Glomerular diseases最新文献

{"title":"Safety and Tolerability of the APOL1 Inhibitor, Inaxaplin, Following Single- and Multiple-ascending Doses in Healthy Adults","authors":"O. Egbuna, Vincent Audard, George Manos, Simon Tian, Fanuel Hagos, Glenn M. Chertow","doi":"10.1159/000538255","DOIUrl":"https://doi.org/10.1159/000538255","url":null,"abstract":"Introduction\u0000Toxic gain-of-function Apolipoprotein L1 (APOL1) variants contribute to the development of proteinuric nephropathies collectively referred to as APOL1-mediated kidney disease (AMKD). Despite standard-of-care treatments, patients with AMKD experience accelerated progression to end stage kidney disease. The identification of two APOL1 variants as the genetic cause of AMKD inspired development of inaxaplin, an inhibitor of APOL1 channel activity that reduces proteinuria in patients with AMKD.\u0000\u0000Methods\u0000We conducted two phase 1 studies evaluating the safety, tolerability, and pharmacokinetics of single-ascending doses (SAD) and multiple-ascending doses (MAD) of inaxaplin in healthy participants. In the SAD cohorts, participants were randomized to receive inaxaplin as a single dose (range, 7.5 mg to 165 mg) or placebo. In the MAD cohorts, participants were randomized to receive multiple doses of inaxaplin (range, 15 to 120 mg daily) or placebo for 14 days. We assessed safety and tolerability based on adverse events (AEs), clinical laboratory values, electrocardiograms (ECGs), and vital signs.\u0000\u0000Results\u0000A total of 178 participants were randomized in the SAD/MAD cohorts of both studies (mean age: 36.7 years; 94.9% male). The proportion of participants with any AEs was similar in the inaxaplin (24.6%) and placebo (22.7%) groups. All AEs were mild or moderate in severity; there were no serious AEs. Headache was the most common AE: 10.4% and 2.3% in the inaxaplin and placebo groups, respectively. There were no drug-related treatment discontinuations and no clinically relevant trends in laboratory values, ECGs, or vital signs.\u0000\u0000Discussion/Conclusion\u0000Inaxaplin is safe and well tolerated at single doses up to 165 mg and multiple doses up to 120 mg daily for 14 days. These results are consistent with the favorable safety profile of inaxaplin in a completed phase 2a proof-of-concept study. Together, these findings support continued evaluation of inaxaplin in an ongoing phase 2/3 pivotal trial as a potential precision medicine for patients with AMKD.\u0000","PeriodicalId":73177,"journal":{"name":"Glomerular diseases","volume":"1 s1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140243487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developmental Causes of Focal Segmental Glomerulosclerosis.","authors":"Luna Shane Klomp, Elena Levtchenko, Rik Westland","doi":"10.1159/000538345","DOIUrl":"10.1159/000538345","url":null,"abstract":"<p><strong>Background: </strong>Focal segmental glomerulosclerosis (FSGS) is a histological pattern of glomerular damage that includes idiopathic conditions as well as genetic and non-genetic forms. Among these various etiologies, different phenotypes within the spectrum of congenital anomalies of the kidney and urinary tract (CAKUT) have been associated with FSGS.</p><p><strong>Summary: </strong>Until recently, the main pathomechanism of how congenital kidney and urinary tract defects lead to FSGS was attributed to a reduced number of nephrons, resulting in biomechanical stress on the remaining glomeruli, detachment of podocytes, and subsequent inability to maintain normal glomerular architecture. The discovery of deleterious single-nucleotide variants in <i>PAX2</i>, a transcription factor crucial in normal kidney development and a known cause of papillorenal syndrome, in individuals with adult-onset FSGS without congenital kidney defects has shed new light on developmental defects that become evident during podocyte injury.</p><p><strong>Key message: </strong>In this mini-review, we challenge the assumption that FSGS in CAKUT is caused by glomerular hyperfiltration alone and hypothesize a multifactorial pathogenesis that includes overlapping cellular mechanisms that are activated in both damaged podocytes as well as nephron progenitor cells.</p>","PeriodicalId":73177,"journal":{"name":"Glomerular diseases","volume":"4 1","pages":"95-104"},"PeriodicalIF":0.0,"publicationDate":"2024-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11216339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141478095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Challenges and Opportunities for the Clinical Translation of Spatial Transcriptomics Technologies.","authors":"Kelly D Smith, David K Prince, James W MacDonald, Theo K Bammler, Shreeram Akilesh","doi":"10.1159/000538344","DOIUrl":"https://doi.org/10.1159/000538344","url":null,"abstract":"<p><strong>Background: </strong>The first spatially resolved transcriptomics platforms, GeoMx (Nanostring) and Visium (10x Genomics) were launched in 2019 and were recognized as the method of the year by <i>Nature Methods</i> in 2020. The subsequent refinement and expansion of these and other technologies to increase -plex, work with formalin-fixed paraffin-embedded tissue, and analyze protein in addition to gene expression have only added to their significance and impact on the biomedical sciences. In this perspective, we focus on two platforms for spatial transcriptomics, GeoMx and Visium, and how these platforms have been used to provide novel insight into kidney disease. The choice of platform will depend largely on experimental questions and design. The application of these technologies to clinically sourced biopsies presents the opportunity to identify specific tissue biomarkers that help define disease etiology and more precisely target therapeutic interventions in the future.