Low vitamin D concentrations are prevalent in chronic kidney disease (CKD) patients. We investigated the relationship between plasma 25-hydroxyvitamin D (25(OH)D) or 1,25-dihydroxyvitamin D (1,25(OH)2D) concentrations with death, cardiovascular events (CVE) and dialysis initiation in patients with advanced CKD. Study Design: The Homocysteine Study was a randomized double-blind trial evaluating the effects of high doses of folic acid on death and chronic dialysis initiation in patients with advanced CKD (stage 4 and 5 not yet on dialysis). 25(OH)D and 1,25(OH)2D concentrations were measured in stored plasma samples obtained 3 months after trial initiation and evaluated at clinically defined cutoffs (<10, 10-30, and >30 ng/mL) and tertiles (< 15, 15-22, and >22 pg/mL), respectively. Cox-proportional hazard models were used to examine the association between vitamin D concentrations and clinical outcomes.
Setting & Participants
1,099 patients with advanced CKD from 36 Veteran Affairs Medical Centers
25(OH)D and 1,25(OH)2D concentrations
Death, CVE and time to initiation of chronic dialysis.
After a median follow-up period of 2.9 years, 41% (n=453) died, while 56% (n=615) initiated dialysis. Mean 25(OH)D and 1,25(OH)2D concentrations were 21±10 ng/mL and 20±11 pg/mL, respectively. After adjustment for potential confounders, the lowest tertile of 1,25(OH)2D was associated with death (HR, 1.33; 95% CI, 1.01-1.74) and initiation of chronic dialysis (HR, 1.78; 95% CI, 1.40-2.26), compared to the highest tertile. The association with death and initiation of dialysis was moderately attenuated after adjustment for plasma fibroblast growth factor-23 (FGF23) concentrations (HRs of lower tertiles of 1.20 [95% CI, 0.91-1.58] and 1.56 [95% CI, 1.23-1.99], respectively, compared to highest tertile). There was no association between 25(OH)D concentrations and outcomes.
Participants were mostly male.
Low plasma 1,25(OH)2D concentrations are associated with death and initiation of chronic dialysis in advanced CKD. Fibroblast growth factor-23 may attentuate this relationship.
Older women have higher phosphorus levels than men. Estradiol causes phosphaturia in rodents. Whether sex hormones associate with phosphorus levels in humans is unknown. In 1,346 community-living older men, we evaluate the cross-sectional association of sex hormones with serum phosphorus, using linear regression with serum phosphorus levels as the dependent variable. Mean age was 76 years, phosphorus was 3.2±0.4mg/dl, and 18% had moderate kidney disease. Each 10pg/ml higher total estradiol associated with 0.05mg/dL lower serum phosphorus levels (95 % CI −0.09 to −0.02; P < 0.01) in a model adjusted for age, race, testosterone, sex hormone binding globulin, calcium, eGFR, intact PTH, 25(OH) vitamin D, body mineral density, and alkaline phosphatase. Results were similar in individuals with or without CKD. Serum testosterone levels were also associated with lower serum phosphorus levels (β per 200ng/dL greater total testosterone = −0.08; 95% CI −0.13 to −0.04; P < 0.001). Results were confirmed in an independent sample of 2,555 older men, and associations were not attenuated when adjusted for fibroblast growth factor-23 levels. Estradiol may induce phosphaturia in humans. Future studies are required to elucidate potential effects of testosterone on phosphorus homeostasis.
Phosphorus; estradiol; testosterone; menopause; sex hormones; kidney disease; cardiovascular disease
There is a gap of knowledge in the long-term outcomes of patients who have complete recovery of kidney function after an episode of acute kidney injury (AKI). We sought to determine if complete recovery of kidney function after an episode of AKI is associated with development of incident stage 3 chronic kidney disease (CKD) and mortality in patients with normal baseline kidney function.
Retrospective cohort study.
SETTING & PARTICIPANTS
3,809 patients from an integrated healthcare delivery system that had a hospitalization between January 1, 1999 and December 31, 2009 with follow-up through March 31, 2010.
AKI defined by ICD-9 codes and using the Acute Kidney Injury Network (AKIN) definition with complete recovery defined by reduction in serum creatinine to less than 1.10 times the baseline value.
OUTCOMES AND MEASUREMENTS
Incident stage 3 CKD persistent for 3 months and all-cause mortality.
