Linda F. Fried

Elevations of Inflammatory and Procoagulant Biomarkers in Elderly Persons With Renal Insufficiency

Background—Renal insufficiency has been associated with cardiovascular disease events and mortality in several prospective studies, but the mechanisms for the elevated risk are not clear. Little is known about the association of renal insufficiency with inflammatory and procoagulant markers, which are potential mediators for the cardiovascular risk of kidney disease. Methods and Results—The cross-sectional association of renal insufficiency with 8 inflammatory and procoagulant factors was evaluated using baseline data from the Cardiovascular Health Study, a population-based cohort study of 5888 subjects aged ≥65 years. C-reactive protein, fibrinogen, factor VIIc, and factor VIIIc levels were measured in nearly all participants; interleukin-6, intercellular adhesion molecule-1, plasmin-antiplasmin complex, and D-dimer levels were measured in nearly half of participants. Renal insufficiency was defined as a serum creatinine level ≥1.3 mg/dL in women and ≥1.5 mg/dL in men. Multivariate linear regression was used to compare adjusted mean levels of each biomarker in persons with and without renal insufficiency after adjustment for other baseline characteristics. Renal insufficiency was present in 647 (11%) of Cardiovascular Health Study participants. After adjustment for baseline differences, levels of C-reactive protein, fibrinogen, interleukin-6, factor VIIc, factor VIIIc, plasmin-antiplasmin complex, and D-dimer were significantly greater among persons with renal insufficiency (P <0.001). In participants with clinical, subclinical, and no cardiovascular disease at baseline, the positive associations of renal insufficiency with these inflammatory and procoagulant markers were similar. Conclusion—Renal insufficiency was independently associated with elevations in inflammatory and procoagulant biomarkers. These pathways may be important mediators leading to the increased cardiovascular risk of persons with kidney disease.

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.).

Renal insufficiency as a predictor of cardiovascular outcomes and mortality in elderly individuals

OBJECTIVES This study was designed to evaluate the relationship between elevated creatinine levels and cardiovascular events. BACKGROUND End-stage renal disease is associated with high cardiovascular morbidity and mortality. The association of mild to moderate renal insufficiency with cardiovascular outcomes remains unclear. METHODS We analyzed data from the Cardiovascular Health Study, a prospective population-based study of subjects, aged >65 years, who had a serum creatinine measured at baseline (n = 5,808) and were followed for a median of 7.3 years. Proportional hazards models were used to examine the association of creatinine to all-cause mortality and incident cardiovascular mortality and morbidity. Renal insufficiency was defined as a creatinine level > or =1.5 mg/dl in men or > or =1.3 mg/dl in women. RESULTS An elevated creatinine level was present in 648 (11.2%) participants. Subjects with elevated creatinine had higher overall (76.7 vs. 29.5/1,000 years, p < 0.001) and cardiovascular (35.8 vs. 13.0/1,000 years, p < 0.001) mortality than those with normal creatinine levels. They were more likely to develop cardiovascular disease (54.0 vs. 31.8/1,000 years, p < 0.001), stroke (21.1 vs. 11.9/1,000 years, p < 0.001), congestive heart failure (38.7 vs. 17/1,000 years, p < 0.001), and symptomatic peripheral vascular disease (10.6 vs. 3.5/1,000 years, p < 0.001). After adjusting for cardiovascular risk factors and subclinical disease measures, elevated creatinine remained a significant predictor of all-cause and cardiovascular mortality, total cardiovascular disease (CVD), claudication, and congestive heart failure (CHF). A linear increase in risk was observed with increasing creatinine. CONCLUSIONS Elevated creatinine levels are common in older adults and are associated with increased risk of mortality, CVD, and CHF. The increased risk is apparent early in renal disease.

