American Journal of Nephrology最新文献

{"title":"Association between Systemic Inflammation and Worsening Renal Function in Cardiovascular-Kidney-Metabolic Syndrome.","authors":"Sunying Wang, Jilang Zeng, Yan Chen, Fuqing Sun, Hanghao Ma, Liwei Zhang, Zhijie Lin, Changxi Wang, Yuwei Wang, Qingyong Yang, Manqing Luo, Kaiyang Lin, Yansong Guo","doi":"10.1159/000546130","DOIUrl":"10.1159/000546130","url":null,"abstract":"<p><strong>Introduction: </strong>As a concept recently proposed by the American Heart Association (AHA), cardiovascular-kidney-metabolic (CKM) syndrome is characterized by the interplay of cardiovascular, renal, and metabolic dysfunctions. However, previous studies constantly focused on the cardiovascular outcomes, and there is scarce evidence addressing the association between chronic systemic inflammation and long-term changes in kidney function in the progression of CKM syndrome. This study aimed to investigate the association between the systemic inflammation and worsening renal function (WRF) in individuals with CKM syndrome.</p><p><strong>Methods: </strong>A cohort of 39,944 outpatients with regular follow-up visits at Fuqing City Hospital from 2014 to 2021 was analyzed. WRF was defined as an absolute increase in serum creatinine of ≥26.5 μmol/L (≥0.3 mg/dL) with a relative increase of ≥25% from baseline during the first year of follow-up. Three logistic regression models were constructed to evaluate the associations between systemic immune inflammation index (SII), systemic inflammatory response index (SIRI), and WRF. Restricted cubic spline (RCS) regression was utilized to illustrate the relationship between SII, SIRI, and WRF. Additionally, we explored this correlation through segmented linear regression as part of our threshold analysis.</p><p><strong>Results: </strong>A total of 10,361 individuals (25.9%) experienced WRF within the first year. Higher levels of SII and SIRI were significantly associated with increased odds of WRF across all CKM stages. After adjusting for multiple conventional variables, SII remained an independent predictor for WRF (OR: 1.298, 95% CI: 1.181-1.427, p < 0.001). Similarly, SIRI also demonstrated a significant positive correlation with WRF (OR: 1.026, 95% CI: 1.021-1.030, p < 0.001). The RCS analysis also revealed a dose-response relationship, indicating higher quartiles of SII and SIRI correlating with greater odds of WRF. Further analysis revealed significant interactions between SII, SIRI, and CKM stages, particularly at stages 4 (p < 0.001 for both). Subgroup analysis suggested that this association between SII, SIRI, and WRF was more prominent in the early stage of CKM. The threshold effect analysis demonstrated that for ln transformed SII, a threshold of above 5.565 indicated significant correlation with WRF (OR: 1.277), while for SIRI, the threshold of 2.34 showed a strong correlation below it (OR: 1.330).</p><p><strong>Conclusion: </strong>Both SII and SIRI were associated with the risk of WRF in individuals with CKM. This association seemed more prominent in the early stage of CKM.</p>","PeriodicalId":7570,"journal":{"name":"American Journal of Nephrology","volume":" ","pages":"1-11"},"PeriodicalIF":4.3,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paraneoplastic Glomerulopathies: Mechanistic and Pathogenic Insights.","authors":"Virginie Royal, Nelson Leung, Sabine Karam, Frank Bridoux, Samih H Nasr","doi":"10.1159/000546050","DOIUrl":"10.1159/000546050","url":null,"abstract":"<p><strong>Background: </strong>Paraneoplastic glomerular diseases are triggered by substances secreted by tumor cells, such as tumor antigens, rather than direct tumor invasion.</p><p><strong>Summary: </strong>These conditions frequently manifest as glomerular disorders, particularly in the elderly, with membranous nephropathy being the most observed lesion. They often present with proteinuria, hematuria, and/or varying levels of kidney dysfunction. In some cases, the initial presentation may precede the diagnosis of malignancy and can be indistinguishable from the idiopathic glomerulopathies, requiring a high level of clinical suspicion to accurately identify a paraneoplastic origin. Although the exact pathophysiologic mechanisms underlying paraneoplastic glomerulopathy are not fully understood, they are thought to involve an immune-mediated response to tumor antigens in most cases.