Pentraxin-3 is an inflammatory marker thought to be more specific to vascular inflammation than C-reactive protein (CRP). Whether pentraxin-3 is independently associated with adverse events among persons with stable coronary heart disease (CHD), independently of CRP, and whether kidney dysfunction influences these associations, is not known.
We evaluated the associations of baseline pentraxin-3 levels with all-cause mortality, cardiovascular events (myocardial infarction, stroke or CHD death), and incident heart failure 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 one unit increase in log pentraxin-3 at baseline was associated with an 80% increased risk of all-cause mortality (HR 1.8, 95% CI 1.5–2.1), a 50% increased risk of cardiovascular events (HR 1.5, 95% CI, 1.2–1.9), and an 80% greater risk of incident heart failure (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 cardiovascular events and 1.5 (1.1–2.1) for incident heart failure. Stratification by eGFR above or below 60 ml/min/1.73m2 did not affect these associations (p interaction >0.3 for all outcomes).
Among persons with stable CHD, higher pentraxin-3 concentrations were associated with increased risk for all-cause mortality, cardiovascular events and incident heart failure independently of systemic inflammation. Adjustment for eGFR modestly attenuated these associations, suggesting that future studies of pentraxin-3 should adjust for kidney function.
cardiovascular diseases; heart failure; coronary disease; kidney
The association of subclinical vascular disease and early declines in kidney function has not been well studied.
Prospective cohort study
Setting & Participants
MESA participants with eGFR ≥60 ml/min/1.73m2 with follow-up of 5 years
Pulse pressure (pulse pressure), small and large arterial elasticity (SAE, LAE), and flow mediated dilation.
kidney function decline
SAE and LAE were measured by pulse contour analysis of the radial artery. Kidney function was measured by serum creatinine- and cystatin C-based eGFR.
Among 4,853 adults, higher pulse pressure and lower SAE and LAE had independent and linear associations with faster rates of kidney function decline. Compared to persons with pulse pressure 40–50mmHg, eGFRSCysC decline was 0.29 (p=0.006), 0.56 (p<0.001), and 0.91 (p<0.001) ml/min/1.73m2/year faster among persons with pulse pressure 50–60, 60–70, and >70mmHg, respectively. Compared to the highest quartile of SAE (most elastic), eGFRSCysC decline was 0.26 (p=0.009), 0.35 (p=0.001), and 0.70 (p<0.001) ml/min/1.73m2/year faster for the second, third and fourth quartiles respectively. For LAE, compared to the highest quartile, eGFRSCysC decline was 0.28 (p=0.004), 0.58 (p<0.001), and 0.83 (p<0.001) ml/min/1.73m2/year faster for each decreasing quartile of LAE. Findings were similar with creatinine-based eGFR. In contrast, among 2,997 adults with flow-mediated dilation and kidney function measures, flow-mediated dilation was not significantly associated with kidney function decline. For every 1-SD greater flow-mediated dilation, eGFRSCysC and eGFRSCr changed by 0.05 ml/min/1.73m2/year (p=0.3) and 0.06 ml/min/1.73m2/year (p=0.04), respectively.
We had no direct measure of GFR, in common with nearly all large population based studies.
Higher pulse pressure and lower arterial elasticity, but not flow-mediated dilation, were linearly and independently associated with faster kidney function decline among persons with eGFR ≥60 ml/min/1.73m2. Future studies investigate whether treatments to lower stiffness of large and small arteries may slow the rate of kidney function loss.
kidney function; arterial elasticity; chronic kidney disease; atherosclerosis
Background: Whether lipoprotein-associated phospholipase A2 (Lp-PLA2) levels are associated with kidney function decline has not been well studied. Methods: We investigated associations of Lp-PLA2 antigen and activity with kidney function decline and rapid decline over 5.7 years in the Cardiovascular Health Study (n = 4,359). We estimated kidney function by cystatin C (eGFRcys) in repeated measures, and defined rapid decline as ≥3 ml/min/1.73 m2 per year. We stratified by baseline preserved GFR (≥60 ml/min/1.73 m2). Results: Mean age was 72 ± 5 years. Average eGFRcys decline was −1.79 ml/min/1.73 m2 (SD = 2.60) per year. Among persons with preserved GFR, compared to the lowest quartile of Lp-PLA2 antigen, eGFRcys decline was faster among persons in the second, β −0.31 (95% CI −0.52, −0.10), third −0.19 (–0.41, 0.02) and fourth quartiles −0.26 (–0.48, −0.04) after full adjustment. Persons in the highest quartile of Lp-PLA2 antigen had increased odds of rapid decline 1.34 (1.03, 1.75), compared to the lowest. There was no significant association between levels of Lp-PLA2 activity and eGFRcys decline or rapid decline. Associations were not statistically significant among persons with low eGFR (<60 ml/min/1.73 m2) at baseline. Conclusion: Higher levels of Lp-PLA2 antigen but not activity were significantly associated with faster rates of kidney function decline. These findings may suggest a novel vascular pathway for kidney disease progression.
