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ObjectiveIn 2020, the Canadian Vasculitis Research Network (CanVasc) published their updated recommendations for the management of ANCA-associated vasculitides (AAV). The current addendum provides further recommendations regarding the use of avacopan in AAV based on a review of newly available evidence.MethodsAn updated systematic literature review on avacopan (formerly, CCX168) using Medline, Embase, and the Cochrane Library was performed for publications up to September 2022. New recommendations were developed and categorized according to the EULAR grading levels, as done for previous CanVasc recommendations. A modified Delphi procedure and videoconferences were used to reach ≥80% consensus on the inclusion, wording and grading of each recommendation.ResultsThree new recommendations were developed. They focus on avacopan therapy indication and duration, as well as timely glucocorticoid tapering.ConclusionThese 2022 addended recommendations provide rheumatologists, nephrologists and other specialists caring for patients with AAV with guidance for the use of avacopan, based on current evidence and consensus from Canadian experts.

Kidney international 100(4), 753-779 (2021). doi:10.1016/j.kint.2021.05.015, Published by Elsevier, New York, NY

The immunopathogenic mechanisms underlying immunoglobulin A nephropathy (IgAN) are poorly understood, yet it is one of the most common causes of kidney failure globally. The commonly referenced syndrome of synpharyngitic gross hematuria as a presenting feature of IgAN has led to a logical association between infections and development of IgAN, however no pathogenic organism has been clearly linked to IgAN. Advances in sequencing technology have enabled more detailed characterization of host microbial communities, and highlighted the interrelationship between microbiota and immune responses in health and disease. This review will summarize current thinking on the relationship between microbiota and development of IgAN with a focus on recent studies relating aberrant mucosal IgA-biased immune responses to microbiota and how this may be related to the immunopathogenesis of IgAN.

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerular disease worldwide. The diagnostic histologic hallmark is dominant or codominant IgA staining on kidney biopsy; however, patients may present with various clinical syndromes ranging from asymptomatic abnormalities noted on urinalysis to rapidly progressive glomerulonephritis. Given substantial heterogeneity in the clinical course of disease, online risk calculators are available that may assist in prognostication and inform discussions with patients. Comprehensive supportive treatment is central in the initial therapy of IgAN; the additive benefit of currently available immunosuppressive agents remains an area of controversy. Although proteinuria is attenuated by the use of corticosteroids, the long-term benefits have been questioned, and the use of corticosteroids is associated with severe adverse effects, notably infection. Recent advances in our understanding of mucosal immunity and the role of the complement system in IgAN pathogenesis are leading to development of novel therapeutic options, which are being evaluated in ongoing clinical trials. In this installment of the AJKD Core Curriculum in Nephrology, IgAN pathogenesis, clinical manifestations, histology, prediction tools, and treatment are reviewed, and case examples are presented to illustrate the approach to the management of patients with IgAN.

Background: The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1’s natural absence in laboratory animals makes studying its pathobiology challenging. Methods: In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes. Results: Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR

Although the clinical benefit of obtaining a remission in proteinuria in nephrotic patients with focal and segmental glomerulosclerosis (FSGS) is recognized, the long-term value of maintaining it and the impact of relapses on outcome are not well described.We examined the impact of remissions and relapses on either a 50% decline in kidney function or ESKD (combined event) using time-dependent and landmark analyses in a retrospective study of all patients from the Toronto Glomerulonephritis Registry with biopsy-proven FSGS, established nephrotic-range proteinuria and at least one remission.In the 203 FSGS individuals with a remission, 89 never relapsed and 114 experienced at least one relapse. The first recurrence was often followed by a repeating pattern of remission and relapse. The 10-year survival from a combined event was 15% higher in those with no relapse versus those with any relapse. This smaller than anticipated difference was related to the favorable outcome in individuals whose relapses quickly remitted. Relapsers who ultimately ended in remission (n = 46) versus in relapse (n = 68) experienced a 91% and 32% 7-year event survival (p0.001). Using time-varying survival analyses that considered all periods of remission and relapse in every patient and adjusting for each period's initial eGFR, the state of relapse was associated with a 2.17 (95%CI,1.32-3.58, p = 0.002) greater risk of experiencing a combined event even in this FSGS remission cohort.In FSGS, unless remissions are maintained and relapses avoided, long-term renal survival remains poor. Treatment strategies addressing remission duration remain poorly defined and should be an essential question in future trials.

The application of deep learning for automated segmentation (delineation of boundaries) of histologic primitives (structures) from whole slide images can facilitate the establishment of novel protocols for kidney biopsy assessment. Here, we developed and validated deep learning networks for the segmentation of histologic structures on kidney biopsies and nephrectomies. For development, we examined 125 biopsies for Minimal Change Disease collected across 29 NEPTUNE enrolling centers along with 459 whole slide images stained with Hematoxylin & Eosin (125), Periodic Acid Schiff (125), Silver (102), and Trichrome (107) divided into training, validation and testing sets (ratio 6:1:3). Histologic structures were manually segmented (30048 total annotations) by five nephropathologists. Twenty deep learning models were trained with optimal digital magnification across the structures and stains. Periodic Acid Schiff-stained whole slide images yielded the best concordance between pathologists and deep learning segmentation across all structures (F-scores: 0.93 for glomerular tufts, 0.94 for glomerular tuft plus Bowman's capsule, 0.91 for proximal tubules, 0.93 for distal tubular segments, 0.81 for peritubular capillaries, and 0.85 for arteries and afferent arterioles). Optimal digital magnifications were 5X for glomerular tuft/tuft plus Bowman's capsule, 10X for proximal/distal tubule, arteries and afferent arterioles, and 40X for peritubular capillaries. Silver stained whole slide images yielded the worst deep learning performance. Thus, this largest study to date adapted deep learning for the segmentation of kidney histologic structures across multiple stains and pathology laboratories. All data used for training and testing and a detailed online tutorial will be publicly available.

