Breast cancer is a leading cause of mortality and morbidity among females worldwide. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, we provided an updated comprehensive assessment of the epidemiological trends, disease burden, and risk factors associated with breast cancer globally, regionally, and nationally from 1990 to 2023. Breast cancer incidence, mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) were estimated by age and sex for 204 countries and territories from 1990 to 2023. Mortality estimates were generated using GBD Cause of Death Ensemble models, leveraging data from population-based cancer registration systems, vital registration systems, and verbal autopsies. Mortality-to-incidence ratios were calculated to derive both mortality and incidence estimates. Prevalence was calculated by combining incidence and modelled survival estimates. YLLs were established by multiplying age-specific deaths with the GBD standard life expectancy at the age of death. YLDs were estimated by applying disability weights to prevalence estimates. The sum of YLLs and YLDs equalled the number of DALYs. Breast cancer burden attributable to seven risk factors was examined through the comparative risk assessment framework. The GBD forecasting framework was used to forecast breast cancer incidence and mortality from 2024 to 2050. Age-standardised rates were calculated for each metric using the GBD 2023 world standard population. In 2023, there were an estimated 2·30 million (95% uncertainty interval [UI] 2·01 to 2·61) breast cancer incident cases, 764 000 deaths (672 000 to 854 000), and 24·1 million (21·3 to 27·5) DALYs among females globally. In the World Bank low-income group, where a low age-standardised incidence rate (ASIR) was estimated (44·2 per 100 000 person-years [31·2 to 58·4]), the age-standardised mortality rate (ASMR) was the highest (24·1 per 100 000 [16·8 to 31·9]). The highest ASIR was in the high-income group (75·7 per 100 000 [67·1 to 84·0]), and the lowest ASMR was in the upper-middle-income group (11·2 per 100 000 [10·2 to 12·3]). Between 1990 and 2023, the ASIR in the low-income group increased by 147·2% (38·1 to 271·7), compared with a 1·2% (-11·5 to 17·2) change in the high-income group. The ASMR decreased in the high-income group, changing by -29·9% (-33·6 to -25·9), but increased by 99·3% (12·5 to 202·9) in the low-income group. The increase in age-standardised DALY rates followed that of ASMRs. Risk factors such as dietary risks, tobacco use, and high fasting plasma glucose contributed to 28·3% (16·6 to 38·9) of breast cancer DALYs in 2023. The risk factors with a decrease in attributable DALYs between 1990 and 2023 were high alcohol use and tobacco. By 2050, the global incident cases of breast cancer among females were forecast to reach 3·56 million (2·29 to 4·83), with 1·37 million (0·841 to 2·02) deaths. The stable incidence and declining mortality rates of female breast cancer in high-income nations reflect success in screening, diagnosis, and treatment. In contrast, the concurrent rise in incidence and mortality in other regions signals health system deficits. Without effective interventions, many countries will fall short of the WHO Global Breast Cancer Initiative's ambitious target of achieving an annual reduction of 2·5% in age-standardised mortality rates by 2040. The mounting breast cancer burden, disproportionately affecting some of the world's most vulnerable populations, will further exacerbate health inequalities across the globe without decisive immediate action. Gates Foundation, St Jude Children's Research Hospital.
Podocyte injury and loss are pivotal early events in the development and progression of chronic kidney disease (CKD). As podocytes have a limited capacity for regeneration and proliferation, quantitative changes in podocyte number, size, and density are critical determinants of kidney health and disease. Experimental studies have shown that podocyte depletion alone is sufficient to induce albuminuria and glomerulosclerosis and that increased podocyte volume occurs in response to glomerular hypertrophy and various stresses on podocytes. These findings led to the emergence of podometrics (i.e., the quantitative assessment of podocyte number, size, density, glomerular volume, and podocyte loss rates in kidney tissue and urine). Although the clinical application of podometrics has long been limited by technical challenges, recent methodological advances have enabled reliable podometric analyses of human kidney specimens. Accumulating clinical evidence indicates that podocyte depletion is closely associated with aging, hypertension, and various kidney diseases and that podometrics provides prognostic information, including short-term therapeutic responsiveness and long-term kidney outcomes. In this article, we summarize recent advances in podometric methodologies and review the clinical and morphological factors associated with podometrics across life courses and disease states. We further introduce the concept of "nephro-podometrics", defined as the integrated quantitative assessment of podometrics and nephron-related parameters, including nephron number and single-nephron indices, within the same kidney. This framework maximizes the information obtainable from kidney specimens and provides a quantitative pathological platform that links structural changes to functional abnormalities, thereby supporting patient feedback and clinical decision making in nephrology.
