Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disease, accounting for 5-10% of incident patients requiring kidney replacement therapy (KRT). Although most cases result from pathogenic variants in PKD1 (≈75%) or PKD2 (≈15%), clinical experience at a major academic hospital in Porto (ULSSJ), suggested a higher regional prevalence of ADPKD-PKD2, particularly involving the truncating variant PKD2 p.(Gln61*). This study aimed to characterize the clinical and genetic epidemiology of ADPKD in patients initiating KRT at ULSSJ, compare ADPKD-PKD1 with ADPKD-PKD2, and contrast local and national ADPKD prevalence among incident KRT patients. Nephrology reports for KRT initiation (NR-KRT) issued at ULSSJ from 1990 to 2023 were reviewed to identify ADPKD cases and extract demographic and clinical data. Genotypes were obtained from the Genetics Laboratory, Faculty of Medicine, University of Porto, or inferred through pedigree analysis. Next-generation sequencing was the first-tier genotyping test, with Sanger sequencing and multiplex ligation-dependent probe amplification for unresolved cases. National prevalence figures for ADPKD among incident KRT were retrieved from the Portuguese Society of Nephrology registry. Among 6791 NR-KRT reviewed, 426 ADPKD patients were identified. Genotyping information was available for 168 individuals (39.4%), including 101 (60.1%) with inferred genotypes. Among genetically resolved cases, 70.2% had ADPKD-PKD1 and 29.8% had ADPKD-PKD2. Mean age at KRT initiation was 54.5 years in ADPKD-PKD1 and 66.9 years in ADPKD-PKD2. The PKD2 p.(Gln61*) variant was present in 39 patients (23.2%). Between 2010 and 2023, ADPKD prevalence among incident KRT patients was 7.48% at ULSSJ versus 5.19% nationwide (p<0.0001). The prevalence of ADPKD among incident KRT patients at ULSSJ exceeded national rates. ADPKD-PKD1 was associated with earlier kidney failure compared to ADPKD-PKD2. PKD2 p.(Gln61*) variant was the most frequent pathogenic allele identified. Given historical patterns of Portuguese emigration, these findings likely have broader international clinical relevance.
Living kidney donation from older individuals is increasingly considered, yet, the long-term trajectories of kidney function and clinical outcomes remain insufficiently characterised. In particular, the impact of different commonly used estimation equations of the glomerular filtration rate (eGFR) on long-term risk assessment in older donors is unclear. We analyzed 131 living kidney donors aged ≥ 60 years at the time of donation with a median follow-up of 12 years. Renal function was assessed using the CKD-EPI, FAS, and BIS1 equations at baseline, one year post-donation, and at long-term follow-up. Outcomes included substantial long-term eGFR decline (> 40%), the annual eGFR change after year 1, perioperative complications, long-term comorbidities, donor mortality, and recipient outcomes. Renal function followed a consistent biphasic pattern across all equations, with an early decline after donation followed by long-term stability. 37.0% of the donors experienced an eGFR decline > 40%, 13.4% >50%). The proportion classified below clinically relevant eGFR thresholds varied substantially depending on the eGFR equation applied, particularly one year after donation. Chronological age, including ≥ 70 years, was not associated with accelerated long-term decline. Impaired renal adaptation at one year, baseline hypertension, higher body mass index, and female sex were independently associated with steeper long-term eGFR decline. Among donors with preserved long-term eGFR (≥ 45 mL/min/1.73 m²), albuminuria identified a subgroup with less favourable renal trajectories. Relevant perioperative complications were rare (2.3%). No donor required renal replacement therapy during follow-up. In carefully selected donors aged ≥ 60 years, living kidney donation is associated with stable long-term renal function and a low rate of clinically relevant eGFR decline. Long-term risk is primarily determined by biological and cardiometabolic factors rather than by age itself. The interpretation of post-donation kidney function is influenced by the estimation equation applied, highlighting the importance of longitudinal assessment rather than reliance on single threshold-based classifications. Eudra-CT 2012-003500-12.
