BACKGROUNDNephronophthisis (NPH) is an autosomal recessive tubulointerstitial kidney disease and a leading genetic cause of chronic kidney failure (KF) in children and young adults. As a ciliopathy, NPH is caused by biallelic variants in genes encoding proteins involved in the structure and function of primary cilia. The broad clinical spectrum of NPH results in a clinically and genetically heterogeneous disease, posing diagnostic challenges and leaving approximately 30% of cases unresolved with current gene panels.METHODSAfter targeted gene panel for ciliopathy-associated genes failed to identify diagnostic variants, exome sequencing (ES) was conducted on 42 unrelated index patients with a clinical diagnosis of NPH, defined as cystic nephropathy progressing to KF within the first two decades of life, or by unspecific chronic kidney disease (CKD) accompanied by extrarenal features indicative of a ciliopathy.RESULTSPathogenic or likely pathogenic variants were identified in 11 out of the 42 patients (26%). Variants were detected in known nephropathy genes (LAMB2, COQ8B, COL4A3, MUC1) and a multisystem disease gene with secondary kidney involvement (AGXT). Additionally, ES elucidated deleterious variants explaining extrarenal phenotypes without corresponding kidney disease in six patients (APTX, TUBB3, DHX38, IQCE, CRX, RPGR). Variants of unknown significance (VUS) were identified in three patients, while heterozygous variants in genes associated with recessive disease were observed in three others. A potential candidate gene for syndromic tubulointerstitial nephropathy, SSBP1, was also identified, suggesting a novel pathway involving mitochondrial dysfunction.CONCLUSIONSES enabled the identification of pathogenic variants in known genes associated with kidney diseases, non-kidney conditions, and multisystem disorders with secondary kidney involvement, thereby improving diagnosis accuracy, even in incomplete or atypical cases, and guiding specific diagnostic and therapeutic approaches. The identification of SSBP1 in association with tubulointerstitial nephropathy may provide new insights into the pathogenesis of ciliopathies.
{"title":"Exome Sequencing in a Large Cohort with Ciliopathy-Related Kidney Disease.","authors":"Friederike Petzold,Cécile Jeanpierre,Xiaoyi Chen,Vincent Morinière,Alexandre Benmerah,Guillaume Dorval,Hassan Saei,Laurence Heidet,Corinne Antignac,Sophie Saunier, ","doi":"10.2215/cjn.0000000905","DOIUrl":"https://doi.org/10.2215/cjn.0000000905","url":null,"abstract":"BACKGROUNDNephronophthisis (NPH) is an autosomal recessive tubulointerstitial kidney disease and a leading genetic cause of chronic kidney failure (KF) in children and young adults. As a ciliopathy, NPH is caused by biallelic variants in genes encoding proteins involved in the structure and function of primary cilia. The broad clinical spectrum of NPH results in a clinically and genetically heterogeneous disease, posing diagnostic challenges and leaving approximately 30% of cases unresolved with current gene panels.METHODSAfter targeted gene panel for ciliopathy-associated genes failed to identify diagnostic variants, exome sequencing (ES) was conducted on 42 unrelated index patients with a clinical diagnosis of NPH, defined as cystic nephropathy progressing to KF within the first two decades of life, or by unspecific chronic kidney disease (CKD) accompanied by extrarenal features indicative of a ciliopathy.RESULTSPathogenic or likely pathogenic variants were identified in 11 out of the 42 patients (26%). Variants were detected in known nephropathy genes (LAMB2, COQ8B, COL4A3, MUC1) and a multisystem disease gene with secondary kidney involvement (AGXT). Additionally, ES