Kidney Diseases最新文献

Introduction: Chronic kidney disease (CKD) presents a significant global health challenge, characterized by increased fibrosis and metabolic disturbances. B56δ, a regulatory B subunit of protein phosphatase 2A (PP2A), is known to mediate the activity of PP2Acα in regulating de novo lipid synthesis and the progression of kidney fibrosis. Due to the potential severe toxic side effects associated with targeting PP2Acα directly, the substrate selectivity of the regulatory B subunits makes it a more favorable alternative.

Methods: Epirubicin (EPI) was identified as a high-affinity binder to B56δ through screening approaches. Its therapeutic effects were evaluated in a murine model of unilateral ureteral obstruction (UUO) and in TGF-β-stimulated NRK-52E cells. Lipid deposition, fibrotic markers, extracellular matrix accumulation, and cell viability were assessed to determine efficacy and safety.

Results: Administration of EPI in UUO mice markedly reduced renal lipid accumulation and attenuated fibrosis progression. In TGF-β-treated NRK-52E cells, EPI significantly decreased lipid droplet formation and extracellular matrix deposition without exerting notable cytotoxic effects.

Conclusions: Targeted inhibition of B56δ using EPI represents a promising adjunctive therapeutic strategy for CKD, effectively mitigating lipid dysmetabolism and fibrotic progression while demonstrating a favorable safety profile.

Introduction: Studies on the long-term outcomes of patients with predominant renal involvement and no significant extra-renal organ involvement in systemic light chain (AL) amyloidosis remain limited. Here we describe the outcomes of this population and examine the impact of the 1 year estimated glomerular filtration rate (eGFR) changes on mortality and renal survival.

Methods: Patients with predominant renal involvement in AL amyloidosis who were diagnosed at the National Clinical Research Center for Kidney Diseases of Jinling Hospital between 2010 and 2023 were included in this study. Medical records and follow-up data were collected. The primary endpoints, encompassing overall survival (OS) and renal survival, were analyzed using Kaplan-Meier and Cox regression.

Results: A total of 351 patients (median age 56, range 31-83; 53.3% male) were enrolled, with 86.9% having an eGFR >60 mL/min/1.73 m² and median 24-h proteinuria of 4.27 g/day. After a median follow-up of 60 months (range, 3-171 months), 65 patients (18.5%) were died and 60 (17.1%) had progressed to end-stage renal disease. The median OS was not reached, and the median renal survival was 157 months. The 5-year OS and renal survival were 83.7% and 86.5%, respectively. Patients achieving at least a hematological and renal very good partial response exhibit significantly better outcomes. Within the first year, an eGFR decline of ≥5 mL/min/1.73 m² (particularly ≥20 mL/min/1.73 m²) was associated with increased dialysis risk, while a decline of ≥20 mL/min/1.73 m² was independently linked to elevated mortality risk.

Conclusion: AL amyloidosis patients with predominant renal involvement have a relatively good prognosis and early eGFR decline has the potential value in prognostic assessment of renal AL amyloidosis.

Introduction: Renal angiomyolipomas (AMLs) are clonal tumors formed by the abnormal differentiation of transformed renal progenitor cells. However, the cytogenetic and malignant transformations of renal AMLs require further investigation. Makorin ring finger protein 1 (MKRN1), a transcriptional co-regulator and E3 ubiquitin ligase, may act as a tumor regulator that mediates tumor biological processes. Although it is known as a prognostic marker of renal cell carcinoma, hepatocellular carcinoma, and pancreatic adenocarcinoma, its expression and function in renal AMLs remain unclear. Therefore, we aimed to investigate the expression and function of MKRN1 in AML cells.

Methods: MKRN1 expression in AML tissues was evaluated by immunohistochemistry, Western blotting, and quantitative real-time PCR. To investigate the functional role of MKRN1 in AML, MKRN1 was overexpressed in AML cells, and cell proliferation was assessed using the Cell Counting Kit-8 assay. Proliferative activity was further confirmed by immunofluorescence staining of Ki-67. To elucidate the molecular mechanisms regulated by MKRN1, gene set enrichment analysis (GSEA) was performed on RNA sequencing data, and the identified signaling pathways were further validated by Western blotting analysis.

