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Metabolites Associated with Coffee Consumption and Incident Chronic Kidney Disease.
He, WJ, Chen, J, Razavi, AC, Hu, EA, Grams, ME, Yu, B, Parikh, CR, Boerwinkle, E, Bazzano, L, Qi, L, et al
Clinical journal of the American Society of Nephrology : CJASN. 2021;(11):1620-1629
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Abstract
BACKGROUND AND OBJECTIVES Moderate coffee consumption has been associated with lower risk of CKD; however, the exact biologic mechanisms underlying this association are unknown. Metabolomic profiling may identify metabolic pathways that explain the association between coffee and CKD. The goal of this study was to identify serum metabolites associated with coffee consumption and examine the association between these coffee-associated metabolites and incident CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Using multivariable linear regression, we identified coffee-associated metabolites among 372 serum metabolites available in two subsamples of the Atherosclerosis Risk in Communities study (ARIC; n=3811). Fixed effects meta-analysis was used to pool the results from the two ARIC study subsamples. Associations between coffee and metabolites were replicated in the Bogalusa Heart Study (n=1043). Metabolites with significant associations with coffee in both cohorts were then evaluated for their prospective associations with incident CKD in the ARIC study using Cox proportional hazards regression. RESULTS In the ARIC study, mean (SD) age was 54 (6) years, 56% were daily coffee drinkers, and 32% drank >2 cups per day. In the Bogalusa Heart Study, mean (SD) age was 48 (5) years, 57% were daily coffee drinkers, and 38% drank >2 cups per day. In a meta-analysis of two subsamples of the ARIC study, 41 metabolites were associated with coffee consumption, of which 20 metabolites replicated in the Bogalusa Heart Study. Three of these 20 coffee-associated metabolites were associated with incident CKD in the ARIC study. CONCLUSIONS We detected 20 unique serum metabolites associated with coffee consumption in both the ARIC study and the Bogalusa Heart Study, and three of these 20 candidate biomarkers of coffee consumption were associated with incident CKD. One metabolite (glycochenodeoxycholate), a lipid involved in primary bile acid metabolism, may contribute to the favorable kidney health outcomes associated with coffee consumption. Two metabolites (O-methylcatechol sulfate and 3-methyl catechol sulfate), both of which are xenobiotics involved in benzoate metabolism, may represent potential harmful aspects of coffee on kidney health.
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Phase 2 studies of oral hypoxia-inducible factor prolyl hydroxylase inhibitor FG-4592 for treatment of anemia in China.
Chen, N, Qian, J, Chen, J, Yu, X, Mei, C, Hao, C, Jiang, G, Lin, H, Zhang, X, Zuo, L, et al
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2017;(8):1373-1386
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Abstract
BACKGROUND FG-4592 (roxadustat) is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (HIF-PHI) promoting coordinated erythropoiesis through the transcription factor HIF. Two Phase 2 studies were conducted in China to explore the safety and efficacy of FG-4592 (USAN name: roxadustat, CDAN name: ), a HIF-PHI, in patients with anemia of chronic kidney disease (CKD), both patients who were dialysis-dependent (DD) and patients who were not dialysis-dependent (NDD). METHODS In the NDD study, 91 participants were randomized to low (1.1-1.75 mg/kg) or high (1.50-2.25 mg/kg) FG-4592 starting doses or to placebo. In the DD study, 87 were enrolled to low (1.1-1.8 mg/kg), medium (1.5-2.3 mg/kg) and high (1.7-2.3 mg/kg) starting FG-4592 doses or to continuation of epoetin alfa. In both studies, only oral iron supplementation was allowed. RESULTS In the NDD study, hemoglobin (Hb) increase ≥1 g/dL from baseline was achieved in 80.0% of subjects in the low-dose cohort and 87.1% in the high-dose cohort, versus 23.3% in the placebo arm (P < 0.0001, both). In the DD study, 59.1%, 88.9% (P = 0.008) and 100% (P = 0.0003) of the low-, medium- and high-dose subjects maintained their Hb levels after 5- and 6-weeks versus 50% of the epoetin alfa-treated subjects. In both studies, significant reductions in cholesterol were noted in FG-4592-treated subjects, with stability or increases in serum iron, total iron-binding capacity (TIBC) and transferrin (without intravenous iron administration). In the NDD study, hepcidin levels were significantly reduced across all FG-4592-treated arms as compared with no change in the placebo arm. In the DD study, hepcidin levels were also reduced in a statistically significant dose-dependent manner in the highest dose group as compared with the epoetin alfa-treated group. Adverse events were similar for FG-4592-treated and control subjects. CONCLUSIONS FG-4592 may prove an effective alternative for managing anemia of CKD. It is currently being investigated in a pivotal global Phase 3 program.
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Periodontal disease, chronic kidney disease and mortality: results from the third National Health and Nutrition Examination Survey.
Ricardo, AC, Athavale, A, Chen, J, Hampole, H, Garside, D, Marucha, P, Lash, JP
BMC nephrology. 2015;:97
Abstract
BACKGROUND Periodontal disease is associated with increased mortality in the general population, however its prognostic significance in chronic kidney disease (CKD) is not known. We evaluated the joint effect of periodontal disease and CKD on all-cause and cardiovascular mortality. METHODS Prospective observational study of 10,755 adult participants in the National Health and Nutrition Examination Survey, 1988-1994 (NHANES III). CKD was defined as estimated glomerular filtration rate < 60 ml/minute/1.73 m(2) or albumin-to-creatinine ratio ≥ 30 mg/g. Periodontal disease was defined as moderate (> 4 mm attachment loss in ≥ 2 mesial sites or 5 mm pocket depth in ≥ 2 mesial sites), or severe (> 6 mm attachment loss in ≥ 2 mesial sites and > 5 mm pocket depth in ≥ 1 mesial site). All-cause and cardiovascular mortality were evaluated using Cox proportional hazards models. RESULTS There were 1,813 deaths over a median follow-up of 14 years. In multivariate analyses, as compared to participants with neither periodontal disease nor CKD, those with periodontal disease only or CKD only had increased all-cause mortality (HR 1.39; 95 % CI, 1.06-1.81 and 1.55; 1.30-1.84, respectively). The presence of both periodontal disease and CKD was associated with HR (95 % CI) 2.07 (1.65-2.59) for all-cause mortality, and 2.11 (1.52-2.94) for cardiovascular mortality. We found no evidence of multiplicativity or additivity between periodontal disease and CKD. In stratified analyses limited to individuals with CKD, periodontal disease (vs. not) was associated with adjusted HR (95 % CI) 1.35 (1.04-1.76) for all-cause, and 1.36 (0.95-1.95) for cardiovascular mortality. CONCLUSIONS These findings confirm the well-established association between periodontal disease and increased mortality in the general population, and provide new evidence of this association among individuals with CKD.