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

Chronic Kidney Disease and Cognitive Impairment in the Elderly: The Health, Aging, and Body Composition Study

Previous studies suggest a link between chronic kidney disease (CKD) and cognitive impairment. Whether the longitudinal course of cognitive impairment differs among people with or without CKD is unknown. Data collected in 3034 elderly individuals who participated in the Health, Aging, and Body Composition study were analyzed. Cognitive function was assessed with the Modified Mini-Mental State Exam (3MS) at baseline and then 2 and 4 yr after baseline. Cognitive impairment was defined as a 3MS score <80 or a decline in 3MS >5 points after 2 or 4 yr of follow-up among participants with baseline 3MS scores > or =80. Participants with CKD, defined as an estimated GFR (eGFR) <60 ml/min per 1.73 m2, were further divided into two eGFR strata. Unadjusted mean baseline 3MS scores and mean declines in 3MS scores over 4 yr were significantly more pronounced for participants with lower baseline eGFR. More advanced stages of CKD were associated with an increased risk for cognitive impairment: Odds ratio (OR) 1.32 (95% confidence interval [CI] 1.03 to 1.69) and OR 2.43 (95% CI, 1.38 to 4.29) for eGFR 45 to 59 ml/min per 1.73 m2 and <45 ml/min per 1.73 m2, respectively, adjusted for case mix, baseline 3MS scores, and other potential confounders. CKD is associated with an increased risk for cognitive impairment in the elderly that cannot be fully explained by other well-established risk factors. Studies aimed at understanding the mechanism(s) responsible for cognitive impairment in CKD and efforts to interrupt this decline are warranted.

