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Background and objectives: C3 glomerulopathy and idiopathic Ig-associated membranoproliferative GN are kidney diseases characterized by abnormal glomerular complement C3 deposition. These conditions are heterogeneous in outcome, but approximately 50% of patients develop kidney failure within 10 years. Design, setting, participants, & measurements: To improve identification of patients with poor prognosis, we performed a detailed analysis of percutaneous kidney biopsies in a large cohort of patients. Using a validated histologic scoring system, we analyzed 156 native diagnostic kidney biopsies from a retrospective cohort of 123patients with C3 glomerulopathy and 33 patients with Ig-associated membranoproliferative GN. We used linear regression, survival analysis, and Cox proportional hazards models to assess the relationship between histologic and clinical parameters with outcome. Results: Frequent biopsy features were mesangial expansion and hypercellularity, glomerular basement membrane double contours, and endocapillary hypercellularity. Multivariable analysis showed negative associations between eGFR and crescents, interstitial inflammation, and interstitialfibrosis/tubular atrophy. Proteinuria positively associated with endocapillary hypercellularity and glomerular basement membrane double contours. Analysis of second native biopsies did not demonstrate associations between immunosuppression treatment and improvement in histology. Using a composite outcome, risk of progression to kidney failure associated with eGFR and proteinuria at the time of biopsy, cellular/fibrocellular crescents, segmental sclerosis, and interstitial fibrosis/tubular atrophy scores. Conclusions: Our detailed assessment of kidney biopsy data indicated that cellular/fibrocellular crescents and interstitial fibrosis/tubular atrophy scores were significant determinants of deterioration in kidney function.

Blocking the complement system as a therapeutic strategy has been proposed for numerous glomerular diseases but presents a myriad of questions and challenges, not the least of which is demonstrating efficacy and safety. In light of these potential issues and because there are an increasing number of anti-complement therapy trials either planned or underway, the National Kidney Foundation (NKF) facilitated an all-virtual format scientific workshop entitled, "Improving Clinical Trials for Anti-complement Therapies in Complement-mediated Glomerulopathies." Attended by patient representatives and experts in glomerular diseases, complement physiology, and clinical trial design, the aim of this workshop was to develop standards applicable for designing and conducting clinical trials for anti-complement therapies across a wide spectrum of complement-mediated glomerulopathies. Discussions focused on study design, subject risk assessment and mitigation, laboratory measurements and biomarkers to support these studies, and identification of optimal outcome measures to detect benefit, specifically for trials in complement-mediated diseases. This report summarizes the discussions from this workshop and outlines consensus recommendations.

Introduction: C3 glomerulopathy (C3G) is a rare, progressive kidney disease resulting from dysregulation of the alternative pathway (AP) of complement. Biomarkers at baseline were investigated in patients with C3G who participated in two phase 2 studies with the factor D (FD) inhibitor, danicopan. Methods: Patients with biopsy-confirmed C3G, proteinuria ≥500 mg/day, and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 were enrolled into two studies (NCT03369236 and NCT03459443). Biomarker analysis was performed for patients with C3G confirmed by central pathology laboratory re-evaluation. Complement and clinical biomarkers, biopsy composite score, and activity and chronicity indices were assessed at baseline and analyzed by pairwise Spearman correlation analysis. Results: Twenty-nine patients were included in the analysis (median [interquartile range] age: 24.0 [10.0] years). Systemic complement AP activation was evident by reduced median concentrations of C3 and C5, elevated sC5b-9, and normal C4, relative to reference ranges. C3 showed strong pairwise correlations with C5 and sC5b-9 (r = 0.80 and −0.73, respectively; p < 0.0001). Baseline Ba and FD concentrations were inversely correlated with eGFR (r = −0.83 and −0.87, respectively; p < 0.0001). Urinary concentrations of sC5b-9 were correlated with both plasma sC5b-9 and proteinuria (r = 0.69 and r = 0.83, respectively; p < 0.0001). Biopsy activity indices correlated strongly with biomarkers of systemic AP activation, including C3 (r = −0.76, p < 0.0001), whereas chronicity indices aligned more closely with eGFR (r = −0.57, p = 0.0021). Conclusion: Associations among complement biomarkers, kidney function, and kidney histology may add to the current understanding of C3G and assist with the characterization of patients with this heterogenous disease.

Hydralazine, a widely used therapy for hypertension and heart failure, can elicit autoimmune disease, including anti-neutrophil cytoplasmic antibody associated glomerulonephritis (ANCA-GN). We identified 80 cases of ANCA-GN complicating treatment with hydralazine, accounting for 4.3% (80/1858 biopsies) of ANCA-GN diagnosed between 2006 and 2019. Over three-fourths of patients were on hydralazine for at least one year, with mean daily dose of approximately 250 mg/day. ANCA testing revealed p-ANCA/myeloperoxidase-ANCA seropositivity in 98%, including 39% with dual p-ANCA/myeloperoxidase-ANCA and cANCA/anti-protinase 3-ANCA positivity, often accompanied by anti-nuclear antibody (89%), anti-histone antibody (98%), and hypocomplementemia (58%). Kidney biopsy revealed necrotizing and crescentic glomerulonephritis, similar to primary ANCA-GN, but significantly less frequently pauci-immune (77 vs. 100%) and more commonly associated with mesangial hypercellularity (30 vs. 5%), electron dense deposits (62 vs. 20%), and endothelial tubuloreticular inclusions (11 vs. 0%); all significant differences. On follow-up, 42 of 51 patients received induction immunosuppression: 19 reached the combined end-points of kidney failure or death and 32 had mean creatinine of 1.49 mg/dL at last follow-up. Thus, hydralazine-associated ANCA-GN often exhibits overlapping clinical and pathologic features of mild immune complex glomerulonephritis resembling lupus nephritis. With discontinuation of hydralazine and immunosuppression, outcomes are similar to primary ANCA-GN.

Background Relapse of the nephrotic syndrome is co mmon among patients with primary membranous nephropathy (MN). Relapses of MN typically occur within a few years of achieving disease remission. There is limited description, to date, regarding patients with MN who have late relapse of MN, i.e., after >5 years of sustained disease remission. The objective of this case series was to report the clinical course of patients with MN who experience late relapse. Methods We analyzed the patient database of the Glomerular Kidney Disease Center at Columbia University to identify patients seen at our center who had relapse of biopsy specimen–proven MN at least 5 years after achieving sustained disease remission. Results We identified 16 patients with late relapse of MN. The median time in sustained remission before relapse was 10.2 (range, 7–29.0) years. Ten patients (63%) were diagnosed with late relapse on the basis of laboratory monitoring alone, without clinical symptoms of the nephrotic syndrome. Fourteen patients (88%) received immunosuppression during their initial presentation and late relapse. Patients had favorable long-term renal outcomes over a median 21 (range, 12–56) year follow-up period, with 14 patients (88%) in remission at study conclusion and a median decline in eGFR per year of −0.63 (range, −6.3 to 17.5) ml/min per 1.73 m2 per year. Conclusions This case series highlights a previously underappreciated, and likely rare, outcome of MN, namely, late relapse. Patients who experience late relapse, and who thus have a longer time in sustained remission, may have a more favorable long-term renal outcome.

