Stephen L. Seliger

Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults.

CONTEXT Older adults comprise the majority of new-onset heart failure (HF) diagnoses, but traditional risk-factor prediction models have limited accuracy in this population to identify those at highest risk for hospitalization or death. OBJECTIVES To determine if cardiac troponin T (cTnT) measured by a highly sensitive assay would be detectable in the majority of community-dwelling older adults, and if serial measures were associated with risk of HF hospitalization and cardiovascular death. DESIGN, SETTING, AND PARTICIPANTS A longitudinal nationwide cohort study (Cardiovascular Health Study) of 4221 community-dwelling adults aged 65 years or older without prior HF who had cTnT measured using a highly sensitive assay at baseline (1989-1990) and repeated after 2 to 3 years (n = 2918). MAIN OUTCOME MEASURES New-onset HF and cardiovascular death were examined through June 2008 with respect to cTnT concentrations, accounting for clinical risk predictors. RESULTS Cardiac troponin T was detectable (≥3.00 pg/mL) in 2794 participants (66.2%). During a median follow-up of 11.8 years, 1279 participants experienced new-onset HF and 1103 cardiovascular deaths occurred, with a greater risk of both end points associated with higher cTnT concentrations. Among those participants with the highest cTnT concentrations (>12.94 pg/mL), there was an incidence rate per 100 person-years of 6.4 (95% confidence interval [CI], 5.8-7.2; adjusted hazard ratio [aHR], 2.48; 95% CI, 2.04-3.00) for HF and an incidence rate of 4.8 (95% CI, 4.3-5.4; aHR, 2.91; 95% CI, 2.37-3.58) for cardiovascular death compared with participants with undetectable cTnT levels (incidence rate, 1.6; 95% CI, 1.4-1.8 and 1.1; 95% CI, 0.9-1.2 for HF and cardiovascular death, respectively). Among individuals with initially detectable cTnT, a subsequent increase of more than 50% (n = 393, 22%) was associated with a greater risk for HF (aHR, 1.61; 95% CI, 1.32-1.97) and cardiovascular death (aHR, 1.65; 95% CI, 1.35-2.03) and a decrease of more than 50% (n = 247, 14%) was associated with a lower risk for HF (aHR, 0.73; 95% CI, 0.54-0.97) and cardiovascular death (aHR, 0.71; 95% CI, 0.52-0.97) compared with participants with 50% or less change. Addition of baseline cTnT measurements to clinical risk factors was associated with only modest improvement in discrimination, with change in C statistic of 0.015 for HF and 0.013 for cardiovascular death. CONCLUSION In this cohort of older adults without known HF, baseline cTnT levels and changes in cTnT levels measured with a highly sensitive assay were significantly associated with incident HF and cardiovascular death.

Combined Angiotensin Inhibition for the Treatment of Diabetic Nephropathy

BACKGROUND Combination therapy with angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain. Methods We provided losartan (at a dose of 100 mg per day) to patients with type 2 diabetes, a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 ml per minute per 1.73 m(2) of body-surface area and then randomly assigned them to receive lisinopril (at a dose of 10 to 40 mg per day) or placebo. The primary end point was the first occurrence of a change in the estimated GFR (a decline of ≥ 30 ml per minute per 1.73 m(2) if the initial estimated GFR was ≥ 60 ml per minute per 1.73 m(2) or a decline of ≥ 50% if the initial estimated GFR was <60 ml per minute per 1.73 m(2)), end-stage renal disease (ESRD), or death. The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD. Safety outcomes included mortality, hyperkalemia, and acute kidney injury. Results The study was stopped early owing to safety concerns. Among 1448 randomly assigned patients with a median follow-up of 2.2 years, there were 152 primary end-point events in the monotherapy group and 132 in the combination-therapy group (hazard ratio with combination therapy, 0.88; 95% confidence interval [CI], 0.70 to 1.12; P=0.30). A trend toward a benefit from combination therapy with respect to the secondary end point (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P=0.10) decreased with time (P=0.02 for nonproportionality). There was no benefit with respect to mortality (hazard ratio for death, 1.04; 95% CI, 0.73 to 1.49; P=0.75) or cardiovascular events. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, vs. 2.6 events per 100 person-years with monotherapy; P<0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P<0.001). Conclusions Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; VA NEPHRON-D ClinicalTrials.gov number, NCT00555217.).

