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Serum and Urine Metabolites and Kidney Function

Yeo, Wan-Jin; Surapaneni, Aditya L; Hasson, Denise; Schmidt, Insa M; Sekula, Peggy; Köttgen, Anna; Eckardt, Kai-Uwe; Rebholz, Casey M; Yu, Bing; Waikar, Sushrut S; Rhee, Eugene P; Schrauben, Sarah J; Feldman, Harold I; Vasan, Ramachandran S; Kimmel, Paul L; Coresh, Josef; Grams, Morgan E; Schlosser, Pascal
BACKGROUND:Metabolites represent a read-out of cellular processes underlying states of health and disease. METHODS:We evaluated cross-sectional and longitudinal associations between 1255 serum and 1398 urine known and unknown (denoted with "X" in name) metabolites (Metabolon HD4, 721 detected in both biofluids) and kidney function in 1612 participants of the Atherosclerosis Risk in Communities (ARIC) Study. All analyses were adjusted for clinical and demographic covariates, including for baseline eGFR and UACR in longitudinal analyses. RESULTS:At visit 5 of the ARIC study, the mean age of participants was 76 years (SD 6), 56% were women, mean eGFR was 62 ml/min/1.73m2 (SD 20), and median urine albumin-to-creatinine level (UACR) was 13 mg/g (IQR 25). In cross-sectional analysis, 675 serum and 542 urine metabolites were associated with eGFR (Bonferroni-corrected p < 4.0E-5 for serum analyses and p < 3.6E-5 for urine analyses), including 248 metabolites shared across biofluids. Fewer metabolites (75 serum and 91 urine metabolites, including 7 shared across biofluids) were cross-sectionally associated with albuminuria. Guanidinosuccinate, N2,N2-dimethylguanosine, hydroxy-N6,N6,N6-trimethyllysine, X-13844, and X-25422 were significantly associated with both eGFR and albuminuria. Over a mean follow-up of 6.6 years, serum mannose (HR 2.3 [1.6,3.2], p = 2.7E-5) and urine X-12117 (HR 1.7 [1.3,2.2], p = 1.9E-5) were risk factors for UACR doubling, whereas urine sebacate (HR 0.86 [0.80,0.92], p = 1.9E-5) was inversely associated. Compared to clinical characteristics alone, including the top 5 endogenous metabolites in serum and urine associated with longitudinal outcomes improved the outcome prediction (AUCs for eGFR decline: clinical model = 0.79, clinical + metabolites model = 0.87, p = 8.1E-6; for UACR doubling: clinical model = 0.66, clinical + metabolites model = 0.73, p = 2.9E-5). CONCLUSIONS:Metabolomic profiling in different biofluids provided distinct and potentially complementary insights into the biology and prognosis of kidney diseases.
PMID: 38844075
ISSN: 1533-3450
CID: 5665692

Proton Pump Inhibitors and CKD: The Evidence Builds

Grams, Morgan E; Wilson, F Perry
PMID: 38809613
ISSN: 1533-3450
CID: 5663602

Associations of Urine and Plasma Metabolites with Kidney Failure and Death in a CKD Cohort

Steinbrenner, Inga; Schultheiss, Ulla T; Bächle, Helena; Cheng, Yurong; Behning, Charlotte; Schmid, Matthias; Yeo, Wan-Jin; Yu, Bing; Grams, Morgan E; Schlosser, Pascal; Stockmann, Helena; Gronwald, Wolfram; Oefner, Peter J; Schaeffner, Elke; Eckardt, Kai-Uwe; Köttgen, Anna; Sekula, Peggy; ,
RATIONALE & OBJECTIVE/OBJECTIVE:Biomarkers that enable better identification of persons with chronic kidney disease (CKD) who are at higher risk for disease progression and adverse events are needed. This study sought to identify urine and plasma metabolites associated with progression of kidney disease. STUDY DESIGN/METHODS:Prospective metabolome-wide association study. SETTING & PARTICIPANTS/METHODS:Persons with CKD enrolled in the German CKD Study (GCKD) with metabolite measurements; with external validation within the Atherosclerosis Risk in Communities Study. EXPOSURES/METHODS:1,513 urine and 1,416 plasma metabolites (Metabolon, Inc.) measured at study entry using untargeted mass spectrometry. OUTCOMES/RESULTS:, or 40% decline in eGFR (CKE). Death from any cause was a secondary endpoint. After a median of 6.5 years follow-up, 500 persons experienced KF, 1,083 experienced CKE and 680 died. ANALYTICAL APPROACH/METHODS:Time-to-event analyses using multivariable proportional hazard regression models in a discovery-replication design, with external validation. RESULTS:5,088 GCKD participants were included in analyses of urine metabolites and 5,144 in analyses of plasma metabolites. Among 182 unique metabolites, 30 were significantly associated with KF, 49 with CKE, and 163 with death. The strongest association with KF was observed for plasma hydroxyasparagine (hazard ratio: 1.95, 95% confidence interval: 1.68-2.25). An unnamed metabolite measured in plasma and urine was significantly associated with KF, CKE, and death. External validation of the identified associations of metabolites with KF or CKE revealed direction-consistency for 88% of observed associations. Selected associations of 18 metabolites with study outcomes have not been previously reported. LIMITATIONS/CONCLUSIONS:Use of observational data and semi-quantitative metabolite measurements at a single time point. CONCLUSIONS:The observed associations between metabolites and KF, CKE or death in persons with CKD confirmed previously reported findings and also revealed several associations not previously described. These findings warrant confirmatory research in other study cohorts.
PMID: 38815646
ISSN: 1523-6838
CID: 5663792