Introduction: C3 glomerulopathy (C3G) is an ultrarare, chronic and progressive nephropathy mediated by dysregulation of the alternative pathway of complement (AP), with poor prognosis and limited treatment options. Targeted inhibition of proximal AP through factor D (FD) blockade represents a rational treatment approach. We present two phase 2 proof-of-concept clinical studies of the orally active FD inhibitor danicopan in patients with C3G and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) (NCT03369236 and NCT03459443). Methods: A double-blind, placebo-controlled study in patients with C3G and a single-arm, open-label study in patients with C3G or IC-MPGN treated with danicopan are reported. The studies evaluated pharmacokinetic/pharmacodynamic (PK/PD), efficacy, and safety outcomes. The co-primary endpoints were change from baseline in composite biopsy score and the proportion of patients with a 30% reduction in proteinuria relative to baseline at 6 or 12 months. Results: Optimal systemic concentrations of danicopan were not achieved for complete and sustained inhibition of AP, although there was evidence that blockade of FD reduced AP activity shortly after drug administration. Consequently, limited clinical response was observed in key efficacy endpoints. While stable disease or improvement from baseline was seen in some patients, response was not consistent. The data confirmed the favorable safety profile of danicopan. Conclusion: While demonstrating a favorable safety profile, danicopan resulted in incomplete and inadequately sustained inhibition of AP, probably due to limitations in its PK/PD profile in C3G, leading to lack of efficacy. Complete and sustained AP inhibition is required for a clinical response in patients with C3G.

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

Leukocytoclastic vasculitis has been reported in the setting of COVID-19 infection and post-COVID-19 vaccination. We report a case of post-COVID-19 vaccination IgA vasculitis with IgA immune deposits in the skin and renal involvement; SARS-CoV spike protein immunohistochemical staining was negative. IgA vasculitis with skin and renal involvement is a potential reaction to COVID-19 vaccination. This article is protected by copyright. All rights reserved.

Introduction Glomerular diseases are characterized by variable disease activity over many years. We aimed to analyze the relationship between clinical disease activity and duration of glomerular disease. Methods Disease activity in adults with chronic minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy (IgAN; first diagnostic biopsy >5 years before enrollment; Of Longstanding Disease [OLD] cohort, n = 256) followed at Columbia University Medical Center (CUMC), was compared with disease activity of an internal and external cohort of patients with first diagnostic biopsy, Graphical abstract

A 26-year-old woman contacted our office asking for an urgent call back. She had a history of steroid-dependent and frequently relapsing minimal change disease, and calls like this usually meant her home dipsticks had turned positive. Instead, she reported that she had just tested positive for the

Background and objectives Actionable genetic findings have implications for care of patients with kidney disease, and genetic testing is an emerging tool in nephrology practice. However, there are scarce data regarding best practices for return of results and clinical application of actionable genetic findings for kidney patients. Design, setting, participants, & measurements We developed a return of results workflow in collaborations with clinicians for the retrospective recontact of adult nephrology patients who had been recruited into a biobank research study for exome sequencing and were identified to have medically actionable genetic findings. Results Using this workflow, we attempted to recontact a diverse pilot cohort of 104 nephrology research participants with actionable genetic findings, encompassing 34 different monogenic etiologies of nephropathy and five single-gene disorders recommended by the American College of Medical Genetics and Genomics for return as medically actionable secondary findings. We successfully recontacted 64 (62%) participants and returned results to 41 (39%) individuals. In each case, the genetic diagnosis had meaningful implications for the patients’ nephrology care. Through implementation efforts and qualitative interviews with providers, we identified over 20 key challenges associated with returning results to study participants, and found that physician knowledge gaps in genomics was a recurrent theme. We iteratively addressed these challenges to yield an optimized workflow, which included standardized consultation notes with tailored management recommendations, monthly educational conferences on core topics in genomics, and a curated list of expert clinicians for patients requiring extranephrologic referrals. Conclusions Developing the infrastructure to support return of genetic results in nephrology was resource-intensive, but presented potential opportunities for improving patient care. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_04_16_12481019.mp3

Alport syndrome is an inherited disease characterized by progressive loss of kidney function. We aimed to evaluate the safety and efficacy of bardoxolone methyl in patients with Alport syndrome.We randomly assigned patients with Alport syndrome, ages 12-70 years and eGFR 30-90 ml/min per 1.73 mPatients randomized to bardoxolone methyl experienced preservation in eGFR relative to placebo at 48 and 100 weeks (between-group differences: 9.2 [97.5% confidence interval, 5.1 to 13.4;In adolescent and adult patients with Alport syndrome receiving standard of care, treatment with bardoxolone methyl resulted in preservation in eGFR relative to placebo after a 2-year study period; off-treatment results using all available data were not significantly different.A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Alport Syndrome - CARDINAL (CARDINAL), NCT03019185.

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.

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.

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.

Background Over the past two decades, the importance of genetic factors in the development of FSGS has become increasingly clear. However, despite many known monogenic causes of FSGS, single gene defects explain only 30% of cases. Methods To investigate mutations underlying FSGS, we sequenced 662 whole exomes from individuals with sporadic or familial FSGS. After quality control, we analyzed the exome data from 363 unrelated family units with sporadic or familial FSGS and compared this to data from 363 ancestry-matched controls. We used rare variant burden tests to evaluate known disease-associated genes and potential new genes. Results We validated several FSGS-associated genes that show a marked enrichment of deleterious rare variants among the cases. However, for some genes previously reported as FSGS related, we identified rare variants at similar or higher frequencies in controls. After excluding such genes, 122 of 363 cases (33.6%) had rare variants in known disease-associated genes, but 30 of 363 controls (8.3%) also harbored rare variants that would be classified as "causal" if detected in cases; applying American College of Medical Genetics filtering guidelines (to reduce the rate of false-positive claims that a variant is disease related) yielded rates of 24.2% in cases and 5.5% in controls. Highly ranked new genes include SCAF1, SETD2, and LY9. Network analysis showed that top-ranked new genes were located closer than a random set of genes to known FSGS genes. Conclusions Although our analysis validated many known FSGS-causing genes, we detected a nontrivial number of purported "disease-causing" variants in controls, implying that filtering is inadequate to allow clinical diagnosis and decision making. Genetic diagnosis in patients with FSGS is complicated by the nontrivial rate of variants in known FSGS genes among people without kidney disease.