To investigate whether the novel proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor Inclisiran exerts protective effects on the kidneys under high-glucose conditions, and to predict whether its mechanism involves the transforming growth factor-β (TGF-β) pathway using proteomic techniques, while constructing its regulatory network. Healthy male C57BL/6J mice were randomly assigned to four groups: Group A (control, n = 9), Group B (diabetes model, n = 9), Group C (diabetes + low-dose Inclisiran, n = 9), and Group D (diabetes + high-dose Inclisiran, n = 9). Groups B, C, and D were induced with type 2 diabetes using a high-fat diet combined with streptozotocin (STZ). Diabetes was confirmed by three consecutive days of fasting blood glucose levels > 16.7 mmol/L after modeling. The experiment ended 8 weeks after modeling. Renal tissue changes were evaluated using hematoxylin-eosin (HE) and periodic acid-Schiff (PAS) staining. Serum creatinine, low-density lipoprotein (LDL), cholesterol, and PCSK9 levels were measured, along with 24 h urinary protein-to-creatinine ratios. Renal tissue samples from Groups A, B, and D (4 mice per group) underwent transcriptomic sequencing to identify differentially expressed proteins. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were performed to assess the potential of Inclisiran to protect the kidneys via the TGF-β pathway. After modeling, blood glucose, urine protein/creatinine ratio, blood creatinine, cholesterol, and other indicators in groups B, C, and D were significantly higher than those in group A, with group B showing the highest values (P < 0.05). In the renal tissues of groups B, C, and D, focal tubular cell degeneration and mesangial proliferation were observed. The glomerular proliferation index in group B was significantly higher than in the other groups. Proteomics identified 1096 differentially expressed proteins (579 upregulated and 517 downregulated) between groups A and B, and 911 differentially expressed proteins (475 upregulated and 436 downregulated) between groups B and D. KEGG enrichment analysis showed that the TGF-β pathway was enriched in both the A-B and B-D group comparisons. There were 11 downregulated differentially expressed proteins (P45481: Crebbp, P70387: Hfe, Q61502: E2f5, Q62312: Tgfbr2, Q62432: Smad2, Q8BSK8: Rps6kb1, Q8BUN5: Smad3, Q8CG19: Ltbp1, Q9CUN6: Smurf1, Q9JKX3: Tfr2, Q9Z1M4: Rps6kb2) related to this pathway between groups B and D. Inclisiran may improve the lipid profile of type 2 diabetic mice and reduce the activity of the TGF-β pathway. Its mechanism of action may be related to effects such as extracellular matrix proliferation. 观察在高脂高糖环境下，新型前蛋白转化酶枯草溶菌素 9（proprotein convertase subtilisin/kexin type 9, PCSK9）抑制剂英克司兰对肾脏功能是否具有保护作用，利用蛋白组学技术预测其作用是否通过转化生长因子β（transforming growth factor-β, TGF-β）通路，并研究其调控机制网络。 取36只健康雄性C57BL/6J小鼠，随机分为A组（正常对照，n=9），B组（2型糖尿病模型，n=9），C组（糖尿病模型+小剂量英克司兰，n=9）及D组（糖尿病模型+大剂量英克司兰，n=9），其中B、C、D组均使用高脂饮食联合链脲佐菌素（streptozotocin, STZ）制备2型糖尿病模型，造模后3 d血糖持续大于16.7 mmol/L即为造模成功，造模后3 d C组、D组分别腹腔一次性注射英克司兰2 mg/kg及5 mg/kg，以成模后8周为实验观察终点。通过HE染色及PAS染色检测肾组织改变，检测血清标本中肌酐、低密度脂蛋白、胆固醇及PCSK9水平，检测24 h尿标本中尿蛋白/肌酐比值。在A、B、D组各选择4各小鼠肾组织样本进行转录组测序，筛选组间差异蛋白，综合KEGG、GO分析等分析评估英克司兰通过TGF-β起到对肾脏保护作用的可能性。 造模后，B、C、D组血糖、尿蛋白/肌酐比值、血肌酐、胆固醇等均明显高于A组，其中B组最高（P<0.05）；B、C、D组肾组织可见肾小管出现灶状小管细胞变性，系膜增生，B组肾小球增生指数明显高于其他各组。蛋白组学显示A-B组之间存在1096种（579种上调，517种下调）差异蛋白，B-D组之间存在911种（475种上调，436种下调）差异蛋白，KEGG富集分析显示在A-B组，B-D组之间均可富集到TGF-β通路。B-D组之间有11种下调的差异蛋白（P45481: Crebbp, P70387: Hfe, Q61502: E2f5, Q62312: Tgfbr2, Q62432: Smad2, Q8BSK8: Rps6kb1, Q8BUN5: Smad3, Q8CG19: Ltbp1, Q9CUN6: Smurf1, Q9JKX3: Tfr2, Q9Z1M4: Rps6kb2）与该通路相关。 英克司兰可能通过改善2型糖尿病小鼠血脂状况，抑制TGF-β通路活性，其作用机制可能与细胞外基质增生等效应有关。
