Kidney Diseases最新文献

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

Introduction: The immunopathogenesis of IgA nephropathy (IgAN) involves mechanisms beyond B-cell dysregulation, yet the full spectrum and clinical relevance of peripheral immune alterations remain insufficiently defined.

Methods: Peripheral blood from 7 IgAN patients and 3 healthy controls was analyzed by 30-marker mass cytometry (CyTOF), revealing 22 immune clusters across lymphoid and myeloid lineages. Independent flow cytometry validated CyTOF findings in 50 IgAN patients and 10 controls. Group differences were assessed by Mann-Whitney U test and associations with clinical measures via Spearman correlation.

Results: CyTOF mapping revealed 22 immune clusters spanning lymphoid and myeloid lineages. Among these, two subsets showed a significant increase in IgAN: switched memory B cells (CD19⁺CD20⁺CD27⁺IgD^-CD38^low) (median 1.75% vs. 0.91%, p = 0.004) and CD56⁺ CD8⁺ TEMRA cells (CD3⁺CD8⁺CD45RA⁺CCR7^-CD56⁺) (median 1.66% vs. 0.21%, p = 0.02). These alterations were validated by flow cytometry in the independent cohort. Switched memory B-cell frequencies negatively correlated with serum C3 (p = 0.01) and positively correlated with proteinuria (p = 0.03) and Oxford T scores (p = 0.03), while CD56⁺ TEMRA frequencies correlated with serum creatinine (p = 0.02), uric acid (p = 0.03), and inversely with eGFR (p = 0.03).

Conclusions: Our study delineates a peripheral immune signature of IgAN characterized by enhanced B-cell activation and cytotoxic T-cell responses, reflecting a dual-axis immune imbalance that may shape disease progression. These findings refine current immunopathogenic models and may guide future therapeutic research.

Introduction: Although large randomized control trials have established the renal benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2is) in chronic kidney disease (CKD), real-world evidence in Chinese CKD populations remains scarce. Here we report a multicenter real-world retrospective cohort study of SGLT2i use in hospitalized CKD patients in China.

Methods: We enrolled 155,053 adults with CKD from the China Renal Data System (CRDS) databases (January 2002-January 2023). We included patients treated with SGLT2i for at least 3 months. SGLT2i users and nonusers were matched (1:2) using propensity score matching (PSM). The main outcomes included renal, safety, and clinical outcomes. Renal outcomes included the first occurrence of CKD progression, end-stage kidney disease (ESKD), or composite outcomes. Multivariable Cox regression models and cumulative incidence were estimated post-PSM.

Results: Overall, the core analysis included 1,477 SGLT2i users and 2,674 nonusers. The progression of CKD (HR 0.81, 95% confidence interval [CI] 0.69-0.95, p < 0.01), incidence of ESKD (HR 0.26, 95% CI 0.18-0.37, p < 0.001), and composite renal outcome (HR 0.68, 95% CI 0.59-0.77, p < 0.001) were significantly lower in the SGLT2i group compared to the non-SGLT2i group. Additionally, the SGLT2i group experienced lower rates of heart failure, stroke, transient ischemic attack, and severe hypoglycemia but a higher risk of acute pancreatitis compared to the non-SGLT2i group. Additionally, eGFR remains better preserved over 3 years in CKD patients treated with SGLT2i.

Conclusion: These findings suggest that SGLT2i offers substantial renal and cardiovascular benefits for Chinese CKD patients.

Introduction: IgA nephropathy (IgAN), the most common primary glomerulonephritis, often presents with advanced renal failure and end-stage renal disease at diagnosis. Till now, there remains a lack of reliable biomarkers for effectively assessing the progression risk of IgAN. Here, we propose lysyl oxidase (LOX), a marker of collagen cross-linking, as a potential biomarker for assessing fibrosis in IgAN.

Method: After evaluating the fibrosis degree by Masson staining, measuring LOX levels in serum and kidney tissues, and collecting clinical information, we analyzed the association between LOX and renal fibrosis. Logistic regression analysis was employed to identify significant variables, which were incorporated into a nomogram and machine-learning model.