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.).

Rationale & Objective C3 glomerulopathy (C3G), a form of glomerulonephritis associated with dysregulation of the alternative complement pathway, occurs either as dense deposit disease (DDD) or C3 glomerulonephritis (C3GN). Few studies have reported outcomes of patients with C3G after transplantation since its formal classification and the advent of complement-targeting therapies such as eculizumab. Study Design Case series of C3G. Setting & Participants We reviewed laboratory testing, native and allograft biopsy reports, and clinical charts of the 19 patients (12, C3GN; and 7, DDD) from our C3G registry who underwent transplantation between 1999 and 2016. Results During a median follow-up of 76 months, 16 patients had recurrent disease (10 of 12, C3GN; and 6 of 7, DDD), with median time to recurrence of 14 months in C3GN versus 15 months in DDD. Graft failure was more frequent in patients with DDD (6 of 7) than in patients with C3GN (3 of 12), occurred at a median time of 42 months posttransplantation, and was attributed to recurrent disease in half the failures. A rare genetic variant or autoantibody associated with alternative complement pathway abnormalities was detected in 9 of 10 screened patients. Treatment of 7 patients (8 allografts) with eculizumab was associated with variable clinical outcomes. Limitations Incomplete testing for complement pathway abnormalities and genetic defects, incomplete records of HLA antigen matching, lack of centralized biopsy review, and limited sample size. Conclusions In a case series of C3G transplant recipients, the proportion of disease recurrence was high in both C3GN and DDD, although graft loss appeared to occur more frequently in DDD. In a small subset of study patients, eculizumab therapy was not consistently followed by salutary outcomes.

BACKGROUND: Exome sequencing is emerging as a first-line diagnostic method in some clinical disciplines, but its usefulness has yet to be examined for most constitutional disorders in adults, including chronic kidney disease, which affects more than 1 in 10 persons globally. METHODS: We conducted exome sequencing and diagnostic analysis in two cohorts totaling 3315 patients with chronic kidney disease. We assessed the diagnostic yield and, among the patients for whom detailed clinical data were available, the clinical implications of diagnostic and other medically relevant findings. RESULTS: In all, 3037 patients (91.6%) were over 21 years of age, and 1179 (35.6%) were of self-identified non-European ancestry. We detected diagnostic variants in 307 of the 3315 patients (9.3%), encompassing 66 different monogenic disorders. Of the disorders detected, 39 (59%) were found in only a single patient. Diagnostic variants were detected across all clinically defined categories, including congenital or cystic renal disease (127 of 531 patients [23.9%]) and nephropathy of unknown origin (48 of 281 patients [17.1%]). Of the 2187 patients assessed, 34 (1.6%) had genetic findings for medically actionable disorders that, although unrelated to their nephropathy, would also lead to subspecialty referral and inform renal management. CONCLUSIONS: Exome sequencing in a combined cohort of more than 3000 patients with chronic kidney disease yielded a genetic diagnosis in just under 10% of cases. (Funded by the National Institutes of Health and others.)

Item does not contain fulltext The C3 glomerulopathies are a group of rare kidney diseases characterized by complement dysregulation occurring in the fluid phase and in the glomerular microenvironment, which results in prominent complement C3 deposition in kidney biopsy samples. The two major subgroups of C3 glomerulopathy - dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) - have overlapping clinical and pathological features suggestive of a disease continuum. Dysregulation of the complement alternative pathway is fundamental to the manifestations of C3 glomerulopathy, although terminal pathway dysregulation is also common. Disease is driven by acquired factors in most patients - namely, autoantibodies that target the C3 or C5 convertases. These autoantibodies drive complement dysregulation by increasing the half-life of these vital but normally short-lived enzymes. Genetic variation in complement-related genes is a less frequent cause. No disease-specific treatments are available, although immunosuppressive agents and terminal complement pathway blockers are helpful in some patients. Unfortunately, no treatment is universally effective or curative. In aggregate, the limited data on renal transplantation point to a high risk of disease recurrence (both DDD and C3GN) in allograft recipients. Clinical trials are underway to test the efficacy of several first-generation drugs that target the alternative complement pathway.

AIMS: Obesity is associated with progression of chronic kidney disease (CKD). Treatment with bardoxolone methyl in a multinational phase 3 trial, Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), resulted in increases in estimated glomerular filtration rate (eGFR) with concurrent reductions in body weight. We performed post-hoc analyses to further characterize reductions in body weight with bardoxolone methyl.METHODS: Eligible patients with type 2 diabetes (T2DM) and CKD stage 4 (eGFR 15 to RESULTS: BEACON enrolled 2185 patients. Patients randomized to bardoxolone methyl experienced significant reductions in body weight from baseline relative to patients randomized to placebo (-5.7 kg; 95% CI: -6.0 to -5.3 kg; p CONCLUSIONS: Bardoxolone methyl resulted in significant weight loss in a generally obese patient population with T2DM and stage 4 CKD, with the magnitude and rate dependent on baseline BMI.

