Background:Patients with kidney failure undergoing maintenance hemodialysis suffer high rates of major adverse cardiovascular events(MACE) that are not accurately predicted by traditional cardiovascular risk models. There is an urgent need to identify novel, modifiable cardiovascular risk factors for these patients. Methods:We analyzed associations of 6287 circulating proteins with MACE among 1048 participants undergoing hemodialysis in the Chronic Renal Insufficiency Cohort(CRIC) (14-year follow-up) with validation in the Predictors of Arrhythmic and Cardiovascular Risk in End-Stage Renal Disease study(PACE) (7-year follow-up). In both cohorts, proteins were measured shortly after dialysis initiation and one year later. We compared protein-based risk models derived by elastic net regression to the Pooled Cohort Equations(PCE) optimized for these cohorts(Refit PCE), and to an Expanded Refit PCE that included Troponin T and N-terminal pro-B-type natriuretic peptide. Results:In CRIC, 149 proteins were associated with MACE at false discovery rate<0.05. Among 22 proteins significant at Bonferroni p<8×10 -6 , proteins that validated in PACE included Sushi von Willebrand factor type A EGF and pentraxin domain-containing protein 1(SVEP1), Complement component C7, R-spondin 4, Tenascin, Fibulin-3 and Fibulin-5. Complement pathways were prominent in network analyses. SVEP1 surpassed other markers by statistical significance, with CRIC HR per log 2 1.8 (p=2.1×10 -12 ) and HR per annual doubling 1.6 (p=6.8×10 -6 ). For 2-year MACE, AUC(95%CI) for SVEP1 alone was 0.72(0.59, 0.84) in CRIC, and 0.73(0.63, 0.81) in PACE. SVEP1 surpassed the Expanded Refit PCE in CRIC (0.61 (0.48, 0.73)) (p=0.038). In the pooled CRIC + PACE cohort, SVEP1 AUC(95%CI) (0.79(0.70, 0.88)) surpassed Refit PCE (0.61(0.51, 0.72)) (p=0.004). Conclusions:SVEP1, a 390 kDa protein unlikely to be renally cleared, surpassed over 6000 other proteins and by itself outperformed traditional clinical risk models in predicting MACE in two populations of patients undergoing maintenance hemodialysis. Future studies should provide mechanistic insights behind these findings. Key Points:Patients with kidney failure undergoing hemodialysis have 20-fold higher cardiovascular mortality compared to the general population, and conventional risk factors have low prognostic utility for these patients.By applying large-scale circulating proteomics in two independent hemodialysis cohorts, we have discovered >20 novel proteins that predict major adverse cardiovascular events(MACE).Sushi von Willebrand factor type A EGF and pentraxin domain-containing protein 1(SVEP1) surpassed >6000 individual proteins and clinical factors for predicting MACE.

BACKGROUND:Chronic kidney disease (CKD) is associated with cardiovascular disease (CVD). Exceptional parental longevity protects against CVD. We examined whether exceptional parental longevity modified the associations of kidney function and kidney aging with CVD in older adults. METHODS:We used data from LonGenity (2008-2023), a cohort of Ashkenazi Jewish adults aged 65-95, comparing the offspring of parents with exceptional longevity to the offspring of parents with usual survival. Exceptional longevity was defined as living beyond 95 years. Kidney function was estimated using glomerular filtration rate (eGFR); CKD was defined as eGFR < 60 mL/min/1.73m2. Kidney aging was assessed using kidney age gap-the difference between proteomic kidney age and chronological age. Logistic and Cox regression tested associations between eGFR and kidney aging with prevalent and incident CVD, respectively. Effect modification was tested using interaction terms and stratified analyses. RESULTS:Among 1180 participants (mean age 76 ± 7 years), 23% had CKD; median kidney age gap was -0.04 years (IQR: -0.67, 0.66); 15% had baseline CVD. eGFR and kidney aging were associated with prevalent CVD, but not incident CVD. Exceptional parental longevity did not modify the association of eGFR with prevalent or incident CVD. However, it did modify the association of kidney age gap with incident, but not prevalent, CVD. In the offspring of parents with exceptional longevity, higher kidney age gap was associated with increased incident CVD hazard (HR: 1.90; 95% CI: 1.23, 2.94), but not in the offspring of parents with usual survival (HR: 0.79 95% CI: 0.59, 1.05). CONCLUSIONS:Kidney age gap may reflect early CVD risk in biologically resilient populations, thus warranting prospective studies.