</p><p><strong>Key message: </strong>Recognizing paraneoplastic glomerulopathies is of significant clinical importance as their management is distinct and has substantial implications for the treatment of the associated malignancy.</p>","PeriodicalId":7570,"journal":{"name":"American Journal of Nephrology","volume":" ","pages":"1-13"},"PeriodicalIF":4.3,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal Changes in Peritoneal Transport and Their Impact on Dialysis Outcomes: A Machine Learning Approach Integrating Clinical and Biomarker Data.","authors":"Chia-Chun Lee, Jo-Yen Chao, Kuan-Hung Liu, Wei-Ren Lin, Te-Hui Kuo, An-Bang Wu, Ming-Cheng Wang, Sheng-Hsiang Lin, Chin-Chung Tseng","doi":"10.1159/000545943","DOIUrl":"10.1159/000545943","url":null,"abstract":"<p><strong>Introduction: </strong>Longitudinal changes in peritoneal transport patterns and the predictive role of dialysate biomarkers remain poorly understood. This study assessed the impact of peritoneal equilibration test (PET) trajectory changes on clinical outcomes, explored biomarker contributions, and developed a machine learning-based model to predict peritoneal transport transitions.</p><p><strong>Methods: </strong>This prospective study enrolled peritoneal dialysis (PD) patients aged ≥18 years from 2016 to 2017, with follow-up until 2020. Patients with missing PET data or acute illness within 2 months of PET were excluded. Based on longitudinal PET changes, patients were classified into four trajectory groups: persistent high (HH), high to low (HL), low to high (LH), and persistent low (LL). Clinical outcomes included technique failure and mortality. Dialysate biomarkers were quantified using ELISA and standardized by appearance rates (ARs). A Support Vector Machine (SVM) model was developed to predict PET trajectory changes using clinical and biomarker data. Model performance was assessed using accuracy, precision, recall, F1-score, and area under the curve (AUC).</p><p><strong>Results: </strong>Among 132 eligible patients, cumulative risk analysis identified the HH group as having the highest risk of adverse outcomes, followed by LH, LL, and HL groups (p = 0.009). Based on prognostic trends, HH and LH were reclassified as the future high (FH) group, while HL and LL were grouped as the future low (FL) group. The FH group had a significantly higher risk of adverse outcomes than the FL group (HR: 7.87, 95% CI: 1.81-34.10, p = 0.005). Matrix metalloproteinase 2 (MMP2) AR and plasminogen activator inhibitor 1 (PAI-1) AR differed significantly across PET trajectory groups (p < 0.001 for both), with the HH group exhibiting the highest biomarker levels (MMP2 AR: 195.0 ng/min, IQR: 145.2-230.0; PAI-1 AR: 2.63 ng/min, IQR: 1.29-4.51). The SVM model integrating clinical and biomarker data outperformed models using clinical data alone, achieving a higher AUC (0.87 vs. 0.71). Risk visualization curves identified males with elevated biomarkers as particularly vulnerable to transitioning to high transporter status.</p><p><strong>Conclusions: </strong>Sustained or transitioning to a high transporter status significantly increases the risk of adverse outcomes in PD patients. Higher MMP2 AR and PAI-1 AR levels are associated with an increased risk of adverse PET trajectory changes, enhancing risk stratification. Integrating biomarker-based predictive models with clinical data improves prognostic accuracy, supporting early intervention strategies for high risk patients.</p>","PeriodicalId":7570,"journal":{"name":"American Journal of Nephrology","volume":" ","pages":"1-14"},"PeriodicalIF":4.3,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neutrophil Percentage-to-Albumin Ratio as a Predictor of Acute Kidney Injury in Cirrhotic Patients: A Novel Approach Utilizing Artificial Intelligence.","authors":"Nasser Mousa, Sherif Elbaz, Alaa Elmetwalli, Mostafa Abdelsalam, Eman Abdelkader, Mohamed Wahba, Mohammed Abdelaziz, Ola El-Emam, Niveen El-Wakeel, Mohamed Shaheen, Badawy Abo-Bakr, Muhammad Diasty, Naglaa Abbas, Mohamed Selim, Marwa Mansour","doi":"10.1159/000545639","DOIUrl":"10.1159/000545639","url":null,"abstract":"<p><strong>Introduction: </strong>Acute kidney injury (AKI) is common in cirrhotic patients and is associated with a poor prognosis. The neutrophil percentage-to-albumin ratio (NAR) is a novel marker of systemic inflammation. This study aimed to evaluate the predictive power of NAR for AKI in cirrhotic patients with ascites using AI tools such as Shapley Additive Explanations and a Random Forest (RF) model.