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1.  Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality: a collaborative meta-analysis of general population cohorts 
Lancet  2010;375(9731):2073-2081.
Background
A comprehensive evaluation of the independent and combined associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality is required for assessment of the impact of kidney function on risk in the general population, with implications for improving the definition and staging of chronic kidney disease (CKD).
Methods
A collaborative meta-analysis of general population cohorts was undertaken to pool standardized data for all-cause and cardiovascular mortality. The two kidney measures and potential confounders from 14 studies (105,872 participants; 730,577 person-years) with urine albumin-to-creatinine ratio (ACR) measurements and seven studies (1,128,310 participants; 4,732,110 person-years) with urine protein dipstick measurements were modeled.
Findings
In ACR studies, mortality risk was unrelated to eGFR between 75-105 ml/min/1·73 m2 and increased at lower eGFR. Adjusted hazard ratios (HRs) for all-cause mortality at eGFR 60, 45, and 15 (versus 95) ml/min/1·73 m2 were 1·18 (95% CI: 1·05-1·32), 1·57 (1·39-1·78), and 3·14 (2·39-4·13), respectively. ACR was associated with mortality risk linearly on the log-log scale without threshold effects. Adjusted HRs for all-cause mortality at ACR 10, 30, and 300 (versus 5) mg/g were 1·20 (1·15-1·26), 1·63 (1·50-1·77), and 2·22 (1·97-2·51). eGFR and ACR were multiplicatively associated with mortality without evidence of interaction. Similar findings were observed for cardiovascular mortality and in dipstick studies.
Interpretation
Lower eGFR (<60 ml/min/1·73 m2) and higher albuminuria (ACR ≥10 mg/g) were independent predictors of mortality risk in the general population. This study provides quantitative data for using both kidney measures for risk evaluation and CKD definition and staging.
doi:10.1016/S0140-6736(10)60674-5
PMCID: PMC3993088  PMID: 20483451
2.  Novel markers of kidney function as predictors of end-stage kidney disease, cardiovascular disease and mortality in the general population 
Background
Cystatin C predicts mortality more strongly than does serum creatinine. It is unknown whether this advantage extends to other outcomes, such as kidney failure, or whether other novel renal filtration markers share this advantage in predicting outcomes.
Study Design
Observational cohort study.
Setting &Participants
9,988 participants in the Atherosclerosis Risk in Communities (ARIC) Study, a population-based study in 4 US communities, followed for approximately 10 years.
Predictors
Serum creatinine-based estimated glomerular filtration rate (eGFRcr), cystatin C, β-trace protein (BTP) and β2-microglobulin (B2M).
Outcomes
Mortality, coronary heart disease, heart failure and kidney failure.
Results
Higher concentrations of cystatin C and B2M were more strongly associated with mortality (n=1425) than was BTP, and all were more strongly associated than eGFRcr (adjusted hazard ratio [95% confidence interval] for the upper 6.7 percentile compared to the lowest quintile: 1.6 [1.3-1.9] for eGFRcr; 2.9 [2.3-3.6] for cystatin C; 1.9 [1.5-2.4] for BTP; 3.0 [2.4-3.8] for B2M). Similar patterns were observed for coronary heart disease (n=1279), heart failure (n=803) and kidney failure (n=130). The addition of cystatin C, BTP and B2M to models including eGFRcr and all covariates, including urinary albumin:creatinine ratio, significantly improved risk prediction for all outcomes (p<0.001).
Limitations
No direct measurement of GFR.
Conclusions
B2M, and to a lesser extent, BTP, share cystatin C′s advantage over eGFRcr in predicting outcomes, including kidney failure. These additional markers may be helpful in improving estimation of risk associated with reduced kidney function beyond current estimates based on eGFRcr.
doi:10.1053/j.ajkd.2011.11.042
PMCID: PMC3880682  PMID: 22305758
3.  sRAGE, Inflammation, and Risk of Atrial Fibrillation: Results from the Atherosclerosis Risk in Communities (ARIC) Study 
Objective
Advanced glycation end products (AGEs) may cause inflammation by binding to their cellular receptors (RAGE). Soluble RAGE (sRAGE) acts as a decoy receptor for AGEs and may prevent inflammation. Chronic low-grade inflammation is a risk factor for cardiovascular disease, including atrial fibrillation (AF).
Methods
We studied 1,068 participants in a subsample of the Atherosclerosis Risk in Communities (ARIC) Study who had baseline measurements of sRAGE (mean age 56, 60% female, 21% black). Inflammation was assessed using measurements of high sensitivity C-reactive protein (hsCRP), fibrinogen, gamma-glutamyl transferase (GGT) and white blood cell (WBC) count. AF events were identified using ECG data, hospitalization discharge codes, and linkage to the National Death Index.
Results
Compared to the highest quartile (>1272.4 pg/mL), the lowest quartile of sRAGE (<714 pg/mL) was associated with higher baseline levels of inflammation (hsCRP ≥3 mg/L: OR=2.21 [95%CI 1.41–3.49], fibrinogen ≥400 mg/dL: OR=4.31 [95%CI 1.50–12.41], GGT ≥36 U/L in women and ≥61 U/L in men: OR= 5.22 [95%CI 2.66–10.22], WBC >6.2×109/L: OR=2.38 [95%CI 1.52–3.72]). sRAGE was not prospectively associated with 6-year change in inflammatory markers (hsCRP or GGT). There was no significant association of sRAGE and risk of AF (HR 1.49 [95% CI: 0.80–2.78] for the 1st vs 4th quartile of sRAGE).
Conclusions
sRAGE was strongly inversely associated with markers of inflammation at baseline, but not prospectively. sRAGE was not significantly associated with incident AF. This supports a role for sRAGE in attenuating current inflammation, but it remains unclear whether sRAGE plays a role in the development of AF.
doi:10.1016/j.jdiacomp.2014.11.008
PMCID: PMC4333077  PMID: 25499973
4.  Estimating Time to ESRD Using Kidney Failure Risk Equations: Results From the African American Study of Kidney Disease and Hypertension (AASK) 
Background
Planning for renal replacement therapy, such as referral for arteriovenous fistula placement and transplantation, is often guided by level of estimated glomerular filtration rate (eGFR). The use of risk equations might enable more accurate estimation of time to end-stage renal disease (ESRD), thus improving patient care.
