Lori D. Bash

Risk implications of the new CKD Epidemiology Collaboration (CKD-EPI) equation compared with the MDRD Study equation for estimated GFR: the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUNDnThe Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) recently published an equation for estimated glomerular filtration rate (eGFR) using the same variables (serum creatinine level, age, sex, and race) as the Modification of Diet in Renal Disease (MDRD) Study equation. Although the CKD-EPI equation estimates GFR more precisely compared with the MDRD Study equation, whether this equation improves risk prediction is unknown.nnnSTUDY DESIGNnProspective cohort study, the Atherosclerosis Risk in Communities (ARIC) Study.nnnSETTING & PARTICIPANTSn13,905 middle-aged participants without a history of cardiovascular disease with median follow-up of 16.9 years.nnnPREDICTORneGFR.nnnOUTCOMES & MEASUREMENTSnWe compared the association of eGFR in categories (>or=120, 90-119, 60-89, 30-59, and <30 mL/min/1.73 m(2)) using the CKD-EPI and MDRD Study equations with risk of incident end-stage renal disease, all-cause mortality, coronary heart disease, and stroke.nnnRESULTSnThe median value for eGFR(CKD-EPI) was higher than that for eGFR(MDRD) (97.6 vs 88.8 mL/min/1.73 m(2); P < 0.001). The CKD-EPI equation reclassified 44.9% (n = 3,079) and 43.5% (n = 151) of participants with eGFR(MDRD) of 60-89 and 30-59 mL/min/1.73 m(2), respectively, upward to a higher eGFR category, but reclassified no one with eGFR(MDRD) of 90-119 or <30 mL/min/1.73 m(2), decreasing the prevalence of CKD stages 3-5 from 2.7% to 1.6%. Participants with eGFR(MDRD) of 30-59 mL/min/1.73 m(2) who were reclassified upward had lower risk compared with those who were not reclassified (end-stage renal disease incidence rate ratio, 0.10 [95% CI, 0.03-0.33]; all-cause mortality, 0.30 [95% CI, 0.19-0.48]; coronary heart disease, 0.36 [95% CI, 0.21-0.61]; and stroke, 0.50 [95% CI, 0.24-1.02]). Similar results were observed for participants with eGFR(MDRD) of 60-89 mL/min/1.73 m(2). More frequent reclassification of younger, female, and white participants explained some of these trends. Net reclassification improvement in participants with eGFR < 120 mL/min/1.73 m(2) was positive for all outcomes (P < 0.001).nnnLIMITATIONSnLimited number of cases with eGFR < 60 mL/min/1.73 m(2) and no measurement of albuminuria.nnnCONCLUSIONSnThe CKD-EPI equation more appropriately categorized individuals with respect to long-term clinical risk compared with the MDRD Study equation, suggesting improved clinical usefulness in this middle-aged population.

Change in Estimated GFR Associates with Coronary Heart Disease and Mortality

Kidney function predicts cardiovascular and all-cause mortality, but little is known about the association of changes in estimated GFR (eGFR) with clinical outcomes. We investigated whether 3- and 9-yr changes in eGFR associated with risk for coronary heart disease (CHD) and all-cause mortality among 13,029 participants of the Atherosclerosis Risk in Communities (ARIC) Study. After adjustment for baseline covariates including eGFR in Cox proportional hazards models, the quartile of participants with the greatest annual decline (annual decline > or =5.65%) in eGFR were at significantly greater risk for CHD and all-cause mortality (hazard ratio 1.30 [95% confidence interval 1.11 to 1.52] and 1.22 [95% confidence interval 1.06 to 1.41], respectively) compared with the third quartile (annual decline between 0.33 and 0.47%). We observed similar results when we analyzed 9-yr changes in eGFR. Adjustment for covariates at the second eGFR used to estimate change reduced the association with CHD but not with mortality. Among participants with stage 3 chronic kidney disease, an increase in eGFR during the first 3 yr also associated with a higher risk for mortality, perhaps as a result of clinical instability. In conclusion, a steeper than average decline in eGFR associates with a higher risk for CHD and all-cause mortality. Increases in eGFR among participants with chronic kidney disease associate with similar increased risks.