</p><p><strong>Methods: </strong>This study involved 322 patients with liver cirrhosis and ascites. AKI was defined based on the International Club of Ascites. The sensitivity and specificity of the NAR were evaluated using receiver operating characteristic curve analysis. Predictors of AKI were identified, and the significance of artificial intelligence features was determined using Shapley Additive Explanations. The RF model was utilized to rank all predictors for AKI.</p><p><strong>Results: </strong>In our study, 130 patients (40.3%) developed AKI, with stages 2 and 3 analyzed for clinical relevance. The NAR at a cutoff of >23.2 revealed a substantial predictive value for AKI stages 2 and 3 (AUC = 0.893, sensitivity = 85.4%, specificity = 72.3%). The RF model identified serum albumin as the top predictor with an importance score of 0.350, followed by NAR with a score of 0.280, and chronic kidney disease ranked third with a score of 0.170. These factors are key drivers in predicting the outcome of AKI. Age, ischemic heart disease, diabetes mellitus, international normalized ratio, and hemoglobin had lower predictive power.</p><p><strong>Conclusion: </strong>NAR could be a new, affordable, and non-invasive test demonstrating a strong discriminative ability to predict AKI in cirrhotic patients.</p>","PeriodicalId":7570,"journal":{"name":"American Journal of Nephrology","volume":" ","pages":"1-13"},"PeriodicalIF":4.3,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glomerular Basement Membrane Thickness Estimation and Stratification via Active Semi-Supervised Learning Model.","authors":"Nico Curti, Gianluca Carlini, Sabrina Valente, Enrico Giampieri, Alessandra Merlotti, Daniel Remondini, Gaetano La Manna, Gastone Castellani, Gianandrea Pasquinelli","doi":"10.1159/000542658","DOIUrl":"10.1159/000542658","url":null,"abstract":"<p><strong>Introduction: </strong>The measure of glomerular basement membrane (GBM) thickness is used as diagnostic criteria for kidney glomerular diseases. The GBM thickness measurement, a time-consuming task, is performed by expert pathologists on transmission electron microscopy (TEM) images; therefore, it is affected by subjectivity and reproducibility issues.</p><p><strong>Methods: </strong>Here we introduce a fully automated pipeline for the GBM segmentation and successive thickness estimation, starting from TEM images. This method is based on an active semi-supervised learning training procedure of a convolutional neural network model. Starting from the areas automatically identified by the model, we provide a robust measurement of membrane thickness using pixels distance matrix and computer vision techniques. Using these values, we trained a machine learning model to automatically determine the GBM thickness. To verify the accuracy of the method, we compared the predicted results with the full iconographic materials and diagnostic record reports from 42 renal biopsies having normal thickness (n = 21), thin (n = 10), thick GBM (n = 11).</p><p><strong>Results: </strong>The obtained segmentations were used for the automated estimation of GBM thickness via computer vision algorithms and compared with manual measurements, obtaining a correlation of Pearson's R2 of 0.85. The GBM thickness was stratified into 3 classes, namely, normal, thin, thick, with a 0.63 Matthews correlation coefficient and a 0.76 accuracy.</p><p><strong>Conclusion: </strong>The proposed pipeline obtained state-of-the-art performance in GBM segmentation, proving its robustness under image variations, such as magnification, contrast, and complex geometrical shapes. Automated measures could assist clinicians in standard clinical practice speeding up routine procedures with high diagnostic accuracy.