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UnlabelledSoluble CD14 (sCD14) is an inflammatory marker associated with osteoclasts. Using Cox proportional hazards models, we found a positive association between plasma levels of sCD14 and risk of incident fracture among participants in the Cardiovascular Health Study. sCD14 may be useful in identifying those at risk for fracture.IntroductionSoluble CD14, a proinflammatory cytokine, is primarily derived from macrophages/monocytes that can differentiate into osteoclasts. The purpose of this study was to examine the relationship between sCD14 levels and osteoporotic fractures.MethodsIn the Cardiovascular Health Study, 5462 men and women had sCD14 levels measured at baseline. Incident hip fractures (median follow-up time 12.5 years) and incident composite fractures (defined as the first hip, pelvis, humerus, or distal radius fracture, median follow-up 8.6 years) were identified from hospital discharge summaries and/or Medicare claims data. Cox proportional hazards models were used to model the association between sCD14 levels and time to incident hip or composite fracture, overall and as a function of race and gender.ResultsIn unadjusted models, there was a positive association between sCD14 levels (per 1 standard deviation increase, i.e., 361.6 ng/mL) and incident hip (HR, 1.26; 95 % CI, 1.17, 1.36) and composite (HR, 1.20; 95 % CI, 1.12, 1.28) fractures. When models were fully adjusted for demographics, lifestyle factors, and medication use, these associations were no longer significant. However, in whites, the association of sCD14 levels with hip fractures remained significant in fully adjusted models (HR, 1.11; 95 % CI, 1.01-1.23). Associations of sCD14 levels with hip and composite fracture did not differ between men and women.ConclusionsIn this large cohort of community-dwelling older adults, higher sCD14 levels were associated with an increased risk of incident hip fractures in whites.

Let $K = \mathbb{Q} (\alpha) $ be a pure number field generated by a complex root $\alpha$ of a monic irreducible polynomial $ F(x) = x^{2^r\cdot3^k\cdot7^s} -m \in\bb{Z}[x]$, where $r$, $k$, $s$ are three positive natural integers. The purpose of this paper is to study the monogenity of $K$. Our results are illustrated by some examples.

Let $K$ be a pure number field with $\alpha$ a complex root of a monic irreducible polynomial $F(x) = x^{120}-m \in \mathbb{Z}[x]$ with $ m \neq \pm 1 $. In this paper, we study the monogenity of $K$. More precisely, we prove that if $m$ is square-free, $m \not \equiv 1\md{4}$, $m \not \equiv \pm 1 \md{9} $, and $\ol{m}\not \in \{ \mp 1, 7, 18 \} \md {25}$, then $K$ is monogenic. On the other hand, if $m \equiv 1\md{4}$, $m \equiv 1 \md{9} $, or $m \equiv 1 \md{25}$, then $K$ is not monogenic. Our results are illustrated by some computational examples.

Background and Objectives: Chronic kidney disease (CKD) is associated with increased cardiovascular risk, which may be mediated by vascular calcification. Based on evidence that bisphosphonates inhibit vascular calcification, we hypothesized use of bisphosphonates in CKD would be associated with lower incident cardiovascular disease (CVD), CVD-related mortality, and all-cause mortality., Materials and Methods: This was a longitudinal observational study including 2,593 Framingham Offspring participants. We used propensity score-adjusted Cox regression models to determine the association between bisphosphonate use and outcomes: time to incident CVD, time to CVD-related mortality, and time to all-cause mortality. The data were stratified by presence or absence of CKD, defined as estimated glomerular filtration rate < 60 mL/min/1.73m 2 . The propensity score included age, sex, hypertension, smoking status, diabetes, total cholesterol, high-density lipoprotein, and self-reported history of fracture., Results: In unadjusted and propensity score-adjusted analyses, those with CKD using bisphosphonates had a trend toward increased incident CVD risk (adjusted hazard ratio (HR) 1.66 (95% CI, 93 - 2.97)) compared to those with CKD not using bisphosphonates. Those with CKD using bisphosphonates also had increased risk of cardiovascular mortality in the propensity score-adjusted model (adjusted HR 2.20 (95% CI, 1.12 - 4.32)). There was no significant association between bisphosphonate use and all-cause mortality in participants with CKD. Among individuals without CKD, bisphosphonate use was significantly associated with an increase in all-cause mortality in the propensity-score adjusted analysis (adjusted HR 1.59 (95% CI, 1.27 - 1.98)). However, there was no significant association between bisphosphonate use and incident CVD events (adjusted HR 0.85 95% CI, 0.63 - 1.16) or CVD-related death (adjusted HR 0.70 (95% CI 0.36 - 1.37) in those without CKD., Conclusion: Contrary to our hypothesis, bisphosphonate use was associated with a trend toward increased incident CVD and a two-fold higher risk of CVD mortality in CKD.

Background: Hypertension afflicts most patients with chronic kidney disease (CKD) and contributes to kidney disease progression, cardiovascular disease, and death in this patient population. The evidence and clinical guidelines support lowering blood pressure (BP) goals in patients with CKD. We evaluated if BP control improved among US adults with CKD., Methods and Results: In the NHANES (National Health and Nutrition Examination Survey) for the periods 2011 to 2014, 2015 to 2016, and 2017 to 2020, we identified individuals with CKD defined as estimated glomerular filtration rate 20 to 59 mL/min per 1.73 m 2 or urinary albumin/creatinine ratio≥30 mg/g. The following systolic BP categories were evaluated: <120, 120 to 129, 130 to 139, and ≥140 mm Hg. All measures were tested for differences between year groups accounting for sample strata, clusters, and weights. During the periods of 2011 to 2014, 2015 to 2016, and 2017 to 2020, the prevalence of CKD was stable at 14%, 13%, and 13%, respectively ( P =0.4). Among those with CKD, the proportion of individuals with self-reported hypertension or taking BP medications increased from 66 in 2011 to 2014, to 69 and 86% in 2015 to 2016 and 2017 to 2020, respectively ( P <0.0001). Although the number of BP medications prescribed increased significantly over time, less than half of the individuals with CKD had well-controlled BP based on the current guidelines., Conclusions: Although BP recognition has improved among those with CKD, a significant number of individuals with CKD do not meet their BP goal.

Women with a history of gestational diabetes mellitus (GDM) have a significantly greater lifetime risk of developing cardiovascular disease and type 2 diabetes compared with women who had an uncomplicated pregnancy (HC). Microvascular endothelial dysfunction, mediated via reduced nitric oxide (NO)-dependent dilation secondary to increases in oxidative stress, persists after pregnancy complicated by GDM. We examined whether this microvascular dysfunction reduces insulin-mediated vascular responses in women with a history of GDM. We assessed in vivo microvascular endothelium-dependent vasodilator function by measuring cutaneous vascular conductance responses to graded infusions of acetylcholine (10 -10 -10 -1 M) and insulin (10 -8 -10 -4 M) in control sites and sites treated with 15 mM l-NAME [ N G -nitro-l-arginine methyl ester; NO-synthase (NOS) inhibitor] or 5 mM l-ascorbate. We also measured protein expression of total endothelial NOS (eNOS), insulin-mediated eNOS phosphorylation, and endothelial nitrotyrosine in isolated endothelial cells from GDM and HC. Women with a history of GDM had reduced acetylcholine ( P < 0.001)- and insulin ( P < 0.001)-mediated dilation, and the NO-dependent responses to both acetylcholine ( P = 0.006) and insulin ( P = 0.006) were reduced in GDM compared with HC. Insulin stimulation increased phosphorylated eNOS content in HC ( P = 0.009) but had no effect in GDM ( P = 0.306). Ascorbate treatment increased acetylcholine ( P < 0.001)- and insulin ( P < 0.001)-mediated dilation in GDM, and endothelial cell nitrotyrosine expression was higher in GDM compared with HC ( P = 0.014). Women with a history of GDM have attenuated microvascular vasodilation responses to insulin, and this attenuation is mediated, in part, by reduced NO-dependent mechanisms. Our findings further implicate increased endothelial oxidative stress in this microvascular insulin resistance. NEW & NOTEWORTHY Women who have gestational diabetes during pregnancy are at a greater risk for cardiovascular disease and type 2 diabetes in the decade following pregnancy. The mechanisms mediating this increased risk are unclear. Herein, we demonstrate that insulin-dependent microvascular responses are reduced in women who had gestational diabetes, despite the remission of glucose intolerance. This reduced microvascular sensitivity to insulin may contribute to increased cardiovascular disease and type 2 diabetes risk in these women.

