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Investigative Ophthalmology & Visual... Jun 2024Lupus-like chronic graft-versus-host disease (cGVHD) has been previously described, but the ocular findings have not been elucidated. Recipient mice in a lupus-like...
PURPOSE
Lupus-like chronic graft-versus-host disease (cGVHD) has been previously described, but the ocular findings have not been elucidated. Recipient mice in a lupus-like cGVHD model manifested notable and persistent ocular surface phenotypes. Herein, we further explored immunopathogenic mechanisms underlying these ocular phenotypes.
METHODS
A previously described lupus-like cGVHD model was established by intraperitoneal injection of splenocytes from bm12 mice into C57BL/6J mice. Systemic findings were evaluated for the presence of splenomegaly, proteinuria, and autoantibodies. Comprehensive evaluations were conducted on ocular manifestations and immunopathological features in this model.
RESULTS
The lupus-like cGVHD model was successfully constructed 2 weeks post-transplantation. The recipient mice developed lupus-like phenotypes, including splenomegaly, proteinuria, and increased autoantibodies, and their ocular presentations included corneal epithelial defects and decreased tear secretion. Histological analysis revealed a reduction in corneal nerve fiber density and corneal endothelial cells, along with conjunctival fibrosis and loss of goblet cells. Moreover, cGVHD induced progressive aggravation of immune cell infiltration and fibrosis in the lacrimal glands. RNA-Sequencing (RNA-seq) results of the lacrimal glands demonstrated that the differentially expressed genes (DEGs) between the control and cGVHD groups were associated with GVHD pathways. Immune infiltration analysis using RNA-seq and flow cytometry confirmed that CD8+ T lymphocytes predominantly constituted the inflammatory infiltrating cells within the lacrimal glands.
CONCLUSIONS
This lupus-like cGVHD model (bm12→C57BL/6J) exhibited persistent ocular surface manifestations, characterized by immune infiltration of CD8+ T lymphocytes in the lacrimal glands. Thus, this ocular cGVHD model may be used to explore the underlying mechanisms and discover novel therapeutic interventions.
Topics: Animals; Graft vs Host Disease; Mice; Disease Models, Animal; Mice, Inbred C57BL; Chronic Disease; Lupus Erythematosus, Systemic; Female; Autoantibodies; Bronchiolitis Obliterans Syndrome
PubMed: 38864812
DOI: 10.1167/iovs.65.6.20 -
Cureus May 2024Chronic kidney disease (CKD) is a progressive condition characterized by gradual loss of kidney function, necessitating timely monitoring and interventions. This... (Review)
Review
Chronic kidney disease (CKD) is a progressive condition characterized by gradual loss of kidney function, necessitating timely monitoring and interventions. This systematic review comprehensively evaluates the application of artificial intelligence (AI) and machine learning (ML) techniques for predicting CKD progression. A rigorous literature search identified 13 relevant studies employing diverse AI/ML algorithms, including logistic regression, support vector machines, random forests, neural networks, and deep learning approaches. These studies primarily aimed to predict CKD progression to end-stage renal disease (ESRD) or the need for renal replacement therapy, with some focusing on diabetic kidney disease progression, proteinuria, or estimated glomerular filtration rate (GFR) decline. The findings highlight the promising predictive performance of AI/ML models, with several achieving high accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve scores. Key factors contributing to enhanced prediction included incorporating longitudinal data, baseline characteristics, and specific biomarkers such as estimated GFR, proteinuria, serum albumin, and hemoglobin levels. Integration of these predictive models with electronic health records and clinical decision support systems offers opportunities for timely risk identification, early interventions, and personalized management strategies. While challenges related to data quality, bias, and ethical considerations exist, the reviewed studies underscore the potential of AI/ML techniques to facilitate early detection, risk stratification, and targeted interventions for CKD patients. Ongoing research, external validation, and careful implementation are crucial to leveraging these advanced analytical approaches in clinical practice, ultimately improving outcomes and reducing the burden of CKD.
PubMed: 38864072
DOI: 10.7759/cureus.60145 -
Biomarker Insights 2024Although, several studies have assessed the association of the phospholipase A2 receptor (PLA2R) and HLA-DQA1 SNPs with primary membranous nephropathy (PMN), results...
BACKGROUND
Although, several studies have assessed the association of the phospholipase A2 receptor (PLA2R) and HLA-DQA1 SNPs with primary membranous nephropathy (PMN), results were inconsistent and between-studies heterogeneity needs to be investigated.
