Faculty Bibliography
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Department/Unit:Population Health
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13299
Clinical journal of the American Society of Nephrology : CJASN. 2013:8(3):434-42.DOI: 10.2215/CJN.04960512
Combined association of creatinine, albuminuria, and cystatin C with all-cause mortality and cardiovascular and kidney outcomes
BACKGROUND:Estimated GFR by serum creatinine (eGFRcreatinine) is a pivotal measure of kidney function in clinical practice but can be affected by several non-GFR determinants, resulting in misclassification. Combining multiple kidney markers to predict risk is an area of substantial interest. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS/METHODS:This study followed 9489 adults from visit 4 (1996-1998) of the Atherosclerosis Risk in Communities Study for a median of 11.2 years, and assessed joint association of eGFRcreatinine, eGFRcystatin, and urinary albumin/creatinine ratio (ACR) with mortality, coronary heart disease, heart failure, AKI, and ESRD using Cox proportional hazards models. The predictive ability of ACR and eGFRcystatin beyond eGFRcreatinine was also investigated. RESULTS:Lower eGFRcreatinine and eGFRcystatin as well as elevated ACR were independently associated with risk for all outcomes. eGFRcreatinine <60 was not associated with risk of mortality, coronary heart disease, or heart failure if eGFRcystatin ≥60 with ACR <30 mg/g compared with those with all three markers above CKD cutoffs (i.e., eGFRcystatin ≥60, eGFRcreatinine ≥60, and ACR<30), whereas risk association with kidney outcomes remained: Hazard ratio (95% confidence interval), 0.96 (0.66, 1.39) for mortality, 0.85 (0.55, 1.31) for coronary heart disease, 0.99 (0.60, 1.63) for heart failure, 1.61 (0.92, 2.82) for AKI, and 3.53 (1.06, 11.68) for ESRD. Adding ACR to the fully adjusted model with eGFRcreatinine or adding eGFRcystatin to both eGFRcreatinine and ACR improved risk classification for all outcomes (P ≤ 0.01). CONCLUSIONS:eGFRcystatin can be a useful confirmatory marker in those with eGFRcreatinine <60 and whose ACR is <30 mg/g. This approach improves risk classification, and provides reassurance to a large group of individuals with eGFRcreatinine <60.
PMCID:3586966
PMID: 23258794
ISSN: 1555-905x
CID: 5582522
No racial differences in the association of glycated hemoglobin with kidney disease and cardiovascular outcomes
OBJECTIVE:There is debate regarding the clinical significance of well-established racial differences in HbA1c. We compared the associations of diabetes diagnostic categories for HbA1c and fasting glucose with clinical outcomes in black and white persons in the community. RESEARCH DESIGN AND METHODS/METHODS:We conducted a prospective cohort analysis of participants without diabetes or cardiovascular disease from the Atherosclerosis Risk in Communities study. We examined the associations of clinical categories of HbA1c (<5.7%, 5.7-6.4%, ≥6.5%) and fasting glucose (<100, 100-125, ≥126 mg/dL) with outcomes separately among 2,484 black and 8,593 white participants and tested for race interactions. RESULTS:Baseline characteristics differed significantly in blacks compared with whites, including HbA1c (5.8 vs. 5.4%; P<0.001). During 18 years of follow-up, there were trends of increased risk of kidney disease, fatal and nonfatal coronary heart disease, and stroke across categories of HbA1c in both blacks and whites. The adjusted hazard ratios for each outcome across categories of HbA1c were similar in blacks and whites (P for interaction>0.05) except for all-cause mortality. Patterns of association were similar, but weaker, for fasting glucose. HbA1c and fasting glucose both were more strongly associated with all-cause mortality in whites compared with blacks, largely explained by racial differences in the rate of cardiovascular deaths. CONCLUSIONS:HbA1c is a risk factor for vascular outcomes and mortality in both black and white adults. Patterns of association for HbA1c were similar to or stronger than those for fasting glucose. With respect to long-term outcomes, our findings support a similar interpretation of HbA1c in blacks and whites for diagnosis and treatment of diabetes mellitus.
PMID: 23723353
ISSN: 1935-5548
CID: 5582692
Associations between metabolomic compounds and incident heart failure among African Americans: the ARIC Study
Heart failure is more prevalent among African Americans than in the general population. Metabolomic studies among African Americans may efficiently identify novel biomarkers of heart failure. We used untargeted methods to measure 204 stable serum metabolites and evaluated their associations with incident heart failure hospitalization (n = 276) after a median follow-up of 20 years (1987-2008) by using Cox regression in data from 1,744 African Americans aged 45-64 years without heart failure at baseline from the Jackson, Mississippi, field center of the Atherosclerosis Risk in Communities (ARIC) Study. After adjustment for established risk factors, we found that 16 metabolites (6 named with known structural identities and 10 unnamed with unknown structural identities, the latter denoted by using the format X-12345) were associated with incident heart failure (P < 0.0004 based on a modified Bonferroni procedure). Of the 6 named metabolites, 4 are involved in amino acid metabolism, 1 (prolylhydroxyproline) is a dipeptide, and 1 (erythritol) is a sugar alcohol. After additional adjustment for kidney function, 2 metabolites remained associated with incident heart failure (for metabolite X-11308, hazard ratio = 0.75, 95% confidence interval: 0.65, 0.86; for metabolite X-11787, hazard ratio = 1.23, 95% confidence interval: 1.10, 1.37). Further structural analysis revealed X-11308 to be a dihydroxy docosatrienoic acid and X-11787 to be an isoform of either hydroxyleucine or hydroxyisoleucine. Our metabolomic analysis revealed novel biomarkers associated with incident heart failure independent of traditional risk factors.