</p><p><strong>Summary: </strong>In this review, we provide a description of the existing and emerging technologies that can be used to capture spatially resolved gene and protein expression data from tissue. These technologies have provided new insight into the spatial heterogeneity of diseases, how reactions to disease are distributed within a tissue, which cells are affected, and molecular pathways that predict disease and response to therapy.</p><p><strong>Key message: </strong>The upcoming years will see intense use of spatial transcriptomics technologies to better define the pathophysiology of kidney diseases and develop novel diagnostic tests to guide personalized treatments for patients.</p>","PeriodicalId":73177,"journal":{"name":"Glomerular diseases","volume":"4 1","pages":"49-63"},"PeriodicalIF":0.0,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11006413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140860923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>APOL1</i> Genotyping Is Incomplete without Testing for the Protective M1 Modifier p.N264K Variant.","authors":"Rasheed Gbadegesin, Elena Martinelli, Yask Gupta, David J Friedman, Matthew G Sampson, Martin R Pollak, Simone Sanna-Cherchi","doi":"10.1159/000537948","DOIUrl":"10.1159/000537948","url":null,"abstract":"","PeriodicalId":73177,"journal":{"name":"Glomerular diseases","volume":"4 1","pages":"43-48"},"PeriodicalIF":0.0,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10942791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140144777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ANCA-associated vasculitis with active kidney involvement in the United States: 2016–2020","authors":"Jianling Tao, Sai Liu, M. Montez-Rath, Vivek Charu, Glenn M. Chertow","doi":"10.1159/000536168","DOIUrl":"https://doi.org/10.1159/000536168","url":null,"abstract":"Introduction. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and its subtypes, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic GPA (EGPA), frequently present with acute kidney injury and can often lead to kidney failure, even with successful induction therapy. Few contemporary, nationally representative studies have described hospital complications of AAV. \u0000Methods. Using data from the 2016–2020 National Inpatient Sample, a nationally representative database, we identified hospitalizations from adults with a new diagnosis of AAV (subtype or unspecified) and an inpatient kidney biopsy during the index hospitalization. We described baseline characteristics, associated inpatient procedures and complications, and compared lengths of stay and costs by geographic region, hospital characteristics, and AAV subtype. \u0000Results. We identified an average of 1329 cases of hospitalized AAV with a concurrent kidney biopsy per year over the 5-year period. More than 50% were not designated as having a specific subtype, likely owing to delays in documentation of histopathology. Kidney involvement was severe as the majority of patients developed acute kidney injury and the proportion of patients who required inpatient dialysis was approximately 24%. Approximately 20% of patients developed hypoxia. Inpatient plasmapheresis was delivered to 20.4% and 20.6% of patients with GPA and MPA, respectively. There were no clinically meaningful or statistically significant differences in adjusted length of stay or inpatient costs among AAV subtypes. Admission in the Midwest region was associated with shorter hospital stays and lower costs than that in the Northeast, South, or West regions of the US (adjusted p=0.007 and <0.001, respectively). \u0000Conclusion. AAV with acute kidney involvement remains a challenging, high-risk condition. Maintaining a high index of suspicion and a low threshold for kidney biopsy should help to ameliorate short- and longer-term complications (281 words)\u0000\u0000","PeriodicalId":73177,"journal":{"name":"Glomerular diseases","volume":"11 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139534163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating sex differences in the characteristics and outcomes of lupus nephritis: a systematic review and meta-analysis","authors":"Salman B. Mahmood, Muhammad Aziz, Deepthi C. Malepati, Wade Lee-Smith, Justin Clark, Ann Brearley, Patrick H. Nachman","doi":"10.1159/000535981","DOIUrl":"https://doi.org/10.1159/000535981","url":null,"abstract":"Introduction: More frequent and severe lupus nephritis (LN) has been reported in men compared to women but data are limited and inconsistent. We conducted a meta-analysis of the literature to compare the histopathologic findings and outcomes between men and women with biopsy-proven LN.