OBJECTIVES
The aim of this review was to summarize existing data on the contribution of 10 SNPs in the PLA2R and HLA-DQA1 genes to PMN susceptibility and to investigate the between-studies heterogeneity by subgroup analyses and meta-regressions.
DESIGN
This study was performed according to the PRISMA guidelines for systematic reviews and meta-analyses.
DATA SOURCES AND METHODS
An electronic literature search for eligible studies among all papers published prior to January 10, 2024, was conducted through PubMed, EMBASE, Web of science and Scopus databases. Meta-analyses together with subgroup analyses and meta-regressions were performed for the 10 following SNPs: rs4664308, rs3749117, rs3749119, rs35771982, rs3828323, rs16844715, rs1511223, rs6757188, rs2715918, and rs2187668.
RESULTS
Combined analyses revealed a significant increase in PMN risk conferred by the following alleles: rs4664308*A, rs3749117*T, rs3749119*C, rs35771982*G, rs3828323*C, rs16844715*C, rs1511223*A, rs2715918*A, and rs2187668*A, all -values < .001. Moreover, the PLA2R-rs4664308/HLA-DQA1-rs2187668 interaction was significantly associated with an increased PMN risk, < .001. However, there was a substantial between-studies heterogeneity for some SNPs. Subgroup analyses by ethnicity for the 9 PLA2R SNPs did not show any cross-ethnic disparity. Inversely, the risk conferred by the HLA-DQA1 rs2187668*A allele was significantly higher in Caucasians (OR [95% CI] = 3.929 [3.251-4.748]) than in Asians (OR [95% CI] = 2.537 [1.94-3.318], = .007. Besides, meta-regressions revealed for the majority of investigated SNPs significant correlations of the effect size with albumin, 24-hours proteinuria, serum creatinine, and eGFR levels. Hence, the influence on PMN risk conferred by the PLA2R and HLA-DQA1 SNPs was rather noted in patients with a severe disease.
CONCLUSION
This meta-analysis showed that 9 out of the 10 investigated SNPs in PLA2R and HLA-DQA1 genes were associated with increased PMN risk. Heterogeneity could be due to disparate patient groups in terms of disease presentation for almost all SNPs, and ethnicity for the HLA-DQA1 rs2187668 SNP.
REGISTRATION
This review has been registered on PROSPERO: CRD42024506729. Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024506729.
PubMed: 38863528
DOI: 10.1177/11772719241259602 -
Journal For Immunotherapy of Cancer Jun 2024A combination of axitinib and immune checkpoint inhibitors (ICIs) demonstrated promising efficacy in the treatment of advanced renal cell carcinoma (RCC). This study...
BACKGROUND
A combination of axitinib and immune checkpoint inhibitors (ICIs) demonstrated promising efficacy in the treatment of advanced renal cell carcinoma (RCC). This study aims to prospectively evaluate the safety, efficacy, and biomarkers of neoadjuvant toripalimab plus axitinib in non-metastatic clear cell RCC.
METHODS
This is a single-institution, single-arm phase II clinical trial. Patients with non-metastatic biopsy-proven clear cell RCC (T2-T3N0-1M0) are enrolled. Patients will receive axitinib 5 mg twice daily combined with toripalimab 240 mg every 3 weeks (three cycles) for up to 12 weeks. Patients then will receive partial (PN) or radical nephrectomy (RN) after neoadjuvant therapy. The primary endpoint is objective response rate (ORR). Secondary endpoints include disease-free survival, safety, and perioperative complication rate. Predictive biomarkers are involved in exploratory analysis.
RESULTS
A total of 20 patients were enrolled in the study, with 19 of them undergoing surgery. One patient declined surgery. The primary endpoint ORR was 45%. The posterior distribution of πORR had a mean of 0.44 (95% credible intervals: 0.24-0.64), meeting the predefined primary endpoint with an ORR of 32%. Tumor shrinkage was observed in 95% of patients prior to nephrectomy. Furthermore, four patients achieved a pathological complete response. Grade ≥3 adverse events occurred in 25% of patients, including hypertension, hyperglycemia, glutamic pyruvic transaminase/glutamic oxaloacetic transaminase (ALT/AST) increase, and proteinuria. Postoperatively, one grade 4a and eight grade 1-2 complications were noted. In comparison to patients with stable disease, responders exhibited significant differences in immune factors such as Arginase 1(ARG1), Melanoma antigen (MAGEs), Dendritic Cell (DC), TNF Superfamily Member 13 (TNFSF13), Apelin Receptor (APLNR), and C-C Motif Chemokine Ligand 3 Like 1 (CCL3-L1). The limitation of this trial was the small sample size.
