Pub Date : 2025-12-26DOI: 10.1016/j.xkme.2025.101234
Zhejia Tian , Samira Soltani , Johann Bauersachs , Kai M. Schmidt-Ott , Anette Melk , Bernhard M.W. Schmidt
<div><h3>Rationale & Objectives</h3><div>The cardiovascular-kidney-metabolic (CKM) syndrome is defined as the intricate interplay among metabolic risks, chronic kidney disease (CKD) and the cardiovascular system. The deteriorating CKM syndrome contributes to untimely morbidity and mortality. We aim to characterize gender- and age-related disparities in the prevalence of CKM syndrome over the last 2 decades.</div></div><div><h3>Study Design</h3><div>A cross-sectional population-based survey.</div></div><div><h3>Setting & Participants</h3><div>A total of 32,848 US adults participating in the NHANES survey from 1999 to 2020.</div></div><div><h3>Exposures</h3><div>Gender, age (18-44, 45-64, and ≥65), and period (1999-2002, 2003-3008, 2009-2014, and 2015-2020).</div></div><div><h3>Outcomes</h3><div>Prevalence of CKM stages.</div></div><div><h3>Analytical approach</h3><div>Sample weights and Taylor series linearization method were applied to estimate prevalence and standard errors representative of the noninstitutionalized US adult population. For trend analysis across cycles, survey-weighted logistic regression was employed.</div></div><div><h3>Results</h3><div>Young women aged < 45 years were classified more often, but with decreasing prevalence, in stages without CKM defining factors (22.7% of women vs 13.5% of men) and more often in stages with cardiovascular organ damage (13.4% of women vs 6.5% of men). Elderly women were increasingly classified in stages with cardiovascular organ damage over the last 20 years, reaching the same prevalence as men in the most recent period (25.3 % [95% CI, 20.0 %-30.6 %] of women vs 30.5 [95% CI, 25.7-35.3%] of men aged > 65 years).</div></div><div><h3>Limitations</h3><div>NHANES data allow for assessing CKM stages with cardiovascular organ damage mainly based on self-reporting during interviews.</div></div><div><h3>Conclusions</h3><div>We demonstrate an increasing proportion of women in advanced CKM stages over the last 20 years. Whereas the overrepresentation of younger women in the low-risk stages almost disappeared, elderly women in the last period showed almost the same risk of being in stages with cardiovascular organ damage as elderly men. Our analysis highlights an urgent need of preventive measures especially tailored to women.</div></div><div><h3>Plain-language Summary</h3><div>Cardiovascular-kidney-metabolic (CKM) syndrome describes the combined impact of heart, kidney, and metabolic health on overall well-being. We examined its prevalence among US adult population and explored differences between women and men across different age groups, using data from over 32,000 adults collected from 1999 to 2020. The results showed that younger women under 45 years were previously more likely to be in the low-risk group; however, this advantage has declined over the past 20 years. Among older adults (over 65 years), women had a comparable risk to men for organ damage associated with cardiovascular-kid
{"title":"Gender-related and Age-related Disparities in Prevalence of the Cardiovascular-Kidney-Metabolic Syndrome Among US Adults From 1999-2020: An Analysis of the NHANES Survey","authors":"Zhejia Tian , Samira Soltani , Johann Bauersachs , Kai M. Schmidt-Ott , Anette Melk , Bernhard M.W. Schmidt","doi":"10.1016/j.xkme.2025.101234","DOIUrl":"10.1016/j.xkme.2025.101234","url":null,"abstract":"<div><h3>Rationale & Objectives</h3><div>The cardiovascular-kidney-metabolic (CKM) syndrome is defined as the intricate interplay among metabolic risks, chronic kidney disease (CKD) and the cardiovascular system. The deteriorating CKM syndrome contributes to untimely morbidity and mortality. We aim to characterize gender- and age-related disparities in the prevalence of CKM syndrome over the last 2 decades.</div></div><div><h3>Study Design</h3><div>A cross-sectional population-based survey.</div></div><div><h3>Setting & Participants</h3><div>A total of 32,848 US adults participating in the NHANES survey from 1999 to 2020.</div></div><div><h3>Exposures</h3><div>Gender, age (18-44, 45-64, and ≥65), and period (1999-2002, 2003-3008, 2009-2014, and 2015-2020).</div></div><div><h3>Outcomes</h3><div>Prevalence of CKM stages.</div></div><div><h3>Analytical approach</h3><div>Sample weights and Taylor series linearization method were applied to estimate prevalence and standard errors representative of the noninstitutionalized US adult population. For trend analysis across cycles, survey-weighted logistic regression was employed.</div></div><div><h3>Results</h3><div>Young women aged < 45 years were classified more often, but with decreasing prevalence, in stages without CKM defining factors (22.7% of women vs 13.5% of men) and more often in stages with cardiovascular organ damage (13.4% of women vs 6.5% of men). Elderly women were increasingly classified in stages with cardiovascular organ damage over the last 20 years, reaching the same prevalence as men in the most recent period (25.3 % [95% CI, 20.0 %-30.6 %] of women vs 30.5 [95% CI, 25.7-35.3%] of men aged > 65 years).</div></div><div><h3>Limitations</h3><div>NHANES data allow for assessing CKM stages with cardiovascular organ damage mainly based on self-reporting during interviews.