Cystatin C concentration as a risk factor for heart failure in older adults

Context Is cystatin-C, a novel marker of kidney function, an independent risk factor for heart failure? Contribution This 9-year observational study of 4384 older adults from 4 communities in the United States found that higher cystatin-C levels were independently associated with a stepwise increased risk for heart failure. Higher creatinine levels were not associated with increased risk for heart failure independent of other known risk factors. Implications These pioneering findings merit replication in other studies: Cystatin-C may be a better measure of renal function than serum creatinine and may better predict some cardiovascular diseases. The Editors Several recent studies suggest that chronic kidney disease is an independent risk factor for ischemic heart disease (1-4), particularly among participants with established cardiovascular disease (1, 2) or those who are at increased cardiovascular risk (3, 5-7). Few studies, however, have evaluated the effect of kidney function on risk for heart failure. Gottdiener and colleagues performed a comprehensive evaluation of risk factors for heart failure in the Cardiovascular Health Study and found that a serum creatinine concentration of 123.2 mol/L or greater (1.4 mg/dL) (present in 8% of the cohort) was an independent predictor of heart failure in older adults (8). Similarly, a recent study in women with coronary artery disease noted that a creatinine clearance less than 0.668 mL/s (<40 mL/min) (present in 10% of the cohort) was associated with an increased risk for heart failure (9). Finally, a recent analysis of the Established Populations for Epidemiologic Studies of the Elderly demonstrated that persons with creatinine clearance less than 0.616 mL/s (<36.9 mL/min) (lowest quartile of the sample) had an increased risk for heart failure compared with persons with creatinine clearance greater than 0.952 mL/s (>57 mL/min) (highest quartile of the sample) (10). All 3 studies, however, may underestimate the importance of kidney function as a risk factor for heart failure because creatinine concentration (or estimated glomerular filtration rate [GFR]) is insensitive in detecting reductions in kidney function. Creatinine concentration is a limited measure of kidney function because creatinine is a breakdown product of muscle and its serum levels are influenced not only by kidney function but also by age, sex, ethnicity, and body mass (11). Cystatin C concentration is a novel measure of kidney function that overcomes many of the limitations of the serum creatinine concentration. Cystatin C is a cysteine proteinase inhibitor that is produced by nearly all human cells and released into the bloodstream, from which it is freely filtered by the kidney glomerulus and metabolized by the proximal tubule (12). Several, but not all (13, 14), studies demonstrate that the cystatin C concentration may be a more sensitive indicator of mild kidney dysfunction and may better estimate GFR than serum creatinine concentration (15-17) and that the association of cystatin C concentration with GFR does not differ by age, sex, or muscle mass (15-20). We hypothesized that the cystatin C concentration would be associated with risk for heart failure and would be a better predictor than the serum creatinine concentration. Methods Participants The Cardiovascular Heath Study is a community-based longitudinal study of adults who were 65 years of age or older at baseline. The objective of the study was to evaluate risk factors for development and progression of cardiovascular disease (21). A main cohort of 5201 participants was recruited between 1989 and 1990 from 4 U.S. communities (Sacramento County, California; Forsyth County, North Carolina; Washington County, Maryland; and Allegheny County, Pennsylvania) (22). An additional 687 African-American persons were recruited in 1992 and 1993 (Figure 1). Eligible participants were sampled from Medicare eligibility lists in each area. Follow-up interviews for events were done semi-annually at annual examinations and through interim 6-month telephone calls. Figure 1. Selection of patients. Cystatin C was measured from frozen samples that were collected at the 19921993 visit of the Cardiovascular Health Study. Because our goal was to assess the risk for incident heart failure, we excluded participants with prevalent heart failure at baseline and those who developed heart failure before the 19921993 visit (Figure 1). To compare the risk associated with cystatin C concentration with that indicated by serum creatinine concentration, only participants who were alive and had had both measurements at the 19921993 visit (n= 4384) were included in this analysis. The investigational review boards of the 4 clinical sites and the Data Coordinating Center (University of Washington) approved the data collection procedures of the Cardiovascular Health Study. In addition, we obtained investigational review board approval for our study from the University of California, San Francisco. Measurement of Markers All assays were performed on serum that was drawn in the morning and stored at 70 C. Cystatin C was measured by using a BNII nephelometer (Dade Behring, Inc., Deerfield, Illinois) with a particle-enhanced immunonepholometric assay (N Latex Cystatin C, Dade-Behring, Inc.) (23). Polystyrene particles were coated with monoclonal antibodies to cystatin C that agglutinate in the presence of antigen (cystatin C) to increase the intensity of scattered light. The increase in scattered light is proportional to the amount of cystatin C in the sample. The assay range is 14.6 to 549.0 nmol/L (0.195 to 7.330 mg/L); the reference range for young, healthy persons is reported to be 40 to 71 nmol/L (0.53 to 0.95 mg/L). The intra-assay coefficient of variation ranges from 2.0% to 2.8%, and the interassay coefficient of variation ranges from 2.3% to 3.1%. Serum creatinine was measured by using the Kodak Ektachem 700 Analyzer (Eastman Kodak, Rochester, New York), which is a colorimetric method. Clinical Assessments and Measurements Information on baseline risk factors for heart failure that may confound the association of kidney function with heart failure was obtained from the 19921993 visit (8). These included demographic characteristics (age, sex, and race); traditional cardiovascular risk factors, such as body mass index, smoking (current versus past or never), diabetes (defined by use of a hypoglycemic agent or insulin or a fasting glucose level 6.99 mmol/L [126 mg/dL]), systolic blood pressure (as measured by using a Hawksley random-zero sphygmomanometer), and fasting levels of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol; novel risk factors (C-reactive protein, hemoglobin, albumin, fibrinogen, and factor VII); noninvasive tests of the extent of disease (anklearm index, common carotid intimamedia thickness, internal carotid intimamedia thickness, and left ventricular hypertrophy and atrial fibrillation on electrocardiography); clinical disease (previous coronary heart disease or stroke, which were adjudicated by a combination of self-report of physician diagnosis and review of medical records); and use of blood pressure medications (diuretics, -blockers, angiotensin-converting enzyme inhibitors, or calcium-channel blockers) (24-26). Echocardiography was not done at the 19921993 visit. Adjudication of Heart Failure For the diagnosis of prevalent heart failure, self-reports were confirmed by components of the physical examination or, if necessary, by a validation protocol that included surveys of treating physicians or review of medical records (24). For the diagnosis of incident heart failure, a physicians diagnosis of heart failure was followed by review of the participants medical records. The Cardiovascular Health Study Cardiovascular Events Committee then determined the incidence of heart failure on the basis of diagnosis from a physician and consideration of symptoms, signs, chest radiographic findings, and treatment of heart failure (current prescription for a diuretic agent and either digitalis or a vasodilator) (8, 26). We examine heart failure events through 30 June 2001. Statistical Analysis We compared the distribution of demographic characteristics, traditional cardiovascular risk factors, novel risk factors, clinical disease, and noninvasive assessment of extent of disease across quintiles of cystatin C concentration. P values for linear trend across the quintiles were calculated. Incidence rates were calculated per 100 person-years and are reported as percentage per year. The association of kidney function and risk for heart failure was compared by using 3 measures of kidney function: serum cystatin C concentration, serum creatinine concentration, and GFR, as estimated by using the 4-variable version of the Modification of Diet in Renal Disease formula. This formula is as follows: GFR = 186.3 (serum creatinine concentration1.154) (age0.203) 1.212 (if black) 0.742 (if female) (27, 28). Each measure of kidney function was then divided into quintiles; for serum creatinine concentration, the quintile cut-offs were sex-specific because the distribution of serum creatinine concentration differed substantially between men and women in the Cardiovascular Health Study (29, 30). We used Cox proportional hazards models to examine the relationship of cystatin C and other known risk factors to incident heart failure in multivariable models. To evaluate the contribution of cystatin C as a marker of risk, models were generated in stages: unadjusted; adjusted for demographic characteristics; adjusted for demographic characteristics, traditional cardiovascular risk factors, and use of blood pressure medications; and adjusted for risk factors from the preceding model, other novel risk factors, measurements of clinical cardiovascular disease, and noninvasive measurements of the extent of the disease. We also included a term to adjust for clustering wi