Chronic kidney disease; Elderly; Estimated GFR; Kidney decline; Lipoprotein-associated phospholipase A2
African-Americans have a disproportionate burden of hypertension compared to Caucasians, while data on Hispanics is less well-defined. Mechanisms underlying these differences are unclear, but could be due in part to ancestral background and vascular function.
Methods and Results
660 African-Americans and 635 Hispanics from the Multi-Ethnic Study of Atherosclerosis (MESA) with complete data on genetic ancestry, pulse pressure (PP), and large and small arterial elasticity (LAE, SAE) were studied. LAE and SAE were obtained using the HDI PulseWave CR-2000 Research CardioVascular Profiling Instrument. Among African-Americans higher European ancestry was marginally associated with higher LAE (p=0.05) and lower PP (p=0.05) among African-Americans; results for LAE were attenuated after adjustment for potential mediators (p=0.30). Ancestry was not associated with SAE in African-Americans. Among Hispanics, higher Native American ancestry was associated with higher SAE (p=0.0006); higher African ancestry was marginally associated with lower SAE (p=0.07). Ancestry was not significantly associated with LAE or PP in Hispanics.
Among African-Americans, higher European ancestry may be associated with less large artery damage as measured by LAE and PP, although these associations warrant further study. Among Hispanics, ancestry is strongly associated with SAE. Future studies should consider information on genetic ancestry when studying hypertension burden in race/ethnic minorities, particularly among Hispanics.
large artery elasticity; small artery elasticity; admixture; pulse pressure
The evidence for the effectiveness of antihypertensive medication use for slowing decline in kidney function in older persons is sparse. We addressed this research question by the application of novel methods in a marginal structural model.
Change in kidney function was measured by two or more measures of cystatin C in 1,576 hypertensive participants in the Cardiovascular Health Study over 7 years of follow-up (1989–1997 in four U.S. communities). The exposure of interest was antihypertensive medication use. We used a novel estimator in a marginal structural model to account for bias due to confounding and informative censoring.
The mean annual decline in eGFR was 2.41 ± 4.91 mL/min/1.73 m2. In unadjusted analysis, antihypertensive medication use was not associated with annual change in kidney function. Traditional multivariable regression did not substantially change these estimates. Based on a marginal structural analysis, persons on antihypertensives had slower declines in kidney function; participants had an estimated 0.88 (0.13, 1.63) ml/min/1.73 m2 per year slower decline in eGFR compared with persons on no treatment. In a model that also accounted for bias due to informative censoring, the estimate for the treatment effect was 2.23 (−0.13, 4.59) ml/min/1.73 m2 per year slower decline in eGFR.
In summary, estimates from a marginal structural model suggested that antihypertensive therapy was associated with preserved kidney function in hypertensive elderly adults. Confirmatory studies may provide power to determine the strength and validity of the findings.
aged; kidney function; hypertension; marginal structural model
Functional biomarkers like large artery elasticity (LAE) and small artery elasticity (SAE) may predict cardiovascular disease (CVD) events beyond blood pressure. The authors examined the prognostic value of LAE and SAE for clinical CVD events among 6,235 Multi-Ethnic Study of Atherosclerosis participants who were initially aged 45–84 years and without symptomatic CVD. LAE and SAE were derived from diastolic pulse contour analysis. During a median 5.8 years of follow-up between 2000 and 2008, 454 adjudicated CVD events occurred, including 256 cases of coronary heart disease (CHD), 93 strokes, and 126 heart failures (multiple diagnoses were possible). After adjustment for age, race/ethnicity, sex, clinic, height, heart rate, body mass index, systolic and diastolic blood pressure, use of antihypertensive and cholesterol-lowering medications, smoking, total cholesterol, high density lipoprotein cholesterol, triglycerides, diabetes, and high-sensitivity C-reactive protein, the hazard ratio for any CVD per standard-deviation increase in SAE was 0.71 (95% confidence interval: 0.61, 0.83; P < 0.0001). The lowest (stiffest) SAE quartile had a hazard ratio of 2.28 (95% confidence interval: 1.55, 3.36) versus the highest (most elastic) quartile. The net reclassification index, conditional on base risk, was 0.11. SAE was significantly associated with future CHD, stroke, and heart failure. After adjustment, LAE was not significantly related to CVD. In asymptomatic participants free of overt CVD, lower SAE added prognostic information for CVD, CHD, stroke, and heart failure events.
arteries; cardiovascular diseases; elasticity; risk factors
Treatment of hypertension is difficult in chronic kidney disease (CKD), and blood pressure goals remain controversial. The association between each blood pressure component and end-stage renal disease (ESRD) risk is less well known.
We studied associations of systolic and diastolic blood pressure (SBP and DBP, respectively) and pulse pressure (PP) with ESRD risk among 16 129 Kidney Early Evaluation Program (KEEP) participants with an estimated glomerular filtration rate of 60 mL/min/1.73 m2 using Cox proportional hazards. We estimated the prevalence and characteristics associated with uncontrolled hypertension (SBP≥150 or DBP≥90 mm Hg).