Cystatin C and Prognosis for Cardiovascular and Kidney Outcomes in Elderly Persons without Chronic Kidney Disease

Context Cystatin C concentration approximates glomerular filtration rate (GFR) more precisely than creatinine concentration. Can it identify people without known kidney disease who have increased risks for cardiovascular disease? Contribution In this longitudinal study involving 3659 elderly persons without known kidney disease (estimated GFR 60 mL/min per 1.73 m2), increasing cystatin C concentration was associated with increased risks for death, stroke, myocardial infarction, heart failure, and progression to chronic kidney disease. Associations were much stronger for cystatin C than for creatinine. Cautions Albuminuria was not measured; some patients may have been misclassified as having no kidney disease. Implications Among elderly persons, cystatin C concentration may be a better biomarker for adverse outcomes than serum creatinine concentration. The Editors Chronic kidney disease is a worldwide health problem that carries a substantial risk for cardiovascular morbidity and death. Chronic kidney disease has been defined as a creatinine-based estimated glomerular filtration rate (GFR) less than 60 mL/min per 1.73 m2 (1), which represents a loss of more than half of normal kidney function. An estimated GFR less than 60 mL/min per 1.73 m2 has been strongly associated with cardiovascular risk and death (2). However, surprisingly little evidence supports an association of kidney function with adverse clinical events at GFR levels of 60 mL/min per 1.73 m2 or greater (1). The absence of risk associated with an estimated GFR of 60 mL/min per 1.73 m2 or greater may reflect a biological threshold effectthat milder reductions of actual GFR are clinically inconsequentialor may be due to inherent limitations of serum creatinine for estimating GFR (35). Cystatin C is an alternative serum measure of kidney function that approximates direct measures of GFR (for example, iothalamate clearance) more precisely than creatinine, because its serum concentrations are independent of muscle mass and do not seem to be affected by age or sex (68). Cystatin C is a 122amino acid, 13-kDa protein that is a member of a family of competitive inhibitors of lysosomal cysteine proteinases. Its functions include involvement in extracellular proteolysis, modulation of the immune system, and antibacterial and antiviral activities. Cystatin C has several properties that make it a good candidate marker of GFR, including a constant production rate regulated by a housekeeping gene expressed in all nucleated cells, free filtration at the glomerulus, complete reabsorption and catabolism by the proximal tubules with no reabsorption into the bloodstream, and no renal tubular secretion (6). Among elderly persons who do not meet standard criteria for chronic kidney disease (estimated GFR 60 mL/min per 1.73 m2), many participants in the Cardiovascular Health Study (CHS) have elevated cystatin C concentrations (1.0 mg/L). We hypothesized that cystatin C would be an important prognostic factor for risk for death, cardiovascular disease, and incident chronic kidney disease, whereas estimated GFR and creatinine would be unable to distinguish levels of risk. Our goal was to determine whether elevated cystatin C concentrations in patients with normal estimated GFR could define a state of preclinical kidney disease. Methods Description of the Cohort The Cardiovascular Health Study (CHS) is a community-based, longitudinal study of adults 65 years of age and older at baseline (9). Enrollment began in 1989, with annual visits thereafter. The study recruited persons from Medicare eligibility lists in Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Pittsburgh, Pennsylvania, with the following inclusion criteria: 1) older than 65 years of age, 2) not institutionalized, 3) expected to remain in the current community for 3 years or longer, 4) not receiving active treatment for cancer, and 5) gave written informed consent without requiring a proxy respondent. The study design, quality control procedures, laboratory methods, and blood pressure measurement procedures have been published previously (9, 10). Our analysis includes 4663 CHS participants who attended the 19921993 annual visit and who had measurements of creatinine and cystatin C concentrations. We excluded 274 participants because creatinine concentration was not available or cystatin C concentration could not be measured due to inadequate serum specimens. Follow-up for events continued until 30 June 2002 with a median of 9.3 years (maximum of 10.1 years). Kidney Function Measurements We measured all assays on fasting plasma specimens that were stored at 70C. We measured cystatin C concentration by using a BNII nephelometer (Dade Behring Inc., Deerfield, Illinois) that utilized a particle-enhanced immunonephelometric assay (N Latex Cystatin C, Dade Behring Inc.) (11). The assay range is 0.195 mg/L to 7.330 mg/L. The