Faculty Bibliography

BACKGROUND: In older adults (aged 70-74 years), African-Americans have 4-fold higher risk of developing hypertension-attributed end-stage renal disease (ESRD) than European-Americans. A hypothesized mechanism linking hypertension and progressive chronic kidney disease (CKD) is the innate immune response and inflammation. Persons with CKD are also more susceptible to infection. Gene expression in peripheral blood can provide a view of the innate immune activation profile. We aimed to identify differentially expressed genes, microRNAs, and pathways in peripheral blood between cases with CKD and high blood pressure under hypertension treatment versus controls without CKD and with controlled blood pressure in African Americans. METHODS: Case and control pairs (N = 15x2) were selected from those without diabetes and were matched for age, sex, body mass index, APOL1 risk allele count, and hypertension medication use. High blood pressure under hypertension treatment was defined as hypertension medication use and systolic blood pressure (SBP) >/= 145 mmHg. CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2. Cases were selected from those with CKD and high blood pressure under hypertension treatment, and controls were selected from those without CKD (eGFR: 75-120 mL/min/1.73m2 and urine albumin-to-creatinine ratio < 30mg/g) and with blood pressure controlled by hypertension medication use (SBP < 135 mmHg and D(diastolic)BP < 90 mm Hg). We perform RNA sequencing of mRNA and microRNA and conducted differential expression and co-expression network analysis. RESULTS: Of 347 miRNAs included in the analysis, 14 were significantly associated with case status (Benjamini-Hochberg adjusted p-value [BH p] < 0.05). Of these, ten were downregulated in cases: three of each belong to the miR-17 and miR-15 families. In co-expression network analysis of miRNA, one module, which included 13 of the 14 significant miRNAs, had significant association with case status. Of the 14,488 genes and 41,739 transcripts included in the analysis, none had significant association with case status. Gene co-expression network analyses did not yield any significant associations for mRNA. CONCLUSION: We have identified 14 differentially expressed miRNAs in the peripheral blood of CKD cases with high blood pressure under hypertension treatment as compared to appropriate controls. Most of the significant miRNAs were downregulated and have critical roles in immune cell functions. Future studies are needed to replicate our findings and determine whether the downregulation of these miRNAs in immune cells may influence CKD progression or complications.

INTRODUCTION/BACKGROUND:The objective of this study was to investigate whether 10 phospholipids/metabolites previously identified as prospectively predictive of mild cognitive impairment (MCI) or dementia in whites would also be predictive in a mostly African-American cohort. METHODS:We repeatedly measured 188 phospholipids/metabolites in plasma samples of 221 participants of the Atherosclerosis Risk in Communities study, 97% African American, who were followed between 2004-2006 and 2011-2013. RESULTS:After a mean follow-up of 7.3 years, 77 were classified as having MCI and 18 as having dementia. Our study failed to replicate previous findings in this mostly African American cohort, in that the 10 phospholipids/metabolites only achieved a C statistic/AUC of 0.609 in predicting development of MCI or dementia (compared to 0.96) and 0.607 in distinguishing normal from MCI or dementia at the follow-up visit. CONCLUSION/CONCLUSIONS:A panel of 10 phospholipids/metabolites previously associated with incident dementia was not predictive of MCI or dementia in an independent cohort.

BACKGROUND:It is uncertain whether being overweight, but not obese, is associated with advanced chronic kidney disease (CKD) and how the size and shape of associations between body-mass index (BMI) and advanced CKD differs among different types of people. METHODS:We used Clinical Practice Research Datalink records (2000-2014) with linkage to English secondary care and mortality data to identify a prospective cohort with at least one BMI measure. Cox models adjusted for age, sex, smoking and social deprivation and subgroup analyses by diabetes, hypertension and prior cardiovascular disease assessed relationships between BMI and CKD stages 4-5 and end-stage renal disease (ESRD). FINDINGS/RESULTS:1,405,016 adults aged 20-79 with mean BMI 27.4kg/m2 (SD 5.6) were followed for 7.5 years. Compared to a BMI of 20 to <25kg/m2, higher BMI was associated with a progressively increased risk of CKD stages 4-5 (hazard ratio 1.34, 95% CI 1.30-1.38 for BMI 25 to <30kg/m2; 1.94, 1.87-2.01 for BMI 30 to <35kg/m2; and 3.10, 2.95-3.25 for BMI ≥35kg/m2). The association between BMI and ESRD was shallower and reversed at low BMI. Current smoking, prior diabetes, hypertension or cardiovascular disease all increased risk of CKD, but the relative strength and shape of BMI-CKD associations, which were generally log-linear above a BMI of 25kg/m2, were similar among those with and without these risk factors. There was direct evidence that being overweight was associated with increased risk of CKD stages 4-5 in these subgroups. Assuming causality, since 2000 an estimated 39% (36-42%) of advanced CKD in women and 26% (22-30%) in men aged 40-79 resulted from being overweight or obese. CONCLUSIONS:This study provides direct evidence that being overweight increases risk of advanced CKD, that being obese substantially increases such risk, and that this remains true for those with and without diabetes, hypertension or cardiovascular disease. Strategies to reduce weight among those who are overweight, as well as those who are obese may reduce CKD risk, with each unit reduction in BMI yielding similar relative reductions in risk.