Given the risk of antibody-mediated rejection, most kidney graft allocation systems define unacceptable antigens to prevent transplantation in the presence of donor-specific antibodies. Anti-HLA-C and anti-HLA-DP antibodies are often not included in these algorithms, including the French allocation system, despite growing evidence supporting their pathogenicity. In routine clinical practice, however, these antibodies are frequently considered by transplant teams when evaluating donor offers, creating a discrepancy between allocation scores and real-world access to transplantation. We aimed to evaluate the impact of this discrepancy on access to kidney transplantation. We conducted a retrospective study including 2160 patients registered on the kidney transplant waiting list at our centre between 2009 and 2018, in whom anti-HLA-C and anti-HLA-DP antibodies were systematically considered in clinical decision-making similarly to other HLA antibodies. Anti-HLA-C/DP antibodies were detected in 325 patients (15.1%). Incorporating these antibodies into cPRA calculations resulted in a near-systematic increase in cPRA values (mean increase, 5.5 ± 11.3). Using relative loss of graft access (RLGA), 83.5% of patients experienced reduced estimated access to transplantation, including 21.5% who lost more than 75% of their access. Patients harbouring anti-HLA-C/DP antibodies also exhibited significantly reduced access to kidney transplantation in both univariable and multivariable analyses (HR = 0.52; 95% CI, 0.42-0.66; p = 2 × 10-8), associated with higher immunological donor offer refusal rates (mean 25.7% vs. 1.8%, p < 2 × 10-16). In conclusion, excluding anti-HLA-C and anti-HLA-DP antibodies from allocation algorithms, despite their consideration in routine clinical decision-making, is associated with reduced access to kidney transplantation, and their integration could improve equity among transplant candidates.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors have emerged as diseasemodifying agents in chronic kidney disease (CKD), demonstrating consistent renoprotective effects in both diabetic and non-diabetic patients. Large randomized outcome trials have shown substantial reductions in clinically significant renal endpoints. Canagliflozin reduced the risk of end-stage kidney disease, doubling of serum creatinine, or renal death by 34% (hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.53-0.81) in the CREDENCE trial. Similarly, dapagliflozin reduced the risk of composite renal outcomes by 39% in DAPA-CKD (HR 0.61; 95% CI 0.51-0.72), with comparable benefits observed in non-diabetic CKD. These findings were further supported by the EMPA-KIDNEY trial, which demonstrated a 28% reduction in kidney disease progression or cardiovascular death with empagliflozin (HR 0.72; 95% CI 0.64- 0.82) across a broad range of baseline eGFR and albuminuria. Beyond their hemodynamic effects, including restoration of tubuloglomerular feedback and an early, reversible decline in eGFR, accumulating experimental and translational evidence indicates that SGLT2 inhibitors attenuate renal inflammation and fibrosis. These effects are mediated through metabolic reprogramming of proximal tubular cells, inhibition of NLRP3 inflammasome activation, improvement of mitochondrial function, and modulation of innate and adaptive immune responses. This review integrates clinical and mechanistic evidence to propose a hierarchical, time-dependent model in which early hemodynamic stabilization creates a permissive environment for sustained metabolic and immunomodulatory effects, ultimately preserving renal function over the long term. Limitations of the current evidence, including reliance on preclinical models and limited access to human kidney tissue, are also discussed.
Extensive literature has documented the psychological burden of chronic kidney disease and kidney failure. Psychological resilience, the ability to adapt to challenging life experiences, offers a critical lens for understanding the variability in how individuals experience and adapt to chronic medical conditions. We aimed to synthesize existing evidence that has explored resilience among patients with kidney diseases. This scoping review followed the JBI Scoping Review framework. Empirical studies that measured resilience with no time restriction were considered and resilience could be an exposure, outcome, or variable. Of the 4525 reports screened, 36 studies (33 observational, 3 interventional) from 11 countries that included 6028 patients met the inclusion criteria. Most studies focused on patients on hemodialysis (n = 30). Multiple studies reported that resilience was negatively correlated/associated with depression (n = 10), and anxiety (n = 7), as well as psychological vulnerabilities. A positive correlation between resilience and post-traumatic growth, coping, and mental well-being was reported. Higher resilience positively correlated with measures of physical health (health-related quality of life, frailty, and instrumental activities of daily living). Factors, such as religiosity, spirituality, health-promoting behaviors, social support, family functioning, and family resilience, were enablers of resilience. Three studies reported positive impacts of resilience-enhancing interventions. Lower resilience is associated with depression and other inferior psychological and physical outcomes in patients with kidney diseases. Psychological resilience is measurable and modifiable. Given the multifaceted and often debilitating nature of kidney diseases and kidney failure, we propose that resilience can help to improve patient outcomes.