elucidated deleterious variants explaining extrarenal phenotypes without corresponding kidney disease in six patients (APTX, TUBB3, DHX38, IQCE, CRX, RPGR). Variants of unknown significance (VUS) were identified in three patients, while heterozygous variants in genes associated with recessive disease were observed in three others. A potential candidate gene for syndromic tubulointerstitial nephropathy, SSBP1, was also identified, suggesting a novel pathway involving mitochondrial dysfunction.CONCLUSIONSES enabled the identification of pathogenic variants in known genes associated with kidney diseases, non-kidney conditions, and multisystem disorders with secondary kidney involvement, thereby improving diagnosis accuracy, even in incomplete or atypical cases, and guiding specific diagnostic and therapeutic approaches. The identification of SSBP1 in association with tubulointerstitial nephropathy may provide new insights into the pathogenesis of ciliopathies.","PeriodicalId":50681,"journal":{"name":"Clinical Journal of the American Society of Nephrology","volume":"1 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145674424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yaacov Frishberg,Jeffrey M Saland,John C Lieske,Weiming Du,Martin Coenen,Julien Hogan,Anne-Laure Sellier-Leclerc,Jaap W Groothoff,Cristin Kaspar,John M Gansner,Sally-Anne Hulton,
BACKGROUNDPrimary hyperoxaluria type 1 (PH1) is characterized by hepatic oxalate overproduction, kidney stones, and progressive kidney disease. Lumasiran is the first approved treatment for PH1.METHODSILLUMINATE-A (NCT03681184) was a 60-month pivotal, phase 3, multinational clinical trial of lumasiran which consisted of a six-month double-blind, placebo-controlled period (6M DB) followed by a treatment extension period of up to 54 months in which all patients received lumasiran. Eligible patients were aged ≥6 years with genetically confirmed PH1, estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73m2, and mean 24-hour urinary oxalate (UOx) excretion ≥0.70 mmol/24h/1.73m2.RESULTSOf 39 patients enrolled, 24 out of 26 randomized to lumasiran in the 6M DB (lumasiran/lumasiran group) and 13 out of 13 randomized to placebo in the 6M DB (placebo/lumasiran group) completed the study. Sustained reductions in 24-hour UOx were observed in both treatment groups. At Month 60 relative to study baseline, mean (standard error of the mean [SEM]) 24-hour UOx percentage reductions were 54% (6%) and 54% (8%) in the lumasiran/lumasiran and placebo/lumasiran groups, respectively, and mean (SEM) plasma oxalate concentrations had decreased by 35% (5%) and 38% (7%). Estimated glomerular filtration rate remained stable through the end of the study in both treatment groups. Kidney stone event rates during the study were 0.47 (95% confidence interval [CI], 0.36, 0.62) and 0.54 (0.37, 0.78) per patient-year in the lumasiran/lumasiran group and placebo/lumasiran group, respectively. Medullary nephrocalcinosis grade improved at the end of the study in 21 out of 28 (75%) patients with nephrocalcinosis at baseline and an end of study assessment. The safety profile of lumasiran was acceptable. Injection site reactions were the most common adverse events during lumasiran treatment. Most adverse events were mild or moderate in severity.CONCLUSIONSLumasiran treatment for up to 60 months in ILLUMINATE-A was associated with sustained reductions in UOx excretion and plasma oxalate concentration, and encouraging clinical outcomes including stable eGFR in a population that would be expected to show eGFR decline, reduced kidney stone event rates, improved medullary nephrocalcinosis, and indications of improved quality of life.