After a median follow-up of 2.5 years, incident stage 3 CKD occurred in 15% and 3% of those with and without AKI, respectively, with an unadjusted HR of 5.93 (95% CI, 4.49-7.84) and a HR of 3.82 (95% CI, 2.81-5.19) in propensity score-stratified analyses. Deaths occurred in 35% and 24% of those with and without AKI, respectively, with an unadjusted HR of 1.46 (95% CI, 1.27-1.68). In the propensity score stratified analyses, HR decreased to 1.08 (95% CI, 0.93-1.27).
Measurements of albuminuria were not available.
Complete recovery of kidney function after an episode of AKI in subjects with normal baseline kidney function is associated with an increased risk of development of incident stage 3 CKD but not all-cause mortality.
To determine the associations of FGF23 with death, HF, and CVD and investigate the influence of CKD in a general community-living population.
FGF23 increases renal phosphorus excretion and inhibits vitamin D activation. In ESRD, high FGF23 levels are associated with mortality. The associations of FGF23 with death, heart failure (HF), and cardiovascular disease (CVD) in teh general population are unknown.
Plasma FGF23 was measured in 3,107 community-living persons ≥ 65 years in 1996–97, and participants were followed through 2008. HF and CVD events were adjudicated by a panel of experts. Associations of FGF23 with each outcome were evaluated using Cox proportional hazards models, and we tested whether associations differed by CKD status.
Both lower eGFR and higher urine ACR were associated with high FGF23 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 FGF23 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 FGF23 quartile had adjusted hazards ratios (HR) of 1.87 (1.47, 2.38) for all-cause death, 1.94 (1.32, 2.83) for incident HF, and 1.49 (1.02, 2.18) for incident CVD events compared to the lowest quartile. Corresponding HRs in those without CKD (n=1,979) were 1.29 (1.05, 1.59), 1.37 (0.99, 1.89), and 1.07 (0.79, 1.45).
FGF23, 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.
Fibroblast growth factor-23; kidney disease; mineral metabolism; cardiovascular disease; heart failure; elderly
Few studies have evaluated the relationship between high-sensitivity C-reactive protein (hs-CRP) and vascular events in the elderly with chronic kidney disease (CKD).
The relationship of hs-CRP with vascular events was examined according to CKD status in 3166 participants of the Intervention Project on Cerebrovascular Diseases and Dementia in the Community of Ebersberg, Bavaria (INVADE study). CKD was defined as a creatinine clearance <60mL/min estimated by the Cockcroft-Gault formula. hs-CRP was used as a binary variable > or < 2.1mg/l (median value). Vascular events were defined as a composite of myocardial infarction, stroke and vascular death.
After 4 years of follow-up, 204 (6.4%) participants experienced a major cardiovascular event. High hs-CRP levels and CKD at baseline were associated with a greater risk of vascular events. Compared to patients with low hs-CRP/non-CKD, the adjusted HR (95% CI) for vascular events was 1.42 (1.11; 2.21) for low hs-CRP/CKD,1.57 (1.21; 2.34) for high hs-CRP/non-CKD, and 1.93 (1.45; 2.89) for high hs-CRP/CKD.
These results suggest that high CRP provides prognostic information in patients with CKD.
C-reactive protein; inflammation; CKD; cardiovascular disease
Insulin resistance is a risk factor for cardiovascular and noncardiovascular diseases. Impaired kidney function is linked with insulin resistance and may affect relationships of insulin resistance with health outcomes.
RESEARCH DESIGN AND METHODS
We performed a cohort study of 3,138 Cardiovascular Health Study participants (age ≥65 years) without diabetes. Insulin sensitivity index (ISI) was calculated from fasting and 2-h postload insulin and glucose concentrations. Associations of ISI and fasting insulin concentration with all-cause mortality were tested using Cox proportional hazards models, adjusting for demographic variables, prevalent cardiovascular disease, lifestyle variables, waist circumference, and LDL cholesterol. Subsequent models were additionally adjusted for or stratified by glomerular filtration rate estimated using serum cystatin C (eGFR).
