A phase 2b, randomized, double-blind, placebo-controlled, clinical trial of atacicept for treatment of IgA nephropathy.

Atacicept is a first-in-class, dual anti-B-cell Activation Factor-A Proliferation-Inducing Ligand fusion protein in clinical evaluation for treatment of IgA nephropathy. To compare efficacy and safety of atacicept versus placebo in patients with IgAN, this randomized, double-blind, placebo-controlled phase 2b clinical trial ORIGIN enrolled 116 individuals with biopsy-proven IgA nephropathy. Participants were randomized to atacicept 150, 75, or 25 mg versus placebo once weekly for up to 36 weeks. Primary and key secondary endpoints were changes in urine protein creatinine ratio based on 24-hour urine collection at weeks 24 and 36, respectively, in the combined atacicept 150 mg and 75 mg group versus placebo. The primary endpoint was met at week 24 as the mean urine protein creatinine ratio was reduced from baseline by 31% in the combined atacicept group versus 8% with placebo, resulting in a significant 25% reduction with atacicept versus placebo. At week 36, the key secondary endpoint was met as the mean urine protein creatinine ratio reduced from baseline by 34% in the combined atacicept group versus a 2% increase with placebo, resulting in a significant 35% reduction with atacicept versus placebo. The reduction in proteinuria was accompanied by stabilization in endpoint eGFR with atacicept compared to a decline with placebo at week 36, resulting in significant between-group geometric mean difference of 11%, approximating an absolute difference of 5.7 mL/min/1.73m2. Endpoint galactose deficient IgA1 levels significantly decreased from baseline by 60% versus placebo. The safety profile of atacicept was like placebo. Thus, our results provide evidence to support a pivotal, phase 3 study of atacicept in IgA nephropathy.

The Association of Class I and II Human Leukocyte Antigen Serotypes With End-Stage Kidney Disease Due to Membranoproliferative Glomerulonephritis and Dense Deposit Disease.

RATIONALE & OBJECTIVE: Membranoproliferative glomerulonephritis (MPGN), encompassing several distinct diseases, is a rare but significant cause of kidney failure in the United States. The potential etiologies of MPGN are unclear, but prior studies have suggested dysregulation of the alternative complement pathway and, recently, autoimmunity as potential mechanisms driving MPGN pathogenesis. In this study, we examined HLA associations with end-stage kidney disease (ESKD) due to MPGN and dense deposit disease (DDD) in a large racially and ethnically diverse US-based cohort. STUDY DESIGN: Case-control study. SETTING & PARTICIPANTS: Using US Renal Data System (USRDS) and United Network for Organ Sharing (UNOS) data, we identified 3,424 patients with kidney failure due to MPGN and 263 due to DDD. We matched patients to kidney donor controls on designated race and ethnicity in a 1:15 ratio. EXPOSURE: 58 class I and II HLA serotypes. OUTCOME: Case-control status. ANALYTICAL APPROACH: For each disease cohort, univariable and multivariable logistic regression analyses were used to investigate associations between the disease and 58 HLA serotypes. In subgroup analyses, we investigated HLA associations in White and Black patients. We also studied antiglomerular basement membrane (anti-GBM) nephritis as a positive-control outcome. We applied a Bonferroni correction to account for multiple comparisons. RESULTS: Eighteen serotypes were significantly associated with the odds of having MPGN in univariable analyses, with DR17 having the strongest association (odds ratio [OR], 1.55 [95% CI, 1.44-1.68], P=4.33e-28). No significant associations were found between any HLA serotype and DDD. Designated race-specific analyses showed comparable findings. We recapitulated known HLA associations in anti-GBM nephritis. LIMITATIONS: Reliance on HLA serotypes (rather than genotype), lack of biopsy-confirmed diagnoses. CONCLUSIONS: HLA-DR17 is associated with ESKD due to MPGN in a racially and ethnically diverse cohort. The strength of association was similar in White and Black patients, suggesting a role in the pathogenesis of MPGN. No HLA associations were observed in patients with DDD. PLAIN-LANGUAGE SUMMARY: Prior studies have suggested dysregulation of the alternative complement pathway as a potential etiology of membranoproliferative glomerulonephritis (MPGN), but recent evidence from a British White population has implicated an autoimmune mechanism in MPGN pathogenesis. We investigated HLA associations between MPGN and dense deposit disease (DDD) in a large racially and ethnically diverse cohort of patients. We found that HLA-DR17 is associated with end-stage kidney disease (ESKD) due to MPGN in both White and Black patients. By contrast, no significant HLA associations with ESKD due to DDD were identified. These results suggest a role for autoimmunity in some cases of MPGN and highlight differences in the disease etiology of MPGN compared with DDD.