Background and Objectives: Chronic kidney disease (CKD) is an increasingly important global health challenge and is frequently accompanied by psychiatric symptoms, including anxiety. A multidimensional assessment of anxiety in hemodialysis (HD) using the Endler Multidimensional Anxiety Scales (EMAS) has not, to our knowledge, been previously reported. We aim to evaluate the reliability, convergent validity, and exploratory domain-level structure of EMAS in HD patients treated at a dialysis center in Craiova, Romania. Materials and Methods: A total of 103 HD patients underwent clinical and sociodemographic/socioeconomic profiling, cognitive screening using the Mini-Mental State Examination (MMSE), and EMAS administration at two time points (4-week interval) for test-retest evaluation. The anxiety subscale of the Depression, Anxiety, and Stress Scale-21R (DASS-21R) was administered to assess convergent validity. Internal consistency (Cronbach's α), temporal stability (test-retest correlations and intraclass correlation coefficients), and convergent validity (Pearson correlations) were computed. Exploratory factor analyses were conducted on EMAS domain scores (state, trait, and perceived anxiety domains) as an exploratory structural check. Results: EMAS state and trait anxiety scores were higher in women than in men, while perceived anxiety showed a more heterogeneous pattern across dimensions. Total state anxiety increased with age, particularly after 50 years. Domain-level internal consistency was good for state and acceptable for trait components (standardized α ≈ 0.84 and 0.78 across administrations), whereas perceived anxiety domains showed low cross-domain coherence, consistent with context-specific appraisal. The DASS-21R anxiety subscale showed good internal consistency (α = 0.863). Convergent validity analyses indicated small, domain-specific associations between EMAS scores and DASS-21R anxiety. Domain-level EFA supported a theoretically coherent pattern in which state and trait domains clustered distinctly, while perceived anxiety domains formed a partially separable factor; this pattern was broadly consistent across both administrations. Conclusions: In this HD cohort, EMAS demonstrated good reliability and limited but domain-specific evidence of convergent validity, and exploratory domain-level analyses supported its multidimensional organization. Further studies with larger samples are warranted for item-level structural testing and to inform feasibility-oriented shortening for potential clinical use.
Background and Objectives: Chronic kidney disease (CKD) and maintenance hemodialysis (HD) are frequently associated with psychological distress and impaired health-related quality of life (HRQoL). However, the relationships between depressive, anxiety, and stress symptoms, clinical factors, and HRQoL remain insufficiently understood in routine care. This study aimed to assess the prevalence of psychological distress and to explore cross-sectional correlates of kidney disease-specific and generic HRQoL in Romanian patients receiving long-term HD, providing one of the first detailed characterizations of these relationships in an Eastern European maintenance HD cohort. Materials and Methods: This single-center cross-sectional study included 125 adult patients undergoing maintenance HD for at least one year. Baseline assessment comprised socioeconomic, demographic and clinical and paraclinical data, including Charlson Comorbidity Index (CCI), dialysis adequacy (spKt/V), cognitive function, psychological distress assessed with the Depression, Anxiety and Stress Scale (DASS-21R), and HRQoL evaluated using the Kidney Disease Quality of Life Short Form (KDQOL-SF™ 1.3). HRQoL domains and physical and mental component summary scores (PCS, MCS) were analyzed using descriptive statistics, correlation analyses, and multivariable linear regression. Follow-up assessments at approximately one year were summarized descriptively. Results: Disease-specific HRQoL revealed marked impairment in perceived disease burden and work status, while physical HRQoL was substantially reduced (PCS 36.5 ± 9.6). Mental HRQoL was relatively preserved (MCS 48.8 ± 8.8). At baseline, 48.0% of patients reported at least mild depressive symptoms, 34.4% anxiety symptoms, and 44.0% stress symptoms. spKt/V showed a modest association with PCS. Psychological distress demonstrated weak associations with HRQoL; stress was independently associated with lower MCS, with limited explained variance (R2 ≤ 0.15). Conclusions: Psychological distress is common among Romanian HD patients and is cross-sectionally associated with markedly impaired physical HRQoL. While the present design does not allow causal inferences, these findings support the implementation of routine psychological screening and the consideration of targeted psychosocial interventions in HD care.