A total of 1,810 participants died during the 14.7-year median follow-up. Compared with the highest quartile of ISI, the lowest quartile (most insulin resistant) was associated with 21% (95% CI 6–41) and 11% (−3 to 29) higher risks of death without and with adjustment for eGFR, respectively. Compared with the lowest quartile of fasting insulin concentration, the highest quartile was associated with 22% (4–43) and 4% (−12 to 22) higher risks of death without and with adjustment for eGFR, respectively. Similar attenuation by eGFR was observed when blood pressure, triglycerides, HDL cholesterol, and C-reactive protein were included in models.
Insulin resistance measured as ISI or fasting insulin concentration is associated with increased risk of death among older adults, adjusting for conventional confounding characteristics. Impaired kidney function may mediate or confound this relationship.
Recent studies have suggested an association between hyperuricemia and adverse renal outcomes in nondiabetic populations. Data on the relationship between hyperuricemia and the risk of incident chronic kidney disease (CKD) in type 2 diabetic patients with normal or near-normal kidney function are lacking. We determined whether baseline serum uric acid levels predict the subsequent development of CKD in patients with type 2 diabetes.
RESEARCH DESIGN AND METHODS
We followed 1,449 type 2 diabetic patients with normal kidney function and without overt proteinuria for 5 years for the occurrence of incident CKD (defined as overt proteinuria or estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2).
During a 5-year follow-up period, 194 (13.4%) patients developed incident CKD. The cumulative incidence of CKD was significantly greater in patients with hyperuricemia than in those without hyperuricemia (29.5 vs. 11.4%, P < 0.001). In univariate logistic regression analysis, the presence of hyperuricemia roughly doubled the risk of developing CKD (odds ratio [OR] 2.55 [95% CI 1.71–3.85], P < 0.001). After adjusting for age, sex, BMI, smoking status, diabetes duration, systolic blood pressure, antihypertensive treatment, insulin therapy, HbA1c, eGFR, and albuminuria, hyperuricemia was associated with an increased risk of incident CKD (adjusted OR 2.10 [1.16–3.76], P < 0.01). In continuous analyses, a 1-SD increment in the serum uric acid level was significantly associated with a 21% increased risk of CKD.
In type 2 diabetic individuals with preserved kidney function, hyperuricemia seems to be an independent risk factor for the development of incident CKD.
Recent studies have demonstrated greater risks of cardiovascular events and mortality among persons who have lower 25-hydroxyvitamin D (25-OHD) and higher parathyroid hormone (PTH) levels. We sought to evaluate the association between markers of mineral metabolism and sudden cardiac death (SCD) among the 2,312 participants from the Cardiovascular Health Study who were free of clinical cardiovascular disease at baseline. We estimated associations of baseline 25-OHD and PTH concentrations individually and in combination with SCD using Cox proportional hazards models after adjustment for demographics, cardiovascular risk factors, and kidney function. During a median follow-up of 14 years, there were 73 adjudicated SCD events. The annual incidence of SCD was greater among subjects who had lower 25-OHD concentrations: 2 events per 10,000 for 25-OHD ≥ 20 ng/ml and 4 events per 10,000 for 25-OHD < 20 ng/ml. Similarly, SCD incidence was greater among subjects who had higher PTH concentrations: 2 events per 10,000 for PTH ≤ 65 pg/ml and 4 events per 10,000 for PTH > 65 pg/ml. Multivariate adjustment attenuated associations of 25-OHD and PTH with SCD. Finally, 267 participants (11.7% of the cohort) had high PTH and low 25-OHD concentrations. This combination was associated with a more than 2-fold risk of SCD after adjustment (hazard ratio 2.19, 95% confidence interval 1.17, 4.10, p=0.017) compared to participants with normal levels of PTH and 25-OHD. The combination of lower 25-OHD and higher PTH concentrations appears to be associated independently with SCD risk among older adults without cardiovascular disease.
Sudden cardiac death; Vitamin D; Parathyroid hormone; Elderly; Risk Factors
M[ND1]enopause is associated with urine phosphorus retention, which is mitigated by estrogen therapy. Fibroblast growth factor 23 (FGF-23) is a hormone originating from bone that regulates urine phosphorus excretion. Whether sex or estrogen therapy is associated with different FGF-23 levels is unknown.
Study Design & Setting
Cross-sectional study among ambulatory individuals with prevalent cardiovascular disease.
Sex, and among women, use or non-use of estrogen.
Serum phosphorus, tubular maximum reabsorption of phosphorus indexed to GFR (TMP/GFR), and plasma FGF-23 concentrations.
