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Abstract Context A comprehensive characterization of racial/ethnic variations in vitamin D metabolism markers may improve our understanding of differences in bone and mineral homeostasis and the risk of vitamin D–related diseases. Objective Describe racial/ethnic differences in vitamin D metabolism markers and their associations with genetic ancestry. Design, Setting, Participants In a cross-sectional study within the Multi-Ethnic Study of Atherosclerosis (MESA), we compared a comprehensive panel of vitamin D metabolism markers across self-reported racial/ethnic groups of Black (N = 1759), White (N = 2507), Chinese (N = 788), and Hispanic (N = 1411). We evaluated associations of proportion African and European ancestry with this panel of markers in Black and Hispanic participants using ancestry informative markers. Latent class analysis evaluated associations between patterns of vitamin D measurements with race/ethnicity. Results Compared with Black participants, White participants had significantly higher serum concentrations of 25-hydroxyvitamin D and fibroblast growth factor-23; lower concentrations of parathyroid hormone and 1,25-dihydroxyvitamin D; circulating vitamin D metabolite ratios suggesting lower CYP27B1 and higher CYP24A1 activity; higher urinary concentrations of calcium and phosphorus with higher urinary fractional excretion of phosphorus; and differences in vitamin D binding globulin haplotypes. Higher percent European ancestry was associated with higher 25-hydroxyvitamin D and lower parathyroid hormone concentrations among Black and Hispanic participants. Latent classes defined by vitamin D measurements reflected these patterns and differed significantly by race/ethnicity and ancestry. Conclusions Markers of vitamin D metabolism vary significantly by race/ethnicity, may serve to maintain bone and mineral homeostasis across ranges of 25-hydroxyvitamin D production, and be attributable, at least partly, to genetic ancestry.

Pentraxin-3 (PTX3) is an inflammatory marker thought to be more specific to vascular inflammation than C-reactive protein (CRP). Whether PTX3 is independently associated with adverse events among persons with stable coronary heart disease (CHD), independently of CRP, and whether kidney dysfunction influences these associations are not known. We evaluated the associations of baseline PTX3 levels with all-cause mortality, cardiovascular (CV) events (myocardial infarction, stroke, or CHD death), and incident heart failure (HF) during 37 months among ambulatory persons with stable CHD participating in the Heart and Soul Study. Cox proportional hazards models were adjusted for age, sex, race, hypertension, diabetes, smoking, and CRP. Among 986 persons with stable CHD, each 1 unit increase in log PTX3 at baseline was associated with an 80% increased risk of all-cause mortality (hazard ratio [HR] 1.8, 95% CI 1.5-2.1), a 50% increased risk of CV events (HR 1.5, 95% CI, 1.2-1.9), and an 80% greater risk of incident HF (HR 1.8, 95% CI, 1.3-2.5). Further adjustment for estimated glomerular filtration rate (eGFR) attenuated these associations to 1.6 (1.3-1.9) for mortality, 1.3 (1.0-1.6) for CV events and 1.5 (1.1-2.1) for incident HF. Stratification by eGFR >60 mL/min per 1.73m2 or <60 mL/min per 1.73m2 did not affect these associations (P interaction > .3 for all outcomes). Among persons with stable CHD, higher PTX3 concentrations were associated with increased risk for all-cause mortality, CV events, and incident HF independently of systemic inflammation. Adjustment for eGFR modestly attenuated these associations, suggesting that future studies of PTX3 should adjust for kidney function.