Randomized Trial on the Effect of an Oral Spleen Tyrosine Kinase Inhibitor in the Treatment of IgA Nephropathy.

Introduction: We reported increased spleen tyrosine kinase (SYK) expression in kidney biopsies of patients with IgA nephropathy (IgAN) and that inhibition of SYK reduces inflammatory cytokines production from IgA stimulated mesangial cells. Methods: This study was a double-blind, randomized, placebo-controlled phase 2 trial of fostamatinib (an oral SYK inhibitor) in 76 patients with IgAN. Patients were randomized to receive placebo, fostamatinib at 100 mg or 150 mg twice daily for 24 weeks on top of maximum tolerated dose of renin-angiotensin system inhibitors. The primary end point was reduction of proteinuria. Secondary end points included change from baseline in estimated glomerular filtration rate (eGFR) and kidney histology. Results: Although we could not detect significant reduction in proteinuria with fostamatinib overall, in a predetermined subgroup analysis, there was a trend for dose-dependent reduction in median proteinuria (from baseline to 24 weeks by 14%, 27%, and 36% in the placebo, fostamatinib 100 mg, and 150 mg groups, respectively) in patients with baseline urinary protein-to-creatinine ratios (UPCR) more than 1000 mg/g. Kidney function (eGFR) remained stable in all groups. Fostamatinib was well-tolerated. Side effects included diarrhea, hypertension, and increased liver enzymes. Thirty-nine patients underwent repeat biopsy showing reductions in SYK staining associated with therapy at low dose (-1.5 vs. 1.7 SYK+ cells/glomerulus in the placebo group, P < 0.05). Conclusions: There was a trend toward reduction in proteinuria with fostamatinib in a predefined analysis of high risk patients with IgAN despite maximal care, as defined by baseline UPCR greater than 1000 mg/g. Further study may be warranted.

Multiomics characterization of cell type repertoires for urine liquid biopsies.

Urine is assayed alongside blood in medicine, yet current clinical diagnostic tests utilize only a small fraction of its total biomolecular repertoire, potentially foregoing high-resolution insights into human health and disease. In this work, we characterized the joint landscapes of transcriptomic and metabolomic signals in human urine. We also compared the urine transcriptome to plasma cell-free RNA, identifying a distinct cell type repertoire and enrichment for metabolic signal. Untargeted metabolomic measurements identified a complementary set of pathways to the transcriptomic analysis. Our findings suggest that urine is a promising biofluid yielding prognostic and detailed insights for hard-to-biopsy tissues with low representation in the blood, offering promise for a new generation of liquid biopsies.

Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial.

BACKGROUND: Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis. METHODS: PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin-angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850. FINDINGS: Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6-110) was -2·7 mL/min per 1·73 m2 per year versus -3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1-week 110) was -2·9 mL/min per 1·73 m2 per year versus -3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI -0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (-42·8%, 95% CI -49·8 to -35·0, with sparsentan versus -4·4%, -15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. INTERPRETATION: Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function. FUNDING: Travere Therapeutics.

Cure Glomerulonephropathy Pathology Classification and Core Scoring Criteria, Reproducibility, and Clinicopathologic Correlations.