Among 987 participants, the mean age was 67 ± 11 years, 182 (18%) were female; 46 (25%) were taking estrogen. The mean eGFR was 71 ± 23 (SD) ml/min/1.73m2. Compared to women who were not taking estrogen, both women on estrogen therapy and men had significantly lower serum phosphorus concentrations, lower TMP/GFR (indicating higher urine phosphorus excretion), and lower FGF-23 concentrations with adjustment for age, demographics, and kidney function (P < 0.001 for each). Mean FGF-23 in RU/ml were 68.7 (95% CI, 59.7–79.0) in non estrogen using women, 43.8 (95% CI, 41.2–46.5) in men, and 45.1 (95% CI, 35.2–57.4) in women using estrogen in adjusted analysis (P< 0.001).
The majority of participants were men. Estrogen therapy was not randomly assigned.
Older women who are not taking estrogen have higher FGF-23 levels than either men or women taking estrogen. In the context of prior literature, these data suggest that post-menopausal phosphorus retention may stimulate higher FGF-23 concentrations after menopause.
Menopause; fibroblast growth factor-23; phosphorus; estradiol; sex hormones
Vascular calcification is associated with significant cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). Factors unique to CKD patients, such as hyperphosphatemia, predispose these patients to early and progressive vascular calcification. Hyperphosphatemia appears to be involved in a number of mechanisms that trigger and advance progression of vascular calcification including (1) transition of vascular smooth muscle cells (VSMC) from a contractile to an osteochondrogenic phenotype and mineralization of VSMC matrix through sodium-dependent phosphate cotransporters; (2) induction of apoptosis of VSMC; (3) inhibition of monocyte/macrophage differentiation into osteoclast-like cells; (4) elevation of fibroblast growth factor 23 levels; and (5) decreases in klotho expression. Whether vascular calcification can be prevented or reversed with strategies aimed at maintaining phosphate homeostasis is currently unknown. The current review discusses these mechanisms in-depth, exploring the interplay among vascular calcification promoters, inhibitors and substrate that affect phosphorus handling leading to vascular calcification in individuals with CKD.
Arterial and ventricular stiffening are characteristics of diabetes and aging which confer significant morbidity and mortality; advanced glycation endproducts (AGE) are implicated in this stiffening pathophysiology. We examined the association between HbA1c, an AGE, with arterial and ventricular stiffness measures in older individuals without diabetes.
Research Design & Methods
Baseline HbA1c was measured in 830 participants free of diabetes defined by fasting glucose or medication use in the Cardiovascular Health Study, a population-based cohort study of adults aged ≥65 years. We performed cross-sectional analyses using baseline exam data including echocardiography, ankle and brachial blood pressure measurement, and carotid ultrasonography. We examined the adjusted associations between HbA1c and multiple arterial and ventricular stiffness measures by linear regression models and compared these results to the association of fasting glucose (FG) with like measures.
HbA1c was correlated with fasting and 2-hour postload glucose levels (r = 0.21; p<0.001 for both) and positively associated with greater body-mass index and black race. In adjusted models, HbA1c was not associated with any measure of arterial or ventricular stiffness, including pulse pressure (PP), carotid intima-media thickness, ankle-brachial index, end-arterial elastance, or left ventricular mass (LVM). FG levels were positively associated with systolic, diastolic and PP and LVM.
In this sample of older adults without diabetes, HbA1c was not associated with arterial or ventricular stiffness measures, whereas FG levels were. The role of AGE in arterial and ventricular stiffness in older adults may be better assessed using alternate AGE markers.
Elevated serum urate levels can lead to gout and are associated with cardiovascular risk factors. We performed genome-wide association to search for genetic susceptibility loci for serum urate and gout, and investigated the causal nature of the associations of serum urate with gout and selected cardiovascular risk factors and coronary heart disease (CHD).
Methods and Results
Meta-analyses of genome-wide association studies (GWAS) were performed in 5 population-based cohorts of the CHARGE consortium for serum urate and gout in 28,283 white individuals. The effect of the most significant SNP at all genome-wide significant loci on serum urate was added to create a genetic urate score. Findings were replicated in the Women’s Genome Health Study (WGHS; n=22,054). SNPs at 8 genetic loci achieved genome-wide significance with serum urate levels (p-values 4×10−8 to 2×10−242; SLC22A11, GCKR, R3HDM2-INHBC region, RREB1, PDZK1, SLC2A9, ABCG2, SLC17A1). Only two loci [SLC2A9, ABCG2] showed genome-wide significant association with gout. The genetic urate score was strongly associated with serum urate and gout (odds ratio 12.4 per 100 umol/L; p-value=3×10−39), but not with blood pressure, glucose, eGFR, chronic kidney disease, or CHD. The lack of association between the genetic score and the latter phenotypes was also observed in WGHS.