Serum Metabolomic Markers of Protein-Rich Foods and Incident CKD: Results From the Atherosclerosis Risk in Communities Study

Bernard, Lauren; Chen, Jingsha; Kim, Hyunju; Wong, Kari E; Steffen, Lyn M; Yu, Bing; Boerwinkle, Eric; Levey, Andrew S; Grams, Morgan E; Rhee, Eugene P; Rebholz, Casey M
RATIONALE & OBJECTIVE/UNASSIGNED:While urine excretion of nitrogen estimates the total protein intake, biomarkers of specific dietary protein sources have been sparsely studied. Using untargeted metabolomics, this study aimed to identify serum metabolomic markers of 6 protein-rich foods and to examine whether dietary protein-related metabolites are associated with incident chronic kidney disease (CKD). STUDY DESIGN/UNASSIGNED:Prospective cohort study. SETTING & PARTICIPANTS/UNASSIGNED:A total of 3,726 participants from the Atherosclerosis Risk in Communities study without CKD at baseline. EXPOSURES/UNASSIGNED:Dietary intake of 6 protein-rich foods (fish, nuts, legumes, red and processed meat, eggs, and poultry), serum metabolites. OUTCOMES/UNASSIGNED:with ≥25% estimated glomerular filtration rate decline relative to visit 1, hospitalization or death related to CKD, or end-stage kidney disease). ANALYTICAL APPROACH/UNASSIGNED:Multivariable linear regression models estimated cross-sectional associations between protein-rich foods and serum metabolites. C statistics assessed the ability of the metabolites to improve the discrimination of highest versus lower 3 quartiles of intake of protein-rich foods beyond covariates (demographics, clinical factors, health behaviors, and the intake of nonprotein food groups). Cox regression models identified prospective associations between protein-related metabolites and incident CKD. RESULTS/UNASSIGNED:). LIMITATIONS/UNASSIGNED:Residual confounding and sample-storage duration. CONCLUSIONS/UNASSIGNED:We identified candidate biomarkers of fish, nuts, red and processed meat, eggs, and poultry. A fish-related metabolite, 1-docosahexaenoylglycerophosphocholine (22:6n3), was associated with a lower risk of CKD.
PMID: 38495599
ISSN: 2590-0595
CID: 5640042

Accuracy of GFR-estimating equations based on creatinine, cystatin C or both in routine care