The mean (SD) age of participants was 69 (12) years; 25% were black, 6% were Hispanic, and 43% had diabetes mellitus. Over 2.87 years, there were 320 ESRD events. Higher SBP was associated with higher ESRD risk, starting at SBP of 140 mm Hg or higher. After sex and age adjustment, compared with SBP lower than 130 mm Hg, hazard ratios (HRs) were 1.08 (95% CI, 0.74–1.59) for SBP of 130 to 139 mm Hg, 1.72 (95% CI, 1.21–2.45) for SBP of 140 to 149 mm Hg, and 3.36 (95% CI, 2.51–4.49) for SBP of 150 mm Hg or greater. After full adjustment, HRs for ESRD were 1.27 (95% CI, 0.88–1.83) for SBP of 140 to 149 mm Hg and 1.36 (95% CI, 1.02–1.85) for SBP of 150 mm Hg or higher. Persons with DBP of 90 mm Hg or higher were at higher risk for ESRD compared with persons with DBP of 60 to 74 mm Hg (HR, 1.81; 95% CI, 1.33–2.45). Higher PP was also associated with higher ESRD risk (HR, 1.44 [95% CI, 1.00–2.07] for PP≥80 mm Hg compared with PP<50 mm Hg). Adjustment for SBP attenuated this association. More than 33% of participants had uncontrolled hypertension (SBP≥150 mm Hg or DBP≥90 mm Hg), mostly due to isolated systolic hypertension (54%).
In this large, diverse, community-based sample, we found that high SBP seemed to account for most of the risk of progression to ESRD. This risk started at SBP of 140 mm Hg rather than the currently recommended goal of less than 130 mm Hg, and it was highest among those with SBP of at least 150 mm Hg. Treatment strategies that preferentially lower SBP may be required to improve BP control in CKD.
The growing burden and morbidity of chronic kidney disease (CKD) warrant effective strategies for identifying those at increased risk. We examined the association of cystatin C and albuminuria with development of CKD stage 3.
Prospective observational study.
Setting and Participants
5,422 participants from the Multi-Ethnic Study of Atherosclerosis with estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73m2.
Participants were categorized into four mutually exclusive groups: presence or absence of microalbuminuria (albumin-creatinine ratio >17 and > 25 µg/mg in men and women, respectively) in those with or without cystatin C ≥ 1.0 mg/L.
Outcomes and Measurements
Incident CKD stage 3 was defined as eGFR < 60 ml/min/1.73m2 at the 3rd or 4th visit and an annual decline of > 1 ml/min/1.73 m2. Poisson regression was used to evaluate incident rate ratios in unadjusted and adjusted analyses that include baseline eGFR.
Mean age was 61 years, 49% were men, 38% white, 11% had diabetes, 13.7% had cystatin C ≥ 1mg/L, 8.4% had microalbuminuria, and 2.7 % had cystatin C ≥ 1 mg/L with microalbuminuria. 554 (10%) participants developed CKD stage 3 over a median follow-up of 4.7 years and the adjusted incidence rate ratios (95% CI) were 1.57 (1.19–2.07), 1.37 (1.13–1.66), and 2.12 (1.61–2.80) in those with microalbuminuria, cystatin C ≥ 1 mg/L, and both, respectively, compared to those with neither.
Relatively short follow up and absence of measured GFR.
Cystatin C and microalbuminuria are independent risk factors for incident CKD stage 3 and could be useful as screening tools to identify those at increased risk.
Background. Pentraxin-3 (PTX3), an inflammatory marker thought to be related to vascular inflammation, is elevated in advanced chronic kidney disease (CKD). Whether PTX3 is associated with mild to moderate kidney dysfunction is unknown.
Methods. We tested associations of proteins in the pentraxin family [PTX3, C-reactive protein (CRP) and serum amyloid protein (SAP)] with estimated glomerular filtration rate by cystatin C (eGFRcys) and microalbuminuria among 2824 participants in the Multi-Ethnic Study of Atherosclerosis. Associations were tested using multivariable linear regression with adjustment for demographics (age, gender, annual income), comorbidities (diabetes, hypertension, smoking, body mass index, low-density lipoprotein, high-density lipoprotein, triglycerides, ACE inhibitor and statin use) and systemic inflammation [interleukin-6 (IL-6)].