</div></div><div><h3>Conclusions</h3><div>We demonstrate an increasing proportion of women in advanced CKM stages over the last 20 years. Whereas the overrepresentation of younger women in the low-risk stages almost disappeared, elderly women in the last period showed almost the same risk of being in stages with cardiovascular organ damage as elderly men. Our analysis highlights an urgent need of preventive measures especially tailored to women.</div></div><div><h3>Plain-language Summary</h3><div>Cardiovascular-kidney-metabolic (CKM) syndrome describes the combined impact of heart, kidney, and metabolic health on overall well-being. We examined its prevalence among US adult population and explored differences between women and men across different age groups, using data from over 32,000 adults collected from 1999 to 2020. The results showed that younger women under 45 years were previously more likely to be in the low-risk group; however, this advantage has declined over the past 20 years. Among older adults (over 65 years), women had a comparable risk to men for organ damage associated with cardiovascular-kid","PeriodicalId":17885,"journal":{"name":"Kidney Medicine","volume":"8 3","pages":"Article 101234"},"PeriodicalIF":3.4,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081234","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}
Pub Date : 2025-12-26DOI: 10.1016/j.xkme.2025.101235
Sarah K. Nelson-Taylor , Jonathan Troost , Courtney Giannini , Colin Bauer , Tarak Srivastava , Jarcy Zee , Markus Bitzer , Laura Barisoni , llse Daehn , Julie A. Dougherty , William E. Smoyer , Bryce A. Kerlin , Audrey Fetsko , Imtiazul Islam , Xin Wang , Christine Sethna , Richard J. Johnson , Carmen de Lucas Collantes , Kazunari Kaneko , Gabriel Cara-Fuentes
<div><h3>Rationale & Objective</h3><div>Idiopathic nephrotic syndrome (INS) is viewed as a podocyte-specific disease. Recent reports indicate endothelial involvement, but its significance is unclear. Here, we investigated the relationship between the glomerular expression of selected genes relevant to endothelial health and clinical markers of disease severity.</div></div><div><h3>Study Design</h3><div>A cross-sectional study.</div></div><div><h3>Setting & Participants</h3><div>Patients with INS (n = 70 minimal change disease and n = 83 focal segmental glomerulosclerosis) from the Nephrotic Syndrome Study Network cohort study and 53 control participants. Validation studies, including animal and cell culture experiments, were performed.</div></div><div><h3>Exposure</h3><div>Gene expression analysis from micro-dissected human glomeruli. The study is focused on 10 genes highly relevant for endothelial homeostasis and barrier integrity (nitric oxide synthase 3 [<em>NOS3</em>], endothelial cell adhesion molecule, and endothelial cell specific molecule 1 [<em>ESM1</em>]), endothelial glycocalyx remodeling (<em>HPSE, HYAL1, MMP2, MMP9</em>, and <em>ADAMTS1</em>), and endothelial activation (<em>ICAM1 and CAV1</em>).</div></div><div><h3>Outcomes</h3><div>Kidney function, ultrastructural changes in podocytes and glomerular endothelium, interstitial fibrosis and tubular atrophy.</div></div><div><h3>Analytical Approach</h3><div>One-way ANOVA and Tukey’s multiple comparisons test, Pearson Correlation and Cohen’s d statistics.</div></div><div><h3>Results</h3><div>Transcriptomic analysis revealed that all genes of interest were highly expressed in glomeruli from INS patients compared with controls, except for <em>ESM1</em> and <em>MMP9</em>, which were decreased. Expression of endothelial-specific genes correlated with those of glycocalyx injury and cell activation. <em>HPSE</em>, <em>ADAMTS1</em>, <em>ICAM1</em>, and <em>CAV1</em> expression was inversely associated with kidney function, whereas ADAMTS1 showed a positive association with proteinuria. <em>NOS3</em>, <em>HPSE</em>, and <em>ADAMTS1</em> were associated with podocyte foot process effacement, and <em>ICAM1</em> with podocyte detachment. <em>HPSE</em> and <em>MMP2</em> were associated with ultrastructural endothelial injury, whereas <em>HPSE</em>, <em>MMP2</em>, <em>ICAM1</em>, and <em>CAV1</em> were associated with interstitial fibrosis and tubular atrophy. Several genes (<em>ESM1</em>, <em>HPSE</em>, <em>HYAL1</em>, <em>MMP2</em>, and <em>ICAM1</em>) were also dysregulated in experimental INS and validated in cultured glomerular endothelial cells (<em>NOS3</em> and heparanase) following exposure to INS sera.</div></div><div><h3>Limitations</h3><div>Observational study, selection bias, unmeasured confounders.</div></div><div><h3>Conclusions</h3><div>INS involves dysregulation of genes relevant for endothelial health.</div></div><div><h3>Plain-Language Summary</h3><div>Idiopathic Nephrotic
