Background The strength and direction of the associations between inflammation and coagulation biomarkers with kidney disease onset and progression remain unclear, especially in a population-based ...setting. Study Design Prospective observational study. Setting & Participants 4,966 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with a cystatin C–based estimate of glomerular filtration rate (eGFRcys ) >60 mL/min/1.73 m2 and at least one follow-up measurement of kidney function. All participants were free of cardiovascular disease at entry. Predictor We evaluated the associations of C-reactive protein (CRP), interleukin 6 (IL-6), fibrinogen, factor VIII, and d -dimer levels with kidney function decrease. Outcomes & Measurements Kidney function decrease was assessed primarily by repeated measurements of eGFRcys over 5 years. Rapid decrease in kidney function was defined as eGFR decrease >3 mL/min/1.73 m2 per year. Incident low eGFR was defined as the onset of eGFRcys <60 mL/min/1.73 m2 at any follow-up examination and eGFRcys decrease ≥1 mL/min/1.73 m2 per year. Results Mean age was 60 years, 39% were white, 52% were women, and 11% had diabetes. Mean eGFRcys was 96 mL/min/1.73 m2 and 7% had albuminuria. Median follow-up was 4.77 years. Higher factor VIII levels (per 1 standard deviation SD of biomarker) had the strongest association with kidney function decrease (β = −0.25; 95% CI, −0.38 to −0.12; P < 0.001), followed by IL-6 (β = −0.16; 95% CI, −0.29 to −0.03; P = 0.01), CRP (β = −0.09; 95% CI, −0.22 to 0.03; P = 0.1), and fibrinogen levels (β = −0.09; 95% CI, −0.22 to 0.04; P = 0.2). Each 1-SD higher concentration of IL-6 (OR, 1.15; 95% CI, 1.07-1.23), factor VIII (OR, 1.11; 95% CI, 1.03-1.18), and CRP (OR, 1.09; 95% CI, 1.02-1.16) at baseline was associated significantly with rapid kidney function decrease. Only IL-6 level was associated significantly with incident low eGFR (OR, 1.09; 95% CI, 1.00-1.19). Limitations Observational study design and absence of measured GFR. Conclusions Inflammation and coagulation biomarkers are associated with decreasing kidney function in ambulatory adults without established cardiovascular disease or chronic kidney disease.
Background Pentraxin-3 (PTX3) is an inflammatory marker thought to be more specific to vascular inflammation than C-reactive protein (CRP). Whether PTX3 is independently associated with adverse ...events among persons with stable coronary heart disease (CHD), independently of CRP, and whether kidney dysfunction influences these associations are not known. Methods We evaluated the associations of baseline PTX3 levels with all-cause mortality, cardiovascular (CV) events (myocardial infarction, stroke, or CHD death), and incident heart failure (HF) during 37 months among ambulatory persons with stable CHD participating in the Heart and Soul Study. Cox proportional hazards models were adjusted for age, sex, race, hypertension, diabetes, smoking, and CRP. Results Among 986 persons with stable CHD, each 1 unit increase in log PTX3 at baseline was associated with an 80% increased risk of all-cause mortality (hazard ratio HR 1.8, 95% CI 1.5-2.1), a 50% increased risk of CV events (HR 1.5, 95% CI, 1.2-1.9), and an 80% greater risk of incident HF (HR 1.8, 95% CI, 1.3-2.5). Further adjustment for estimated glomerular filtration rate (eGFR) attenuated these associations to 1.6 (1.3-1.9) for mortality, 1.3 (1.0-1.6) for CV events and 1.5 (1.1-2.1) for incident HF. Stratification by eGFR >60 mL/min per 1.73m2 or <60 mL/min per 1.73m2 did not affect these associations ( P interaction > .3 for all outcomes). Conclusions Among persons with stable CHD, higher PTX3 concentrations were associated with increased risk for all-cause mortality, CV events, and incident HF independently of systemic inflammation. Adjustment for eGFR modestly attenuated these associations, suggesting that future studies of PTX3 should adjust for kidney function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Kidney function monitoring using creatinine-based glomerular filtration rate estimation is a routine part of clinical practice. Emerging evidence has shown that cystatin C may improve classification ...of glomerular filtration rate for defining chronic kidney disease in certain clinical populations and assist in understanding the complications of chronic kidney disease. In this review and update, we summarize the overall literature on cystatin C, critically evaluate recent high-impact studies, highlight the role of cystatin C in recent kidney disease guidelines, and suggest a practical approach for clinicians to incorporate cystatin C into practice. We conclude by addressing frequently asked questions related to implementing cystatin C use in a clinical setting.