Immunoglobulin A vasculitis with nephritis (IgAVN) is the most common form of secondary glomerulonephritis in children. Some individuals have acute kidney disease (AKD) early on in their illness. The purpose of this study was to examine the prognosis and clinicopathological characteristics of children with IgAVN complicated by AKD. Five medical centers in China provided data on pediatric patients with biopsy-proven IgAVN. The patients were divided into two groups: AKD group and non-AKD group, depending on whether AKD was present at disease onset. Clinical manifestations, laboratory findings, pathological characteristics, and prognostic outcomes were compared between the two groups. Among 1862 children with IgAVN, 213 (11.44%) presented with AKD. Compared to children in the non-AKD group, children in the AKD group had more severe clinical and pathological findings. Kaplan-Meier analysis revealed statistically significant differences in kidney survival among the three stages of AKD (χ² = 15.68, P < 0.0001), and showed that kidney survival in the AKD group was significantly lower than that in the non-AKD group (χ² = 14.75, P < 0.0001) over a median follow-up of 66 months. AKD was identified as an independent risk factor for progression to chronic kidney disease stage 5 (CKD 5) in both short-term (6 months) and long-term (five- and ten-year) follow-ups. The clinicopathological and pathological features are much more severe in IgAVN children with AKD. AKD is a significant risk factor for unfavorable short- and long-term outcomes in pediatric IgAVN.
Kidney stones represent a common urological disorder affecting approximately 14.8% of the global population, with calcium oxalate (CaOx) stones constituting nearly 80% of all cases. Recent studies have revealed a potential association between the gut microbiome and the risk of forming CaOx stones. Additionally, urinary microbiota has been implicated to influence stone development, although the relationship between urinary microbiota and urinary metabolites in patients with calcium oxalate kidney stones remains incompletely characterized. In this pilot cross-sectional study, we used 2bRAD sequencing for microbiome profiling (2bRAD-M) and liquid chromatography-mass spectrometry (LC-MS)-based metabolomics to characterize urinary microbial and metabolic features. We analyzed urine samples from a pilot cohort of 12 patients with calcium oxalate kidney stones and 10 healthy controls. Statistical analyses of microbial diversity and metabolomic profiles were conducted to explore between-group differences. To explore microbiome-metabolite associations, we performed Spearman correlation analysis with multiple-testing correction and provided stratified correlation heatmaps as supplementary analyses. This study is registered in the National Medical Research Registry filing system of China (https://www.medicalresearch.org.cn) (No. MR-37-23-016317). Compared with healthy controls, patients with calcium oxalate kidney stones showed exploratory differences in urinary microbial diversity and community composition. Shannon and Simpson diversity were nominally higher in the CaOx group but did not remain significant after multiple-testing correction. At the genus level, Lactobacillus showed a nominally lower relative abundance in the CaOx group, whereas Escherichia showed a nominally higher relative abundance; however, no genus remained significant after BH-FDR correction. Untargeted metabolomics identified 131 candidate metabolites using exploratory screening criteria of VIP > 1 and nominal P < 0.05, including 33 higher-abundance and 98 lower-abundance candidates in the CaOx group; however, no metabolite remained significant after BH-FDR correction. Microbiome-metabolome correlation analyses suggested exploratory association patterns but did not establish direct biological interactions. This pilot cross-sectional study describes exploratory voided urine-associated microbiome and metabolome profiles in patients with calcium oxalate kidney stones. The findings are hypothesis-generating and require validation in larger, multicenter, longitudinal studies with rigorous contamination-control strategies and paired urine, stone, and fecal sampling.