Study Design
Prospective observational study.
Setting & Participants
1,094 participants in the African-American Study of Kidney Disease and Hypertension (AASK) cohort.
Predictor
Age, sex, urine protein-creatinine ratio ≥1 g/g, APOL1 high-risk status, and 3-year antecedent eGFR decline.
Outcome
Cumulative incidence of ESRD from five different starting points: eGFR values of 30 and 15 ml/min/1.73 m2, and a 5%, 10%, and 20% 1-year ESRD risk, estimated by a published, 4-variable kidney failure risk equation.
Results
There were 566 participants who developed an eGFR of 30 ml/min/1.73 m2, 244 who developed eGFR of 15 ml/min/1.73 m2, and 437, 336, and 259 who developed a 5%, 10%, and 20% 1-year ESRD risk, respectively. The 1-year cumulative incidence of ESRD was 4.3% from eGFR 30 ml/min/1.73 m2, 49.0% from eGFR 15 ml/min/1.73 m2, 6.7% from 5% ESRD risk, 15.0% from 10% ESRD risk, and 29% from 20% ESRD risk. From eGFR 30 ml/min/1.73 m2, there were several risk factors that predicted ESRD risk. From eGFR 15 ml/min/1.73 m2, only level of proteinuria did; median time to ESRD was 9 and 19 months in those with higher and lower proteinuria, respectively. Median times were less variable from corresponding ESRD risk thresholds. For example, median time to ESRD from 20% ESRD risk was 22 and 25 months among those with higher and lower proteinuria, respectively.
Limitations
Relatively homogeneous population of African Americans with hypertensive kidney disease.
Conclusions
The results of the present study suggest the potential benefit of incorporating kidney failure risk equations into clinical care, with selection of a specific threshold guided by its intended use.
doi:10.1053/j.ajkd.2014.07.026
PMCID: PMC4339439  PMID: 25441435
end-stage renal disease (ESRD); estimated glomerular filtration rate (eGFR); proteinuria; kidney failure risk equations; risk; disease trajectory; disease progression; prognosis; clinical decision making; African-American Study of Kidney Disease and Hypertension (AASK); hypertensive kidney disease
6.  Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Kidney Injury Molecule 1 (KIM-1) as Predictors of Incident CKD Stage 3: The Atherosclerosis Risk in Communities (ARIC) Study 
Background
Identifying individuals at risk for chronic kidney disease (CKD) is critical for timely treatment initiation to slow progression of the disease. Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) are known biomarkers of acute kidney injury, but it is unknown whether these markers are associated with incident CKD stage 3 in the general population.
Study Design
Matched case-control study
Setting and Participants
African American and Caucasian participants from the Atherosclerosis Risk in Communities (ARIC) study who at baseline had an estimated glomerular filtration rate ≥ 60 ml/min/1.73 m2 and urinary albumin-creatinine ratio (UACR) ≤ 30 mg/g. A total of 143 controls were matched on age, sex and race to 143 cases of incident CKD stage 3 after 8.6 years of follow-up.
Predictors
Quartile of NGAL and KIM-1.
Outcomes & Measurements
Incident CKD stage 3 (eGFR < 60 ml/min/1.73 m2 at follow-up and a decrease in eGFR from baseline to follow-up of ≥25%)
Results
Both NGAL (p=0.05) and KIM-1 (p<0.001) were positively correlated with baseline UACR; neither was associated with baseline eGFR. Participants with NGAL concentrations in the fourth quartile had more than 2-fold higher odds (adjusted OR, 2.11, 95% CI, 0.96–4.64) of incident CKD stage 3 compared to participants in the first quartile after multivariable adjustment (p-trend=0.03). Adjustment for urinary creatinine and albumin resulted in a non-significant association (highest quartile adjusted OR. 1.52; 95% CI, 0.64–3.58; p=0.2). No significant association between KIM-1 levels and incident CKD was observed in crude or adjusted models.
Limitations
The relatively small sample size of the study limits precision and power to detect weak associations.
Conclusions
Higher NGAL levels, but not KIM-1 levels, were associated with incident CKD stage 3. Adjustment for urinary creatinine and albumin concentration attenuated this association. Additional studies are needed to confirm these findings and assess the utility of urinary NGAL as a marker of CKD risk.
doi:10.1053/j.ajkd.2012.02.336
PMCID: PMC3399971  PMID: 22542304
7.  Association of apolipoprotein A1 and B with kidney function and chronic kidney disease in two multiethnic population samples 
Nephrology Dialysis Transplantation  2012;27(7):2839-2847.
lipoprotein risk factors for atherosclerosis, i.e., increased LDL cholesterol, increased triglycerides and decreased HDL cholesterol, also are associated with progression of loss of kidney function...Goek and coworkers describe the association of the apoliproteins A1 and B and eGFR in two large cohorts derived from the general polulation [the NHANES III (N=7,023) and the ARIC study (n=10,292)]. The results were similar in both cohorts...
Background
Circulating lipoproteins and their protein constituents, apolipoproteins, are risk factors for chronic kidney disease (CKD). The associations between apolipoprotein A1, apolipoprotein B and their ratio with glomerular filtration rate estimated from the new CKD Epidemiology Collaboration (CKD-EPI) equation (eGFR) are not well studied in the general population.
Methods
Associations between apolipoprotein A1, B and their ratio with the outcomes of eGFR, CKD (eGFR <60 mL/min/1.73m2) and albuminuria were examined in the Atherosclerosis Risk in Communities study (ARIC, n = 10 292, 1996–98) and the Third National Health and Nutrition Examination Survey (NHANES III, n = 7023, 1988–91). Cross-sectional multivariable-adjusted analyses were performed using linear and logistic regression. Prospective analyses related baseline apolipoprotein levels to subsequent CKD incidence over 10 years using the ARIC Carotid MRI follow-up cohort (n = 1659).