PMCID:3736751
PMID: 23788672
ISSN: 1476-6256
CID: 5582722
Genome-wide association analyses identify 18 new loci associated with serum urate concentrations
Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
PMID: 23263486
ISSN: 1546-1718
CID: 5582532
Retained organic solutes, patient characteristics and all-cause and cardiovascular mortality in hemodialysis: results from the retained organic solutes and clinical outcomes (ROSCO) investigators
BACKGROUND:Multiple solutes are retained in uremia, but it is currently unclear which solutes are toxic. Small studies suggest that protein-bound solutes, such as p-cresol sulfate and indoxyl sulfate and intracellular solutes, such as methylamine (MMA) and dimethylamine (DMA), may be toxic. Our objective was to test whether elevated levels of these solutes were associated with mortality. METHODS:We conducted a prospective cohort study in 521 U.S. incident hemodialysis patients to evaluate associations between these solutes and all-cause and cardiovascular mortality. P-cresol sulfate, indoxyl sulfate, MMA and DMA levels were measured from frozen plasma samples obtained 2 to 6 months after initiation of dialysis. Mortality data was available through 2004 using the National Death Index. RESULTS:Elevated (greater than the population median) p-cresol sulfate, MMA or DMA levels were not associated with all-cause or cardiovascular mortality. Elevated indoxyl sulfate levels were associated with all-cause mortality but not cardiovascular mortality (hazard ratio 1.30 (95% confidence interval 1.01, 1.69) p-value 0.043). CONCLUSIONS:In this cohort of 521 incident hemodialysis patients, only elevated indoxyl sulfate levels were associated with all-cause mortality. Further research is needed to identify causes of the toxicity of uremia to provide better care for patients with kidney disease.
PMCID:3698023
PMID: 23806101
ISSN: 1471-2369
CID: 5582732
Cardiovascular risk factor burden, treatment, and control among adults with chronic kidney disease in the United States
BACKGROUND:Cardiovascular disease is a major concern in persons with chronic kidney disease (CKD). We assessed the current burden of cardiovascular risk factors and differences in risk factor treatment and control in the general US adult population by CKD status. METHODS:A cross-sectional study of 10,741 adults aged 20+ years from the 2007-2010 National Health and Nutrition Examination Survey was performed. Persons were categorized into 3 groups: CKD stages 3 to 5 (estimated glomerular filtration rate <60 mL/min/1.73 m(2)), CKD stages 1 and 2 (urinary albumin-to-creatinine ratio ≥30 mg/g and estimated glomerular filtration rate ≥60 mL/min/1.73 m(2)), and no CKD. RESULTS:The majority of adults with CKD stages 3 to 5 (79.8%) and stages 1 and 2 (59.1%) had ≥2 cardiovascular risk factors, substantially higher than adults without CKD (32.7%, P < .001). Diabetes was the most strongly associated risk factor and was highly specific for CKD stages 1 and 2 (prevalence ratio 2.53, 95% CI 2.21-2.89) and, to a lesser extent, CKD stages 3 to 5 (prevalence ratio 1.59, 95% CI 1.38-1.84). Most adults with diagnosed risk factors reported medication use for risk factor control, and pharmacologic treatment was more common among those with than without CKD. However, poor risk factor control was also common among persons treated for risk factors with CKD compared with those without CKD. CONCLUSIONS:There continues to be a substantial cardiovascular risk factor burden among adults with CKD stages 3 to 5 and, to a lesser extent, adults with CKD stages 1 and 2 when compared with adults without CKD. Overall, optimal risk factor control is low in adults with CKD, highlighting the need for aggressive cardiovascular risk reduction in adults with CKD.