Introduction Narsoplimab is a human monoclonal antibody against mannan-associated lectin-binding serine protease−2 (MASP-2). Now in a phase 3 study, narsoplimab was evaluated in a staged phase 2 study assessing safety and effectiveness in high-risk patients with IgA nephropathy (IgAN). Methods Substudy 1 was a single-arm open-label study of 12 weekly infusions and tapered corticosteroids, with 6 weeks of follow-up. In substudy 2, patients were randomized 1:1 to receive a course of treatment consisting of once-weekly narsoplimab or vehicle infusions for 12 weeks. After 6 weeks of follow-up, both substudy 2 groups could continue in an open-label extension, receiving 1 or more narsoplimab courses at the investigator’s discretion. Results The most commonly reported adverse events (AEs) included headache, upper respiratory infection, and fatigue. Most AEs were mild or moderate and transient. No treatment-related serious AEs were reported. All 4 patients who were enrolled in substudy 1 had reductions in 24-hour urine protein excretion (UPE) at week 18, ranging from 54% to 95% compared with baseline. In substudy 2, the vehicle and narsoplimab groups had similar proteinuria reductions at week 18. Eight patients (3 vehicle, 5 narsoplimab) continued in the dosing extension; all received narsoplimab. Median reduction in 24-hour UPE in these 8 patients was 61.4% at 31 to 54 weeks postbaseline. Estimated glomerular filtration rates (eGFR) remained stable in both substudies. Conclusion This interim analysis suggests that narsoplimab treatment is safe, is well tolerated, and may result in clinically meaningful reductions in proteinuria and stability of eGFR in high-risk patients with advanced IgAN., Graphical abstract

ObjectiveIn 2015, the Canadian Vasculitis Research Network (CanVasc) created recommendations for the management of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) in Canada. The current update aims to revise existing recommendations and create additional recommendations, as needed, based on a review of new available evidence.MethodsA needs assessment survey of CanVasc members informed questions for an updated systematic literature review (publications spanning May 2014 to September 2019) using Medline, Embase, and Cochrane. New and revised recommendations were developed and categorized according to the level of evidence and strength of each recommendation. The CanVasc working group used a 2-step modified Delphi procedure to reach > 80% consensus on the inclusion, wording, and grading of each new and revised recommendation.ResultsEleven new and 16 revised recommendations were created and 12 original (2015) recommendations were retained. New and revised recommendations are discussed in detail within this document. Five original recommendations were removed, of which 4 were incorporated into the explanatory text. The supplementary material for practical use was revised to reflect the updated recommendations.ConclusionThe 2020 updated recommendations provide rheumatologists, nephrologists, and other specialists caring for patients with AAV in Canada with new management guidance, based on current evidence and consensus from Canadian experts.

Background: SGLT2 inhibition decreases albuminuria and reduces the risk of kidney disease progression in patients with type 2 diabetes. These benefits are unlikely to be mediated by improvements in glycaemic control alone. Therefore, we aimed to examine the kidney effects of the SGLT2 inhibitor dapagliflozin in patients with proteinuric kidney disease without diabetes. Methods: DIAMOND was a randomised, double-blind, placebo-controlled crossover trial done at six hospitals in Canada, Malaysia, and the Netherlands. Eligible participants were adult patients (aged 18–75 years) with chronic kidney disease, without a diagnosis of diabetes, with a 24-h urinary protein excretion greater than 500 mg and less than or equal to 3500 mg and an estimated glomerular filtration rate (eGFR) of at least 25 mL/min per 1·73 m2, and who were on stable renin–angiotensin system blockade. Participants were randomly assigned (1:1) to receive placebo and then dapagliflozin 10 mg per day or vice versa. Each treatment period lasted 6 weeks with a 6-week washout period in between. Participants, investigators, and study personnel were masked to assignment throughout the trial and analysis. The primary outcome was percentage change from baseline in 24-h proteinuria during dapagliflozin treatment relative to placebo. Secondary outcomes were changes in measured GFR (mGFR; via iohexol clearance), bodyweight, blood pressure, and concentrations of neurohormonal biomarkers. Analyses were done in accordance with the intention-to-treat principle. This study is registered with ClinicalTrials.gov, NCT03190694. Findings: Between Nov 22, 2017, and April 5, 2019, 58 patients were screened, of whom 53 (mean age 51 years [SD 13]; 32% women) were randomly assigned (27 received dapagliflozin then placebo and 26 received placebo then dapagliflozin). One patient discontinued during the first treatment period. All patients were included in the analysis. Mean baseline mGFR was 58·3 mL/min per 1·73 m2 (SD 23), median proteinuria was 1110 mg per 24 h (IQR 730–1560), and mean HbA1c was 5·6% (SD 0·4). The difference in mean proteinuria change from baseline between dapagliflozin and placebo was 0·9% (95% CI −16·6 to 22·1; p=0·93). Compared with placebo, mGFR was changed with dapagliflozin treatment by −6·6 mL/min per 1·73 m2 (–9·0 to −4·2; p

Thrombotic microangiopathy (TMA) is a pathological lesion observed in a wide spectrum of diseases, triggered by endothelial injury and/or dysfunction. Although TMA lesions are often accompanied by clinical features of microangiopathic hemolytic anemia, thrombocytopenia and ischemic end organ injury, renal-limited forms of TMA are not infrequently encountered in clinical practice. The presence of renal-limited manifestations can be diagnostically challenging, often delaying initiation of targeted therapy. Prompt investigation and empiric treatment of TMA is warranted to reduce associated morbidity and mortality. Major advances have been made with respect to the pathophysiology of primary TMA entities, with the subsequent development of novel diagnostic tools and lifesaving therapies for diseases like thrombotic thrombocytopenic purpura and complement-mediated TMA. This article will review the clinical presentation and pathologic hallmarks of TMA involving the kidney, and the disease-specific mechanisms that contribute to the endothelial injury that characterizes TMA lesions. Diagnostic approach, and both empiric and disease-specific treatment strategies will be discussed, along with the potential role for emerging targeted disease-specific therapies.

