Dena E. Rifkin

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.

Calcium Density of Coronary Artery Plaque and Risk of Incident Cardiovascular Events

IMPORTANCE Coronary artery calcium (CAC), measured by computed tomography (CT), has strong predictive value for incident cardiovascular disease (CVD) events. The standard CAC score is the Agatston, which is weighted upward for greater calcium density. However, some data suggest increased plaque calcium density may be protective for CVD. OBJECTIVE To determine the independent associations of CAC volume and CAC density with incident CVD events. DESIGN, SETTING, AND PARTICIPANTS Multicenter, prospective observational MESA study (Multi-Ethnic Study of Atherosclerosis), conducted at 6 US field centers of 3398 men and women from 4 race/ethnicity groups; non-Hispanic white, African American, Hispanic, and Chinese. Participants were aged 45-84 years, free of known CVD at baseline, had CAC greater than 0 on their baseline CT, and were followed up through October 2010. MAIN OUTCOMES AND MEASURES Incident coronary heart disease (CHD) and all CVD events RESULTS During a median of 7.6 years of follow-up, there were 175 CHD events and an additional 90 other CVD events for a total of 265 CVD events. With both lnCAC volume and CAC density scores in the same multivariable model, the lnCAC volume score showed an independent association with incident CHD, with a hazard ratio (HR) of 1.81 (95% CI, 1.47-2.23) per standard deviation (SD = 1.6) increase, absolute risk increase 6.1 per 1000 person-years, and for CVD an HR of 1.68 (95% CI, 1.42-1.98) per SD increase, absolute risk increase 7.9 per 1000 person-years. Conversely, the CAC density score showed an independent inverse association, with an HR of 0.73 (95% CI, 0.58-0.91) per SD (SD = 0.7) increase for CHD, absolute risk decrease 5.5 per 1000 person-years, and an HR of 0.71 (95% CI, 0.60-0.85) per SD increase for CVD, absolute risk decrease 8.2 per 1000 person years. Area under the receiver operating characteristic curve analyses showed significantly improved risk prediction with the addition of the density score to a model containing the volume score for both CHD and CVD. In the intermediate CVD risk group, the area under the curve for CVD increased from 0.53 (95% CI, 0.48-0.59) to 0.59 (95% CI, 0.54-0.64), P = .02. CONCLUSIONS AND RELEVANCE CAC volume was positively and independently associated with CHD and CVD risk. At any level of CAC volume, CAC density was inversely and significantly associated with CHD and CVD risk. The role of CAC density should be considered when evaluating current CAC scoring systems.

Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health Study).

OBJECTIVES This study sought to determine the association of fibroblast growth factor (FGF)-23 with death, heart failure (HF), and cardiovascular disease (CVD) in the general population, as well as the influence of chronic kidney disease (CKD) in this setting. BACKGROUND FGF-23 increases renal phosphorus excretion and inhibits vitamin D activation. In end-stage renal disease, high FGF-23 levels are associated with mortality. The association of FGF-23 with death, HF, and CVD in the general population, and the influence of CKD in this setting, are unknown. METHODS Plasma FGF-23 was measured in 3,107 community-living persons ≥ 65 years of age in 1996 and 1997, and participants were followed through 2008. HF and CVD events were adjudicated by a panel of experts. Associations of FGF-23 with each outcome were evaluated using Cox proportional hazards models, and we tested whether associations differed by CKD status. RESULTS Both lower estimated glomerular filtration rate and higher urine albumin to creatinine ratios were associated with high FGF-23 at baseline. During 10.5 years (median) follow-up, there were 1,730 deaths, 697 incident HF events, and 797 incident CVD events. Although high FGF-23 concentrations were associated with each outcome in combined analyses, the associations were consistently stronger for those with CKD (p interactions all <0.006). In the CKD group (n = 1,128), the highest FGF-23 quartile had adjusted hazards ratios (HR) of 1.87 (95% confidence interval [CI]: 1.47 to 2.38) for all-cause death, 1.94 (95% CI: 1.32 to 2.83) for incident HF, and 1.49 (95% CI: 1.02 to 2.18) for incident CVD events compared with the lowest quartile. Corresponding HRs in those without CKD (n = 1,979) were 1.29 (95% CI: 1.05 to 1.59), 1.37 (95% CI: 0.99 to 1.89), and 1.07 (95% CI: 0.79 to 1.45). CONCLUSIONS FGF-23, a hormone involved in phosphorous and vitamin D homeostasis, is independently associated with all-cause death and incident HF in community-living older persons. These associations appear stronger in persons with CKD.