The genetic urate score analysis suggested a causal relationship between serum urate and gout but did not provide evidence for one between serum urate and cardiovascular risk factors and CHD.
urate; gout; cardiovascular disease risk factors; genome-wide association study; Mendelian randomization
We tested the hypothesis that vascular endothelial function, assessed by endothelium-dependent dilation, is related to serum vitamin D status among middle-aged and older adults without clinical disease, and that this is linked to inflammation. Brachial artery flow-mediated dilation (FMD), a measure of endothelium-dependent dilation, was lower (P<0.01) in vitamin D insufficient (3.7±0.2%; serum 25-hydroxyvitamin D [25(OH)D]: 20-29ng/mL, 62±1yr, n=31, mean±S.E.) and deficient (3.2±0.3%; 25(OH)D: <20ng/mL, 63±2 yr, n=22) vs. sufficient (4.6±0.4%; 25(OH)D: >29ng/mL; 61±1yr, n=22) subjects, whereas endothelium-independent dilation (brachial dilation to sublingual nitroglycerine) did not differ (P=0.45). Among all subjects, brachial FMD was positively related to serum 25(OH)D (%Δ: r=0.35, P<0.01), but not 1,25-dihydroxyvitamin D (r=-0.06, P=0.61), the active form of vitamin D. Vascular endothelial cell expression of the pro-inflammatory transcription factor nuclear factor κB (NFκB) was greater in deficient vs. sufficient subjects (0.59±0.07 vs. 0.44±0.05, P<0.05), and inhibition of NFκB (4d oral salsalate) improved FMD to a greater extent in subjects with lower vs. higher 25(OH)D (+3.7±0.6 vs. +2.0±0.2%, P<0.05). Endothelial cell expression of the downstream pro-inflammatory cytokine interleukin 6 also was higher in deficient vs. sufficient subjects (0.67±0.08 vs. 0.47±0.05, P<0.01) and inversely related to serum 25(OH)D level (r=-0.62; P<0.01), whereas vitamin D receptor and 1-α hydroxylase, the 25(OH)D to 1,25-dihydroxyvitamin D converting enzyme, were lower (P<0.05). Inadequate serum 25(OH)D is associated with vascular endothelial dysfunction among healthy middle-aged/older adults and this is mediated in part by NFκB-related inflammation. Reduced vitamin D receptor and 1-α hydroxylase may be molecular mechanisms linking vitamin D insufficiency to endothelial dysfunction.
aging; endothelium-dependent dilation; NFκB; interleukin-6; 1-α hydroxylase; VDR
Recent systematic reviews have cast doubt on the association between vitamin D and cardiovascular disease. No prior studies have investigated the association between 25-hydroxyvitamin D (25[OH]D), 1,25-dihydroxyvitamin D (1,25[OH]2D) and intact parathyroid hormone (iPTH) and cardiovascular disease mortality in a temperate climate.
1073 community-dwelling older adults were evaluated in 1997-99; serum levels of 25(OH)D (mean 42ng/mL), 1,25(OH)2D (median 29pg/mL) and iPTH (median 46pg/mL) were measured; mean estimated glomerular filtration rate (eGFR) was 74mL/min/1.73m2. Participants were followed up to 10.4 (mean 6.4) years with 111 cardiovascular disease deaths.
In unadjusted Cox proportional hazards models, higher levels of 1,25(OH)2D were protective against cardiovascular mortality, while higher levels of iPTH predicted increased risk of cardiovascular death. After adjusting for age alone or multiple covariates, there was no significant association between 25(OH)D, 1,25(OH)2D or iPTH and cardiovascular mortality; results did not differ by eGFR≥60mL/min/1.73m2 or <60mL/min/1.73m2.