In Japan, where the annual number of deceased donor kidney transplantation (DDKT) is limited, candidates typically wait about 15 years for transplantation, and many leave the waitlist before a graft becomes available. We investigated baseline factors that influence the chance of DDKT and the risk of dropout to guide individualized care. This retrospective single-center study included 1,050 candidates who were actively listed for DDKT between 1997 and 2024. Kaplan-Meier curves described time to DDKT and dropout. Independent predictors were identified with multivariable Cox proportional hazards models, with a focused analysis of adult solitary kidney candidates (n = 842). Transplant likelihood differed markedly across listing categories; only 8.6% of adult solitary kidney candidates received DDKT with a median wait of 18.7 years. In this group, HLA-A33 (HR:2.10, p = 0.0227), B62 (HR:2.20, p = 0.0127), B75 (HR:6.93, p = 0.0126), DR9 (HR:2.00, p = 0.0136) and DR15 (HR:2.47, p = 0.0005) increased the likelihood of DDKT, whereas prior transplantation trended toward lower likelihood (HR:0.14, p = 0.0530). Of 770 non-transplanted adult kidney candidates, 442 (57.4%) dropped out with a median of 8.4 years. Older age (HR:1.02 per year, p = 0.0017), diabetes mellitus as a primary renal disease (HR:1.39, p = 0.015) and peritoneal dialysis predicted dropout; hemodialysis was protective (HR:0.39, p < 0.0001). Our findings suggest that baseline clinical variables and HLA profiles could stratify Japanese DDKT candidates by both their likelihood of receiving DDKT and their risk of dropping out. Applying this risk prediction into practice may support more personalized planning, including earlier consideration of living donor kidney transplantation or intensified management for high-risk patients.
Although advanced age is no longer a contraindication for renal transplantation, real-world data on elderly transplant recipients remain limited. This multicenter, prospective study enrolled de novo kidney transplant recipients aged 60 years or older receiving once-daily tacrolimus immunosuppression, following recovery of renal function and referral to the transplant clinic. The primary objective was to describe clinical characteristics and post-transplant outcomes over a 12-month follow-up. Secondary objectives included assessing changes in quality of life and the relationship between biopsy-proven acute rejection (BPAR) and tacrolimus levels. Of 280 evaluable patients, 239 completed the 12-month follow-up (mean recipient age: 69.8 years; mean donor age: 69.1 years) and 41 (14.6%) terminated due to graft loss (13, 31.7%), tacrolimus termination (12, 29.3%), death (10, 24.4%), loss to follow-up (3, 7.3%), other (2, 4.9%), and temporary tacrolimus interruption (1, 2.4%). BPAR occurred in 8.2% of patients who showed significantly higher tacrolimus levels vs those without BPAR over the follow-up (9.8 ng/mL vs. 8.9 ng/mL; p = 0.01). Opportunistic infections were reported in 78.3% patients with BPAR vs 58.8% without BPAR (p = 0.07). Quality of life improved across different domains of the Kidney Transplant Questionnaire and the ESRD-SCL. This study monitored clinical outcomes during the first year post-transplant in older de novo kidney transplant recipients receiving grafts from older donors and under a once-daily tacrolimus-based immunosuppressive regimen. The incidence of BPAR, graft loss, and mortality was low, and patients generally experienced an improvement in quality of life, indicating an effective and safe procedure in this population.
Contrast-induced acute kidney injury (CIAKI) is a common complication after percutaneous coronary intervention (PCI) in type 2 diabetes mellitus (T2DM). The protective role of sodium-glucose co-transporter 2 inhibitors (SGLT2i) against CIAKI remains unclear. We aimed to evaluate the effects of SGLT2i using nationwide database analysis and experimental models. A nationwide nested case-control study using Taiwan's National Health Insurance Research Database assessed the association between SGLT2i use and risk of post-PCI dialysis. Parallel in vitro experiments examined dapagliflozin in iopamidol-treated HK-2 cells, and in vivo studies tested dapagliflozin in diabetic rats exposed to iopamidol. Clinically, SGLT2i use significantly reduced the risk of post-PCI dialysis (adjusted OR 0.33, 95% CI 0.14-0.76; p = 0.0094). In vitro, dapagliflozin attenuated iopamidol-induced cytotoxicity and NLRP3 inflammasome activation in HK-2 cells. In diabetic rats, dapagliflozin improved renal function, reduced tubular injury, and suppressed inflammasome-driven inflammation. In conclusion, SGLT2i protect against CIAKI by mitigating tubular injury and inflammasome activation. These findings highlight their potential as a preventive strategy for CIAKI in T2DM patients undergoing PCI.
