Filippos Anagnostakis

BACKGROUND: Chronic kidney disease (CKD) is common and ranks among the leading causes of mortality and morbidity. This analysis aimed to present global CKD estimates using the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 to inform evidence-based policies for CKD identification and treatment. METHODS: This analysis focused on adults aged 20 years and older over the period 1990 to 2023, from 204 countries and territories. Data sources used were published literature, vital registration systems, kidney failure treatment registries, and household surveys. Estimates of CKD burden, including deaths, incidence, prevalence, and disability-adjusted life-years (DALYs), were produced using a Cause of Death Ensemble model and a Bayesian meta-regression analytical tool. A comparative risk assessment approach estimated the proportion of cardiovascular deaths attributable to impaired kidney function and estimated risk factors for CKD. FINDINGS: Globally, in 2023, 788 million (95% uncertainty interval 743-843) people aged 20 years and older were estimated to have CKD, up from 378 million (354-407) in 1990. The global age-standardised prevalence of CKD in adults was 14·2% (13·4-15·2), a relative rise of 3·5% (2·7-4·1) from 1990. The region with the highest age-standardised prevalence was north Africa and the Middle East (18·0%; 16·9-19·4). Most people had stage 1-3 CKD, with a combined prevalence of 13·9% (13·1-15·0). In 2023, CKD was the ninth leading cause of death globally, accounting for 1·48 million (1·30-1·65) deaths, and the 12th leading cause of DALYs, with an age-standardised DALY rate of 769·2 (691·8-857·4) per 100 000. Impaired kidney function as a risk factor accounted for 11·5% (8·4-14·5) of cardiovascular deaths. High fasting plasma glucose, body-mass index, and systolic blood pressure were all leading risk factors for CKD DALYs. INTERPRETATION: CKD is a major global health issue, with rising prevalence and increasing importance as a cause of death and as a risk factor for cardiovascular death. A better understating of aetiology, appropriate screening, and implementation programmes are needed to translate advances in CKD treatment into improved patient outcomes. FUNDING: Gates Foundation, Wellcome, US National Kidney Foundation, and US National Institute of Diabetes and Digestive and Kidney Diseases.

BACKGROUND: The global burden of sepsis, a life-threatening dysregulated host response to infection leading to organ dysfunction, remains challenging to quantify. We aimed to comprehensively estimate the global, regional, and national burden of sepsis, including the impact of the COVID-19 pandemic and underlying causes of sepsis-related deaths with co-occurring infectious syndromes. METHODS: We used multiple cause-of-death, hospital, minimally invasive tissue sampling, and linked death certificate and hospital record data representing 149 million deaths, covering 4290 location-years with mortality estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 to capture explicit and implicit sepsis cases and deaths. We estimated age-location-sex-specific fractions of sepsis-related deaths from 195 underlying causes of death and 22 infectious syndromes from 1990 to 2021 using binomial logistic regression models, and estimated sepsis-related deaths using GBD cause-specific mortality estimates. Using 250 million hospital admissions and 7·82 million deaths from hospital data, representing 1310 location-years, we modelled case fatality rates by use of binomial logistic regression, applied to sepsis death estimates to estimate sepsis incidence by age, location, and year. FINDINGS: In 2021, we estimated 166 million (95% uncertainty interval 135-201) sepsis cases and 21·4 million (20·3-22·5) all-cause sepsis-related deaths globally, representing 31·5% of total global deaths. Sepsis-related deaths decreased between 1990 and 2019, followed by a surge in 2020 and 2021. As of 2021, individuals aged 15 years and older experienced increases across incidence (230%) and mortality (26·3%) since 1990. Those aged 70 years and older had the highest sepsis-related mortality in 2021 (9·28 million [8·74-9·86] deaths). Sepsis-related deaths from infectious underlying causes decreased from 11·8 million (11·1-12·5) in 1990 to 8·34 million (7·72-9·01) in 2019, then increased by 86·4% to 15·5 million (14·7-16·4) in 2021. Sepsis-related mortality due to non-infectious underlying causes of death increased from 4·69 million (4·35-5·05) in 1990 to 5·81 million (5·40-6·25) in 2021; the leading non-infectious underlying causes of death with sepsis were stroke, chronic obstructive pulmonary disease, and cirrhosis. In 2021, bloodstream infections inclusive of HIV and malaria (3·08 million [2·83-3·35]) and lower respiratory infections inclusive of COVID-19 (11·33 million [1·20-1·47]) were the most prominent infectious syndromes complicating sepsis-related deaths from non-infectious underlying causes, representing a consistent trend since 1990. INTERPRETATION: The global burden of sepsis increased in 2020 and 2021, reversing progress from 1990. Sepsis incidence and mortality increased in people aged 15 years and older, especially those aged 70 years and older, and as a complication of non-infectious underlying causes of death such as stroke, primarily through bloodstream infections and lower respiratory infections. The global burden of sepsis is substantial, and sepsis is increasingly a complication of non-infectious causes of death. FUNDING: Gates Foundation, Wellcome Trust, and Department of Health and Social Care using UK aid funding managed by the Fleming Fund.