As there are effective treatments to reduce hip fractures, identification of patients at high risk of hip fracture is important to inform efficient intervention strategies. To obtain a new tool for hip fracture prediction, we developed a protein-based risk score in the Cardiovascular Health Study using an aptamer-based proteomic platform. The proteomic risk score predicted incident hip fractures and improved hip fracture discrimination in two Trøndelag Health Study validation cohorts using the same aptamer-based platform. When transferred to an antibody-based proteomic platform in a UK Biobank validation cohort, the proteomic risk score was strongly associated with hip fractures (hazard ratio per s.d. increase, 1.64; 95% confidence interval 1.53-1.77). The proteomic risk score, but not available polygenic risk scores for fractures or bone mineral density, improved the C-index beyond the fracture risk assessment tool (FRAX), which integrates information from clinical risk factors (C-index, FRAX 0.735 versus FRAX + proteomic risk score 0.776). The developed proteomic risk score constitutes a new tool for stratifying patients according to hip fracture risk; however, its improvement in hip fracture discrimination is modest and its clinical utility beyond FRAX with information on femoral neck bone mineral density remains to be determined., (© 2024. The Author(s).)

Advancing age increases cardiovascular disease risk, in part, because of impaired glycocalyx thickness and endothelial dysfunction. Glycocalyx-targeted therapies, such as Endocalyx Pro, could improve both glycocalyx thickness and endothelial function in older adults; however, this has yet to be tested. We hypothesized that Endocalyx Pro supplementation would increase glycocalyx thickness and endothelial function in older adults. Twenty-three older adults aged 66 ± 7 yr (52% female) were enrolled in a randomized, double-blind, placebo-controlled, parallel-arms study to investigate the effect of 12-wk Endocalyx Pro supplementation (3,712 mg/day) on glycocalyx thickness and endothelial function. Glycocalyx thickness was assessed using the GlycoCheck, and endothelial function was determined via brachial artery flow-mediated dilation (FMD). Between-group comparisons revealed Endocalyx Pro did not increase glycocalyx thickness in microvessels 4-25 µm ( P = 0.33), 4-7 µm ( P = 0.07), or 10-25 µm ( P = 0.47) in diameter when compared with placebo. In addition, Endocalyx Pro did not significantly improve FMD [mean ratio (95%) confidence interval [CI]) for between-group comparisons, 1.16 (0.77-1.74); P = 0.48]. However, Endocalyx Pro improved FMD normalized to shear rate (SR) area under the curve [mean ratio (95% CI) for between-group comparisons, 2.41 (1.14,4.13); P = 0.001]. Moreover, Endocalyx Pro increased capillary glycocalyx thickness more than placebo in individuals not taking antihypertensive medication [mean difference (95% CI) for between-group comparison, -0.08 (-0.15, -0.01); P = 0.02]. Our pilot study suggests that Endocalyx Pro supplementation is feasible in older adults but has no measurable effect on overall glycocalyx thickness and FMD. However, Endocalyx Pro may have select effects on capillary glycocalyx thickness and FMD normalized to shear rate among older adults, but further investigation is warranted. NEW & NOTEWORTHY Endothelial glycocalyx thickness and vascular endothelial function decline with advancing age. Endocalyx Pro is a glycocalyx-targeted therapy that may improve endothelial glycocalyx thickness and vascular endothelial function in older adults. This study demonstrated that 12-wk Endocalyx Pro supplementation did not improve overall endothelial glycocalyx thickness or flow-mediated dilation in older adults; however, Endocalyx Pro did increase capillary glycocalyx thickness in individuals not taking antihypertensive medication and improve flow-mediated dilation normalized to the shear stimulus.

Importance: Acute kidney injury (AKI) complicates 20% to 25% of hospital admissions and is associated with long-term mortality, especially from cardiovascular disease. Lower systolic blood pressure (SBP) following AKI may be associated with lower mortality, but potentially at the cost of higher short-term complications., Objective: To determine associations of SBP with mortality and hospital readmissions following AKI, and to determine whether time from discharge affects these associations., Design, Setting, and Participants: This retrospective cohort study of adults with AKI during a hospitalization in Veteran Healthcare Association (VHA) hospitals was conducted between January 2013 and December 2018. Patients with 1 year or less of data within the VA system prior to admission, severe or end-stage liver disease, stage 4 or 5 chronic kidney disease, end-stage kidney disease, metastatic cancer, and no blood pressure values within 30 days of discharge were excluded. Data analysis was conducted from May 2022 to February 2024., Exposure: SBP was treated as time-dependent (categorized as <120 mm Hg, 120-129 mm Hg, 130-139 mm Hg, 140-149 mm Hg, 150-159 mm Hg, and ≥160 mm Hg [comparator]). Time spent in each SBP category was accumulated over time and represented in 30-day increments., Main Outcomes and Measures: Primary outcomes were time to mortality and time to all-cause hospital readmission. Cox proportional hazards regression was adjusted for demographics, comorbidities, and laboratory values. To evaluate associations over time, hazard ratios (HRs) were calculated at 60 days, 90 days, 120 days, 180 days, 270 days, and 365 days from discharge., Results: Of 237 409 admissions with AKI, 80 960 (57 242 aged 65 years or older [70.7%]; 77 965 male [96.3%] and 2995 female [3.7%]) were included. The cohort had high rates of diabetes (16 060 patients [20.0%]), congestive heart failure (22 516 patients [28.1%]), and chronic lung disease (27 682 patients [34.2%]), and 1-year mortality was 15.9% (12 876 patients). Overall, patients with SBP between 130 and 139 mm Hg had the most favorable risk level for mortality and readmission. There were clear, time-dependent mediations on associations in all groups. Compared with patients with SBP of 160 mm Hg or greater, the risk of mortality for patients with SBP between 130 and 139 mm Hg decreased between 60 days (adjusted HR, 1.20; 99% CI, 1.00-1.44) and 365 days (adjusted HR, 0.58; 99% CI, 0.45-0.76). SBP less than 120 mm Hg was associated with increased risk of mortality at all time points., Conclusions and Relevance: In this retrospective cohort study of post-AKI patients, there were important time-dependent mediations of the association of blood pressure with mortality and readmission. These findings may inform timing of post-AKI blood pressure treatment.