</p>","PeriodicalId":7570,"journal":{"name":"American Journal of Nephrology","volume":" ","pages":"1-14"},"PeriodicalIF":4.3,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144059203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Renal Ischemia Induces Endoplasmic Reticulum Stress and Impairs the Reparative Potency of Scattered Tubular-Like Cells.","authors":"Sara Kazeminia, Barnit Kaur, Kumar Shivam, Xiang-Yang Zhu, Hui Tang, Kyra L Jordan, Shivam Bajpai, Ailing Xue, Alejandro R Chade, Maria V Irazabal, Lilach O Lerman, Alfonso Eirin","doi":"10.1159/000545795","DOIUrl":"10.1159/000545795","url":null,"abstract":"<p><strong>Introduction: </strong>CD24+/CD133+ scattered tubular-like cells (STCs) are surviving renal cells that acquire progenitor-like characteristics to repair other damaged kidney cells. Renal artery stenosis (RAS) impairs the reparative capacity of STCs, but the underlying mechanisms remain unknown. STCs contain abundant endoplasmic reticulum (ER), but its capacity to fold proteins could become saturated (ER stress), leading to STC dysfunction. We hypothesized that RAS alters the expression of genes implicated in ER stress in swine STCs.</p><p><strong>Methods: </strong>STCs were harvested from pig kidneys after 10 weeks of RAS or sham (n = 6 each) and expression of ER stress genes was assessed using mRNA-seq (n = 3 each). To elucidate mechanisms regulating ER stress genes in RAS-STCs, integrated mRNA-seq/microRNA (miRNA)-seq and transcription factor (TF) prediction analysis were performed. STC ER stress was assessed in vitro using Western blotting, serial block-face electron microscopy, and mass spectrometry. The involvement of ER stress in regulating the STC-protective effects was also assessed in vitro by their capacity to improve viability of injured human tubular epithelial cells.</p><p><strong>Results: </strong>RAS pigs developed significant renal dysfunction. mRNA-seq identified 25 ER stress genes upregulated and 30 downregulated in RAS-STCs versus normal-STCs. miRNAs were found to target over a third of all differentially expressed ER stress genes, and almost half of genes encoding for the top 50 TFs involved in regulation of ER stress genes were dysregulated in RAS-STCs. RAS-STCs exhibited higher ER stress compared to normal-STCs, reflected in significant ER dilation and formation of ER-mitochondria contacts and increased levels of ER stress-related amino acids. Importantly, ER stress inhibition improved the reparative capacity of RAS-STCs in vitro.</p><p><strong>Conclusion: </strong>Renal ischemia alters expression of ER stress-related genes in swine STCs, likely through post-transcriptional- and TF-regulatory mechanisms, which induces ER stress and impairs their reparative potency. These alterations may limit the potential of STCs to repair damaged kidneys in subjects with RAS.</p>","PeriodicalId":7570,"journal":{"name":"American Journal of Nephrology","volume":" ","pages":"1-17"},"PeriodicalIF":4.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relationship between Cumulative Exposure and Time Course of Plasma Aldosterone Concentrations and Chronic Kidney Disease in Hypertensive Patients: A Real-World Cohort Study.","authors":"Shuaiwei Song, Xintian Cai, Di Shen, Junli Hu, Qing Zhu, Huimin Ma, Yingying Zhang, Rui Ma, Pan Zhou, Zhiqiang Zhang, Wenbo Yang, Wen Jiang, Jing Hong, Delian Zhang, Nanfang Li","doi":"10.1159/000545451","DOIUrl":"10.1159/000545451","url":null,"abstract":"<p><strong>Introduction: </strong>This study aimed to investigate the effects of cumulative exposure to plasma aldosterone concentration (PAC) and its time course on chronic kidney disease (CKD) in hypertensive patients, with the goal of providing insights into preventing future CKD events, especially in younger hypertensive patients.</p><p><strong>Methods: </strong>This study enrolled a total of 7,142 hypertensive participants, each of whom had undergone at least two PAC measurements before the age of 60. We calculated the annual PAC area under the curve (AUC) and used Cox regression analyses to examine the association between annual PAC_AUC and CKD risk. We also explored how the timing course of PAC accumulation affected CKD risk, as different stages of PAC accumulation, even with the same annual PAC_AUC, may lead to varying risks. Additionally, we conducted a comparative analysis to assess the predictive performance of annual PAC_AUC versus single PAC measurements.