{"title":"Glomerular Transcriptome Analysis Reveals Endothelial Disturbances in Patients With Idiopathic Nephrotic Syndrome","authors":"Sarah K. Nelson-Taylor , Jonathan Troost , Courtney Giannini , Colin Bauer , Tarak Srivastava , Jarcy Zee , Markus Bitzer , Laura Barisoni , llse Daehn , Julie A. Dougherty , William E. Smoyer , Bryce A. Kerlin , Audrey Fetsko , Imtiazul Islam , Xin Wang , Christine Sethna , Richard J. Johnson , Carmen de Lucas Collantes , Kazunari Kaneko , Gabriel Cara-Fuentes","doi":"10.1016/j.xkme.2025.101235","DOIUrl":"10.1016/j.xkme.2025.101235","url":null,"abstract":"<div><h3>Rationale & Objective</h3><div>Idiopathic nephrotic syndrome (INS) is viewed as a podocyte-specific disease. Recent reports indicate endothelial involvement, but its significance is unclear. Here, we investigated the relationship between the glomerular expression of selected genes relevant to endothelial health and clinical markers of disease severity.</div></div><div><h3>Study Design</h3><div>A cross-sectional study.</div></div><div><h3>Setting & Participants</h3><div>Patients with INS (n = 70 minimal change disease and n = 83 focal segmental glomerulosclerosis) from the Nephrotic Syndrome Study Network cohort study and 53 control participants. Validation studies, including animal and cell culture experiments, were performed.</div></div><div><h3>Exposure</h3><div>Gene expression analysis from micro-dissected human glomeruli. The study is focused on 10 genes highly relevant for endothelial homeostasis and barrier integrity (nitric oxide synthase 3 [<em>NOS3</em>], endothelial cell adhesion molecule, and endothelial cell specific molecule 1 [<em>ESM1</em>]), endothelial glycocalyx remodeling (<em>HPSE, HYAL1, MMP2, MMP9</em>, and <em>ADAMTS1</em>), and endothelial activation (<em>ICAM1 and CAV1</em>).</div></div><div><h3>Outcomes</h3><div>Kidney function, ultrastructural changes in podocytes and glomerular endothelium, interstitial fibrosis and tubular atrophy.</div></div><div><h3>Analytical Approach</h3><div>One-way ANOVA and Tukey’s multiple comparisons test, Pearson Correlation and Cohen’s d statistics.</div></div><div><h3>Results</h3><div>Transcriptomic analysis revealed that all genes of interest were highly expressed in glomeruli from INS patients compared with controls, except for <em>ESM1</em> and <em>MMP9</em>, which were decreased. Expression of endothelial-specific genes correlated with those of glycocalyx injury and cell activation. <em>HPSE</em>, <em>ADAMTS1</em>, <em>ICAM1</em>, and <em>CAV1</em> expression was inversely associated with kidney function, whereas ADAMTS1 showed a positive association with proteinuria. <em>NOS3</em>, <em>HPSE</em>, and <em>ADAMTS1</em> were associated with podocyte foot process effacement, and <em>ICAM1</em> with podocyte detachment. <em>HPSE</em> and <em>MMP2</em> were associated with ultrastructural endothelial injury, whereas <em>HPSE</em>, <em>MMP2</em>, <em>ICAM1</em>, and <em>CAV1</em> were associated with interstitial fibrosis and tubular atrophy. Several genes (<em>ESM1</em>, <em>HPSE</em>, <em>HYAL1</em>, <em>MMP2</em>, and <em>ICAM1</em>) were also dysregulated in experimental INS and validated in cultured glomerular endothelial cells (<em>NOS3</em> and heparanase) following exposure to INS sera.</div></div><div><h3>Limitations</h3><div>Observational study, selection bias, unmeasured confounders.</div></div><div><h3>Conclusions</h3><div>INS involves dysregulation of genes relevant for endothelial health.</div></div><div><h3>Plain-Language Summary</h3><div>Idiopathic Nephrotic ","PeriodicalId":17885,"journal":{"name":"Kidney Medicine","volume":"8 3","pages":"Article 101235"},"PeriodicalIF":3.4,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146142844","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}
Pub Date : 2025-12-26DOI: 10.1016/j.xkme.2025.101232
Nathan Meyer , Maxwell Donelan , Hossein Moradi Rekabdarkolaee , Brandon M. Varilek , Surachat Ngorsuraches , Patti Brooks , Jerry Schrier , Semhar Michael
<div><h3>Rationale & Objective</h3><div>Traditional survival models assume all patients receiving kidney replacement therapy (KRT) may be grouped into one population, overlooking long-term survivors, particularly successful transplant recipients, and may fail to appreciate the disparities in minority populations. On the other hand, a mixture survival model allows for the estimation of hazard and odds ratios of all-cause mortality in patients with kidney failure undergoing either dialysis or transplantation.</div></div><div><h3>Study Design</h3><div>This retrospective cohort study analyzed survival outcomes using a proportional hazards mixture survival model, comparing results to a traditional Cox proportional hazards model with time-varying modality of treatment.</div></div><div><h3>Setting & Participants</h3><div>Data from the United States Renal Data System included 2,228,693 patients initiating KRT between 2000 and 2020.</div></div><div><h3>Predictors</h3><div>Key predictors included demographics, comorbid conditions, socioeconomic status, geographic location, and rurality.</div></div><div><h3>Outcomes</h3><div>The primary outcome was all-cause mortality. The mixture survival model distinguishes between patients’ characteristics associated with long-term survival (ie, primarily those with successful transplants) and short-term survival (ie, those at a greater risk of mortality over time, such as patients treated with dialysis).</div></div><div><h3>Analytical Approach</h3><div>Both a Cox proportional hazards model and a proportional hazards mixture survival model were applied to all patients.