Nephron最新文献

Background: Previous studies have linked primary aldosteronism to simple renal cysts (SRCs), but the relationship between plasma aldosterone concentration (PAC) and SRC remains unclear. This study aimed to investigate the association between PAC and SRC in hypertensive patients.

Methods: A total of 30,135 hypertensive patients who visited our hospital from January 2014 to December 2023 were included. Logistic regression analyses were conducted to explore the relationship between PAC and SRC, while restricted cubic splines (RCS) assessed the dose-response relationship. SRC were further categorized by size (≥2 cm) and number ≥2). Subgroup analyses were performed to evaluate PAC effects across different conditions.

Results: Multivariate logistic regression showed a positive association between PAC levels (per 5-ng/dL increase) and SRC (OR: 1.20, 95% CI: 1.17-1.23) after adjusting for confounders. Compared to the lowest PAC quartile (Q1), the Q2, Q3, and Q4 groups had progressively higher risks of SRC, with ORs of 1.03 (95% CI: 0.95-1.12), 1.25 (95% CI: 1.15-1.35), and 1.65 (95% CI: 1.52-1.78), respectively. Combining Q3 and Q4 (PAC ≥14.92) yielded an OR of 1.41 compared to Q1 and Q2 (<14.92). Similar trends were observed for SRC size ≥2 cm and number ≥2. RCS analysis confirmed a linear dose-response relationship between PAC and SRC risk. Subgroup and sensitivity analyses consistently supported these findings.

Conclusions: Elevated PAC levels have been linked to an increased risk of SRC in hypertensive patients. Regulating PAC levels may help mitigate SRC formation; however, further prospective studies are required to confirm this causal relationship.

Background: Artificial intelligence, initiated in the 1950s, has matured after two setbacks into deep neural networks (DNNs) and large language models (LLMs). Key drivers of success were the adoption of nonlinear models and autonomous learning. DNNs function as discriminative models that hierarchically interpret features to classify images, while LLMs, as generative models trained on vast datasets, generate text based on contextual meaning.

Summary: Digital pathology (DP) employing DNNs and LLMs is advancing globally, yet Japan lags behind. To standardize diagnostic interpretation and reduce the workload of pathologists, integration of DP into renal transplant pathology (RTP) is essential. The CAMELYON16 challenge demonstrated that AI can achieve diagnostic accuracy comparable to or surpassing expert pathologists. In the USA, over ten DP systems have been approved by the FDA as class II medical devices for primary diagnosis. Moreover, US law assigns liability for AI-related misdiagnosis jointly to pathologists and institutions, promoting both accuracy and legal protection for pathologists. In 2019, the Banff Digital Pathology Working Group was established to build a pathology repository, share AI algorithms, and foster model standardization through competitions. With numerous AI systems emerging, DP platforms should evolve in parallel with biennial Banff classification updates.

Key messages: AI in RTP can enhance diagnostic objectivity and alleviate pathologists' workload. Linking Banff updates with AI retraining enables continuously updated, globally standardized DP. Advanced DP requires close collaboration between transplant pathologists, AI engineers, and cutting-edge graphics processing unit resources.

Background: The cellular proteostasis machinery is essential for maintaining protein homeostasis by employing quality control systems that identify, sequester, and eliminate damaged or misfolded proteins. However, the accumulation of misfolded proteins can overwhelm these protective mechanisms, disrupting proteostasis. This phenomenon is a hallmark of numerous pathologies, including a variety of genetic disorders. In the secretory pathway, the buildup of misfolded proteins triggers endoplasmic reticulum (ER) stress, which activates the unfolded protein response (UPR). The UPR serves as an adaptive mechanism, aiming to alleviate stress and restore cellular homeostasis. However, if ER stress is prolonged or severe, the UPR may fail to restore balance and apoptosis is induced.

Summary: This review introduces the intricate signaling pathways activated by the three UPR transmembrane sensors: protein-kinase R-like endoplasmic reticulum kinase (PERK), inositol requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). We briefly present the roles of the distinct transcriptional programs activated by each sensor in modulating the cellular response to protein stress and in determining cell fate. We discuss how genetic variants and environmental factors contribute to the heterogeneity observed in protein misfolding diseases. Finally, we critically evaluate select therapeutic strategies, specifically protein stabilization, trafficking modulation, and UPR sensor targeting approaches.