Background and Aims C3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN) are rare, progressive kidney diseases requiring a biopsy for definite diagnosis. Both C3G and IC-MPGN are attributed to complement dysregulation, with dysregulation of the alternative pathway established in C3G and implicated in IC-MPGN (alongside classical pathway activation by immune complexes). We describe the baseline biomarker and clinical characteristics of patients participating in two C3G/IC-MPGN phase II studies of the investigational, oral complement factor D (FD) inhibitor, danicopan (ALXN2040/ACH-4471). Method The first study (NCT03369236) was a double-blind, placebo-controlled, randomised, 6-month (+open label extension) trial of patients with biopsy-confirmed C3G of the native kidney treated with danicopan or placebo. The second study (NCT03459443) was a single-arm, open-label, 12-month (+extension) trial of patients with biopsy-confirmed C3G or IC-MPGN treated with danicopan. In both studies, all patients were to have proteinuria ≥500 mg/day and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 (calculated by the Modification of Diet in Renal Disease equation for patients ≥18 years and the Schwartz equation for patients Results A total of 35 patients were included in this analysis (13 from study 1 and 22 from study 2). The majority of patients were male (9 [69%] in study 1, 12 [55%] in study 2), with mean (SD) ages at baseline of 25.2 (7.63) years in study 1 and 24.3 (9.90) years in study 2. Most patients had received prior angiotensin converting enzyme inhibitors/receptor blockers (12 [92%] in study 1, 19 [86%] in study 2), and/or immunosuppressants (10 [77%] in study 1, 12 [55%] in study 2). Baseline clinical and biomarker data are shown in Table 1. Baseline eGFR was moderately correlated with proteinuria (uPCR24, rs=-0.40 [p=0.022]); baseline uPCR24 was also moderately correlated with Ba (rs=0.42 [p=0.016]) and FD (rs=0.53 [p=0.002]). Ba and FD elevations showed strong correlations with lower eGFR (rs=-0.79 and -0.88, respectively [p Conclusion Data from two danicopan clinical studies in C3G patients show correlations with renal impairment and proteinuria were observed for some, but not all, complement biomarkers. Factor Ba and FD are strongly associated with eGFR, suggesting that these biomarkers cannot easily be used as markers of complement dysregulation or activity. Interpretation of changes in these complement proteins needs to include not only the nature of the complement dysregulation and influence of the complement therapeutic being tested, but also eGFR. Additional urinary biomarkers, biopsy findings, autoantibodies, and genetic variants are currently being analysed and findings from this study will contribute to a better understanding of C3G and IC-MPGN.

Rationale & Objective: An early change in proteinuria is considered a reasonably likely surrogate end point in immunoglobulin A nephropathy (IgAN) and can be used as a basis for accelerated approval of therapies, with verification in a postmarketing confirmatory trial. Glomerular filtration rate (GFR) slope is a recently validated surrogate end point for chronic kidney disease progression and may be considered as the end point used for verification. We undertook a metaanalysis of clinical trials in IgAN to compare treatment effects on change in proteinuria versus change in estimated GFR (eGFR) slope.Study Design: Individual patient-level metaanalysis.Setting & Study Populations: Individual data of 1,037 patients from 12 randomized trials. Selection Criteria for Studies: Randomized trials of IgAN with proteinuria measurements at baseline and 6 (range, 2.5-14) months and at least a further 1 year of follow-up for the clinical outcome.Analytical Approach: For each trial, we estimated the treatment effects on proteinuria and on the eGFR slope, computed as the total slope starting at baseline or the chronic slope starting 3 months after randomization. We used a Bayesian mixed-effects analysis to relate the treatment effects on proteinuria to effects on GFR slope across these studies and developed a prediction model for the treatment effect on the GFR slope based on the effect on proteinuria.Results: Across all studies, treatment effects on proteinuria accurately predicted treatment effects on the total slope at 3 years (median R-2 = 0.88; 95% Bayesian credible interval [BCI], 0.06-1) and on the chronic slope (R-2 = 0.98; 95% BCI, 0.29-1). For future trials, an observed treatment effect of approximately 30% reduction in proteinuria would confer probabilities of at least 90% for nonzero treatment benefits on the total and chronic slopes of eGFR. We obtained similar results for proteinuria at 9 and 12 months and total slope at 2 years. Limitations: Study population restricted to 12 trials of small sample size, leading to wide BCIs. There was heterogeneity among trials with respect to study design and interventions.Conclusions: These results provide new evidence supporting that early reduction in proteinuria can be used as a surrogate end point for studies of chronic kidney disease progression in IgAN.

Introduction: Alport syndrome is a rare genetic disorder that affects as many as 60,000 persons in the USA and a total of 103,000 persons (200 pg/mL at baseline or with significant cardiovascular histories were excluded. Patients were randomized 1:1 to bardoxolone methyl or placebo, with stratification by baseline UACR. Results: A total of 371 patients were screened, and 157 patients were randomly assigned to receive bardoxolone methyl ( n = 77) or placebo ( n = 80). The average age at screening was 39.2 years, and 23 (15%) were