Background Chronic kidney disease (CKD) and hyperuricemia often coexist, and both conditions are increasing in prevalence in the United States. However, their shared role in cardiovascular risk ...remains highly debated. Study Design Cross-sectional and longitudinal. Setting & Participants Participants in the National Health and Nutrition Examination Survey (NHANES) from 1988 to 2002 (n = 10,956); data were linked to mortality data from the National Death Index through December 31, 2006. Predictors Serum uric acid concentration, categorized as the sex-specific lowest (<25th), middle (25th-<75th), and highest (≥75th) percentiles; and kidney function assessed by estimated glomerular filtration rate (eGFR) based on the CKD-EPI (CKD Epidemiology Collaboration) creatinine-cystatin C equation and urinary albumin-creatinine ratio (ACR). Outcomes Cardiovascular death and all-cause mortality. Results Uric acid levels were correlated with eGFRcr-cys ( r = −0.29; P < 0.001) and were correlated only slightly with ACR ( r = 0.04; P < 0.001). There were 2,203 deaths up until December 31, 2006, of which 981 were due to cardiovascular causes. Overall, there was a U-shaped association between uric acid levels and cardiovascular mortality in both women and men, although the lowest risk of cardiovascular mortality occurred at a lower level of uric acid for women compared with men. There was an association between the highest quartile of uric acid level and cardiovascular mortality even after adjustment for potential confounders (HR, 1.48; 95% CI, 1.13-1.96), although this association was attenuated after adjustment for ACR and eGFRcr-cys (HR, 1.25; 95% CI, 0.89-1.75). The pattern of association between uric acid levels and all-cause mortality was similar. Limitations GFR not measured; mediating events were not observed. Conclusions High uric acid level is associated with cardiovascular and all-cause mortality, although this relationship was no longer statistically significant after accounting for kidney function.
Background Higher urine albumin-creatinine ratio (ACR) is associated with cardiovascular disease (CVD) events, an association that is stronger than that between spot urine albumin on its own and CVD. ...Urine creatinine excretion is correlated with muscle mass, and low muscle mass also is associated with CVD. Whether low urine creatinine concentration in the denominator of the ACR contributes to the association of ACR with CVD is uncertain. Study Design Prospective cohort study. Setting & Participants 6,770 community-living individuals without CVD. Predictors Spot urine albumin concentration, the reciprocal of the urine creatinine concentration (1/UCr), and ACR. Outcome Incident CVD events. Results During a mean of 7.1 years of follow-up, 281 CVD events occurred. Geometric mean values for spot urine creatinine concentration, urine albumin concentration, and ACR were 95 ± 2 (SD) mg/dL, 0.7 ± 3.7 mg/dL, and 7.0 ± 3.1 mg/g. Urine creatinine concentration was lower in older, female, and low-weight individuals. Adjusted HRs per 2-fold higher increment in each urinary measure with CVD events were similar (1/UCr: 1.07 95% CI, 0.94-1.22; urine albumin concentration: 1.08 95% CI, 1.01-1.14; and ACR: 1.11 95% CI, 1.04-1.18). ACR ≥10 mg/g was associated more strongly with CVD events in individuals with low weight (HR for lowest vs highest tertile: 4.34 vs 1.97; P for interaction = 0.006). Low weight also modified the association of urine albumin concentration with CVD ( P for interaction = 0.06), but 1/UCr did not ( P for interaction = 0.9). Limitations We lacked 24-hour urine data. Conclusions Although ACR is associated more strongly with CVD events in persons with low body weight, this association is not driven by differences in spot urine creatinine concentration. Overall, the associations of ACR with CVD events appear to be driven primarily by urine albumin concentration and less by urine creatinine concentration.
