Association of urinary uromodulin with kidney function decline and mortality: the health ABC study .

BackgroundUrine uromodulin (uUMOD) is a protein secreted by the kidney tubule. Recent studies have suggested that higher uUMOD may be associated with improved kidney and mortality outcomes.MethodsUsing a case-cohort design, we evaluated the association between baseline uUMOD levels and ≥ 30% estimated glomerular filtration rate (eGFR) decline, incident chronic kidney disease (CKD), rapid kidney function decline, and mortality using standard and modified Cox proportional hazards regression.ResultsThe median value of uUMOD was 25.8 µg/mL, mean age of participants was 74 years, 48% were women, and 39% were black. Persons with higher uUMOD had lower prevalence of diabetes and coronary artery disease (CAD), and had lower systolic blood pressure. Persons with higher uUMOD also had higher eGFR, lower urinary albumin to creatinine ratio (ACR), and lower C-reactive protein (CRP). There was no association of uUMOD with > 30% eGFR decline. In comparison to those in the lowest quartile of uUMOD, those in the highest quartile had a significantly (53%) lower risk of incident CKD (CI 73%, 18%) and a 51% lower risk of rapid kidney function decline (CI 76%, 1%) after multivariable adjustment. Higher uUMOD was associated with lower risk of mortality in demographic adjusted models, but not after multivariable adjustment.ConclusionHigher levels of uUMOD are associated with lower risk of incident CKD and rapid kidney function decline. Additional studies are needed in the general population and in persons with advanced CKD to confirm these findings.


Femoral Artery Atherosclerosis Is Associated With Physical Function Across the Spectrum of the Ankle-Brachial Index: The San Diego Population Study.

BackgroundThe ankle-brachial index (ABI) is inadequate to detect early-stage atherosclerotic disease, when interventions to prevent functional decline may be the most effective. We determined associations of femoral artery atherosclerosis with physical functioning, across the spectrum of the ABI, and within the normal ABI range.Methods and resultsIn 2007-2011, 1103 multiethnic men and women participated in the San Diego Population Study, and completed all components of the summary performance score. Using Doppler ultrasound, superficial and common femoral intima media thickness and plaques were ascertained. Logistic regression was used to assess associations of femoral atherosclerosis with the summary performance score and its individual components. Models were adjusted for demographics, lifestyle factors, comorbidities, lipids, and kidney function. In adjusted models, among participants with a normal-range ABI (1.00-1.30), the highest tertile of superficial intima media thickness was associated with lower odds of a perfect summary performance score of 12 (odds ratio=0.56 [0.36, 0.87], P=0.009), and lower odds of a 4-m walk score of 4 (0.34 [0.16, 0.73], P=0.006) and chair rise score of 4 (0.56 [0.34, 0.94], P=0.03). Plaque presence (0.53 [0.29, 0.99], P=0.04) and greater total plaque burden (0.61 [0.43, 0.87], P=0.006) were associated with worse 4-m walk performance in the normal-range ABI group. Higher superficial intima media thickness was associated with lower summary performance score in all individuals (P=0.02).ConclusionsFindings suggest that use of femoral artery atherosclerosis measures may be effective in individuals with a normal-range ABI, especially, for example, those with diabetes mellitus or a family history of peripheral artery disease, when detection can lead to earlier intervention to prevent functional declines and improve quality of life

Fibroblast Growth Factor–23 and Cardiac Structure and Function

Background: Fibroblast growth factor–23 (FGF‐23) is a phosphaturic factor previously associated with left ventricular hypertrophy and systolic dysfunction among individuals with chronic kidney disease. Whether FGF‐23 acts directly to induce left ventricular hypertrophy, potentially independent of its klotho coreceptor, remains uncertain. We investigated associations of FGF‐23 with cardiac structural abnormalities among individuals with a broad range of kidney function and explored potential biological mechanisms using cardiac magnetic resonance imaging and histology in klotho‐null mice, an established model of constitutively elevated FGF‐23. Methods and Results: Among 887 participants with coronary artery disease in the Heart and Soul Study, FGF‐23 was modestly associated with worse left ventricular ejection fraction (−1.0% per standard deviation increase in lnFGF‐23; standard error, 0.4%), but was not associated with the overall prevalence of concentric hypertrophy (odds ratio, 1.5; CI, 0.9 to 2.4) or eccentric hypertrophy (odds ratio, 1.1; CI, 0.9 to 1.3). FGF‐23 was only associated with concentric hypertrophy among individuals with diminished kidney function (eGFR <60 mL/min per 1.73 m2; odds ratio, 2.3; CI, 1.0 to 5.3; P‐interaction=0.28). Comparing klotho‐null with wild‐type mice, null mice did not have greater left ventricular mass (P=0.37) or a lower ejection fraction (P=0.94). Conclusions: Together, our results suggest that FGF‐23 is unlikely to have major effects on cardiovascular structure and function among patients free of substantial chronic kidney disease, and these effects may not be independent of the klotho coreceptor