Kidney Function as a Predictor of Noncardiovascular Mortality

Chronic kidney disease is associated with a higher risk for cardiovascular mortality, as well as all-cause mortality. Whether chronic kidney disease is a predictor of noncardiovascular mortality is less clear. To further explore the latter, the association of kidney function with total noncardiovascular mortality and cause-specific mortality was assessed in the Cardiovascular Health Study, a community-based cohort of older individuals. Kidney disease was assessed using cystatin C and estimated GFR in 4637 participants in 1992 to 1993. Participants were followed until June 30, 2001. Deaths were adjudicated as cardiovascular or noncardiovascular disease by committee, and an underlying cause of death was assigned. The associations of kidney function with total noncardiovascular mortality and cause-specific mortality were analyzed by proportional hazards regression. Noncardiovascular mortality rates increased with higher cystatin C quartiles (16.8, 17.1, 21.6, and 50.0 per 1000 person-years). The association of cystatin C with noncardiovascular mortality persisted after adjustment for demographic factors; the presence of diabetes, C-reactive protein, hemoglobin, and prevalent cardiovascular disease; and measures of atherosclerosis (hazard ratio 1.69; 95% confidence interval 1.33 to 2.15, for the fourth quartile versus the first quartile). Results for estimated GFR were similar. The risk for noncardiac deaths attributed to pulmonary disease, infection, cancer, and other causes was similarly associated with cystatin C levels. Kidney function predicts noncardiovascular mortality from multiple causes in the elderly. Further research is needed to understand the mechanisms and evaluate interventions to reduce the high mortality rate in chronic kidney disease.

Rapid kidney function decline and mortality risk in older adults

BACKGROUND Impaired kidney function is associated with increased mortality risk in older adults. It remains unknown, however, whether longitudinal declines in kidney function are independently associated with increased cardiovascular and all-cause mortality in older adults. METHODS The Cardiovascular Health Study evaluated a cohort of community-dwelling older adults enrolled from 1989 to 1993 in 4 US communities with follow-up through 2005. Among 4380 participants, the slope of annual decline in estimated glomerular filtration rate (eGFR) was estimated using both serum creatinine (eGFR(creat)) and cystatin C (eGFR(cys)) rates, which were measured at baseline, year 3, and year 7 of follow-up. Rapid decline in eGFR was defined as a loss greater than 3 mL/min/1.73 m(2) per year, and cardiovascular and all-cause mortality were assessed over a mean of 9.9 years of follow-up. RESULTS Mean (SD) levels of creatinine and cystatin C were 0.93 (0.30) mg/dL and 1.03 (0.25) mg/L, respectively; mean (SD) eGFR(creat) and eGFR(cys) were 79 (23) mL/min/1.73 m(2) and 79 (19) mL/min/1.73 m(2), respectively. Individuals with rapid decline measured by eGFR(creat) (n = 714; 16%) had increased risk of cardiovascular (adjusted hazard ratio [AHR], 1.70; 95% confidence interval [CI], 1.40-2.06) and all-cause (AHR, 1.73; 95% CI, 1.54-1.94) mortality. Individuals with rapid decline measured by eGFR(cys) (n = 1083; 25%) also had increased risk of cardiovascular (AHR, 1.53; 95% CI, 1.29-1.80) and all-cause (AHR, 1.53; 95% CI, 1.38-1.69) mortality. The association of rapid decline in eGFR with elevated mortality risk did not differ across subgroups based on baseline kidney function, age, sex, race, or prevalent coronary heart disease. CONCLUSION Rapid decline in eGFR is associated with an increased risk of cardiovascular and all-cause mortality in older adults, independent of baseline eGFR and other demographic variables.