</div></div><div><h3>Results</h3><div>Findings from both models were largely consistent, but the mixture survival model revealed new insights into racial disparities. In the Cox model, American Indian individuals had an adjusted hazard ratio of 0.63 compared with White individuals (95% CI. 0.62-0.63) and 0.74 for Black individuals compared with White (95% CI, 0.74-0.74). The mixture model confirmed these trends but also showed that American Indian individuals were 1.59 times more likely to not have a long-term survival than White individuals (95% CI, 1.415-1.797) and Black individuals were 1.35 times more likely to not be in the long-term surviving group than White individuals (95% CI, 1.310-1.397). Additional disparities were observed by socioeconomic and geographic factors.</div></div><div><h3>Limitations</h3><div>Data collected at the beginning of dialysis may not fully capture patients’ health trajectories.</div></div><div><h3>Conclusions</h3><div>The mixture survival model provides a more comprehensive understanding of mortality disparities for patients with kidney failure receiving KRT by distinguishing between short-term and long-term survivability. The findings highlight the need for targeted interventions to improve long-term outcomes for minority patients.</div></div><div><h3>Plain-language Summary</h3><div>Kidney failure affects minority
{"title":"Estimating Short-Term and Long-Term Survival for Patients With Kidney Failure Using a Mixture Survival Model","authors":"Nathan Meyer , Maxwell Donelan , Hossein Moradi Rekabdarkolaee , Brandon M. Varilek , Surachat Ngorsuraches , Patti Brooks , Jerry Schrier , Semhar Michael","doi":"10.1016/j.xkme.2025.101232","DOIUrl":"10.1016/j.xkme.2025.101232","url":null,"abstract":"<div><h3>Rationale & Objective</h3><div>Traditional survival models assume all patients receiving kidney replacement therapy (KRT) may be grouped into one population, overlooking long-term survivors, particularly successful transplant recipients, and may fail to appreciate the disparities in minority populations. On the other hand, a mixture survival model allows for the estimation of hazard and odds ratios of all-cause mortality in patients with kidney failure undergoing either dialysis or transplantation.</div></div><div><h3>Study Design</h3><div>This retrospective cohort study analyzed survival outcomes using a proportional hazards mixture survival model, comparing results to a traditional Cox proportional hazards model with time-varying modality of treatment.</div></div><div><h3>Setting & Participants</h3><div>Data from the United States Renal Data System included 2,228,693 patients initiating KRT between 2000 and 2020.</div></div><div><h3>Predictors</h3><div>Key predictors included demographics, comorbid conditions, socioeconomic status, geographic location, and rurality.</div></div><div><h3>Outcomes</h3><div>The primary outcome was all-cause mortality. The mixture survival model distinguishes between patients’ characteristics associated with long-term survival (ie, primarily those with successful transplants) and short-term survival (ie, those at a greater risk of mortality over time, such as patients treated with dialysis).</div></div><div><h3>Analytical Approach</h3><div>Both a Cox proportional hazards model and a proportional hazards mixture survival model were applied to all patients.</div></div><div><h3>Results</h3><div>Findings from both models were largely consistent, but the mixture survival model revealed new insights into racial disparities. In the Cox model, American Indian individuals had an adjusted hazard ratio of 0.63 compared with White individuals (95% CI. 0.62-0.63) and 0.74 for Black individuals compared with White (95% CI, 0.74-0.74). The mixture model confirmed these trends but also showed that American Indian individuals were 1.59 times more likely to not have a long-term survival than White individuals (95% CI, 1.415-1.797) and Black individuals were 1.35 times more likely to not be in the long-term surviving group than White individuals (95% CI, 1.310-1.397). Additional disparities were observed by socioeconomic and geographic factors.</div></div><div><h3>Limitations</h3><div>Data collected at the beginning of dialysis may not fully capture patients’ health trajectories.</div></div><div><h3>Conclusions</h3><div>The mixture survival model provides a more comprehensive understanding of mortality disparities for patients with kidney failure receiving KRT by distinguishing between short-term and long-term survivability. The findings highlight the need for targeted interventions to improve long-term outcomes for minority patients.</div></div><div><h3>Plain-language Summary</h3><div>Kidney failure affects minority ","PeriodicalId":17885,"journal":{"name":"Kidney Medicine","volume":"8 3","pages":"Article 101232"},"PeriodicalIF":3.4,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081368","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}
Pub Date : 2025-12-24DOI: 10.1016/j.xkme.2025.101231
Steven Fishbane MD, Pratap Upadrista MBBS, Hitesh H. Shah MD
Composite study endpoints have made it possible to reduce the sample size and lower the cost of certain clinical trials. In nephrology trials, the use of composite endpoints has led to opportunities but has also created challenges in the interpretation of study results. In this perspective, we review how composite outcomes work and why there are risks attendant to their use. We also provide examples of the use of composite outcomes from specific nephrology trials and certain problems that resulted.