CONCLUSION
Neoadjuvant toripalimab combined with axitinib shows encouraging activity and acceptable toxicity in locally advanced clear cell RCC and warrants further study.
TRIAL REGISTRATION NUMBER
clinicaltrials.gov, NCT04118855.
Topics: Humans; Carcinoma, Renal Cell; Axitinib; Male; Female; Kidney Neoplasms; Middle Aged; Neoadjuvant Therapy; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Adult; Prospective Studies; Nephrectomy
PubMed: 38862251
DOI: 10.1136/jitc-2023-008475 -
PloS One 2024The potential influence of hyperuricemia on the genesis and progression of chronic kidney disease (CKD) remains controversial. In general, the correlation between blood...
BACKGROUND
The potential influence of hyperuricemia on the genesis and progression of chronic kidney disease (CKD) remains controversial. In general, the correlation between blood levels of uric acid (UA) and the rate of progression of CKD is considered to be modest, if any, and the results of relevant trials oriented to disclose the effect of urate-lowering therapies on this outcome have been disappointing. Urinary excretion rates of UA could reflect more accurately the potential consequences of urate-related kidney injury.
METHOD
Using a cross-sectional design, we investigated the correlation between different estimators of the rates of urinary excretion of UA (total 24-hour excretion, mean urinary concentration, renal clearance and fractional excretion)(main study variables), on one side, and urinary levels of selected biomarkers of kidney injury and CKD progression (DKK3, KIM1, NGAL, interleukin 1b and MCP)(main outcome variables), in 120 patients with advanced CKD (mean glomerular filtration rate 21.5 mL/minute). We took into consideration essential demographic, clinical and analytic variables with a potential confounding effect on the explored correlations (control variables). Spearman's rho correlation and nonlinear generalized additive regression models (GAM) with p-splines smoothers were used for statistical analysis.
MAIN RESULTS
Multivariate analysis disclosed independent correlations between urinary UA concentrations, clearances and fractional excretion rates (but not plasma UA or total 24-hour excretion rates of UA), on one side, and the scrutinized markers. These correlations were more consistent for DKK3 and NGAL than for the other biomarkers. Glomerular filtration rate, proteinuria and treatment with statins or RAA axis antagonists were other independent correlates of the main outcome variables.
CONCLUSIONS
Our results support the hypothesis that urinary excretion rates of UA may represent a more accurate marker of UA-related kidney injury than plasma levels of this metabolite, in patients with advanced stages of CKD. Further, longitudinal studies will be necessary, to disclose the clinical significance of these findings.
Topics: Humans; Uric Acid; Biomarkers; Male; Female; Middle Aged; Renal Insufficiency, Chronic; Aged; Cross-Sectional Studies; Glomerular Filtration Rate; Disease Progression; Adult
PubMed: 38861521
DOI: 10.1371/journal.pone.0304105 -
Frontiers in Nutrition 2024High sodium intake and fluid overhydration are common factors of and strongly associated with adverse outcomes in chronic kidney disease (CKD) patients. Yet, their...
BACKGROUND
High sodium intake and fluid overhydration are common factors of and strongly associated with adverse outcomes in chronic kidney disease (CKD) patients. Yet, their effects on cardiac dysfunction remain unclear.
AIMS
The study aimed to explore the impact of salt and volume overload on cardiac alterations in non-dialysis CKD.
METHODS
In all, 409 patients with CKD stages 1-4 (G1-G4) were enrolled. Daily salt intake (DSI) was estimated by 24-h urinary sodium excretion. Volume status was evaluated by the ratio of extracellular water (ECW) to total body water (TBW) measured by body composition monitor. Recruited patients were categorized into four groups according to DSI (6 g/day) and median ECW/TBW (0.439). Echocardiographic and body composition parameters and clinical indicators were compared. Associations between echocardiographic findings and basic characteristics were performed by Spearman's correlations. Univariate and multivariate binary logistic regression analysis were used to determine the associations between DSI and ECW/TBW in the study groups and the incidence of left ventricular hypertrophy (LVH) and elevated left ventricular filling pressure (ELVFP). In addition, the subgroup effects of DSI and ECW/TBW on cardiac abnormalities were estimated using Cox regression.