reference ranges for young, healthy individuals and healthy persons older than 50 years of age are reported to be 0.53 mg/L to 0.92 mg/L and 0.58 mg/L to 1.02 mg/L, respectively (12). We measured serum creatinine concentration by using the Kodak Ektachem 700 Analyzer (Eastman Kodak, Rochester, New York), a colorimetric method. The mean coefficient of variation was 1.94% (creatinine level range, 102.5 mol/L [1.16 mg/dL] to 344.8 mol/L [3.90 mg/dL]). We calculated the estimated GFR from serum creatinine by using the modified 4-variable version of the Modification of Diet in Renal Disease (MDRD) formula (13). We indirectly calibrated the creatinine levels in our study with those from the Cleveland Clinic laboratorythe core laboratory of the MDRD trialas previously described (14, 15). As recommended by the Kidney Disease: Improving Global Outcomes (KDIGO) group, we defined chronic kidney disease on the basis of an estimated GFR less than 60 mL/min per 1.73 m2 (1). Secondary Predictors We chose demographic characteristics (age, sex, and race); traditional cardiovascular risk factors (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol levels, presence of diabetes and hypertension, current smoking, height, weight, and physical activity); C-reactive protein level; and prevalent heart failure, myocardial infarction, or stroke as adjustment variables for all analyses. We defined hypertension by a seated blood pressure average of 140/90 mm Hg or greater or a history of treated hypertension. We determined the presence of diabetes by clinical history of diabetes, use of hypoglycemic agent or insulin, or fasting glucose level of 7.0 mmol/L or greater (126 mg/dL). We adjudicated the self-report of prevalent myocardial infarction, stroke, and heart failure as previously described (16). Outcomes Follow-up visits occurred by telephone every 6 months and in person annually. The primary outcomes included in our study were all-cause death, cardiovascular death, noncardiovascular death, incident heart failure, stroke, and myocardial infarction. A CHS outcome assessment committee adjudicated these events. We identified deaths by review of obituaries, medical records, death certificates, the Centers for Medicare & Medicaid Services health care utilization database for hospitalizations, and household contacts. We have actively followed all persons through clinical visits, telephone calls, or surveillance of death registries. We defined cardiovascular death as death caused by coronary heart disease, heart failure, peripheral vascular disease, or cerebrovascular disease (16). Methods used to diagnose incident heart failure, stroke, and myocardial infarction have been previously described (1719). We also compared the rate of progression to incident chronic kidney disease at the 19961997 examination among participants with estimated GFR greater than 60 mL/min per 1.73 m2 at baseline (19921993). Unlike the primary outcomes that occurred on specific dates during follow-up, incident chronic kidney disease was a discrete outcome that could only occur at the time of the 19961997 examination when we measured follow-up creatinine concentration. Statistical Analysis Our analysis began by separating the cohort into persons with and without estimated GFR less than 60 mL/min per 1.73 m2 at the 19921993 clinical visit. We compared the mean cystatin C concentration, creatinine concentration, and estimated GFR within each stratum and Pearson correlations among the 3 measures. We used a Fisher 2-sample Z-test for correlations to determine whether the correlations of cystatin C with estimated GFR and creatinine differed between persons with and persons without chronic kidney disease. We limited our next analyses to participants without chronic kidney disease (estimated GFR 60 mL/min per 1.73 m2). We compared the distributions of creatinine and cystatin C concentrations graphically. We used penalized smoothing splines (P-splines) to depict the association of each measure with mortality risk across the full range in the subcohort without chronic kidney disease (20). Results are similar to smoothing splines with a knot at each data point but are computationally simpler. We used multivariate Cox proportional hazards models to compare the association of cystatin C and creatinine concentrations as linear variables (per SD) with each outcome. Evaluations of incident heart failure, stroke, and myocardial infarction excluded participants with prevalent disease. We tested for a nonlinear association by adding a quadratic term to each model, but these were not statistically significant. We verified the proportional hazards assumption by using graphical methods, as well as formal hypothesis testing. To test for proportionality of hazards, we used KaplanMeier curves. The graph of the survival function versus the survival time resulted in parallel curves. Similarly, the graph of the log(log(survival)) versus log(survival time) also resulted in parallel lines. We also used tests and