Fu, Edouard L; Levey, Andrew S; Coresh, Josef; Grams, Morgan E; Faucon, Anne-Laure; Elinder, Carl-Gustaf; Dekker, Friedo W; Delanaye, Pierre; Inker, Lesley A; Carrero, Juan-Jesus
BACKGROUND AND HYPOTHESIS/OBJECTIVE:New equations to estimate GFR based on creatinine (eGFRcr), cystatin C (eGFRcys) or both (eGFRcr-cys) have been developed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and the European Kidney Function Consortium (EKFC). There is a need to evaluate the performance of these equations in diverse European settings to inform implementation decisions, especially among people with key comorbid conditions. METHODS:We performed a cross-sectional study including 6174 adults referred for single-point plasma clearance of iohexol in Stockholm, Sweden, with 9579 concurrent measurements of creatinine and cystatin C. We assessed the performance of the CKD-EPI 2009/2012/2021, EKFC 2021/2023, revised Lund-Malmö (RLM) 2011 and CAPA 2014 equations against measured GFR (mGFR). RESULTS:Mean age was 56 years, mGFR was 62 mL/min/1.73m2 and 40% were female. Comorbid conditions were common: cardiovascular disease (30%), liver disease (28%), diabetes (26%) and cancer (26%). All eGFRcr-cys equations had small bias and P30 close to 90%, and performed better than eGFRcr or eGFRcys equations. Among eGFRcr equations, CKD-EPI 2009 and CKD-EPI 2021 showed larger bias and lower P30 than EKFC 2021 and RLM. There were no meaningful differences in performance across eGFRcys equations. Findings were consistent across comorbid conditions, and eGFRcr-cys equations showed good performance in patients with liver disease, cancer and heart failure. CONCLUSIONS:In conclusion, eGFRcr-cys equations performed best, with minimal variation among equations in this Swedish cohort. The lower performance of CKD-EPI eGFRcr equations compared with EKFC and Lund-Malmö may reflect differences in population characteristics and mGFR methods. Implementing eGFRcr equations will require a trade-off between accuracy and uniformity across regions.
PMID: 37813817
ISSN: 1460-2385
CID: 5604822

Association of Estimated Glomerular Filtration Rate and Albuminuria with Venous Thromboembolism

Zheng, Zhong; Pandit, Krutika; Chang, Alex R; Shin, Jung-Im; Charytan, David M; Grams, Morgan E; Surapaneni, Aditya
BACKGROUND:Chronic kidney disease (CKD) has been implicated as a risk factor for venous thromboembolism, but the evidence is limited to relatively healthy populations. The objective of the current study was to discern whether parameters of kidney function and damage are associated with the occurrence of venous thromboembolism after hospitalization. METHODS:We conducted a retrospective study including 23,899 and 11,552 adult individuals hospitalized within Geisinger Health System and NYU Langone Health from 2004 to 2019 and 2012 to 2022, respectively. A Poisson model was used to evaluate adjusted incidence rates of venous thromboembolism according to estimated glomerular filtration rate (eGFR) and albuminuria categories in each cohort. Cox proportional hazards models were used to analyze associations of eGFR and urinary albumin to creatinine ratio (UACR) with venous thromboembolism and hazard ratios were meta-analyzed across cohorts. RESULTS:Both lower eGFR and higher UACR were associated with higher risks of venous thromboembolism. In the Geisinger cohort, the incidence of venous thromboembolism after hospital discharge ranged from 10.7 (95% CI 9.2 - 12.6) events per 1000 person-years in individuals in G1A1 (eGFR >90 mL/min/1.73 m2 and UACR <30 mg/g) to 27.7 (95% CI 20.6 - 37.2) events per 1000 person-years in individuals with G4-5A3 (eGFR <30 mL/min/1.73 m2 and UACR >300 mg/g). A similar pattern was observed in the NYU cohort. Meta-analyses of the two cohorts showed that every 10 mL/min/1.73m2 reduction in eGFR below 60 mL/min/1.73m2 was associated with a 6% higher risk of venous thromboembolism (HR 1.06 [1.02 - 1.11], P = 0.01), and each two-fold higher UACR was associated with a 5% higher risk of venous thromboembolism (HR 1.05 [1.03 - 1.07], P <0.001). CONCLUSIONS:Both eGFR and UACR were independently associated with higher risk of venous thromboembolism after hospitalization. The incidence rate was higher with greater severity of CKD.
PMID: 37971889
ISSN: 1555-905x
CID: 5610872

Association of Low Glomerular Filtration Rate With Adverse Outcomes at Older Age in a Large Population With Routinely Measured Cystatin C

Fu, Edouard L; Carrero, Juan-Jesus; Sang, Yingying; Evans, Marie; Ishigami, Junichi; Inker, Lesley A; Grams, Morgan E; Levey, Andrew S; Coresh, Josef; Ballew, Shoshana H
BACKGROUND/UNASSIGNED:), which may be less accurate in older adults. OBJECTIVE/UNASSIGNED:) and 8 outcomes. DESIGN/UNASSIGNED:Population-based cohort study. SETTING/UNASSIGNED:Stockholm, Sweden, 2010 to 2019. PARTICIPANTS/UNASSIGNED:82 154 participants aged 65 years or older with outpatient creatinine and cystatin C testing. MEASUREMENTS/UNASSIGNED:Hazard ratios for all-cause mortality, cardiovascular mortality, and kidney failure with replacement therapy (KFRT); incidence rate ratios for recurrent hospitalizations, infection, myocardial infarction or stroke, heart failure, and acute kidney injury. RESULTS/UNASSIGNED:, and for KFRT they were 2.6 (CI, 1.2 to 5.8) and 1.4 (CI, 0.7 to 2.8), respectively. Similar findings were observed in subgroups, including those with a urinary albumin-creatinine ratio below 30 mg/g. LIMITATION/UNASSIGNED:No GFR measurements. CONCLUSION/UNASSIGNED:was more strongly associated with adverse outcomes and the associations were more uniform. PRIMARY FUNDING SOURCE/UNASSIGNED:Swedish Research Council, National Institutes of Health, and Dutch Kidney Foundation.
PMID: 38285982
ISSN: 1539-3704
CID: 5627392