Rapid Decline of Kidney Function Increases Cardiovascular Risk in the Elderly

Chronic kidney disease (CKD), defined at a specific time point, is an important risk factor for cardiovascular disease. Whether the rate of kidney function decline contributes additional cardiovascular risk is unknown. In the Cardiovascular Health Study, we compared the associations of changes in kidney function during the first 7 yr with the incidence of heart failure (HF), myocardial infarction (MI), stroke, and peripheral arterial disease (PAD) during the subsequent 8 yr. We defined a rapid decline in cystatin C-based estimated GFR as >3 ml/min per 1.73 m(2)/yr, on the basis of determination at baseline, year 3, and year 7. Among eligible participants, 1083 (24%) had rapid kidney decline. The incidence of each type of cardiovascular event was significantly higher among patients with rapid decline (all P < 0.001). After multivariate adjustment for demographics, cardiovascular disease risk factors, and baseline kidney function, rapid kidney function decline was significantly associated with HF (adjusted hazard ratio [HR] 1.32; 95% confidence interval [CI] 1.13 to 1.53), MI (HR 1.48; 95% CI 1.21 to 1.83), and PAD (HR 1.67; 95% CI 1.02 to 2.75) but not with stroke (HR 1.19; 95% CI 0.97 to 1.45). The association of rapid decline with each outcome did not differ by the presence or absence of CKD. In conclusion, declining kidney function associates with higher risk for HF, MI, and PAD among patients with or without CKD.

Does AKI Truly Lead to CKD

Acute kidney injury (AKI) has been implicated as an independent risk factor for the development of CKD in recent observational studies. The presumption in the nephrology community is that this association represents a causal relationship. However, because of potential problems related to residual confounding (shared risk factors), ascertainment bias (sicker patients have more follow-up assessments), misclassification of exposure (problems with defining baseline kidney function and AKI representing a discrete event versus progression of renal disease), and misclassification of outcome (de novo CKD versus CKD progression), it is difficult to conclude with certainty that AKI is truly causal for CKD. In this review we highlight several of the Hill causality criteria to examine the existing evidence and point out the missing elements that preclude defining AKI as a cause of CKD in the general population. Only well-designed studies with rigorous assessment of kidney function in all participants (AKI and non-AKI) before and after the episode or hospitalization or randomized, controlled trials demonstrating that prevention or treatment of AKI reduces the incidence of subsequent CKD can clarify the causal nature of the AKI-CKD relationship.

Cystatin C, Albuminuria, and Mortality Among Older Adults With Diabetes

OBJECTIVE Albuminuria and impaired glomerular filtration rate (GFR) are each associated with poor health outcomes among individuals with diabetes. Joint associations of albuminuria and impaired GFR with mortality have not been comprehensively evaluated in this population. RESEARCH DESIGN AND METHODS This is a cohort study among Cardiovascular Health Study participants with diabetes, mean age 78 years. GFR was estimated using serum cystatin C and serum creatinine. Albumin-to-creatinine ratio (ACR) was measured in single-voided urine samples. RESULTS Of 691 participants, 378 died over 10 years of follow-up. Cystatin C–estimated GFR <60 ml/min per 1.73 m2, creatinine-based estimated GFR <60 ml/min per 1.73 m2, and urine ACR ≥30 mg/g were each associated with increased mortality risk with hazard ratios of 1.73 (95% CI 1.37–2.18), 1.54 (1.21–1.97), and 1.73 (1.39–2.17), respectively, adjusting for age, sex, race, diabetes duration, hypoglycemic medications, hypertension, BMI, smoking, cholesterol, lipid-lowering medications, prevalent cardiovascular disease (CVD), and prevalent heart failure. Cystatin C–estimated GFR and urine ACR were additive in terms of mortality risk. Cystatin C–estimated GFR predicted mortality more strongly than creatinine-based estimated GFR. CONCLUSIONS Albuminuria and impaired GFR were independent, additive risk factors for mortality among older adults with diabetes. These findings support current recommendations to regularly assess both albuminuria and GFR in the clinical care of patients with diabetes; a focus on interventions to prevent or treat CVD in the presence of albuminuria, impaired GFR, or both; and further consideration of cystatin C use in clinical care.

Long-term Assessment of Inflammation and Healthy Aging in Late Life: The Cardiovascular Health Study All Stars

BACKGROUND Associations of inflammation with age-related pathologies are documented; however, it is not understood how changes in inflammation over time impact healthy aging. METHODS We examined associations of long-term change in C-reactive protein (CRP) and interleukin-6 (IL-6) with concurrent onset of physical and cognitive impairment, subsequent cardiovascular disease (CVD), and mortality in 1,051 participants in the Cardiovascular Health Study All Stars Study. Biomarkers were measured in 1996-1997 and 2005-2006. RESULTS In 2005-2006, median age was 84.9 years, 63% were women and 17% non-white; 21% had at least a doubling in CRP over time and 23% had at least a doubling in IL-6. Adjusting for demographics, CVD risk factors, and 1996-1997 CRP level, each doubling in CRP change over 9 years was associated with higher risk of physical or cognitive impairment (odds ratio 1.29; 95% confidence interval 1.15, 1.45). Results were similar for IL-6 (1.45; 1.20, 1.76). A doubling in IL-6 change over time, but not CRP, was associated with incident CVD events; hazard ratio (95% confidence interval) 1.34 (1.03, 1.75). Doubling in change in each biomarker was individually associated with mortality (CRP: 1.12 [1.03, 1.22]; IL-6 1.39 [1.16, 1.65]). In models containing both change and 2005-2006 level, only level was associated with CVD events and mortality. CONCLUSIONS Although increases in inflammation markers over 9 years were associated with higher concurrent risk of functional impairment and subsequent CVD events and mortality, final levels of each biomarker appeared to be more important in determining risk of subsequent events than change over time.