Background Mortality is high within the first few months of starting chronic dialysis. Pre-ESKD trajectory of kidney function has been shown to be predictive of early death after dialysis initiation. We aim to better understand how two key aspects of pre-dialysis kidney function—an abrupt transition pattern and an episode of dialysis-requiring AKI (AKI-D) leading directly to ESKD—are associated with early mortality after dialysis initiation. Methods We extracted national data from U.S. Veterans Health Administration cross-linked with the United States Renal Data System (USRDS) to identify patients who initiated hemodialysis during 2009–2013. We defined abrupt transition as having a mean outpatient eGFR ≥ 30 ml/min/1.73m 2 within 1 year prior to ESKD. AKI-D was identified using inpatient serum creatinine measurements (serum Cr increase by at least 50% from baseline) along with billing codes for inpatient receipt of dialysis for AKI within 30 days prior to the ESKD start date. We used multivariable proportional hazards models to examine the association between patterns of kidney function prior to ESKD and all-cause mortality within 90 days after ESKD. Results Twenty-two thousand eight hundred fifteen patients were identified in the final analytic cohort of Veterans who initiated hemodialysis and entered the USRDS. We defined five patterns of kidney function decline. Most (68%) patients ( N  = 15,484) did not have abrupt transition and did not suffer an episode of AKI-D prior to ESKD (reference group). The remaining groups had abrupt transition, AKI-D, or both. Patients who had an abrupt transition with ( N  = 503) or without ( N  = 3611) AKI-D had the highest risk of early mortality after ESKD onset after adjustment for demographics and comorbidities (adjusted HR 2.10, 95% CI 1.66–2.65 for abrupt transition with AKI-D; adjusted HR 2.10, 95% CI 1.90–2.33 for abrupt transition without AKI-D). In contrast, patients who experienced AKI-D without an abrupt transition pattern ( N  =  2141 had only a modestly higher risk of early death (adjusted HR 1.19, 95% CI 1.01–1.40). Conclusions An abrupt decline in kidney function within 1 year prior to ESKD occurred in nearly 1 in 5 incident hemodialysis patients (18%) in this national cohort of Veterans and was strongly associated with higher early mortality after ESKD onset.

Background Electronic health record (EHR) data is increasingly used to identify patients with chronic kidney disease (CKD). EHR queries used to capture CKD status, identify comorbid conditions, measure awareness by providers, and track adherence to guideline-concordant processes of care have not been validated. Methods We extracted EHR data for primary-care patients with two eGFRcreat 15-59 mL/min/1.73 m^2 at least 90 days apart. Two nephrologists manually reviewed a random sample of 50 charts to determine CKD status, associated comorbidities, and physician awareness of CKD. We also assessed the documentation of a CKD diagnosis with guideline-driven care. Results Complete data were available on 1767 patients with query-defined CKD of whom 822 (47%) had a CKD diagnosis in their chart. Manual chart review confirmed the CKD diagnosis in 34 or 50 (68%) patients. Agreement between the reviewers and the EHR diagnoses on the presence of comorbidities was good (κ > 0.70, p  < 0.05), except for congestive heart failure, (κ = 0.45, p  < 0.05). Reviewers felt the providers were aware of CKD in 23 of 34 (68%) of the confirmed CKD cases. A CKD diagnosis was associated with higher odds of guideline-driven care including CKD-specific laboratory tests and prescriptions for statins. After adjustment, CKD diagnosis documentation was not significantly associated with ACE/ARB prescription. Conclusions Identifying CKD status by historical eGFRs overestimates disease prevalence. A CKD diagnosis in the patient chart was a reasonable surrogate for provider awareness of disease status, but CKD awareness remains relatively low. CKD in the patient chart was associated with higher rates of albuminuria testing and use of statins, but not use of ACE/ARB.

Using ~60,000 SNPs selected for minimal linkage disequilibrium, we perform population structure analysis of 1,374 unrelated Hispanic individuals from the Multi-Ethnic Study of Atherosclerosis (MESA), with self-identification corresponding to Central America (n = 93), Cuba (n = 50), the Dominican Republic (n = 203), Mexico (n = 708), Puerto Rico (n = 192), and South America (n = 111). By projection of principal components (PCs) of ancestry to samples from the HapMap phase III and the Human Genome Diversity Panel (HGDP), we show the first two PCs quantify the Caucasian, African, and Native American origins, while the third and fourth PCs bring out an axis that aligns with known South-to-North geographic location of HGDP Native American samples and further separates MESA Mexican versus Central/South American samples along the same axis. Using k-means clustering computed from the first four PCs, we define four subgroups of the MESA Hispanic cohort that show close agreement with self-identification, labeling the clusters as primarily Dominican/Cuban, Mexican, Central/South American, and Puerto Rican. To demonstrate our recommendations for genetic analysis in the MESA Hispanic cohort, we present pooled and stratified association analysis of triglycerides for selected SNPs in the LPL and TRIB1 gene regions, previously reported in GWAS of triglycerides in Caucasians but as yet unconfirmed in Hispanic populations. We report statistically significant evidence for genetic association in both genes, and we further demonstrate the importance of considering population substructure and genetic heterogeneity in genetic association studies performed in the United States Hispanic population.