Cardiorenal syndrome (CRS) is characterized by a bidirectional impairment of cardiac and renal function, associated with high mortality and limited effective therapeutic options. This study evaluated the cardiorenal protective effects of combined sodium-glucose cotransporter-2 inhibition (empagliflozin) and angiotensin receptor-neprilysin inhibition (sacubitril/valsartan) in an experimental model of CRS. Adult Sprague-Dawley rats were subjected to 5/6 nephrectomy and doxorubicin administration, followed by a high-protein diet to induce CRS. Animals were randomized to receive empagliflozin, sacubitril/valsartan, a combination of both agents, and no treatment for 60 days. Endpoints included survival, assessment of cardiorenal function, circulating biomarkers, histopathological analysis, and evaluation of signaling pathways implicated in fibrosis, oxidative stress, and inflammation. Combination therapy resulted in a 60-day survival rate of 89%, compared to 50% in untreated controls and 75%-78% with either monotherapy. All active treatments significantly preserved both cardiac and renal function, reduced levels of oxidized low-density lipoproteins, and attenuated interstitial fibrosis by inhibiting the TGF-β/Smad3 pathway. Furthermore, these therapies activated the AMPK-PGC-1α-SIRT1 signaling axis and suppressed angiotensin II/AT1 receptor signaling, resulting in decreased reactive oxygen species and inflammatory mediators, including NOX2, NOX4, IL-6, IL-1β, TNF-α, and phosphorylated NF-κB. Across all evaluated parameters, combination therapy consistently demonstrated the most pronounced protective effects. Collectively, these findings provide compelling preclinical evidence that concomitant administration of empagliflozin and sacubitril/valsartan confers superior cardiorenal protection and enhances survival in a rodent CRS model, supporting further clinical investigation of this combinatory therapeutic approach.
Ionized calcium (iCa) has physiological activity in the body; however, the direct measurement of iCa is technically limited. Although total serum calcium (tCa) and corrected serum calcium (cCa) using the Payne correction formula have been used to assess calcium levels, their limitations have been noted. We aimed to clarify the degree of correlation and dissociation among iCa, tCa, and cCa levels in patients undergoing hemodialysis. This cross-sectional study assessed the correlation between iCa, tCa, and cCa levels in patients undergoing hemodialysis. Factors involved in the correlation between iCa and tCa levels were evaluated using multiple regression analysis. Based on these results, we proposed a novel iCa prediction equation. Two hundred and thirteen patients were enrolled. The median patient age was 65 (standard deviation, 10.2) years, and 68.2% of patients were male. The correlation coefficients were 0.867 for iCa and tCa and 0.854 for iCa and cCa. Correlations were also observed when albumin concentrations and pH were divided, both of which are known correlation factors. In multiple regression analysis of the relationship between tCa and iCa, sex, pH, albumin, phosphate, and magnesium levels were significant factors. We established a new corrected calcium equation using age and albumin level: (mg/dL) = 0.828 × total calcium - 0.314 × albumin (g/dL) + 0.007 × age + 2.922. iCa, tCa, and cCa had a correlation in patients undergoing hemodialysis, with a stronger correlation with tCa in iCa assessments.
TAFRO syndrome (TAFRO) and POEMS syndrome (POEMS) are rare systemic inflammatory diseases with significant clinical, histological, and immunological overlaps with idiopathic multicentric Castleman disease (iMCD). While a high incidence of renal symptoms is observed in TAFRO and POEMS, the specific histopathological differences in their renal manifestations are not fully understood. This retrospective, multicenter study was conducted by the Japanese Renal Pathology Society (JRPS). Eighteen patients with TAFRO (n = 7), POEMS (n = 6), and iMCD (n = 5) were registered by members of the JRPS, and their clinicopathological findings were analyzed. Morphological examinations were performed using light, fluorescence, and electron microscopy. Immunohistochemical studies and semi-quantitative scoring systems have been used for detailed assessment of glomerular lesions. Clinical data indicated that the time from disease onset to biopsy was significantly shorter in TAFRO patients than POEMS patients. Although immunosuppressive therapy induced improvement in all TAFRO patients, some POEMS patients exhibited a poor renal prognosis. Glomerular endothelial injury was observed in both the TAFRO and POEMS; however, the characteristics differed: the former displayed endotheliosis, whereas the latter exhibited membranoproliferative glomerulonephritis (MPGN)-pattern injury. Laminated short-linear structures of the subendothelial space were observed in both the TAFRO and POEMS using electron microscopy. Morphological characteristics of the process of renal glomerular damage and repair in TAFRO and POEMS were revealed. The differences in endotheliosis and MPGN-pattern injury in these diseases may reflect differences in the timing of renal biopsy and the clinical course.