Introduction: Cure Glomerulonephropathy (CureGN) is an observational cohort study of patients with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), or IgA nephropathy. We developed a conventional, consensus-based scoring system to document pathologic features for application across multiple pathologists and herein describe the protocol, reproducibility, and correlation with clinical parameters at biopsy. Methods: Definitions were established for glomerular, tubular, interstitial, and vascular lesions evaluated semiquantitatively using digitized light microscopy slides and electron micrographs, and reported immunofluorescence. Cases with curated pathology materials as of April 2019 were scored by a randomly assigned pathologist, with at least 10% of cases scored by a second pathologist. Scoring reproducibility was assessed using Gwet's agreement coefficient (AC)1 statistic and correlations with clinical variables were performed. Results: Of 800 scored biopsies (134 MCD, 194 FSGS, 206 MN, 266 IgA), 94 were scored twice (11.8%). Of 60 pathology features, 46 (76.7%) demonstrated excellent (AC1>0.8), and 12 (20.0%) had good (AC1 0.6-0.8) reproducibility. Mesangial hypercellularity scored as absent, focal, or diffuse had moderate reproducibility (AC1 = 0.58), but good reproducibility (AC1 = 0.71) when scored as absent or focal versus diffuse. The percent glomeruli scored as no lesions had fair reproducibility (AC1 = 0.34). Strongest correlations between pathologic features and clinical characteristics at biopsy included interstitial inflammation, interstitial fibrosis, and tubular atrophy with estimated glomerular filtration rate, foot process effacement with urine protein/creatinine ratio, and active crescents with hematuria. Conclusions: Most scored pathology features showed excellent reproducibility, demonstrating consistency for these features across multiple pathologists. Correlations between certain pathologic features and expected clinical characteristics show the value of this approach for future studies on clinicopathologic correlations and biomarker discovery.

The Significance of Hematuria in Podocytopathies.

BACKGROUND: Hematuria is frequently present in podocytopathies, but its significance and prognostic value is not well described in these proteinuric kidney diseases. This study describes the prevalence and association between hematuria and kidney-related outcomes in these disorders. METHODS: Hematuria was assessed at the initial urinalysis in participants with the following podocytopathies, membranous nephropathy, minimal change disease, and focal segmental glomerulosclerosis, in the Nephrotic Syndrome Study Network (NEPTUNE) and Cure Glomerulonephropathy (CureGN) cohorts with >24 months of follow-up. Multivariable Cox proportional hazards models were fit for time to composite outcome (end-stage kidney disease or 40% decline in estimated glomerular filtration rate (eGFR) and eGFR <60 ml/min/1.73 m2) and proteinuria remission (UPCR <0.3 mg/mg). RESULTS: Among the 1,516 adults and children in the study, 528 (35%) participants had focal segmental glomerulosclerosis, 499 (33%) had minimal change disease, and 489 (32%) had membranous nephropathy. Median (IQR) time from biopsy until the initial study urinalysis was 260 days (49, 750), and 498 (33%) participants were positive for hematuria. Participants with hematuria compared to those without, were older (37 [16, 55] vs 33 years [12, 55]), more likely to have an underlying diagnosis of membranous nephropathy (44% vs 27%), had shorter time since biopsy (139 [27, 477] vs 325 [89, 878] days) and higher UPCR (3.8 [1.4, 8.0] vs 0.9 [0.1, 3.1]g/g). After adjusting for diagnosis, age, sex, UPCR, eGFR, time since biopsy, and study cohort, hematuria was associated with a higher riskof reaching the composite outcome (HR 1.31 [1.04, 1.65], p-value 0.02) and lower rate of reaching proteinuria remission (HR 0.80 [0.65-0.98], p-value 0.03). CONCLUSIONS: Hematuria is prevalent among participants with the three podocytopathies and is significantly and independently associated with worse kidney-related outcomes, including both progressive loss of kidney function remission of proteinuria.

Expert Discussion on Challenges in C3G Diagnosis: A Podcast Article on Best Practices in Kidney Biopsies.

Complement 3 glomerulopathy (C3G) is an ultra-rare, progressive kidney disease resulting from dysregulation of the alternative complement pathway. Clinical presentation of C3G is heterogeneous and definitive diagnosis relies on kidney biopsy and immunofluorescence staining. The term C3G encompasses two subgroups, dense deposit disease and C3 glomerulonephritis, distinguished via electron microscopy. In this podcast article, the authors discuss the challenges associated with C3G diagnosis and the central role of kidney biopsy. Using an illustrative case study, key histological observations are described, and best practices are discussed from the perspectives of a nephrologist and a nephropathologist. Podcast Audio (MP4 141866 KB).

pSTAT1 Is Activated during the Progression of IgA Nephropathy.