RESULTS
Of the enrolled patients with CKD, the median urinary protein was 0.94 (0.28-3.14) g/d and estimated glomerular filtration rate (eGFR) was 92.05 (IQR: 64.52-110.99) mL/min/1.73 m. The distributions of CKD stages G1-G4 in the four groups was significantly different ( = 0.020). Furthermore, compared to group 1 (low DSI and low ECW/TBW), group 4 (high DSI and high ECW/TBW) showed a 2.396-fold (95%CI: 1.171-4.902; = 0.017) excess risk of LVH and/or ELVFP incidence after adjusting for important CKD and cardiovascular disease risk factors. Moreover, combined with eGFR, DSI and ECW/TBW could identify patients with higher cardiac dysfunction risk estimates with an AUC of 0.704 (sensitivity: 75.2%, specificity: 61.0%). The specificity increased to 85.7% in those with nephrotic proteinuria (AUC = 0.713). The magnitude of these associations was consistent across subgroups analyses.
CONCLUSION
The combination of high DSI (>6 g/d) and high ECW/TBW (>0.439) independently predicted a greater risk of LVH or ELVFP incidence in non-dialysis CKD patients. Moreover, the inclusion of eGFR and proteinuria improved the risk stratification ability of DSI and ECW/TBW in cardiac impairments in CKD.
PubMed: 38860161
DOI: 10.3389/fnut.2024.1388591 -
International Journal of Nephrology and... 2024X-linked Alport syndrome (XLAS) is caused by pathogenic variants in which lead to abnormalities of the glomerular basement membrane (GBM) structural and is...
INTRODUCTION
X-linked Alport syndrome (XLAS) is caused by pathogenic variants in which lead to abnormalities of the glomerular basement membrane (GBM) structural and is characterized by progressive kidney disease, hearing loss, and ocular abnormalities. The aim of this study was to identify gene mutations in a Chinese family with XLAS by whole-exome sequencing (WES) and verified the pathogenicity of the mutation in vitro experiments.
CASE PRESENTATION
A five-generation pedigree with a total of 49 family members originating from Hainan province of China was investigated in this study. The proband was a 23-year-old male who developed microscopic hematuria, proteinuria and end-stage kidney disease (ESKD) at age 17. WES identified a novel splicing mutation c.321+5G>A of , which cause exon skip. Further co-segregation analysis confirmed that this mutation exists in relatives who had renal abnormalities using Sanger sequencing. According to American College of Medical Genetics and Genomics guidelines (ACMG), the mutation was determined to be of uncertain significance (VUS). In vitro splicing experiments have shown that the variant induces aberrant mRNA splicing and transcript deletion.
CONCLUSION
We identified a novel intronic pathogenic mutation (c.321+5G>A) in a Chinese XLAS family and described the phenotypes of affected relatives. This study expands the mutation spectrum of gene in XLAS and demonstrates the importance of gene screening for AS.
PubMed: 38855711
DOI: 10.2147/IJNRD.S459363 -
Clinical Kidney Journal Jun 2024Phospholipase A2 receptor (PLA2R) is a major target antigen in idiopathic membranous nephropathy (MN). Anti-PLA2R antibodies are mainly of the immunoglobulin G (IgG)...
BACKGROUND
Phospholipase A2 receptor (PLA2R) is a major target antigen in idiopathic membranous nephropathy (MN). Anti-PLA2R antibodies are mainly of the immunoglobulin G (IgG) subclass IgG4, although other IgG subclass depositions in glomeruli may also be detected. However, the importance of the subclass of the IgG deposit has not been proven. Thus we investigated clinical findings from patients with idiopathic MN in relation to glomerular PLA2R deposition and IgG subclass.
METHODS
We enrolled 132 Japanese patients with biopsy-proven idiopathic MN in a multicentre retrospective observational study. We investigated the complete remission rate as the primary outcome and the development of end-stage kidney disease (ESKD) as the secondary outcome in relation to glomerular PLA2R deposition. Moreover, we evaluated prognostic factors, including glomerular IgG subclass, in the PLA2R-positive group.
RESULTS
The percentage of cases with glomerular PLA2R deposition was 76.5% ( = 101). The first complete remission rate of the PLA2R-positive group was worse than that of the PLA2R-negative group (logrank test < .001). ESKD incidence did not significantly differ between the glomerular PLA2R-negative and PLA2R-positive MN groups (logrank test = .608). In the PLA2R-positive group, higher PLA2R intensities and IgG2 staining were associated with a poorer first complete remission rate (logrank test < .001 and = .032, respectively). Cox proportional hazards analysis also showed that strong PLA2R deposition and positive IgG2 staining were significantly associated with a failure to reach complete remission [hazard ratio 2.09 ( = .004) and 1.78 ( = .030), respectively].