{"title":"Final Results of the ILLUMINATE-A Phase 3 Clinical Trial of Lumasiran for Primary Hyperoxaluria 1.","authors":"Yaacov Frishberg,Jeffrey M Saland,John C Lieske,Weiming Du,Martin Coenen,Julien Hogan,Anne-Laure Sellier-Leclerc,Jaap W Groothoff,Cristin Kaspar,John M Gansner,Sally-Anne Hulton, ","doi":"10.2215/cjn.0000000916","DOIUrl":"https://doi.org/10.2215/cjn.0000000916","url":null,"abstract":"BACKGROUNDPrimary hyperoxaluria type 1 (PH1) is characterized by hepatic oxalate overproduction, kidney stones, and progressive kidney disease. Lumasiran is the first approved treatment for PH1.METHODSILLUMINATE-A (NCT03681184) was a 60-month pivotal, phase 3, multinational clinical trial of lumasiran which consisted of a six-month double-blind, placebo-controlled period (6M DB) followed by a treatment extension period of up to 54 months in which all patients received lumasiran. Eligible patients were aged ≥6 years with genetically confirmed PH1, estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73m2, and mean 24-hour urinary oxalate (UOx) excretion ≥0.70 mmol/24h/1.73m2.RESULTSOf 39 patients enrolled, 24 out of 26 randomized to lumasiran in the 6M DB (lumasiran/lumasiran group) and 13 out of 13 randomized to placebo in the 6M DB (placebo/lumasiran group) completed the study. Sustained reductions in 24-hour UOx were observed in both treatment groups. At Month 60 relative to study baseline, mean (standard error of the mean [SEM]) 24-hour UOx percentage reductions were 54% (6%) and 54% (8%) in the lumasiran/lumasiran and placebo/lumasiran groups, respectively, and mean (SEM) plasma oxalate concentrations had decreased by 35% (5%) and 38% (7%). Estimated glomerular filtration rate remained stable through the end of the study in both treatment groups. Kidney stone event rates during the study were 0.47 (95% confidence interval [CI], 0.36, 0.62) and 0.54 (0.37, 0.78) per patient-year in the lumasiran/lumasiran group and placebo/lumasiran group, respectively. Medullary nephrocalcinosis grade improved at the end of the study in 21 out of 28 (75%) patients with nephrocalcinosis at baseline and an end of study assessment. The safety profile of lumasiran was acceptable. Injection site reactions were the most common adverse events during lumasiran treatment. Most adverse events were mild or moderate in severity.CONCLUSIONSLumasiran treatment for up to 60 months in ILLUMINATE-A was associated with sustained reductions in UOx excretion and plasma oxalate concentration, and encouraging clinical outcomes including stable eGFR in a population that would be expected to show eGFR decline, reduced kidney stone event rates, improved medullary nephrocalcinosis, and indications of improved quality of life.","PeriodicalId":50681,"journal":{"name":"Clinical Journal of the American Society of Nephrology","volume":"159 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145674414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jennifer Bragg-Gresham,Fang Xu,Yun Han,Ana Laura Licon,Jenna Kiryakos,Michael Heung,Hal Morgenstern,William Weitzel,Tiffany Veinot,Brenda Gillespie,Zubin J Modi,William Herman,Tracey Pérez Koehlmoos,Robert Nee,James D Oliver,Sola Han,Meda E Pavkov,Rajiv Saran
Kidney diseases are an important public health problem, rising in global significance. In place for nearly two decades, the Centers for Disease Control and Prevention's Kidney Disease Surveillance System (KDSS) is the first comprehensive surveillance system developed in the United States, focused exclusively on tracking kidney disease prior to end-stage kidney disease. The KDSS incorporates key data and trends from multiple, large national-level survey data sources (National Health and Nutrition Examination Survey), electronic medical record data (Military and Veterans Affairs Health Systems), health care claims (Medicare, Optum), and social determinants of health (American Community Survey). The prevalence of chronic kidney disease (CKD) among civilian US adults remains steady between 13%─14%. Prevalence is higher among older, female, non-Hispanic Black adults, and those with diabetes or hypertension. Among US veterans, the incidence of CKD and rates of diagnosis of acute kidney injury (AKI) increased from 2008 to 2022 (Incidence: 62.8 to 71.5/1,000 person-years, AKI: 84.9 to 241.7 cases/1,000 person-years. Awareness of the disease nationwide among persons with CKD has historically been low (<10%), but starting in 2013, has increased to approximately 25%. Persons with CKD self-report more problems with sleep, and those aged 65 and older self-report a higher prevalence of functional limitations. Improvements in quality-of-care measures, including medication prescription and increases in both serum creatinine and albuminuria testing were observed. Increased self-reported physical activity was observed among persons with CKD. Food insecurity increased among persons with CKD, with the highest prevalence in young, female, non-Hispanic Black, and Hispanic adults. While population-level prevalence of CKD remains stable, higher AKI and CKD rates are being observed in health systems settings. Robust surveillance is key to raising awareness of kidney disease, its risk factors, care quality, and outcomes. Surveillance findings may inform policy and evidence-based practices that reduce premature morbidity and mortality, improve quality of life, and reduce cost.