Results: MKRN1 expression was significantly lower in renal AML tissues than in para-tumorous tissues (p < 0.0001). MKRN1 overexpression notably inhibited the survival and proliferation of SV7 and UMB cells. GSEA and Western blotting analyses indicated that MKRN1 downregulates the ERK/MAPK signaling pathway. MKRN1 expression was correlated negatively with phosphorylated ERK (p-ERK) levels in clinical AML samples, which were significantly elevated. MKRN1 overexpression in AML cells reduced p-ERK expression.

Conclusion: This study demonstrates that MKRN1 mediates AML cell proliferation by regulating the ERK/MAPK signaling pathway. These findings suggest that MKRN1 plays a crucial role in AML progression and may serve as a potential diagnostic and therapeutic biomarker for AML.

[This corrects the article DOI: 10.1159/000540973.].

Introduction: Gut microbiota alterations had been implicated in the pathogenesis of IgA nephropathy (IgAN). However, how did the gut microbiota participated in the onset and development of IgAN was unclear. This study investigated the causal effects of gut microbiota on IgAN and identifies potential mediators, including lipids, inflammatory factors, metabolites, and immune cells.

Methods: Genome-wide association study (GWAS) data for gut microbiota, IgAN, and mediators were analyzed. Two-sample Mendelian randomization (MR) assessed the causal relationship between gut microbiota and IgAN, followed by two-step MR mediation analysis to identify indirect effects via mediators. Mediation effects were quantified using the coefficient product method.

Results: MR analysis identified six genera and one phylum of gut microbiota with potential causal linked to IgAN. Two-step MR revealed one lipid, two inflammatory factors, ten metabolites, and sixteen immune cell types as mediators. Specifically, Oscillospira, Clostridium innocuum group, and Actinobacteria exerted effected via IgD⁺CD24^- B cells, CD24 on IgD⁺CD38⁺ B cells, and CD4 on naïve CD4⁺ T cells, respectively.

Conclusion: Gut microbiota alterations could causally influence IgAN, with specific immune cell subsets mediating these effects. Specific subsets of B cells and T cells could be involved in the development of IgAN, which would need our attention in the future.

Introduction: Light chain cast nephropathy (LCCN) results from the coprecipitation of monoclonal light chains with Tamm-Horsfall protein (THP) within the distal nephron, which forms obstructive casts. Although previous studies have suggested that crystalline LCCN variants may develop independently of THP, the role of THP in classic LCCN remains unclear. We investigated THP involvement in diverse LCCN variants and compared the clinicopathological profiles and outcomes of THP-positive and THP-negative cohorts.

Methods: We retrospectively analyzed 32 patients with newly diagnosed multiple myeloma and biopsy-proven LCCN. Cases were classified as THP-positive (n = 19) or THP-negative (n = 13) based on THP immunohistochemical staining. Clinical, laboratory, and histopathological data were compared and supplemented by a proteomic analysis of cast composition using laser microdissection coupled with liquid chromatography-tandem mass spectrometry.

Results: Immunoreactive-negative THP LCCN, accounting for 40.6% (13/32) of the cohort, presented with significantly lower hemoglobin, higher serum creatinine, more frequent acute kidney injury (AKI), and greater dialysis dependence than their THP-immunoreactive-positive counterparts. Immunoreactive-negative THP patients exhibited exacerbated tubular atrophy, interstitial inflammation, and acute tubular injury. Mass spectrometry further confirmed that THP was undetectable in a portion of immunoreactive-negative THP casts. No significant between-group difference was observed in survival.