\u0000Methods: A systematic search of MEDLINE, Embase, Cochrane, and Web of Science databases was conducted through February 2021. Clinical information was extracted and synthesized from 25 studies that met inclusion criteria (1210 men and 6635 women). Pooled odds ratios (OR) with corresponding 95% confidence intervals (CI) were generated via meta-analysis, and meta-regression was performed to assess the impact of several covariates, both using random-effects models.\u0000Results: Twenty studies reported kidney histopathology, eleven reported kidney outcomes and eight reported mortality rates. Men had greater odds of class IV ± V LN (OR 1.26, 95% CI 1.01-1.56), and the composite of end-stage kidney disease, persistent eGFR <15 mL/min or doubling of serum creatinine (OR 2.20, 95% CI 1.59-3.06), and lower odds of complete remission (OR 0.52, 95% CI 0.39-0.68). Mortality was not statistically significantly different between sexes (OR 1.50, 95% CI 0.92-2.46). Meta-regression did not reveal statistically significant study-level relationships between sex differences in any of the covariates that could account for the greater odds of worse kidney outcome in males.\u0000Conclusion: Our analysis confirms the association between male sex and increased severity of LN as well as worse kidney outcomes. Larger prospective studies are needed to validate this association and inform treatment strategies adapted to this population.","PeriodicalId":73177,"journal":{"name":"Glomerular diseases","volume":"60 51","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139385525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing Treatments for Rare Renal Diseases: New Hopes and Opportunities to Address a High Unmet Need.","authors":"Davide Garrisi, Andrew Bevan, Carmichael Angeles","doi":"10.1159/000535955","DOIUrl":"https://doi.org/10.1159/000535955","url":null,"abstract":"Background The etiology of chronic kidney disease (CKD) is varied and complex, with diabetes mellitus and hypertension responsible for the 2/3 of cases and rare conditions, including inherited genetic diseases such as autosomal dominant polycystic kidney disease (ADPKD) and glomerulonephritis (GN), comprising 1/3. We previously reported a 54% increase in clinical studies in CKD in the last 10 years. Summary CT.gov was searched for 39 conditions determined to be rare renal diseases posted between 01-Jan-2003 and 31-Dec-2022. Of 876 records returned, 50 were excluded. 826 in the analysis were divided into 2 time periods: P1(2003-2012) and P2 (2013-2022) and analyzed by study type, phase, primary indication, primary endpoint, population and funding. Studies increased 123% in P2 with the greatest rise in observational studies (283%). Interventional studies increased 93%, with the greatest rise in early phases (205%). The most frequent indications were lupus nephritis (22%), ADPKD (16%) and IgA nephropathy (IGAN) (15%); all increased 77-166% in P2. Proteinuria, measured by 24-hour urine protein (24hUP) excretion or urine protein-creatinine ratio (UPCR), was the most frequent primary endpoint in both periods. Most studies were in adult-only populations (P1 60%; P2 68%); however, there was a 78% increase in studies with pediatric populations in P2. Most studies were non-industry funded (P1 64%; P2 57%); however, the number of industry funded studies increased by 225% in P2. Key Messages Our data provides evidence of a marked rise in clinical research in rare renal diseases in the last 10 years, particularly in GN and ADPKD. Proteinuria correlates with outcomes in GN, which explains the high percentage of studies with this as a primary endpoint. Rare renal diseases disproportionately affect children and the rise in the number of studies with pediatric populations is encouraging. The rise in observational studies signals an increased focus on understanding the natural course and pathophysiology of disease, which may lead to new potential therapeutic targets and future interventional studies.","PeriodicalId":73177,"journal":{"name":"Glomerular diseases","volume":"580 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139160417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FSGS Recurrence Collaboration: Report of a symposium","authors":"Debbie S. Gipson, Chia-shi Wang, Eloise Salmon, Rasheed Gbadegesin, Abhijit Naik, Simone Sanna-Cherchi, Alessia Fornoni, Matthias Kretzler, Sandra Merscher, Paul Hoover, Kelley Kidwell, Moin Saleem, Leonardo Riella, Lawrence Holzman, Annette Jackson, Opeyemi Olabisi, Paolo Cravedi, Benjamin Solomon Freedman, Jonathan Himmelfarb, Marina Vivarelli, Jennifer Harder, Jon Klein, George Burke, Michelle Rheault, Cathie Spino, Hailey E. Desmond, Howard Trachtman","doi":"10.1159/000535138","DOIUrl":"https://doi.org/10.1159/000535138","url":null,"abstract":"Since it was first described more than 50 years ago, recurrence of FSGS in kidney allografts has frustrated the transplant community. This rare condition is associated with considerable morbidity, and it is the most