 OBJECTIVES: To evaluate the clinical associations of elevated serum IgG1 and to assess the utility of integrating IgG1 with IgG4 for patient stratification in IgG4-related disease (IgG4-RD). This retrospective study included 344 treatment-naïve IgG4-RD patients. Patients were first classified into elevated and non-elevated IgG1 groups based on the institutional laboratory upper limit of normal (ULN) (cutoff: 10.11 g/L). Subsequently, to explore distinct immunopathological phenotypes, patients were further stratified into four groups by integrating this IgG1 cutoff with an IgG1/IgG4 ratio cutoff of 1.0. Subgroup analyses were performed based on gender and the presence of lung, kidney, or liver involvement. Patients with elevated IgG1 (> 10.11 g/L, n = 137) were older, more frequently male, and had higher disease activity, more organ involvement, and increased lung, kidney, and liver involvement (all P < 0.05). They exhibited profound hypocomplementemia, with serum IgG1 levels showing strong negative correlations with both C3 (r = -0.43, P < 0.001) and C4 (r = -0.48, P < 0.001). Crucially, the most severe phenotype was defined by the "Elevated IgG1, non-IgG1-dominant" signature (IgG1 > 10.11 g/L and IgG1/IgG4 < 1.0). Subgroup analyses revealed exceptionally strong IgG1-complement correlations in males and in patients with kidney or liver involvement. Elevated serum IgG1 marks a severe IgG4-RD phenotype. The "Elevated IgG1, non-IgG1-dominant" serological signature specifically identifies a more severe phenotype, characterized by complement consumption and multi-organ injury. This composite marker may serve as a useful tool for risk stratification. Keypoints • Elevated serum IgG1 (>10.11 g/L) defines a severe IgG4-RD phenotype with higher disease activity, multi-organ involvement, and profound complement consumption. • A novel serological signature, "Elevated IgG1, non-IgG1-dominant" (IgG1>10.11 g/L and IgG1/IgG 4<1.0), identifies a more severe phenotype of IgG4-RD patients. • Serum IgG1 correlates strongly with hypocomplementemia, with exceptionally strong correlations in male patients and those with kidney or liver involvement.
The present study aimed to examine the association between oral microbiome alpha diversity and the severity of cardiovascular-kidney-metabolic (CKM) syndrome among US adults. Emerging evidence suggests that the oral microbiome may influence systemic cardiometabolic health; however, its relationship with integrated CKM syndrome remains unclear. We conducted a cross-sectional analysis of adults aged ≥20 years from the 2009 to 2012 National Health and Nutrition Examination Survey, a nationally representative survey of the US population, including participants with available oral microbiome data (n = 4834). Alpha diversity was assessed using observed amplicon sequence variants richness, Faith's phylogenetic diversity Shannon index, and Simpson index. CKM syndrome was classified into 5 stages (0-4), with advanced CKM defined as stages 3-4, representing subclinical or clinical cardiovascular disease and/or significant kidney involvement. Weighted multivariable logistic regression models were used to estimate odds ratios and 95% confidence intervals. Higher oral microbiome diversity was consistently associated with lower odds of advanced CKM. In fully adjusted models, each unit increase in observed amplicon sequence variants was associated with a 2% lower odds of advanced CKM (odds ratio = 0.98, 95% confidence interval = 0.97-1.00). Participants in the highest tertile of diversity had 10% to 12% lower odds of advanced CKM compared with the lowest tertile across diversity indices, with significant trends. Associations were consistent across demographic and clinical subgroups. Greater oral microbial diversity was inversely associated with advanced CKM syndrome in US adults. These findings support a potential association between oral microbial ecology and integrated cardiometabolic-renal health, although longitudinal and mechanistic studies are required to clarify temporality and causality.
urinary neutrophil gelatinase-associated lipocalin (uNGAL) has emerged as a promising biomarker in clinical settings for the differential diagnosis of acute kidney injury (AKI) in chronic liver disease (CLD). This prospective study aims to evaluate the efficiency of uNGAL in the differential diagnosis of AKI among patients with CLD and in predicting short-term mortality in this population. This prospective observational study was conducted from September 2021 to March 2024 at Kasturba Medical College, Manipal, among patients with AKI and CLD. The study was initiated after obtaining institutional ethics committee approval. Demographic and clinical data, including urine samples for NGAL analysis, were collected. Patients were followed for 90 days to record clinical outcomes.Results: Among the 188 CLD patients, 42.6% (N = 80) exhibited prerenal AKI, 41.5% (N = 78) were diagnosed with hepatorenal syndrome (HRS), and 16% (n = 30) were identified as having acute tubular necrosis (ATN). u-NGAL Cutoffs of 631 ng/ml distinguish HRS from ATN [AUC: 0.949, 95% C.I (0.895-1)], with a sensitivity of 92% and specificity of 93%, while 257 ng/ml and 236 ng/ml predict 30-day [AUC: 0.807, 95% C.I (0.740-0.875)] and 90-day [AUC: 0.809, 95% C.I (0.745-0.873)] mortality, respectively. Elevated alanine transaminase (ALT), Model for End-stage Liver Disease-sodium (MELD-Na), and uNGAL levels serve as independent predictors of mortality. Patients with uNGAL >236 ng/ml show higher 90-day mortality, underscoring uNGAL's diagnostic, and prognostic value in AKI. This study shows that uNGAL distinguishes HRS from ATN and serves as a valuable predictor of 30-day and 90-day mortality. Additionally, higher levels of ALT, MELD-Na score, and uNGAL were identified as independent risk factors for mortality.