High blood pressure is an important risk factor for cardiovascular disease and disease progression in chronic kidney disease (CKD). Evidence on the effects of home blood pressure monitoring (HBPM) is limited. This review aimed to determine the effect of HBPM on systolic (SBP) and diastolic blood pressure (DBP) in patients with CKD. We searched medical literature databases for eligible studies presenting pre- and post-data for interventions utilizing HBPM. Study quality was assessed using the NHLBI tools for quality assessment. Heterogeneity prohibited a meta-analysis so estimates of effects were calculated along a sign test to examine the probability of observing the given pattern of positive effect direction. Eighteen studies were included (n = 1187 participants, mean age 56.7 [± 7.7] years). In 15 studies, HBPM was conducted within the context of additional high-level tailored support. Overall, the quality of n = 7/18 studies was rated as "good"; n = 6/18 were "fair," and n = 5/18 were rated as "poor." Interventions utilizing HBPM had a significant effect on SBP, with 14/16 studies favoring the intervention (88% [95% CI: 62%-98%], P = .002). Favorable effects were also seen on DBP (73% [95% CI: 45%-92%], P = .059). HBPM had a favorable effect on blood pressure goal attainment (86% [95% CI: 42%-100%], P = .062). HBPM in patients with CKD as part of a multicomponent intervention may lead to clinically significant reductions in blood pressure; however, research is needed to support the validity of this claim due to the high heterogeneity across the studies included., (© 2024 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Hip fractures are associated with significant disability, high cost, and mortality. However, the exact biological mechanisms underlying susceptibility to hip fractures remain incompletely understood. In an exploratory search of the underlying biology as reflected through the circulating proteome, we performed a comprehensive Circulating Proteome Association Study (CPAS) meta-analysis for incident hip fractures. Analyses included 6430 subjects from two prospective cohort studies (Cardiovascular Health Study and Trøndelag Health Study) with circulating proteomics data (aptamer-based 5 K SomaScan version 4.0 assay; 4979 aptamers). Associations between circulating protein levels and incident hip fractures were estimated for each cohort using age and sex-adjusted Cox regression models. Participants experienced 643 incident hip fractures. Compared with the individual studies, inverse-variance weighted meta-analyses yielded more statistically significant associations, identifying 23 aptamers associated with incident hip fractures (conservative Bonferroni correction 0.05/4979, P < 1.0 × 10-5). The aptamers most strongly associated with hip fracture risk corresponded to two proteins of the growth hormone/insulin growth factor system (GHR and IGFBP2), as well as GDF15 and EGFR. High levels of several inflammation-related proteins (CD14, CXCL12, MMP12, ITIH3) were also associated with increased hip fracture risk. Ingenuity pathway analysis identified reduced LXR/RXR activation and increased acute phase response signaling to be overrepresented among those proteins associated with increased hip fracture risk. These analyses identified several circulating proteins and pathways consistently associated with incident hip fractures. These findings underscore the usefulness of the meta-analytic approach for comprehensive CPAS in a similar manner as has previously been observed for large-scale human genetic studies. Future studies should investigate the underlying biology of these potential novel drug targets., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Background: Patients with CKD and diabetes are at higher risk of developing cardiovascular disease, in part, because of impaired endothelial function. Cardioprotective compounds such as resveratrol could improve endothelial function and attenuate the cardiovascular burden in patients with CKD and diabetes. We hypothesized that resveratrol supplementation would improve endothelial function in patients with CKD and diabetes., Methods: Twenty-eight adults aged 68±7 years (84% men) with stage 3 CKD and diabetes were enrolled in a randomized, double-blind, placebo-controlled, crossover study to investigate the effects of 6-week resveratrol supplementation (400 mg/d) on endothelial function. Endothelial function was determined through brachial artery flow-mediated dilation., Results: The mean values for eGFR and hemoglobin A 1c were 40±9 ml/min per 1.73 m 2 and 7.36%±0.72%, respectively. Compared with placebo, resveratrol supplementation increased flow-mediated dilation (ratio of geometric mean changes and 95% confidence interval for between-group comparisons, 1.43 (1.15 to 1.77); P value = 0.001). eGFR, hemoglobin A 1c , BP, and nitroglycerin-mediated dilation were unchanged with resveratrol or placebo ( P = 0.15), suggesting the observed change in flow-mediated dilation was likely independent of changes in traditional cardiovascular risk factors., Conclusions: Resveratrol supplementation improved endothelial function in patients with CKD and diabetes., Clinical Trial Registry Name and Registration Number: Resveratrol and Vascular Function in CKD, NCT03597568 ., Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023&#95;11&#95;20&#95;CJN0000000000000337.mp3., (Copyright © 2023 by the American Society of Nephrology.)

The endothelial glycocalyx is a dynamic, gel-like layer that is critical to normal vascular endothelial function. Heparin impairs the endothelial glycocalyx and reduces vascular endothelial function in a murine model; however, this has yet to be tested in healthy humans. We hypothesized that a single bolus dose of heparin would increase circulating glycocalyx components and decrease endothelial glycocalyx thickness resulting in blunted brachial artery vasodilation in healthy younger adults. Healthy adults ( n = 19, aged 18-39 yr, 53% female) underwent measurements of the endothelial glycocalyx and vascular endothelial function at baseline and after a single bolus 5,000 U dose of heparin. The glycocalyx components syndecan-1 and heparan sulfate were measured from plasma samples using enzyme-linked immunosorbent assays. Glycocalyx thickness was determined as perfused boundary region (PBR) in sublingual microvessels using the GlycoCheck. Endothelial function was measured via ultrasonography and quantified as brachial artery flow-mediated dilation (FMD). Following acute heparin administration, there was no increase in syndecan-1 or heparan sulfate ( P = 0.90 and P = 0.49, respectively). In addition, there was no change in PBR 4-7 µm ( P = 0.55), PBR 10-25 µm ( P = 0.63), or 4-25 µm ( P = 0.49) after heparin treatment. Furthermore, we did not observe a change in FMDmm ( P = 0.23), FMD% ( P = 0.35), or plasma nitrite concentrations ( P = 0.10) in response to heparin. Finally, time to peak dilation and peak FMD normalized to shear stress were unchanged following heparin ( P = 0.59 and P = 0.21, respectively). Our pilot study suggests that a single bolus intravenous dose of heparin does not result in endothelial glycocalyx degradation or vascular endothelial dysfunction in healthy younger adults. NEW & NOTEWORTHY The endothelial glycocalyx's role in modulating vascular endothelial dysfunction with aging and disease is becoming increasingly recognized. This study presents novel findings that acute heparin administration is not a feasible method to experimentally degrade the endothelial glycocalyx and measure concurrent changes in vascular endothelial function in healthy humans. Alternative approaches will be needed to translate findings from preclinical studies and test the effects of acute endothelial glycocalyx degradation on vascular endothelial function in humans.

Objective: Hypertension is the most common risk factor for cardiovascular disease (CVD). Several guidelines have lowered diagnostic blood pressure (BP) thresholds and treatment targets for hypertension. We evaluated the impact of the more stringent guidelines among Veterans, a population at high risk of CVD., Methods: We conducted a retrospective analysis of Veterans with at least two office BP measurements between January 2016 and December 2017. Prevalent hypertension was defined as diagnostic codes related to hypertension, prescribed antihypertensive drugs, or office BP values according to the BP cutoffs at least 140/90 mmHg (Joint National Committee 7 [JNC 7]), at least 130/80 mmHg [American College of Cardiology/American Heart Association (ACC/AHA)], or the 2020 Veterans Health Administration (VHA) guideline (BP ≥130/90 mmHg). Uncontrolled BP was defined per the VHA guideline as mean SBP ≥130 mmHg or DBP ≥90 mmHg., Results: The prevalence of hypertension increased from 71% for BP at least 140/90 to 81% for BP at least 130/90 mmHg and further to 87% for BP at least 130/80 mmHg. Among Veterans with known hypertension ( n  = 2 768 826), a majority [ n  = 1 818 951 (66%)] were considered to have uncontrolled BP per the VHA guideline. Lowering the treatment targets for SBP and DBP significantly increased the number of Veterans who would require initiation of or intensification of pharmacotherapy. The majority of Veterans with uncontrolled BP and at least one CVD risk factor remained uncontrolled after 5 years of follow-up., Conclusion: Lowering the BP diagnostic and treatment cutoffs increases the burden on healthcare systems significantly. Targeted interventions are needed to achieve the BP treatment goals.