Albuminuria and Estimated Glomerular Filtration Rate Independently Associate with Acute Kidney Injury

Acute kidney injury (AKI) is increasingly common and a significant contributor to excess death in hospitalized patients. CKD is an established risk factor for AKI; however, the independent graded association of urine albumin excretion with AKI is unknown. We analyzed a prospective cohort of 11,200 participants in the Atherosclerosis Risk in Communities (ARIC) study for the association between baseline urine albumin-to-creatinine ratio and estimated GFR (eGFR) with hospitalizations or death with AKI. The incidence of AKI events was 4.0 per 1000 person-years of follow-up. Using participants with urine albumin-to-creatinine ratios <10 mg/g as a reference, the relative hazards of AKI, adjusted for age, gender, race, cardiovascular risk factors, and categories of eGFR were 1.9 (95% CI, 1.4 to 2.6), 2.2 (95% CI, 1.6 to 3.0), and 4.8 (95% CI, 3.2 to 7.2) for urine albumin-to-creatinine ratio groups of 11 to 29 mg/g, 30 to 299 mg/g, and ≥300 mg/g, respectively. Similarly, the overall adjusted relative hazard of AKI increased with decreasing eGFR. Patterns persisted within subgroups of age, race, and gender. In summary, albuminuria and eGFR have strong, independent associations with incident AKI.

Poor Glycemic Control in Diabetes and the Risk of Incident Chronic Kidney Disease Even in the Absence of Albuminuria and Retinopathy: Atherosclerosis Risk in Communities (ARIC) Study

BACKGROUNDnDiabetic nephropathy is the leading cause of kidney failure in the United States. The extent to which an elevated glycated hemoglobin (HbA(1c)) concentration is associated with increased risk of chronic kidney disease (CKD) in the absence of albuminuria and retinopathy, the hallmarks of diabetic nephropathy, is uncertain.nnnMETHODSnGlycated hemoglobin concentration was measured in 1871 adults with diabetes mellitus followed up for 11 years in the Atherosclerosis Risk in Communities (ARIC) Study. Incident CKD was defined as an estimated glomerular filtration rate less than 60 mL/min/1.73 m(2) after 6 years of follow-up or a kidney disease-related hospitalization. We categorized HbA(1c) concentrations into 4 clinically relevant categories. Albuminuria and retinopathy were measured midway through follow-up.nnnRESULTSnHigher HbA(1c) concentrations were strongly associated with risk of CKD in models adjusted for demographic data, baseline glomerular filtration rate, and cardiovascular risk factors. Compared with HbA(1c) concentrations less than 6%, HbA(1c) concentrations of 6% to 7%, 7% to 8%, and greater than 8% were associated with adjusted relative hazard ratios (95% confidence intervals) of 1.4 (0.97-1.91), 2.5 (1.70-3.66), and 3.7 (2.76-4.90), respectively. Risk of CKD was higher in individuals with albuminuria and retinopathy, and the association between HbA(1c) concentration and incident CKD was observed even in participants without either abnormality: adjusted relative hazards, 1.46 (95% confidence intervals, 0.80-2.65), 1.17 (0.43-3.19), and 3.51 (1.67-7.40), respectively; P(trend) = .004.nnnCONCLUSIONSnWe observed a positive association between HbA(1c) concentration and incident CKD that was strong, graded, independent of traditional risk factors, and present even in the absence of albuminuria and retinopathy. Hyperglycemia is an important indicator of risk of both diabetic nephropathy with albuminuria or retinopathy and of less specific forms of CKD.

Heart Rate Variability Predicts ESRD and CKD-Related Hospitalization

Autonomic imbalance, a feature of both diabetes and hypertension, may contribute to adverse cardiovascular outcomes. In animal models, sympathetic nerve activity contributes to renal damage but the extent to which autonomic dysfunction precedes the development of CKD and ESRD in humans is unknown. We measured resting heart rate and heart rate variability in 13,241 adults (45- to 64-years old) followed for a median of 16 years in the Atherosclerosis Risk in Communities (ARIC) Study. We examined heart rate parameters by quartiles, defining those in the lowest quartile (by time and frequency domain measures separately) as the risk group of interest. We identified 199 cases of incident ESRD and 541 patients with CKD-related hospitalizations; higher resting heart rate and lower heart rate variability associated with both outcomes. The fully adjusted hazard ratios for ESRD were 1.98 (95% confidence interval [CI] 1.45 to 2.70) among those in the highest heart rate quartile and 1.56 (95% CI 1.14 to 2.14) for high-frequency power. Other time and frequency domain measures were similarly and significantly associated with ESRD and CKD-related hospitalizations. These results suggest that autonomic dysfunction may be an important risk factor for ESRD and CKD-related hospitalizations and call for further studies to define the mechanisms that underlie these associations.