Results
Higher apolipoprotein A1 quartiles were associated with a lower prevalence of CKD [Q4 versus Q1: odds ratio (OR) 0.73, P-trend = 0.02 in ARIC; Q4 versus Q1: OR 0.53, P-trend <0.01 in NHANES III] as well as with higher eGFR (P-trend <0.01 in ARIC and NHANES III). No consistent significant associations were found for apolipoprotein B in either study. The apolipoprotein B/A1 ratio was significantly associated with eGFR across quartiles in both studies (P-trend <0.01) and with CKD in ARIC (Q4 versus Q1: OR 1.23, P-trend = 0.01). Prospectively, there were trends for the association of apolipoproteins with incident CKD [Q4 versus Q1: incidence rate ratio (IRR) = 0.68 for apolipoprotein A1, P-trend = 0.1; Q4 versus Q1: IRR = 1.35 for apolipoprotein B, P-trend = 0.2]. Associations were not systematically stronger when comparing traditional lipids (total cholesterol, low-density lipoprotein or high-density lipoprotein) to apolipoproteins.
Conclusions
Higher serum apolipoprotein A1 was associated with lower prevalence of CKD and higher eGFR estimated by the CKD-EPI equation in two large multiethnic population-based samples. While apolipoprotein B showed no consistent associations, a higher apolipoprotein B/A1 ratio was significantly associated with lower eGFR in both studies. The direction and magnitude of the longitudinal associations between apolipoproteins and CKD incidence were overall similar to those observed cross-sectionally. No consistent differences became apparent between traditional lipids and apolipoproteins.
doi:10.1093/ndt/gfr795
PMCID: PMC3471548  PMID: 22287661
apolipoprotein; ARIC; chronic kidney disease; epidemiology; NHANES
8.  Association of plasma levels of soluble receptor for advanced glycation end products and risk of kidney disease: the Atherosclerosis Risk in Communities study 
Background
Advanced glycation end products and their cell-bound receptors are thought to mediate the adverse effects of vascular disease through oxidative stress, inflammation and endothelial dysfunction. We examined the association between the soluble form of receptor for advanced glycation end products (sRAGE) and kidney disease.
Methods
In this case-cohort study nested within the Atherosclerosis Risk in Communities (ARIC) study, baseline sRAGE levels were measured in a cohort random sample of participants without kidney disease (n= 1218), and among participants who developed incident chronic kidney disease (CKD) [estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 and ≥25% eGFR decline, n = 151] and end-stage renal disease (ESRD) [entry in the US Renal Data System (USRDS) registry, n = 152].
Results
Baseline sRAGE levels were inversely related to baseline eGFR (r = −0.13). After adjusting for age, sex and race, one interquartile range higher log10-transformed sRAGE was associated with development of CKD [odds ratio: 1.39; 95% confidence interval (95% CI) 1.06–1.83; P = 0.02] and ESRD (hazard ratio: 1.97; 95% CI 1.47–2.64; P < 0.001). These associations were not significant after eGFR adjustment.
Conclusions
High sRAGE levels are associated with incident CKD and ESRD risk, but not after adjustment for kidney function at baseline. Future studies are needed to investigate specific mechanisms underlying the association of sRAGE with kidney disease risk.
doi:10.1093/ndt/gfu282
PMCID: PMC4351358  PMID: 25147225
advanced glycation end product receptor; chronic kidney failure; risk factors
9.  Association of Kidney Function and Albuminuria With Prevalent and Incident Hypertension: The Atherosclerosis Risk in Communities (ARIC) Study 
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
Cross-sectional for prevalent and prospective observational study for incident hypertension.
Setting & Participants
9,593 participants from the Atherosclerosis Risk in Communities (ARIC) Study, aged 53-75 years during 1996-1998.
Predictors
Several markers of kidney function (estimated glomerular filtration rate [eGFR] using serum creatinine and/or cystatin C and two novel markers [β-trace protein and β2-microglobulin]) and one marker of kidney damage (urinary albumin-creatinine ratio [ACR]). Every kidney marker was categorized by its quintiles (top quintile as a reference for eGFRs and bottom quintile for the rest).
Outcomes
Prevalent and incident hypertension.
Measurements
Prevalence 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. While all five kidney function markers were significantly associated with prevalent hypertension, prevalent hypertension was most notably associated with higher ACR (adjusted prevalence ratio, 1.60 [95% CI, 1.50-1.71] for the highest vs lowest ACR quintile). Similarly, ACR was consistently associated 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 (9.14-14.0 mg/g) was significantly associated with incident hypertension.
Limitations
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 consistently associated with incident hypertension, suggesting that kidney damage is more closely related to hypertension than moderate reduction in overall kidney function.
doi:10.1053/j.ajkd.2014.06.025
PMCID: PMC4272637  PMID: 25151408
incident hypertension; prevalent hypertension; kidney filtration markers; albuminuria; kidney damage; decreased kidney function; renal impairment; cohort study
10.  Comparison of Measured GFR, Serum Creatinine, Cystatin C, and Beta-Trace Protein to Predict ESRD in African Americans With Hypertensive CKD 
Background
Identification of persons with chronic kidney disease (CKD) who are at highest risk to progress to end stage renal disease (ESRD) is necessary to reduce the burden of kidney failure. The relative utility of traditional markers of kidney function, including estimated glomerular filtration rate (GFR) and serum creatinine, and emerging markers of kidney function, including cystatin C and beta-trace protein (BTP), to predict ESRD and mortality has yet to be established.
Study Design
Randomized clinical trial followed by an observational cohort study.
Setting & Participants
865 African American individuals with hypertensive CKD enrolled in a clinical trial of two levels of blood pressure control and three different antihypertensive drugs as initial therapy and subsequently followed by an observational cohort study.
Predictors
Quintile of measured GFR (mGFR) by iothalamate clearance, serum creatinine, serum creatinine-based estimated GFR (eGFRSCr), cystatin C, and BTP.
Outcomes and Measurements
Incidence of ESRD and mortality.
Results
A total of 246 participants reached ESRD over a median follow-up of 102 months. The incidence rate of ESRD was higher with higher quintiles of each marker. The association between higher BTP and ESRD was stronger than those for the other markers, including mGFR. All the markers remained significantly associated with ESRD after adjustment for mGFR and relevant covariates (all p<0.05), with BTP retaining the strongest association (HR for highest versus lowest quintile, 5.7; 95% CI, 2.2-14.9). Associations with the combined endpoint of ESRD or mortality (n=390) were weaker, but remained significant for cystatin C (p=0.05) and BTP (p=0.004).