Vogt, Bruno/0000-0002-1548-6387; Dufek, Stephanie/0000-0002-6323-6673; Liu, Lili/0000-0002-2622-9669; Paczek, Leszek/0000-0003-0160-3009; Cui, Zhao/0000-0002-5837-1926; amoroso, antonio/0000-0002-9437-9407; Rosen, Raphael/0000-0003-1025-1965; Loos, Ruth/0000-0002-8532-5087; coenen, marieke/0000-0001-8796-2031; zanoni, francesca/0000-0001-9567-6713; CUCCA, Francesco/0000-0002-7414-1995; Ars, Elisabet/0000-0002-4118-4358; Hamilton, Patrick/0000-0001-6703-3745 WOS:000563559600001 PubMed ID: 32231244 Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 x 10(-12)) and IRF4 (rs9405192, OR = 1.29, P = 1.4 x 10(-14)), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 x 10(-103)) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 x 10(-49)), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 x 10(-93)), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 x 10(-23) and OR = 3.39, P = 5.2 x 10(-82), respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk. National Institute for Diabetes and Digestive Kidney Diseases (NIDDK) [RC2-DK116690, R01-DK105124, R01-DK097053, R01-DK108805]; National Institute on Minority Health and Health Disparities (NIMHD)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Minority Health & Health Disparities (NIMHD) [R01-MD009223]; Charles Woodson Clinical Research Fund; Nephrotic Syndrome Study Network Consortium (NEPTUNE) [U54-DK-083912]; Columbia University, Columbia Glomerular Center; Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS); National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK); University of MichiganUniversity of Michigan System; NephCure Kidney International; Halpin Foundation; National Key Research and Development Program of China [2016YFC0904100]; Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81621092]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81870460, 81570598]; Science and Technology Innovation Action Plan of Shanghai Science and Technology Committee [17441902200]; Shanghai Municipal Education Commission, Gaofeng, Clinical Medicine Grant [20152207]; Shanghai Jiao Tong University School of Medicine, Multi-Center Clinical Research Project [DLY201510]; International Cooperation and Exchange Projects of Shanghai Science and Technology Committee [14430721000]; Outstanding Young Scholar Award [81622009]; Shanghai Health and Family Planning Committee Hundred Talents Program [2018BR37]; Seoul National University Hospital Human Biobank, a member of the National Biobank of Korea - Ministry of Health and Welfare, Republic of Korea; MRCMedical Research Council UK (MRC) [MR/J010847/1]; Manchester Academic Health Science Centre [MAHSC 186/200]; Greater Manchester Local Clinical Research Network; Kidneys for Life Charity; David and Elaine Potter Charitable Foundation; St Peter's Trust for Kidney, Bladder and Prostate Research; Kids Kidney Research UKKidney Research UK (KRUK); Kidney Research UKKidney Research UK (KRUK); Italian Ministry of Health grantMinistry of Health, Italy [GR-2011-02350438]; Department of Excellence Grant 2018-2022 - Italian Ministry of Education for the Department of Medical Sciences of the University of Turin; Columbia University; Poznan University of Medical Sciences, Poland; German Ministry of Education and Research (BMBF)Federal Ministry of Education & Research (BMBF) [01ER0804]; KfH Foundation for Preventive Medicine; Bayer Pharma AG; German Research FoundationGerman Research Foundation (DFG) [CRC 1140, KO 3598/3-1, CRC 992]; European Research CouncilEuropean Research Council (ERC) [ERC-2012ADG_2012-0314, 322947]; 7th Framework Programme of the European Community contract [2012-305608]; National Research Agency grant MNaims [ANR-17-CE17-0012-01]; Dutch Kidney Foundation [OW08, KJPB11.021]; National Human Genome Research Institute (NHGRI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI); NIMHD We are grateful to all study participants across multiple nephrology centres worldwide for their contributions to this work. This work was supported by the following institutions, grants and funding agencies in the US: Columbia University, Columbia Glomerular Center, National Institute for Diabetes and Digestive Kidney Diseases (NIDDK) grants RC2-DK116690 (K.K., M.K.), R01-DK105124 (K.K.), R01-DK097053 (L.H.B., M.K.), R01-DK108805 (M.G.S.), and National Institute on Minority Health and Health Disparities (NIMHD) grant R01-MD009223 (K.K., A.G.G., A.B.). M.G.S. is additionally supported by the Charles Woodson Clinical Research Fund. The Nephrotic Syndrome Study Network Consortium (NEPTUNE), U54-DK-083912, is a part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported through a collaboration between the Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS) and the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK). Additional funding and/or programmatic support for this project has also been provided by the University of Michigan, the NephCure Kidney International and the Halpin Foundation. The recruitment and analysis of the Chinese cohorts were supported by the National Key Research and Development Program of China (2016YFC0904100), Natural Science Foundation of China to the Innovation Research Group (81621092), National Natural Science Foundation of China (No. 81870460, 81570598), Science and Technology Innovation Action Plan of Shanghai Science and Technology Committee (No.17441902200), Shanghai Municipal Education Commission, Gaofeng, Clinical Medicine Grant (No.20152207), Shanghai Jiao Tong University School of Medicine, Multi-Center Clinical Research Project (No.DLY201510), International Cooperation and Exchange Projects of Shanghai Science and Technology Committee (No.14430721000), the Outstanding Young Scholar Award for Zhao Cui (No.81622009), and Shanghai Health and Family Planning Committee Hundred Talents Program for Jingyuan Xie (No.2018BR37). The recruitment of the Korean cohort was supported by the Seoul National University Hospital Human Biobank, a member of the National Biobank of Korea, financed by the Ministry of Health and Welfare, Republic of Korea. P.B. and P.H. acknowledge financial support from MRC project "Autoimmunity in Membranous Nephropathy", grant MR/J010847/1 which funded the sample collection from MN patients across the UK. P.B., P.H. and S.H. acknowledge support from Manchester Academic Health Science Centre (MAHSC 186/200), the Greater Manchester Local Clinical Research Network and Kidneys for Life Charity for supporting research in MN in Manchester. We are grateful to the MENTOR study (clinical trials no. NCT01180036), for contributing blood samples of trial participants. The UK cohort was supported in part by grants from the David and Elaine Potter Charitable Foundation (to S.H.P. and R.K.), St Peter's Trust for Kidney, Bladder and Prostate Research (to D.B., H.C.S., S.H.P. and R.K.), Kids Kidney Research UK and Kidney Research UK (to D.B. and R.K.). The Italian cohorts were supported by the Italian Ministry of Health grant GR-2011-02350438 (G.Z., S.G.) and the Department of Excellence Grant 2018-2022 funded by the Italian Ministry of Education for the Department of Medical Sciences of the University of Turin (A.A.).; The recruitment of Polish cases was sponsored by the Polish Kidney Genetics Network (POLYGENES), a collaborative effort between Columbia University and Poznan University of Medical Sciences, Poland. The full list of POLYGENES collaborators can be found in the Supplementary Materials. The GCKD (German Chronic Kidney Disease) study was funded by grants from the German Ministry of Education and Research (BMBF, No. 01ER0804) and the KfH Foundation for Preventive Medicine, with genotyping supported by Bayer Pharma AG. The list of GCKD investigators can be found in the Supplementary Materials. The work of M.W. and A.K. was funded by the CRC 1140 Initiative and by KO 3598/3-1 and CRC 992 (A.K.) of the German Research Foundation. The work of E.H. and R.A.K.S. was funded by the CRC 1192 from the German Research Foundation (Projects B1 and C1). P.R. is a recipient of European Research Council ERC-2012ADG_2012-0314 grant 322947, 7th Framework Programme of the European Community contract 2012-305608 (European Consortium for High-Throughput Research in Rare Kidney Diseases), and the National Research Agency grant MNaims (ANR-17-CE17-0012-01). The Dutch studies were supported by grants from the Dutch Kidney Foundation to JMH and JFW (Nierstichting Nederland grant OW08 and grant KJPB11.021). We would like to thank the Population Architecture Using Genomics and Epidemiology (PAGE) consortium, funded by the National Human Genome Research Institute (NHGRI) with co-funding from the NIMHD, for providing population controls for this study. For full acknowledgment of the PAGE consortium, please see Supplementary Materials. The funding sources were not involved in the study design, collection, analysis, and interpretation of data, writing of the report, or in the decision to submit the paper for publication.

BACKGROUND AND OBJECTIVES: C3 glomerulopathy is a complement-mediated disease arising from abnormalities in complement genes and/or antibodies against complement components. Previous studies showed that treatment with corticosteroids plus mycophenolate mofetil (MMF) was associated with improved outcomes, although the genetic profile of these patients was not systematically analyzed. This study aims to analyze the main determinants of disease progression and response to this therapeutic regimen. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a retrospective, multicenter, observational cohort study in 35 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases. Patients diagnosed with C3 glomerulopathy (n=81) or dense deposit disease (n=16) between January 1995 and March 2018 were enrolled. Multivariable and propensity score matching analyses were used to evaluate the association of clinical and genetic factors with response to treatment with corticosteroids and MMF as measured by proportion of patients with disease remission and kidney survival (status free of kidney failure). RESULTS: The study group comprised 97 patients (84% C3 glomerulopathy, 16% dense deposit disease). Forty-two patients were treated with corticosteroids plus MMF, and this treatment was associated with a higher rate of remission and lower probability of kidney failure (79% and 14%, respectively) compared with patients treated with other immunosuppressives (24% and 59%, respectively), or ecluzimab (33% and 67%, respectively), or conservative management (18% and 65%, respectively). The therapeutic superiority of corticosteroids plus MMF was observed both in patients with complement abnormalities and with autoantibodies. However, patients with pathogenic variants in complement genes only achieved partial remission, whereas complete remissions were common among patients with autoantibody-mediated forms. The main determinant of no remission was baseline proteinuria. Relapses occurred after treatment discontinuation in 33% of the patients who had achieved remission with corticosteroids plus MMF, and a longer treatment length of MMF was associated with a lower risk of relapse. CONCLUSIONS: The beneficial response to corticosteroids plus MMF treatment in C3 glomerulopathy appears independent of the pathogenic drivers analyzed in this study.