Results. Among the 2824 participants, mean age was 62 years and mean eGFRcys was 94 mL/min/1.73 m2; 25% were white, 25% Chinese, 25% African-American and 25% Hispanic. Among all participants after full adjustment, higher PTX3 was associated with lower eGFRcys independently of IL-6 (β − 3.0 mL/min/1.73 m2 per unit increase in lnPTX3, P < 0.001). In contrast, CRP and SAP were associated with eGFRcys in demographic adjusted models, but these associations were attenuated after adjustment for comorbidities and IL-6 (lnCRP β − 0.06, P = 0.9; lnSAP β − 0.35, P = 0.7). There was a significant interaction with race/ethnicity (P < 0.001) in the association of PTX3 and eGFRcys. After adjustment for demographics, comorbidities and IL-6, this association was significant in blacks (β − 5.7 mL/min/1.73 m2 per unit increase in lnPTX3, P = 0.002) but not in Hispanics (β − 2.4, P = 0.1), Chinese (β − 0.91, P = 0.5) or whites (β − 0.26, P = 0.9). PTX3 and CRP, but not SAP, had correlations with microalbuminuria in unadjusted models (Spearman coefficients PTX3 0.05, P = 0.005; CRP 0.07, P < 0.001; SAP 0.013, P = 0.5), but these were attenuated after full adjustment.
Conclusions. Endovascular inflammation may be an important mechanism associated with early kidney dysfunction, particularly among blacks. This mechanism appears to be independent of IL-6-regulated pathways.
C-reactive protein; estimated glomerular filtration rate by cystatin; pentraxin-3; race/ethnicity; serum amyloid protein
Background. Acculturation affects health, but it has never been studied with kidney disease.
Methods. We studied the association of language spoken at home, generation and birth place with kidney function among Hispanics and Chinese in the Multi-Ethnic Study of Atherosclerosis (n = 2999). Kidney function was determined by cystatin C (eGFRcys) and albumin/creatinine ratio (ACR). We evaluated mediators in models: Model 1 = age, sex, income, education; Model 2 = Model 1 + behaviors; and Model 3 = Model 1 + comorbidities.
Results. Among Hispanics, speaking mixed Spanish/English was significantly associated with lower eGFRcys (− 2.83 mL/min/1.73 m2, − 5.69–0.04) and higher ACR (RD 40%, 17–68%) compared with speaking Spanish only; this was mildly attenuated by behaviors (− 2.29, − 5.33–0.75; RD 42%, 18–72%) but not comorbidities (− 3.04, − 5.83 to − 0.23); RD 35%, 14–59%). US-born Hispanics had lower eGFRcys compared with foreign-born Hispanics [1.83 mL/min/1.73 m2 lower (0.97–1.31) for Generation 1; 1.37 mL/min/1.73 m2 lower (0.75–1.57) for Generation ≥ 2].
In contrast, Chinese who spoke any English had higher eGFRcys (2.53, 95% CI: − 1.70–6.78), but similar ACR (RD − 5%, 95% CI: − 26–23%) compared with those speaking Chinese only, but associations were not statistically significant.
Conclusion. Higher acculturation was associated with worse kidney function in Hispanics, mediated perhaps by behavioral factors but not comorbidities. Associations may be in the opposite direction among Chinese. Future studies are needed to elucidate these mechanisms.
acculturation; cystatin C; kidney function
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.
Using genotype data from about 60,000 distinct genetic markers, we examined population structure in 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 comparing genetic ancestry of MESA Hispanic participants to reference samples representing worldwide diversity, we show major differences in ancestry of MESA Hispanics reflecting their Caucasian, African, and Native American origins, with finer differences corresponding to North-South geographic origins that separate MESA Mexican versus Central/South American samples. Based on our analysis, we define four subgroups of the MESA Hispanic cohort that show close agreement with the following self-identified regions of origin: Dominican/Cuban, Mexican, Central/South American, and Puerto Rican. We examine association of triglycerides with selected genetic markers, and we further demonstrate the importance of considering differences in genetic ancestry (or factors associated with genetic ancestry) when performing genetic studies of the United States Hispanic population.
Background. Despite a higher incidence of end-stage renal disease (stage 5), blacks have been shown to have the same or lower prevalence of chronic kidney disease (CKD stages 3 and 4). Current creatinine-based glomerular filtration rate (GFR)-estimating equations may misclassify young, healthy blacks.
Methods. Among 3501 young adults (mean age 45), we compared the prevalence of CKD in blacks and whites using the Modification of Diet in Renal Disease (MDRD) and the CKD Epidemiology Collaboration (CKD-EPI) equations. In addition, we used measured creatinine excretion rates to determine the actual excretion ratio for CARDIA (race coefficient 12%) and applied this to the CKD-EPI equation. We also studied the prevalence of CKD risk factors among black and white participants near the CKD threshold cut-off (eGFR CKD-EPI 60–80 mL/min/1.73 m2) to estimate the relative likelihood of misclassification in blacks and whites.
Results. Using the MDRD equation, prevalence of CKD stages 4 and 5 was higher for blacks compared with whites (0.6% vs. 0.1%, P-value 0.05). In contrast, prevalence of eGFR <60 mL/min/1.73 m2 was significantly higher for whites (3.6%) compared with blacks (1.9%), due to higher prevalence of stage 3 among whites. Prevalence of CKD was similar for blacks and whites using CKD-EPI equation (1.2%), but was higher among blacks when using the CARDIA-derived race coefficient (1.6% vs.1.2%, P-value = 0.03). Among persons with eGFR by CKD-EPI of 60–80 mL/min/1.73 m2, blacks had higher levels of albuminuria, uric acid, systolic blood pressure and higher diabetes prevalence.