Vascular endothelial growth factor (VEGF)-pathway inhibitors improve outcomes across solid tumors, but proteinuria, hypertension and kidney dysfunction can be difficult to translate into oncology decisions. Most abnormalities are manageable on-target toxicities; a smaller subset may signal glomerular microvascular injury or kidney-limited thrombotic microangiopathy, sometimes without overt hemolysis or thrombocytopenia. This narrative review synthesizes mechanistic, clinical, pharmacovigilance and biopsy-based evidence to support an oncology-facing approach to renal toxicity during VEGF/VEGF receptor (VEGFR) inhibition. We emphasize baseline renal assessment, longitudinal interpretation of proteinuria and blood pressure, exclusion of competing causes, earlier nephrology input when findings are progressive or treatment-relevant, and selective biopsy when histology may change continuation, dose reduction, interruption, switching or rechallenge. The framework is pragmatic and hypothesis-generating rather than guideline-level or prospectively validated, aiming to preserve effective anticancer therapy while avoiding delayed recognition of clinically meaningful glomerular injury.
Histoplasma capsulatum var. capsulatum is a thermally dimorphic fungus endemic in regions like the Midwestern USA, Africa, and Central/South America. It grows as a mold in the environment and as yeast in human tissues. The disease's severity and presentation depend mostly on the host's immunity. In immunocompromised individuals, it often causes progressive disseminated histoplasmosis (PDH), a severe systemic condition. PDH symptoms include pneumonia, enlarged spleen and liver, enteritis, pancytopenia, lymphadenopathy, skin and mucosal lesions, and joint pain, making the diagnosis a challenge. Though more described in Acquired Immunodeficiency Syndrome (AIDS) patients, PDH can also occur in kidney transplant (KT) recipients, although it is rare even in endemic areas. It can also complicate with acute kidney injury (AKI), graft loss, disease recurrence, hemophagocytic lymphohistiocytosis, and treatment toxicity. This review summarizes key aspects of PDH, including its epidemiology, pathophysiology, clinical and laboratorial features, diagnostic approaches, acute kidney injury, treatment options and prophylaxis among KT recipients with histoplasmosis.
Kidney transplantation greatly improves survival and quality of life for children and adolescents with kidney failure. However, it also brings psychological and social challenges, including anxiety, depression, and difficulties with adaptation. Families often face ongoing stress even after successful transplantation. Although qualitative studies have explored these issues, no systematic review has synthesized their findings. This study aims to fill that gap by reviewing qualitative research on the post-transplant experiences of children and adolescents, providing insights to support their psychosocial well-being. This was a systematic review of qualitative studies. Literature searches were conducted in PubMed, Web of Science, CINAHL, Embase, Scopus, ProQuest, China National Knowledge Infrastructure (CNKI), and Wanfang database. The search period was from the inception of the databases up to January 2025. This review was conducted in accordance with the Joanna Briggs Institute Manual for Evidence Synthesis for qualitative research. Two reviewers independently carried out the screening process and data extraction. Studies meeting the inclusion criteria were evaluated using the Joanna Briggs Institute's critical appraisal tool for qualitative studies. Thematic synthesis was performed following the approach outlined by Thomas and Harden. A total of ten descriptive themes were extracted from the included qualitative studies. Through a process of thematic synthesis, these were consolidated into three overarching analytical themes: (1) Rebirth and Transformation - capturing the personal growth, psychological adaptation, and evolving identity experienced by children and adolescents following kidney transplantation; (2) Facing Challenges - reflecting the physical, emotional, and social difficulties encountered during recovery and reintegration into daily life; and (3) Future Uncertainty and Lack of Support - highlighting ongoing concerns related to long-term health outcomes, fear of graft failure, and the perceived inadequacy of informational, and systemic support. Kidney transplantation offers children and adolescents a renewed chance at life, boosting their self-esteem and overall well-being. However, they often face considerable psychological stress, including anxiety about the future and limited support. To address these challenges, healthcare providers and social organizations must focus on their unique needs through comprehensive psychological assessments, identification of unmet needs, and strengthened collaboration among medical teams, families, and communities. PROSPERO: (CRD420250654624).