Introduction: IgA nephropathy is the most common primary glomerular disease. Its pathogenesis is still poorly understood. Alterations of the Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway may play an important role in IgA nephropathy. Methods: We evaluated the clinical features, pathology, and tissue staining for lymphocytes and phosphorylated STAT1 (pSTAT1) in 43 patients with biopsy proven IgA nephropathy. They were followed to determine their disease outcomes. All had biopsy tissue and multiple laboratory measurements to assess their kidney disease progression. Sixteen patients underwent repeat kidney biopsy to further assess their clinical status. Results: The median eGFR at baseline was 61 mL/min/1.73 m2 and the median proteinuria was 2,600 mg/d. The median follow-up was 5 years with an average annual decline in eGFR of 2.25 mL/min/1.73 m2. There was significant inflammation and atrophy seen in the first biopsy, which progressed among those who undertook a 2nd biopsy. Compared to healthy kidney tissue, glomeruli and tubulointerstitium demonstrated increased lymphocyte (CD3+) infiltrates and increased pSTAT1 staining by immunohistochemistry. Increased CD3 (p = 0.001) staining and increased pSTAT1 (p = 0.03) correlated with reduced eGFR levels. In repeat biopsy samples, increasing pSTAT1 staining correlated with loss of eGFR over time (p = 0.02). Conclusion: These findings support the hypothesis that pSTAT1 is activated in IgA nephropathy and may play a role in the progression toward kidney failure.

Precision nephrology identified tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis.

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.

Racial and Ethnic Disparities in Acute Care Utilization Among Patients With Glomerular Disease.

RATIONALE & OBJECTIVE: The effects of race, ethnicity, socioeconomic status (SES), and disease severity on acute care utilization in patients with glomerular disease are unknown. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 1,456 adults and 768 children with biopsy-proven glomerular disease enrolled in the Cure Glomerulonephropathy (CureGN) cohort. EXPOSURE: Race and ethnicity as a participant-reported social factor. OUTCOME: Acute care utilization defined as hospitalizations or emergency department visits. ANALYTICAL APPROACH: Multivariable recurrent event proportional rate models were used to estimate associations between race and ethnicity and acute care utilization. RESULTS: Black or Hispanic participants had lower SES and more severe glomerular disease than White or Asian participants. Acute care utilization rates were 45.6, 29.5, 25.8, and 19.2 per 100 person-years in Black, Hispanic, White, and Asian adults, respectively, and 55.8, 42.5, 40.8, and 13.0, respectively, for children. Compared with the White race (reference group), Black race was significantly associated with acute care utilization in adults (rate ratio [RR], 1.76 [95% CI, 1.37-2.27]), although this finding was attenuated after multivariable adjustment (RR, 1.31 [95% CI, 1.03-1.68]). Black race was not significantly associated with acute care utilization in children; Asian race was significantly associated with lower acute care utilization in children (RR, 0.32 [95% CI 0.14-0.70]); no significant associations between Hispanic ethnicity and acute care utilization were identified. LIMITATIONS: We used proxies for SES and lacked direct information on income, household unemployment, or disability. CONCLUSIONS: Significant differences in acute care utilization rates were observed across racial and ethnic groups in persons with prevalent glomerular disease, although many of these difference were explained by differences in SES and disease severity. Measures to combat socioeconomic disadvantage in Black patients and to more effectively prevent and treat glomerular disease are needed to reduce disparities in acute care utilization, improve patient wellbeing, and reduce health care costs.

The role of BAFF and APRIL in IgA nephropathy: pathogenic mechanisms and targeted therapies.

Immunoglobulin A nephropathy (IgAN), characterized by mesangial deposition of galactose-deficient-IgA1 (Gd-IgA1), is the most common biopsy-proven primary glomerulonephritis worldwide. Recently, an improved understanding of its underlying pathogenesis and the substantial risk of progression to kidney failure has emerged. The "four-hit hypothesis" of IgAN pathogenesis outlines a process that begins with elevated circulating levels of Gd-IgA1 that trigger autoantibody production. This results in the formation and deposition of immune complexes in the mesangium, leading to inflammation and kidney injury. Key mediators of the production of Gd-IgA1 and its corresponding autoantibodies are B-cell activating factor (BAFF), and A proliferation-inducing ligand (APRIL), each playing essential roles in the survival and maintenance of B cells and humoral immunity. Elevated serum levels of both BAFF and APRIL are observed in patients with IgAN and correlate with disease severity. This review explores the complex pathogenesis of IgAN, highlighting the pivotal roles of BAFF and APRIL in the interplay between mucosal hyper-responsiveness, B-cell activation, and the consequent overproduction of Gd-IgA1 and its autoantibodies that are key features in this disease. Finally, the potential therapeutic benefits of inhibiting BAFF and APRIL in IgAN, and a summary of recent clinical trial data, will be discussed.