Limitations
The ability of these markers to predict ESRD and mortality in other racial and ethnic groups and among individuals with CKD due to other causes is unknown.
Conclusions
Plasma BTP and cystatin C may be useful adjuncts to serum creatinine and mGFR in evaluating risk for progression of kidney disease.
doi:10.1053/j.ajkd.2011.07.018
PMCID: PMC3221777  PMID: 21944667
End-stage renal disease; beta trace protein; cystatin C; serum creatinine; iothalamate glomerular filtration rate
11.  Predictors of Carotid Thickness and Plaque Progression Over a Decade: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Background and Purpose
Carotid artery intima-media thickness (IMT) and plaque are non-invasive markers of subclinical arterial injury that predict incident cardiovascular disease. We evaluated predictors of longitudinal changes in IMT and new plaque over a decade in a longitudinal multiethnic cohort.
Methods
Carotid IMT and plaque were evaluated in Multi-Ethnic Study of Atherosclerosis participants at exams 1 and 5, a mean (standard deviation) of 9.4 (0.5) years later. Far wall carotid IMT was measured in both common (CCA) and internal carotid arteries. A plaque score was calculated from all carotid segments. Mixed effects longitudinal and multivariate regression models evaluated associations of baseline risk factors and time-updated medication use with IMT progression and plaque formation.
Results
The 3,441 MESA participants were 60.3 (9.4) years old (53% female; 26% African-American, 22% Hispanic, 13% Chinese); 1,620 (47%) had carotid plaque. Mean CCA IMT progression was 11.8 (12.8) μm/year. 1,923 (56%) of subjects developed new plaque. IMT progressed more slowly in Chinese (β=−2.89, p=0.001) and Hispanic participants (β=−1.81, p=0.02), and with higher baseline high-density lipoprotein cholesterol (per 5 mg/dL, β=−0.22, p=0.03), antihypertensive use (β=−2.06, p=0.0004), and time on antihypertensive medications (years) (β=−0.29, p<0.0001). Traditional risk factors were associated with new plaque formation, with strong associations for cigarette use (odds ratio 2.31, p<0.0001) and protection by African-American ethnicity (odds ratio 0.68, p<0.0001).
Conclusions
In a large, multi-ethnic cohort with a decade of follow-up, ethnicity is a strong, independent predictor of carotid IMT and plaque progression. Anti-hypertensive medication use was associated with less subclinical disease progression.
doi:10.1161/STROKEAHA.114.005669
PMCID: PMC4213289  PMID: 25213342
Carotid arteries; Risk Factors; Epidemiology; Atherosclerosis
12.  B-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies 
Europace  2014;16(10):1426-1433.
Aims
B-type natriuretic peptide (BNP) and C-reactive protein (CRP) predict atrial fibrillation (AF) risk. However, their risk stratification abilities in the broad community remain uncertain. We sought to improve risk stratification for AF using biomarker information.
Methods and results
We ascertained AF incidence in 18 556 Whites and African Americans from the Atherosclerosis Risk in Communities Study (ARIC, n=10 675), Cardiovascular Health Study (CHS, n = 5043), and Framingham Heart Study (FHS, n = 2838), followed for 5 years (prediction horizon). We added BNP (ARIC/CHS: N-terminal pro-B-type natriuretic peptide; FHS: BNP), CRP, or both to a previously reported AF risk score, and assessed model calibration and predictive ability [C-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI)]. We replicated models in two independent European cohorts: Age, Gene/Environment Susceptibility Reykjavik Study (AGES), n = 4467; Rotterdam Study (RS), n = 3203. B-type natriuretic peptide and CRP were significantly associated with AF incidence (n = 1186): hazard ratio per 1-SD ln-transformed biomarker 1.66 [95% confidence interval (CI), 1.56–1.76], P < 0.0001 and 1.18 (95% CI, 1.11–1.25), P < 0.0001, respectively. Model calibration was sufficient (BNP, χ2 = 17.0; CRP, χ2 = 10.5; BNP and CRP, χ2 = 13.1). B-type natriuretic peptide improved the C-statistic from 0.765 to 0.790, yielded an IDI of 0.027 (95% CI, 0.022–0.032), a relative IDI of 41.5%, and a continuous NRI of 0.389 (95% CI, 0.322–0.455). The predictive ability of CRP was limited (C-statistic increment 0.003). B-type natriuretic peptide consistently improved prediction in AGES and RS.
Conclusion
B-type natriuretic peptide, not CRP, substantially improved AF risk prediction beyond clinical factors in an independently replicated, heterogeneous population. B-type natriuretic peptide may serve as a benchmark to evaluate novel putative AF risk biomarkers.
doi:10.1093/europace/euu175
PMCID: PMC4197895  PMID: 25037055
Atrial fibrillation; Risk prediction; Epidemiology; Biomarker; B-type natriuretic peptide; C-reactive protein
13.  Results from the Atherosclerosis Risk in Communities study suggest that low serum magnesium is associated with incident kidney disease 
Kidney international  2014;87(4):820-827.
Low serum magnesium has been associated with kidney function decline in persons with diabetes as well as cardiovascular disease in the general population. Since the association of serum magnesium with incident kidney disease in the general population is unknown, we assessed this in 13,226 participants (aged 45 to 65) in the Atherosclerosis Risk in Communities study with baseline estimated glomerular filtration rate of at least 60 ml/min/1.73m2 in years 1987–89 and followed through 2010. The risks for incident chronic kidney disease (CKD) and end-stage renal disease (ESRD) associated with baseline total serum magnesium levels were evaluated using Cox regression. There were 1,965 CKD and 208 ESRD events during a median follow-up of 21 years. In adjusted analysis, low serum magnesium levels (0.7mmol/L or less) had significant associations with incident CKD and ESRD compared with the highest quartile with adjusted hazard ratio of 1.58 (95% CI: 1.35–1.87) for CKD and 2.39 (95% CI: 1.61–3.56) for ESRD. These associations remained significant after excluding users of diuretics and across subgroups stratified by hypertension, diabetes, and self-reported race. Thus, in a large sample of middle-aged adults, low total serum magnesium was independently associated with incident CKD and ESRD. Further studies are needed to determine whether modification of serum magnesium levels might alter subsequent incident kidney disease rates.
doi:10.1038/ki.2014.331
PMCID: PMC4382401  PMID: 25272232
renal failure; chronic kidney disease; end-stage renal disease; magnesium
14.  A Multi-Center, Randomized, Controlled, Pivotal Study to Assess the Safety and Efficacy of a Selective Cytopheretic Device in Patients with Acute Kidney Injury 
PLoS ONE  2015;10(8):e0132482.