{"title":"Composite Primary Outcomes in Nephrology Clinical Trials","authors":"Steven Fishbane MD, Pratap Upadrista MBBS, Hitesh H. Shah MD","doi":"10.1016/j.xkme.2025.101231","DOIUrl":"10.1016/j.xkme.2025.101231","url":null,"abstract":"<div><div>Composite study endpoints have made it possible to reduce the sample size and lower the cost of certain clinical trials. In nephrology trials, the use of composite endpoints has led to opportunities but has also created challenges in the interpretation of study results. In this perspective, we review how composite outcomes work and why there are risks attendant to their use. We also provide examples of the use of composite outcomes from specific nephrology trials and certain problems that resulted.</div></div>","PeriodicalId":17885,"journal":{"name":"Kidney Medicine","volume":"8 3","pages":"Article 101231"},"PeriodicalIF":3.4,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081367","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}
Pub Date : 2025-12-24DOI: 10.1016/j.xkme.2025.101233
Chloe Borden , Iman Chaudhry , Rhyan Maditz , Sarah Mazzola , Ronit Salomon Kent , Kristen Tomaszewski , Xiangling Wang
Genetic testing is increasingly used to assist the precise diagnosis and clinical management of suspected genetic kidney diseases; however, mitochondrial DNA (mtDNA) analysis remains underutilized. Here we report a 61-year-old man who presented with chronic kidney disease (CKD), microscopic hematuria since childhood, bilateral sensorineural hearing loss (SNHL), and peripheral polyneuropathy. Laboratory reports showed serum creatinine 1.5 mg/dL with an estimated glomerular filtration rate of 55 mL/min/1.73m2, no proteinuria, and a negative serological workup. Kidney biopsy demonstrated focal segmental glomerulosclerosis (FSGS) with segmental thinning of glomerular basement membrane and dysmorphic mitochondria. A 401 renal disease gene panel was negative, including type IV collagen genes. mtDNA analysis identified a pathogenic variant in the MT-TV gene (m.1642 G>A; NC_012920.1) with 2% heteroplasmy in leukocyte-derived DNA, confirmed in urine-derived DNA at 5% heteroplasmy. Genetic counseling was offered along with systemic evaluation revealing left ventricular hypertrophy on echocardiogram. The patient was started on levocarnitine and coenzyme Q10 with multidisciplinary care. This is the first reported case of FSGS with dysmorphic mitochondria and a pathogenic MT-TV variant confirmed via both leukocyte-derived and urine-derived DNA. It supports the role of mitochondrial dysfunction in CKD and highlights the importance of mtDNA analysis in the evaluation of FSGS and unexplained CKD.
{"title":"Mitochondrial DNA Analysis Should Be Considered in the Genetic Assessment of Focal Segmental Glomerulosclerosis or Unexplained Chronic Kidney Disease: A Case Report","authors":"Chloe Borden , Iman Chaudhry , Rhyan Maditz , Sarah Mazzola , Ronit Salomon Kent , Kristen Tomaszewski , Xiangling Wang","doi":"10.1016/j.xkme.2025.101233","DOIUrl":"10.1016/j.xkme.2025.101233","url":null,"abstract":"<div><div>Genetic testing is increasingly used to assist the precise diagnosis and clinical management of suspected genetic kidney diseases; however, mitochondrial DNA (mtDNA) analysis remains underutilized. Here we report a 61-year-old man who presented with chronic kidney disease (CKD), microscopic hematuria since childhood, bilateral sensorineural hearing loss (SNHL), and peripheral polyneuropathy. Laboratory reports showed serum creatinine 1.5 mg/dL with an estimated glomerular filtration rate of 55 mL/min/1.73m<sup>2</sup>, no proteinuria, and a negative serological workup. Kidney biopsy demonstrated focal segmental glomerulosclerosis (FSGS) with segmental thinning of glomerular basement membrane and dysmorphic mitochondria. A 401 renal disease gene panel was negative, including type IV collagen genes. mtDNA analysis identified a pathogenic variant in the <em>MT-TV</em> gene (m.1642 G>A; NC_012920.1) with 2% heteroplasmy in leukocyte-derived DNA, confirmed in urine-derived DNA at 5% heteroplasmy. Genetic counseling was offered along with systemic evaluation revealing left ventricular hypertrophy on echocardiogram. The patient was started on levocarnitine and coenzyme Q10 with multidisciplinary care. This is the first reported case of FSGS with dysmorphic mitochondria and a pathogenic <em>MT-TV</em> variant confirmed via both leukocyte-derived and urine-derived DNA. It supports the role of mitochondrial dysfunction in CKD and highlights the importance of mtDNA analysis in the evaluation of FSGS and unexplained CKD.</div></div>","PeriodicalId":17885,"journal":{"name":"Kidney Medicine","volume":"8 3","pages":"Article 101233"},"PeriodicalIF":3.4,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048953","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}
Pub Date : 2025-12-16DOI: 10.1016/j.xkme.2025.101228
Yujia Wang , Kaiqi Huang , Caiming Chen , Keng Ye , Kunmei Lai , Xuan Tao , Hong Chen , Yanfang Xu
Drug-induced type II crescentic glomerulonephritis is an uncommon but severe renal syndrome, rarely linked to pharmaceutical agents, with no established association to Chinese herbal medicines to date. In this case report, we described 4 patients who developed biopsy-confirmed type II crescentic glomerulonephritis within 1-4 weeks following exposure to Chinese herbal products. Key histopathologic findings included crescent formation in ≥50% of glomeruli and immunofluorescence demonstrating granular mesangial deposits of immunoglobulin G and C3, accompanied by prominent acute tubulointerstitial injury. Clinically, 75% of cases presented with macroscopic hematuria, reflecting severe glomerular capillary damage. The therapeutic regimen comprised intravenous methylprednisolone, cyclophosphamide, and plasma exchange. Persistent hematuria and a longer duration of drug exposure were associated with slower and incomplete renal recovery during follow-up. Our case report suggested that Chinese herbal medicine may be a potential environmental trigger for crescentic glomerulonephritis and highlight the value of clinical inquiry into herbal product use in cases of rapidly progressive glomerulonephritis. Further toxicovigilance and compound-specific risk assessments are urgently needed.