Comparing Kidney Health Outcomes in Children, Adolescents, and Adults With Focal Segmental Glomerulosclerosis.

Importance: Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease (ESKD) across the lifespan. While 10% to 15% of children and 3% of adults who develop ESKD have FSGS, it remains uncertain whether the natural history differs in pediatric vs adult patients, and this uncertainty contributes to the exclusion of children and adolescents in clinical trials. Objective: To examine whether there are differences in the kidney health outcomes among children, adolescents, and adults with FSGS. Design, Setting, and Participants: This cohort study used pooled and parallel analyses, completed July 5, 2022, from 3 complimentary data sources: (1) Nephrotic Syndrome Rare Disease Clinical Research Network (NEPTUNE); (2) FSGS clinical trial (FSGS-CT); and (3) Kidney Research Network (KRN). NEPTUNE is a multicenter US/Canada cohort study; FSGS-CT is a multicenter US/Canada clinical trial; and KRN is a multicenter US electronic health record-based registry from academic and community nephrology practices. NEPTUNE included 166 patients with incident FSGS enrolled at first kidney biopsy; FSGS-CT included 132 patients with steroid-resistant FSGS randomized to cyclosporine vs dexamethasone with mycophenolate; and KRN included 184 patients with prevalent FSGS. Data were collected from November 2004 to October 2019 and analyzed from October 2020 to July 2022. Exposures: Age: children (age <13 years) vs adolescents (13-17 years) vs adults (≥18 years). Covariates of interest included sex, disease duration, APOL1 genotype, urine protein-to-creatinine ratio, estimated glomerular filtration rate (eGFR), edema, serum albumin, and immunosuppressive therapy. Main Outcomes and Measures: ESKD, composite outcome of ESKD or 40% decline in eGFR, and complete and/or partial remission of proteinuria. Results: The study included 127 (26%) children, 102 (21%) adolescents, and 253 (52%) adults, including 215 (45%) female participants and 138 (29%) who identified as Black, 98 (20%) who identified as Hispanic, and 275 (57%) who identified as White. Overall, the median time to ESKD was 11.9 years (IQR, 5.2-19.1 years). There was no difference in ESKD risk among children vs adults (hazard ratio [HR], 0.67; 95% CI, 0.43-1.03) or adolescents vs adults (HR, 0.85; 95% CI, 0.52-1.36). The median time to the composite end point was 5.7 years (IQR 1.6-15.2 years), with hazard ratio estimates for children vs adults of 1.12 (95% CI, 0.83-1.52) and adolescents vs adults of 1.06 (95% CI, 0.75-1.50). Conclusions and Relevance: In this study, the association of FSGS with kidney survival and functional outcomes was comparable at all ages.

C5a receptor inhibitor avacopan in immunoglobulin A nephropathy-an open-label pilot study.

Background: Improvement of proteinuria as a marker for disease activity is associated with a better renal outcome in immunoglobulin A nephropathy (IgAN). Complement is an effector pathway in IgA-mediated kidney injury. Avacopan, a selective C5a receptor inhibitor, has previously shown efficacy in anti-neutrophil cytoplasmic antibody-associated vasculitis. The aim of this study was to evaluate the safety and efficacy of avacopan in patients with IgAN with persistent proteinuria despite a maximally tolerated dose of renin-angiotensin-aldosterone system blockade. The efficacy evaluation was based on the change in proteinuria. Methods: This open-label pilot trial enrolled adult patients with biopsy-proven IgAN, urinary protein:creatinine ratio (UPCR) >1 g/g creatinine and an estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m2 or >45 mL/min/1.73 m2 if eGFR has not declined >10 mL/min/1.73 m2 over the previous 24 weeks. If the UPCR remained at >1 g/g creatinine after an 8-week run-in period, patients started avacopan 30 mg twice daily. The primary efficacy endpoint was the change in the slope of the UPCR from the 8-week run-in period to the slope in the 12-week avacopan dosing period. Results: A total of 10 of 15 screened patients entered the run-in period. Seven patients with a UPCR >1 g/g creatinine received avacopan. Six of seven patients had numerical improvement in the UPCR during the avacopan treatment period, three of whom had a numerical improvement of ∼50% at week 12. At week 24, five of seven patients still showed numerical improvement in the UPCR compared with baseline. The urinary monocyte chemoattractant protein-1:creatinine ratio decreased numerically 30% by week 8, possibly reflecting the anti-inflammatory activity of avacopan. Avacopan was well tolerated. There was one serious adverse event of unstable angina, which was deemed to be unrelated to avacopan. Conclusions: This short-term pilot study showed an improvement in the slope of the UPCR, with ∼50% improvement in three of seven patients with IgAN. Longer avacopan treatment duration may be indicated for maximal benefit.