In this prospective study of Caucasian, middle-income, community-dwelling older adults living in sunny southern California, serum levels of 25(OH)D, 1,25(OH)2D, or iPTH were not independently associated with cardiovascular mortality.
aging; cardiovascular mortality; chronic kidney disease; parathyroid hormone; vitamin D
Higher levels of serum phosphorus that remain within the reference range are associated with increased risk of cardiovascular disease (CVD). However, the mechanisms by which higher serum phosphorus concentrations may contribute to the development of CVD remain unclear. Cross-sectional association between serum phosphorus levels and arterial stiffness as estimated by an ankle brachial pressure index (ABPI) >1.3, was examined in 581 participants in the Third National Health and Nutrition Examination Survey. Logistic regression analysis was performed to evaluate whether higher serum phosphorus levels were associated with high ABPI, independently of several potential confounders. Among the 581 participants, 38% and 10% had a serum phosphorus levels >3.5 and >4.0 mg/dL, respectively. An ABPI >1.3 was present in 7.3% of participants. Higher quartiles of serum phosphorus levels were associated with a greater prevalence of high ABPI: 5.4%, 3.7%, 7.8%, and 12.9% for quartiles 1 (<3.1 mg/dL), 2 (3.1 to 3.4 mg/dL), 3 (3.4 to 3.7 mg/dL) and 4 (3.7 to 5.0 mg/dL), respectively. There was a strong, positive association between the highest quartile of serum phosphorus (3.7 to 5.0 mg/dL) and high ABPI when compared to the reference group (3.1 to 3.4 mg/dL) after adjustment for demographics, traditional CVD risk factors, kidney function, C-reactive protein, serum calcium, and 25-hydroxyvitamin D levels (adjusted odds ratio 4.78, 95% CI 1.73 to 13.2; p=0.003). In conclusion, serum phosphorus levels, even within the reference range, are independently associated with high ABPI, a marker of arterial stiffness, in the US adult population.
Serum phosphorus; arterial stiffness and ankle brachial pressure index
Latinos in the United States have a higher prevalence of type 2 diabetes than non-Latino whites, even after controlling for adiposity. Decreased adiponectin is associated with insulin resistance and predicts T2DM, and therefore may mediate this ethnic difference. We compared total and high-molecular-weight (HMW) adiponectin in Latino versus white individuals, identified factors associated with adiponectin in each ethnic group, and measured the contribution of adiponectin to ethnic differences in insulin resistance.
We utilized cross-sectional data from subjects in the Latinos Using Cardio Health Actions to reduce Risk study. Participants were Latino (n = 119) and non-Latino white (n = 60) men and women with hypertension and at least one other risk factor for CVD (age 61 ± 10 yrs, 49% with T2DM), seen at an integrated community health and hospital system in Denver, Colorado. Total and HMW adiponectin was measured by RIA and ELISA respectively. Fasting glucose and insulin were used to calculate the homeostasis model insulin resistance index (HOMA-IR). Variables independently associated with adiponectin levels were identified by linear regression analyses. Adiponectin's contribution to ethnic differences in insulin resistance was assessed in multivariate linear regression models of Latino ethnicity, with logHOMA-IR as a dependent variable, adjusting for possible confounders including age, gender, adiposity, and renal function.
Mean adiponectin levels were lower in Latino than white patients (beta estimates: -4.5 (-6.4, -2.5), p < 0.001 and -1.6 (-2.7, -0.5), p < 0.005 for total and HMW adiponectin), independent of age, gender, BMI/waist circumference, thiazolidinedione use, diabetes status, and renal function. An expected negative association between adiponectin and waist circumference was seen among women and non-Latino white men, but no relationship between these two variables was observed among Latino men. Ethnic differences in logHOMA-IR were no longer observed after controlling for adiponectin levels.
Among patients with CVD risk, total and HMW adiponectin is lower in Latinos, independent of adiposity and other known regulators of adiponectin. Ethnic differences in adiponectin regulation may exist and future research in this area is warranted. Adiponectin levels accounted for the observed variability in insulin resistance, suggesting a contribution of decreased adiponectin to insulin resistance in Latino populations.
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 m2); preclinical kidney disease (cystatin C level > 1.0 mg/l but eGFR > 60 mL/min/1.73 m2); and chronic kidney disease (CKD) (eGFR < 60 mL/min/1.73 m2). 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.
albuminuria; aging; cardiovascular diseases; kidney function; mortality
Recent studies have demonstrated an association between moderate kidney dysfunction and sudden cardiac death in people with cardiovascular disease.