Background There are major gaps in the implementation of guideline-concordant care for persons with chronic kidney disease (CKD). The CKD Cascade of Care (C 3 ) initiative seeks to improve CKD care by improving detection and treatment of CKD in primary care. Methods C 3 is a multi-modal initiative deployed in three major academic medical centers within the Department of Veterans Affairs (VA) Health Care System: San Francisco VA, San Diego VA, and Houston VA. The main objective of the first phase of C 3 described in this protocol is to establish the infrastructure for universal CKD detection among primary care patients at high-risk for CKD with a triple-marker screen comprising cystatin C, creatinine, and albuminuria. Across the three sites, a comprehensive educational intervention and the integration of primary care-based clinical champions will be employed with the goal of improving CKD detection and treatment. The San Francisco VA will also implement a practice-facilitation intervention leveraging telehealth and health informatics tools and capabilities for enhanced CKD detection. Parallel formative evaluation across the three sites will assess the feasibility and acceptability of integrating cystatin C as part of routine CKD detection in primary care practice. The effectiveness of the interventions will be assessed using a pre-post observational design for change in the proportion of patients tested annually for CKD. Secondary outcomes will assess change in the initiation of cardio-kidney protective therapies and in nephrology referrals of high-risk patients. Discussion The first phase of C 3 is a multi-facility multi-modal initiative that aims to improve CKD care by implementing a triple-marker screen for enhanced CKD detection in primary care.

OBJECTIVE: Insulin resistance is a risk factor for cardiovascular and noncardiovascular diseases. Impaired kidney function is linked with insulin resistance and may affect relationships of insulin resistance with health outcomes. RESEARCH DESIGN AND METHODS: We performed a cohort study of 3,138 Cardiovascular Health Study participants (age ≥65 years) without diabetes. Insulin sensitivity index (ISI) was calculated from fasting and 2-h postload insulin and glucose concentrations. Associations of ISI and fasting insulin concentration with all-cause mortality were tested using Cox proportional hazards models, adjusting for demographic variables, prevalent cardiovascular disease, lifestyle variables, waist circumference, and LDL cholesterol. Subsequent models were additionally adjusted for or stratified by glomerular filtration rate estimated using serum cystatin C (eGFR). RESULTS: A total of 1,810 participants died during the 14.7-year median follow-up. Compared with the highest quartile of ISI, the lowest quartile (most insulin resistant) was associated with 21% (95% CI 6–41) and 11% (–3 to 29) higher risks of death without and with adjustment for eGFR, respectively. Compared with the lowest quartile of fasting insulin concentration, the highest quartile was associated with 22% (4–43) and 4% (–12 to 22) higher risks of death without and with adjustment for eGFR, respectively. Similar attenuation by eGFR was observed when blood pressure, triglycerides, HDL cholesterol, and C-reactive protein were included in models. CONCLUSIONS: Insulin resistance measured as ISI or fasting insulin concentration is associated with increased risk of death among older adults, adjusting for conventional confounding characteristics. Impaired kidney function may mediate or confound this relationship.

Background Although microvascular dysfunction is known to result from diabetes, it might also lead to diabetes. Lower values of C2, a derivative of the radial artery pressure waveform, indicate microvascular dysfunction and predict hypertension and cardiovascular disease (CVD). We studied the association of C2 with incident diabetes in subjects free of overt CVD. Methods Among multi-ethnic participants (n = 5214), aged 45–84 years with no diabetes, C2 was derived from the radial artery pressure waveform. Incident diabetes (N = 651) was diagnosed as new fasting glucose ≥ 126 mg/dL or antidiabetic medicine over ~ 10 years. The relative incidence density (RID) for incident diabetes per standard deviation (SD) of C2 was studied during ~ 10 years follow-up using four levels of adjustment. Results Mean C2 at baseline was 4.58 ± 2.85 mL/mmHg × 100. The RID for incident diabetes per SD of C2 was 0.90 (95% CI 0.82–0.99, P = 0.03). After adjustment for demographics plus body size, the corresponding RID was 0.81 (95% CI 0.73–0.89, P < 0.0001); body mass index (BMI) was the dominant covariate here. After adjustment for demographics plus cardiovascular risk factors, the RID was 0.98 (95% CI 0.89, 1.07, P = 0.63). After adjustment for all the parameters in the previous models, the RID was 0.87 (95% CI 0.78, 0.96, P = 0.006). Conclusions In a multi-ethnic sample free of overt CVD and diabetes at baseline, C2 predicted incident diabetes after adjustment for demographics, BMI and CVD risk factors. Differences in arterial blood pressure wave morphology may indicate a long-term risk trajectory for diabetes, independently of body size and the classical risk factors.