Key messages: This review introduces the potential consequences of protein misfolding, which may not only impair protein function but can also lead to toxic protein accumulation and stress induction. Using Fabry disease as a compelling example, we suggest that future therapeutic intervention may require nuanced, combination approaches that address both loss and gain of protein function.

Introduction: The efficacy of telitacicept treatment in reducing proteinuria in patients with IgA nephropathy (IgAN) was indicated in a phase II clinical trial with small sample size. In this study, we conducted a large multicenter retrospective study to explore the efficacy and safety of telitacicept in patients with IgAN.

Methods: This study recruited patients with IgAN from 19 sites from China who were treated with telitacicept and had been followed up at least once or with side effect reported, since April 1, 2021, to April 1, 2023. The primary outcomes of the study were the changing in proteinuria and eGFR over time.

Results: A cohort of 97 patients with IgAN who were treated with telitacicept were recruited, with a median follow-up duration of 3 months. The median baseline proteinuria was 2.3 [1.3, 3.9] g/day and eGFR was 45.0 [26.8, 73.7] mL/min/1.73 m2. There was a significant reduction of proteinuria at 2, 4, 6 months when compared with baseline (2.3 [1.5, 4.1] vs. 1.5 [0.8, 2.3] g/day; 2.3 [1.1, 3.7] vs. 1.1 [0.6, 1.9] g/day; 2.1 [1.0, 2.7] vs. 0.9 [0.5, 1.7] g/day, all p values <0.01). The level of eGFR were comparable between at the baseline and 2, 4, 6 months of follow-up time (41.5 [29.7, 72.0] vs. 42.5 [28.8, 73.3] mL/min/1.73 m2; 41.0 [26.8, 67.7] vs. 44.7 [31.0, 67.8] mL/min/1.73 m2; 33.7 [24.0, 58.5] vs. 32.6 [27.8, 57.5] mL/min/1.73 m2, all p values >0.26). Telitacicept was well tolerated in the patients.

Conclusions: This study indicates that telitacicept alone or on top of steroids therapy can significantly and safely reduce proteinuria in patients with IgAN. The long-term kidney protection still needs to be confirmed in large phase III trial.

Introduction: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a prevalent liver condition commonly associated with obesity, metabolic syndrome, and type 2 diabetes mellitus. It has also been linked to an increased risk of cardiovascular events and overall mortality. Recent studies have established pathophysiological connections between MAFLD and chronic kidney disease (CKD). This study aimed to determine the prevalence of MAFLD in patients with advanced chronic kidney disease (ACKD), identify associated factors, and evaluate its impact on patient survival.

Methods: A retrospective longitudinal cohort study was conducted with incident patients diagnosed with stage 4 or 5 CKD, not on dialysis, who initiated care for ACKD between 2011 and 2015. Clinical and laboratory data were collected, and the presence of MAFLD was estimated using the Fatty Liver Index (FLI). To assess the impact of FLI and other variables on survival, Kaplan-Meier univariate analysis and Cox regression multivariate analysis were performed, with follow-up through February 2024.

Results: Among 367 patients, 60.2% had diabetes, and 70.8% had an FLI ≥60. Age and diabetes mellitus were significant factors associated with a higher likelihood of FLI ≥60. FLI was identified as an independent risk factor for decreased survival in patients with diabetes, after adjusting for other variables (HR, 1.015; 95% CI 1.004-1.027; p = 0.009). However, in non-diabetic patients, FLI was not a significant predictor of lower survival in multivariate Cox regression analysis.

Conclusions: MAFLD is highly prevalent in patients with ACKD, particularly among those with diabetes, for whom it may represent an independent risk factor for reduced survival. This association was not observed in non-diabetic ACKD patients. These results suggest the need to design preventive and treatment strategies for MAFLD in this population.

Introduction: Acute kidney injury (AKI) is associated with adverse outcomes, including death and dialysis. The goal of this study was to identify prognostic biomarkers of AKI that could be used across multiple phenotypes of AKI and across different species.