Rationale & Objective Anti–glomerular basement membrane (GBM) disease is a rapidly progressive glomerulonephritis which, in some instances, occurs concurrently with other diseases such as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Rarely, it also occurs with membranous nephropathy (MN). We report a series of such patients, characterizing their long-term follow up. Study Design Case series. Setting & Participants Twelve patients referred to 1 medical center between 2001 and 2019 with anti-GBM disease and MN whose clinical characteristics and course were described. Results Patients’ ages ranged from 20 to 81 years old, and all presented with severe acute kidney injury requiring dialysis on presentation or shortly thereafter. Only 1 patient had pulmonary findings on presentation. The predominant pathology was crescentic and necrotizing glomerulonephritis with linear staining for immunoglobulin G along the GBM associated with epimembranous electron-dense immune-type deposits. All 11 patients who were tested had significant titers of anti-GBM antibodies, but only 1 of the 5 tested for phospholipase A2 receptor (PLA2R) on biopsy was positive. Eight patients received therapy with cyclophosphamide, prednisone, and plasmapheresis; 2 patients with prednisone and plasmapheresis; and 2 with rituximab-based regimens. Progression to a requirement for kidney replacement therapy occurred in all 12 patients, but 2 patients later recovered kidney function. Recurrence of anti-GBM disease did not occur for any of the patients studied. Limitations Incomplete testing for PLA2R in biopsy and serum, limited sample size, and lack of uniform treatment regimen. Conclusions In this case series, the presentation of concurrent anti-GBM disease and MN was characterized by rapidly progressive glomerulonephritis and poor kidney outcomes. These findings suggest possible value from earlier diagnosis and the need for identification of more effective treatment regimens.

Background and Aims IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world. Despite being described over 50 years ago, there remains no approved therapy for this common global cause of kidney failure. The central pathogenic feature in IgAN is the formation of circulating IgA containing immune complexes which have the propensity to deposit in the kidneys and trigger glomerular inflammation and tubulointerstitial scarring. The primary substrate for immune complex formation is an excess of poorly O-galactosylated polymeric IgA1 (Gd-IgA1) in the circulation. These IgA1 O-glycoforms are thought to trigger the formation of IgA and IgG autoantibodies. Atacicept is a human TACI-Ig fusion protein that inhibits B cell-stimulating factors, BLyS and APRIL, and has been associated with reductions in levels of serum IgA and IgG, as well as reductions in mature B cells and plasma cells. A number of studies have shown elevated levels of BLyS, APRIL and Gd-IgA1 in IgAN patients which have been linked to worse clinical outcomes. IgAN patients with persistent proteinuria >1 g/day are at increased risk of progression to end-stage renal disease. This Phase II study examines the safety and efficacy of atacicept in reducing pathogenic Gd-IgA1 levels and measures of renal activity in IgAN. Method This Phase II study (NCT02808429) enrolled patients with IgAN and proteinuria ≥1 g/day or 0.75 mg/mg on 24-hour urine protein-creatinine ratio (UPCR) despite maximal standard of care therapy (angiotensin converting enzyme inhibitor and/or angiotensin receptor blocker). Enrolled patients were randomized 1:1:1 to receive placebo or atacicept 25mg or 75mg once weekly by subcutaneous injection. The primary endpoint was a change in proteinuria by 24-hour UPCR at Week 48; key secondary endpoints included change in eGFR, serum immunoglobulin and Gd-IgA1 levels. Results Data from the 24-week interim analysis are reported here for enrolled patients (placebo=5; atacicept 25mg=6; atacicept 75mg=5). A consistent, dose-dependent reduction in serum immunoglobulins (IgA, IgG and IgM) and, in particular, Gd-IgA1 (Figure) were observed through Week 24. In parallel, proteinuria (24-hour UPCR) showed a higher median % reduction from baseline with atacicept at Week 24: -18.67% and -25.34% with atacicept 25 mg and 75 mg, respectively, vs +0.098% with placebo (Figure). eGFR remained stable over time. TEAEs were reported by 81% of the subjects. TEAEs were mild or moderate in severity, with no severe TEAEs reported. No serious related events, events with severe hypogammaglobulinemia or fatal outcome were reported. Conclusion These 24-week interim analysis results provide early proof of concept for the potential treatment of atacicept in patients with IgAN and persistent proteinuria.

RATIONALE AND OBJECTIVES: Post-transplant membranous nephropathy (MN) represents a rare complication of kidney transplantation that can be classified as recurrent or de novo. The clinical, pathological, and immunogenetic characteristics of post-transplant MN and the differences between de novo and recurrent MN are not well understood. STUDY DESIGN: Multicenter case series. SETTING AND PARTICIPANTS: We included 77 patients from five North American and European Medical Centers with post-kidney transplant MN (27 de novo and 50 recurrent). Patients with MN in the native kidney who received kidney allografts but did not develop recurrent MN were used as non-recurrent controls (n=43). To improve understanding of post-transplant MN, we compared de novo MN with recurrent MN and then contrasted recurrent MN with non-recurrent controls. FINDINGS: Compared to recurrent MN, de novo MN was less likely to be classified as primary MN (OR, 0.04; P

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Background Understanding the relationship between clinical and patient-reported outcomes (PROs) will help support clinical care and future clinical trial design of novel therapies for focal segmental glomerulosclerosis (FSGS). Methods FSGS patients ≥8 years of age enrolled in the Nephrotic Syndrome Study Network completed Patient-Reported Outcomes Measurement Information System PRO measures of health-related quality of life (HRQoL) (children: global health, mobility, fatigue, pain interference, depression, anxiety, stress and peer relationships; adults: physical functioning, fatigue, pain interference, sleep impairment, mental health, depression, anxiety and social satisfaction) at baseline and during longitudinal follow-up for a maximum of 5 years. Linear mixed-effects models were used to determine which demographic, clinical and laboratory features were associated with PROs for each of the eight children and eight adults studied. Results There were 45 children and 114 adult FSGS patients enrolled that had at least one PRO assessment and 519 patient visits. Multivariable analyses among children found that edema was associated with global health (−7.6 points, P = 0.02) and mobility (−4.2, P = 0.02), the number of reported symptoms was associated with worse depression (−2.7 per symptom, P = 0.009) and anxiety (−2.3, P = 0.02) and the number of emergency room (ER) visits in the prior 6 months was associated with worse mobility (−2.8 per visit, P Conclusions PROs provide important information about HRQoL for persons with FSGS that is not captured solely by the examination of laboratory-based markers of disease. However, it is critical that instruments capture the patient experience and FSGS clinical trials may benefit from a disease-specific instrument more sensitive to within-patient changes.