CONCLUSIONS
Our results suggest that intense glomerular PLA2R and IgG2 positivity predict a poor proteinuria remission rate in idiopathic MN.
PubMed: 38854426
DOI: 10.1093/ckj/sfae104 -
Cureus May 2024Introduction Systemic lupus erythematosus (SLE) is a complex autoimmune disease with heterogeneous clinical and laboratory features. The incidence increases markedly in...
Introduction Systemic lupus erythematosus (SLE) is a complex autoimmune disease with heterogeneous clinical and laboratory features. The incidence increases markedly in women. The reason for the predominance of the female gender is still under study. The ethnicity could influence the clinical and serological features of SLE. Material and methods This is a retrospective, descriptive, and longitudinal study. We studied 89 patients diagnosed with childhood-onset systemic lupus erythematosus (cSLE) in our center in 2000-2020 for men and 2010-2020 for women. We investigated disease manifestations, ranging from clinical symptoms to renal involvement, at the time of diagnosis and compared them by gender. Results We studied 89 patients, comprising 23 males and 66 females. The mean age for both groups was 12 years. Concerning clinical manifestations, serositis exhibited a higher prevalence among males, while hair loss was more prominent among females. In the paraclinical evaluation, noteworthy differences were observed regarding average hemoglobin levels and the prevalence of positive anti-DNA antibodies. Males demonstrated an average hemoglobin level of 11.47 g/dL, whereas females displayed 9.84 g/dL (p=0.017). The prevalence of anti-DNA antibodies exhibited marked elevation in males, at 88.9%, compared to females' 42.9% (p=0.024). On a contrary note, our male cohort displayed heightened prevalence in using hydroxychloroquine, cyclophosphamide, and mycophenolate. Similarly, renal involvement presented a higher prevalence in males (100% against 83.3%), albeit lacking statistical significance. Nevertheless, significant disparities emerged in the occurrence of granular casts, proteinuria, and the average glomerular filtration rate, with males experiencing greater impact in each instance. Finally, it is noteworthy that the application of mycophenolate and azathioprine was more frequently observed among patients with renal involvement. Conclusion cSLE patients in our inception cohort showed statistical significance in dermatological and vascular manifestations, serositis, granular casts, low kidney glomerular filtration, and high proteinuria, which are predominant in male patients. Immunological features were predominantly positive in ds-DNA antibodies for male patients. Separation by gender for future studies might identify a better treatment strategy.
PubMed: 38854180
DOI: 10.7759/cureus.59851 -
Kidney & Blood Pressure Research Jun 2024Breakfast-skipping habits are associated with adverse health outcomes including coronary heart disease, metabolic syndrome and diabetes mellitus. However, it remains...
Skipping Breakfast and Progression of Chronic Kidney Disease in the General Japanese Population: the Iki City Epidemiological Study of Atherosclerosis and Chronic Kidney Disease (ISSA-CKD).
INTRODUCTION
Breakfast-skipping habits are associated with adverse health outcomes including coronary heart disease, metabolic syndrome and diabetes mellitus. However, it remains uncertain whether skipping breakfast affects chronic kidney disease (CKD) risk. This study aimed to examine the association between skipping breakfast and progression of CKD.
METHODS
We retrospectively conducted a population-based cohort study using the data from the Iki City Epidemiological Study of Atherosclerosis and Chronic Kidney Disease (ISSA-CKD). Between 2008 and 2019, we included 922 participants aged 30 years or older who had CKD (estimated glomerular filtration rate <60 mL/min/1.73m2 and/or proteinuria) at baseline. Breakfast-skippers were defined as participants who skipped breakfast more than 3 times per week. The outcome was CKD progression defined as a decline of at least 30% in the eGFR from the baseline status. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for CKD progression, adjusted for other CKD risk factors.
RESULTS
During a follow-up period with a mean of 5.5 years, CKD progression occurred in 60 (6.5%) participants. The incidence rate (per 1,000 person-years) of CKD progression was 21.5 in the breakfast-skipping group and 10.7 in the breakfast-eating group (p=0.029), respectively. The multivariable-adjusted HR (95% CI) for CKD progression was 2.60 (95% CI 1.29‒5.26) for the breakfast-skipping group (p=0.028) compared with the group eating breakfast. There were no clear differences in the association of skipping breakfast with CKD progression in subgroup analyses by sex, age, obesity, hypertension, diabetes mellitus, baseline eGFR and baseline proteinuria.
CONCLUSION
Skipping breakfast was significantly associated with higher risk of CKD progression in the general Japanese population.
PubMed: 38852587
DOI: 10.1159/000539653