Kidney international / Reports 7(9), 2076-2080 (2022). doi:10.1016/j.ekir.2022.05.022, Published by Elsevier, Amsterdam

IgA nephropathy (IgAN) differs from other glomerular diseases by the frequently predominant lambda over kappa light chain deposition. Using the Cure Glomerulonephropathy (CureGN) IgAN cohort, we aimed to determine whether predominant lambda chain deposition is associated with worse clinical outcomes or histopathologic markers of more active disease.Patients were categorized based on the intensity of light chain staining. The lambda dominant (LD) group was defined by a difference in intensity score of lambda minus kappa ≥ 1+ and the kappa-lambda codominant (KL) group by a difference 1+. We compared the clinical course of patients in each category from the time of kidney biopsy and time of enrollment into CureGN to the time of remission (proteinuria 0.3 g/g), 50% reduction in estimated glomerular filtration rate (eGFR), or progression to end-stage kidney disease (ESKD). We also analyzed differences in histopathologic characteristics between the 2 groups.Among 440 patients, we found no significant differences between groups in baseline clinical characteristics nor in rates of remission, 50% reduction in eGFR, or progression to ESKD. Patients in the LD group had a modestly greater frequency of IgG staining ≥ 1+. The biopsy results of 234 patients reviewed by CureGN pathologists revealed a greater frequency of endocapillary hypercellularity (51.1% vs. 36.3%,In IgAN, we found an association between lambda predominance and increased endocapillary hypercellularity, but no association with clinical outcomes.

IgA nephropathy (IgAN) is a leading cause of kidney failure, yet little is known about the immunopathogenesis of this disease. IgAN is characterized by deposition of IgA in the kidney glomeruli, but the source and stimulus for IgA production are not known. Clinical and experimental data suggest a role for aberrant immune responses to mucosal microbiota in IgAN, and in some countries with high disease prevalence, tonsillectomy is regarded as standard-of-care therapy. To evaluate the relationship between microbiota and mucosal immune responses, we characterized the tonsil microbiota in patients with IgAN versus nonrelated household-matched control group participants and identified increased carriage of the genus Neisseria and elevated Neisseria-targeted serum IgA in IgAN patients. We reverse-translated these findings in experimental IgAN driven by BAFF overexpression in BAFF-transgenic mice rendered susceptible to Neisseria infection by introduction of a humanized CEACAM-1 transgene (B × hC-Tg). Colonization of B × hC-Tg mice with Neisseria yielded augmented levels of systemic Neisseria-specific IgA. Using a custom ELISPOT assay, we discovered anti-Neisseria-specific IgA-secreting cells within the kidneys of these mice. These findings suggest a role for cytokine-driven aberrant mucosal immune responses to oropharyngeal pathobionts, such as Neisseria, in the immunopathogenesis of IgAN. Furthermore, in the presence of excess BAFF, pathobiont-specific IgA can be produced in situ within the kidney.

The diagnosis of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies, but not specific to underlying pathobiology. Consequently, there are variable rates of progression and response to therapy within diagnoses. Here, an unbiased transcriptomic-driven approach was used to identify molecular pathways which are shared by subgroups of patients with either minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). Kidney tissue transcriptomic profile-based clustering identified three patient subgroups with shared molecular signatures across independent, North American, European, and African cohorts. One subgroup had significantly greater disease progression (Hazard Ratio 5.2) which persisted after adjusting for diagnosis and clinical measures (Hazard Ratio 3.8). Inclusion in this subgroup was retained even when clustering was limited to those with less than 25% interstitial fibrosis. The molecular profile of this subgroup was largely consistent with tumor necrosis factor (TNF) pathway activation. Two TNF pathway urine markers were identified, tissue inhibitor of metalloproteinases-1 (TIMP-1) and monocyte chemoattractant protein-1 (MCP-1), that could be used to predict an individual's TNF pathway activation score. Kidney organoids and single nucleus RNA-sequencing of participant kidney biopsies, validated TNF-dependent increases in pathway activation score, transcript and protein levels of TIMP-1 and MCP-1, in resident kidney cells. Thus, molecular profiling identified a subgroup of patients with either MCD or FSGS who shared kidney TNF pathway activation and poor outcomes. A clinical trial testing targeted therapies in patients selected using urinary markers of TNF pathway activation is ongoing.