common cause of graft loss in patients with CKD stage 5 due to FSGS. However, the problem remains insufficiently studied. It is an ultra-orphan disease and incidence rates at individual centers are often very low and unpredictable. The published literature contains conflicting reports in basic epidemiologic data. Progress in defining the mechanisms of disease and advancing therapeutic options has been limited. The treatment options that are currently available are limited and largely ineffective. The range in time to recurrence and variability in responsiveness to treatment suggest that recurrence is not a single entity, but rather multiple phenotypes resulting from diverse pathogenetic mechanisms grouped under a larger umbrella. There is an urgent need for innovative basic science and translational research to [1] better understand FSGS recurrence from a mechanistic perspective; [2] improve risk stratification to predict this outcome; and [3] develop effective therapies. In this conference report, we describe the work of investigators whose state-of-the-art research paves the way for innovative approaches to diagnosis and treatment of the problem and provides hope that we can achieve these objectives for affected patients.","PeriodicalId":73177,"journal":{"name":"Glomerular diseases","volume":"9 6","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134956846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combing Genome-Wide Association Studies and Single-Cell Analysis to Elucidate the Mechanisms of Kidney Disease: Proceedings of the Henry Shavelle Professorhip","authors":"Jonathan Levinsohn, Shen Li, Eunji Ha, Katalin Susztak","doi":"10.1159/000534678","DOIUrl":"https://doi.org/10.1159/000534678","url":null,"abstract":"Background: Kidney diseases pose a significant global health burden, there is an urgent need to deepen our understanding of their underlying mechanisms. Summary: This review focuses on new innovative approaches that merge Genome-Wide Association Studies (GWAS) and single-cell omics (including transcriptomics) in kidney disease research. We begin by detailing how GWAS have identified numerous genetic risk factors, offering valuable insight into disease susceptibility. Then, we explore the application of scRNA-seq, highlighting its ability to unravel how genetic variants influence cellular phenotypes. Through a synthesis of recent studies, we illuminate the synergy between these two powerful methodologies, demonstrating their potential in elucidating the complex etiology of kidney diseases. Moreover, we discuss how this integrative approach could pave the way for precise diagnostics and personalized treatments. Key Message: This review underscores the transformative potential of combining GWAS and scRNA-seq in the journey towards a deeper understanding of kidney diseases.","PeriodicalId":73177,"journal":{"name":"Glomerular diseases","volume":"17 3","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136105014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal Analysis of Prophylactic Anticoagulation in Primary Nephrotic Syndrome: Low Incidence of Thromboembolic Complications","authors":"Thomas McDonnell, John Hartemink, Omar Ragy, Kathrine Parker, Meshaal Shukkur, Jecko Thachil, Durga Kanigicherla","doi":"10.1159/000534652","DOIUrl":"https://doi.org/10.1159/000534652","url":null,"abstract":"Introduction Thromboembolic events (TEEs) are a serious and potentially fatal complication of nephrotic syndrome (NS). Despite this there is a lack of evidence examining the benefits of prophylactic anticoagulation (PAC) in NS. It was our objective to review the risk factors, rates of TEEs and patterns of PAC in patients with primary NS, with the aim to provide a pragmatic approach to PAC in primary NS. Methods This is a retrospective longitudinal cohort study of adult patients with primary NS. Included were: biopsy proven Minimal Change Disease and Focal Segmental Glomerulosclerosis (described as a combined podocytopathy cohort) plus Membranous Nephropathy (MN) over an 8-year period from a single centre. Anticoagulation practice, TEEs and longer-term outcomes were recorded. Results 54 patients with MN and 48 with podocytopathies were included. Baseline demographics and severity of NS was comparable. Those with MN were more likely to develop TEE 12(22%) vs 4(8%) (p=0.027) though this difference was predominantly seen at index diagnosis. Only 2 patients developed TEEs during active incident nephrotic syndrome. Rates of PAC were similar comparing MN (53%) and podocytopathies (58%). Those with a serum albumin < 20 g/L and HAS BLED score <3 were most likely to receive PAC (22/30, 73% in MN vs 21/30, 70% in iNS). Warfarin was the most common agent used in MN cohort 18/26 (69%) vs prophylactic dose low molecular weight heparin in the podocytopathy cohort 12/28 (43%). Discussion/Conclusion PAC practices applied in this cohort of patients were pragmatic and effective, with low TEE rates during active nephrotic syndrome.","PeriodicalId":73177,"journal":{"name":"Glomerular diseases","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136104243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}