Glycated Hemoglobin and the Risk of Kidney Disease and Retinopathy in Adults With and Without Diabetes

OBJECTIVE Glycated hemoglobin was recently recommended for use as a diagnostic test for diabetes. We examined the association between 2010 American Diabetes Association diagnostic cut points for glycated hemoglobin and microvascular outcomes (chronic kidney disease, end-stage renal disease [ESRD], and retinopathy) and formally tested for the presence of risk thresholds in the relationships of glycated hemoglobin with these outcomes. RESEARCH DESIGN AND METHODS Prospective cohort and cross-sectional analyses of 11,357 participants (773 with a history of diagnosed diabetes) from the Atherosclerosis Risk in Communities (ARIC) Study. RESULTS During a median of 14 years of follow-up of individuals without diagnosed diabetes at baseline, clinical categories of glycated hemoglobin were associated with risk of chronic kidney disease, with adjusted hazard ratios (HRs) of 1.12 (0.94–1.34) and 1.39 (1.04–1.85) for glycated hemoglobin 5.7–6.4% and ≥6.5%, respectively, as compared with <5.7% (P trend = 0.002). The corresponding HRs for ESRD were 1.51 (0.82–2.76) and 1.98 (0.83–4.73), respectively (P trend = 0.047). In the absence of diagnosed diabetes, glycated hemoglobin was cross sectionally associated with the presence of moderate/severe retinopathy, with adjusted odds ratios of 1.42 (0.69–2.92) and 2.91 (1.19–7.11) for glycated hemoglobin 5.7–<6.5% and ≥6.5%, respectively, compared with <5.7% (P trend = 0.011). Risk associations were stronger among individuals with a history of diabetes. We did not observe significant thresholds in the associations of glycated hemoglobin with kidney disease risk or retinopathy. CONCLUSIONS These data from a community-based, biracial population support the use of new 2010 American Diabetes Association glycated hemoglobin cut points for the diagnosis of diabetes.

Risk of Incident ESRD: A Comprehensive Look at Cardiovascular Risk Factors and 17 Years of Follow-up in the Atherosclerosis Risk in Communities (ARIC) Study

BACKGROUNDnDiabetes and hypertension are potent risk factors for end-stage renal disease (ESRD). Previous studies suggest that other cardiovascular risk factors also may increase the risk of ESRD; however, risk associated with a comprehensive cardiovascular risk-factor assessment has not been quantified in a population-based sample.nnnSTUDY DESIGNnThe Atherosclerosis Risk in Communities (ARIC) Study, a prospective observational cohort.nnnSETTING & PARTICIPANTSn15,324 white and African American participants aged 45-64 years from 4 US communities were followed up after a baseline visit that occurred in 1987-1989.nnnPREDICTORnA comprehensive collection of cardiovascular risk factors were examined.nnnOUTCOMES & MEASUREMENTSnIncidence of ESRD (transplant, dialysis, catheter placement or kidney failure, and death) exclusive of acute kidney failure was ascertained through active surveillance of hospitalizations through 2004.nnnRESULTSnDuring a median 16-year follow-up, 241 cases of ESRD developed (incidence rate, 1.04 cases/1,000 person-years). Male sex, African American race, diabetes, hypertension, history of coronary heart disease, smoking, older age, body mass index, and triglyceride concentration were associated with increased risk of ESRD after adjustment for baseline estimated glomerular filtration rate (eGFR) and each other. There was a graded curvilinear association between risk of ESRD and lower baseline eGFR at levels < 90 mL/min/1.73 m(2) and moderately increased levels > 120 mL/min/1.73 m(2). The relative risk of eGFR on ESRD risk generally was greater in women and individuals with diabetes than in their counterparts.nnnLIMITATIONSnOnly events occurring in acute-care hospitals were investigated (but there was long-term continuous active surveillance of events).nnnCONCLUSIONSnWe quantify the relative risk of ESRD in a community-based African American and white population associated with established cardiovascular risk factors (diabetes, hypertension, male sex, and African American race) and report prospective data identifying greater risk of ESRD associated with other cardiovascular risk factors: moderately decreased eGFR, increased eGFR, higher body mass index, smoking, and increased triglyceride level.

Defining Incident Chronic Kidney Disease in the Research Setting The ARIC Study

Deaths of participants and losses to follow-up pose challenges for defining outcomes in epidemiologic studies. The authors compared several definitions of incident chronic kidney disease (CKD) in terms of incidence, agreement, and risk factor associations. They used data from 14,873 participants in the community-based, multicenter, biracial Atherosclerosis Risk in Communities Study (1987-1999). The estimated glomerular filtration rate (eGFR) was based on serum creatinine at baseline and the 3- and 9-year follow-up visits. Hospitalizations were ascertained continuously. The authors compared 4 definitions of incident CKD: 1) low eGFR (<60 mL/minute/1.73 m(2)); 2) low and declining (> or =25%) eGFR; 3) an increase in serum creatinine (> or =0.4 mg/dL) at 3- or 9-year follow-ups; and 4) CKD-related hospitalization or death. From these definitions, they identified 1,086, 677, 457, and 163 cases, respectively. There was relatively good agreement among definitions 1-3, but definition 4 identified mostly different cases. Risk factor associations were consistent across definitions for hypertension and lipids. Diabetes showed weaker associations with definition 1 (incidence rate ratio = 1.5, 95% confidence interval: 1.2, 1.7) than with definition 4 (incidence rate ratio = 6.3, confidence interval: 4.4, 8.9). Associations with gender differed in direction and magnitude across definitions. Case definition can impact relative risk estimates for CKD risk factors.