Conclusions. CKD classification among young blacks is very sensitive to the race coefficients. Despite whites having higher rates of CKD stage 3, blacks with eGFRs just above the CKD threshold had higher rates of CKD risk factors. Current equations used to define CKD may systematically miss a high-risk group of blacks at a time in the disease course when interventions are crucial.
chronic kidney disease; glomerular filtration rate; race
Despite a higher burden of standard atrial fibrillation (AF) risk factors, African Americans have a lower risk of AF than whites. It is unknown if the higher riskis due to genetic or environmental factors. As African Americans have varying degrees of European ancestry, we sought to test the hypothesis that European ancestry is an independent risk factor for AF.
Methods and Results
We studied whites (n=4,543) and African Americans (n=822) in the Cardiovascular Health Study (CHS) and whites (n=10,902) and Africa Americans (n=3,517) in the Atherosclerosis Risk in Communities (ARIC) Study (n=3,517). Percent European ancestry in African Americans was estimated using 1,747 ancestry informative markers (AIMs) from the Illumina custom ITMAT-Broad-CARe (IBC) array. Among African Americans without baseline AF, 120 of 804 CHS participants and 181 of 3,517 ARIC participants developed incident AF. A meta-analysis from the two studies revealed that every 10% increase in European ancestry increased the risk of AF by 13% (HR 1.13, 95% CI 1.03–1.23, p=0.007). After adjusting for potential confounders, European ancestry remained a predictor of incident AF in each cohort alone, with a combined estimated hazard ratio for each 10% increase in European ancestry of 1.17 (95% CI 1.07–1.29, p=0.001). A second analysis using 3,192 AIMs from a genome wide Affymetrix 6.0 array in ARIC African Americans yielded similar results.
European ancestry predicted risk of incident AF. Our study suggests that investigating genetic variants contributing to differential AF risk in individuals of African versus European ancestry will be informative.
Atrial Fibrillation Genetics; Ancestry; African Americans
Chronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR <60 mL/min/1.73 m2), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR >30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3×10−7) and FNDC1 (p-value = 3.0×10−7) for UACR, and KCNQ1 with eGFR (p = 3.6×10−6). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish.
Chronic kidney disease (CKD) is an increasing global public health problem and disproportionately affects populations of African ancestry. Many studies have shown that genetic variants are associated with the development of CKD; however, similar studies are lacking in African ancestry populations. The CARe consortium consists of more than 8,000 individuals of African ancestry; genome-wide association analysis for renal-related phenotypes was conducted. In cross-ethnicity analyses, we found that 23 of 24 previously identified SNPs in European ancestry populations have the same effect direction in our samples of African ancestry. We also identified 3 suggestive genetic variants associated with measurement of kidney function. We then tested these genes in zebrafish knockdown models and demonstrated that kcnq1 is involved in kidney development in zebrafish. These results highlight the similarity of genetic variants across ethnicities and show that cross-species modeling in zebrafish is feasible for genes associated with chronic human disease.
Some studies suggest that polymorphisms in angiotensin-converting enzyme (ACE), angiotensinogen (AGT), angiotensin II type I receptor (AGTR1) and angiotensin II type II receptor (AGTR2) genes may contribute to renal function variation.
Genotyping for single nucleotide polymorphisms (SNPs) in these candidate genes was performed in 2,847 participants from four racial/ethnic groups (African American, Chinese, White and Hispanic) without known cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis. SNP and haplotype analyses were performed to determine associations between genotypes and cross-sectional renal function measurements, including urine albumin excretion (UAE) and estimated glomerular filtration rate (eGFR) using serum creatinine and cystatin C.
Twenty-four ACE SNPs, 10 AGT SNPs, 15 AGTR1 SNPs and 6 AGTR2 SNPs were typed successfully. After adjusting for ancestry, age and gender, 3 SNPs (AGT M235T, AGT rs2148582 and AGTR1 rs2131127) showed associations with an empiric p value <0.05 with the same phenotype in multiple racial/ethnic groups, suggesting replication. The AGT M235T SNP has been shown previously to be associated with diabetic and hypertensive nephropathy. Conclusions: These data suggest that genetic polymorphisms in the renin-angiotensin system are associated with renal phenotypes in the general population, but that many associations differ across racial/ethnic groups.
Renin-angiotensin; ACE; AGT; AGTR1; AGTR2; Albuminuria; Creatinine clearance epidemiology; Genetics
Disorders in mineral metabolism are associated with risk for cardiovascular disease (CVD) events in patients with kidney disease as well as in the general population. This risk is thought to be mediated, in part, through the mechanism of stiffening of the arteries.