The frequency of hyperkalemia and its significance in chronic kidney disease.

BACKGROUND Hyperkalemia is a potential threat to patient safety in chronic kidney disease (CKD). This study determined the incidence of hyperkalemia in CKD and whether it is associated with excess mortality. METHODS This retrospective analysis of a national cohort comprised 2 103 422 records from 245 808 veterans with at least 1 hospitalization and at least 1 inpatient or outpatient serum potassium record during the fiscal year 2005. Chronic kidney disease and treatment with angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers (blockers of the renin-angiotensin-aldosterone system [RAAS]) were the key predictors of hyperkalemia. Death within 1 day of a hyperkalemic event was the principal outcome. RESULTS Of the 66 259 hyperkalemic events (3.2% of records), more occurred as inpatient events (n = 34 937 [52.7%]) than as outpatient events (n = 31 322 [47.3%]). The adjusted rate of hyperkalemia was higher in patients with CKD than in those without CKD among individuals treated with RAAS blockers (7.67 vs 2.30 per 100 patient-months; P < .001) and those without RAAS blocker treatment (8.22 vs 1.77 per 100 patient-months; P < .001). The adjusted odds ratio (OR) of death with a moderate (potassium, >or=5.5 and <6.0 mEq/L [to convert to mmol/L, multiply by 1.0]) and severe (potassium, >or=6.0 mEq/L) hyperkalemic event was highest with no CKD (OR, 10.32 and 31.64, respectively) vs stage 3 (OR, 5.35 and 19.52, respectively), stage 4 (OR, 5.73 and 11.56, respectively), or stage 5 (OR, 2.31 and 8.02, respectively) CKD, with all P < .001 vs normokalemia and no CKD. CONCLUSIONS The risk of hyperkalemia is increased with CKD, and its occurrence increases the odds of mortality within 1 day of the event. These findings underscore the importance of this metabolic disturbance as a threat to patient safety in CKD.

Association of Serum Phosphate with Vascular and Valvular Calcification in Moderate CKD

Within the normal range, higher serum phosphate concentrations are associated with cardiovascular events and mortality in individuals with chronic kidney disease (CKD) and in those with normal kidney function. Experimental models suggest that phosphate has a direct calcifying effect on vascular smooth muscle. We examined associations of serum phosphate concentrations with vascular and valvular calcification in 439 participants from the Multi-Ethnic Study of Atherosclerosis who had moderate CKD and no clinical cardiovascular disease. Serum phosphate concentrations were within the normal range (2.5 to 4.5 mg/dl) in 95% of study participants. The prevalence of calcification in the coronary arteries, descending thoracic aorta, aortic valve, and mitral valve was 67, 49, 25, and 20%, respectively, measured by electron-beam or multi-detector row computed tomography. After adjustment for demographics and estimated GFR, each 1-mg/dl increment in serum phosphate concentration was associated with a 21% (P = 0.002), 33% (P = 0.001), 25% (P = 0.16), and 62% (P = 0.007) greater prevalence of coronary artery, thoracic, aortic valve, and mitral valve calcification, respectively. Adjustment for traditional risk factors for atherosclerosis, parathyroid hormone, or 1,25-dihydroxyvitamin D levels did not alter these associations. In conclusion, higher serum phosphate concentrations, although still within the normal range, are associated with a greater prevalence of vascular and valvular calcification in people with moderate CKD. It remains to be determined whether lowering phosphate concentrations will impact calcification risk in the setting of kidney disease.