Results: A total of 128 IgAN patients were enrolled in the study, of which 89 were included in the training cohort and 39 patients in the validation cohort. Serum LOX levels correlated with the area of renal fibrosis (r = 0.673, p < 0.001). ROC analysis of LOX showed an AUC of 0.793 and 0.785 with optimal cutoff values of 297.59 pg/mL and 395.02 pg/mL for the prediction of mild and moderate-to-severe renal fibrosis, respectively. The diagnostic nomogram model for predicting renal function decline within 3 years incorporated traditional clinical determinants along with the Oxford MEST histological score (model 1), achieving an AUC of 0.740 (95% CI: 0.565-0.914, p < 0.05). In contrast, a model (model 2) that combined traditional clinical determinants with LOX instead of the Oxford MEST histological score demonstrated improved predictive performance, yielding an AUC of 0.806 (95% CI: 0.655-0.956, p < 0.01).

Conclusions: Serum LOX has the potential to predict renal fibrosis in IgAN. When combined with traditional clinical indicators, it may enhance the prediction of IgAN prognosis.

Introduction: Conventional ultrafiltration (CUF) is employed during cardiopulmonary bypass to remove excess fluid and concentrate specific blood components. The study aimed to investigate the impact of CUF volume on postoperative cardiac surgery-associated acute kidney injury (CSA-AKI).

Methods: This single-center, retrospective study included adult patients undergoing on-pump cardiac surgery between 2018 and 2023. Patients were classified into four categories for comparative analysis: the none-CUF group and three groups according to tertiles of the weight-adjusted CUF volume (tertile 1, 0.1-15.2 mL/kg; tertile 2, 15.3-25.0 mL/kg; tertile 3, >25.0 mL/kg). The primary outcome was postoperative CSA-AKI according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria, and secondary outcomes included perioperative blood transfusion, pulmonary complications, chest drainage volume, urine output, hospital and ICU lengths of stay, and in-hospital mortality. The association between weight-adjusted CUF volume and patient outcomes was assessed by multivariable logistic regression model.

Results: A total of 22,403 patients were included and the incidence of CSA-AKI was 28.1%. Weight-adjusted CUF volume (per 10 mL/kg increase) was independently associated with higher risk of any-stage CSA-AKI (adjusted odds ratio [aOR], 1.25; 95% confidence interval [CI], 1.14-1.38; p < 0.001) and stage 2/3 CSA-AKI (aOR, 1.42; 95% CI, 1.22-1.66; p < 0.001). The restricted cubic splines model illustrated a nonlinear relationship between weight-adjusted CUF volume and any-stage CSA-AKI (p for nonlinearity 0.025), while a J-shaped relationship for stage 2/3 CSA-AKI (p for nonlinearity < 0.001). A higher CUF volume was associated with increased odds of prolonged mechanical ventilation (aOR, 1.38; 95% CI, 1.18-1.64; p < 0.001) and perioperative red blood cell (RBC) transfusion (aOR, 1.13; 95% CI, 1.03-1.25; p = 0.011).

Conclusion: Excess weight-adjusted CUF volume was significantly associated with increasing incidence of CSA-AKI and prolonged mechanical ventilation, but did not reduce the requirement for perioperative RBC transfusion. These findings highlight the cautious application of CUF in fluid management during cardiac surgery.

Background: IgA nephropathy (IgAN) is a common cause of renal failure among young people in China. The heterogeneity of the clinical and histological characteristics of this disease is predominant, which limits the development of targeted therapeutic drugs for different patient subgroups. In recent years, there has been increasing attention paid to the role of the complement system in the occurrence and development of IgAN, and the research and development of new drugs targeting complement components have made rapid progress. This article examines the connection between IgAN and the complement system, as well as the most recent advancements in the use of novel complement-targeted medications to treat IgAN.