Objective
Acute kidney injury (AKI) is a highly morbid condition in critically ill patients that is associated with high mortality. Previous clinical studies have demonstrated the safety and efficacy of the Selective Cytopheretic Device (SCD) in the treatment of AKI requiring continuous renal replacement therapy in the intensive care unit (ICU).
Design, Setting, Patients
A randomized, controlled trial of 134 ICU patients with AKI, 69 received continuous renal replacement therapy (CRRT) alone and 65 received SCD therapy.
Results
No significant difference in 60-day mortality was observed between the treated (27/69; 39%) and control patients (21/59; 36%, with six patients lost to follow up) in the intention to treat (ITT) analysis. Of the 19 SCD subjects (CRRT+SCD) and 31 control subjects (CRRT alone) who maintained a post-filter ionized calcium (iCa) level in the protocol’s recommended range (≤ 0.4mmol/L) for greater or equal to 90% of the therapy time, 60-day mortality was 16% (3/19) in the SCD group compared to 41% (11/27) in the CRRT alone group (p = 0.11). Dialysis dependency showed a borderline statistically significant difference between the SCD treated versus control CRRT alone patients maintained for ≥ 90% of the treatment in the protocol’s recommended (r) iCa target range of ≤ 0.4 mmol/L with values of, 0% (0/16) and 25% (4/16), respectively (P = 0.10). When the riCa treated and control subgroups were compared for a composite index of 60 day mortality and dialysis dependency, the percentage of SCD treated subjects was 16% versus 58% in the control subjects (p<0.01). The incidence of serious adverse events did not differ between the treated (45/69; 65%) and control groups (40/65; 63%; p = 0·86).
Conclusion
SCD therapy may improve mortality and reduce dialysis dependency in a tightly controlled regional hypocalcaemic environment in the perfusion circuit.
Trial Registration
ClinicalTrials.gov NCT01400893 http://clinicaltrials.gov/ct2/show/NCT01400893
doi:10.1371/journal.pone.0132482
PMCID: PMC4526678  PMID: 26244978
15.  Cardiac and kidney markers for cardiovascular prediction in individuals with chronic kidney disease: the Atherosclerosis Risk in Communities Study 
Objective
Traditional predictors suboptimally predict cardiovascular disease (CVD) in individuals with chronic kidney disease (CKD). This study compared five non-traditional cardiac and kidney markers regarding the improvement of cardiovascular prediction among those with CKD.
Approach and Results
Among 8,622 participants aged 52–75 years in the ARIC Study, cardiac troponin T [cTnT], N-terminal pro-B-type natriuretic peptide [NT-proBNP], cystatin C, β2-microglobulin, and β-trace protein were compared for improvement in predicting incident CVD after stratifying by CKD status (940 participants with CKD [kidney dysfunction or albuminuria]). During a median follow-up of 11.9 years, there were 1,672 CVD events including coronary disease, stroke, and heart failure (336 cases in CKD). Every marker was independently associated with incident CVD in participants with and without CKD. The adjusted HRs (per 1 SD) were larger for cardiac markers than kidney markers, particularly in CKD (1.61 [95% CI, 1.43–1.81] for cTnT, 1.50 [1.34–1.68] for NT-proBNP, and <1.26 for kidney markers). Particularly in CKD group, cardiac markers compared to kidney markers contributed to greater c-statistic increment (0.032–0.036 vs. 0.012–0.015 from 0.679 with only conventional predictors in CKD and 0.008–0.011 vs. 0.002–0.010 from 0.697 in non-CKD) and categorical net reclassification improvement (0.086–0.127 vs. 0.020–0.066 in CKD and 0.057–0.077 vs. 0.014–0.048 in non-CKD). The superiority of cardiac markers was largely consistent in individual CVD outcomes.
Conclusions
A greater improvement in cardiovascular prediction was observed for cardiac markers than kidney markers in persons with CKD. These results suggest that cTnT and NT-proBNP are useful for better CVD risk classification in this population.
doi:10.1161/ATVBAHA.114.303465
PMCID: PMC4172337  PMID: 24876355
Chronic kidney disease; cardiovascular disease; cardiovascular disease risk factors; risk prediction; biomarkers
16.  Association of kidney disease measures with ischemic versus hemorrhagic strokes: Pooled analyses of 4 prospective community-based cohorts 
Background and purpose
Although low glomerular filtration rate (GFR) and albuminuria are associated with increased risk of stroke, few studies compared their contribution to risk of ischemic versus hemorrhagic stroke separately. We contrasted the association of these kidney measures with ischemic versus hemorrhagic stroke.
Methods
We pooled individual participant data from four community-based cohorts: three from the United States and one from The Netherlands. GFR was estimated by using both creatinine and cystatin C, and albuminuria was quantified by urinary albumin-to-creatinine ratio (ACR). Associations of eGFR and ACR were compared for each stroke type (ischemic vs. intraparenchymal hemorrhagic) using study-stratified Cox-regression.
Results
Amongst 29,595 participants (mean age 61 [SD 12.5] years, 46% males, 17% black), 1,261 developed stroke (12% hemorrhagic) during 280,549 person-years. Low eGFR was significantly associated with increased risk of ischemic, but not hemorrhagic, stroke risk, while high ACR was associated with both stroke types. Adjusted HRs for ischemic and hemorrhagic stroke at eGFR of 45 (vs. 95) ml/min/1.73m2 were 1.30 (95% CI, 1.01–1.68) and 0.92 (0.47–1.81), respectively. In contrast, the corresponding HR for ACR 300 (vs. 5) mg/g were 1.62 (1.27–2.07) for ischemic and 2.57 (1.37–4.83) for hemorrhagic stroke, with significantly stronger association with hemorrhagic stroke (P =0.04). For hemorrhagic stroke, the association of elevated ACR was of similar magnitude as that of elevated systolic blood pressure.