Cystatin C and Mortality Risk in the Elderly: The Health, Aging, and Body Composition Study

Kidney dysfunction is known to decrease life expectancy in the elderly. Cystatin C is a novel biomarker of kidney function that may have prognostic utility in older adults. The association of cystatin C with mortality was evaluated in a biracial cohort of black and white ambulatory elderly and compared with that of serum creatinine concentrations. The Health, Aging and Body Composition study is a cohort of well-functioning elderly that was designed to evaluate longitudinal changes in weight, body composition, and function. A total of 3075 participants who were aged 70 to 79 yr and had no disability were recruited at sites in Memphis, TN, and Pittsburgh, PA, between April 1997 and June 1998 with a follow-up of 6 yr. At entry, the mean cystatin C was 1.05 mg/L and the mean creatinine was 1.06 mg/dl. After 6 yr of follow-up, 557 participants had died. The mortality rates in each ascending cystatin C quintile were 1.7, 2.7, 2.9, 3.1, and 5.4%/yr. After adjustment for demographic risk factors, comorbid health conditions, and inflammatory biomarkers (C-reactive protein, IL-6. and TNF-alpha), each quintile of cystatin C was significantly associated with increased mortality risk compared with the lowest: Hazard ratios (HR; 95% confidence intervals) quintile 1, -1.0 (referent); quintile 2, -1.74 (1.21 to 2.50); quintile 3, -1.51 (1.05 to 2.18); quintile 4, -1.49 (1.04 to 2.13); and quintile 5, -2.18 (1.53 to 3.10). These associations did not differ by gender or race. Results were consistent for cardiovascular and other-cause mortality, but not cancer mortality. Creatinine quintiles were not associated with mortality after multivariate adjustment (HR: 1.0 [referent], 1.00 [0.72 to 1.39], 0.95 [0.68 to 1.32], 1.11 [0.79 to 1.57], 1.16 [0.86 to 1.58]). Cystatin C is a strong, independent risk factor for mortality in the elderly. Future studies should investigate whether cystatin C has a role in clinical medicine.

HYPONATREMIA AND HYPERNATREMIA

Hyponatremia and hypernatremia are common electrolyte disorders resulting from disorders in water homeostasis. Hyponatremia usually results from defects in free water excretion, although increased intake may also contribute. The treatment of hyponatremia has been controversial because of the high associated morbidity and mortality and the observation that rapid correction of hyponatremia is associated with the development of central pontine myelinolysis. Mild hyponatremia should be treated with water restriction alone, whereas severe acute or symptomatic hyponatremia should initially be corrected rapidly until symptoms resolve followed by more gradual correction. In all cases, treatment should be individualized on the basis of severity, cause, and duration of the hyponatremia. Hypernatremia results from impaired water ingestion, although increased water losses are often contributory. Hospital-acquired hypernatremia is usually iatrogenic because of inadequate water prescription and is therefore preventable. Hypernatremia is also associated with high morbidity and mortality, both as a result of the underlying disease and inadequate treatment. The primary treatment of hypernatremia is water replacement-repleting water deficits and replacing ongoing losses. Additional treatment should be directed at eliminating excess water losses.