Summary: This paper systematically summarizes the association between the complement system and IgAN, as well as the research advances in complement-targeted therapy. In terms of pathogenesis, the four-hit hypothesis states that complement system is involved in the development of IgAN. Among complement activation pathways, the alternative pathway serves as the dominant one, while other pathways also contribute to the renal injury process. In the field of targeted therapy, a variety of inhibitors targeting key components of the complement cascade have entered clinical trials, exhibiting variable therapeutic efficacies. At present, this therapeutic approach faces challenges such as difficulty in patient selection, unclear long-term efficacy and safety profiles, and high drug costs. It is still necessary to improve the therapeutic system by identifying beneficiary populations, developing biomarkers for monitoring drug responses, and supplementing large-scale clinical evidence.

Key messages: Complement-targeted therapy represents a promising novel approach for IgAN treatment, and overcoming current barriers is essential to facilitate the advancement of individualized precision therapy for the condition.

Introduction: During renal fibrosis, macrophages play a crucial role in multiple processes, such as initiating inflammation, mediating tissue repair, and promoting interstitial fibrosis. Macrophage polarization is a key determinant of their functional properties. This study aimed to investigate the roles and mechanism of macrophages with distinct phenotype in renal fibrosis.

Methods: We established unilateral ureteral obstruction and ischemia-reperfusion injury models using macrophage-specific Ucp2-KO mice induced by tamoxifen. Bone marrow-derived macrophages treated with TGF-β1 and IL-4 were used for in vitro experiments. We also employed a chimeric model via adoptive transfer of macrophages.

Results: We indicated that the energy metabolism pattern is a key factor during macrophage phenotypic switching. Specifically, uncoupling protein 2 (UCP2), a mitochondrial inner membrane protein, was found to regulate the metabolic profile of macrophages. Knockout of Ucp2 in macrophages led to reduced fatty acid oxidation, downregulation of M2 phenotype markers, and alleviation of renal fibrosis. Attenuation of renal interstitial fibrosis was observed in wild-type mice receiving Ucp2-deficient (Ucp2-KO) macrophages. In contrast, adoptive transfer of wild-type macrophages into Ucp2-KO mice resulted in a marked aggravation of renal fibrosis.

Conclusion: In summary, we identified UCP2 as a key regulator of macrophage metabolic reprogramming and a critical promoter of renal fibrosis, suggesting that targeting UCP2 represents a promising therapeutic strategy.

Introduction: Primary membranous nephropathy (PMN) is one of the leading causes of nephrotic syndrome in adults, but reliable prognostic assessment tools remain limited. Although traditional clinical parameters and serum anti-PLA2R antibodies constitute cornerstones of prognosis assessment, they fail to fully capture the heterogeneity of PMN treatment responses. Identification of multidimensional prognostic risk factors facilitates further guidance for treatment in PMN patients. This study aimed to identify novel urinary protein signatures predictive of clinical remission and delineate molecular subtypes associated with relapse.​.

Methods: We performed quantitative proteomic profiling on extracellular vesicles (uEVs) isolated from baseline urine samples of 86 biopsy-confirmed PMN patients using nanoflow high-performance liquid chromatography-tandem mass spectrometry (nanoHPLC-MS/MS). The primary endpoints were clinical remission (complete or partial remission) and time to clinical remission. A prognostic model was developed by screening 101 machine learning algorithms, with the final risk score derived from a random survival forest and stepwise Cox regression, internally validated via bootstrap resampling. Relapse-associated molecular subtypes were identified using nonnegative matrix factorization (NMF).

Results: During a median follow-up of 8 months (IQR: 3.4-18.5), 76.1% of patients achieved remission, with a median time to remission of 11.2 months (95% CI: 6.2-18.0). The four-protein risk model (PON1, ACTBL2, RDX, TPP1) effectively stratified patients into high- and low-risk groups (Harrell's C-index = 0.729). The combined model integrating this proteomic signature with clinical features (anti-PLA2R Ab, age, eGFR) demonstrated superior predictive performance (Harrell's C-index = 0.744) compared to the clinical-feature-only model (Harrell's C-index = 0.636). To improve clinical applicability, we developed a web-based interactive Shiny application for individualized risk prediction in PMN patients. Additionally, proteomic clustering identified three distinct molecular subtypes (PMN1-3), with subtype PMN2 emerging as an independent predictor of relapse (OR = 10.26, 95% CI: 1.68-81.97; p < 0.05).