People of recent African ancestry develop kidney disease at much higher rates than most other groups. Two specific coding variants in the Apolipoprotein-L1 gene APOL1 termed G1 and G2 are the causal drivers of much of this difference in risk, following a recessive pattern of inheritance. However, most individuals with a high-risk APOL1 genotype do not develop overt kidney disease, prompting interest in identifying those factors that interact with APOL1. We performed an admixture mapping study to identify genetic modifiers of APOL1-associated kidney disease. Individuals with two APOL1 risk alleles and focal segmental glomerulosclerosis (FSGS) have significantly increased African ancestry at the UBD (also known as FAT10) locus. UBD is a ubiquitin-like protein modifier that targets proteins for proteasomal degradation. African ancestry at the UBD locus correlates with lower levels of UBD expression. In cell-based experiments, the disease-associated APOL1 alleles (known as G1 and G2) lead to increased abundance of UBD mRNA but to decreased levels of UBD protein. UBD gene expression inversely correlates with G1 and G2 APOL1-mediated cell toxicity, as well as with levels of G1 and G2 APOL1 protein in cells. These studies support a model whereby inflammatory stimuli up-regulate both UBD and APOL1, which interact in a functionally important manner. UBD appears to mitigate APOL1-mediated toxicity by targeting it for destruction. Thus, genetically encoded differences in UBD and UBD expression appear to modify the APOL1-associated kidney phenotype.

Background and objectives C3 glomerulopathy is a form of complement-mediated GN. Immunosuppressive therapy may be beneficial in the treatment of C3 glomerulopathy. Mycophenolate mofetil is an attractive treatment option given its role in the treatment of other complement-mediated diseases and the results of the Spanish Group for the Study of Glomerular Diseases C3 Study. Here, we study the outcomes of patients with C3 glomerulopathy treated with steroids and mycophenolate mofetil. Design, setting, participants, & measurements We conducted a retrospective chart review of patients in the C3 glomerulopathy registry at Columbia University and identified patients treated with mycophenolate mofetil for at least 3 months and follow-up for at least 1 year. We studied clinical, histologic, and genetic data for the whole group and compared data for those who achieved complete or partial remission (responders) with those who did not achieve remission (nonresponders). We compared remission with mycophenolate mofetil with remission with other immunosuppressive regimens. Results We identified 30 patients who met inclusion criteria. Median age was 25 years old (interquartile range, 18-36), median creatinine was 1.07 mg/dl (interquartile range, 0.79-1.69), and median proteinuria was 3200 mg/g creatinine (interquartile range, 1720-6759). The median follow-up time was 32 months (interquartile range, 21-68). Twenty (67%) patients were classified as responders. There were no significant differences in baseline characteristics between responders and nonresponders, although initial proteinuria was lower (median 2468 mg/g creatinine) in responders compared with nonresponders (median 5000 mg/g creatinine) and soluble membrane attack complex levels were higher in responders compared with nonresponders. For those tapered off mycophenolate mofetil, relapse rate was 50%. Genome-wide analysis on complement genes was done, and in 12 patients, we found 18 variants predicted to be damaging. None of these variants were previously reported to be pathogenic. Mycophenolate mofetil with steroids outperformed other immunosuppressive regimens. Conclusions Among patients who tolerated mycophenolate mofetil, combination therapy with steroids induced remission in 67% of this cohort. Heavier proteinuria at the start of therapy and lower soluble membrane attack complex levels were associated with treatment resistance.

As the population worldwide ages, the epidemic of kidney disease will also increase. Anti-neutrophil cytoplasmic antibodies (ANCA) positive rapidly progressive positive glomerulonephritis (RPGN) is the most common etiology for biopsied patients among the very elderly. Its pathological features and clinical course are well described, though there is still debate about the mechanism of injury involved in individual patients. From very ancient times, the cornerstone of treatment historically has been high-dose cyclophosphamide and a lengthy course of high-dose corticosteroids. Although this regimen has diminished the immediate mortality rate of RPGN, its intermediate and long-term adverse effects are not insignificant. Attempts to minimize toxicity and improve efficacy have been made through the years to allow physicians some options for therapy. Lower cumulative cyclophosphamide regimens, shorter corticosteroid courses, and the introduction of rituximab have modified the armamentarium for treatment of ANCA positive RPGN. As progress is made in understanding the molecular pathogenesis of this disease, new targets will be found for potential therapeutic attack. The complement system is an area of active interest for all glomerular diseases at this time. Indeed, animal studies and preliminary human studies suggest that targeting the complement system can ameliorate the course of ANCA-positive RPGN. Hopefully, as the population ages, we will see more and safer therapeutic options to treat this once rapidly fatal disease.

Interstitial fibrosis (IF), tubular atrophy (TA) and interstitial inflammation (II) are known determinants of progression of renal disease. Standardized quantification of these features could add value to current classification of glomerulopathies.We studied 315 participants in the Nephrotic Syndrome Study Network (NEPTUNE) study, including biopsy-proven minimal change disease (MCD = 98), focal segmental glomerulosclerosis (FSGS = 121), membranous nephropathy (MN = 59) and IgA nephropathy (IgAN = 37). Cortical IF, TA and II were quantified (%) on digitized whole-slide biopsy images, by five pathologists with high inter-reader agreement (intra-class correlation coefficient0.8). Tubulointerstitial messenger RNA expression was measured in a subset of patients. Multivariable Cox proportional hazards models were fit to assess association of IF with the composite of 40% decline in estimated glomerular filtration rate (eGFR) and end-stage renal disease (ESRD) and separately as well, and with complete remission (CR) of proteinuria.IF was highly correlated with TA (P 0.001) and II (P 0.001). Median IF varied by diagnosis: FSGS 17, IgAN 21, MN 7, MCD 1 (P 0.001). IF was strongly correlated with baseline eGFR (P 0.001) and proteinuria (P = 0.002). After adjusting for clinical pathologic diagnosis, age, race, global glomerulosclerosis, baseline proteinuria, eGFR and medications, each 10% increase in IF was associated with a hazard ratio of 1.29 (P 0.03) for ESRD/40% eGFR decline, but was not significantly associated with CR. A total of 981 genes were significantly correlated with IF (|r|0.4, false discovery rate (FDR)0.01), including upstream regulators such as tumor necrosis factor, interferon gamma (IFN-gamma), and transforming growth factor beta 1 (TGF-B1), and signaling pathways for antigen presentation and hepatic fibrosis.The degree of IF is associated with risk of eGFR decline across different types of proteinuric glomerulopathy, correlates with inflammatory and fibrotic gene expression, and may have predictive value in assessing risk of progression.