Abstract Fibrotic extracellular matrix (ECM) is not merely a structural scaffold but an instructive signaling interface that shapes epithelial cell state. However, the molecular cues by which matrix remodeling controls tubular metabolism during kidney fibrosis remain poorly defined. Here, we identify Fibulin-2 (FBLN2) as a fibroblast-derived matrix cue that transduces fibrotic ECM remodeling into tubular mitochondrial metabolic reprogramming. Using fibroblast-selective deletion of Smoothened (Smo) across distinct fibroblast subpopulations, we found that loss of fibroblast Smo preserved kidney function and attenuated fibrosis in mouse models of chronic kidney injury. Multi-omics profiling revealed coordinated remodeling of the fibrotic matrisome, highlighted by suppression of FBLN2, an ECM glycoprotein genetically linked to kidney function in humans. Mechanistically, FBLN2 engaged EGFR in tubular epithelial cells and activated EGFR-AKT signaling in a non-canonical ligand-like manner. This signaling axis suppressed acetyl-CoA acetyltransferase 1 (ACAT1), a mitochondrial regulator of fatty acid oxidation and amino acid metabolism. Disruption of fibroblast Smo-FBLN2 signaling restored ACAT1-dependent oxidative metabolism and reduced tubular fibrotic activation. Spatial lipidomics revealed compartment-specific lipid remodeling associated with altered mitochondrial fatty acid metabolism, including acylcarnitine and phospholipid changes linked to reduced fibrotic injury. Together, these findings define a Fibulin-2-EGFR-ACAT1 matrix-to-metabolism signaling axis that couples fibrotic ECM remodeling to tubular mitochondrial metabolism during kidney fibrosis.

Omega-3 polyunsaturated fatty acids (PUFAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), possess anti-inflammatory properties, yet their association with obesity-depression comorbidity remains unclear. This study investigated the association among US adults and explored underlying mechanisms. We performed a cross-sectional analysis of 4,423 individuals participating in the National Health and Nutrition Examination Survey (NHANES) 2003-2004 & 2011-2014. Serum fatty acids were quantified by gas chromatography. Obesity was defined using anthropometric criteria, and depression was assessed using the PHQ-9 or antidepressant use. Multivariable logistic regression estimated odds ratios (ORs) per standard deviation (SD) increase in PUFA levels. Mechanistic explore through network pharmacology identified potential pathways, which were examined using correlation analyses with inflammatory indices. Higher omega-3 PUFA levels were associated with lower odds of central obesity comorbid depression in females (OR: 0.82, 95% CI: 0.69-0.96) and older adults (OR: 0.79, 95% CI: 0.64-0.97). DHA was significantly associated with lower odds of central obesity (OR: 0.83, 95% CI: 0.73-0.95), depressive symptoms (OR: 0.88, 95% CI: 0.77-1.00), and their comorbidity (OR: 0.85, 95% CI: 0.74-0.98), whereas no significant associations were found for EPA. Mechanistic exploration implicated DHA in TNF and IL-17 signaling pathways, supported by inverse correlations with monocyte-to-HDL ratio (r: -0.138, P < 0.001) and lymphocyte-to-HDL ratio (r: -0.108, P < 0.001). In conclusion, serum DHA is inversely associated with obesity-depression comorbidity, with potential involvement of anti-inflammatory pathways. These findings underscore the potential of DHA for the management of obesity comorbid depression and the need for further interventional trials.