Background Whether elevations in levels of urinary biomarkers of tubular injury (urine neutrophil gelatinase-associated lipocalin NGAL and kidney injury molecule 1 KIM-1) are associated with future ...risk of kidney disease has not been investigated. Study Design 1:1 nested case-control study. Setting & Participants 686 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Predictor NGAL and KIM-1 were measured at baseline, expressed as log-transformed continuous variables, and categorized into deciles. Outcomes Kidney function was estimated by cystatin C level using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. Incident CKD stage 3 was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 and an eGFR decrease >1 mL/min/1.73 m2 per year, and rapid kidney function decrease was defined as decrease ≥3 mL/min/1.73 m2 per year. Measurements Cases were defined as persons with eGFR >60 mL/min/1.73 m2 who subsequently developed incident CKD stage 3 and/or had rapid kidney function decrease by the MESA year-5 visit. Controls were matched for age, sex, race, diabetes, and baseline eGFR. We adjusted for age, hypertension, and presence of albuminuria (albumin-creatinine ratio ≥30 mg/g). Results Of 343 cases, 145 had incident CKD stage 3, 141 had rapid kidney function decrease, and 57 had both. Mean eGFR for controls was 81 ± 10 mL/min/1.73 m2 at baseline and 80 ± 10 mL/min/1.73 m2 at follow-up compared with 82 ± 13 and 58 ± 10 mL/min/1.73 m2 for cases. Each doubling of KIM-1 level (in picograms per milliliter) was associated with an OR of 1.15 (95% CI, 1.02-1.29) for incident CKD stage 3 and/or rapid kidney function decrease. Compared with the lowest 90%, the highest decile of KIM-1 level was associated with an OR of 2.02 (95% CI, 1.15-3.56) for the outcome; these associations were independent of albuminuria. NGAL levels (in nanograms per milliliter) were not associated with incident CKD stage 3 and/or rapid kidney function decrease (OR, 1.04; 95% CI, 0.99-1.10). Results were similar when KIM-1 and NGAL levels were standardized for urine creatinine. Limitations The case-control design limits the ability to account for persons who died or were not available for follow-up. Conclusions Urinary KIM-1 level is associated with future risk of kidney disease independent of albuminuria. Urinary biomarkers of tubular injury are a promising tool for identifying persons at risk of CKD.
Background Kidney disease has been associated with venous thromboembolism (VTE) risk, but results conflict and there is little information regarding blacks. Study Design Prospective cohort study. ...Setting & Participants 30,239 black and white adults 45 years or older enrolled in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study 2003 to 2007. Predictors Estimated glomerular filtration rate (eGFR) using the combined creatinine–cystatin C (eGFRcr-cys ) equation and urinary albumin-creatinine ratio (ACR). Outcomes The primary outcome was adjudicated VTE, and secondary outcomes were provoked and unprovoked VTE, separately. Mortality was a competing-risk event. Results During 4.6 years of follow-up, 239 incident VTE events occurred over 124,624 person-years. Cause-specific HRs of VTE were calculated using proportional hazards regression adjusted for age, sex, race, region of residence, and body mass index. Adjusted VTE HRs for eGFRcr-cys of 60 to <90, 45 to <60, and <45 versus ≥90 mL/min/1.73 m2 were 1.28 (95% CI, 0.94-1.76), 1.30 (95% CI, 0.77-2.18), and 2.13 (95% CI, 1.21-3.76). Adjusted VTE HRs for ACR of 10 to <30, 30 to <300, and ≥300 versus <10 mg/g were 1.14 (95% CI, 0.84-1.56), 1.15 (95% CI, 0.79-1.69), and 0.64 (95% CI, 0.25-1.62). Associations were similar for provoked and unprovoked VTE. Limitations Single measurement of eGFR and ACR may have led to misclassification. Smaller numbers of events may have limited power. Conclusions There was an independent association of low eGFR (<45 vs ≥90 mL/min/1.73 m2 ) with VTE risk, but no association of ACR and VTE.
Background Strong racial discrepancies in end-stage renal disease exist. Whether there are race differences in kidney function loss in younger healthy persons is not well established. Study Design ...Longitudinal. Setting & Participants 3,348 black and white adults with at least 2 measurements of cystatin C–based estimated glomerular filtration rate (eGFRcys ) at scheduled Coronary Artery Risk Development in Young Adults (CARDIA) examinations (years 10, 15, and 20). Predictor Race. Outcomes & Measurements We used linear mixed models to examine race differences in annualized rates of eGFRcys decline, adjusting for age, sex, lifetime exposure to systolic blood pressure >120 mm Hg, diabetes, and albumin-creatinine ratio. We used Poisson regression to compare racial differences in rapid decline (eGFRcys decline >3% per year) by study period (10-15 years after baseline examination defining period 1 and >15-20 years after baseline examination defining period 2). Results Mean age was 35 ± 3.6 (SD) years, and mean eGFRcys was 110 ± 20 mL/min/1.73 m2 for blacks and 104 ± 17 mL/min/1.73 m2 for whites at baseline. For both blacks and whites, eGFRcys decline was minimal at younger ages (<35 years) and eGFRcys loss accelerated at older ages. However, acceleration of eGFRcys decline occurred at earlier ages for blacks than whites. Blacks had somewhat faster annualized rates of decline compared with whites, but differences were attenuated after adjustment in period 1 (0.13 mL/min/1.73 m2 per year faster; P = 0.2). In contrast, during period 2, blacks had significantly faster annualized rates of decline, even after adjustment (0.32 mL/min/1.73 m2 per year faster; P = 0.003). The prevalence of rapid decline was significantly higher for blacks versus whites, with prevalence rate ratios of 1.31 (95% CI, 1.04-1.63) for period 1 and 1.24 (95% CI, 1.09-1.41) for period 2. Differences were attenuated after full adjustment: adjusted prevalence rate ratios were 1.20 (95% CI, 0.95-1.49) for period 1 and 1.10 (95% CI, 0.96-1.26) for period 2. Limitations No measured GFR. Conclusions eGFRcys decline differs by race at early ages, with faster annualized rates of decline for blacks. Future studies are required to explain the observed differences.
