Faculty Bibliography

BACKGROUND:Decreased kidney function and kidney damage may predate hypertension, but only a few studies have investigated both types of markers simultaneously, and these studies have obtained conflicting results. STUDY DESIGN/METHODS:Cross-sectional for prevalent and prospective observational study for incident hypertension. SETTING & PARTICIPANTS/METHODS:9,593 participants from the ARIC (Atherosclerosis Risk in Communities) Study, aged 53-75 years in 1996-1998. PREDICTORS/METHODS:Several markers of kidney function (estimated glomerular filtration rate using serum creatinine and/or cystatin C and 2 novel markers [β-trace protein and β2-microglobulin]) and 1 marker of kidney damage (urinary albumin-creatinine ratio [ACR]). Every kidney marker was categorized by its quintiles (top quintile as a reference for estimated glomerular filtration rates and bottom quintile for the rest). OUTCOMES/RESULTS:Prevalent and incident hypertension. MEASUREMENTS/METHODS:Prevalence ratios and HRs of hypertension based on modified Poisson regression and Cox proportional hazards models, respectively. RESULTS:There were 4,378 participants (45.6%) with prevalent hypertension at baseline and 2,175 incident hypertension cases during a median follow-up of 9.8 years. Although all 5 kidney function markers were associated significantly with prevalent hypertension, prevalent hypertension was associated most notably with higher ACR (adjusted prevalence ratio, 1.60 [95% CI, 1.50-1.71] for the highest vs lowest ACR quintile). Similarly, ACR was associated consistently with incident hypertension in all models tested (adjusted HR, 1.28 [95% CI, 1.10-1.49] for top quintile), while kidney function markers demonstrated significant associations in some, but not all, models. Even mildly increased ACR (9.14-14.0mg/g) was associated significantly with incident hypertension. LIMITATIONS/CONCLUSIONS:Self-reported use of antihypertensive medication for defining incident hypertension, single assessment of kidney markers, and relatively narrow age range. CONCLUSIONS:Although all kidney markers were associated with prevalent hypertension, only elevated albuminuria was associated consistently with incident hypertension, suggesting that kidney damage is related more closely to hypertension than moderate reduction in overall kidney function.

BACKGROUND:Natriuretic peptides promote natriuresis, diuresis, and vasodilation. Experimental deficiency of natriuretic peptides leads to hypertension (HTN) and cardiac hypertrophy, conditions more common among African Americans. Hospital-based studies suggest that African Americans may have reduced circulating natriuretic peptides, as compared to Caucasians, but definitive data from community-based cohorts are lacking. METHODS AND RESULTS/RESULTS:We examined plasma N-terminal pro B-type natriuretic peptide (NTproBNP) levels according to race in 9137 Atherosclerosis Risk in Communities (ARIC) Study participants (22% African American) without prevalent cardiovascular disease at visit 4 (1996-1998). Multivariable linear and logistic regression analyses were performed adjusting for clinical covariates. Among African Americans, percent European ancestry was determined from genetic ancestry informative markers and then examined in relation to NTproBNP levels in multivariable linear regression analysis. NTproBNP levels were significantly lower in African Americans (median, 43 pg/mL; interquartile range [IQR], 18, 88) than Caucasians (median, 68 pg/mL; IQR, 36, 124; P<0.0001). In multivariable models, adjusted log NTproBNP levels were 40% lower (95% confidence interval [CI], -43, -36) in African Americans, compared to Caucasians, which was consistent across subgroups of age, gender, HTN, diabetes, insulin resistance, and obesity. African-American race was also significantly associated with having nondetectable NTproBNP (adjusted OR, 5.74; 95% CI, 4.22, 7.80). In multivariable analyses in African Americans, a 10% increase in genetic European ancestry was associated with a 7% (95% CI, 1, 13) increase in adjusted log NTproBNP. CONCLUSIONS:African Americans have lower levels of plasma NTproBNP than Caucasians, which may be partially owing to genetic variation. Low natriuretic peptide levels in African Americans may contribute to the greater risk for HTN and its sequalae in this population.