Background: Filter clotting is a major issue in continuous kidney replacement therapy (CKRT) that interrupts treatment, reduces delivered effluent dose, and increases cost of care. While a number of variables are involved in filter life, treatment modality is an understudied factor. We hypothesized that filters in pre-filter continuous venovenous hemofiltration (CVVH) would have shorter lifespans than in continuous venovenous hemodialysis (CVVHD)., Methods: This was a single center, pragmatic, unblinded, quasi-randomized cluster trial conducted in critically ill adult patients with severe acute kidney injury (AKI) at the University of Iowa Hospitals and Clinics (UIHC) between March 2020 and December 2020. Patients were quasi-randomized by time block to receive pre-filter CVVH (convection) or CVVHD (diffusion). The primary outcome was filter life, and secondary outcomes were number of filters used, number of filters reaching 72 hours, and in-hospital mortality., Results: In the intention-to-treat analysis, filter life in pre-filter CVVH was 79% of that observed in CVVHD (mean ratio 0.79, 95% CI 0.65-0.97, p = 0.02). Median filter life (with interquartile range) in pre-filter CVVH was 21.8 (11.4-45.3) and was 26.6 (13.0-63.5) for CVVHD. In addition, 11.8% of filters in pre-filter CVVH were active for >72 hours, versus 21.2% in the CVVHD group. Finally, filter clotting accounted for the loss of 26.7% of filters in the CVVH group compared to 17.5% in the CVVHD group. There were no differences in overall numbers of filters used or mortality between groups., Conclusions: Among critically patients with severe AKI requiring CKRT, use of pre-filter CVVH resulted in significantly shorter filter life compared to CVVHD., Trial Registration: ClinicalTrials.gov, NCT04762524. Registered 02/21/21-Retroactively registered, https://clinicaltrials.gov/ct2/show/NCT04762524?cond=The+Impact+of+CRRT+Modality+on+Filter+Life&draw=2&rank=1., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Mann et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Women with a history of gestational diabetes mellitus (GDM) are twice as likely to develop cardiovascular disease (CVD) and ∼7 times as likely to develop type 2 diabetes as their age-matched counterparts. However, the mechanism(s) mediating these associations remain unclear. We hypothesized that endothelium- and (nitric oxide) NO-dependent dilation would be attenuated through oxidant stress mechanisms in the microvasculature of women with a history of GDM compared with control women with a history of uncomplicated pregnancy (HC). Ten HC (35 ± 4 yr) and 10 GDM (34 ± 4 yr) underwent a standard local heating protocol (42°C; 0.1°C·s -1 ). Two intradermal microdialysis fibers were placed in the ventral forearm for local delivery of lactated Ringer's (control) or 5 mM l-ascorbate. After full expression of the local heating response, 15 mM N G -nitro-l-arginine methyl ester (NO synthase inhibition) was perfused. Red cell flux was measured continuously by laser-Doppler flowmetry, and cutaneous vascular conductance (CVC = flux/MAP) was standardized to maximum (% CVCmax; 28 mM SNP + 43°C). Urine albumin:creatinine ratio (ACR) was measured. GDM had attenuated endothelium-dependent (GDM: 67 ± 7 vs. HC: 90 ± 4% CVCmax; P < 0.001) and NO-dependent (GDM: 54 ± 7 vs. HC: 71 ± 3% CVCmax; P = 0.001) dilation at the control site and tended to have higher urine ACR ( P = 0.06). Both endothelium-dependent ( R 2 = 0.53, P = 0.02) and NO-dependent ( R 2 = 0.56, P = 0.01) dilation were related to urine ACR in GDM. l-ascorbate perfusion improved endothelium-dependent (82 ± 5% CVCmax; P = 0.03 vs. control) and NO-dependent (68 ± 5% CVCmax; P = 0.02 vs. control) dilation in GDM but had no effect in HC ( P > 0.05). Otherwise healthy women with a history of GDM have attenuated microvascular endothelial function and this dysfunction is mediated, in part, by oxidative stress. NEW & NOTEWORTHY Women who have gestational diabetes during pregnancy are at greater risk for cardiovascular disease and type 2 diabetes in the decade following pregnancy. However, the mechanisms mediating this increased risk are unclear. Herein, we demonstrate that microvascular dysfunction, mediated by increase in oxidative stress, persists after pregnancy in women who had gestational diabetes, despite the remission of glucose tolerance.

Xanthine oxidase (XO) contributes to oxidative stress and vascular disease. Hyperuricemia and gout are common in patients with chronic kidney disease (CKD), a population at increased risk of vascular disease. We evaluated effects of allopurinol on serum XO activity and metabolome of CKD patients who had participated in a randomized double-blind clinical trial of allopurinol vs. placebo. XO activity was measured in participants' serum. XO expression in venous endothelial cells was evaluated via immunofluorescence. Gas chromatography mass spectrometry (GC/MS) was utilized for metabolomics analysis. We found that in patients with stage 3 CKD and hyperuricemia, allopurinol lowered serum urate while increasing serum xanthine levels. Allopurinol, however, did not significantly suppress measured serum XO activity. Of note, baseline serum XO activity was low. Additionally, neither baseline serum XO activity nor XO protein expression were associated with measures of vascular dysfunction or with systemic or endothelial biomarkers of oxidative stress. Allopurinol affected several pathways, including pentose phosphate, pyrimidine, and tyrosine metabolism. Our findings suggest that circulating XO does not contribute to vascular disease in CKD patients. In addition to inhibition of XO activity, allopurinol was observed to impact other pathways; the implications of which require further study.

Background/objective: Hospital readmissions in the United States, especially in patients at high-risk, cost more than $17 billion annually. Although care transitions is an important area of research, data are limited regarding its efficacy, especially among rural patients. In this study, we describe a novel transitions-of-care clinic (TOCC) to reduce 30-day readmissions in a Veterans Health Administration setting that serves a high proportion of rural veterans., Methods: In this quality improvement initiative we conducted a pre-post study evaluating clinical outcomes in adult patients at high risk for 30-day readmission (Care Assessment Needs score > 85) discharged from the Iowa City Veterans Affairs (ICVA) Health Care System from 2017 to 2020. The ICVA serves 184,000 veterans across 50 counties in eastern Iowa, western Illinois, and northern Missouri, with more than 60% of these patients residing in rural areas. We implemented a multidisciplinary TOCC to provide in-person or virtual follow-up to high-risk veterans after hospital discharge. The main purpose of this study was to assess how TOCC follow-up impacted the monthly 30-day patient readmission rate., Results: The TOCC resulted in a 19.2% relative reduction in 30-day readmission rates in the 12-month postimplementation period compared to the preimplementation period (9.2% vs 11.4%, P = .04). Virtual visits were more popular than in-person visits among both urban and rural veterans. There was no difference in outcomes between these two follow-up options, and both groups had reduced readmission rates compared to non-TOCC follow-up., Conclusions: A multidisciplinary TOCC within the ICVA featuring both virtual and in-person visits reduced the 30-day readmission rate. This reduction was particularly notable among patients with congestive heart failure.