The nonsteroidal mineralocorticoid receptor antagonist finerenone has been reported to improve kidney and cardiovascular outcomes in persons with type 2 diabetes and chronic kidney disease (CKD). The efficacy and safety of finerenone in persons with type 1 diabetes and CKD are unknown. We conducted a phase 3 trial involving adults who had type 1 diabetes, CKD (estimated glomerular filtration rate [eGFR], 25 to <90 ml per minute per 1.73 m2 of body-surface area), and albuminuria (urinary albumin-to-creatinine ratio [with albumin measured in milligrams and creatinine measured in grams], 200 to <5000) and were receiving an angiotensin-converting-enzyme (ACE) inhibitor or an angiotensin-receptor blocker. Participants were randomly assigned to receive finerenone (10 or 20 mg per day, depending on the eGFR) or matching placebo. The primary outcome was the relative change in the urinary albumin-to-creatinine ratio over a period of 6 months. A total of 242 participants underwent randomization. The median urinary albumin-to-creatinine ratio decreased from 574.6 at baseline to 373.5 at 6 months among all the participants assigned to receive finerenone and from 506.4 to 475.6 among those assigned to receive placebo. Over a period of 6 months, the urinary albumin-to-creatinine ratio decreased by 34% with finerenone (geometric mean ratio to baseline, 0.66; 95% confidence interval [CI], 0.60 to 0.73) and 12% with placebo (geometric mean ratio to baseline, 0.88; 95% CI, 0.79 to 0.98), which corresponded to a 25% greater reduction with finerenone than with placebo (geometric mean ratio for finerenone vs. placebo, 0.75; 95% CI, 0.65 to 0.87; P<0.001). The most common adverse event was hyperkalemia (in 12 participants [10.1%] with finerenone and in 4 [3.3%] with placebo); 2 participants (1.7%) discontinued finerenone because of hyperkalemia. At 6 months, the change in the eGFR was -5.6 ml per minute per 1.73 m2 with finerenone and -2.7 ml per minute per 1.73 m2 with placebo (difference, -2.9 ml per minute per 1.73 m2; 95% CI, -5.1 to -0.7); eGFR values approached baseline levels during the washout period. In adults with type 1 diabetes and CKD, finerenone resulted in a significantly greater decrease in the urinary albumin-to-creatinine ratio than placebo. (Funded by Bayer; FINE-ONE ClinicalTrials.gov number, NCT05901831.).
Cisplatin nephrotoxicity involves oxidative stress, with NADPH oxidase 4 (NOX4) in renal tubular epithelial cells (RTECs) as a potential source of key reactive oxygen species (ROS). Although G protein-coupled receptor kinase 2 (GRK2) contributes to tissue injury, its regulatory role in cisplatin nephrotoxicity via NOX4 remains undefined. We have investigated the underlying mechanisms of GRK2 in cisplatin-induced acute and chronic nephrotoxicity. Hemizygous Grk2 knockout mice and homozygous Grk2 knockout RTECs were utilised. The GRK2-NOX4 interaction was investigated by co-immunoprecipitation or glutathione S-transferase pull-down. Kinase assays and ubiquitination experiments were performed to investigate the regulatory effect of GRK2 on the phosphorylation and ubiquitination of NOX4. Acute, sub-chronic and chronic cisplatin models, as well as syngeneic tumour models, evaluated the renoprotection afforded by the GRK2 inhibitor CP-25 and its impact on chemotherapy efficacy. Grk2 deficiency attenuated cisplatin-induced nephrotoxicity in vivo and reduced RTEC death and epithelial-mesenchymal transition (EMT) in vitro. Grk2 knockout or knockdown downregulated NOX4 expression, which repressed NOX4-mediated ROS release and oxidative stress, preventing cisplatin-induced RTEC death and EMT. GRK2 promoted NOX4 phosphorylation and suppressed ubiquitin-mediated degradation, thereby increasing NOX4 stability and ROS production. CP-25 effectively ameliorated cisplatin-induced nephrotoxicity, suppressed oxidative stress, and reduced renal apoptosis and EMT without compromising its anticancer efficacy. These protective effects also were observed in vitro. GRK2 plays a crucial role in cisplatin-induced nephrotoxicity by modulating NOX4, suggesting that targeting GRK2 is an effective renoprotective strategy for cisplatin-based cancer therapy.
Nephropathy 1 Formula (N1F), a traditional Chinese medicine (TCM), has demonstrated promising clinical efficacy in diabetic nephropathy (DN). However, its underlying protective mechanisms remain insufficiently defined. In this study, a type 2 diabetes mellitus (T2DM) mouse model was established using a high-fat diet (HFD) and streptozotocin (STZ). Additionally, DN was simulated in vitro via exposure of mouse glomerular mesangial cells (MES-13) to high glucose (HG) and trimethylamine-N-oxide (TMAO). To elucidate the mechanistic basis of N1F's renoprotective effects, an integrative approach combining metabolomics, transcriptomics, and 16S ribosomal ribonucleic acid (rRNA) gene sequencing was employed. N1F treatment reduced the urinary albumin-to-creatinine ratio (UACR), preserved renal function, and attenuated histopathological damage and renal fibrosis in diabetic mice. Mechanistically, N1F modulated systemic TMAO levels and energy metabolism, altered gut microbiota composition, and suppressed microbial production of TMAO-related metabolites. Under hyperglycemic conditions, TMAO induced excessive mitochondrial reactive oxygen species (mROS), impaired mitochondrial dynamics, and disrupted cellular energy metabolism. In contrast, N1F normalized mROS levels, restored mitochondrial structure and function, enhanced oxidative phosphorylation (OXPHOS), increased ATP production, and reduced glycolytic dependency. Furthermore, N1F downregulated the expression of key pyroptosis-related proteins-including NOD-like receptor family pyrin domain-containing 3 (NLRP3), N-terminal gasdermin D (GSDMD), cleaved-Casp1, interleukin-1β (IL-1β), and IL-18-in both in vivo and in vitro models, indicating suppression of pyroptosis via inhibition of the TMAO-mROS-NLRP3 signaling axis. Collectively, these findings demonstrate that N1F exerts protective effects against DN by targeting mitochondrial dysfunction and pyroptotic injury, supporting its potential as a therapeutic strategy for DN.