Thrombotic thrombocytopenic purpura, Shiga toxin hemolytic uremic syndrome, atypical hemolytic uremic syndrome, and antiphospholipid syndrome are thrombotic microangiopathies that present similarly but arise from different causes. Management depends on distinguishing them promptly and providing targeted therapy.

Background Monoclonal immunoglobulin (MIg)-associated renal disease (MIgARD) comprises a group of disorders caused by direct deposition of paraproteins in the kidney. Allograft MIgARD is infrequently encountered and poorly characterized. Methods First, we assessed our allograft biopsies diagnosed with MIgARD between 2007 and 2018. The cohort included the following 26 patients: proliferative glomerulonephritis with MIg deposits (PGNMID) (n = 13), AL amyloidosis (n = 5), light chain deposition disease (n = 5), light chain proximal tubulopathy (n = 2), and light chain cast nephropathy (n = 1). Second, we conducted a literature review to evaluate the rare non-PGNMID entities. We identified 20 studies describing 29 patients that were added to our cohort (total n = 42). Results Part 1: Patients' median age was 55 years; 31% were women, and 19% were blacks. Twelve patients (46%) lost their grafts at a median of 8 months after diagnosis. Compared to non-PGNMID, PGNMID patients had lower frequency of detectable paraproteins (31% versus 92%, P = 0.004) and hematologic neoplasms (23% versus 77%, P = 0.02). Within PGNMID group, 6 patients changed their apparent immunofluorescence phenotype between monotypic and polytypic, while all 3 patients with hematologic neoplasms had substructure on electron microscopy. Part 2: Whereas light chain cast nephropathy occurred the earliest and had the worst graft survival, AL amyloidosis occurred the latest and had the best graft survival. Conclusions MIgARD in the kidney allograft is associated with poor prognosis. While posttransplant PGNMID can change its apparent clonality by immunofluorescence supporting oligoclonal immune responses, the presence of deposit substructure is an important indicator of underlying hematologic neoplasm. Non-PGNMID are often associated with hematologic neoplasms and varied prognosis.

Membranous nephropathy (MN) is either primary or associated with various etiologies, each with unique glomerular antigens. The discovery of the phospholipase A2 receptor (PLA2R) antigen in primary MN revolutionized our understanding of MN and led to major clinical progress. Other recently discovered antigens in MN include the THSD7A antigen and exostosin. Sethi et al. have now identified a new antigen, NELL-1, in primary MN, again decreasing the number of patients whose antigen remains unknown.

Background Change in albuminuria has strong biological plausibility as a surrogate endpoint for progression of chronic kidney disease, but empirical evidence to support its validity is lacking. We aimed to determine the association between treatment effects on early changes in albuminuria and treatment effects on clinical endpoints and surrograte endpoints, to inform the use of albuminuria as a surrogate endpoint in future randomised controlled trials.Methods In this meta-analysis, we searched PubMed for publications in English from Jan 1, 1946, to Dec 15, 2016, using search terms including "chronic kidney disease", "chronic renal insufficiency", "albuminuria", "proteinuria", and "randomized controlled trial"; key inclusion criteria were quantifiable measurements of albuminuria or proteinuria at baseline and within 12 months of follow-up and information on the incidence of end-stage kidney disease. We requested use of individual patient data from the authors of eligible studies. For all studies that the authors agreed to participate and that had sufficient data, we estimated treatment effects on 6-month change in albuminuria and the composite clinical endpoint of treated end-stage kidney disease, estimated glomerular filtration rate of less than 15 mL/min per 1.73 m(2), or doubling of serum creatinine. We used a Bayesian mixed-effects meta-regression analysis to relate the treatment effects on albuminuria to those on the clinical endpoint across studies and developed a prediction model for the treatment effect on the clinical endpoint on the basis of the treatment effect on albuminuria.Findings We identified 41 eligible treatment comparisons from randomised trials (referred to as studies) that provided sufficient patient-level data on 29 979 participants (21 206 [71%] with diabetes). Over a median follow-up of 3.4 years (IQR 2.3-4.2), 3935 (13%) participants reached the composite clinical endpoint. Across all studies, with a meta-regression slope of 0.89 (95% Bayesian credible interval [BCI] 0.13-1.70), each 30% decrease in geometric mean albuminuria by the treatment relative to the control was associated with an average 27% lower hazard for the clinical endpoint (95% BCI 5-45%; median R-2 0.47, 95% BCI 0.02-0.96). The association strengthened after restricting analyses to patients with baseline albuminuria of more than 30 mg/g (ie, 3.4 mg/mmol; R-2 0.72, 0.05-0.99]). For future trials, the model predicts that treatments that decrease the geometric mean albuminuria to 0.7 (ie, 30% decrease in albuminuria) relative to the control will provide an average hazard ratio (HR) for the clinical endpoint of 0.68, and 95% of sufficiently large studies would have HRs between 0.47 and 0.95.Interpretation Our results support a role for change in albuminuria as a surrogate endpoint for the progression of chronic kidney disease, particularly in patients with high baseline albuminuria; for patients with low baseline levels of albuminuria this association is less certain. Copyright (c) 2019 Elsevier Ltd. All rights reserved.

IgA nephropathy frequently leads to progressive CKD. Although interest surrounds use of immunosuppressive agents added to standard therapy, several recent studies have questioned efficacy of these agents. Depleting antibody–producing B cells potentially offers a new therapy. In this open label, multicenter study conducted over 1-year follow-up, we randomized 34 adult patients with biopsy–proven IgA nephropathy and proteinuria >1 g/d, maintained on angiotensin–converting enzyme inhibitors or angiotensin receptor blockers with well controlled BP and eGFR