Conclusions
Whereas albuminuria showed significant association with both stroke types, the association of decreased eGFR was only significant for ischemic stroke. The strong association of albuminuria with both stroke types warrants clinical attention and further investigations.
doi:10.1161/STROKEAHA.114.004900
PMCID: PMC4517673  PMID: 24876078
17.  Genetics of Plasma Soluble Receptor for Advanced Glycation End-Products and Cardiovascular Outcomes in a Community-based Population: Results from the Atherosclerosis Risk in Communities Study 
PLoS ONE  2015;10(6):e0128452.
Plasma soluble Receptor for Advanced Glycation End-products (sRAGE) is a strong marker of vascular outcomes although evidence on the direction of association is mixed. Compared to whites, blacks have lower levels of sRAGE. We hypothesized that genetic determinants of sRAGE would help clarify the causal role of sRAGE and the black-white difference in sRAGE levels. We conducted a genome-wide analysis of sRAGE in whites and blacks from the Atherosclerosis Risk in Communities Study. Median plasma sRAGE levels were lower in blacks than whites (728 vs. 1067 pg/ml; P<0.0001). The T (vs. C) allele of rs2070600, a missense variant in AGER, the gene encoding RAGE, was associated with approximately 50% lower sRAGE levels in both whites (N = 1,737; P = 7.26x10-16; minor allele frequency (MAF) = 0.04) and blacks (N = 581; P = 0.02; MAF = 0.01). In blacks, the T (vs. C) allele of rs2071288, intronic to AGER, was associated with 43% lower sRAGE levels (P = 2.22x10-8; MAF = 0.10) and was nearly absent in whites. These AGER SNPs explained 21.5% and 26% of the variation in sRAGE in blacks and whites, respectively, but did not explain the black-white difference in sRAGE. These SNPs were not significantly associated with incident death, coronary heart disease, diabetes, heart failure, or chronic kidney disease in whites (N = 8,130–9,017) or blacks (N = 2,293–2,871) (median follow up ~20 years). We identified strong genetic determinants of sRAGE that did not explain the large black-white difference in sRAGE levels or clearly influence risk of clinical outcomes, suggesting that sRAGE may not be a causal factor in development of these outcomes.
doi:10.1371/journal.pone.0128452
PMCID: PMC4471120  PMID: 26083729
18.  Relative risks of Chronic Kidney Disease for mortality and End Stage Renal Disease across races is similar 
Kidney international  2014;86(4):819-827.
Some suggest race-specific cutpoints for kidney measures to define and stage chronic kidney disease (CKD), but evidence for race-specific clinical impact is limited. To address this issue, we compared hazard ratios of estimated glomerular filtration rates (eGFR) and albuminuria across races using meta-regression in 1.1 million adults (75% Asians, 21% whites, and 4% blacks) from 45 cohorts. Results came mainly from 25 general population cohorts comprising 0.9 million individuals. The associations of lower eGFR and higher albuminuria with mortality and end-stage renal disease (ESRD) were largely similar across races. For example, in Asians, whites, and blacks, the adjusted hazard ratios (95% confidence interval) for eGFR 45-59 vs. 90-104 ml/min/1.73m2 were 1.3 (1.2-1.3), 1.1 (1.0-1.2) and 1.3 (1.1-1.7) for all-cause mortality, 1.6 (1.5-1.7), 1.4 (1.2-1.7), and 1.4 (0.7-2.9) for cardiovascular mortality, and 27.6 (11.1-68.7), 11.2 (6.0-20.9), and 4.1 (2.2-7.5) for ESRD, respectively. The corresponding HRs for ACR 30-299 mg/g or dipstick 1+ compared with ACR <10 or dipstick negative were 1.61 (1.41-1.84), 1.7 (1.5-1.9) and 1.8 (1.7-2.1) for all-cause mortality, 1.7 (1.4-2.0), 1.8 (1.5-2.1), and 2.8 (2.2-3.6) for cardiovascular mortality, and 7.4 (2.0-27.6), 4.0 (2.8-5.9), and 5.6 (3.4-9.2) for ESRD, respectively. Thus, the relative mortality or ESRD risks of lower eGFR and higher albuminuria were largely similar among three major races, supporting similar clinical approach to CKD definition and staging, across races.
doi:10.1038/ki.2013.553
PMCID: PMC4048178  PMID: 24522492
19.  Relative risks of Chronic Kidney Disease for mortality and End Stage Renal Disease across races is similar 
Kidney international  2014;86(4):819-827.
Some suggest race-specific cutpoints for kidney measures to define and stage chronic kidney disease (CKD), but evidence for race-specific clinical impact is limited. To address this issue, we compared hazard ratios of estimated glomerular filtration rates (eGFR) and albuminuria across races using meta-regression in 1.1 million adults (75% Asians, 21% whites, and 4% blacks) from 45 cohorts. Results came mainly from 25 general population cohorts comprising 0.9 million individuals. The associations of lower eGFR and higher albuminuria with mortality and end-stage renal disease (ESRD) were largely similar across races. For example, in Asians, whites, and blacks, the adjusted hazard ratios (95% confidence interval) for eGFR 45–59 vs. 90–104 ml/min/1.73m2 were 1.3 (1.2–1.3), 1.1 (1.0–1.2) and 1.3 (1.1–1.7) for all-cause mortality, 1.6 (1.5–1.8), 1.4 (1.2–1.7), and 1.4 (0.7–2.9) for cardiovascular mortality, and 27.6 (11.1–68.7), 11.2 (6.0–20.9), and 4.1 (2.2–7.5) for ESRD, respectively. The corresponding hazard ratios for urine albumin-to-creatinine ratio 30–299 mg/g or dipstick 1-positive vs. an albumin-to-creatinine ratio under 10 or dipstick negative were 1.6 (1.4–1.8), 1.7 (1.5–1.9) and 1.8 (1.7–2.1) for all-cause mortality, 1.7 (1.4–2.0), 1.8 (1.5–2.1), and 2.8 (2.2–3.6) for cardiovascular mortality, and 7.4 (2.0–27.6), 4.0 (2.8–5.9), and 5.6 (3.4–9.2) for ESRD, respectively. Thus, the relative mortality or ESRD risks of lower eGFR and higher albuminuria were largely similar among three major races, supporting similar clinical approach to CKD definition and staging, across races.