Conclusion: Immunoreactive-negative THP LCCN correlates with severe anemia, AKI requiring dialysis, and marked tubular damage. Therefore, immunohistochemical staining for THP should be carefully evaluated in patients with LCCN. Further exploration of the mechanisms underlying LCCN pathogenesis is warranted.

Introduction: Arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis (HD) patients, yet AVF dysfunction remains a prevalent complication in maintenance HD. The risk factors influencing AVF patency are not fully defined. This study aimed to identify key clinical predictors and develop a practical model for predicting AVF dysfunction in HD patients.

Methods: We retrospectively reviewed medical records of HD patients treated between January 1, 2020, and February 28, 2025, at the Hemodialysis Center of the People's Hospital of Baoan, Shenzhen. Demographic characteristics, history of cardiometabolic disease, and laboratory parameters were evaluated. A Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression model was used to select the most relevant predictors, followed by multivariate Cox proportional hazards regression to construct the final prediction model. Model discrimination was assessed using the concordance index (C-index), and internal validation was performed via bootstrap resampling.

Results: Among 439 patients (median age 53 years; 61.3% male), 46 (10.5%) developed AVF dysfunction over a median follow-up of 2.9 years. LASSO regression identified five variables - total protein, albumin, left ventricular ejection fraction (LVEF), history of hypertension, and history of heart disease - as the most predictive. In the multivariate Cox model, all five variables remained statistically significant: total protein (hazard ratio [HR]: 0.604; 95% confidence interval [CI]: 0.372-0.983), albumin (HR: 0.468; 95% CI: 0.225-0.969), LVEF (HR: 0.627; 95% CI: 0.522-0.753), history of hypertension (HR: 2.234; 95% CI: 1.086-4.598), and history of heart disease (HR: 1.950; 95% CI: 1.024-3.715). The final model yielded a C-index of 0.812 (95% CI: 0.753-0.871), with consistent performance in internal bootstrap validation.

Conclusion: This study identified five routinely available clinical variables as independent predictors of AVF dysfunction in HD patients and developed a nomogram with strong predictive accuracy. This tool may support early risk stratification and guide timely interventions to reduce AVF failure and improve dialysis efficacy.

Introduction: Drug-related problems (DRPs) are common in hemodialysis (HD) patients, but the impact of different healthcare delivery models on DRP prevalence, characteristics, and medication-related outcomes remains underexplored. This study aimed to investigate and compare DRP prevalence and characteristics among HD patients across two healthcare settings.

Methods: This prospective cross-sectional study involved adult chronic HD patients from hospital-based (with pharmacist-led medication management program) and nonhospital-based (without) ambulatory centers. Patients on temporary HD or who had language barrier were excluded. Clinical characteristics and DRP data, identified through structured clinical review and classified using Pharmaceutical Care Network Europe (version 9.0), were analyzed using descriptive statistics, Mann-Whitney U, and chi-square tests.

Results: A total of 76 hospital-based and 149 nonhospital-based patients were recruited with significant differences between settings observed. Nonhospital-based patients showed a markedly higher DRP burden (n = 145 [97.7%], 4.6 DRPs/patient) compared to hospital-based patients (n = 42 [55.3%], 0.8 DRPs/patient). DRPs categorized as "other" predominated the nonhospital-based group (n = 345 [50.2%], z = +5.296, p < 0.001, Bonferroni-adjusted) and were driven by nonclinical factors such as patient-related, patient transfer-related, and work processes (z = +5.904), with the majority of the DRPs associated with antihypertensive agents (n = 145, 21.0%). Conversely, treatment-effectiveness DRPs were significantly more prevalent than expected in the hospital-based group (n = 45 [67.2%], z = +5.159, p < 0.001, Bonferroni-adjusted) and were primarily due to clinical factors such as drug selection, drug form, dose, and duration that had direct effects on treatment (z = +5.904). Phosphate binders (n = 21, 31.3%) were the most common medication class associated with DRPs in this group.