Background Risk of kidney function decline in immunoglobulin A (IgA) nephropathy (IgAN) is significant and may not be predicted by available clinical and histological tools. To serve this unmet need, we aimed at developing a urinary biomarker-based algorithm that predicts rapid disease progression in IgAN, thus enabling a personalized risk stratification. Methods In this multicentre study, urine samples were collected in 209 patients with biopsy-proven IgAN. Progression was defined by tertiles of the annual change of estimated glomerular filtration rate (eGFR) during follow-up. Urine samples were analysed using capillary electrophoresis coupled mass spectrometry. The area under the receiver operating characteristic curve (AUC) was used to evaluate the risk prediction models. Results Of the 209 patients, 64% were male. Mean age was 42 years, mean eGFR was 63 mL/min/1.73 m2 and median proteinuria was 1.2 g/day. We identified 237 urine peptides showing significant difference in abundance according to the tertile of eGFR change. These included fragments of apolipoprotein C-III, alpha-1 antitrypsin, different collagens, fibrinogen alpha and beta, titin, haemoglobin subunits, sodium/potassium-transporting ATPase subunit gamma, uromodulin, mucin-2, fractalkine, polymeric Ig receptor and insulin. An algorithm based on these protein fragments (IgAN237) showed a significant added value for the prediction of IgAN progression [AUC 0.89; 95% confidence interval (CI) 0.83–0.95], as compared with the clinical parameters (age, gender, proteinuria, eGFR and mean arterial pressure) alone (0.72; 95% CI 0.64–0.81). Conclusions A urinary peptide classifier predicts progressive loss of kidney function in patients with IgAN significantly better than clinical parameters alone., Graphical Abstract Graphical Abstract

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Kidney international 102(1), 160-172 (2022). doi:10.1016/j.kint.2022.02.042, Published by Elsevier, New York, NY

IgA 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.

Kidney international 100(4, Supplement) S1-S276 (2021). doi:10.1016/j.kint.2021.05.021 special issue: "KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases", Published by Elsevier, New York, NY

Little is known about the risk of cardiovascular disease (CVD) in patients with various primary glomerular diseases. In a population-level cohort of adults with primary glomerular disease, we sought to describe the risk of CVD compared with the general population and the impact of traditional and kidney-related risk factors on CVD risk.Observational cohort study.Adults with membranous nephropathy (n = 387), minimal change disease (n = 226), IgA nephropathy (n = 759), and focal segmental glomerulosclerosis (n = 540) from a centralized pathology registry in British Columbia, Canada (2000-2012).Traditional CVD risk factors (diabetes, age, sex, dyslipidemia, hypertension, smoking, prior CVD) and kidney-related risk factors (type of glomerular disease, estimated glomerular filtration rate [eGFR], proteinuria).A composite CVD outcome of coronary artery, cerebrovascular, and peripheral vascular events, and death due to myocardial infarction or stroke.Subdistribution hazards models to evaluate the outcome risk with non-CVD death treated as a competing event. Standardized incidence rates (SIR) calculated based on the age- and sex-matched general population.During a median 6.8 years of follow-up, 212 patients (11.1%) experienced the CVD outcome (10-year risk, 14.7% [95% CI, 12.8%-16.8%]). The incidence rate was high for the overall cohort (24.7 per 1,000 person-years) and for each disease type (range, 12.2-46.1 per 1,000 person-years), and was higher than that observed in the general population both overall (SIR, 2.46 [95% CI, 2.12-2.82]) and for each disease type (SIR range, 1.38-3.98). Disease type, baseline eGFR, and proteinuria were associated with a higher risk of CVD and, when added to a model with traditional risk factors, led to improvements in model fit (RAscertainment of outcomes and comorbidities using administrative data.Patients with primary glomerular disease have a high absolute risk of CVD that is approximately 2.5 times that of the general population. Consideration of eGFR, proteinuria, and type of glomerular disease may improve risk stratification of CVD risk in these individuals.Patients with chronic kidney disease are known to be at high risk of cardiovascular disease. Cardiovascular risk in patients with primary glomerular diseases is poorly understood because these conditions are rare and require a kidney biopsy for diagnosis. In this study of 1,912 Canadian patients with biopsy-proven IgA nephropathy, minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy, the rate of cardiovascular events was 2.5 times higher than in the general population and was high for each disease type. Consideration of disease type, kidney function, and proteinuria improved the prediction of cardiovascular events. In summary, our population-level study showed that patients with primary glomerular diseases have a high cardiovascular risk, and that inclusion of kidney-specific risk factors may improve risk stratification.

Deciphering immune recognition is critical for understanding a broad range of diseases and for the development of effective vaccines and immunotherapies. Efforts to do so are limited by a lack of technologies capable of simultaneously capturing the complexity of adaptive immune receptor repertoires and the landscape of potential antigens. To address this, we present RAPTR (Receptor-Antigen Pairing by Targeted Retroviruses). RAPTR combines viral pseudotyping and molecular engineering approaches to enable one-pot library on library interaction screens by displaying antigens on the surface of lentiviruses and encoding their identity in the viral genome. Antigen-specific viral infection of cells allows readout of both antigen and receptor identities via single-cell sequencing. The resulting system is modular, scalable, and compatible with any cell type, making it easily implemented. These techniques provide a suite of new tools for targeted viral entry, molecular engineering, and interaction screens with broad potential applications.

Deciphering immune recognition is critical for understanding a broad range of diseases and for the development of effective vaccines and immunotherapies. Efforts to do so are limited by a lack of technologies capable of simultaneously capturing the complexity of adaptive immunoreceptor repertoires and the landscape of potential antigens. To address this, we present receptor-antigen pairing by targeted retroviruses, which combines viral pseudotyping and molecular engineering approaches to enable one-pot library-on-library interaction screens by displaying antigens on the surface of lentiviruses and encoding their identity in the viral genome. Antigen-specific viral infection of cell lines expressing human T or B cell receptors allows readout of both antigen and receptor identities via single-cell sequencing. The resulting system is modular, scalable and compatible with any cell type. These techniques provide a suite of tools for targeted viral entry, molecular engineering and interaction screens with broad potential applications.