Abstract Understanding the genetic basis of biological aging in multi-organ systems is vital for elucidating age-related disease mechanisms and identifying therapeutic interventions. This study characterized the genetic architecture of the biological age gap (BAG) across nine human organ systems in 377,028 individuals of European ancestry from the UK Biobank. We discovered 393 genomic loci-BAG pairs (P-value<5×10 -8 ) linked to the brain, eye, cardiovascular, hepatic, immune, metabolic, musculoskeletal, pulmonary, and renal systems. We observed BAG-organ specificity and inter-organ connections. Genetic variants associated with the nine BAGs are predominantly specific to the respective organ system while exerting pleiotropic effects on traits linked to multiple organ systems. A gene-drug-disease network confirmed the involvement of the metabolic BAG-associated genes in drugs targeting various metabolic disorders. Genetic correlation analyses supported Cheverud’s Conjecture 1 – the genetic correlation between BAGs mirrors their phenotypic correlation. A causal network revealed potential causal effects linking chronic diseases (e.g., Alzheimer’s disease), body weight, and sleep duration to the BAG of multiple organ systems. Our findings shed light on promising therapeutic interventions to enhance human organ health within a complex multi-organ network, including lifestyle modifications and potential drug repositioning strategies for treating chronic diseases. All results are publicly available at https://labs-laboratory.com/medicine .

Multi-organ biological aging clocks across different organ systems have been shown to predict human disease and mortality. Here, we extend this multi-organ framework to plasma metabolomics, developing five organ-specific metabolome-based biological age gaps (MetBAGs) using 107 plasma non-derivatized metabolites from 274,247 UK Biobank participants. Our age prediction models achieve a mean absolute error of approximately 6 years (0.25<r < 0.42). Crucially, including composite metabolites (e.g. sums or ratios of raw metabolites) results in poor generalizability to independent test data due to multicollinearity. Genome-wide associations identify 405 MetBAG-locus pairs (P < 5 × 10−8/5). Using SBayesS, we estimate the SNP-based heritability (0.09< $${h}_{{SNP}}^{2}$$ < 0.18), negative selection signatures (−0.93 < S < −0.76), and polygenicity (0.001<Pi < 0.003) for the 5 MetBAGs. Genetic correlation and Mendelian randomization analyses reveal potential causal links between the 5 MetBAGs and cardiometabolic conditions (e.g., metabolic disorders and hypertension). Integrating multi-organ and multi-omics features improves disease category and mortality predictions. The 5 MetBAGs extend existing biological aging clocks to study human aging and disease across multiple biological scales. All results are publicly available at https://labs-laboratory.com/medicine/ . Aging affects multiple organs and tracking these changes could improve our understanding of disease risk. Here, the authors show that metabolomics-based organ-specific aging clocks can predict future risk of cardiometabolic disease and mortality.