Background: A computable phenotype is an algorithm used to identify a group of patients within an electronic medical record system. Developing a computable phenotype that can accurately identify patients with autosomal dominant polycystic kidney disease (ADPKD) will assist researchers in defining patients eligible to participate in clinical trials and other studies. Our objective was to assess the accuracy of a computable phenotype using International Classification of Diseases 9th and 10th revision (ICD-9/10) codes to identify patients with ADPKD., Methods: We reviewed four random samples of approximately 250 patients on the basis of ICD-9/10 codes from the EHR from the Kansas University Medical Center database: patients followed in nephrology clinics who had ICD-9/10 codes for ADPKD (Neph+), patients seen in nephrology clinics without ICD codes for ADPKD (Neph-), patients who were not followed in nephrology clinics with ICD codes for ADPKD (No Neph+), and patients not seen in nephrology clinics without ICD codes for ADPKD (No Neph-). We reviewed the charts and determined ADPKD status on the basis of internationally accepted diagnostic criteria for ADPKD., Results: The computable phenotype to identify patients with ADPKD who attended nephrology clinics has a sensitivity of 99% (95% confidence interval [95% CI], 96.4 to 99.7) and a specificity of 84% (95% CI, 79.5 to 88.1). For those who did not attend nephrology clinics, the sensitivity was 97% (95% CI, 93.3 to 99.0), and a specificity was 82% (95% CI, 77.4 to 86.1)., Conclusion: A computable phenotype using the ICD-9/10 codes can correctly identify most patients with ADPKD, and can be utilized by researchers to screen health care records for cohorts of patients with ADPKD with acceptable accuracy., Competing Interests: A. Yu reports having consultancy agreements with Calico, Otsuka, Navitor, and Regulus Therapeutics; reports having an ownership interest in Amgen Corp., Gilead Sciences, and Prothena; reports receiving honoraria from Elsevier and Wolters Kluwer; reports being a scientific advisor or member of the Otsuka Advisory Board; and reports having other interests/relationships with the Jared Grantham Kidney Institute, which receives royalties from Otsuka for tolvaptan, and The University of Kansas Medical Center. D. Jalal reports receiving research funding from AstraZeneca and Corvidia; reports receiving honoraria from Kansas Idea Network of Biomedical Research Excellence (K-INBRE) and Reata; and reports being a scientific advisor or member of Reata. K. McGreal reports receiving Medical Center research funding from the Sanofi Staged PKD trial sub-investigator and Reata as principle investigator on the FAlcon study. R. Mustafa reports being a scientific advisor to or member of The American College of Physicians Clinical Guideline Committee, The Canadian Society of Nephrology Clinical Practice Guidelines Committee, and The GRADE guidance group; reports having other interests/relationships with the advisory board for the renal round table, and the National Kidney Foundation Midwest. All remaining authors have nothing to disclose., (Copyright © 2021 by the American Society of Nephrology.)

Low muscle mass (sarcopenia) is a prevalent and major concern in the aging population as well as in patients with chronic kidney disease (CKD). We hypothesized that sarcopenia is an independent predictor of incident and progressive CKD and increased mortality in older men and women (≥65 years) from the Cardiovascular Health Study. Sarcopenia was defined by bioimpedance-estimated skeletal muscle mass index (SMI) as a continuous variable and categorically (normal, class I, and class II). Cox regression hazard ratios (HRs) estimated the risk of incident and prevalent CKD and mortality in individuals with and without CKD. Low SMI was associated with increased prevalence of CKD in men (p<0.001), but lower prevalence of CKD in women (p=0.03). Low muscle mass was not associated with incident CKD or rapid CKD progression (>3 ml/minute/1.73m 2 /year decline in eGFR) in men, but was associated with lower risk of incident CKD in women ([adjusted RR=0.69, 95% (0.51,0.94)]. Low muscle mass (class II) was independently associated with higher mortality only in men [(adjusted HR=1.26, 95% (1.05,1.50)]. Neither definition of sarcopenia was associated with mortality in men or women with CKD. Further studies are needed to understand the mechanisms by which sarcopenia contributes to higher mortality in aging men.

Anemia is a complication that affects a majority of individuals with advanced CKD. Although relative deficiency of erythropoietin production is the major driver of anemia in CKD, iron deficiency stands out among the mechanisms contributing to the impaired erythropoiesis in the setting of reduced kidney function. Iron deficiency plays a significant role in anemia in CKD. This may be due to a true paucity of iron stores (absolute iron deficiency) or a relative (functional) deficiency which prevents the use of available iron stores. Several risk factors contribute to absolute and functional iron deficiency in CKD, including blood losses, impaired iron absorption, and chronic inflammation. The traditional biomarkers used for the diagnosis of iron-deficiency anemia (IDA) in patients with CKD have limitations, leading to persistent challenges in the detection and monitoring of IDA in these patients. Here, we review the pathophysiology and available diagnostic tests for IDA in CKD, we discuss the literature that has informed the current practice guidelines for the treatment of IDA in CKD, and we summarize the available oral and intravenous (IV) iron formulations for the treatment of IDA in CKD. Two important issues are addressed, including the potential risks of a more liberal approach to iron supplementation as well as the potential risks and benefits of IV versus oral iron supplementation in patients with CKD., (Copyright © 2020 by the American Society of Nephrology.)

Obesity is a risk factor for hypertension, diabetes mellitus (DM), dyslipidemia, and hyperuricemia. Here, we evaluated whether the same body mass index (BMI) for the U.S. population conferred similar metabolic risk in Japan. This was a cross-sectional analysis involving 90,047 Japanese adults (18⁻85 years) from St. Luke's International Hospital, Tokyo, Japan and 14,734 adults from National Health and Nutrition Examination Survey (NHANES) collected in the U.S. We compared the prevalence of hypertension, DM, dyslipidemia, and hyperuricemia according to BMI in Japan and the U.S. The prevalence of hypertension, DM, and dyslipidemia were significantly higher in the U.S. than Japan, whereas the prevalence of hyperuricemia did not differ between countries. Higher BMI was an independent risk factor for hypertension, DM, dyslipidemia, and hyperuricemia both in Japan and in the U.S. after adjusting for age, sex, smoking and drinking habits, chronic kidney disease, and other cardiovascular risk factors. The BMI cut-off above which the prevalence of these cardio-metabolic risk factors increased was significantly higher in the U.S. than in Japan (27 vs. 23 kg/m² for hypertension, 29 vs. 23 kg/m² for DM, 26 vs. 22 kg/m² for dyslipidemia, and 27 vs. 23 kg/m² for hyperuricemia). Higher BMI is associated with an increased prevalence of hypertension, DM, dyslipidemia, and hyperuricemia both in Japan and U.S. The BMI cut-off above which the prevalence of cardio-metabolic risk factors increases is significantly lower in Japan than the U.S., suggesting that the same definition of overweight/obesity may not be similarly applicable in both countries.