Mechanisms of action of the SGLT2 inhibitor canagliflozin on tubular inflammation and damage:A post-hoc mediation analysis of the CANVAS trial

AIMS: Exposure of tubular cells to albumin stimulates pro-inflammatory pathways including the release of Monocyte Chemoattractant Protein-1 (MCP-1) which may result in interstitial fibrosis and tubular damage reflected by increased urinary kidney injury molecule-1 (KIM-1). SGLT2 inhibition reduces urine albumin-creatinine ratio (UACR) and small studies suggest it also reduces MCP-1 and KIM-1. We hypothesised that the reduction in KIM-1 observed with the SGLT2 inhibitor canagliflozin is mediated through its effect on UACR and MCP-1. To test this hypothesis, we assessed the proportion of effect of canagliflozin on KIM-1 mediated through its effects on MCP-1 and UACR in patients with type 2 diabetes and albuminuric kidney disease. MATERIAL AND METHODS: KIM-1 and MCP-1 were measured in urine samples of the CANVAS trial at baseline and week 52 with the Mesoscale QuickPlex SQ 120 platform. KIM-1 and MCP-1 were standardized by urinary creatinine. The proportion of mediated effect of canagliflozin through UACR and MCP-1/Cr on KIM-1/Cr was estimated with G-computation. RESULTS: In total, 763 (17.6% of total cohort) patients with micro- or macroalbuminuria were included. Baseline characteristics were well balanced between the canagliflozin and placebo group. At year 1, canagliflozin compared to placebo reduced UACR, MCP-1/Cr, and KIM-1/Cr by 40.4% (95%CI 31.0, 48.4), 18.1% (95%CI 8.9, 26.4), and 30.9% (95%CI 23.0, 38.0), respectively. The proportion of the effect of canagliflozin on KIM-1/Cr mediated by its effect on UACR and in turn on MCP-1/Cr was 15.2% (95%CI 9.4, 24.5). CONCLUSION: Canagliflozin reduces urinary KIM-1 suggesting decreased tubular damage. This effect was partly mediated through a reduction in MCP-1, indicative of reduced tubular inflammation, which was in turn mediated by a reduction in UACR. This post-hoc analysis suggest that urinary albumin leakage may lead to tubular inflammation and induction of injury, and provide mechanistic insight for how canagliflozin may ameliorate tubular damage, but further research is required to confirm these findings. This article is protected by copyright. All rights reserved

Genetically Elevated Fetuin-A Levels, Fasting Glucose Levels, and Risk of Type 2 Diabetes: The Cardiovascular Health Study*

OBJECTIVE Fetuin-A levels are associated with higher risk of type 2 diabetes, but it is unknown if the association is causal. We investigated common (>5%) genetic variants in the fetuin-A gene (AHSG) fetuin-A levels, fasting glucose, and risk of type 2 diabetes. RESEARCH DESIGN AND METHODS Genetic variation, fetuin-A levels, and fasting glucose were assessed in 2,893 Caucasian and 542 African American community-living individuals 65 years of age or older in 1992–1993. RESULTS Common AHSG variants (rs4917 and rs2248690) were strongly associated with fetuin-A concentrations (P < 0.0001). In analyses of 259 incident cases of type 2 diabetes, the single nucleotide polymorphisms (SNPs) were not associated with diabetes risk during follow-up and similar null associations were observed when 579 prevalent cases were included. As expected, higher fetuin-A levels were associated with higher fasting glucose concentrations (1.9 mg/dL [95% CI, 1.2–2.7] higher per SD in Caucasians), but Mendelian randomization analyses using both SNPs as unbiased proxies for measured fetuin-A did not support an association between genetically predicted fetuin-A levels and fasting glucose (−0.3 mg/dL [95% CI, −1.9 to 1.3] lower per SD in Caucasians). The difference between the associations of fasting glucose with actual and genetically predicted fetuin-A level was statistically significant (P = 0.001). Results among the smaller sample of African Americans trended in similar directions but were statistically insignificant. CONCLUSIONS Common variants in the AHSG gene are strongly associated with plasma fetuin-A concentrations, but not with risk of type 2 diabetes or glucose concentrations, raising the possibility that the association between fetuin-A and type 2 diabetes may not be causal