</p><p><strong>Results: </strong>During a median follow-up of 5.83 years, 754 participants developed CKD. The results showed a progressive increase in CKD risk with higher annual PAC_AUC (hazard ratio: 1.19; 95% confidence interval: 1.17, 1.21). Moreover, the timing course of PAC accumulation modulates this risk; Kaplan-Meier curves indicated that participants with similar annual PAC_AUC, but earlier PAC exposure had a higher CKD risk compared to those exposed later (Log-rank test, p < 0.001). Furthermore, annual PAC_AUC outperformed single PAC measurements in predictive accuracy.</p><p><strong>Conclusion: </strong>CKD risk is influenced by both annual PAC_AUC and the time course of PAC exposure. Participants exposed to elevated PAC earlier had a higher CKD risk than those exposed later, even at the same annual PAC_AUC. This highlights the importance of early PAC control to prevent CKD.</p>","PeriodicalId":7570,"journal":{"name":"American Journal of Nephrology","volume":" ","pages":"1-16"},"PeriodicalIF":4.3,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of Neutrophils in Venous Thrombosis in Primary Membranous Nephropathy.","authors":"Qiuhan Wang, Benxia Bing, Liang Xu, Chenghua Wang, Chunjuan Zhai, Jing Sun, Xiaowei Yang","doi":"10.1159/000545296","DOIUrl":"10.1159/000545296","url":null,"abstract":"<p><strong>Introduction: </strong>Patients with primary membranous nephropathy (PMN) are at high risk of developing venous thromboembolic events (VTEs), while neutrophils are involved in the onset of VTEs in PMN remains unclear.</p><p><strong>Methods: </strong>The association of neutrophils with VTEs was retrospectively analyzed in a large cohort of patients with PMN. Plasma cell-free DNA (cfDNA) levels were evaluated in PMN patients with and without VTEs. In addition, we established a rat model of passive Heymann nephritis (PHN) by immunization with sheep anti-rat Fx1A serum. The inferior vena cava (IVC) was ligated to establish the deep vein thrombosis model. Thrombus weight and length were evaluated at 4 h after IVC stenosis in rats. GSK484 was administered via intraperitoneal injection to assess the role of NETosis inhibition in thrombosis formation in PHN rats.</p><p><strong>Results: </strong>Circulating neutrophils in PMN patients with VTEs were significantly higher than in patients without VTEs. Neutrophil counts were positively correlated with the activity of factor IX, factor XI, protein C, protein S, and AT-III (r = 0.328, p = 0.002; r = 0.378, p < 0.001; r = 0.380, p < 0.001; r = 0.243, p = 0.029; r = 0.254, p = 0.020). In multivariate logistic regression, neutrophils were the independent risk factors for VTEs in PMN patients (OR = 1.608, 95% CI: 1.293-2.000; p < 0.05). Significantly increased plasma levels of cfDNA were detected in PMN patients, especially in PMN patients with VTEs, relative to controls. In animal experiments, the plasma cfDNA levels elevated significantly after IVC stenosis in PHN rats, and GSK484 decreased the plasma cfDNA levels in PHN rats with IVC stenosis. Four hours after IVC stenosis surgery, thrombi formed in PHN rats were both longer and heavier compared to those observed in control rats, and GSK484 administration significantly inhibits the thrombus formation in PHN rats.</p><p><strong>Conclusion: </strong>This study preliminarily indicated that neutrophils were involved in the hypercoagulation state and increased thrombosis propensity in PMN, offering novel insights into the pathogenesis of thrombosis formation in PMN and potential therapeutic targets for its management.</p>","PeriodicalId":7570,"journal":{"name":"American Journal of Nephrology","volume":" ","pages":"1-11"},"PeriodicalIF":4.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adverse Prognosis in Membranous Nephropathy with Phospholipase A2 Receptor 1 Epitope Spreading: A Prospective Study.","authors":"Liling Wu, Zhihang Su, Bo Tang, Yuna Chen, Haofei Hu, Yuan Cheng, Jianyu Chen, Qijun Wan","doi":"10.1159/000545133","DOIUrl":"10.1159/000545133","url":null,"abstract":"<p><strong>Introduction: </strong>In primary membranous nephropathy (MN), 80% of patients harbor antibodies (Abs) against phospholipase A2 receptor 1 (PLA2R1), closely linked to disease prognosis. Prior research has validated the correlation between Abs directed toward the cysteine-rich (CysR) and C-type lectin 1, 7, and 8 (CTLD1, CTLD7, and CTLD8) domains of PLA2R1 and outcomes in MN.