Genome-wide association studies (GWAS) using single nucleotide polymorphisms (SNPs) have identified more than 50 loci associated with estimated glomerular filtration rate (eGFR), a measure of kidney function. However, significant SNPs account for a small proportion of eGFR variability. Other forms of genetic variation have not been comprehensively evaluated for association with eGFR. In this study, we assess whether changes in germline DNA copy number are associated with GFR estimated from serum creatinine, eGFRcrea. We used hidden Markov models (HMMs) to identify copy number polymorphic regions (CNPs) from high-throughput SNP arrays for 2,514 African (AA) and 8,645 European ancestry (EA) participants in the Atherosclerosis Risk in Communities (ARIC) study. Separately for the EA and AA cohorts, we used Bayesian Gaussian mixture models to estimate copy number at regions identified by the HMM or previously reported in the HapMap Project. We identified 312 and 464 autosomal CNPs among individuals of EA and AA, respectively. Multivariate models adjusted for SNP-derived covariates of population structure identified one CNP in the EA cohort near genome-wide statistical significance (Bonferroni-adjusted p = 0.067) located on chromosome 5 (876-880kb). Overall, our findings suggest a limited role of CNPs in explaining eGFR variability.

BACKGROUND:Kidney dysfunction is prevalent and impacts prognosis in patients with acute decompensated heart failure (ADHF). However, most previous reports were from a single hospital, limiting their generalizability. Also, contemporary data using new equation for estimated glomerular filtration rate (eGFR) are needed. METHODS AND RESULTS/RESULTS:We analyzed data from the ARIC Community Surveillance for ADHF conducted for residents aged ≥55 years in four US communities between 2005-2011. All ADHF cases (n = 5, 391) were adjudicated and weighted to represent those communities (24,932 weighted cases). The association of kidney function (creatinine-based eGFR by the CKD-EPI equation and blood urea nitrogen [BUN]) during hospitalization with 1-year mortality was assessed using logistic regression. Based on worst and last serum creatinine, there were 82.5% and 70.6% with reduced eGFR (<60 ml/min/1.73m2) and 37.4% and 26.6% with severely reduced eGFR (<30 ml/min/1.73m2), respectively. Lower eGFR (regardless of last or worst eGFR), particularly eGFR <30 ml/min/1.73m2, was significantly associated with higher 1-year mortality independently of potential confounders (odds ratio 1.60 [95% CI 1.26-2.04] for last eGFR 15-29 ml/min/1.73m2 and 2.30 [1.76-3.00] for <15 compared to eGFR ≥60). The association was largely consistent across demographic subgroups. Of interest, when both eGFR and BUN were modeled together, only BUN remained significant. CONCLUSIONS:Severely reduced eGFR (<30 ml/min/1.73m2) was observed in ~30% of ADHF cases and was an independent predictor of 1-year mortality in community. For prediction, BUN appeared to be superior to eGFR. These findings suggest the need of close attention to kidney dysfunction among ADHF patients.

BACKGROUND:Arteriovenous accesses (AVA) in patients performing hemodialysis (HD) are labeled "permanent" for AV fistulas (AVF) or grafts (AVG) and "temporary" for tunneled central venous catheters (TCVC). Durability and outcomes of permanent vascular accesses based on the sequence in which they were placed or used receives little attention. This study analyzed longitudinal transitions between TCVC-based and AVA-based HD outcomes according to the order of placement. METHODS:All 391 patients initiating chronic HD via a TCVC between 2012 and 2013 at 12 outpatient academic dialysis units were included in this study. Chronological distributions of HD vascular accesses were recorded over a mean (SD) of 2.8 (0.9) years and sequentially grouped into periods for TCVC-delivered and AVA-delivered (AVF or AVG) HD. Primary AVA failure and cumulative access survival were evaluated based on access placement sequence and type, adjusting for age. RESULTS:In total, 92.3% (361/391) of patients underwent 497 AVA placement surgeries. Analyzing the initial 3 surgeries, primary AVF failure rates increased with each successive fistula placement (p = 0.008). Among the 82.9% (324/391) of TCVC patients successfully converted to an AVA, 30.9% returned to a TCVC, followed by a 58.0% conversion rate to another AVA. Annual per-patient vascular access transition rates were 2.02 (0.09) HD periods using a TCVC and 0.54 (0.03) HD periods using an AVA. Comparing the first AVA used with the second, cumulative access survivals were 701.0 (370.0) vs. 426.5 (275.0) days, respectively. Excluding those never converting to an AVF or AVG, 169 (52.2%) subsequently converted from a TCVC to a permanent access and received HD via AVA for ≥80% of treatments. CONCLUSIONS:HD vascular access outcomes differ based on the sequence of placement. In spite of frequent AVA placements, only half of patients effectively achieved a "permanent" vascular access and used an AVA for the majority of HD treatments.

Purpose: To date, no studies utilizing global positioning system (GPS) technologies to measure mobility and environmental exposures have been conducted among a sample of transgender women despite the potential salient role neighborhood contexts may play in the health of this population. As such, the purpose of this study was to assess the acceptability and feasibility of a weeklong GPS protocol among a sample of transgender women in New York City. Methods: A sample of 14 transgender women residing in the New York City metropolitan area were recruited through community based methods to wear and charge a GPS device for 7 days to measure daily mobility. The acceptability of these methods was assessed using a pre- and postprotocol survey and their feasibility was measured using objective data derived from the GPS device. Pre- and postprotocol survey measures were compared using McNemar's test. Results: Participants reported high ratings of preprotocol acceptability, as well as few concerns regarding safety, appearance, and losing the device, all of which were maintained after completing the protocol. All 14 devices that were distributed were returned. In addition, all 14 participants had GPS data for at least 1 h on 1 day, and nine participants (64.3%) had at least 8 h of GPS data on all days. Conclusion: The findings of this pilot study demonstrate that the GPS methods are both acceptable and feasible among this sample of transgender women. GPS devices may be used in research among transgender women to understand neighborhood determinants of HIV and other STIs.