Hemoglobin A1c and Arterial and Ventricular Stiffness in Older Adults

Objective: Arterial and ventricular stiffening are characteristics of diabetes and aging which confer significant morbidity and mortality; advanced glycation endproducts (AGE) are implicated in this stiffening pathophysiology. We examined the association between HbA1c, an AGE, with arterial and ventricular stiffness measures in older individuals without diabetes. Research Design & Methods: Baseline HbA1c was measured in 830 participants free of diabetes defined by fasting glucose or medication use in the Cardiovascular Health Study, a population-based cohort study of adults aged ≥65 years. We performed cross-sectional analyses using baseline exam data including echocardiography, ankle and brachial blood pressure measurement, and carotid ultrasonography. We examined the adjusted associations between HbA1c and multiple arterial and ventricular stiffness measures by linear regression models and compared these results to the association of fasting glucose (FG) with like measures. Results: HbA1c was correlated with fasting and 2-hour postload glucose levels (r = 0.21; p<0.001 for both) and positively associated with greater body-mass index and black race. In adjusted models, HbA1c was not associated with any measure of arterial or ventricular stiffness, including pulse pressure (PP), carotid intima-media thickness, ankle-brachial index, end-arterial elastance, or left ventricular mass (LVM). FG levels were positively associated with systolic, diastolic and PP and LVM. Conclusions: In this sample of older adults without diabetes, HbA1c was not associated with arterial or ventricular stiffness measures, whereas FG levels were. The role of AGE in arterial and ventricular stiffness in older adults may be better assessed using alternate AGE markers

Total and High-Molecular-Weight Adiponectin and Risk of Incident Diabetes in Older People

OBJECTIVE To delineate the associations of total adiponectin, high-molecular-weight (HMW) adiponectin, and the HMW-to-total adiponectin ratio with diabetes in older adults. RESEARCH DESIGN AND METHODS Total and HMW adiponectin were measured in a population-based study of older adults. The relations of total adiponectin, HMW adiponectin, and their ratio with incident diabetes (n = 309) were assessed in 3,802 individuals. RESULTS Total and HMW adiponectin were highly correlated (r = 0.94). Analysis using cubic splines revealed that the associations between total and HMW adiponectin and new-onset diabetes were not linear. Specifically, after adjustment for confounders, there were similar inverse relationships for total (hazard ratio per SD 0.49 [95% CI 0.39–0.63]) and HMW adiponectin (0.42 [0.32–0.56]) with diabetes up to values of 20 and 10 mg/L, respectively, above which the associations plateaued. These associations persisted after adjustment for potential mediators (blood pressure, lipids, C-reactive protein, and homeostasis model assessment of insulin resistance [HOMA-IR]). There was, however, evidence of interaction by HOMA-IR in the lower range of adiponectin, with stronger inverse associations among insulin-sensitive than insulin-resistant participants. HMW-to-total adiponectin ratio showed a linear adjusted association with outcome, but this was abolished by inclusion of mediating variables. CONCLUSIONS In this older cohort, increasing concentrations of total and HMW adiponectin were associated with comparably lower risks of diabetes, but these associations leveled off with further increases above concentrations of 20 and 10 mg/L, respectively. The more pronounced risk decreases at the lower range among participants without insulin resistance support a role for adiponectin that is independent of baseline hyperinsulinemia, but this will require further investigation

Main technical-productive characteristics of meliponiculture in two locations of the municipality of Calkiní, Campeche

Objective: to identify the main technical-productive characteristics of two production systems (traditional and technified) dedicated to meliponiculture in two locations in the municipality of Calkiní, Campeche. Design/methodology/approach: From August to December 2021, applications of semi-structured interviews of 60 reagents were carried out to the meliponiculturists of Pucnanchen and Santa Cruz. Where by means of the snowball method the population of meliponiculturists was found. Results: A total of 43 colonies of bees of the species M. beecheii (39 hobones and 14 technified boxes) were found. The meliponiculturists interviewed are over 49 years old and have an average of 10.75 colonies per meliponary. Likewise, the modern meli-ponarios have replaced the roofing with huano, by the use of galvanized sheet and the hobones have been replaced by the use of technified boxes for the breeding of native bees. Limitations of the study/implications: this study describes the technical-productive characteristics of the two production systems used in meliponiculture (traditional and technical) in two locations in the municipality of Calkiní, Campeche. Findings/conclusions: there is a reduction in the number of people who practice meliponiculture, which is an activity that is still rooted in rural communities and that still retains importance from the economic, cultural and cultural point of view. Social. The uses of melipona honey in the health of people belonging to rural communities, is an activity that still persists, as well as the customs associated with the religious context.Objective: To identify the main technical-productive characteristics of two meliponiculture production systems—traditional and technical—in two locations of the municipality of Calkiní, Campeche. Design/Methodology/Approach: Semi-structured interviews of 60 items were applied to bee growers from Pucnanchen and Santa Cruz between August and December 2021. The population of meliponiculturists was established by using the snowball method. Results: We found a total of 43 bee colonies of the M. beecheii species (39 hobones and 14 technified boxes). The interviewed meliponiculturists are over 49 years old and have an average of 10.75 colonies per meliponary. In modern meliponaries, galvanized metal sheets have replaced huano (Sabal yapa) leaf roofing. Likewise, some hobones have been replaced by technified boxes to breed native bees. Study limitations/Implications: This study describes the technical-productive characteristics of the two production systems (traditional and technical) used in meliponiculture in two locations of the municipality of Calkiní, Campeche. Findings/Conclusions: There is a decline in the number of people practicing meliponiculture, an activity still rooted in rural communities and that retains its economic, cultural, and social importance. In rural communities, the use of melipona honey for health purposes persists, as well as the religious customs associated with this type of honey