</p><p><strong>Methods: </strong>In a prospective cohort of 52 patients with newly diagnosed PLA2R1-MN, with urine protein ≥ 3.5 g/24 h and estimated glomerular filtration rate ≥30 mL/min/1.73 m2, we studied epitope spreading patterns and domain-specific PLA2R1-Ab clinically using Western blot and ELISA. The primary outcome was a combination of remission at 12 months. Kaplan-Meier curves and multivariable Cox regression were employed to compare the single and multiple epitope patients.</p><p><strong>Results: </strong>All patients had anti-CysR-Abs. 26 (50.0%) exhibited multi-domain recognition, with 1 patient specifically recognizing the CTLD8 domain. A significant association was observed between PLA2R1-Ab and CysR-Ab (r = 0.869, p < 0.001), as well as with anti-CTLD1 Ab (r = 0.803, p < 0.001). During a median follow-up of 11 months (IQR, 6.0-17.0), 27 patients (65.9%) experienced complete or partial nephrotic syndrome remission. Notably, the multi-domain recognition exhibited a reduced remission rate compared to the single-domain (44.44% vs. 82.61%, p = 0.011, alongside higher concentrations of anti-PLA2R1-Abs. A higher baseline level of anti-CTLD1 was notably linked to a lower likelihood of remission. In a univariate analysis, multi-domain recognition decreases the probability of remission (HR, 0.38 [95% CI, 0.16-0.87], p = 0.022). After the Kaplan-Meier analysis, the multi-domain group showed lower remission rates than the single-domain group at various time points.</p><p><strong>Conclusion: </strong>The PLA2R1 epitope spreading (ES) is a potent tool for monitoring disease severity and stratifying patients based on renal outcomes for prognostic purposes. Hence, we advocate evaluating ES at the baseline stage when determining early therapeutic interventions for individuals diagnosed with MN.</p>","PeriodicalId":7570,"journal":{"name":"American Journal of Nephrology","volume":" ","pages":"1-12"},"PeriodicalIF":4.3,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic Properties of Dapagliflozin in Patients with Stage 4 Chronic Kidney Disease.","authors":"Dan Li, Di Xie, Ancheng Gu, Yaya Yang, Zhijian Guo, Xianglan Huang, Jun Li, Jun Wang, Lei Zhang, Bianxiang Hu, Xiaobing Yang, Yan Huang, Wanwen Cao, Yerong Wei, Jiali He, Zhongyuan Xu, Min Liang","doi":"10.1159/000544936","DOIUrl":"10.1159/000544936","url":null,"abstract":"<p><strong>Introduction: </strong>The pharmacokinetic data on dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, are limited in patients with severe renal impairment. We aimed to evaluate the pharmacokinetic properties and safety of dapagliflozin in patients with chronic kidney disease (CKD) stage 4.</p><p><strong>Methods: </strong>This was a single-center, open-label, pharmacokinetic trial involving single, and multiple doses. Patients with an estimated glomerular filtration rate (eGFR) of 15-<30 mL/min/1.73 m2 were enrolled. The single-dose group received 10 mg of oral dapagliflozin once daily, while the multiple-dose group received 10 mg daily for 5 days. Pharmacokinetic parameters, pharmacodynamic response, and tolerability were assessed.</p><p><strong>Results: </strong>A total of 12 participants completed the single-dose study, and 9 participants completed the multiple-dose study. The mean eGFR was 23.4 and 23.2 mL/min/1.73 m2 in single- and multiple-dose group, respectively. In the single-dose group, dapagliflozin was rapidly absorbed and metabolized to produce dapagliflozin 3-O-glucuronide (D3OG), with a mean Tmax of 0.7 h and 1.8 h, and a mean T1/2 of 16.7 h and 14.9 h, respectively. Participants with an eGFR of 15-24 mL/min/1.73 m2 exhibited higher AUC0-∞ and mean residence time for D3OG compared to those with an eGFR of 25-30 mL/min/1.73 m2. In the multiple-dose group, there was no significant accumulation of dapagliflozin, as indicated by the ratio of AUCTau (918.6 ± 155.2 h × ng/mL) to AUC0-24 h (917.1 ± 154.7 h × ng/mL) was close to 1. In the multiple-dose group, urinary albumin/creatinine ratio decreased by 21% and 24-h urinary protein decreased by 23% from baseline to 24 h after the last dose.</p><p><strong>Conclusion: </strong>In conclusion, no clinically significant accumulation of dapagliflozin was observed in patients with stage 4 CKD.</p>","PeriodicalId":7570,"journal":{"name":"American Journal of Nephrology","volume":" ","pages":"1-12"},"PeriodicalIF":4.3,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}