(18)Fluorine-Sodium Fluoride Positron Emission Tomography (F-18-NaF PET) allows for the detection of arterial micro-calcification, but its data on people with chronic kidney disease (CKD) is limited. This pilot study aimed to determine the optimal time to perform F-18-NaF PET static scan and to characterize arterial macro- and micro-calcification in CKD. In 7 patients with CKD stages 3b-4 and 3 non-CKD individuals, following the injection of F-18-NaF, an electrocardiogram-gated chest CT, a 30-min dynamic PET, and three 10-min static PET were acquired. Radiopharmaceutical uptake was quantified for regions including the lumbar spine and 4 aortic segments. Arterial macro-calcification was quantified using Agatston scoring and micro-calcification using tissue-to-background ratio (TBR; reference: right atrium). The standardized uptake value (SUV) in lumbar spine reached a steady state similar to 60 min after injection and was comparable at each time point between CKD and non-CKD (p: 0.58-0.92). Among CKD participants, 6 had macro-calcification in coronary arteries. Abdominal aorta had the greatest macro-calcification, and ascending aorta had the lowest TBRpeak. In the ascending aorta, macro-calcification negatively correlated with TBRpeak (rho = - 0.86, p = 0.01). In descending thoracic aorta, TBRpeak negatively correlated with serum calcium (rho = - 0.81, p = 0.03), and positively correlated with parathyroid hormone (rho = 0.93, p = 0.003) and thrombomodulin (rho = 0.79, p = 0.04). The optimal time for F-18-NaF PET static scan is similar to 60 min for people with and without CKD. Evaluation of macro- and micro-calcification in aorta revealed preliminary spatial patterns and their associated serum markers. Our findings help to establish technical specifications for image acquisition and analyses of F-18-NaF PET/CT in CKD.

We aimed to investigate the association of healthy diet scores (HDS), comprising major components (fruits and vegetables, soybean, fish, and sugar-sweetened beverages), with non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). In this cross-sectional study of 2,404 T2DM individuals aged 35-70 years, individuals with higher HDS (≥3 components) had a lower odds of NAFLD (adjusted odds ratio [OR]: 0.64; 95% confidence interval [CI]: 0.48, 0.84) and lower fatty liver index (FLI) levels (β: -4.70; 95% CI: -7.61, -1.79). Each one-component increase in HDS was associated with a 14% reduction in the odds of NAFLD (OR: 0.86; 95% CI: 0.75, 0.98) and a 1.95-unit reduction in FLI levels (β: -1.95; 95% CI: -3.21, -0.70). These results suggest that adherence to a higher HDS pattern may be protective against NAFLD in T2DM.

Immune-inflammatory deregulation in depression may contribute to elevated risk of subsequent mortality. While dietary omega-3 polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA), are known to confer neuroprotective effects for their anti-inflammatory properties, population-based evidence regarding their survival benefits and underlying mechanisms in depression remain scarce. This study aimed to investigate association between dietary omega-3 PUFAs and mortality risk in depressed individuals and identify immune-inflammatory mediation underlying mortality reductions. Totally, 6,782 depressed individuals aged 20 years and above in 10 cycles (1999–2018) of the National Health and Nutrition Examination Survey (NHANES) were analyzed. Omega-3 PUFAs intake (total and individual) was assessed through 24-hour dietary recalls. Cox proportional hazard models were used to calculated hazard ratios (HRs) and 95

More than 50% of patients with kidney failure undergoing maintenance hemodialysis die within 5 years, a fate unexplained by traditional risk factors. To identify biological risk factors, we analyze 6287 circulating proteins and mortality in 893 participants undergoing hemodialysis in the Chronic Renal Insufficiency Cohort (CRIC) and Predictors of Arrhythmic and Cardiovascular Risk in End-Stage Renal Disease (PACE) studies. Proteins are measured shortly after (incident period) and one year after (prevalent period) dialysis initiation. In CRIC prevalent period, Sushi von Willebrand factor type A EGF and pentraxin domain-containing protein 1(SVEP1), R-spondin 4, tetranectin and 24 other proteins attain Bonferroni significance (p < 7 × 10-6). At false discovery rate<0.05, 184 proteins are significant in CRIC; 123/184 remain significant after adjustment for covariates including those linked to inflammation. Pathways related to insulin-like growth factor are prominent. In the pooled CRIC + PACE cohort, prevalent time period, AUC(95%CI) for a 3-protein model of 5-year mortality is 0.826 (0.742, 0.896), compared to 0.629 (0.528, 0.722) for a Cohort Clinical model (p < 0.001). Adding the 3 proteins (SVEP1, R-spondin 4 and tetranectin) to the Cohort Clinical model significantly improves the AUC (p < 0.001). These biomarkers should be validated in future studies and their roles as potential disease mediators elucidated.