To investigate the factors influencing the occurrence of intermediate and long-term renal failure in patients with chronic kidney disease (CKD), to construct a risk prediction model, and to provide a reference for the timing of substitution therapy in these patients. A total of 354 patients who attended the Nephrology Department of Guizhou Medical University Hospital from January 2018 to July 2019 were used as the training set. The variables were screened using methods such as LASSO regression and the model was visualized using a nomogram. A total of 139 patients who attended the Department of Nephrology of the First People's Hospital of Bijie between November 2018 and June 2021 were used as an external validation cohort, and analyses were performed to verify the judgmental ability and clinical utility of the model. Multifactorial Cox regression analysis revealed that hypertension, mesangial proliferation, renal tubular atrophy, serum potassium, and estimated glomerular filtration rate were independent risk factors for renal failure. The 1-year AUC values of internal validation and external validation were 0.978 (0.970-0.984) and 0.919 (0.853-0.986), respectively. The 2-year AUCs were 0.945 (0.914-0.961) and 0.902 (0.822-0.982), respectively. The AUC values over three years were 0.933 (0.897-0.945) and 0.915 (0.846-0.985), respectively. The bias correction curves were close to the ideal curves and revealed a high degree of consistency between actual observations and predictions. We have developed a nomogram with excellent predictive power regarding the likelihood and time to progression to end-stage renal disease in CKD patients at 1, 2, and 3 years, which may help to classify patients and select the appropriate treatment plan in advance.
Periodontitis and chronic kidney disease (CKD) are inter-related conditions that can significantly impact patient health. This study aims to evaluate the efficacy of active non-surgical periodontal therapy (NSPT) combined with supportive periodontal care (SPC) in reducing tooth loss and improving masticatory function in patients with CKD and stage III periodontitis. This randomised controlled trial will recruit 86 patients diagnosed with both stage III periodontitis and CKD. Participants will be randomly assigned at a 1:1 ratio to either an experimental group receiving active NSPT supplemented with SPC or a control group receiving oral hygiene instruction with scheduled periodontal monitoring. The intervention will last for 24 months, with assessments conducted at baseline and 3, 6, 12, 18 and 24 months. The primary outcome is the incidence of tooth loss due to periodontitis over the 2-year follow-up period. Secondary outcomes include the number of lost teeth, masticatory function, clinical periodontal parameters and oral health-related quality of life. The study protocol and informed consent form were approved by the Institutional Ethics Committee of Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SH9H-2022-T404-1). Findings will be disseminated to participants and published in peer-reviewed journals. ChiCTR2300068923.
Single antigen (SA) tests are indispensable for an accurate HLA antibody identification in sera of transplant patients. Three commercial tests using purified single antigens combined with microbead or microarray technology are currently available. This study aims to determine the prognostic value of these tests prior to kidney transplantation. Forty-nine pretransplant sera with donor-specific antibodies (DSA) from patients who underwent kidney transplantation from a living donor were selected from a previous multicentre study. All sera were tested by a new microspot SA test from BAG and bead array SA assays from Immucor/Werfen (IMM) and One Lambda/ThermoFisher (OLI). AMR-free survival within 6 months (AMR-S) and 10-year death-censored graft survival (10yGS) were compared to DSA-negative patients from the original study and evaluated according to (1) number of SA tests classifying the serum as DSA-positive (DSA+), and (2) number of SA tests detecting at least one identical DSA specificity. In part (1), the 22 patients classified as DSA-positive by all tests had lowest AMR-S and 10yGS. OLI was most sensitive and classified all sera as DSA-positive that were DSA-positive by BAG and/or IMM. However, the 14 patients who were DSA-negative by both BAG and IMM, had similar AMR-S and 10yGS like patients without any DSA. Overall, BAG and IMM had comparable sensitivities. In part (2), at least one identical DSA was detected by all tests in 18 patients, who had worse AMR-S and 10yGS. In 14 patients, the same DSA was detected by IMM and OLI, or by BAG and OLI, respectively. These patients had lower AMR-S, but no significant difference in 10yGS. In 17 sera, DSA were detectable by one or more tests, but no specificity was positive in more than one assay (in all sera DSA were detected by OLI, in one additionally another DSA by IMM and in two another DSA by BAG). AMR-S and 10yGS were similar to DSA-negative patients. Overall, all three SA assays were suitable for the reliable detection of strong DSA. OLI was shown to be the most sensitive assay, but also prone to possible false positive results defined by the lack of an association with impaired outcomes. Future studies are needed to determine how many OLI-only reactions are caused by very weak DSA and how many by reactions with denatured beads. While such reactions were rare for BAG and IMM assays, these tests missed some DSA associated with an increased risk for AMR.