Inflammation, Hemostasis, and the Risk of Kidney Function Decline in the Atherosclerosis Risk in Communities (ARIC) Study

BACKGROUNDnInflammation and hemostasis may increase the risk of kidney function decline; however, data from prospective studies are sparse.nnnSTUDY DESIGNnThe Atherosclerosis Risk in Communities (ARIC) Study, a prospective observational cohort.nnnSETTING & PARTICIPANTSnWe used data from 14,854 middle-aged adults from 4 different US communities.nnnPREDICTORnMarkers of inflammation and hemostasis were examined.nnnOUTCOMES & MEASUREMENTSnThe risk of kidney function decrease associated with these markers was studied. Glomerular filtration rate (GFR) was calculated from serum creatinine levels using the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation. Chronic kidney disease (CKD) was defined as: (1) a decrease in estimated GFR to less than 60 mL/min/1.73 m2 from greater than 60 mL/min/1.73 m2 at baseline, or (2) a hospitalization discharge or death coded for CKD. Serum creatinine was measured at baseline and the 3- and 9-year follow-up visits. Hazard ratios (HRs) of CKD associated with increased levels of inflammatory and hemostatic variables were estimated by using multivariate Cox proportional hazards regression.nnnRESULTSn1,787 cases of CKD developed between 1987 and 2004. After adjusting for demographics, smoking, blood pressure, diabetes, lipid levels, prior myocardial infarction, antihypertensive use, alcohol use, year of marker measurement, and baseline renal function using estimated GFR, the risk of incident CKD increased with increasing quartiles of white blood cell count (HR quartile 4 versus quartile 1, 1.30; 95% confidence interval [CI], 1.12 to 1.50; P trend = 0.001), fibrinogen (HR, 1.25; 95% CI, 1.09 to 1.44; P < 0.001), von Willebrand factor (HR, 1.46; 95% CI, 1.26 to 1.68; P < 0.001), and factor VIIIc (HR, 1.39; 95% CI, 1.20 to 1.60; P < 0.001). A strong inverse association was found between serum albumin level and risk of CKD (HR, 0.63; 95% CI, 0.55 to 0.72; P < 0.001). No independent association was found with factor VIIc level.nnnLIMITATIONSnAlthough we lacked a direct measure of kidney function, associations were robust to case definitions.nnnCONCLUSIONSnMarkers of inflammation and hemostasis are associated with greater risk of kidney function decrease. Findings suggest that inflammation and hemostasis are antecedent pathways for CKD.

Prevalence, Awareness, Treatment, and Predictors of Control of Hypertension in New York City

Background—Hypertension-related risk in urban areas may vary from national estimates; however, objective data on prevalence and treatment in local areas are scarce. We assessed hypertension prevalence, awareness, treatment, and control among New York City (NYC) adults. Methods and Results—The NYC Health And Nutrition Examination Survey (HANES), modeled on the national HANES, was conducted in 2004 with a representative sample of noninstitutionalized NYC residents ≥20 years of age. Hypertension outcomes were examined with interview and examination data (n=1975). Multiple logistic regression was used to assess factors associated with control among adults with hypertension. We found that 25.6% of NYC adults had hypertension. Blacks had a higher prevalence than whites (32.8% versus 21.1%, P<0.001), as did Hispanics (26.5% versus 21.1%, P<0.05). Foreign-born residents who had lived in the United States for <10 years had lower rates than those who had lived in the United States longer (20.0% versus 27.5%, P<0.05). Among adults with hypertension, 83.0% were diagnosed, 72.7% were treated, and 47.1% had hypertension controlled. Of those treated, 64.8% had hypertension controlled. After adjustment for sociodemographic variables among all adults with treated hypertension, lack of a routine place of medical care was most strongly associated with poor control levels (adjusted odds ratio 0.21, 95% confidence interval 0.07 to 0.66). Among nonelderly adults with treated hypertension, blacks had 4-fold lower odds than whites of having hypertension controlled (adjusted odds ratio 0.24, 95% confidence interval 0.06 to 0.92). Conclusions—In NYC, hypertension is common and frequently uncontrolled. Low levels of control are associated with poor access to care. Racial disparities in prevalence and control are evident among nonelderly adults.