{"title":"Chinese Herb-Induced Type II Crescentic Glomerulonephritis: A Case Report of Four Patients","authors":"Yujia Wang , Kaiqi Huang , Caiming Chen , Keng Ye , Kunmei Lai , Xuan Tao , Hong Chen , Yanfang Xu","doi":"10.1016/j.xkme.2025.101228","DOIUrl":"10.1016/j.xkme.2025.101228","url":null,"abstract":"<div><div>Drug-induced type II crescentic glomerulonephritis is an uncommon but severe renal syndrome, rarely linked to pharmaceutical agents, with no established association to Chinese herbal medicines to date. In this case report, we described 4 patients who developed biopsy-confirmed type II crescentic glomerulonephritis within 1-4 weeks following exposure to Chinese herbal products. Key histopathologic findings included crescent formation in ≥50% of glomeruli and immunofluorescence demonstrating granular mesangial deposits of immunoglobulin G and C3, accompanied by prominent acute tubulointerstitial injury. Clinically, 75% of cases presented with macroscopic hematuria, reflecting severe glomerular capillary damage. The therapeutic regimen comprised intravenous methylprednisolone, cyclophosphamide, and plasma exchange. Persistent hematuria and a longer duration of drug exposure were associated with slower and incomplete renal recovery during follow-up. Our case report suggested that Chinese herbal medicine may be a potential environmental trigger for crescentic glomerulonephritis and highlight the value of clinical inquiry into herbal product use in cases of rapidly progressive glomerulonephritis. Further toxicovigilance and compound-specific risk assessments are urgently needed.</div></div>","PeriodicalId":17885,"journal":{"name":"Kidney Medicine","volume":"8 2","pages":"Article 101228"},"PeriodicalIF":3.4,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146023174","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}
Fanconi syndrome is a generalized dysfunction of the renal proximal tubule, leading to growth failure and rickets during childhood. There are few reports of this syndrome in neonates, especially in extremely low-birth-weight infants. We present a case of an extremely low-birth-weight Asian girl with bone fragility because of Fanconi syndrome without underlying diseases. She was born at 29 weeks of gestation and weighed 418 g (–5.2SD). Based on blood and urine analyses, she was diagnosed with Fanconi syndrome. Metabolic acidosis was easily corrected with bicarbonate supplementation. However, the control of the rickets was very difficult, with multiple bone fractures observed despite supplementation of calcium, phosphorus, and vitamin D. Her renal tubular function finally improved at 6 months of age, and oral supplementation of bicarbonate, calcium, and phosphorus was discontinued before discharge. The genetic test for inherited causes of Fanconi syndrome showed no abnormalities. Hypoperfusion during the fetal period was assumed to be one of the causes of Fanconi syndrome in this case.