BackgroundClassification of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies. This approach does not reflect underlying disease biology, limiting the ability to predict progression or treatment response.MethodsSystems biology approaches were used to categorize patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) based on kidney biopsy tissue transcriptomics across three cohorts and assessed association with clinical outcomes. Patient-level tissue pathway activation scores were generated using differential gene expression. Then, functional enrichment and non-invasive urine biomarker candidates were identified. Biomarkers were validated in kidney organoid models and single nucleus RNA-seq (snRNAseq) from kidney biopsies.ResultsTranscriptome-based categorization identified three subgroups of patients with shared molecular signatures across independent North American, European and African cohorts. One subgroup demonstrated worse longterm outcomes (HR 5.2, p = 0.001) which persisted after adjusting for diagnosis and clinical measures (HR 3.8, p = 0.035) at time of biopsy. This subgroup’s molecular profile was largely (48%) driven by tissue necrosis factor (TNF) activation and could be predicted based on levels of TNF pathway urinary biomarkers TIMP-1 and MCP-1 and clinical features (correlation 0.63, p ConclusionsMolecular profiling identified a patient subgroup within nephrotic syndrome with poor outcome and kidney TNF pathway activation. Clinical trials using non-invasive biomarkers of pathway activation to target therapies are currently being evaluated.Significance StatementMechanistic, targeted therapies are urgently needed for patients with nephrotic syndrome. The inability to target an individual’s specific disease mechanism using currently used diagnostic parameters leads to potential treatment failure and toxicity risk. Patients with focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) were grouped by kidney tissue transcriptional profiles and a subgroup associated with poor outcomes defined. The segregation of the poor outcome group was driven by tumor necrosis factor (TNF) pathway activation and could be identified by urine biomarkers, MCP1 and TIMP1. Based on these findings, clinical trials utilizing non-invasive biomarkers of pathway activation to target therapies, improve response rates and facilitate personalized treatment in nephrotic syndrome have been initiated.

Our understanding of the mechanisms responsible for the progression of chronic kidney disease (CKD) is incomplete. Microarray analysis of kidneys at 4 and 7 weeks of age in Col4a3-/- mice, a model of progressive nephropathy characterized by proteinuria, interstitial fibrosis, and inflammation, revealed that Follistatin-like-1 (Fstl1) was one of only four genes significantly overexpressed at 4 weeks of age. mRNA levels for the Fstl1 receptors, Tlr4 and Dip2a, increased in both Col4a-/- mice and mice subjected to unilateral ureteral obstruction (UUO). RNAscope® (Advanced Cell Diagnostics, Newark CA, USA) localized Fstl1 to interstitial cells, and in silico analysis of single cell transcriptomic data from human kidneys showed Fstl1 confined to interstitial fibroblasts/myofibroblasts. In vitro, FSTL1 activated AP1 and NFκB, increased collagen I (COL1A1) and interleukin-6 (IL6) expression, and induced apoptosis in cultured kidney cells. FSTL1 expression in the NEPTUNE cohort of humans with focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), and IgA nephropathy (IgAN) was positively associated with age, eGFR, and proteinuria by multiple linear regression, as well as with interstitial fibrosis and tubular atrophy. Clinical disease progression, defined as dialysis or a 40 percent reduction in eGFR, was greater in patients with high baseline FSTL1 mRNA levels. FSTL1 is a fibroblast-derived cytokine linked to the progression of experimental and clinical CKD.

A previously healthy 55-year-old woman with no history of kidney disease presented for a routine physical examination and was found to havenephrotic-range proteinuria of approximately 6 g/day. For the past year, the patient and her 50-year-old sister had been taking a weight loss supplement (MetaSwitchTM) they purchased online. The younger sister was found to have nephrotic syndrome, and subsequent kidney biopsies from both sisters were consistent with membranous nephropathy (MN). This disease can be idiopathic in nature or it can occur secondary to a wide range of etiologies, such as autoimmunity and toxin exposure (1); however, familial variants are exceedingly rare. The proteinuria gradually resolved in both sisters within 6 months of ceasing the intake of the supplements; this result raises strong suspicion of a nephrotoxic agent in the supplement. The claimed contents of the supplement were unremarkable in terms of ingredients with overt nephrotoxic potential: α lipoic acid, ginseng,citrulline, leucine, d-ribose-l-cysteine, potassium, and vitamins [vitamin D2, B1 (thiamine), B5 (pantetheine), B6, B12]. The laboratory was contacted to further investigate this case of suspected supplement contamination after common causes of MN were ruled out with extensive studies including serum and urine protein electrophoresis, antinuclear antibody and infectious disease screens, complement levels, and age-appropriate malignancy screens. Supplement capsules were …

There is little known about geographic variability in the incidence of glomerular disease and its potential implications for care delivery. To evaluate this, we performed a population-level cohort study using a provincial renal pathology database (2000-2012) to capture all incident cases of glomerulonephritis in British Columbia, Canada. This included 401 patients with membranous nephropathy (MN), 824 patients with IgA nephropathy (IgAN), 385 patients with focal segmental glomerulosclerosis (FSGS), 397 patients with lupus nephritis (LN) and 399 patients with ANCA-related glomerulonephritis (ANCA-GN). Geographic clusters were identified using Bayesian spatial models to estimate the incidence of each disease in 74 regions compared to the mean incidence in the entire province (incidence rate ratio, [IRR]), adjusted for region-level age, sex and race. The proportion of overall variability in incidence attributed to inter-regional differences varied by disease: 18% in MN, 81% in IgAN, 18% in FSGS, 59% in ANCA-GN, and 89% in LN. Except for LN, clustering was not explained by demographics. All IgAN and LN clusters were in urban regions close to nephrology centers, whereas ANCA-GN, MN and FSGS clustered mainly in rural regions. All ANCA-GN clusters were rural with median population density 1.2 persons/km2 and driving distances of 10-676 km to the nearest nephrology center. Thus, we found significant geographic clustering in the incidence of different glomerular diseases. MN, FSGS and ANCA-GN clustered in sparsely populated regions with limited access to care, underscoring the importance of regional variability in glomerular diseases to inform health services delivery.