OBJECTIVE:To determine whether hospitalization is associated with subsequent cognitive decline or changes on brain MRI in a community-based cohort. METHODS:Baseline and follow-up cognitive testing (n = 2,386) and MRI scans with standardized assessments (n = 885) were available from a subset of white and black participants in the Atherosclerosis Risk in Communities study. Cognitive tests included the Delayed Word Recall Test (DWRT), Digit Symbol Substitution Test (DSST), and Word Fluency Test (WFT). Hospitalization characteristics were determined using ICD-9 codes. Regression models adjusted for demographics, education, comorbidities, and APOE ε4 were used to estimate the independent association of hospitalization with changes in cognition or neuroimaging. RESULTS:Over a mean 14.1 years between visits, 1,266 participants (53.1%) were hospitalized. Hospitalization compared with no hospitalization was associated with greater decline in DSST scores (1.25 points greater decline, p < 0.001) but no difference in DWRT or WFT score change. Each additional hospitalization, as well as a critical illness vs noncritical illness hospitalization, was associated with greater decline in DSST scores. A subset of participants (n = 885) underwent MRI scans separated by 10.5 years. Hospitalization (n = 392) compared with no hospitalization was associated with a 57% higher odds of increasing ventricular size at follow-up. Each additional hospitalization, as well as having a critical illness vs noncritical illness hospitalization, and having a hospitalization with major surgery vs no surgery was associated with greater odds of increased ventricular size. CONCLUSIONS:Cognitive decline and neuroimaging changes may occur after hospitalization, independent of baseline demographics and comorbidities.

OBJECTIVE:To determine whether duration and degree of weight gain are differentially associated with diabetes risk in younger versus middle-aged black and white adults. RESEARCH DESIGN AND METHODS/METHODS:We combined data from three cohort studies: Atherosclerosis Risk in Communities (ARIC), Coronary Artery Risk Development in Young Adults (CARDIA), and the Framingham Heart Study. A total of 17,404 participants (56% women; 21% black) were stratified by baseline age (younger: ≥30 and <45 years; middle-aged: ≥45 and <60 years) and examined for incident diabetes (median follow-up 9 years). Duration and degree of gain in BMI were calculated as "BMI-years" above one's baseline BMI. RESULTS:Diabetes incidence per 1,000 person-years in the younger and middle-aged groups was 7.2 (95% CI 5.7, 8.7) and 24.4 (22.0, 26.8) in blacks, respectively, and 3.4 (2.8, 4.0) and 10.5 (9.9, 11.2) in whites, respectively. After adjusting for sex, baseline BMI and other cardiometabolic factors, and age and race interaction terms, gains in BMI-years were associated with higher risk of diabetes in the younger compared with middle-aged groups: hazard ratios for 1-unit increase in log BMI-years in younger versus middle-aged blacks were 1.18 (P = 0.02) and 1.02 (P = 0.39), respectively (P for interaction by age-group = 0.047), and in whites were 1.35 (P < 0.001) and 1.11 (P < 0.001), respectively (P for interaction by age-group = 0.008). CONCLUSIONS:Although middle-aged adults have higher rates of diabetes, younger adults are at greater relative risk of developing diabetes for a given level of duration and degree of weight gain.

BACKGROUND:A growing number of serum filtration markers are associated with mortality and end-stage renal disease (ESRD) in adults. Whether β-trace protein (BTP) and β2-microglobulin (B2M) are associated with these outcomes in adults with type 2 diabetes is not known. STUDY DESIGN/METHODS:Longitudinal cohort study. SETTING & PARTICIPANTS/METHODS:250 Pima Indians with type 2 diabetes (69% women; mean age, 42 years; mean diabetes duration, 11 years). PREDICTORS/METHODS:Serum BTP, B2M, and glomerular filtration rate measured by iothalamate clearance (mGFR) or estimated using creatinine (eGFRcr) or cystatin C level (eGFRcys). OUTCOMES & MEASUREMENTS/METHODS:Incident ESRD and all-cause mortality through December 2013. HRs were reported per interquartile range decrease of the inverse of BTP and B2M (1/BTP and 1/B2M) using Cox regression. Improvement in risk prediction with the addition of BTP or B2M level to established markers (eGFRcys with mGFR or eGFRcr) was evaluated using C statistics, continuous net reclassification improvement, and relative integrated discrimination improvement (RIDI). RESULTS:During a median follow-up of 14 years, 69 participants developed ESRD and 95 died. Both novel markers were associated with ESRD in multivariable models. BTP level remained statistically significant after further adjustment for mGFR (1/BTP, 1.53 [95% CI, 1.01-2.30]; 1/B2M, 1.54 [95% CI, 0.98-2.42]). B2M level was associated with mortality in multivariable models and after further adjustment for mGFR (HR, 2.12; 95% CI, 1.38-3.26). The addition of B2M level to established markers increased the C statistic for mortality but only weakly when assessed by either continuous net reclassification improvement or RIDI; none was improved for ESRD by the addition of these markers. LIMITATIONS/CONCLUSIONS:Small sample size, single measurements of markers. CONCLUSIONS:In Pima Indians with type 2 diabetes, BTP and, to a lesser extent, B2M levels were associated with ESRD. B2M level was associated with mortality after adjustment for traditional risk factors and established filtration markers. Further studies are warranted to confirm whether inclusion of B2M level in a multimarker approach leads to improved risk prediction for mortality in this population.