{"title":"An Extremely Low-Birth-Weight Infant With Bone Fragility Due to Fanconi Syndrome","authors":"Rei Yoshida, Miku Hosokawa, Toshiko Ukawa, Chisa Tsurisawa, Yoshiya Hisaeda, Shusuke Amagata, Tomohiro Takeda, Atsushi Nakao","doi":"10.1016/j.xkme.2025.101227","DOIUrl":"10.1016/j.xkme.2025.101227","url":null,"abstract":"<div><div>Fanconi syndrome is a generalized dysfunction of the renal proximal tubule, leading to growth failure and rickets during childhood. There are few reports of this syndrome in neonates, especially in extremely low-birth-weight infants. We present a case of an extremely low-birth-weight Asian girl with bone fragility because of Fanconi syndrome without underlying diseases. She was born at 29 weeks of gestation and weighed 418 g (–5.2SD). Based on blood and urine analyses, she was diagnosed with Fanconi syndrome. Metabolic acidosis was easily corrected with bicarbonate supplementation. However, the control of the rickets was very difficult, with multiple bone fractures observed despite supplementation of calcium, phosphorus, and vitamin D. Her renal tubular function finally improved at 6 months of age, and oral supplementation of bicarbonate, calcium, and phosphorus was discontinued before discharge. The genetic test for inherited causes of Fanconi syndrome showed no abnormalities. Hypoperfusion during the fetal period was assumed to be one of the causes of Fanconi syndrome in this case.</div></div>","PeriodicalId":17885,"journal":{"name":"Kidney Medicine","volume":"8 2","pages":"Article 101227"},"PeriodicalIF":3.4,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146023175","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}
Pub Date : 2025-12-16DOI: 10.1016/j.xkme.2025.101223
Savino Sciascia , Massimo Radin , Irene Cecchi , Alice Barinotti , Francesco Trevisani , Roberta Fenoglio , Emanuele De Simone , Dario Roccatello , Paola Cassoni , Antonella Barreca
<div><h3>Rationale & Objective</h3><div>Thrombotic microangiopathy (TMA) as seen in antiphospholipid syndrome nephropathy (APSN) is associated with poor kidney outcomes. Caveolin-1 (Cav-1) has emerged as a potential marker of endothelial damage and microvascular injury.</div></div><div><h3>Study Design</h3><div>This retrospective study investigates the diagnostic potential value of Cav-1 immunohistochemistry in APSN-related TMA.</div></div><div><h3>Setting & Participants</h3><div>Patients were retrieved from the Piedmont and Aosta Valley Rare Disease Registry, from which a total of 771 APS cases had been recorded.</div></div><div><h3>Exposure</h3><div>Only case with biopsy-proven renal involvement were included.</div></div><div><h3>Outcomes</h3><div>Cases were classified into three histopathological clusters: TMA (APSN-TMA), hyperplastic vasculopathy, and subendothelial edema. Immunohistochemical staining for Cav-1 was performed and graded based on expression in peritubular and glomerular capillaries.</div></div><div><h3>Analytical Approach</h3><div>Clinical and laboratory data, including antiphospholipid antibody profiles, were correlated with Cav-1 expression.</div></div><div><h3>Results</h3><div>Out of 771 patients with APS, a total of 11 patients with primary APS and renal involvement were retrieved (1.43%). APSN-TMA was identified in 7 (63.3%) cases, hyperplastic vasculopathy in 2 (18.1%), and subendothelial edema in 2 (18.1%). Cav-1 expression was significantly higher in APSN-TMA cases in both glomerular (<em>P</em> < 0.001) and peritubular (<em>P</em> < 0.05) capillaries compared with other clusters, with 5 of 7 APSN-TMA cases exhibiting diffuse (grade III) staining. Triple antiphospholipid antibody positive testing was more prevalent in APSN-TMA cases, reinforcing their distinct pathophysiological profile.</div></div><div><h3>Limitations</h3><div>The small sample size warrants validation in larger cohorts, and Cav-1 expression, although associated with APSN, might not be disease-specific.</div></div><div><h3>Conclusions</h3><div>APSN-TMA is a rare manifestation of a rare disease. Cav-1 is strongly associated with APSN-TMA and may serve as a novel marker for its diagnosis and stratification. Given the poor renal prognosis of APSN-TMA, identifying affected patients is crucial for optimizing management strategies.</div></div><div><h3>Plain-Language Summary</h3><div>Antiphospholipid syndrome (APS) is an autoimmune condition that can cause blood clots in many organs, including the kidneys. In some patients, a type of severe small-vessel injury called thrombotic microangiopathy develops, leading to poor kidney outcomes. Diagnosing this form of kidney damage can be challenging. In our study, we examined kidney tissue from people with APS using a special stain for a protein called Caveolin-1, which is found in damaged blood vessel cells. We found that high Caveolin-1 levels were strongly linked to the most aggressive form of APS-rel
{"title":"Caveolin-1 as a Marker of Endothelial Damage in Primary Antiphospholipid Syndrome Nephropathy","authors":"Savino Sciascia , Massimo Radin , Irene Cecchi , Alice Barinotti , Francesco Trevisani , Roberta Fenoglio , Emanuele De Simone , Dario Roccatello , Paola Cassoni , Antonella Barreca","doi":"10.1016/j.xkme.2025.101223","DOIUrl":"10.1016/j.xkme.2025.101223","url":null,"abstract":"<div><h3>Rationale & Objective</h3><div>Thrombotic microangiopathy (TMA) as seen in antiphospholipid syndrome nephropathy (APSN) is associated with poor kidney outcomes. Caveolin-1 (Cav-1) has emerged as a potential marker of endothelial damage and microvascular injury.</div></div><div><h3>Study Design</h3><div>This retrospective study investigates the diagnostic potential value of Cav-1 immunohistochemistry in APSN-related TMA.</div></div><div><h3>Setting & Participants</h3><div>Patients were retrieved from the Piedmont and Aosta Valley Rare Disease Registry, from which a total of 771 APS cases had been recorded.