doi:10.1038/ki.2013.553
PMCID: PMC4048178  PMID: 24522492
20.  Longitudinal Effects of a Decade of Aging on Carotid Artery Stiffness: The Multi-Ethnic Study of Atherosclerosis 
Background and Purpose
Arterial stiffening is associated with hypertension, stroke, and cognitive decline; however, the effects of aging and cardiovascular disease risk factors on carotid artery stiffening have not been assessed prospectively in a large multi-ethnic, longitudinal study.
Methods
Distensibility coefficient and Young’s elastic modulus of the right common carotid artery were calculated at baseline and after a mean (standard deviation) of 9.4 (0.5) years in 2,650 participants. Effects of age and cardiovascular disease risk factors were evaluated by multivariable mixed regression and analysis of covariance models.
Results
At baseline, participants were 59.9 (9.4) years old (53% female; 25% Black, 22% Hispanic, 14% Chinese). Young’s elastic modulus increased from 1,581 (927) to 1,749 (1,306) mmHg (p<0.0001) and distensibility coefficient decreased from 3.1 (1.3) to 2.7 (1.1) x 10−3 mmHg−1 (p<0.001), indicating progressive arterial stiffening. Young’s elastic modulus increased more among participants who were >75 years old at baseline (p<0.0001). In multivariable analyses, older age and less education independently predicted worsening Young’s elastic modulus and distensibility coefficient. Stopping antihypertensive medication during the study period predicted more severe worsening of Young’s elastic modulus (β=360.2 mmHg, p=0.008). Starting antihypertensive medication after exam 1 was predictive of improvements in distensibility coefficient (β =1.1 x 10−4, mmHg−1; p=0.024).
Conclusions
Arterial stiffening accelerates with advanced age. Older individuals experience greater increases in Young’s elastic modulus than do younger adults, even after considering the effects of traditional risk factors. Treating hypertension may slow the progressive decline in carotid artery distensibility observed with aging and improve cerebrovascular health.
doi:10.1161/STROKEAHA.113.002649
PMCID: PMC3888489  PMID: 24253542
Aging; Carotid arteries; Elasticity; Hypertension; Cardiovascular disease risk factors
21.  Three-Year Variability in Plasma Concentrations of the Soluble Receptor for Advanced Glycation End Products (sRAGE) 
Clinical biochemistry  2013;47(0):132-134.
Objectives
The soluble receptor for advanced glycation end products (sRAGE) has been implicated in the development of diabetes-related vascular complications, but the variability of concentrations of sRAGE in the blood is unknown. The objective of this study was to characterize within-person three-year variability of plasma levels of sRAGE.
Methods
We measured sRAGE in plasma samples from 179 men and women in the community-based Atherosclerosis Risk in Communities (ARIC) Study at two time points, three years apart. We calculated correlation coefficients and the within-person coefficient of variation (CVw) to characterize variability in sRAGE. We compared these estimates to total cholesterol and white blood cell count (WBC) in the same participants.
Results
Mean sRAGE concentrations at the two time points (mean time between measurements = 2.9 years) were 1096.2 pg/mL and 990.2 pg/mL, respectively (mean difference = −106.0 pg/mL, p-value < 0.001). The Pearson’s correlation was 0.78 (Spearman’s, 0.73). The intra-class correlation coefficient was 0.76 and the CVw was 26.6%. Compared to sRAGE, Pearson’s and Spearman’s correlations for total cholesterol (0.76 and 0.77) and white blood cell count (0.61 and 0.72) were similar, although CVw for both were lower (8.7% for cholesterol, 15.6% for WBC). Less than 4% of participants’ values changed substantially (50% or greater) over the three-year interval.
Conclusions
We observed that sRAGE concentrations remained relatively stable over three years. Our findings suggest that a single measure of circulating sRAGE tracks well in a community-based population and could be a useful measure in clinical and epidemiologic studies of long-term risk.
doi:10.1016/j.clinbiochem.2013.11.005
PMCID: PMC4263345  PMID: 24246851
sRAGE; Advanced glycation end products; reliability and validity; biological markers
22.  Troponin T and NT–Pro B-Type Natriuretic Peptide: A Biomarker Approach to Predict Heart Failure Risk—the Atherosclerosis Risk in Communities Study 
Clinical chemistry  2013;59(12):1802-1810.
Background
Among the various cardiovascular diseases, heart failure (HF) is projected to have the largest increases in incidence over the coming decades; therefore, improving HF prediction is of significant value. We evaluated whether cardiac troponin T (cTnT) measured with a high-sensitivity assay and N-terminal-pro-B-type natriuretic peptide (NT-proBNP), biomarkers strongly associated with incident HF, improve HF risk prediction in the Atherosclerosis Risk In Communities (ARIC) study.
Methods
Using gender-specific models, cTnT and NT-proBNP were added to age and race (“laboratory report” model), and to the ARIC HF model (includes age, race, systolic blood pressure, antihypertensive-medication use, current/former smoking, diabetes, body mass index, prevalent coronary heart disease and heart rate) in 9868 subjects without prevalent HF; area under the receiver operating characteristic curve (AUC), integrated discrimination improvement, net reclassification improvement (NRI) and model fit were described.
Results
Over a mean follow-up of 10.4 years, 970 subjects developed incident HF. Adding cTnT and NT-proBNP to the ARIC HF model significantly improved all statistical parameters (AUCs increased by 0.040 and 0.057; the continuous NRI was 50.7% and 54.7% in women and men, respectively). Interestingly, the simpler laboratory report model was statistically no different than the ARIC HF model.