Moderate Renal Impairment and Risk of Dementia among Older Adults: The Cardiovascular Health Cognition Study

Renal impairment is associated with an increased risk of carotid atherosclerosis and stroke, determinants of cognitive dysfunction and dementia. The purpose of this study was to determine whether moderate renal impairment is associated with incident dementia among community-dwelling older adults. Participants in the Cardiovascular Health Cognition Study without prevalent dementia (n = 3349) were included in the analysis. Incident dementia was confirmed through neurologic testing. Renal function at baseline was estimated by the inverse of serum creatinine (1/SCr); moderate renal impairment was defined as SCr > or = 1.3 mg/dl for women and > or = 1.5 mg/dl for men. Cox regression models were used to estimate the association of renal impairment with incident dementia. Because SCr is also a function of muscle mass, the authors determined whether the relationship between SCr and dementia was particularly strong among individuals without severe co-morbidity at baseline, as reflected by self-reported general health status. There were 477 incident dementia cases over a median 6 yr follow-up. After adjustment for potential confounders, moderate renal insufficiency was associated with a 37% increased risk of dementia (95% CI = 1.06 to 1.78). Similarly, a 0.5-unit decrement in 1/SCr (equivalent to an increase in SCr from 1.0 to 2.0 mg/dl) was associated with a 26% increased risk (95% CI = 1.02 to 1.60). These associations were present only among the 84% of older adults who reported good-excellent health. Among those in good-excellent health, higher SCr was associated with vascular-type dementia but not Alzheimer-type dementia. Moderate renal impairment, reflected by a higher SCr, is associated with an excess risk of incident dementia among individuals in good-excellent health. Strategies to prevent or delay the onset of dementia in patients with moderate renal impairment are needed.

Frequency of Hypoglycemia and Its Significance in Chronic Kidney Disease

BACKGROUND AND OBJECTIVES This study set out to determine the incidence of hypoglycemia in patients with chronic kidney disease (CKD), with and without diabetes, and the association of hypoglycemia with mortality. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a retrospective cohort analysis of 243,222 patients who had 2,040,206 glucose measurements and were cared for at the Veterans Health Administration. CKD was defined as an estimated GFR of <60 ml/min per 1.73 m(2). Hypoglycemia was set at <70 mg/dl. Mortality was measured 1 day after glucose measurement. RESULTS The incidence of hypoglycemia was higher in patients with CKD versus without CKD. Among patients with diabetes, the rate was 10.72 versus 5.33 per 100 patient-months and among patients without diabetes was 3.46 versus 2.23 per 100 patient-months, for CKD versus no CKD, respectively. The odds of 1-d mortality were increased at all levels of hypoglycemia but attenuated in CKD versus no CKD. Adjusted odds ratios for 1-d mortality that were associated with glucose values of <50, 50 to 59, and 60 to 69 mg/dl, respectively, versus glucose of >or=70 mg/dl were 6.09, 4.10, and 1.85 for inpatient records from patients with CKD; 9.95, 3.79, and 2.54 for inpatients records from patients without CKD; 6.84, 3.28, and 3.98 for outpatient records from patients with CKD; and 13.28, 7.36, and 4.34 for outpatient records from patients without CKD. CONCLUSIONS CKD is a risk for hypoglycemia, with or without diabetes. The excessive mortality associated with hypoglycemia makes this complication a significant threat to patient safety in CKD.