BACKGROUND: B-cell anomalies play a role in the pathogenesis of membranous nephropathy. B-cell depletion with rituximab may therefore be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria in patients with this condition.METHODS: We randomly assigned patients who had membranous nephropathy, proteinuria of at least 5 g per 24 hours, and a quantified creatinine clearance of at least 40 ml per minute per 1.73 m2 of body-surface area and had been receiving angiotensin-system blockade for at least 3 months to receive intravenous rituximab (two infusions, 1000 mg each, administered 14 days apart; repeated at 6 months in case of partial response) or oral cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed for 24 months. The primary outcome was a composite of complete or partial remission of proteinuria at 24 months. Laboratory variables and safety were also assessed.RESULTS: A total of 130 patients underwent randomization. At 12 months, 39 of 65 patients (60%) in the rituximab group and 34 of 65 (52%) in the cyclosporine group had a complete or partial remission (risk difference, 8 percentage points; 95% confidence interval [CI], -9 to 25; P = 0.004 for noninferiority). At 24 months, 39 patients (60%) in the rituximab group and 13 (20%) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95% CI, 25 to 55; PCONCLUSIONS: Rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months. (Funded by Genentech and the Fulk Family Foundation; MENTOR ClinicalTrials.gov number, NCT01180036.).

American journal of nephrology 52(10/11), 827-836 (2021). doi:10.1159/000519812, Published by Karger, Basel [u.a.]

The immunopathogenic mechanisms underlying immunoglobulin A nephropathy (IgAN) are poorly understood, yet it is one of the most common causes of kidney failure globally. The commonly referenced syndrome of synpharyngitic gross hematuria as a presenting feature of IgAN has led to a logical association between infections and development of IgAN, however no pathogenic organism has been clearly linked to IgAN. Advances in sequencing technology have enabled more detailed characterization of host microbial communities, and highlighted the interrelationship between microbiota and immune responses in health and disease. This review will summarize current thinking on the relationship between microbiota and development of IgAN with a focus on recent studies relating aberrant mucosal IgA-biased immune responses to microbiota and how this may be related to the immunopathogenesis of IgAN.

Rationale & Objective Pathogenic variants in type IV collagen have been reported to account for a significant proportion of chronic kidney disease. Accordingly, genetic testing is increasingly used to diagnose kidney diseases, but testing also may reveal rare missense variants that are of uncertain clinical significance. To aid in interpretation, computational prediction (called in silico) programs may be used to predict whether a variant is clinically important. We evaluate the performance of in silico programs for COL4A3/A4/A5 variants. Study Design, Setting, & Participants Rare missense variants in COL4A3/A4/A5 were identified in disease cohorts, including a local focal segmental glomerulosclerosis (FSGS) cohort and publicly available disease databases, in which they are categorized as pathogenic or benign based on clinical criteria. Tests Compared & Outcomes All rare missense variants identified in the 4 disease cohorts were subjected to in silico predictions using 12 different programs. Comparisons between the predictions were compared with: (1) variant classification (pathogenic or benign) in the cohorts and (2) functional characterization in a randomly selected smaller number (17) of pathogenic or uncertain significance variants obtained from the local FSGS cohort. Results In silico predictions correctly classified 75% to 97% of pathogenic and 57% to 100% of benign COL4A3/A4/A5 variants in public disease databases. The congruency of in silico predictions was similar for variants categorized as pathogenic and benign, with the exception of benign COL4A5 variants, in which disease effects were overestimated. By contrast, in silico predictions and functional characterization classified all 9 pathogenic COL4A3/A4/A5 variants correctly that were obtained from a local FSGS cohort. However, these programs also overestimated the effects of genomic variants of uncertain significance when compared with functional characterization. Each of the 12 in silico programs used yielded similar results. Limitations Overestimation of in silico program sensitivity given that they may have been used in the categorization of variants labeled as pathogenic in disease repositories. Conclusions Our results suggest that in silico predictions are sensitive but not specific to assign COL4A3/A4/A5 variant pathogenicity, with misclassification of benign variants and variants of uncertain significance. Thus, we do not recommend in silico programs but instead recommend pursuing more objective levels of evidence suggested by medical genetics guidelines.

