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Disruptions in gut microbiome are implicated in cardiometabolic disorders and other health outcomes. Antibiotics are known gut microbiome disruptors, but their long-term consequences remain underexplored. Here we combined individual-level data from the Swedish Prescribed Drug Register with fecal metagenomes of 14,979 adults to examine the association between oral antibiotic use over 8 years and gut microbiome. In multivariable confounder-adjusted regression models, antibiotic use <1 year before fecal sampling was associated with the greatest reduction in species diversity, but significant associations were also observed for use 1-4 and 4-8 years earlier. Clindamycin, fluoroquinolones and flucloxacillin accounted for most of the associations with the abundance of individual species. Use of these antibiotics 4-8 years earlier was associated with altered abundance of 10-15% of the species studied; penicillin V, extended-spectrum penicillins and nitrofurantoin were associated with only a few species. Similar results were found comparing one antibiotic course 4-8 years before sampling versus none in the past 8 years. These findings indicate that antibiotics may have long-lasting consequences for the gut microbiome.

In response to Campbell and Cappuccio's comments, this letter clarifies and defends the appropriate use of spot-urine sodium estimates in population-level and exploratory analyses. The critique misrepresents key aspects of the study design and overstates the limitations of spot-urine equations. While acknowledging that these methods are unsuitable for precise individual assessment, they perform adequately for ranking individuals and examining population-level associations, as supported by extensive validation studies. The reported associations with metabolic traits were internally consistent, biologically plausible, and in agreement with findings from studies using 24-hour urine collections. Dismissing such analyses as "invalid" undermines constructive scientific dialogue and disregards the exploratory value of transparent, hypothesis-generating research.

INTRODUCTION: Evidence for gut-kidney interactions in early kidney disease is limited, particularly in community-dwelling adults with largely preserved kidney function. Here, we quantified links between gut microbiota and estimated glomerular filtration rate (eGFR) in two population-based Swedish cohorts.

METHODS: Deep shotgun metagenomics profiled fecal samples from 9788 adults in the Swedish CArdioPulmonary BioImage Study (SCAPIS) discovery cohort (mean age 58 ± 4 years; 52% women) and 2080 adults in the Malmö Offspring Study (MOS) replication cohort (mean age 40 ± 14 years; 52% women). Linear regression related the relative abundance of 494 metagenome-assembled species to the creatinine-based eGFR (by CKD-EPI equation), adjusting for demographics, albuminuria, cardiovascular risk factors and technical variables. Species passing false discovery rate under 0.05 in SCAPIS were tested in MOS for significant concordant direction. Functional enrichment linked eGFR-associated species to gut metabolic modules and plasma metabolites; partial Spearman correlations were used to assessed metabolite/species/eGFR relationships.

RESULTS: The alpha diversity showed a modest inverse association with eGFR across both cohorts. We identified 44 bacterial species consistently associated with eGFR in both cohorts, collectively explaining 7% of its variance. Enrichment analysis highlighted histidine and carnitine metabolism among the top three pathways involved. Their key products, trimethylamine N-oxide and imidazole propionate, were inversely related to eGFR, and a metabolite panel accounted for 51% of eGFR variation, underscoring metabolite-mediated microbial effects. Sensitivity analyses upheld these findings.

CONCLUSIONS: Gut microbial diversity and 44 reproducible species are independently linked to kidney function in community-dwelling adults. Enrichment of histidine and carnitine pathways and their circulating metabolites implicates microbial metabolism as a contributor to eGFR variability, suggesting tractable targets for early kidney protection.

INTRODUCTION: Acute kidney injury (AKI) criteria and staging are based on serum creatinine and urine output, but serum cystatin C performs better at estimating glomerular filtration rate (GFR) in critically ill patients. Accordingly, a cystatin C-based AKI staging system was developed and its performance studied in critically ill patients.

METHODS: AKI stages according to Kidney Disease: Improving Global Outcomes (KDIGO) creatinine criteria were converted to corresponding cystatin C-based stages using 14-day mortality in 9424 critically ill patients from 3 Swedish hospitals followed for 5.6 years (median interquartile range: 2.8-7.2). Model performance was evaluated using Cox regression on long-term mortality adjusted for age, gender, comorbidities, and unit type. An independent cohort (n = 434) was used for validation.