Higher serum phosphorus concentrations are associated with cardiovascular disease events and mortality. Low socioeconomic status is linked with higher serum phosphorus concentration, but the reasons ...are unclear. Poor individuals disproportionately consume inexpensive processed foods commonly enriched with phosphorus-based food preservatives. Accordingly, we hypothesized that excess intake of these foods accounts for a relationship between lower socioeconomic status and higher serum phosphorus concentration.
Cross-sectional analysis.
We examined a random cohort of 2,664 participants with available phosphorus measurements in the Multi-Ethnic Study of Atherosclerosis, a community-based sample of individuals free of clinically apparent cardiovascular disease from across the United States.
Socioeconomic status, the intake of foods commonly enriched with phosphorus-based food additives (processed meats, sodas), and frequency of fast-food consumption.
Fasting morning serum phosphorus concentrations.
In unadjusted analyses, lower income and lower educational achievement categories were associated with modestly higher serum phosphorus concentration (by 0.02 to 0.10 mg/dL, P < .05 for all). These associations were attenuated in models adjusted for demographic and clinical factors, almost entirely due to adjustment for female gender. In multivariable-adjusted analyses, there were no statistically significant associations of processed meat intake or frequency of fast-food consumption with serum phosphorus. In contrast, each serving per day higher soda intake was associated with 0.02 mg/dL lower serum phosphorus concentration (95% confidence interval, -0.04, -0.01).
Greater intake of foods commonly enriched with phosphorus additives was not associated with higher serum phosphorus concentration in a community-living sample with largely preserved kidney function. These results suggest that excess intake of processed and fast foods may not impact fasting serum phosphorus concentrations among individuals without kidney disease.
Background Left ventricular hypertrophy is common and is associated with cardiovascular events and death among patients with known chronic kidney disease. However, the link between reduced glomerular ...filtration rate (GFR) and left ventricular mass index (LVMI) remains poorly explored among young and middle-aged adults with preserved kidney function. In this study, we examined the association of cystatin C–based estimated GFR (eGFRcys ) and rapid decline in eGFR with subsequent LVMI. Study Design Observational study. Setting & Participants We included 2,410 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort with eGFRcys > 60 mL/min/1.73 m2 at year 15 and who had an echocardiogram obtained at year 25. Predictor eGFRcys at year 15 and rapid decline in eGFRcys (defined as >3% per year over 5 years from years 15 to 20). Outcome LVMI measured at year 25. Measurements We adjusted for age, sex, race, diabetes, body mass index, low- and high-density lipoprotein cholesterol levels, cumulative systolic blood pressure, and albuminuria. Results Mean age was 40 ± 4 (SD) years, 58% were women, and 43% were black. After 10 years of follow-up, mean LVMI was 39.6 ± 13.4 g/m2.7 . Compared with eGFRcys > 90 mL/min/1.73 m2 (n = 2,228), eGFRcys of 60 to 75 mL/min/1.73 m2 (n = 29) was associated with 5.63 (95% CI, 0.90-10.36) g/m2.7 greater LVMI ( P = 0.02), but there was no association of eGFRcys of 76 to 90 mL/min/1.73 m2 (n = 153) with LVMI after adjustment for confounders. Rapid decline in eGFRcys was associated with higher LVMI compared with participants without a rapid eGFRcys decline (β coefficient, 1.48; 95% CI, 0.11-2.83; P = 0.03) after adjustment for confounders. Limitations There were a limited number of participants with eGFRcys of 60 to 90 mL/min/1.73 m2. Conclusions Among young and middle-aged adults with preserved kidney function, eGFRcys of 60 to 75 mL/min/1.73 m2 and rapid decline in eGFRcys were significantly associated with subsequently higher LVMI. Further studies are needed to understand the mechanisms that contribute to elevated LVMI in this range of eGFRcys.
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