{"title":"Epidemiology of Kidney Disease in the United States: Highlights from the Centers for Disease Control and Prevention Kidney Disease Surveillance System.","authors":"Jennifer Bragg-Gresham,Fang Xu,Yun Han,Ana Laura Licon,Jenna Kiryakos,Michael Heung,Hal Morgenstern,William Weitzel,Tiffany Veinot,Brenda Gillespie,Zubin J Modi,William Herman,Tracey Pérez Koehlmoos,Robert Nee,James D Oliver,Sola Han,Meda E Pavkov,Rajiv Saran","doi":"10.2215/cjn.0000000867","DOIUrl":"https://doi.org/10.2215/cjn.0000000867","url":null,"abstract":"Kidney diseases are an important public health problem, rising in global significance. In place for nearly two decades, the Centers for Disease Control and Prevention's Kidney Disease Surveillance System (KDSS) is the first comprehensive surveillance system developed in the United States, focused exclusively on tracking kidney disease prior to end-stage kidney disease. The KDSS incorporates key data and trends from multiple, large national-level survey data sources (National Health and Nutrition Examination Survey), electronic medical record data (Military and Veterans Affairs Health Systems), health care claims (Medicare, Optum), and social determinants of health (American Community Survey). The prevalence of chronic kidney disease (CKD) among civilian US adults remains steady between 13%─14%. Prevalence is higher among older, female, non-Hispanic Black adults, and those with diabetes or hypertension. Among US veterans, the incidence of CKD and rates of diagnosis of acute kidney injury (AKI) increased from 2008 to 2022 (Incidence: 62.8 to 71.5/1,000 person-years, AKI: 84.9 to 241.7 cases/1,000 person-years. Awareness of the disease nationwide among persons with CKD has historically been low (<10%), but starting in 2013, has increased to approximately 25%. Persons with CKD self-report more problems with sleep, and those aged 65 and older self-report a higher prevalence of functional limitations. Improvements in quality-of-care measures, including medication prescription and increases in both serum creatinine and albuminuria testing were observed. Increased self-reported physical activity was observed among persons with CKD. Food insecurity increased among persons with CKD, with the highest prevalence in young, female, non-Hispanic Black, and Hispanic adults. While population-level prevalence of CKD remains stable, higher AKI and CKD rates are being observed in health systems settings. Robust surveillance is key to raising awareness of kidney disease, its risk factors, care quality, and outcomes. Surveillance findings may inform policy and evidence-based practices that reduce premature morbidity and mortality, improve quality of life, and reduce cost.","PeriodicalId":50681,"journal":{"name":"Clinical Journal of the American Society of Nephrology","volume":"80 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145674412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sagar U Nigwekar,Laura M Dember,Sahir Kalim,David M Charytan,Natalie Kuzla,Paul L Kimmel,Daniel Cukor,Denise Esserman,Puneet Mishra,Kimberly Silva,Alana D Steffen,Svetlana Vassilieva,Joey Williams,James B Wetmore
{"title":"Approach to Quality Control Used for the HOPE Consortium Trial to Reduce Pain and Opioid Use in Hemodialysis.","authors":"Sagar U Nigwekar,Laura M Dember,Sahir Kalim,David M Charytan,Natalie Kuzla,Paul L Kimmel,Daniel Cukor,Denise Esserman,Puneet Mishra,Kimberly Silva,Alana D Steffen,Svetlana Vassilieva,Joey Williams,James B Wetmore","doi":"10.2215/cjn.0000000970","DOIUrl":"https://doi.org/10.2215/cjn.0000000970","url":null,"abstract":"","PeriodicalId":50681,"journal":{"name":"Clinical Journal of the American Society of Nephrology","volume":"40 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lipoprotein(a) [Lp(a)] was discovered more than six decades ago. Since then, it has evolved from a subject of curious experiments performed by a few scientists to an extensively explored therapeutic target for prevention and management of cardiovascular disease (CVD). This has prompted an intense search for therapies and agents with potent Lp(a)-specific lowering effects on the horizon. Some of these agents are already in clinical trials to clarify whether lowering high Lp(a) levels would result in reductions in CVD events. The road to this point has been filled with many challenges, where landmark genetic discoveries opened new avenues and set the stage for interventions. While there is no doubt that genetics play a key role in determining Lp(a) level, accumulating evidence also support a role for some clinical conditions in influencing Lp(a) levels. Chronic kidney disease (CKD) is a prevalent condition associated with elevated Lp(a) levels. Most available data show elevated Lp(a) levels predict CVD risk in patients with CKD. Given the growing evidence for a relationship between Lp(a), CVD, and CKD as well as ongoing cardiovascular outcomes trials of Lp(a)-specific agents, we provide an overview of recent evidence on this topic. We focus on recent studies in CKD patients on treatment modalities affecting Lp(a) level as well as on existing gaps in knowledge and future research directions related to clinical care and CVD risk reduction in patients with CKD.