Hyperuricemia may contribute to endothelial dysfunction in CKD. We evaluated whether lowering serum uric acid levels with allopurinol improves endothelial dysfunction in 80 participants ≥18 years of age with stage 3 CKD and asymptomatic hyperuricemia (≥7 mg/dl in men and ≥6 mg/dl in women) randomized in a double-blinded manner to receive placebo or allopurinol for 12 weeks. Randomization was stratified according to presence or absence of diabetes mellitus. We measured vascular endothelial function by brachial artery flow-mediated dilation. No significant differences existed between groups at baseline; 61% of the participants had diabetes mellitus in both groups. The placebo and the allopurinol groups had baseline serum uric acid levels (SDs) of 8.7 (1.6) mg/dl and 8.3 (1.4) mg/dl, respectively, and baseline flow-mediated dilation values (SDs) of 6.0% (5.0%) and 4.8% (5.0%), respectively. Compared with placebo, allopurinol lowered serum uric acid significantly but did not improve endothelial function. In participants without diabetes mellitus, allopurinol associated with a trend toward improved flow-mediated dilation (+1.4% [3.9%] versus -0.7% [4.1%] with placebo), but this was not statistically significant ( P =0.26). Furthermore, we did not detect significant differences between groups in BP or serum levels of markers of inflammation and oxidative stress. In conclusion, allopurinol effectively and safely lowered serum uric acid levels in adults with stage 3 CKD and asymptomatic hyperuricemia but did not improve endothelial function in this sample of patients., (Copyright © 2017 by the American Society of Nephrology.)

Iron stores assuring optimal efficacy/safety for erythropoiesis are unknown in the dialysis population. Using multicenter trial data, we related safety profiles, erythropoiesis-stimulating agent (ESA), and intravenous iron dosing to achieved iron stores in 441 subjects randomized 2 : 1 to ferric citrate or active control as their phosphate binder over 52 weeks. Intravenous iron was given at each site's discretion if ferritin ≤ 1,000 ng/mL and transferrin saturation ≤ 30%. Multivariable time-dependent Cox regression jointly related the primary safety outcome (composite of cardiac, infection, gastrointestinal, and hepatobiliary serious adverse events) to moving averages of ferritin and transferrin saturation over the preceding 90 days with covariate adjustment. Multivariable generalized estimating equations related elevated ESA and intravenous iron doses to trailing 90-day averages of ferritin and transferrin saturation with covariate adjustment. The adjusted hazard ratio for the safety composite per 10% increase in transferrin saturation was 0.84 (95% confidence interval 0.68 - 1.02, p = 0.08) and 1.09 (0.86 - 1.35, p = 0.48) per 400 ng/mL increase in ferritin. The adjusted hazard ratio for the safety composite was 0.50 (0.29 - 0.88, p = 0.016) for the highest transferrin saturation tertile vs. the lowest. Adjusted odds ratios for higher intravenous iron dose were lower in the highest (0.23 [0.16 - 0.35], p < 0.001) and middle transferrin saturation tertile (0.42 [0.31 - 0.57], p < 0.001) vs. lowest. Incidence of elevated ESA dose was lower in the highest transferrin saturation tertile (p = 0.01). Ferritin did not predict clinical events or ESA dose. Transferrin saturation may be a better marker than serum ferritin to judge optimal iron stores in dialysis patients. Transferrin saturations > 34% are safe and provide maximal efficacy.
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Here we report that abnormal brain white matter and, to a lesser extent, albuminuria are associated with reduced bone mineral density in the hip, spine, and total body in men and women. These findings may explain the increased hip fracture risk reported in some studies in association with microvascular disorders., Introduction: Markers of microvascular disease have been individually associated with increased risk of osteoporotic fractures in some studies. Here, we examine whether these markers are associated with reduced bone mineral density (BMD) individually and together., Methods: BMD testing using dual x-ray absorptiometry of the hip, lumbar spine, and total body was performed in 1473 participants from the Cardiovascular Health Study (mean age ~ 78 years): 1215 were assessed for urinary albumin-creatinine ratio, 944 for abnormal white matter disease (AWMD) by brain MRI, and 541 for retinal vascular disease with fundus photographs. Linear regression models were used to evaluate the cross-sectional association of each marker with BMD accounting for potentially confounding factors., Results: AWMD was associated with lower hip, spine, and total body BMD in women (β -3.08 to -4.53; p < 0.01 for all) and lower hip and total body BMD in men (β -2.90 to -4.24; p = 0.01-0.03). Albuminuria was associated with lower hip (β -3.37; p = .05) and total body (β -3.21; p = .02) BMD in men, but not in women. The associations of AWMD and albuminuria with BMD persisted with mutual adjustment and appeared to be additive to each other. Retinal vascular disease was not associated with BMD in men or women., Conclusion: AWMD and, to a lesser extent, albuminuria were independently associated with lower BMD, suggesting that microvascular disease may play a role in the pathogenesis of reduced BMD. These findings need to be confirmed by longitudinal studies.

Hyperuricemia (elevated serum uric acid) is prevalent, and an important mediator of gout, an increasingly common condition. In addition, hyperuricemia is associated with metabolic syndrome, diabetes, hypertension, and kidney and cardiovascular diseases. Although it remains controversial whether hyperuricemia is a causal factor for kidney disease, the kidneys play a major role in the regulation of serum uric acid levels. Approximately two-thirds of the uric acid produced in humans is excreted by the kidneys. The handling of urate in the renal proximal tubule is extensive, as uric acid undergoes filtration, reabsorption, and secretion. Variations in renal urate handling have been shown to influence the risk of gout. In observational studies, hyperuricemia has been shown to predict kidney disease onset and progression, with a variety of mechanisms implicated. Because of this close association between hyperuricemia and kidney disease, and due to limited studies on the topic, it is important to conduct future studies on the treatment of hyperuricemia to slow kidney disease progression and improve cardiovascular survival in patients with chronic kidney disease. Furthermore, it is important to monitor for gout in patients with kidney disease and to follow the guidelines for treatment of hyperuricemia in this group of patients. This narrative review provides an in-depth discussion of the link between serum uric acid levels, renal handling of uric acid, and diseases associated with dysfunction in uric acid homeostasis.

Ferric citrate (FC) is a phosphate binder with shown efficacy and additional effects on iron stores and use of intravenous (iv) iron and erythropoiesis-stimulating agents (ESAs). We provide detailed analyses of changes in iron/hematologic parameters and iv iron/ESA use at time points throughout the active control period of a phase 3 international randomized clinical trial. In all, 441 subjects were randomized (292 to FC and 149 to sevelamer carbonate and/or calcium acetate [active control (AC)]) and followed for 52 weeks. Subjects on FC had increased ferritin and transferrin saturation (TSAT) levels compared with subjects on AC by week 12 (change in ferritin, 114.1±29.35 ng/ml; P<0.001; change in TSAT, 8.62%±1.57%; P<0.001). Change in TSAT plateaued at this point, whereas change in ferritin increased through week 24, remaining relatively stable thereafter. Subjects on FC needed less iv iron compared with subjects on AC over 52 weeks (median [interquartile range] dose=12.9 [1.0-28.9] versus 26.8 [13.4-47.6] mg/wk; P<0.001), and the percentage of subjects not requiring iv iron was higher with FC (P<0.001). Cumulative ESA over 52 weeks was lower with FC than AC (median [interquartile range] dose=5303 [2023-9695] versus 6954 [2664-12,375] units/wk; P=0.04). Overall, 90.3% of subjects on FC and 89.3% of subjects on AC experienced adverse events. In conclusion, treatment with FC as a phosphate binder results in increased iron parameters apparent after 12 weeks and reduces iv iron and ESA use while maintaining hemoglobin over 52 weeks, with a safety profile similar to that of available binders., (Copyright © 2015 by the American Society of Nephrology.)