RESULTS: KDIGO stages corresponded to the following: Stage 1: increase in cystatin C 1.40 to 1.59 times baseline within 7 days or ≥ 0.44 mg/l within 48 hours; Stage 2: 1.60 to 2.09 times baseline; and Stage 3: above 2.10 times baseline or ≥ 2.80 mg/l. Cystatin C-based versus creatinine-based staging identified 11% more AKI and 10% more Stage 3. Patients reclassified to AKI by cystatin C from no AKI had a higher risk of death of 1.36 (1.24-1.49), whereas those reclassified vice versa had a lower risk 0.71 (0.56-0.91). These findings were consistent irrespective of infection status for 30-day mortality. In the validation cohort, reclassification to a higher stage by cystatin C was an independent predictor of increased risk of death.

CONCLUSION: In critically ill patients, cystatin C-based staging identified more AKI than KDIGO criteria, and these patients had increased short- and long-term mortality.

Despite the importance of the gut microbiome to health, the role of human genetic variation in shaping its composition remains poorly understood. Here we report genome-wide association analyses of harmonized metagenomic data from 16,017 adults in four Swedish population-based studies, with replication in 12,652 people from the Norwegian HUNT study. We identified variants in the OR51E1-OR51E2 locus, encoding sensors for microbiome-derived fatty acids, associated with microbial richness. We further identified 15 study-wide significant genetic associations (P < 5.4 × 10^-11) involving eight loci and 14 common bacterial species, of which 11 associations at six loci were replicated. The results confirm previously reported associations at LCT, ABO and FUT2, and provide evidence for new loci MUC12, CORO7-HMOX2, SLC5A11, FOXP1 and FUT3-FUT6, with supporting data from metabolomics and gene expression analyses. Our findings link gut microbial variation genetically to gastrointestinal functions, including enteroendocrine fatty acid sensing, bile composition and mucosal layer composition.

Introduction: Patients with chronic kidney disease (CKD) have an increased risk of cardiovascular morbidity. Circulating endostatin is associated with both cardiovascular morbidity and impaired kidney function in the general population, but the utility of endostatin as a prognostic marker for CKD progression and mortality in patients with CKD is not well studied. The aim was to study association between serum endostatin and mortality, and also kidney function decline in a cohort of CKD patients (Salford Kidney Study [SKS]). Methods: Analyses were performed on baseline and annual follow-up samples from 970 adults in the SKS cohort with CKD stage 3–5. Association with mortality was studied using Cox proportional hazard models adjusted for age, gender, systolic and diastolic blood pressure, smoking status, diabetes mellitus, prior cardiovascular disease, creatinine-based estimated glomerular filtration rate (eGFR), and urine protein-to-creatinine ratio (uPCR). Associations between endostatin and eGFR decline were studied with linear regression analyses. eGFR decline was defined as the percentage difference between baseline eGFR and follow-up eGFR (median follow-up, 6.2 years). Results: Median age of the cohort was 66 years, with a median eGFR of 30 mL/min/1.73 m2. Multivariate Cox regression models revealed an association between higher endostatin levels and mortality with adjustments for established cardiovascular risk factors (HR: 1.14; CI: 1.02–1.28; p = 0.02) but was attenuated and nonsignificant after adjustments for baseline eGFR and uPCR. Baseline levels of endostatin were associated with eGFR decline but were nonsignificant after adjustments for baseline eGFR and uPCR. Changes of endostatin concentrations during the study were significantly associated with eGFR decline in all models (regression coefficient 0.0023% decrease per month [95% confidence intervals 0.0012–0.0034, p < 0.001]). Conclusion: The clinical utility of plasma endostatin for risk prediction in CKD patients seems limited. Importantly, longitudinal changes of endostatin were significantly associated with eGFR decline. The clinical relevance of this warrants further studies. 

BACKGROUND: Studies examining the association of chronic kidney disease (CKD) with cancer risk have demonstrated conflicting results.

METHODS: This was an individual participant data meta-analysis including 54 international cohorts contributing to the CKD Prognosis Consortium. Included cohorts had data on albuminuria [urine albumin-to-creatinine ratio (ACR)], estimated glomerular filtration rate (eGFR), overall and site-specific cancer incidence, and established risk factors for cancer. Included participants were aged 18 years or older, without previous cancer or kidney failure.

RESULTS: Among 1,319,308 individuals, the incidence rate of overall cancer was 17.3 per 1000 person-years. Higher ACR was positively associated with cancer risk [adjusted hazard ratio 1.08 (95% CI 1.06-1.10) per 8-fold increase in ACR]. No association of eGFR with overall cancer risk was seen. For site-specific cancers, lower eGFR was associated with urological cancer and multiple myeloma, whereas higher ACR was associated with many cancer types (kidney, head/neck, colorectal, liver, pancreas, bile duct, stomach, larynx, lung, hemolymphatic, leukaemia, and multiple myeloma). Results were similar in a 1-year landmark analysis.