Obesity, hyperlipidemia, intensive immunosuppressive use, and hypertension have detrimental effects on vascular structure and function after renal replacement therapy. Pulse wave velocity (PWV) is the gold standard for evaluating arterial stiffness. We aimed to determine cardiovascular target organ damage in adolescent kidney transplant patients using noninvasive PWV measurements and to investigate the risk factors that influence it. T his study included 4 5 adolescent patients who had u ndergone renal replacement therapy between 1994 and 2020 at Ege University Children's Hospital. Cardiovascular evaluation included PWV and augmentation index (AIx@75) measurements, expressed as Z-scores adjusted for sex and height. Biochemical, demographic, and clinical data were compared with height-adjusted PWV Z-scores (PWV Z-height) and AIx@75. Twenty-four male and 21 female patients underwent transplantation at a mean age of 7.69±4.77 years. Systolic blood pressure (BP) Z-scores correlated significantly with PWV Z-height (ρ=0.56, P=0.001) and AIx@75 (ρ=0.29, P=0.049). Weak positive correlations were detected between PWV Z-height and triglyceride levels (ρ=0.45, P=0.02), mean arterial pressure (ρ=0.44, P=0.02), and C-reactive protein (ρ=0.42, P=0.04). Patients with higher AIx@75 (≥30) had significantly higher systolic BP Z-scores and PWV Z-height scores. Arterial stiffness indices did not differ by pretransplant dialysis modality. On multivariable linear regression, systolic BP Z-score was the only independent predictor of PWV Z-height (β=0.854, P<0.001). Posttransplant treatment of hypertension and hyperlipidemia is important to reduce cardiovascular burden in pediatric kidney transplant patients, highlighting the need for close monitoring and management of BP and lipid levels.
Escherichia coli O157:H7 is a non-invasive Shiga toxin (Stx)-producing pathogen that causes gastroenteritis and hemolytic uremic syndrome characterized by acute kidney injury. Stx binding to cells induces release of extracellular vesicles (EVs) containing the toxin. This study aimed to demonstrate the lethal effects of toxin-positive vesicles, and the importance of the Stx receptor, globotriaosylceramide (Gb3), for these effects. HeLa cells were stimulated with Stx2 to induce vesicle release. EVs < 450 nm were isolated and cytotoxicity confirmed. BALB/c mice were injected intravenously with Stx2 126 ng/kg, the same toxin concentration in Stx2-EVs or EVs without toxin. Mortality was significantly increased in mice challenged with Stx2-EVs (n = 8/8) compared to mice challenged with free Stx2 (n = 4/7). Urea levels were high, and kidney tubulointerstitial pathology and fibrinogen staining prominent in mice challenged with Stx2-EVs. Mice challenged with EVs alone (n = 7) remained unaffected. C57BL/6 mice and Gb3-negative littermates were injected with Stx2-EVs at toxin concentrations of 126 or 200 ng/kg. Gb3-negative mice (n = 9) injected with Stx2-EVs at both toxin concentrations were totally protected whereas wild-type mice developed disease, n = 2/4 at the lower and 4/5 at the higher toxin concentration. These mice remained unaffected by the same concentrations of free toxin (n = 10) suggesting that toxin delivered in vesicles was lethal. This study shows that Stx2 delivered systemically within EVs is lethal, causing severe kidney damage, and the Gb3 toxin receptor is crucial for disease induction by circulating Stx2-EVs.
This final analysis of a multicenter, prospective postmarketing surveillance study evaluated the safety of daprodustat in patients with chronic kidney disease anemia in routine clinical practice in Japan. Patients who initiated daprodustat between September 2020 and July 2022 were registered. The observation period was 52 weeks from treatment start or until discontinuation to assess overall safety, with an additional 52-week follow-up for cancer-related events. Of 1634 patients in the safety analysis set, adverse drug reactions (ADRs) occurred in 5.6% (4.8% not undergoing dialysis; 6.9% undergoing peritoneal dialysis; 6.6% undergoing hemodialysis) and serious ADRs in 2.2%. ADRs related to thromboembolism, hypertension, cardiovascular events, cancer, and retinal hemorrhage were reported in less than 1%, with no progression of autosomal dominant polycystic kidney disease. During follow-up, no increase in cancer-related events was observed. No new safety concerns were identified for daprodustat in the real-world setting in Japan. GSK study: 214119.