Development and Validation of the American Heart Association Predicting Risk of Cardiovascular Disease EVENTs (PREVENT) Equations

Khan, Sadiya S; Matsushita, Kunihiro; Sang, Yingying; Ballew, Shoshana H; Grams, Morgan E; Surapaneni, Aditya; Blaha, Michael J; Carson, April P; Chang, Alexander R; Ciemins, Elizabeth; Go, Alan S; Gutierrez, Orlando M; Hwang, Shih-Jen; Jassal, Simerjot K; Kovesdy, Csaba P; Lloyd-Jones, Donald M; Shlipak, Michael G; Palaniappan, Latha P; Sperling, Laurence; Virani, Salim S; Tuttle, Katherine; Neeland, Ian J; Chow, Sheryl L; Rangaswami, Janani; Pencina, Michael J; Ndumele, Chiadi E; Coresh, Josef; ,
PMID: 37947085
ISSN: 1524-4539
CID: 5607782

Trial Emulation Methods

Shin, Jung-Im; Grams, Morgan E
PMID: 37783304
ISSN: 1523-6838
CID: 5614162

Glucagon-like peptide-1 receptor agonists and the risk of atrial fibrillation in adults with diabetes: a real-world study

Xu, Yunwen; Boyle, Thomas A; Lyu, Beini; Ballew, Shoshana H; Selvin, Elizabeth; Chang, Alexander R; Inker, Lesley A; Grams, Morgan E; Shin, Jung-Im
BACKGROUND:Glucagon-like peptide-1 receptor agonists (GLP-1RA) have cardiovascular benefits in type 2 diabetes, but none of the cardiovascular trials studied atrial fibrillation/atrial flutter (AF) as a primary endpoint. Data from post-marketing surveillance studies remains sparse. OBJECTIVE:To examine the real-world risk of AF comparing GLP-1RA with other non-insulin glucose-lowering agents. DESIGN/METHODS:Cohort study using de-identified electronic health record data from the Optum Labs Data Warehouse. PARTICIPANTS/METHODS:Adult patients with diabetes who were newly prescribed add-on non-insulin glucose-lowering agents and were on metformin between 2005-2020. EXPOSURES/METHODS:New users of GLP-1RA were separately compared with new users of dipeptidyl peptidase-4 inhibitors (DPP4i) and sodium-glucose cotransporter 2 inhibitors (SGLT2i), using 1:1 propensity score matching to adjust for differences in patient characteristics. MAIN MEASURES/METHODS:The primary outcome was incident AF, defined and captured by diagnosis code for AF. Incidence rate difference (IRD) and hazard ratio (HR) were estimated in the matched cohorts. KEY RESULTS/RESULTS:In the matched cohort of 14,566 pairs of GLP-1RA and DPP4i followed for a median of 3.8 years, GLP-1RA use was associated with a lower risk of AF (IRD, -1.0; 95% CI, -1.8 to -0.2 per 1000 person-years; HR, 0.82; 95% CI, 0.70 to 0.96). In the matched cohort of 9,424 pairs of patients on GLP-1RA and SGLT2i with a median follow-up of 2.9 years, there was no difference in the risk for AF (IRD, 0.4; 95% CI -0.7 to 1.5 per 1000 person-years; HR, 1.12; 95% CI, 0.89 to 1.42). CONCLUSIONS:In this real-word study, GLP-1RA was associated with a lower risk of AF compared with DPP4i, but no difference compared with SGLT2i, suggesting that cardiovascular benefits of GLP-1RA use may extend to prevention for AF in patients with diabetes. Our findings call for future randomized controlled trials to focus on the effects of GLP-1RA on AF prevention.
PMID: 38191976
ISSN: 1525-1497
CID: 5642282