Methods: Liquid chromatography/tandem mass spectrometry analysis of urine samples from three species (human, rat, and mouse) and four etiologies of AKI identified five potential biomarkers, of which two were validated, complement C3 and vitamin D-binding protein, in a cohort of 157 patients that developed AKI following cardiothoracic surgery. We studied the relationship between the biomarker's concentration in the urine and the development of a composite primary endpoint (stage 3 AKI within 10 days or death within 30 days).

Results: Of the 153 patients who developed AKI following cardiovascular surgery, 17 met the combined primary outcome. The median concentration of urine complement C3 adjusted to urine creatinine had the best predictive value and was significantly higher in the primary outcome group than in the controls. Similarly, the median concentration of vitamin D-binding protein was higher in the primary outcome group.

Conclusions: The studies provide proof in principle that cross-species discovery analyses could be a valuable tool for identifying novel prognostic biomarkers in AKI. Urine complement C3 and vitamin D-binding protein could be promising early predictors of adverse outcomes in patients who develop AKI after cardiac surgery.

The development of the human kidney leads to the establishment of nephron endowment through a process influenced by both genetic and environmental factors. There is individual variability regarding nephron endowment and factors including aging and pathological conditions contribute to the decline in the number of nephrons, impacting renal function. Genetic determinants, such as mutations in crucial developmental genes like Pax2, and epigenetic mechanisms mediated by key enzymes including sirtuin 3, play critical roles in the regulation of the number of nephrons, with implications for kidney disease susceptibility. Sexual dimorphism significantly influences kidney development and function, with the number of nephrons being significantly lower in females, consistent with lower female birth weight, which is considered a surrogate for nephron endowment. Also, although females have fewer nephrons, they experience a slower decline in GFR compared to males. Gender disparity in chronic kidney disease progression has been attributed to factors such as metabolism, oxidative stress, renal hemodynamics, and sex hormones. Understanding the complexities of nephron endowment variability, genetic determinants, and sexual dimorphism in kidney development and function is crucial for elucidating the mechanisms underlying individual kidney disease susceptibility and progression. Further research in this field holds promise for the development of personalized approaches to kidney disease prevention, management, and treatment.

Introduction: With the increasing prevalence of membranous nephropathy (MN), the gut microbiome (GM) is increasingly implicated in its cause, yet the intricate mechanisms remain unclear. Whether changes in the diversity and richness of gut microbial populations among MN patients contribute to disease prevalence is still unanswered, necessitating further exploration into the potential causative link between the GM and MN.

Methods: We conducted a comprehensive bidirectional mendelian randomization (MR) study. We selected 211 bacterial taxa using genome-wide association study (GWAS) data provided by the MiBioGen consortium, while GWAS data relevant to MN were obtained from ebi-a-GCST010005. The inverse-variance weighted (IVW) method was the primary technique used to delineate the causal relationship between exposures and outcomes. To confirm the robustness of our results, we used additional methods, including MR-Egger, weighted median, simple mode, and weighted mode. Sensitivity analyses included tests for pleiotropy, heterogeneity, and leave-one-out sensitivity to ensure the integrity of our conclusions. Finally, reverse MR analyses were conducted to assess the likelihood of reverse causality.

Results: Using various analytical methods, including the IVW approach, MR-Egger, weighted median, simple mode, and weighted mode, our study identified six microbial taxa with a statistically significant causal link to MN, as indicated by p values <0.05. The implicated taxa are Butyrivibrio (OR = 1.25, 95% CI: 1.001-1.565, p = 0.048), Butyricicoccus (OR = 2.15, 95% CI: 1.005-4.621, p = 0.048), Catenibacterium (OR = 1.49, 95% CI: 1.043-2.134, p = 0.028), Ruminiclostridium 5 (OR = 1.78, 95% CI: 1.140-2.763, p = 0.03), Ruminococcaceae UCG-003 (OR = 1.78, 95% CI: 1.140-2.763, p = 0.011), and Bacillales (OR = 1.52, 95% CI: 1.135-2.025, p = 0.005). Each of these taxa has been established as a risk factor for MN. Notably, Ruminococcaceae UCG-003 and Bacillales were identified as having a bidirectional causal relationship with the disease.

Conclusion: Our MR study has revealed a causal link between six microbial taxa and MN, highlighting their potential involvement in the disease's development. These findings represent an initial step into this complex field and underscore the need for more in-depth research.