Background Defined as estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2, chronic kidney disease (CKD) is strongly and independently associated with cardiovascular and overall mortality. We hypothesized that reduced kidney function would be characterized by abnormalities of hemostasis. Methods We tested cross-sectional associations between (eGFR) and multiple hemostatic markers among 6751 participants representing a broad spectrum of kidney function in the Multi-Ethnic Study of Atherosclerosis (MESA). Kidney function was measured using cystatin C (eGFRcys) or creatinine, using CKD Epidemiology Collaboration (eGFRcr). Hemostatic markers included soluble thrombomodulin (sTM), soluble tissue factor (sTF), D-Dimer, von Willebrand factor (vWF), factor VIII, plasmin-antiplasmin complex (PAP), tissue factor pathway inhibitor (TFPI), plasminogen activator inhibitor-1 (PAI-1), and fibrinogen. Associations were tested using multivariable linear regression with adjustment for demographics and comorbidities. Results In comparison to persons with eGFRcys >90 ml/min/1.73 m 2 , subjects with eGFRcys < 60 ml/min/1.73 m 2 had adjusted levels of sTM, sTF, D-Dimer, PAP, Factor VIII, TFPI, vWF and fibrinogen that were respectively 86%, 68%, 44%, 22%, 17%, 15%, 12% and 6% higher. Subjects with eGFRcys 60-90 ml/min/1.73 m 2 had adjusted levels that were respectively 16%, 14%, 12%, 6%, 6%, 6%, 11% and 4% higher (p < 0.05 for all). Percent differences were not significantly different when groups were categorized by eGFRcr. Conclusions Throughout a broad spectrum of kidney function, lower eGFR was associated with higher levels of hemostatic markers. Dysregulation of hemostasis may be a mechanism by which reduced kidney function promotes higher cardiovascular risk.

Background Whether screening for chronic kidney disease (CKD) can improve the care of persons at high risk for complications remains uncertain. We describe the design and early implementation experience of a pilot, cluster-randomized pragmatic trial to evaluate the feasibility, implementation, and effectiveness of a “triple marker” CKD screening program (creatinine, cystatin C and albumin to creatinine ratio) for improving care among hypertensive veterans seen in primary care at one Veterans Administration Hospital. Methods/design Non-diabetic hypertensive veterans age 18–80 without known CKD were randomized in clusters determined by primary care provider (unit of randomization) into three arms. Usual care will be compared with two incrementally intensified treatment strategies: (1) screen for CKD followed by patient and provider education or (2) screen-educate plus a clinical pharmacist-led CKD and BP management program. The primary clinical outcome is systolic blood pressure (BP) change from baseline. Secondary clinical outcome is BP control. The primary process outcomes is triple marker screening (across three arms), and secondary process outcomes include use of inhibitors of the renin-angiotensin system (ACE/ARB) overall and in persons with albuminuria, CKD recognition by PCP, use of non-steroidal anti-inflammatory drugs (NSAIDs) and NSAID education by PCP. The design uses the Veterans Health Administration electronic health record (EHR) to identify participants, deliver the interventions and ascertain study outcomes. Assessment of the program implementation will use the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework. Study duration is 12 months. Results A total of 1,819 patients have been randomized within 41 provider clusters. The median age (interquartile range) is 68 years (61–72), and 99% of participants are male. Approximately 16% are Black, and 5% Hispanic. In the first 6 months of the trial, 434 triple marker screening tests have been ordered, and 217(50%) have been tested. A total of 48 new CKD cases have been identified among those tested, for a preliminary yield of 22%. Conclusion We have successfully implemented a pragmatic protocol that uses the EHR to identify and characterize eligible participants, deliver the intervention, and ascertain study outcomes with high rates of participation by providers and patients. Results from this study can guide design of pragmatic trials in the field of CKD. Trial registration NCT02059408 ; Date or Registration: 1/17/2014.