The objective of this study was to evaluate the relationships between serum calcium, phosphorus, intact parathyroid hormone (iPTH), and 25-hydroxyvitamin D levels and arterial pulse wave velocity (aPWV) among 2,229 community-dwelling elderly persons participating in the Health Aging and Body Composition (Health ABC) study.
The mean age of the participants was 72 years; 52% were woman, 39% were black, and 17% had chronic kidney disease (CKD) (estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2). In parallel unadjusted analyses, the following associations were observed: 2.86% greater aPWV per 12 ng/ml (s.d.) lower 25-hydroxyvitamin D (95% confidence interval −4.38%, −1.31%), 3.04% greater aPWV per 28 pg/ml (s.d.) higher iPTH (95% confidence interval 1.42–4.68%), and 2.37% lower aPWV per 0.5 mg/dl (s.d.) higher phosphorus (95% confidence interval −3.90% to − 0.81%). Except for phosphorus, these associations were attenuated and rendered no longer statistically significant after adjustment for demographic risk factors, clinical site, season, medications and other CVD risk factors. The results were similar in men and women and were not dependent on the presence of CKD.
Among well-functioning community-dwelling elderly persons, only serum phosphorus was associated with aPWV; and this association was in the opposite direction of the one hypothesized. Factors other than vascular stiffening may mediate the relationship between disordered mineral metabolism and CVD events in community-living elders.
arterial stiffness; blood pressure; cardiovascular disease; hypertension; kidney disease; mineral metabolism; PWV
Reports show higher prevalence of albuminuria among Hispanics compared to whites. Differences by country of origin or genetic background are unknown.
Methods and Results
In MESA, we studied the associations of both genetic ancestry and country of origin with albumin to creatinine ratio among 1,417 Hispanic vs. White participants using multivariable linear regression and back transforming beta-coefficients into relative difference (%RD, 95%CI). Percentage European, Native American and African ancestry components for Hispanics were estimated using genetic admixture analysis.
The proportions of European, Native American and African genetic ancestry differed significantly by country of origin (p-value<0.0001); Mexican/Central Americans had the highest Native American (41±13%), Puerto Ricans had the highest European (61±15 %), and Dominicans had the highest African (39±21%) ancestry. Hispanic ethnicity was associated with higher albumin/creatinine ratio compared to whites, but the association varied country of origin (adjusted p interaction=0.04). Mexican/Central Americans and Dominicans had higher albumin/creatinine ratio compared to whites after adjustment (RD 19%, 2-40% and (RD 27%, 1-61%), but not Puerto Ricans (RD 8%, −12-34%). Higher Native American ancestry was associated with higher albuminuria after age and sex adjustment among all Hispanics (RD 11%, 1-21%), but was attenuated after further adjustment. Higher European ancestry was independently associated with lower albumin/creatinine ratio among Puerto Ricans (−21%, −34 to −6), but not among Mexican/Central Americans and Dominicans.
Hispanics are a heterogeneous group with varying genetic ancestry. Risks of albuminuria differ across country of origin groups. These differences may be due, in part, to differences in genetic ancestral components.
genetics; kidney; albuminuria; ancestry
Kidney disease and hypertension commonly coexist, yet the direction of their association is still debated.
To evaluate whether early kidney dysfunction, measured by serum cystatin C levels and urinary albumin excretion, predates hypertension in adults without clinically recognized kidney or cardiovascular disease.
Observational cohort study using data from 2000 to 2005.
The MESA (Multi-Ethnic Study of Atherosclerosis), a community-based study of subclinical cardiovascular disease in adults age 45 to 84 years.
2767 MESA participants without prevalent hypertension, cardiovascular disease, or clinically recognized kidney disease (an estimated glomerular filtration rate <60 mL/min per 1.73 m2 or microalbuminuria).
Cystatin C was measured by using a nephelometer, and urinary albumin and creatinine were measured from a spot morning collection. The primary outcome was incident hypertension, defined as systolic blood pressure of at least 140 mm Hg, diastolic blood pressure of at least 90 mm Hg, or use of an antihypertensive medication.
During a median follow-up of 3.1 years, 19.7% of the cohort (545 participants) developed hypertension. After adjustment for established hypertension risk factors, each 15-nmol/L increase in cystatin C was associated with a statistically significant 15% greater incidence of hypertension (P = 0.017). The highest sex-specific quartile of urinary albumin–creatinine ratio was associated with a statistically insignificant 16% greater incidence of hypertension (P = 0.192) compared with the lowest quartile. No statistical evidence suggested a multiplicative interaction.
Unmeasured characteristics may have confounded observed associations of kidney markers with hypertension. Follow-up was relatively short. Hypertension that may have occurred between study visits or hypertension that was not captured by standard cuff measurements may have been missed.
Differences in kidney function, indicated by cystatin C levels, are associated with incident hypertension among individuals without clinical kidney or cardiovascular disease. These population-based findings complement experimental work implicating early kidney damage in the pathogenesis of essential hypertension.