Hyperuricemia is prevalent in patients with chronic kidney disease (CKD) and diabetes mellitus (DM), but its prognostic significance in this population remains unclear. This study investigated the association between serum uric acid (SUA) levels and all-cause, cardiovascular, and cancer mortality in patients with DM and CKD. Using the National Health and Nutrition Examination Survey (NHANES) 1999-2010 data, adults with DM and CKD (estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m²) were stratified by SUA: <5, 5-7, 7-9, and > 9 mg/dL. Weighted Cox proportional hazards models assessed all-cause, cardiovascular disease (CVD), and cancer mortality after adjusting for body mass index (BMI), sex, age, race/ethnicity, high-density lipoprotein-cholesterol (HDL-C), systolic blood pressure, glycated hemoglobin (HbA1c), eGFR, and albumin. Stratified analyses were performed by glycemic control (HbA1c < 7% vs. ≥7%), kidney function (eGFR < 30 vs. ≥30 mL/min/1.73 m²), and CVD status. CVD status was incorporated as a covariate in multivariable models, and stratified analyses were additionally performed by CVD history. Among 672 participants (mean age 71.0 years, 41.8% male), after full multivariable adjustment including eGFR and albumin, SUA levels were not significantly associated with all-cause mortality in the overall cohort. SUA > 9 mg/dL was significantly associated with increased cancer mortality (Hazard ratio (HR) 8.77, 95% confidence interval (CI) 1.97-39.01, p = 0.005) and the composite CVD-or-cancer endpoint (HR 3.92, 95% CI 1.26-12.24, p = 0.019) compared with the 5-7 mg/dL reference group. Associations with all-cause and CVD mortality were attenuated after adjustment for eGFR and albumin and did not reach statistical significance in the overall cohort. Notably, among patients without established CVD at baseline, SUA > 9 mg/dL was significantly associated with CVD mortality (HR 7.63, 95% CI 1.16-50.40, p = 0.035). Associations were strongest in patients with HbA1c < 7% and eGFR ≥ 30 mL/min/1.73 m². Elevated SUA is independently associated with increased cancer mortality and the composite CVD-or-cancer endpoint in patients with DM and CKD. Among those without established CVD, SUA > 9 mg/dL confers a significantly elevated risk of CVD mortality, suggesting that SUA may serve as a potential risk marker. These findings are hypothesis-generating and support serum uric acid as a potential prognostic biomarker in this high-risk population; prospective studies with repeated SUA measurements and randomized trials are warranted to establish causality before clinical recommendations can be made.
Hypertension is a leading cause of cardio-kidney outcomes (CKO). However, distinct blood pressure (BP) phenotypes and their effect on CKO remain underexplored. This study aimed to evaluate the independent contributions of BP phenotypes to CKO. This prospective, population-based study included UK Biobank participants enrolled between 2006 and 2010 with baseline systolic BP ≥90 mm Hg and estimated glomerular filtration rate ≥60 mL/min per 1.73 m2, excluding those with prior chronic kidney disease and cardiovascular disease. Five BP phenotypes were constructed based on the 2017 American Heart Association hypertension criteria (≥130/80 mm Hg): normotension, systolic-diastolic hypertension, isolated systolic hypertension, isolated diastolic hypertension, and isolated low diastolic BP. The primary outcome was CKO, a composite of incident chronic kidney disease, 3-point major cardiovascular events, and all-cause mortality based on the International Classification of Diseases and Office of Population Censuses and Surveys Classification of Interventions and Procedures, Version 4, codes. Associations between BP phenotypes and CKO were evaluated using multivariable Cox proportional hazards models adjusted for demographic, lifestyle, and clinical covariates. Among 322 328 participants (mean age, 55.8±8.1 years; 42.5% men), 61 918 (19.2%) had normotension, 159 853 (49.6%) had systolic-diastolic hypertension, 43 939 (13.6%) had isolated systolic hypertension, 28 169 (8.7%) had isolated diastolic hypertension, and 28 339 (8.8%) had isolated low diastolic BP. Over a median follow-up of 13.6 years, 32 440 CKO events occurred. All BP phenotypes were associated with an increased CKO risk compared with normotension: isolated systolic hypertension (hazard ratio, 1.22 [95% CI, 1.17-1.27]), systolic-diastolic hypertension (hazard ratio, 1.21 [95% CI, 1.16-1.25]), isolated diastolic hypertension (hazard ratio, 1.11 [95% CI, 1.05-1.17]), and isolated low diastolic BP (hazard ratio, 1.10 [95% CI, 1.05-1.17]). Distinct BP phenotypes beyond absolute BP thresholds confer differential risks for CKO. Interventional studies are needed to evaluate strategies targeting combined systolic-diastolic phenotypes to reduce CKO risk.