Background and Objective: Dapagliflozin, a sodium-glucose co-transporter inhibitor, was originally developed as an oral glucose-lowering drug for the treatment of type 2 diabetes mellitus. Emerging data suggest that cardiovascular and kidney benefits extend to patients without diabetes. Limited pharmacological data are, however, available in patients without diabetes. We aimed to characterise the pharmacokinetic profile of dapagliflozin in patients with chronic kidney disease without type 2 diabetes. Methods: Plasma samples were collected in a randomised, placebo-controlled, double-blind, cross-over trial (DIAMOND, NCT03190694, n = 53) that assessed the effects of 10 mg of dapagliflozin in patients with a glomerular filtration rate ≥ 25 mL/min/1.73 m2 and proteinuria > 500 mg/day. Mixed-effects models were used to develop a pharmacokinetic model and to evaluate the association between plasma exposure and response. Results: Plasma concentrations (n = 430 observations) from 48 patients (mean age 50.8 years, mean glomerular filtration rate 57.9 mL/min/1.73 m2, median proteinuria 1115 mg/24 h) were best described using a two-compartment model with first-order elimination. Apparent clearance and volume of distribution were 11.7 (95% confidence interval 10.7–12.7) L/h and 44.9 (95% confidence interval 39.0–50.9) L, respectively. Median dapagliflozin plasma exposure was 740.9 ng h/mL (2.5th–97.5th percentiles: 434.0–1615.3). Plasma exposure increased with decreasing kidney function. Every 100-ng h/mL increment in dapagliflozin plasma exposure was associated with a decrease in the urinary albumin:creatinine ratio (β = − 2.8%, p = 0.01), glomerular filtration rate (β = − 0.5 mL/min/1.73 m2, p

Recent clinical trial results on the role of corticosteroids for prevention of progression of IgA nephropathy (IgAN) are challenging to reconcile, and the use of corticosteroids in the management of IgAN remains controversial. However, there is a clear mechanistic rationale to support the use of these medications, and compelling data supporting efficacy. We argue that corticosteroids are effective in slowly progressive IgAN and propose ways to optimize, personalize, and improve the safety of this approach. There is a strong biologic underpinning for corticosteroid use in addressing the underlying pathophysiology of IgAN. Glucocorticoids exert potent immunosuppressive activity via genomic and nongenomic effects on immune cells and tissue. A central mechanism includes interruption of the activity of key nuclear transcription factors (ex. NFκB), affecting genes encoding the mediators involved in the regulation of inflammation (1). Modulation of expression of cytokines, chemokines, and adhesion molecule synthesis has important downstream effects on the activity, proliferation, and survival of contributors to glomerular inflammation including monocytes, macrophages, and T cells. Evidence derived both in vivo and in vitro support the potential for corticosteroids to interfere with several core pathophysiologic processes implicated in IgAN pathogenesis. For example, serum levels of total and galactose-deficient IgA1 are reduced after treatment of patients with IgAN with glucocorticoids, and in patients with IgAN initiating glucocorticoid-containing treatment for transplant (2,3). One potential explanation for this reduction in galactose-deficient IgA1 is the effect of glucocorticoids on the expression of cytokines such as IL6, which affect Ig production by IgA-secreting plasma cells, or may affect the activity of glycosyltransferases responsible for IgA1 glycosylation (4). On the basis of in vitro models of GN, where mesangial and tubular cells are exposed to protein and immune complexes, corticosteroids are hypothesized to affect glomerular and interstitial inflammation induced by infiltrating lymphocytes and resident kidney cells …

Contains fulltext : 225968.pdf (Publisher’s version ) (Closed access) Immunosuppression in IgA nephropathy (IgAN) should be reserved for patients at high-risk of disease progression, which KDIGO guidelines determine based solely on proteinuria 1g or more/day. To investigate if treatment decisions can be more accurately accomplished using individualized risk from the International IgAN Prediction Tool, we simulated allocation of a hypothetical immunosuppression therapy in an international cohort of adults with IgAN. Two decision rules for treatment were applied based on proteinuria of 1g or more/day or predicted risk from the Prediction Tool above a threshold probability. An appropriate decision was defined as immunosuppression allocated to patients experiencing the primary outcome (50% decline in eGFR or ESKD) and withheld otherwise. The net benefit and net reduction in treatment are the proportion of patients appropriately allocated to receive or withhold immunosuppression, adjusted for the harm from inappropriate decisions, calculated for all threshold probabilities from 0-100%. Of 3299 patients followed for 5.1 years, 522 (15.8%) experienced the primary outcome. Treatment allocation based solely on proteinuria of 1g or more/day had a negative net benefit (was harmful) because immunosuppression was increasingly allocated to patients without progressive disease. Compared to using proteinuria, treatment allocation using the Prediction Tool had a larger net benefit up to 23.4% (95% confidence interval 21.5-25.2%) and a larger net reduction in treatment up to 35.1% (32.3-37.8%). Thus, allocation of immunosuppression to high-risk patients with IgAN can be substantially improved using the Prediction Tool compared to using proteinuria.