Arterial stiffness leads to left ventricular (LV) mass through non-atherosclerotic pathways in mice. In humans, a high ankle brachial index (ABI) indicates stiff peripheral arteries, and is associated with cardiovascular disease (CVD) events. Whether high ABI is associated with LV mass in humans, and whether this may reflect consequences of arterial stiffness, atherosclerosis, or both is unknown.
Among 4,972 MESA participants without clinical CVD, we used linear regression to evaluate the association of low (< 0.90) and high (>1.40 or incompressible) ABI with LV mass by cardiac magnetic resonance imaging (MRI). Intermediate ABIs served as the reference category. To determine the effect of subclinical atherosclerosis, models were adjusted for common and internal carotid intima media thickness (cIMT) and log-transformed coronary artery calcification (Ln[CAC+1]).
Compared to subjects with intermediate ABI, LV mass was higher with either low (2.70g/m2 higher, 95% CI 0.65–4.75) or high ABI (6.84 g/m2 higher, 95% CI 3.2–10.47) after adjustment for traditional CVD risk factors, kidney function, and CRP. However, further adjustment for cIMT and CAC substantially attenuated the association of low ABI with LVMI (1.24 g/m2 higher, 95% CI −0.84–3.33), whereas the association of high ABI was minimally altered (6.01 g/m2 higher, 95% CI 2.36–9.67).
High ABI is associated with greater LV mass; an association that is not attenuated with adjustment for subclinical atherosclerosis in non-peripheral arterial beds. High ABI may lead to greater LV mass through non-atherosclerotic pathways.
vascular stiffness; medial arterial calcification; left ventricular mass; heart failure; cardiovascular disease
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.
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.
In comparison to persons with eGFRcys >90 ml/min/1.73 m2, subjects with eGFRcys < 60 ml/min/1.73 m2 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 m2 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.
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.
Vascular abnormalities may exist before clinical hypertension. Using Poisson regression, the authors studied the association of coronary artery calcium (CAC), common carotid intima-media thickness (CIMT), aortic distensibility, and large and small arterial elasticity with incident hypertension among 2,512 normotensive US adults free of cardiovascular disease. Incidence rate ratios for incident hypertension (blood pressure ≥140/90 mm Hg or new antihypertensive medication) were calculated. Increased CAC was associated with incident hypertension in demographics-adjusted models (incidence rate ratio (IRR) = 1.35, 95% confidence interval (CI): 1.04, 1.75; IRR = 1.35, 95% CI: 1.02, 1.78; and IRR = 1.59, 95% CI: 1.12, 2.25 for CAC scores of 30–99, 100–399, and ≥400, respectively) but was attenuated after further adjustment. Increased common CIMT was associated with incident hypertension (IRR = 1.77, 95% CI: 1.28, 2.46 for quintile 4; IRR = 1.80, 95% CI: 1.28, 2.53 for quintile 5). Participants with the lowest, compared with the highest, aortic distensibility had an increased risk of hypertension (IRR = 1.75, 95% CI: 1.10, 2.79), as did those with the lowest large arterial elasticity (IRR = 1.49, 95% CI: 1.11, 1.99). Lower small arterial elasticity was incrementally associated with incident hypertension starting at quintile 2 (IRR = 2.01, 95% CI: 1.39, 2.91; IRR = 2.47, 95% CI: 1.71, 3.57; IRR = 2.73, 95% CI: 1.88, 3.95; and IRR = 2.85, 95% CI: 1.95, 4.16). Structural and functional vascular abnormalities are independent predictors of incident hypertension. These findings are important for understanding the pathogenesis of hypertension.
arteries; elasticity; hypertension
Differences in cardiovascular disease (CVD) burden exist among racial/ethnic groups in the United States, with African Americans having the highest prevalence. Subclinical CVD measures have also been shown to differ by race/ethnicity. In the United States, there has been significant intermixing among racial/ethnic groups creating admixed populations. Very little research exists on the relationship of genetic ancestry and subclinical CVD measures.
Methods and Results
These associations were investigated in 712 African-American and 705 Hispanic participants from the MESA candidate gene sub-study. Individual ancestry was estimated from 199 genetic markers using STRUCTURE. Associations of ancestry and coronary artery calcium (CAC) and common and internal carotid intima media thickness (cIMT) were evaluated using log-binomial and linear regression models. Splines indicated linear associations of ancestry with subclinical CVD measures in African-Americans, but presence of threshold effects in Hispanics. Among African Americans, each standard deviation (SD) increase in European ancestry was associated with an 8% (95% CI (1.02, 1.15), p=0.01) greater CAC prevalence. Each SD increase in European ancestry was also associated with a 2% (95% CI (−3.4%, −0.5%), p=0.008) lower common cIMT in African Americans. Among Hispanics, the highest tertile of European ancestry was associated with a 34% greater CAC prevalence, p=0.02 as compared to lowest tertile.