Racial-ethnic differences in health-related quality of life among adults and children with glomerular disease.

INTRODUCTION: Disparities in health-related quality of life (HRQOL) have been inadequately studied in patients with glomerular disease. The aim of this study was to identify relationships between race/ethnicity, socioeconomic status, disease severity, and HRQOL in an ethnically and racially diverse cohort of patients with glomerular disease. METHODS: Cure Glomerulonephropathy (CureGN) is a multinational cohort study of patients with biopsy-proven glomerular disease. Associations between race/ethnicity and HRQOL were determined by the following: 1. Missed school or work due to kidney disease; 2. Responses to Patient Reported Outcomes Measurement Information System (PROMIS) questionnaires. We adjusted for demographics, socioeconomic status, and disease characteristics using multivariable logistic and linear regression. RESULTS: Black and Hispanic participants had worse socioeconomic status and more severe glomerular disease than White or Asian participants. Black adults missed work or school most frequently due to kidney disease (30% versus 16-23% in the other three groups, p=0.04), and had the worst self-reported global physical health (median score 44.1 versus 48.0-48.2, p<0.001) and fatigue (53.8 versus 48.5-51.1, p=0.002), compared to other racial/ethnic groups. However, these findings were not statistically significant with adjustment for socioeconomic status and disease severity, both of which were strongly associated with HRQOL in adults. Among children, disease severity but not race/ethnicity or socioeconomic status were associated with HRQOL. CONCLUSIONS: Among patients with glomerular disease enrolled in CureGN, the worse HRQOL reported by Black adults was attributable to lower socioeconomic status and more severe glomerular disease. No racial/ethnic differences in HRQOL were observed in children.

APOL1 genotype-associated morphologic changes among patients with focal segmental glomerulosclerosis.

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 <0.1) with decreased global mesangial hypercellularity, decreased condensation of cytoskeleton, and increased tubular microcysts. No significant correlations were detected in MCD cohort. Independent of risk alleles, glomerular APOL1 expression in FSGS patients was not correlated with morphologic features. CONCLUSIONS: While APOL1-associated FSGS is associated with two risk alleles, both one and two risk alleles are associated with cellular/tissue changes in this study of FSGS patients. Our lack of discovery of a large group of tissue differences in FSGS and no significant difference in MCD may be due to the lack of power but also supports investigating whether machine learning methods may more sensitively detect APOL1-associated changes.

The Development and Use of an EHR-Linked Database for Glomerular Disease Research and Quality Initiatives.

Background and Objective: The use of electronic health record (EHR) data can facilitate efficient research and quality initiatives. The imprecision of ICD-10 codes for kidney diagnoses has been an obstacle to discrete data-defined diagnoses in the EHR. This manuscript describes the Kidney Research Network (KRN) registry and database that provide an example of a prospective, real-world data glomerular disease registry for research and quality initiatives. Methods: KRN is a multicenter collaboration of patients, physicians, and scientists across diverse health-care settings with a focus on improving treatment options and outcomes for patients with glomerular disease. The registry and data warehouse amasses retrospective and prospective data including EHR, active research study, completed clinical trials, patient reported outcomes, and other relevant data. Following consent, participating sites enter the patient into KRN and provide a physician-confirmed primary kidney diagnosis. Kidney biopsy reports are redacted and uploaded. Site programmers extract local EHR data including demographics, insurance type, zip code, diagnoses, encounters, laboratories, procedures, medications, dialysis/transplant status, vitals, and vital status monthly. Participating sites transform data to conform to a common data model prior to submitting to the Data Analysis and Coordinating Center (DACC). The DACC stores and reviews each site's EHR data for quality before loading into the KRN database. Results: As of January 2021, 1,192 patients have enrolled in the registry. The database has been utilized for research, clinical trial design, clinical trial end point validation, and supported quality initiatives. The data also support a dashboard allowing enrolling sites to assist with clinical trial enrollment and population health initiatives. Conclusion: A multicenter registry using EHR data, following physician- and biopsy-confirmed glomerular disease diagnosis, can be established and used effectively for research and quality initiatives. This design provides an example which may be readily replicated for other rare or common disease endeavors.