Fetuin-A, a serum protein that regulates calcium mineralization, has been associated with bone mineral density (BMD) in several cross-sectional human studies, suggesting a possible beneficial effect on clinically important measures of bone health. Fetuin-A and incidence of subsequent fracture was assessed in 4714 men and women ≥65 years of age. Proportional hazards models were used to estimate risk of incident hip (hospital discharge ICD-9 codes) and composite fracture (hip, pelvis, humerus, or proximal forearm; hospital discharge ICD-9 codes and Medicare claims data). A total of 576 participants had an incident hip fracture (median follow-up 11.2 years) and 768 had an incident composite fracture (median follow-up 6.9 years). In unadjusted analyses, there was no association between fetuin-A (per SD increase) and risk of hip fracture (hazard ratio [HR], 0.96; 95% CI, 0.88 to 1.05) or composite fracture (HR, 0.99; 95% CI, 0.92 to 1.06). Results were not significantly changed after adjustment for potential confounding variables. Analyses modeling fetuin-A in quartiles or within a subset with available BMD measures also showed no statistically significant association with risk of hip or composite fracture. Though fetuin-A was positively associated with areal BMD in partially adjusted models (total hip: β, 0.013 g/cm(2) ; 95% CI, 0.005 to 0.021; femoral neck: β, 0.011 g/cm(2) ; 95% CI, 0.004 to 0.018; and lumbar spine: β, 0.007 g/cm(2) ; 95% CI, 0.001 to 0.028), these associations were no longer significant after further adjustment for BMI and in final multivariate models. In this large sample of community-dwelling older adults, a small positive association between fetuin-A and areal BMD appeared attributable to confounding variables and we found no evidence of an association between fetuin-A and risk of clinical fracture., (© 2015 American Society for Bone and Mineral Research.)

Objective: Experimental and observational studies suggest a role for uric acid in non-alcoholic fatty liver disease (NAFLD). We examined the association between serum uric acid levels and NAFLD in a large population-based study from the United States., Materials/methods: A cross-sectional analysis of 10,732 nondiabetic adults who participated in the National Health and Nutrition Examination Survey 1988-1994. Sex specific uric acid quartiles were defined: ≤5.2, 5.3-6.0, 6.1-6.9, and >6.9mg/dL for men and ≤3.7, 3.8-4.5, 4.6-5.3, and >5.3mg/dL for women. NAFLD presence and severity were defined by ultrasonographic detection of steatosis in the absence of other liver diseases. We modeled the probability that more severe NAFLD would be associated with the highest quartiles of uric acid., Results: Compared to the 1st quartile, the odds ratio for NAFLD was 1.79 (95% C.I. 1.49-2.15, p<0.001) and 3.14 (95% C.I. 2.63-3.75, p<0.001) for the 3rd and 4th quartiles, respectively. After adjusting for demographics, hypertension, waist circumference, triglycerides, high-density lipoprotein-cholesterol, homeostasis model assessment-estimated insulin resistance, estimated glomerular filtration rate, and aspartate aminotransferase, uric acid (4th quartile) was significantly associated with NAFLD (odds ratio 1.43; 95% C.I. 1.16-1.76, p<0.001). Positive parameter estimates suggest increasing uric acid is associated with greater severity of NAFLD., Conclusions: Elevated uric acid level is independently associated with ultrasound-diagnosed NAFLD in a nationally representative sample of United States nondiabetic adults. Increasing uric acid is associated with increasing severity of NAFLD on ultrasonography. These findings warrant further studies on the role of uric acid in NAFLD., (Published by Elsevier Inc.)

The prevalence of chronic kidney disease (CKD) has increased and will continue to increase in the United States and worldwide. This is alarming considering that CKD is an irreversible condition and patients who progress to chronic kidney failure have reduced quality of life and high mortality rates. As such, it is imperative to identify modifiable risk factors to develop strategies to slow CKD progression. One such factor is hyperuricemia. Recent observational studies have associated hyperuricemia with kidney disease. In addition, hyperuricemia is largely prevalent in patients with CKD. Data from experimental studies have shown several potential mechanisms by which hyperuricemia may contribute to the development and progression of CKD. In this article, we offer a critical review of the experimental evidence linking hyperuricemia to CKD, highlight gaps in our knowledge on the topic as it stands today, and review the observational and interventional studies that have examined the potential nephroprotective effect of decreasing uric acid levels in patients with CKD. Although uric acid also may be linked to cardiovascular disease and mortality in patients with CKD, this review focuses only on uric acid as a potential therapeutic target to prevent kidney disease onset and progression., (Copyright © 2012 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Some experimental evidence suggests that uric acid impairs endothelial function. It is controversial if high uric acid levels and impaired endothelial function are related in healthy adults. In addition, the effect of uric acid on endothelial cells (ECs) of humans is unexplored., Methods: Data of 107 healthy adult volunteers were analyzed. The association between serum uric acid and endothelial-dependant dilation (EDD) and endothelial-independent dilation (EID) was evaluated by linear regression models. We also examined the relations between uric acid and systemic and cellular markers of inflammation and oxidative stress in all or subsets of participants., Results: Uric acid levels and EDD were not related in unadjusted or adjusted models. There was a significant negative correlation between uric acid and EID in the pooled sample (r = -0.34, P = 0.005). This correlation remained significant after adjusting for demographics (P = 0.04) and was attenuated after adjusting for other cardiac risk factors (P = 0.12). Higher serum uric acid levels were found to correlate significantly with C-reactive protein (CRP) (r = 0.31, P = 0.002). Serum uric acid levels were not associated with brachial artery EC nuclear factor-κB (NF-κB) p65 or NADPH oxidase p47(phox) expression or with nitrotyrosine staining, but were inversely associated with EC manganese superoxide dismutase (MnSOD) expression (r = -0.5, P = 0.01, n = 25)., Conclusion: Elevated serum uric acid is not associated with endothelial dysfunction among healthy adults, but is inversely related to EID and EC MnSOD, and positively related to systemic inflammation. These findings may have implications for cardiovascular risk in healthy adults.

Background/aims: Nonalcoholic fatty liver disease (NAFLD) has been proposed to contribute to chronic kidney disease (CKD) independently of traditional cardiometabolic risk factors. We hypothesized that NAFLD is associated with CKD and that greater severity of NAFLD is associated with higher odds of CKD., Methods: A cross-sectional analysis of 11,469 adults who participated in the National Health and Nutrition Examination Survey (NHANES) 1988-1994. NAFLD was defined by ultrasonographic detection of steatosis in the absence of other liver diseases. CKD was defined as an estimated glomerular filtration rate of ≤60 ml/min/1.73 m(2) or the presence of albuminuria in subjects with an estimated glomerular filtration rate of >60 ml/min/1.73 m(2)., Results: 2,891 (25.4%) patients in the cohort had CKD. The prevalence of NAFLD was higher in individuals with CKD compared to those without CKD (42.2 vs. 34.5%, p < 0.0001). NAFLD was associated with CKD in unadjusted logistic regression analysis (OR = 1.47, 95% CI: 1.29-1.67, p < 0.0001). Adjustment for demographics and components of metabolic syndrome attenuated this relationship (OR = 1.04, 95% CI: 0.88-1.23, p = 0.64). Moderate and severe NAFLD on ultrasound were increasingly associated with prevalent CKD in unadjusted analysis, but not after adjustment for metabolic syndrome components., Conclusion: After adjusting for features of metabolic syndrome, ultrasound-diagnosed NAFLD is not associated with prevalent CKD among US adults. Aggressive public health efforts are needed to prevent and treat metabolic syndrome., (Copyright © 2012 S. Karger AG, Basel.)