BACKGROUND:The way a construct is measured can differ across cohort study visits, complicating longitudinal comparisons. We demonstrated the use of factor analysis to link differing cognitive test batteries over visits to common metrics representing general cognitive performance, memory, executive functioning, and language. METHODS:We used data from three visits (over 26 years) of the Atherosclerosis Risk in Communities Neurocognitive Study (N = 14,252). We allowed individual tests to contribute information differentially by race, an important factor to consider in cognitive aging. Using generalized estimating equations, we compared associations of diabetes with cognitive change using general and domain-specific factor scores versus averages of equally weighted standardized test scores. RESULTS:Factor scores provided stronger associations with diabetes at the expense of greater variability around estimates (e.g., for general cognitive performance, -0.064 standard deviation units/year, standard error = 0.015, vs. -0.041 standard deviation units/year, standard error = 0.014), which is consistent with the notion that factor scores more explicitly address error in measuring assessed traits than averages of standardized tests. CONCLUSIONS:Factor analysis facilitates use of all available data when measures change over time, and further, it allows objective evaluation and correction for differential item functioning.

Significant advances are needed to improve the diagnosis, prognosis, and management of persons with CKD. Discovery of new biomarkers and improvements in currently available biomarkers for CKD hold great promise to achieve these necessary advances. Interest in identification and evaluation of biomarkers for CKD has increased substantially over the past decade. In 2009, the National Institute of Diabetes and Digestive and Kidney Diseases established the CKD Biomarkers Consortium (http://www.ckdbiomarkersconsortium.org/), a multidisciplinary, collaborative study group located at over a dozen academic medical centers. The main objective of the consortium was to evaluate new biomarkers for purposes related to CKD in established prospective cohorts, including those enriched for CKD. During the first 5 years of the consortium, many insights into collaborative biomarker research were gained that may be useful to other investigators involved in biomarkers research. These lessons learned are outlined in this Special Feature and include a wide range of issues related to biospecimen collection, storage, and retrieval, and the internal and external quality assessment of laboratories that performed the assays. The authors propose that investigations involving biomarker discovery and validation are greatly enhanced by establishing and following explicit quality control metrics, including the use of blind replicate and proficiency samples, by carefully considering the conditions under which specimens are collected, handled, and stored, and by conducting pilot and feasibility studies when there are concerns about the condition of the specimens or the accuracy or reproducibility of the assays.

Genome-wide association studies (GWASs) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, single-nucleotide polymorphisms (SNPs) at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1, and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus, which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFR decline of 3 ml/min per 1.73 m(2) or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11, and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72 h after gentamicin treatment compared with controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline.

BACKGROUND:Despite advances in prevention and treatment of cardiovascular disease, sudden cardiac death (SCD) remains a clinical challenge. Risk stratification in the general population is needed. METHODS AND RESULTS/RESULTS:Beat-to-beat spatiotemporal variability in the T vector was measured as the mean angle between consecutive T-wave vectors (mean TT' angle) on standard 12-lead ECGs in 14 024 participants in the Atherosclerosis Risk in Communities (ARIC) study. Subjects with left ventricular hypertrophy, atrial arrhythmias, frequent ectopy, ventricular pacing, or QRS duration ≥120 ms were excluded. The mean spatial TT' angle was 5.21±3.55°. During a median of 14 years of follow-up, 235 SCDs occurred (1.24 per 1000 person-years). After adjustment for demographics, coronary heart disease risk factors, and known ECG markers for SCD, mean TT' angle was independently associated with SCD (hazard ratio 1.089; 95% CI 1.044 to 1.137; P<0.0001). A mean TT' angle >90th percentile (>9.57°) was associated with a 2-fold increase in the hazard for SCD (hazard ratio 2.01; 95% CI 1.28 to 3.16; P=0.002). In a subgroup of patients with T-vector amplitude ≥0.2 mV, the association with SCD was almost twice as strong (hazard ratio 3.92; 95% CI 1.91 to 8.05; P<0.0001). A significant interaction between mean TT' angle and age was found: TT' angle was associated with SCD in participants aged <55 years (hazard ratio 1.096; 95% CI 0.043 to 1.152; P<0.0001) but not in participants aged ≥55 years (P(interaction)=0.009). CONCLUSIONS:In a large, prospective, community-based cohort of left ventricular hypertrophy-free participants, increased beat-to-beat spatiotemporal variability in the T vector, as assessed by increasing TT' angle, was associated with SCD.