DISCUSSION: Albuminuria, but not necessarily eGFR, was independently associated with the subsequent risk of cancer. Our results warrant an investigation into mechanisms that explain the link between albuminuria and cancer.

IMPORTANCE: Estimated glomerular filtration rates (eGFRs) can differ according to whether creatinine or cystatin C is used for the eGFR calculation, but the prevalence and importance of these differences remain unclear.

OBJECTIVES: To evaluate the prevalence of a discordance between cystatin C-based eGFR (eGFRcys) and creatinine-based eGFR (eGFRcr), identify characteristics associated with greater discordance, and evaluate associations of discordance with adverse outcomes.

DATA SOURCES: Participants in the Chronic Kidney Disease Prognosis Consortium (CKD-PC).

STUDY SELECTION: Participants with concurrent cystatin C and creatinine measurements and clinical outcome measurement.

DATA EXTRACTION AND SYNTHESIS: Between April 2024 and August 2025, data were synthesized using individual-level meta-analysis.

MAIN OUTCOMES AND MEASURES: The primary independent measurement was a large negative eGFR difference (eGFRdiff), defined as an eGFRcys that was at least 30% lower than eGFRcr. Secondary (dependent) outcomes included all-cause and cardiovascular mortality, atherosclerotic cardiovascular disease, heart failure, and kidney failure with replacement therapy.

RESULTS: A total of 821 327 individuals from 23 outpatient cohorts (mean [SD] age, 59 [12] years; 48% female; 13.5% with diabetes; 40% with hypertension) and 39 639 individuals from 2 inpatient cohorts (mean [SD] age, 67 [16] years; 31% female; 30% with diabetes; 72% with hypertension) were included. Among outpatient participants, 11% had a large negative eGFRdiff (range, 3%-50%). Among inpatients, 35% had a large negative eGFRdiff. Among outpatient participants, at a mean (SD) follow-up of 11 (4) years, a large negative eGFRdiff, compared with an eGFRdiff between -30% and 30%, was associated with higher rates of all-cause mortality (28.4 vs 16.8 per 1000 person-years [PY]; hazard ratio [HR], 1.69 [95% CI, 1.57-1.82]), cardiovascular mortality (6.1 vs 3.8 per 1000 PY; HR, 1.61 [95% CI, 1.48-1.76]), atherosclerotic cardiovascular disease (13.3 vs 9.8 per 1000 PY; HR, 1.35 [95% CI, 1.27-1.44]), heart failure (13.2 vs 8.6 per 1000 PY; HR, 1.54 [95% CI, 1.40-1.68]), and kidney failure with replacement therapy (2.7 vs 2.1 per 1000 PY; HR, 1.29 [95% CI, 1.13-1.47]).

CONCLUSIONS AND RELEVANCE: In the CKD-PC, 11% of outpatient participants and 35% of hospitalized patients had an eGFRcys that was at least 30% lower than their eGFRcr. In the outpatient setting, presence of eGFRcys at least 30% lower than eGFRcr was associated with significantly higher rates of all-cause mortality, cardiovascular events, and kidney failure.

CONTEXT: Type 2 diabetes is a growing global concern with serious complications, including kidney damage and cardiovascular morbidity and mortality. Monitoring albuminuria, which is associated with these complications, is crucial in optimal diabetes management. Gut microbiota composition has been suggested to impact albuminuria, but large studies with granular data are lacking.

METHODS: We investigated the relationship between 1002 gut microbial species, 1308 plasma metabolites and albuminuria in 752 participants with type 2 diabetes from the Swedish CArdioPulmonary BioImage Study. To determine the relative abundance of species, we employed deep shotgun metagenomic sequencing of fecal samples. Plasma metabolites were analyzed using mass spectrometry-based methods.

RESULTS: We identified three species that were associated with albuminuria, including Sellimonas intestinalis, Eggerthellales sp., Ellagibacter isourolithinifaciens. Two of these species were replicated in an independent pre-diabetic population (n=3,423) in SCAPIS. In total, 36 annotated metabolites were associated with the three albuminuria-signature species. Functional mapping of the signature species suggests a role in the regulation of the metabolites of imidazole propionate and trigonelline, which have previously been reported to play roles in the progression of albuminuria.

CONCLUSIONS: These findings provide additional evidence of the potential impact of microbial species and contribute to our understanding of the complex relationship between the gut microbiome, plasma metabolites, and albuminuria in individuals with diabetes.