Conclusion
cTnT and NT-proBNP have significant value in HF risk prediction. A simple gender-specific model that includes age, race, cTnT and NT-proBNP (which can be incorporated in a laboratory report) provides a good model, whereas adding cTnT and NT-proBNP to clinical characteristics results in an excellent HF prediction model.
doi:10.1373/clinchem.2013.203638
PMCID: PMC4208068  PMID: 24036936
cardiac troponin T; NT-proBNP; heart failure; ARIC; risk prediction
23.  Primary Care Detection of Chronic Kidney Disease in Adults with Type-2 Diabetes: The ADD-CKD Study (Awareness, Detection and Drug Therapy in Type 2 Diabetes and Chronic Kidney Disease) 
PLoS ONE  2014;9(11):e110535.
This US, multicenter, observational study assessed the CKD prevalence in adult patients with type-2 diabetes mellitus (T2DM) and characterized the proportion of detected and undiagnosed CKD in the primary care setting using the following: a clinician survey; a patient physical exam and medical history; a single blood draw for estimated glomerular filtration rate (eGFR) and glycosolated hemoglobin (HbA1c); urine dipstick for protein; urine albumin-creatinine ratio (ACR); two patient quality of life questionnaires; and a 15-month medical record review. The study consisted of 9339 adults with T2DM and 466 investigator sites. Of the 9339 enrolled, 9307 had complete data collection for analysis. The 15-month retrospective review showed urine protein, urine ACR, and eGFR testing were not performed in 51.4%, 52.9% and 15.2% of individuals, respectively. Of the 9307 patients, 5036 (54.1%) had Stage 1–5 CKD based on eGFR and albuminuria; however, only 607 (12.1%) of those patients were identified as having CKD by their clinicians. Clinicians were more successful in diagnosing patients with Stage 3–5 CKD than Stages 1 and 2. There were no differences in clinicians’ likelihood of identification of CKD based on practice setting, number of years in practice, or self-reported patients seen per week. Awareness or patient self-reported CKD was 81.1% with practitioner detection versus 2.6% in the absence of diagnosis. Primary care of T2DM demonstrates recommended urine CKD testing is underutilized, and CKD is significantly under-diagnosed. This is the first study to show CKD detection is associated with awareness.
doi:10.1371/journal.pone.0110535
PMCID: PMC4245114  PMID: 25427285
24.  Elevated High-Sensitivity C-Reactive Protein as a Risk Marker of the Attenuated Relationship Between Serum Cholesterol and Cardiovascular Events at Older Age 
American Journal of Epidemiology  2013;178(7):1076-1084.
The relationship between cholesterol and coronary heart disease (CHD) is attenuated at older age. We analyzed cholesterol level as a predictor of CHD in 8,947 participants from the Atherosclerosis Risk in Communities (ARIC) Study, a large multicenter cohort study that enrolled participants in 1987–1989 at 4 field centers in Washington County, Maryland; Forsyth County, North Carolina; Jackson, Mississippi; and Minneapolis, Minnesota. Participants in the present analysis had no history of CHD and were stratified by age (<65 or ≥65 years) and high-sensitivity C-reactive protein (hs-CRP) level (<2 or ≥2 mg/L). Visit 4 (1996–1997) was the baseline for this analysis, with follow-up through 2008. Cholesterol level was significantly associated with CHD among younger participants, and cholesterol level was similarly predictive of CHD among older participants with an hs-CRP level of <2 mg/L. In contrast, among older participants with an hs-CRP level of 2 mg/L or higher, the association of CHD with total cholesterol level was borderline significant (hazard ratio = 1.14, 95% confidence interval: 1.00, 1.29), and the association of CHD with low-density lipoprotein cholesterol level was nonsignificant (hazard ratio = 1.10; 95% confidence interval: 0.96, 1.26). Among older persons with an elevated hs-CRP level, cholesterol level was significantly less predictive of CHD (P < 0.05), whereas for those with an hs-CRP level of <2 mg/L, there was no significant difference compared with younger participants. In conclusion, we found that among the young-old, the association of cholesterol level with CHD was strong when hs-CRP level was not elevated and weak when hs-CRP level was elevated. Therefore, hs-CRP level could be useful for stratifying the young-old to assess the strength of cholesterol level in CHD risk prediction.
doi:10.1093/aje/kwt086
PMCID: PMC3783092  PMID: 24026395
C-reactive protein; elderly persons; serum cholesterol
25.  Pilot Study of the Effect of Lanthanum Carbonate (Fosrenol®) In Patients with Calciphylaxis: A Wisconsin Network for Health Research (WiNHR) Study 
Background
Currently there is a lack of effective treatment options for patients with calciphylaxis. There is anecdotal evidence that non-calcium based phosphorus binders may offer some benefit. The aim of this pilot study is to determine if lanthanum carbonate is effective in inducing remission of calciphylaxis lesions and demonstrate an improved DLQI (Dermatology Life Quality Index).
Methods
This is a multi-site exploratory pilot study conducted through the Wisconsin Network for Health Research (WiNHR), a collaboration of health services researchers across the state of Wisconsin. Dialysis patients were recruited from in-center dialysis units, clinics and hospital admissions over a period of 24-months.
Results
Due to the low inclusion rate, the trial was terminated after which 4 patients were prospectively analyzed. Dose of lanthanum carbonate was escalated to 3750 mg divided into 3 meals and titrated according to level of serum phosphorus. Gastrointestinal symptoms were the most common adverse effect. All 4 patients achieved complete remission by definition of skin re-epithelialization. Secondary outcome measurements showed a significant improvement in serum albumin (B coeff 0.17, 95% CI 0.002-0.031; p=0.023) and a significant improvement in overall DLQI score (B coeff -0.46, 95% CI -0.85- -0.08; p=0.019).
Conclusions
Lanthanum carbonate appears to be efficacious as an adjunctive therapy to improve calciphylaxis lesions and symptom burden. More prospective clinical trials are warranted to determine the feasibility of this novel treatment strategy.
doi:10.4172/2161-0959.1000162
PMCID: PMC4170220  PMID: 25254144
Calcific uremic arteriolopathy; Calciphylaxis; Lanthanum

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