing if BSE can be used as an alternative or add-on to improve glucose control in patients with T2D and CKD stages 3-4 type and to see if this ‘high risk’ patient group could benefit from treatment with BSE.