</div></div><div><h3>Exposure</h3><div>Only case with biopsy-proven renal involvement were included.</div></div><div><h3>Outcomes</h3><div>Cases were classified into three histopathological clusters: TMA (APSN-TMA), hyperplastic vasculopathy, and subendothelial edema. Immunohistochemical staining for Cav-1 was performed and graded based on expression in peritubular and glomerular capillaries.</div></div><div><h3>Analytical Approach</h3><div>Clinical and laboratory data, including antiphospholipid antibody profiles, were correlated with Cav-1 expression.</div></div><div><h3>Results</h3><div>Out of 771 patients with APS, a total of 11 patients with primary APS and renal involvement were retrieved (1.43%). APSN-TMA was identified in 7 (63.3%) cases, hyperplastic vasculopathy in 2 (18.1%), and subendothelial edema in 2 (18.1%). Cav-1 expression was significantly higher in APSN-TMA cases in both glomerular (<em>P</em> < 0.001) and peritubular (<em>P</em> < 0.05) capillaries compared with other clusters, with 5 of 7 APSN-TMA cases exhibiting diffuse (grade III) staining. Triple antiphospholipid antibody positive testing was more prevalent in APSN-TMA cases, reinforcing their distinct pathophysiological profile.</div></div><div><h3>Limitations</h3><div>The small sample size warrants validation in larger cohorts, and Cav-1 expression, although associated with APSN, might not be disease-specific.</div></div><div><h3>Conclusions</h3><div>APSN-TMA is a rare manifestation of a rare disease. Cav-1 is strongly associated with APSN-TMA and may serve as a novel marker for its diagnosis and stratification. Given the poor renal prognosis of APSN-TMA, identifying affected patients is crucial for optimizing management strategies.</div></div><div><h3>Plain-Language Summary</h3><div>Antiphospholipid syndrome (APS) is an autoimmune condition that can cause blood clots in many organs, including the kidneys. In some patients, a type of severe small-vessel injury called thrombotic microangiopathy develops, leading to poor kidney outcomes. Diagnosing this form of kidney damage can be challenging. In our study, we examined kidney tissue from people with APS using a special stain for a protein called Caveolin-1, which is found in damaged blood vessel cells. We found that high Caveolin-1 levels were strongly linked to the most aggressive form of APS-rel","PeriodicalId":17885,"journal":{"name":"Kidney Medicine","volume":"8 2","pages":"Article 101223"},"PeriodicalIF":3.4,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146023239","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}
Low birth weight (LBW), which is indicative of impaired fetal growth, is associated with the development of both nephrons and podocytes, increasing the risk of kidney disease later in life. However, the clinical evidence remains limited. We herein reported 3 patients with a history of LBW who developed overt proteinuria during adolescence. Using kidney biopsy samples from these patients, we conducted a comprehensive morphometric analysis of nephrons and podocytes. Compared with healthy and diseased kidney controls, all 3 cases exhibited a profoundly reduced number of nephrons, lower podocyte density, and pronounced hypertrophy of both glomeruli and podocytes. Lifestyle modifications and treatment with renin-angiotensin-aldosterone system inhibitors and/or sodium-glucose cotransporter 2 inhibitors led to a reduction in proteinuria but did not achieve complete remission. Our findings highlighted the limitations of current therapeutic strategies and emphasized the urgent need for early and targeted interventions in this high-risk population. An integrated approach that simultaneously evaluates nephrons and podocytes holds promise for advancing research and for enhancing clinical strategies for LBW individuals across diverse causes and life stages.
{"title":"Nephron and Podocyte Metrics in Adolescents With a History of Low Birth Weight: A Three-Case Report","authors":"Yuya Yamaguchi , Takaya Sasaki , Kotaro Haruhara , Takeshi Tosaki , Daisuke Nakashima , Yu Honda , Shinya Yokote , Nobuo Tsuboi , Takashi Yokoo","doi":"10.1016/j.xkme.2025.101230","DOIUrl":"10.1016/j.xkme.2025.101230","url":null,"abstract":"<div><div>Low birth weight (LBW), which is indicative of impaired fetal growth, is associated with the development of both nephrons and podocytes, increasing the risk of kidney disease later in life. However, the clinical evidence remains limited. We herein reported 3 patients with a history of LBW who developed overt proteinuria during adolescence. Using kidney biopsy samples from these patients, we conducted a comprehensive morphometric analysis of nephrons and podocytes. Compared with healthy and diseased kidney controls, all 3 cases exhibited a profoundly reduced number of nephrons, lower podocyte density, and pronounced hypertrophy of both glomeruli and podocytes. Lifestyle modifications and treatment with renin-angiotensin-aldosterone system inhibitors and/or sodium-glucose cotransporter 2 inhibitors led to a reduction in proteinuria but did not achieve complete remission. Our findings highlighted the limitations of current therapeutic strategies and emphasized the urgent need for early and targeted interventions in this high-risk population. An integrated approach that simultaneously evaluates nephrons and podocytes holds promise for advancing research and for enhancing clinical strategies for LBW individuals across diverse causes and life stages.</div></div>","PeriodicalId":17885,"journal":{"name":"Kidney Medicine","volume":"8 2","pages":"Article 101230"},"PeriodicalIF":3.4,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146023655","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}
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