The linear association of ancestry and subclinical CVD suggests that genetic effects may be important in determining CAC and cIMT among African-Americans. Our results also suggest that CAC and common cIMT may be important phenotypes for further study with admixture mapping.
atherosclerosis; calcium; ancestry; epidemiology; genetics
Vascular remodeling may be a mechanism linking chronic kidney disease to cardiovascular disease. Whether early kidney dysfunction is associated with small and large arterial remodeling is not well understood. Using multivariable linear regression, back-transforming beta-coefficients to relative difference, the authors studied the association of cystatin C, creatinine-based estimated glomerular filtration rate (GFR), and albuminuria with small (SAE) and large (LAE) arterial elasticity and aortic distensibility among 6,282 participants in the Multiethnic Study of Atherosclerosis at baseline (2000–2002). Compared with the lowest quintile, higher quintiles of cystatin C were incrementally associated with lower SAE: third quintile relative difference = −5% (95% confidence interval (CI): −8, −2); fourth quintile relative difference = −10% (95% CI: −13, −8); and highest quintile relative difference = −16% (95% CI: −20, −12). By use of creatinine, the association was observed only among those with chronic kidney disease (estimated GFR, <60 mL/minute/1.73 m2): relative difference = −9% (95% CI: −13, −4). Albuminuria was significantly associated with lower SAE: relative difference = −6% (95% CI: −10, −1). Cystatin C was associated with lower LAE only at the highest quintile (relative difference = −3%, 95% CI: −6, 0) compared with the lowest quintile. By use of creatinine, chronic kidney disease was not independently associated with LAE (P = 0.912). Cystatin C, estimated GFR, and albuminuria were not associated with aortic distensibility (P = 0.26, 0.48, 0.45). Early kidney dysfunction is significantly associated with decreased arterial elasticity in smaller arteries and, to a lesser degree, in larger arteries.
albuminuria; cystatin C; elasticity; kidney; kidney diseases
Whether genetic factors account for differences in early kidney disease among blacks in a young healthy population is not well known. We evaluated the association of self-reported race and genetic African ancestry with elevated creatinine (≥1.3 mg/dl for men, ≥1.1 mg/dl for women) among 3,113 black and white participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study, ages 38–50 years. We estimated individual African ancestry using 42 ancestry informative markers. Blacks were more likely to have elevated creatinine than whites, and this effect was more pronounced in men: adjusted odds ratio (AOR) for black versus white men = 7.03, 4.15–11.91; AOR for women = 2.40, 1.15–5.02. Higher African ancestry was independently associated with elevated creatinine among black men (AOR = 1.53,1.08–2.16 per SD increase in African ancestry), but not women. A graded increase in odds of elevated creatinine by African Ancestry was observed among black men compared with white men: AOR = 4.27 (2.26–10.06) for black men with 40–70% African ancestry; AOR = 8.09 (4.19–15.61) for black men with 70–80% African ancestry; AOR = 9.05 (4.81–17.02) for black men with >80% African ancestry. Genetic factors common to African ancestry may be associated with increased risk of early kidney dysfunction in a young, healthy population, particularly among black men.
Ancestry; Creatinine; Race; Kidney
Control of hypertension is paramount in treating chronic kidney disease. The relationship between kidney function and blood pressure (BP) components has been studied in persons with diagnosed CKD, diabetes, or hypertension. Whether kidney function in the normal range is associated with systolic BP (SBP), diastolic BP (DBP), and pulse pressure is unclear.
We evaluated the association between kidney function and each BP component using cystatin C and 24-h creatinine clearance (CrCl) among 906 participants in the Heart and Soul Study.
We observed that SBP was linearly associated with cystatin C concentrations (1.19 ± 0.55 mm Hg increase per 0.4 mg/L cystatin C, P = .03) across the range of kidney functions. In contrast, using CrCl, SBP was significantly associated with kidney function only in subjects with CrCl <60 mL/min (6.4 ± 2.13 mm Hg increase per 28 mL/min, P = .003) but not >60 mL/min (0.36 ± 0.77 mm Hg per 28 mL/min, P = .64). Slopes differed significantly (for spline term P = .001). We found that DBP was not associated with cystatin C (0.34 ± 0.40 mm Hg per 0.4 mg/L cystatin, P = .39) or CrCl (0.62 ± 0.44 mm Hg per 28 mL/min clearance, P = .16). Pulse pressure was linearly associated with cystatin C (1.28 ± 0.55 mm Hg per 0.4 mg/L cystatin, P = .02) and with CrCl <60 mL/min (7.27 ± 2.16 mm Hg per 28 mL/min, P = .001).
Both SBP and pulse pressure were significantly associated with kidney function across a wide range of cystatin C concentrations, even in subjects with presumably normal kidney function, by creatinine-based measures. Cystatin C may provide new insights into the association of CKD and hypertension, a relationship that may be an underappreciated barrier to hypertension control.
Kidney; hypertension; cystatin C; systolic blood pressure