JAK-STAT Activity in Peripheral Blood Cells and Kidney Tissue in IgA Nephropathy.

BACKGROUND AND OBJECTIVES: IgA nephropathy is the most common primary glomerular disease in the world. Marked by mesangial inflammation and proliferation, it generally leads to progressive kidney fibrosis. As the Janus kinase signal transducer and activator of transcription pathway has been implicated as an important mediator of diabetic kidney disease and FSGS, detailed investigation of this pathway in IgA nephropathy was undertaken to establish the basis for targeting this pathway across glomerular diseases. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Well characterized patients with IgA nephropathy and controls were studied, allowing us to compare 77 patients with biopsy-proven IgA nephropathy with 45 healthy subjects. STAT phosphorylation was assessed in peripheral blood monocytes (PBMCs) by phosphoflow before and after cytokine stimulation. Kidney Janus kinase signal transducer and activator of transcription activity was studied by immunofluorescence and by transcriptomic studies. An STAT1 activity score was established using downstream transcriptional targets of pSTAT1 and associated with disease and clinical outcomes. RESULTS: We found PBMCs to have upregulated pSTAT production at baseline in patients with IgA nephropathy with a limited reserve to respond to cytokine stimulation compared with controls. Increased staining in glomerular mesangium and endothelium was seen for Jak-2 and pSTAT1 and in the tubulointerstitial for JAK2, pSTAT1, and pSTAT3. Activation of the Janus kinase signal transducer and activator of transcription pathway was further supported by increased pSTAT1 and pSTAT3 scores in glomerular and tubulointerstitial sections of the kidney (glomerular activation Z scores: 7.1 and 4.5, respectively; P values: <0.001 and <0.001, respectively). Clinically, phosphoflow results associated with proteinuria and kidney function, and STAT1 activation associated with proteinuria but was not associated with progression. CONCLUSIONS: Janus kinase signal transducer and activator of transcription signaling was activated in patients with IgA nephropathy compared with controls. There were altered responses in peripheral immune cells and increased message and activated proteins in the kidney. These changes variably related to proteinuria and kidney function.

Organ responses with daratumumab therapy in previously treated AL amyloidosis.

Immunoglobulin light chain amyloidosis (AL amyloidosis) involves deposition of abnormally folded light chains into a wide range of tissues causing organ dysfunction, including in the heart and kidney. Daratumumab, a CD38-targeted antibody, has recently demonstrated efficacy in producing hematologic responses in previously treated disease. However, data on survival outcomes and organ responses to daratumumab are lacking. Seventy-two patients with previously treated AL amyloidosis who received daratumumab monotherapy with dexamethasone were retrospectively evaluated. With a median follow-up of 27 months, 2-year overall survival (OS) was 86.9% (median OS, not reached) and 2-year time-to-next treatment or death (TTNT)-free survival was 62% (median TTNT, not reached). Forty of 52 evaluable patients achieved a hematologic response (77%), with >60% of patients achieving a very good partial response or better; median time-to-hematologic response was 1 month. Fifty-seven patients (79%) had cardiac involvement, and 55% of evaluable patients achieved a cardiac response, with a median response time of 3.2 months among responders. Cardiac responses were associated with an improvement in OS, with landmark analysis for cardiac responses at 3 months trending toward statistical significance (100% vs 55% at 30 months, P = .051). Forty-seven patients (65%) had renal involvement, and 52% of evaluable patients achieved a renal response, with a median response time of 6 months among responders; there was no significant difference in OS between renal responders and nonresponders. This study demonstrates that daratumumab is highly effective in the treatment of previously treated AL amyloidosis, and a significant proportion of patients can achieve deep hematologic responses, as well as improvements in organ function.