Background and Aims A relative reduction in proteinuria has been proposed as a surrogate outcome for therapeutic trials in IgA nephropathy. It is currently unknown how long a reduction in proteinuria needs to be maintained in order to mitigate the long-term risk of disease progression. To address this knowledge gap we sought to quantify the association between duration of proteinuria remission and the risk of disease progression in IgA nephropathy. Method In this retrospective multi-ethnic international cohort of adult patients with biopsy-proven IgA nephropathy, we defined proteinuria remission based on three criteria: (i) peak proteinuria on/after biopsy ≥1g/day; (ii) an absolute reduction in proteinuria to Results A total of 1864 patients met criteria for remission, which occurred a median of 8.3 months after biopsy (IQR 3.6-22). They had a median age of 36.8 (IQR 29.4-46.6) years and a median eGFR of 78 (IQR 55-104) mL/min/1.73m2. Median proteinuria was 1.54 (IQR 1.09-2.4) g/day at the time of biopsy and 0.55 (IQR 0.33-0.76) g/day at the time of entering remission. During a median follow-up of 3.9 years, 274 patients (14.7%) experienced the primary outcome. The relationship between duration of proteinuria remission and the primary outcome was non-linear (Figure). Each 3 months in sustained remission up to 51 months was associated with an additional 9% reduction in the risk of disease progression (hazard ratio 0.91, 95% confidence interval 0.89-0.93). In contrast, each additional 3 months in remission beyond 51 months was associated with a smaller non-significant risk reduction (hazard ratio 0.99, 95% confidence interval 0.96-1.03). These finding were robust to multivariable adjustment and were consistent across subgroups based on the MEST histology score, and whether or not the remission occurred while on renin-angiotensin-aldosterone-system blockade or after immunosuppression treatment. Results were similar when relapse was defined as either a 50% or 100% increase in proteinuria from the nadir value after remission to an absolute value of ≥1g/day. Conclusion We observed a strong non-linear dose-response relationship between the duration of proteinuria remission and the risk of disease progression in patients with IgA nephropathy. The ability to quantitate the renal survival benefit related to the duration of remission is an important advance for patients and their physicians. Rather than there being a minimum duration of proteinuria remission in IgA nephropathy, our results demonstrate that even short durations in remission, or small increases in remission duration, are both associated with significant reductions in the risk of disease progression. For future therapeutic trials in IgA nephropathy using proteinuria as a surrogate outcome, our findings illustrate the need to consider the duration of proteinuria reduction, in addition to the magnitude of proteinuria reduction, when evaluating the anticipated treatment effect on long-term clinical endpoints.

Background and objectives FSGS and nephrotic syndrome studies have shown that single gene causes are more likely to be found in pediatric cases than adults. Consequently, many studies have examined limited gene panels in largely pediatric cohorts. Design, setting, participants, & measurements Whole-exome sequencing was performed in adults with FSGS diagnosed between 1976 and 2017 in the Toronto GN Registry. An expanded panel of 109 genes linked to FSGS, glomerular basement membrane abnormalities, as well as causes of pediatric ESKD including congenital abnormalities of the kidney and urinary tract (CAKUT) and nephronophthisis, were examined. Results The cohort was composed of 193 individuals from 179 families. Nearly half (49%) developed ESKD at a mean age of 47±17 years. The genetic diagnostic rate was 11%. Of definitely pathogenic variants, 55% were in COL4A (A3/A4/A5), 40% were in podocyte genes, and 5% were in CAKUT genes. Many, but not all individuals with COL4A definitely pathogenic variants had some evidence of glomerular basement membrane abnormalities. The estimated mean survival/age of kidney failure for individuals with COL4A definitely pathogenic variants was 58 years (95% confidence interval, 49 to 69), far later than what has been reported in the literature. Likely pathogenic variants were identified in an additional 9% of the cohort, with most in COL4A. Correlation with glomerular basement membrane morphology suggested a causal role for at least some of these likely pathogenic variants. Conclusions Even with an expanded gene panel, we find that COL4A disorders are the leading monogenic cause in adults diagnosed with FSGS. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_01_15_CJASNPodcast_19_02_.mp3

Purpose of program: This article will provide guidance on how to best manage patients with glomerulonephritis (GN) during the COVID-19 pandemic. Sources of information: We reviewed relevant published literature, program-specific documents, and guidance documents from international societies. An informal survey of Canadian nephrologists was conducted to identify practice patterns and expert opinions. We hosted a national webinar with invited input and feedback after webinar. Methods: The Canadian Society of Nephrology (CSN) Board of Directors invited physicians with expertise in GN to contribute. Specific COVID-19-related themes in GN were identified, and consensus-based recommendations were made by this group of nephrologists. The recommendations received further peer input and review by Canadian nephrologists via a CSN-sponsored webinar. This was attended by 150 kidney health care professionals. The final consensus recommendations also incorporated review by Editors of the Canadian Journal of Kidney Health and Disease. Key findings: We identified 9 areas of GN management that may be affected by the COVID-19 pandemic: (1) clinic visit scheduling, (2) clinic visit type, (3) provision of multidisciplinary care, (4) blood and urine testing, (5) home-based monitoring essentials, (6) immunosuppression, (7) other medications, (8) patient education and support, and (9) employment. Limitations: These recommendations are expert opinion, and are subject to the biases associated with this level of evidence. To expedite the publication of this work, a parallel review process was created that may not be as robust as standard arm’s length peer review processes. Implications: These recommendations are intended to provide optimal care during the COVID-19 pandemic. Our recommendations may change based on the evolving evidence.

IgA nephropathy (IgAN) is an important cause of ESKD for which there are no approved therapies. A challenge for evaluating treatments for IgAN is the usual long time course for progression to ESKD. The aim of this Kidney Health Initiative project was to identify surrogate end points that could serve as reliable predictors of a treatment’s effect on long-term kidney outcomes in IgAN and be used as a basis for approval. Proteinuria was identified as the most widely recognized and well studied risk factor for progression to ESKD in IgAN. The workgroup performed a critical review of the data on proteinuria reduction as a surrogate end point for a treatment’s effect on progression to ESKD in IgAN. Epidemiologic data indicate a strong and consistent relationship between the level and duration of proteinuria and loss of kidney function. Trial-level analyses of data from 13 controlled trials also show an association between treatment effects on percent reduction of proteinuria and treatment effects on a composite of time to doubling of serum creatinine, ESKD, or death. We conclude that data support the use of proteinuria reduction as a reasonably likely surrogate end point for a treatment’s effect on progression to ESKD in IgAN. In the United States, reasonably likely surrogate end points can be used as a basis for accelerated approval of therapies intended to treat serious or life-threatening conditions, such as IgAN. The clinical benefit of products approved under this program would need to be verified in a postmarketing confirmatory trial.