Sepsis-associated acute kidney injury (SA-AKI) is a significant clinical challenge due to its prevalence in intensive care units. This study evaluated the diagnostic utility of serum miR-151a-3p for SA-AKI, aiming to provide new insights into early diagnosis and mechanistic research. Serum miR-151a-3p levels were determined via qRT-PCR and assessed for clinical correlations (Pearson correlation), risk association with SA-AKI (logistic regression), and diagnostic efficacy (ROC curve analysis). In vitro, the injury model was constructed by inducing TCMK-1 cells with LPS, and the miR-151a-3p mimic was transfected to observe its effects on inflammatory and oxidative stress. Finally, a binding relationship between miR-151a-3p and AKT3 was validated by employing both bioinformatics and dual-luciferase assay. In SA-AKI patients, miR-151a-3p was significantly decreased, and its expression level showed a significant negative correlation with disease severity and representative indicators of renal function. MiR-151a-3p is an independent protective factor for SA-AKI, with an AUC of 0.883 for predicting SA-AKI. In vitro experiments confirmed that overexpression of miR-151a-3p significantly alleviated LPS-induced inflammatory responses and oxidative stress damage. The dual-luciferase assay confirmed the binding relationship between AKT3 and miR-151a-3p. MiR-151a-3p is closely related to the severity of SA-AKI. It can be used as a potential biomarker for the early prediction of the occurrence of SA-AKI. Overexpression of miR-151a-3p alleviates LPS-induced renal tubular epithelial cell injury.
While insulin resistance (IR) and frailty are mechanistically intertwined via shared pathways of chronic inflammation and metabolic dysregulation, their synergistic impact on cardiovascular risk has yet to be fully elucidated. We aimed to evaluate the joint association of IR and frailty index (FI) with the risk of incident atherosclerotic cardiovascular disease (ASCVD) and major adverse cardiovascular events (MACE) in individuals with Cardiovascular-Kidney-Metabolic (CKM) syndrome stages 0-3. This study enrolled 259,714 and 2632 CKM syndrome stages 0-3 from the UK Biobank (UKB), and China Health and Retirement Longitudinal Study (CHARLS). Three IR-related indices, namely the triglyceride-glucose index (TyG), metabolic score for IR (METS-IR), and estimated glucose disposal rate (eGDR), were each combined with two frailty assessments, the FI and physical FI (PFI), yielding six composite IR-FI indices for analysis. In the UKB, MACE and ASCVD were the co-primary outcomes, with heart disease and stroke as secondary outcomes. In the CHARLS, the outcomes included CVD, heart disease, and stroke. Multivariate Cox proportional hazards models, restricted cubic spline analyses, Kaplan-Meier analyses and time-dependent receiver operating characteristic curves were employed to assess associations. Mediation analysis and functional proteomic enrichment provided a framework for exploring the potential biological mechanisms. In the UKB, elevated levels of the IR-FI were associated with increased risks of ASCVD and MACE, with consistent findings observed for CVD, heart disease, and stroke in the CHARLS. Significant positive nonlinear relationships were established for the METS-IR-FI and eGDR-FI regarding cardiovascular outcomes. Mediation analysis revealed that Creactive protein, neutrophils, and leucocyte partially mediated these associations (ratio range: 1.5-12%). Proteomic analyses identified Cytokine-cytokine receptor interaction as a primary regulatory hub, while leukocyte migration, chemotaxis, and neutrophil degranulation were characterized as the central pathological execution mechanisms in this process. The IR-FI are significantly associated with the incidence of cardiovascular events, an association that appears to be mediated through systemic inflammatory pathways. These novel integrated indices represent promising biomarkers for early screening and targeted clinical intervention among individuals with CKM syndrome stages 0-3.