{"title":"Lipoprotein(a) and Chronic Kidney Disease: Insights into New Therapeutic Opportunities.","authors":"Byambaa Enkhmaa,Baback Roshanravan,Lars Berglund","doi":"10.2215/cjn.0000000968","DOIUrl":"https://doi.org/10.2215/cjn.0000000968","url":null,"abstract":"Lipoprotein(a) [Lp(a)] was discovered more than six decades ago. Since then, it has evolved from a subject of curious experiments performed by a few scientists to an extensively explored therapeutic target for prevention and management of cardiovascular disease (CVD). This has prompted an intense search for therapies and agents with potent Lp(a)-specific lowering effects on the horizon. Some of these agents are already in clinical trials to clarify whether lowering high Lp(a) levels would result in reductions in CVD events. The road to this point has been filled with many challenges, where landmark genetic discoveries opened new avenues and set the stage for interventions. While there is no doubt that genetics play a key role in determining Lp(a) level, accumulating evidence also support a role for some clinical conditions in influencing Lp(a) levels. Chronic kidney disease (CKD) is a prevalent condition associated with elevated Lp(a) levels. Most available data show elevated Lp(a) levels predict CVD risk in patients with CKD. Given the growing evidence for a relationship between Lp(a), CVD, and CKD as well as ongoing cardiovascular outcomes trials of Lp(a)-specific agents, we provide an overview of recent evidence on this topic. We focus on recent studies in CKD patients on treatment modalities affecting Lp(a) level as well as on existing gaps in knowledge and future research directions related to clinical care and CVD risk reduction in patients with CKD.","PeriodicalId":50681,"journal":{"name":"Clinical Journal of the American Society of Nephrology","volume":"115 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145656826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
L Parker Gregg,Biykem Bozkurt,Sankar D Navaneethan
{"title":"Risk Assessment in Cardiovascular-Kidney-Metabolic Syndrome: An Opportunity to Individualize Evidence-Based Therapy in CKD.","authors":"L Parker Gregg,Biykem Bozkurt,Sankar D Navaneethan","doi":"10.2215/cjn.0000000973","DOIUrl":"https://doi.org/10.2215/cjn.0000000973","url":null,"abstract":"","PeriodicalId":50681,"journal":{"name":"Clinical Journal of the American Society of Nephrology","volume":"147 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marcelle Tuttle,Hocine Tighiouart,Tatsufumi Oka,Wendy McCallum,Nicholas S Hill,Sankar Navaneethan,Steven M Kawut,Mark J Sarnak
{"title":"Incident Pulmonary Hypertension and Its Risk Factors in CKD.","authors":"Marcelle Tuttle,Hocine Tighiouart,Tatsufumi Oka,Wendy McCallum,Nicholas S Hill,Sankar Navaneethan,Steven M Kawut,Mark J Sarnak","doi":"10.2215/cjn.0000000938","DOIUrl":"https://doi.org/10.2215/cjn.0000000938","url":null,"abstract":"","PeriodicalId":50681,"journal":{"name":"Clinical Journal of the American Society of Nephrology","volume":"155 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Kidney Volume as a Predictor and Modifier of Acute Kidney Injury with Renin-Angiotensin System Inhibitors.","authors":"Takahisa Kasugai,Miho Murashima,Tatsuya Tomonari,Kodai Suzuki,Yuki Miyaguchi,Maki Hiratsuka,Masashi Mizuno,Yosuke Nakai,Hisao Suda,Takayuki Hamano","doi":"10.2215/cjn.0000000911","DOIUrl":"https://doi.org/10.2215/cjn.0000000911","url":null,"abstract":"","PeriodicalId":50681,"journal":{"name":"Clinical Journal of the American Society of Nephrology","volume":"39 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kaylia M Reynolds,Daohang Sha,Quan Sun,Afshin Parsa,Jing Chen,Hernan Rincon Choles,Ruth Dubin,Jiang He,Chi-Yuan Hsu,Kristine Yaffe,Vallabh Shah,Dominic Raj,Sylvia E Rosas,James P Lash,Andrew P Morris,Nora Franceschini,