Inflammatory and Prothrombotic Markers and the Progression of Renal Disease in Elderly Individuals

Inflammatory and prothrombotic markers are elevated in individuals with mild to moderate renal disease. It was hypothesized that these markers may also be determinants of the progression of renal disease. The association of six markers-serum C-reactive protein (CRP), white blood cell (WBC) count, fibrinogen, factor VII, albumin, and hemoglobin-with subsequent elevations of creatinine and decline in estimated GFR in the Cardiovascular Health Study, a community-based cohort of elderly individuals, was analyzed. Linear regression was used to determine predictors of an annualized change in serum creatinine as the main outcome. Duration of follow-up was 7 yr for the original cohort and 4 yr for the more recently recruited black cohort. A total of 588 (12.7%) individuals had a decline in estimated GFR of at least 3 ml/min per yr per 1.73 m(2). Higher CRP (P < 0.001), WBC count (P < 0.001), fibrinogen (P < 0.001), and factor VII (P < 0.001) levels and lower albumin (P < 0.001) and hemoglobin levels (P < 0.001) were associated with a rise in creatinine, after adjusting for age. With additional adjustments for race, gender, baseline creatinine, systolic and diastolic BP, lipid levels, weight, and pack-years smoking, higher CRP, factor VII, fibrinogen, WBC count, and lower albumin and hemoglobin levels remained associated with a rise in creatinine. Similar results were found for decline in estimated GFR. The decline in GFR was greater with increasing number of inflammatory or prothrombotic markers that were above the median (below for hemoglobin and albumin). Inflammatory and prothrombotic markers are predictors for a change in kidney function in elderly individuals. Interventions that reduce inflammation might confer significant cardiovascular and renal benefits.

Chronic Kidney Disease and Cognitive Function in Older Adults: Findings from the Chronic Renal Insufficiency Cohort Cognitive Study

OBJECTIVES: To investigate cognitive impairment in older, ethnically diverse individuals with a broad range of kidney function, to evaluate a spectrum of cognitive domains, and to determine whether the relationship between chronic kidney disease (CKD) and cognitive function is independent of demographic and clinical factors.

Age and Sex Dependent Upper Reference Limits for the High Sensitivity Cardiac Troponin T Assay

OBJECTIVES The study sought to determine the 99th percentile upper reference limit for the high-sensitivity cardiac troponin T assay (hs-cTnT) in 3 large independent cohorts. BACKGROUND The presently recommended 14 ng/l cut point for the diagnosis of myocardial infarction using the hs-cTnT assay was derived from small studies of presumably healthy individuals, with relatively little phenotypic characterization. METHODS Data were included from 3 well-characterized population-based studies: the Dallas Heart Study (DHS), the Atherosclerosis Risk in Communities (ARIC) Study, and the Cardiovascular Health Study (CHS). Within each cohort, reference subcohorts were defined excluding individuals with recent hospitalization, overt cardiovascular disease, and kidney disease (subcohort 1), and further excluding those with subclinical structural heart disease (subcohort 2). Data were analyzed stratified by age, sex, and race. RESULTS The 99th percentile values for the hs-cTnT assay in DHS, ARIC, and CHS were 18, 22, and 36 ng/l (subcohort 1) and 14, 21, and 28 ng/l (subcohort 2), respectively. These differences in 99th percentile values paralleled age differences across cohorts. Analyses within sex/age strata yielded similar results between cohorts. Within each cohort, 99th percentile values increased with age and were higher in men. More than 10% of men 65 to 74 years of age with no cardiovascular disease in our study had cardiac troponin T values above the current myocardial infarction threshold. CONCLUSIONS Use of a uniform 14 ng/l cutoff for the hs-cTnT assay may lead to over-diagnosis of myocardial infarction, particularly in men and the elderly. Clinical validation is needed of new age- and sex-specific cutoff values for this assay.