Albuminuria, impaired kidney function and cardiovascular outcomes or mortality in the elderly

BACKGROUND Kidney disease is a risk factor for mortality and cardiovascular disease in older adults, but the separate and combined effects of albuminuria and cystatin C, a novel marker of glomerular filtration, are not known. METHODS We examined associations of these markers with mortality and cardiovascular outcomes during a median follow-up of 8.3 years in 3291 older adults in the Cardiovascular Health Study. Kidney disease was assessed using urinary albumin/creatinine ratio (ACR), cystatin C and Modification of Diet in Renal Disease estimated glomerular filtration rate (eGFR). We defined subgroups based on presence of microalbuminuria (MA, ACR > 30 mg/g) and categories of normal kidney function (cystatin C < 1.0 mg/L and eGFR > 60 mL/min/1.73 m(2)); preclinical kidney disease (cystatin C level > 1.0 mg/l but eGFR > 60 mL/min/1.73 m(2)); and chronic kidney disease (CKD) (eGFR < 60 mL/min/1.73 m(2)). Cox proportional hazards models were used to examine associations between these six subgroups and all-cause or cardiovascular mortality, myocardial infarction and heart failure. RESULTS One thousand one hundred fifty (34.9%) had normal kidney function (12.2% with MA), 1518 (46.1%) had preclinical kidney disease (17.9% with MA) and 622 (18.9%) had CKD (47% with MA). After adjustment, the presence of either preclinical kidney disease or MA was associated with an over 50% increase in mortality risk; the presence of both was associated with a 2.4-fold mortality risk. Those with CKD and MA were at highest risk, with a nearly 4-fold mortality risk. CONCLUSION Elevated cystatin C and albuminuria are common, identify different subsets of the older population, and are independent, graded risk factors for cardiovascular disease and mortality.

Cystatin C and Aging Success

BACKGROUND To our knowledge, the effect of kidney function on successful aging has not been examined. METHODS We evaluated the relationship between cystatin C and aging success during a 6-year follow-up in the Cardiovascular Health Study, a community-based cohort of older adults (aged >or= 65 years). Successful aging was defined as remaining free of cardiovascular disease, cancer, and chronic obstructive pulmonary disease and having intact physical and cognitive functioning. In adjusted analysis, an accelerated failure time model was used to evaluate the percentage reduction in successful years by level of cystatin C. A separate Cox proportional hazards model evaluated whether cystatin C was related to incident physical and cognitive disability. RESULTS A total of 2140 participants had cystatin C measured and were free of the previously mentioned conditions at baseline. Their mean age was 74 years. The mean cystatin C level, creatinine level, and estimated glomerular filtration rate were 1.06 mg/L, 0.93 mg/dL, and 78 mL/min/1.73 m(2), respectively (to convert cystatin C to nanomoles per liter, multiply by 75; and to convert creatinine to micromoles per liter, multiply by 88.4). A total of 873 participants reached a first event in follow-up, 138 because of cognitive disability, 238 because of physical disability, 34 because of chronic obstructive pulmonary disease, 146 because of cancer, and 317 because of cardiovascular disease. The adjusted percentage reduction in successful life years in the highest vs the lowest quartile of cystatin C was 27% (95% confidence interval, 11%-39%). The highest vs lowest quartile of cystatin C also was independently associated with incident cognitive or physical disability (hazard ratio, 1.39; 95% confidence interval, 1.00-1.98). CONCLUSION A higher cystatin C level, even within a range of relatively normal kidney function, was associated with unsuccessful aging.

Estimating Risks of De Novo Kidney Diseases After Living Kidney Donation

De novo postdonation renal diseases, such as glomerulonephritis or diabetic nephropathy, are infrequent and distinct from the loss of GFR at donation that all living kidney donors experience. Medical findings that increase risks of disease (e.g. microscopic hematuria, borderline hemoglobin A1C) often prompt donor refusal by centers. These risk factors are part of more comprehensive risks of low GFR and end‐stage renal disease (ESRD) from kidney diseases in the general population that are equally relevant. Such data profile the ages of onset, rates of progression, prevalence and severity of loss of GFR from generically characterized kidney diseases. Kidney diseases typically begin in middle age and take decades to reach ESRD, at a median age of 64. Diabetes produces about half of yearly ESRD and even more lifetime near‐ESRD. Such data predict that (1) 10‐ to 15‐year studies will not capture the lifetime risks of postdonation ESRD; (2) normal young donors are at demonstrably higher risk than normal older candidates; (3) low normal predonation GFRs become risk factors for ESRD when kidney diseases arise and (4) donor nephrectomy always increases individual risk. Such population‐based risk data apply to all donor candidates and should be used to make acceptance standards and counseling more uniform and defensible.