Conclusion: This study demonstrates that variations across healthcare settings, compounded by frequent transitions of care, significantly influenced DRP prevalence and characteristics among the highly vulnerable HD patients. Structured support services such as pharmacist-led medication management program play a critical role in mitigating these risks and supporting patients through complex treatment pathways. These findings underscored the importance of addressing both system-level disparities and patient-level challenges, where future research should adopt mixed-method approaches to uncover the contextual drivers of DRPs and guide the development of sustainable, pharmacist-integrated care models that would improve medication safety across diverse dialysis settings.

Introduction: This study explores the potential of estimated glomerular filtration rate (eGFR) slope as a noninvasive marker for predicting renal survival and patient survival in myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody-associated glomerulonephritis (AAGN).

Methods: A total of 377 MPO-AAGN patients were included. Kaplan-Meier and Cox regression analyses were performed to assess the predictive value of eGFR slopes for renal survival and patient survival. Then, the models were validated by discrimination, calibration, and decision curve analysis.

Results: The eGFR slope (calculated using a linear mixed-effects model with baseline and follow-up eGFR values up to defined timepoints), higher with better renal recovery, had a median of 2.54 (IQR: 0.49-6.02) mL/min/1.73 m²/month for 3 months and 1.90 (IQR: -0.07-4.76) mL/min/1.73 m²/month for 1 year. Multivariate Cox regression identified baseline eGFR (HR = 0.96, 95% CI 0.95-0.98, p < 0.001) and the 3-month eGFR slope (HR = 0.79, 95% CI 0.75-0.85, p < 0.001) as independent protective factors for kidney failure. The model incorporating baseline eGFR and the 3-month eGFR slope outperformed existing risk scores for predicting renal survival. The prediction value of the eGFR slope for patient survival was also found. Both a 3-month eGFR slope >1 mL/min/1.73 m²/month (HR = 0.47, 95% CI 0.31-0.70, p < 0.001) and a 1-year eGFR slope >1 mL/min/1.73 m²/month (HR = 0.42, 95% CI 0.28-0.63, p < 0.001) were independent protective factors for patient survival. The prediction model with a 1-year eGFR slope showed a prediction ability similar to that of the classical model with kidney failure events.

Conclusion: eGFR slopes are valuable predictors of renal and patients' survival in MPO-AAGN, providing valuable prognostic information that could enhance risk stratification and clinical decision-making.

Introduction: This study aimed to investigate the interaction between the ABCG2 rs4148155 and SLC22A12 rs75786299 variants and their association with incident gout and nephrolithiasis in the Taiwanese population to better understand the genetic loci regulating hyperuricemia and their contribution to nephrolithiasis development.

Methods: This retrospective case-control study involved 35,280 adults from the Taiwan Precise Medicine Initiative database. We examined the prevalence of gout and ultrasound confirmed nephrolithiasis as the primary and secondary outcome. Logistic regression models were used to explore the associations between genetic variants, serum uric acid levels, incident gout, and nephrolithiasis.

Results: The frequencies of the rs4148155 variant and the rs75786299 variant were 63.2% and 3.7%, respectively. Among participants, 7,056 were gout, and 4,110 had nephrolithiasis. Multivariable odds ratios (ORs) for gout were 1.67 and 1.96 among rs4148155 and rs75786299 carriers, respectively (p = 0.01 and p < 0.001). For nephrolithiasis, the multivariable ORs were 1.1 and 1.11 for rs4148155 and rs75786299 carriers, respectively (p = 0.004 and p = 0.32). Sex-stratified analysis revealed an additive risk of gout and nephrolithiasis among carriers of these genetic variants, regardless of gender. Independent risk factors for nephrolithiasis included higher age, male gender, and the presence of gout, hypertension, and hyperlipidemia.

Conclusion: The study highlights a significant association between the rs4148155, rs75786299 variants and the development of gout and nephrolithiasis, indicating an additive risk among carriers. These findings support precision healthcare approaches for individuals with risk genetic variants to target hyperuricemia, gout, and systemic comorbidities, ultimately preventing nephrolithiasis.