BACKGROUNDType 2 diabetes (T2D) exhibits biological and pathophysiological heterogeneity, which may contribute to variations in diabetes-related complications, particularly in high-risk populations such as individuals with chronic kidney disease (CKD). Prior research has explored T2D mechanisms using partitioned polygenic scores (PGS), derived from distinct clusters of variants according to their associations with cardiometabolic traits. In this study, we investigated whether cluster-specific partitioned PGS are associated with cardiovascular outcomes and CKD progression in individuals with CKD.METHODSWe used genome-wide genotype data from the Chronic Renal Insufficiency Cohort (CRIC) to calculate both a total PGS for T2D and partitioned PGS for T2D clusters. We examined their associations with cardiometabolic traits and conducted time-to-event analysis to assess their association with mortality (overall and cardiovascular), incident cardiovascular outcomes (myocardial infarction, stroke, heart failure, atrial fibrillation, peripheral artery disease, and a composite of major cardiovascular events) and CKD progression.RESULTSAmong 3,577 CRIC participants (mean age 58 years, 45% were women, 49% had T2D), the total PGS was significantly associated with higher hemoglobin A1C (p=4.8 x 10-21) among nondiabetic participants. Cluster-specific partitioned PGS in CRIC captured distinct cardiometabolic profiles corresponding to T2D mechanistic subtypes, particularly the obesity cluster, the β-cell dysfunction with positive proinsulin cluster, and the lipodystrophy cluster. The obesity cluster partitioned PGS was significantly associated with incident atrial fibrillation (p=2.89 x 10-4) and overall mortality (p= 4.29 x 10-4), but the association with atrial fibrillation was attenuated when accounting for competing risk of death (p=0.002). The β-cell dysfunction with negative proinsulin cluster was inversely associated with CKD progression (p=2.48 x 10-5).CONCLUSIONSOur findings suggest that T2D driven by insulin resistance and obesity contributes to a higher risk of overall death in individuals with CKD and explain in part the higher risk of atrial fibrillation. These results highlight the importance of considering T2D heterogeneity when assessing cardiovascular risk in this population.
背景：2型糖尿病（T2D）表现出生物学和病理生理的异质性，这可能导致糖尿病相关并发症的变化，特别是在慢性肾脏疾病（CKD）患者等高危人群中。先前的研究利用分区多基因评分（PGS）探索了T2D的机制，该评分根据与心脏代谢特征的关联从不同的变异群中得出。在这项研究中，我们调查了簇特异性分区PGS是否与CKD患者的心血管结局和CKD进展相关。方法：我们使用来自慢性肾功能不全队列（CRIC）的全基因组基因型数据来计算T2D的总PGS和T2D群集的分区PGS。我们检查了它们与心脏代谢特征的相关性，并进行了事件时间分析，以评估它们与死亡率（总体和心血管）、心血管事件结局（心肌梗死、中风、心力衰竭、心房颤动、外周动脉疾病和主要心血管事件的复合）和CKD进展的相关性。结果在3577名CRIC参与者（平均年龄58岁，45%为女性，49%为T2D）中，非糖尿病参与者的总PGS与较高的血红蛋白A1C显著相关（p=4.8 x 10-21）。在CRIC中，簇特异性分区PGS捕获了与T2D机制亚型相对应的不同的心脏代谢谱，特别是肥胖簇、胰岛素原阳性的β细胞功能障碍簇和脂肪营养不良簇。肥胖群集分割的PGS与房颤事件（p=2.89 x 10-4）和总死亡率（p= 4.29 x 10-4）显著相关，但考虑到竞争死亡风险时，与房颤的相关性减弱（p=0.002）。β细胞功能障碍伴胰岛素原阴性簇与CKD进展呈负相关（p=2.48 x 10-5）。结论：我们的研究结果表明，胰岛素抵抗和肥胖导致的T2D增加了CKD患者总体死亡的风险，并在一定程度上解释了房颤风险的增加。这些结果强调了在评估这一人群心血管风险时考虑t2dm异质性的重要性。