PMCID:3933201
PMID: 23816034
ISSN: 1097-6744
CID: 5582742
The association of plasma lactate with incident cardiovascular outcomes: the ARIC Study
We examined the association of plasma lactate at rest, a marker of oxidative capacity, with incident cardiovascular outcomes in 10,006 participants in the Atherosclerosis Risk in Communities (ARIC) Study visit 4 (1996-1998). We used Cox proportional-hazards models to estimate hazard ratios of incident coronary heart disease, stroke, heart failure, and all-cause mortality by quartiles of plasma lactate (Q1, ≤5.3 mg/dL; Q2, 5.4-6.6; Q3, 6.7-8.6; and Q4 ≥8.7). During a median follow-up time of 10.7 years, there were 1,105 coronary heart disease cases, 379 stroke cases, 820 heart failure cases, and 1,408 deaths. A significant graded relation between lactate level and cardiovascular events was observed in the demographically adjusted model (all P for trend < 0.001). After further adjustment for traditional and other potential confounders, the association remained significant for heart failure (Q4 vs. Q1: hazard ratio (HR) = 1.35, 95% confidence interval (CI): 1.07, 1.71) and all-cause mortality (HR = 1.27, 95% CI: 1.07, 1.51) (P for trend < 0.02 for these outcomes) but not for coronary heart disease (HR = 1.02, 95% CI: 0.84, 1.24) and stroke (HR = 1.26, 95% CI: 0.91, 1.75). The results for heart failure were robust across multiple subgroups, after further adjustment for N-terminal pro-B-type natriuretic peptide and after exclusion of participants with incident heart failure within 3 years. The independent associations of plasma lactate with heart failure and all-cause mortality suggest an important role for low resting oxidative capacity.
PMCID:3727342
PMID: 23817916
ISSN: 1476-6256
CID: 5582752
A stable definition of chronic kidney disease improves knowledge and patient care [Comment]
PMID: 24048299
ISSN: 1756-1833
CID: 5582772
Cystatin C versus creatinine in determining risk based on kidney function
BACKGROUND:Adding the measurement of cystatin C to that of serum creatinine to determine the estimated glomerular filtration rate (eGFR) improves accuracy, but the effect on detection, staging, and risk classification of chronic kidney disease across diverse populations has not been determined. METHODS:We performed a meta-analysis of 11 general-population studies (with 90,750 participants) and 5 studies of cohorts with chronic kidney disease (2960 participants) for whom standardized measurements of serum creatinine and cystatin C were available. We compared the association of the eGFR, as calculated by the measurement of creatinine or cystatin C alone or in combination with creatinine, with the rates of death (13,202 deaths in 15 cohorts), death from cardiovascular causes (3471 in 12 cohorts), and end-stage renal disease (1654 cases in 7 cohorts) and assessed improvement in reclassification with the use of cystatin C. RESULTS:In the general-population cohorts, the prevalence of an eGFR of less than 60 ml per minute per 1.73 m(2) of body-surface area was higher with the cystatin C-based eGFR than with the creatinine-based eGFR (13.7% vs. 9.7%). Across all eGFR categories, the reclassification of the eGFR to a higher value with the measurement of cystatin C, as compared with creatinine, was associated with a reduced risk of all three study outcomes, and reclassification to a lower eGFR was associated with an increased risk. The net reclassification improvement with the measurement of cystatin C, as compared with creatinine, was 0.23 (95% confidence interval [CI], 0.18 to 0.28) for death and 0.10 (95% CI, 0.00 to 0.21) for end-stage renal disease. Results were generally similar for the five cohorts with chronic kidney disease and when both creatinine and cystatin C were used to calculate the eGFR. CONCLUSIONS:The use of cystatin C alone or in combination with creatinine strengthens the association between the eGFR and the risks of death and end-stage renal disease across diverse populations. (Funded by the National Kidney Foundation and others.).
PMID: 24004120
ISSN: 1533-4406
CID: 5582762
Serum fructosamine and glycated albumin and risk of mortality and clinical outcomes in hemodialysis patients
OBJECTIVE:Assays for serum total glycated proteins (fructosamine) and the more specific glycated albumin may be useful indicators of hyperglycemia in dialysis patients, either as substitutes or adjuncts to standard markers such as hemoglobin A1c, as they are not affected by erythrocyte turnover. However, their relationship with long-term outcomes in dialysis patients is not well described. RESEARCH DESIGN AND METHODS/METHODS:We measured fructosamine and glycated albumin in baseline samples from 503 incident hemodialysis participants of a national prospective cohort study, with enrollment from 1995-1998 and median follow-up of 3.5 years. Outcomes were all-cause and cardiovascular disease (CVD) mortality and morbidity (first CVD event and first sepsis hospitalization) analyzed using Cox regression adjusted for demographic and clinical characteristics, and comorbidities. RESULTS:Mean age was 58 years, 64% were white, 54% were male, and 57% had diabetes. There were 354 deaths (159 from CVD), 302 CVD events, and 118 sepsis hospitalizations over follow-up. Both fructosamine and glycated albumin were associated with all-cause mortality; adjusted HR per doubling of the biomarker was 1.96 (95% CI 1.38-2.79) for fructosamine and 1.40 (1.09-1.80) for glycated albumin. Both markers were also associated with CVD mortality [fructosamine 2.13 (1.28-3.54); glycated albumin 1.55 (1.09-2.21)]. Higher values of both markers were associated with trends toward a higher risk of hospitalization with sepsis [fructosamine 1.75 (1.01-3.02); glycated albumin 1.39 (0.94-2.06)]. CONCLUSIONS:Serum fructosamine and glycated albumin are risk factors for mortality and morbidity in hemodialysis patients.
PMCID:3661814
PMID: 23250799
ISSN: 1935-5548
CID: 5582572