Conclusion: The combined model incorporating four noninvasive urinary proteomic signatures and clinical characteristics significantly improved performance of predicting clinical remission in PMN patients compared to the clinical-feature-only model. Furthermore, molecular subtyping of the urinary proteome can identify patients at high risk for relapse. These findings provide a foundation for integrating advanced proteomics into personalized prognostic assessment for PMN patients, pending external validation in larger cohorts.

Introduction: Anemia is a common complication in patients undergoing peritoneal dialysis (PD), significantly impacting quality of life and increasing cardiovascular risk. Enarodustat, an oral hypoxia-inducible factor-prolyl hydroxylase inhibitor, has been developed for the treatment of anemia in chronic kidney disease (CKD) patients, but evidence for its use in PD patients is limited. This study aimed to evaluate the efficacy and safety of enarodustat in PD patients with anemia.

Methods: This was an open-label, multicenter, phase 3 trial. PD patients with anemia received enarodustat at an initial dose of 2 mg orally once daily for 4 weeks with dose adjustments every 4 weeks thereafter to achieve the target hemoglobin (Hb) range of 100-120 g/L. The primary efficacy endpoint was the mean Hb level and its 95% confidence interval (CI) during the evaluation period (weeks 20-24 or the end of the treatment). Secondary endpoints included several Hb and treatment-related parameters, as well as iron supplementation use. Exploratory endpoints assessed parameters related to red blood cell indices and iron metabolism.

Results: A total of 37 patients enrolled in this study, with a mean ± SD adherence of 99.21 ± 3.03%. The mean Hb level (95% CI) during the evaluation period was 110.50 g/L (95% CI: 107.72, 113.28), with 83.8% (31/37) patients achieving target Hb levels (≥100 and ≤120 g/L) during the evaluation period. The change from baseline in Hb level at week 4 was -3.1 g/L. Enarodustat improved iron-related parameters compared to baseline, including serum iron, total iron-binding capacity, transferrin, and hepcidin levels. Drug-related AEs occurred in 21.6% (8/37) of patients, with no grade 3 or higher drug-related AEs reported. Serious AEs occurred in 21.6% (8/37), none were considered related to enarodustat.

Conclusion: Enarodustat effectively maintained target Hb levels in PD patients with anemia, demonstrating favorable safety and tolerability. Its convenient once-daily oral dosing regimen may enhance patient adherence, highlighting its potential as a promising therapeutic option for anemia management in PD patients.

Introduction: Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease and is increasingly recognized to involve early and progressive tubulointerstitial injury. However, the key molecular drivers of this process and their therapeutic potential remain poorly defined.

Methods: We conducted an integrative analysis of three DKD transcriptomic datasets using weighted gene correlation network analysis and differential expression analysis, followed by single-cell RNA sequencing to localize candidate genes to specific renal cell types. Functional validation was performed using in vitro assays in HK-2 and THP-1 cells, in vivo DKD mouse models, and patient kidney tissue. A virtual screening approach was applied to identify candidate inhibitors.

Results: We identified CXCL6, a C-X-C motif chemokine, as a central hub gene selectively upregulated in tubular epithelial cells of DKD kidneys. Urinary CXCL6 levels strongly correlated with markers of renal dysfunction. Mechanistically, high-glucose-induced CXCL6 expression in tubular cells, promoting macrophage recruitment, polarization toward a pro-inflammatory phenotype, and increased cytokine release. Through virtual screening, we identified salvianolic acid B (Sal-B) as a putative CXCL6 inhibitor. Sal-B treatment suppressed CXCL6 secretion, macrophage infiltration, and inflammatory cytokine production in vitro.

Conclusion: Our study uncovers CXCL6 as a key mediator of tubulointerstitial inflammation in DKD, linking tubular injury to immune cell recruitment and cytokine-driven damage. Furthermore, we identify Sal-B as a promising therapeutic candidate targeting this newly characterized pathway, offering potential for diagnostic and therapeutic advancement in DKD.