{"title":"Diabetes Genetic Clusters and Clinical Outcomes in the Chronic Renal Insufficiency Cohort.","authors":"Kaylia M Reynolds,Daohang Sha,Quan Sun,Afshin Parsa,Jing Chen,Hernan Rincon Choles,Ruth Dubin,Jiang He,Chi-Yuan Hsu,Kristine Yaffe,Vallabh Shah,Dominic Raj,Sylvia E Rosas,James P Lash,Andrew P Morris,Nora Franceschini, ","doi":"10.2215/cjn.0000000882","DOIUrl":"https://doi.org/10.2215/cjn.0000000882","url":null,"abstract":"BACKGROUNDType 2 diabetes (T2D) exhibits biological and pathophysiological heterogeneity, which may contribute to variations in diabetes-related complications, particularly in high-risk populations such as individuals with chronic kidney disease (CKD). Prior research has explored T2D mechanisms using partitioned polygenic scores (PGS), derived from distinct clusters of variants according to their associations with cardiometabolic traits. In this study, we investigated whether cluster-specific partitioned PGS are associated with cardiovascular outcomes and CKD progression in individuals with CKD.METHODSWe used genome-wide genotype data from the Chronic Renal Insufficiency Cohort (CRIC) to calculate both a total PGS for T2D and partitioned PGS for T2D clusters. We examined their associations with cardiometabolic traits and conducted time-to-event analysis to assess their association with mortality (overall and cardiovascular), incident cardiovascular outcomes (myocardial infarction, stroke, heart failure, atrial fibrillation, peripheral artery disease, and a composite of major cardiovascular events) and CKD progression.RESULTSAmong 3,577 CRIC participants (mean age 58 years, 45% were women, 49% had T2D), the total PGS was significantly associated with higher hemoglobin A1C (p=4.8 x 10-21) among nondiabetic participants. Cluster-specific partitioned PGS in CRIC captured distinct cardiometabolic profiles corresponding to T2D mechanistic subtypes, particularly the obesity cluster, the β-cell dysfunction with positive proinsulin cluster, and the lipodystrophy cluster. The obesity cluster partitioned PGS was significantly associated with incident atrial fibrillation (p=2.89 x 10-4) and overall mortality (p= 4.29 x 10-4), but the association with atrial fibrillation was attenuated when accounting for competing risk of death (p=0.002). The β-cell dysfunction with negative proinsulin cluster was inversely associated with CKD progression (p=2.48 x 10-5).CONCLUSIONSOur findings suggest that T2D driven by insulin resistance and obesity contributes to a higher risk of overall death in individuals with CKD and explain in part the higher risk of atrial fibrillation. These results highlight the importance of considering T2D heterogeneity when assessing cardiovascular risk in this population.","PeriodicalId":50681,"journal":{"name":"Clinical Journal of the American Society of Nephrology","volume":"20 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Suzanne M Boyle,Andrew S Parsons,Stephen M Sozio,Lili Chan,Karen M Warburton
{"title":"Keeping In-the-Loop: Supporting Clinical Reasoning Skills for Nephrology Learners in the Age of Artificial Intelligence.","authors":"Suzanne M Boyle,Andrew S Parsons,Stephen M Sozio,Lili Chan,Karen M Warburton","doi":"10.2215/cjn.0000000942","DOIUrl":"https://doi.org/10.2215/cjn.0000000942","url":null,"abstract":"","PeriodicalId":50681,"journal":{"name":"Clinical Journal of the American Society of Nephrology","volume":"20 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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