Objective: To evaluate the therapeutic potential of the curcumin analog J7 in protecting the liver and regulating glucose and lipid metabolism in rats with type 2 diabetes. Methods: Bioinformatics methods were used to identify signaling pathways linked to diabetic liver disease. Diabetic rats were treated with curcumin, low-dose J7, or high-dose J7, and liver function and fibrosis were assessed through biochemical analyses, histopathology, immunohistochemistry, and ELISA. Results: J7 administration significantly improved lisver function, reduced fibrosis, and regulated metabolic profiles in diabetic rats. J7 downregulated TGF-(31, NF-kappa B p65, and BAX, while upregulating BCL-2, showing superior effects to traditional curcumin in reducing TGF-(31 and inhibiting alpha-SMA expression. Conclusion: J7 demonstrates potential as a therapeutic agent for managing liver complications in type 2 diabetes, effectively attenuating liver fibrosis and regulating metabolism through the modulation of key signaling pathways and proteins. Plain Language Summary: Diabetes is a common condition that can cause serious problems in the liver, such as damage and scarring (fibrosis). These problems are linked to how the body handles sugar and fat. Right now, there are not many effective treatments for diabetes- related liver issues. Our study looked at a new drug called J7, which is based on curcumin, a natural compound found in turmeric, to see if it could help protect the liver and improve sugar and fat metabolism. We used a rat model of type 2 diabetes to test J7. Rats were given either curcumin, a low dose of J7, or a high dose of J7. We then measured how well their livers were working and examined their liver tissue under a microscope. We also looked at the levels of specific molecules in the liver that are involved in inflammation, scarring, and cell survival. We found that J7 worked better than regular curcumin. It reduced liver damage, improved how the liver handled sugar and fat, and lessened scarring. J7 achieved this by affecting certain biological pathways, like the TGF-(3/Smad pathway and NF-kappa B signaling, which are key players in liver damage and inflammation. These results suggest that J7 could be a promising new treatment for liver problems in people with diabetes. This study highlights the potential of improving natural compounds like curcumin to make them more effective as medicines. Further research is needed to explore how J7 might help people with diabetes and liver issues.

We aimed to characterize the underlying genetics of kidney stone disease (KSD) in an urban and diverse population using the Natera Renasight genetic panel. This was a single-center prospective study of high-risk KSD patients, defined as recurrent stone formers or those with a family history with KSD. Buccal saliva DNA samples were collected with the commercially available Natera Renasight genetic panel and were analyzed using next-generation sequencing. The panel assesses 385 kidney disease related genes, including 45 linked to KSD. One hundred eleven high-risk KSD patients were enrolled. The majority were female (56%) with a median age of 50 (IQR 39.5–59.5), compromising a diverse ethnic background with 62% Hispanic, 23% White and 11% Black. Patients had median 3 (IQR 2–5) lifetime stone episodes, and 41% had family history of KSD. Genetic analysis was possible for 105 patients (95%). Eight (8%) had positive tests with only one patient found to have a pathogenic mutation associated with KSD (SLC7A9, cystinuria). The other 7 positive tests included amyloidosis (TTR, N = 3), Alport syndrome (COL4A3, N = 2), polycystic kidney disease (PKD1, N = 1), and susceptibility to ESRD (APOL1, N = 1). Patients with positive tests were more likely to have chronic kidney disease (38% vs 5%, p < 0.01), gout (13% vs 1%, p = 0.02) and carbonate apatite stones (38% vs 7%, p < 0.01). Our study sheds light on genetic factors of KSD in a diverse patient population. The results suggest that KSD is unlikely monogenetic in nature, but is more likely due to a complex interplay of polygenetic and environmental influences. Genetic testing may be most useful in KSD patients with chronic kidney disease.