Dietary Phosphorus, Blood Pressure, and Incidence of Hypertension in the Atherosclerosis Risk in Communities Study and the Multi-Ethnic Study of Atherosclerosis

Greater phosphorus intake has been associated with lower levels of blood pressure in cross-sectional studies. This association, however, has not been assessed prospectively. We studied 13444 participants from the Atherosclerosis Risk in Communities cohort and the Multi-Ethnic Study of Atherosclerosis, with diet assessed at baseline using validated food frequency questionnaires. Blood pressure and use of antihypertensive medication were determined at baseline and during follow-up visits. Compared to individuals in the lowest quintile of phosphorus intake at baseline, those in the highest quintile had lower baseline systolic and diastolic blood pressure after adjustment for dietary and non-dietary confounders (−2.0 mmHg, 95% confidence interval −3.6, −0.5; p for trend=0.01; and −0.6, 95% confidence interval −1.6, +0.3, p for trend=0.20, respectively). During an average 6.2 years of follow-up, 3345 cases of hypertension were identified. Phosphorus intake was associated with the risk of hypertension (hazard ratio 0.80, 95% confidence interval 0.80-1.00, comparing extreme quintiles; p for trend=0.02) after adjustment for non-dietary factors, but not after additional adjustment for dietary variables (hazard ratio 1.01, 95% confidence interval 0.82-1.23, p for trend=0.88). Phosphorus from dairy products but not from other sources was associated with lower baseline blood pressure and reduced risk of incident hypertension. Hazard ratios (95% confidence interval) comparing extreme quintiles were 0.86 (0.76-0.97), p for trend=0.01, for phosphorus from dairy foods and 1.04 (0.93-1.17), p for trend=0.48, for phosphorus from other foods. These findings could indicate an effect of phosphorus in conjunction with other dairy constituents or of dairy itself without involvement of phosphorus

Fibroblast growth factor 23 is related to profiles indicating volume overload, poor therapy optimization and prognosis in patients with new-onset and worsening heart failure

Background: Fibroblast growth factor (FGF) 23 is a hormone that increases urinary phosphate excretion and regulates renal sodium reabsorption and plasma volume. We studied the role of plasma FGF23 in therapy optimization and outcomes in patients with new-onset and worsening heart failure (HF). Methods: We measured plasma C-terminal FGF23 levels at baseline in 2399 of the 2516 patients included in the BIOlogy Study to Tailored Treatment in Chronic HF (BIOSTAT-CHF) trial. The association between FGF23 and outcome was evaluated by Cox regression analysis adjusted for potential confounders. Results: Median FGF23 was 218.0 [IQR: 117.1–579.3] RU/ml; patients with higher FGF23 levels had a worse NYHA class, more signs of congestion, and were less likely to use an ACE-inhibitor (ACEi) or angiotensin receptor blocker (ARBs) at baseline (all P &lt; 0.01). Higher FGF23 levels were independently associated with higher BNP, lower eGFR, the presence of oedema and atrial fibrillation (all P &lt; 0.001). In addition, higher FGF23 was independently associated with impaired uptitration of ACEi/ARBs after 3 months, but not of beta-blockers. In multivariable Cox regression analysis, FGF23 was independently associated with all-cause mortality (hazard ratio: 1.17 (1.09–1.26) per log increase, P &lt; 0.001), and the combined endpoint of all-cause mortality and HF hospitalization (1.15 (1.08–1.22) per log increase, P &lt; 0.001). Conclusions: In patients with new-onset and worsening HF, higher plasma FGF23 levels were independently associated with volume overload, less successful uptitration of ACEi/ARBs and an increased risk of all-cause mortality and HF hospitalization