Background: High body mass index (BMI) is a major modifiable risk factor for chronic kidney disease (CKD), significantly contributing to its global burden. This study aimed to systematically evaluate the global burden of CKD attributable to high BMI from 1990 to 2021, identify demographic and regional variations, evaluate contributing risk factors, and project future trends through 2035.Methods: The population-based analysis utilized data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021, encompassing 204 countries and territories across 21 GBD regions. Age-standardized mortality rate (ASMR) and age-standardized disability-adjusted life years rate (ASDR) were assessed using percentage change (PC) and estimated annual percentage change (EAPC). Decomposition analysis quantified drivers of mortality and DALYs changes, while Bayesian age-period-cohort models projected future trends.Findings: From 1990 and 2021, the ASMR of CKD attributable to high BMI increased from 2.69 (95% UI: 1.37–4.14) to 5.06 (95% UI: 2.7–7.5) per 100,000, and the ASDR rose from 69.13 (95% UI: 35.06–106) to 122.08 (95% UI: 66.25–180.18) per 100,000. Projections estimate continued to increase by 2035, with ASMR reaching 5.81 (95% UI: 3.55–8.07) and ASDR 149.42 (95% UI: 99.45–199.39) per 100,000. Sex and age disparities were evident: males showed higher ASR increases and earlier onset of disease burden, while older females experienced a higher overall burden. Regionally, low- and low-middle SDI areas exhibited the most rapid burden escalation, while some high-income countries achieved burden reduction. Among the attributable etiologies, hypertension and type 2 diabetes mellitus (T2DM) were predominant, with hypertension more common in males (42.05%) and T2DM in females (43.71%).Conclusion: The global burden of CKD attributable to high BMI has risen markedly over the past three decades, with widening disparities by geography, age, and sex. The COVID-19 pandemic may have further complicated risk dynamics and data quality. These findings highlight an urgent need for globally coordinated, locally adapted prevention strategies, particularly targeting younger males and populations in low-SDI regions.

Renal interstitial fibrosis (RIF) is a hallmark pathological process in the progression of chronic kidney disease (CKD). However, effective therapies to ha

ATP-citrate lyase (ACLY) is a crucial cytosolic and nuclear enzyme that catalyzes the synthesis of acetyl-CoA from citrate, serving as a central metabolic node linking carbohydrate metabolism to de novo lipogenesis and histone acetylation. Accumulating evidence positions ACLY not merely as a metabolic enzyme but as a key pathogenic driver in various kidney diseases. This review systematically examines the multifaceted roles of ACLY in renal physiology and pathology. During development, ACLY is essential for nephron progenitor cell maintenance and nephrogenesis. In diabetic kidney disease, hyperglycemia upregulates and promotes nuclear translocation of ACLY, fueling histone acetylation and the transcription of pro-fibrotic genes, while also contributing to oxidative stress and lipid peroxidation. In obesity-related kidney injury, ACLY drives renal ectopic lipid accumulation and inflammation by providing substrates for adipogenic enzymes and inducing histone hyperacetylation. ACLY also promotes renal fibrosis in chronic kidney disease via pathways such as AKT/ACLY signaling. In clear cell renal cell carcinoma, ACLY expression is upregulated through HIF-2α/LPCAT1/FBXW7 and VHL/PPARγ axes, promoting lipid synthesis, tumor proliferation, and metastasis. Furthermore, ACLY activity influences hypocitraturia, a key factor in nephrolithiasis, and is upregulated in polycystic kidney disease, where its inhibition attenuates cystic growth. Given its central role across diverse renal pathologies, ACLY emerges as a promising therapeutic target. Several inhibitors, including bempedoic acid, SB-204990, and natural compounds, show potential in modulating ACLY activity. This review consolidates current knowledge on ACLY in kidney diseases, highlighting its mechanistic contributions, and underscoring its significant potential for diagnostic and therapeutic innovation.

Background: Microscopic polyangiitis (MPA), a severe antineutrophil cytoplasmic antibody associated vasculitis (ANCA-associated vasculitis, AAV), demonstrates strong clinical association with myeloperoxidase/perinuclear anti-neutrophilic cytoplasmic antibodies (MPO/P-ANCA). While genetic factors are known to contribute to MPA susceptibility, the potential roles of AKT signaling components remain incompletely characterized, with limited data available for AKT1 and even less for its homologous gene AKT2 in this specific disease context. Methods: This case-control analysis included 798 participants (202 MPA patients and 596 controls, the latter comprising 387 individuals from the 1,000 Genomes Project), with control groups pooled after confirmation of genetic homogeneity. Genotypes of seven single-nucleotidepolymorphisms (SNPs) (four in AKT1, three in AKT2) with divergent allele frequencies across populations were analyzed. Association analyses were conducted under multiple genetic models, with gene-level and set-based approaches employed to evaluate aggregate effects. Secondary analyses included haplotype reconstruction, SNP-SNP interaction testing, and functional characterization through expression quantitative trait locus (eQTL) mapping. Results: Specific AKT1 variants (rs2498786 and rs1130233) demonstrated significant associations with reduced MPA risk, particularly in P-ANCA-positive patients. Gene-level analyses revealed a strong association for the AKT1 gene set (OR = 0.884, P = 0.002) but not for AKT2. Haplotype analysis identified protective AKT1 haplotypes, while interaction testing revealed high-risk genotype combinations. eQTL analysis indicated that protective alleles correlate with enhanced AKT1 expression in immune-relevant tissues, suggesting a potential regulatory mechanism. Conclusions: AKT1 emerges from this study as a likely genetic contributor to MPA, with its influence potentially involving neutrophil regulatory functions and vascular maintenance. The consistent absence of association signals for AKT2 across all analytical approaches could be viewed as reinforcing the specificity of AKT1’s involvement. These insights help refine the genetic architecture of MPA and position AKT1 signaling as a candidate pathway for future therapeutic exploration.

Background: The PI3K–AKT–mTOR signaling pathway plays a central role in immune regulation and has been implicated in autoimmune diseases. However, the contribution of genetic variation within key components of this pathway to microscopic polyangiitis (MPA) remains incompletely understood. Methods: We conducted a genetic association study in a Chinese cohort including MPA patients and controls. Four single nucleotide polymorphisms (SNPs) within core genes of the PI3K–AKT–mTOR pathway (PIK3CA, AKT1, and MTOR) were analyzed. A cumulative genetic burden score was constructed by summing the number of risk alleles across loci. Participants were stratified into burden categories based on the distribution in controls. Logistic regression, trend analysis, and sensitivity analyses restricted to hospital-based controls were performed. Results: A high genetic burden within the PI3K-AKT-mTOR pathway was associated with increased susceptibility to MPA, with a significant linear trend across burden categories, whereas the intermediate burden group showed no significant association, suggesting a threshold-dependent effect. In sex−stratified analyses, associations appeared more evident among females, although a formal test for interaction did not indicate statistical significance. Analyses suggest a potential sex-related trend that warrants further investigation. Sensitivity analyses restricted to hospital-based controls yielded consistent results. Several common haplotypes spanning PIK3CA, AKT1, and MTOR were less frequent among patients, indicating potential protective effects. Pathway-level genetic burden was also associated with MPO-ANCA positivity. Single-variant analyses revealed generally concordant but modest effects. Conclusions: Genetic variation across selected core components of the PI3K--AKT--mTOR pathway may contribute to susceptibility to MPA. The observed patterns, including potential sex-related differences, should be interpreted cautiously and require validation in larger and independent cohorts. These findings highlight a potential pathway-level genetic architecture underlying MPA susceptibility.