Despite advances in the management of patients with diabetes, diabetic nephropathy (DN) remains the most common cause of end-stage renal disease in the United States and worldwide. Inflammation and endothelial dysfunction appear to play a central role in the onset and the progression of DN. Recent evidence has emerged in the past decade to suggest uric acid is an inflammatory factor and may play a role in endothelial dysfunction. This has lead our group and others to explore the role of uric acid in the onset and progression of DN. In this review, we highlight some of the animal and human studies that implicate uric acid in DN. Based on the evidence we review, we conclude the need for properly planned randomized controlled studies to decrease uric acid levels and assess the impact of such therapy on diabetic kidney disease., (Published by Elsevier Inc.)

Objective: To examine uric acid (UA) as a possible predictor of the progression of coronary artery calcification (CAC) using data from the prospective Coronary Artery Calcification in Type 1 Diabetes (CACTI) Study., Research Design and Methods: CAC was measured by electron beam tomography at the baseline and at a follow-up 6.0±0.5 years later. The study population included 443 participants with type 1 diabetes and 526 control subjects who were free of diagnosed coronary artery disease at baseline. The presence of renal disease was defined by the presence of albuminuria and/or low glomerular filtration rate., Results: In subjects without renal disease, serum UA predicted CAC progression (odds ratio 1.30 [95% CI 1.07-1.58], P=0.007) independent of conventional cardiovascular risk factors including diabetes and the presence of metabolic syndrome., Conclusions: Serum UA levels predict the progression of coronary atherosclerosis and may be useful in identifying who is at risk for vascular disease in the absence of significant chronic kidney disease.

The recent increase in fructose consumption in industrialized nations mirrors the rise in the prevalence of hypertension, but epidemiologic studies have inconsistently linked these observations. We investigated whether increased fructose intake from added sugars associates with an increased risk for higher BP levels in US adults without a history of hypertension. We conducted a cross-sectional analysis using the data collected from the National Health and Nutrition Examination Survey (NHANES 2003 to 2006) involving 4528 adults without a history of hypertension. Median fructose intake was 74 g/d, corresponding to 2.5 sugary soft drinks each day. After adjustment for demographics; comorbidities; physical activity; total kilocalorie intake; and dietary confounders such as total carbohydrate, alcohol, salt, and vitamin C intake, an increased fructose intake of > or =74 g/d independently and significantly associated with higher odds of elevated BP levels: It led to a 26, 30, and 77% higher risk for BP cutoffs of > or =135/85, > or =140/90, and > or =160/100 mmHg, respectively. These results suggest that high fructose intake, in the form of added sugar, independently associates with higher BP levels among US adults without a history of hypertension.

Background: Recent studies suggest that uric acid is a mediator of diabetic nephropathy. We hypothesized that elevated serum uric acid levels are a strong predictor of albuminuria in patients with type 1 diabetes., Methods: We analyzed data from the Coronary Artery Calcification in Type 1 Diabetes study, a prospective observational study. A stepwise logistic regression model was applied to predict the development of micro- or macroalbuminuria after 6 years of follow-up in 324 participants who had no evidence of micro- or macroalbuminuria at baseline. A P-value <0.1 was used as the criteria for entry into and removal from the model., Results: The following factors were selected in the stepwise multivariate model as predictors of micro- or macroalbuminuria at the 6-year follow-up visit: baseline serum uric acid levels, HbA(1c) and pre-albuminuria. For every 1-mg/dl increase in serum uric acid levels at baseline, there was an 80% increased risk of developing micro- or macroalbuminuria at 6 years (odds ratio 1.8; 95% confidence interval 1.2, 2.8; P = 0.005). Additional covariates considered in the stepwise model were sex, age, duration of diabetes, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker treatment, waist circumference, waist/hip ratio, body mass index, systolic and diastolic blood pressure, smoking, serum creatinine, cystatin C, high-density lipoprotein cholesterol and triglycerides., Conclusion: Elevated serum uric acid levels are a strong predictor of the development of albuminuria in patients with type 1 diabetes.

Chronic kidney disease (CKD) is a growing global health problem. CKD is typically associated with a prothrombotic tendency in the early stages of the disease, whereas in its more advanced stage, that is, end-stage renal disease, patients suffer from a prothrombotic tendency and, in many cases, a bleeding diathesis. The exact etiology behind the coexistence of these conflicting hemostatic disorders is poorly understood. This review critically appraises studies examining the abnormalities in the hemostasis pathway in patients with CKD, as well as the therapeutic options that are currently available to treat these individuals.

Aldosterone is a major regulator of epithelial Na(+) absorption. One of its principal targets is the epithelial Na(+) channel alpha-subunit (ENaCalpha), principally expressed in the kidney collecting duct, lung, and colon. Models of aldosterone-mediated trans-activation of the ENaCalpha gene have focused primarily on interactions of liganded nuclear receptors with the ENaCalpha gene promoter. Herein, we demonstrate that the murine histone H3 lysine-79 methyltransferase, murine disruptor of telomeric silencing alternative splice variant "a" (mDot1a), is a novel component in the aldosterone signaling network controlling transcription of the ENaCalpha gene. Aldosterone downregulated mDot1a mRNA levels in murine inner medullary collecting ducts cells, which was associated with histone H3 K79 hypomethylation in bulk histones and at specific sites in the ENaCalpha 5'-flanking region, and trans-activation of ENaCalpha. Knockdown of mDot1a by RNA interference increased activity of a stably integrated ENaCalpha promoter-luciferase construct and expression of endogenous ENaCalpha mRNA. Conversely, overexpression of EGFP-tagged mDot1a resulted in hypermethylation of histone H3 K79 at the endogenous ENaCalpha promoter, repression of endogenous ENaCalpha mRNA expression, and decreased activity of the ENaCalpha promoter-luciferase construct. mDot1a-mediated histone H3 K79 hypermethylation and repression of ENaCalpha promoter activity was abolished by mDot1a mutations that eliminate its methyltransferase activity. Collectively, our data identify mDot1a as a novel aldosterone-regulated histone modification enzyme, and, through binding the ENaCalpha promoter and hypermethylating histone H3 K79 associated with the ENaCalpha promoter, a negative regulator of ENaCalpha transcription.

NF-kappaB is a critical transcription factor that is involved in glomerulonephritis and inflammatory host responses and a critical transactivator of the inducible nitric oxide (NO) synthase gene in mesangial cells. The Src protein tyrosine kinases (SFK) are involved in several signaling pathways and have been proposed to mediate cytokine activation of NF-kappaB in a few cell types. However, the specific involvement of SFK in IL-1beta induction of NO production has not been clearly established. Accordingly, pharmacologic and molecular tools were used to clarify this issue in cultured murine mesangial cells. The SFK antagonist 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo(3,4-d)pyrimidine (PP2) dramatically inhibited IL-1beta-mediated induction of endogenous NO production as measured by the Griess reaction, as well as the induction of NF-kappaB p50/p65 DNA-binding activity in gel shift assays and the activity of an NF-kappaB-responsive promoter-reporter construct transiently transfected into the cells. Immunoprecipitation and immunoblotting with anti-IkappaBalpha and anti-phosphotyrosine antibodies revealed that PP2 also inhibited IL-1beta-stimulated tyrosine phosphorylation of IkappaBalpha, a requisite step in NF-kappaB activation in this signaling cascade. In agreement with the pharmacologic inhibition studies, siRNA directed against c-Src specifically limited c-Src protein expression and inhibited IL-1beta-mediated induction of NF-kappaB DNA-binding activity, whereas control siRNA had no effect. Conversely, overexpression of constitutively active c-Src augmented basal and IL-1beta-mediated induction of NF-kappaB DNA-binding activity and NO production. Thus, SFK play a key role in IL-1beta-induced NO production in mesangial cells and do so via tyrosine phosphorylation of IkappaBalpha and consequent NF-kappaB activation.