Real-world practice patterns of eosinophilic granulomatosis with polyangiitis (EGPA) remain poorly defined. This study aimed to describe current diagnostic and therapeutic approaches across experienced European centres, identifying areas of convergence and variability to inform future standardization of care. We distributed a 44-item online survey covering diagnostic evaluation, treatment strategies, patient-reported outcome measures (PROMs) and the role of patient advocacy groups. The survey was reviewed by an expert panel and disseminated within the European EGPA Study Group. Responses were collected anonymously between April and August 2025 for statistical analysis. Fifty-four experts from six countries participated, most with long-standing experience and substantial EGPA caseloads. Multidisciplinary care and screening for cardiac and renal involvement were widely adopted; histological confirmation was reported in fewer than 25% of cases. Treatment strategies varied considerably: over half of respondents initiated anti-IL-5 therapy at diagnosis, and the combination of glucocorticoids, rituximab and mepolizumab was the preferred induction regimen in severe disease. CS tapering protocols differed, with most clinicians targeting withdrawal within 12 months. PROMs and disease-specific questionnaires were used inconsistently, despite broad recognition of their value. Advocacy groups were viewed as crucial, particularly for patient education and referral. This first multinational survey reveals substantial heterogeneity in real-world diagnostic and therapeutic practice, reflecting gaps in validated criteria, standardized activity measures and treatment algorithms. These findings highlight the need for coordinated prospective research and harmonized evidence-based guidance to optimize outcomes for patients with EGPA.
Diabetic nephropathy (DN) remains a leading cause of end-stage kidney disease despite current therapies. Experimental data implicate Toll-like receptor 4 (TLR4) in DN pathogenesis; however, human evidence, particularly on histological severity and long-term outcomes, is limited. We hypothesized that renal TLR4 expression is correlated with tissue injury and adverse prognosis in DN. In 146 adults with biopsy-confirmed DN, we evaluated TLR4 expression in the glomeruli and proximal tubules using immunohistochemical staining. Histological injuries were scored according to the Renal Pathology Society classification. TLR4 expression was graded in the proximal tubular and glomerular epithelial cells. We subsequently investigated whether TLR4 expression is associated with kidney histological damage and whether it relates to renal prognosis. There was a significant difference in the severity of glomerular lesions across different levels of glomerular epithelial TLR4 expression. Additionally, the extent of interstitial fibrosis and tubular atrophy (IFTA) and interstitial inflammation significantly differed across different levels of proximal tubular TLR4 expression. Overall, TLR4 status did not predict kidney failure-free survival; however, among patients with IFTA < 50% (n = 63), moderate-to-severe tubular TLR4 expression was associated with worse survival than negative-to-mild expression (p = 0.021). In the low-IFTA subgroup, there were significant differences in systolic blood pressure, proteinuria, and total cholesterol levels across the levels of tubular TLR4 expression. These findings indicate possible involvement of TLR4 expression in histological injury and poor renal prognosis in DN, especially before the development of extensive fibrosis. TLR4 and its endogenous ligands are potential novel therapeutic targets for DN.
Long-term transitions in physical function among patients receiving hemodialysis remain poorly characterised. We aimed to describe 8-year trajectories of physical function and examine their associations with baseline dialysis duration and physical function status. This nationwide cohort study analysed data from 223,501 Japanese adults undergoing hemodialysis registered in the 2010 Japanese Society for Dialysis Therapy Renal Data Registry. Baseline dialysis duration was categorised as < 5, 5- < 10, 10- < 20, 20- < 30, or ≥ 30 years. Physical function at baseline was assessed using the Eastern Cooperative Oncology Group Performance Status and classified as non-frail, frail, or bedridden. Physical function at 8 years was categorised as non-frail, frail, bedridden, or deceased. Multinomial logistic regression estimated adjusted odds ratios, average marginal effects, and predicted probabilities. Over 8 years, 59.9% died, 8.8% became frail, 2.4% were bedridden, and 28.9% remained non-frail. Longer dialysis duration and baseline frailty or bedridden status were associated with higher odds of subsequent frailty, bedridden status, and mortality. Compared with patients with < 5 years of dialysis, those with ≥ 30 years had a 1.6% higher probability of frailty and a 13.2% higher probability of death. Compared with baseline non-frail status, frailty was associated with a 0.04% change in frailty and a 15.8% increase in death; bedridden status was associated with a 1.7% increase in being bedridden and a 26.0% increase in death. Long-term dialysis duration and baseline physical function strongly influence mortality, whereas absolute frailty progression is modest. These findings support early, values-based shared decision-making in dialysis care.