Methods and Results
The study was a longitudinal analysis among 4465 participants from the Cardiovascular Health Study without prevalent cardiovascular disease at baseline. Cystatin C and creatinine were measured from baseline sera. SCD was defined as a sudden pulseless condition from a cardiac origin in a previously stable individual that occurred out of the hospital or in the emergency room. The association between cystatin C tertiles and SCD was determined with multivariate Cox proportional hazards. A similar analysis compared SCD incidence across creatinine-based eGFR tertiles. Over a median follow-up of 11.2 years, 91 adjudicated SCD events occurred. The annual incidence of SCD events increased across cystatin C tertiles: 10 events per 10,000 person years in tertile 1, 25 events per 10,000 person years in tertile 2 and 32 events per 10,000 person years in the highest cystatin C tertile. These associations persisted after multivariate adjustment: [HR = 2.72, 95% CI (1.44–5.16) in tertile 2 and HR = 2.67, 95% CI (1.33–5.35) in tertile 3]. After multivariate adjustment, the rate of SCD also increased in a linear distribution across creatinine-based eGFR tertiles: 15 events per 10,000 person years in tertile 1, 22 events per 10,000 person years in tertile 2 and 27 events per 10,000 person years in tertile 3. No significant associations, however, remained between creatinine-based eGFR and SCD after multivariable adjustment.
Impaired kidney function, as measured by cystatin C, has an independent association with SCD risk among elderly persons without clinical cardiovascular disease.
Cystatin C; kidney; sudden cardiac death; epidemiology
Chronic kidney disease (CKD) is associated with an increased risk for incident cardiovascular disease (CVD), but the role of statin for the primary prevention of acute cardiovascular events in CKD and the effect of statins on kidney function loss in persons without prevalent CVD have not been studied.
Post-hoc analysis of the Air Force/Texas Coronary Atherosclerosis Prevention Study.
Setting and Participants
Multicenter, randomized, double-blind, placebo-controlled trial of 5608 men and 997 women without CVD randomized to lovastatin or placebo.
Placebo or lovastatin 20 mg daily
Outcomes and Measurements
First major acute cardiovascular event in participants with mild CKD and kidney function loss among persons with or without CKD. Estimated glomerular filtration rate was calculated using the 4-variable Modification of Diet in Renal Disease Study equation.
At baseline, the mean estimated glomerular filtration rate among CKD participants (n=304) was 53.3 ± 6.0 mL/min/1.73m2. After an average follow-up of 5.3 ± 0.8 years, the incidence of a fatal and non-fatal cardiovascular disease event was lower in CKD participants receiving lovastatin than in those on placebo (adjusted relative risk (RR): 0.31, 95% CI 0.13–0.72; p=0.01). Tests for interaction suggested that the benefit of lovastatin was independent of the presence of CKD. Lovastatin did not reduce the annualized mean decline in estimated glomerular filtration rate (−1.3 ± 0.07 vs. −1.4 ± 0.07 mL/min/1.73m2/year, respectively, p=0.1), the frequency of ≥ 25% decrease in kidney function [adjusted RR: 1.10, 95% CI 0.96 to 1.28, p=0.2] or incident CKD (adjusted RR 1.04, 95% CI 0.86 to 1.27, p=0.6).
Unable to determine cause and duration of kidney disease and information regarding proteinuria was not available.
Lovastatin is effective for the primary prevention of CVD in CKD, but is not effective in decreasing kidney function loss in persons with no CVD.
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.
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 (eGFRcreat) and cystatin C (eGFRcys) 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 m2 per year, and cardiovascular and all-cause mortality were assessed over a mean of 9.9 years of follow-up.
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) eGFRcreat and eGFRcys were 79 (23) mL/min/1.73 m2 and 79 (19) mL/min/1.73 m2, respectively. Individuals with rapid decline measured by eGFRcreat (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 eGFRcys (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.
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.
Background. Little is known about the decline of kidney function in patients with normal kidney function at baseline. Our objectives were to (i) identify predictors of incident chronic kidney disease (CKD) and (ii) to estimate rate of decline in kidney function.
Methods. The study used a retrospective cohort of adult patients in a hypertension registry in an inner-city health care delivery system in Denver, Colorado. The primary outcome was development of incident CKD, and the secondary outcome was rate of change of estimated glomerular filtration rate (eGFR) over time.
Results. After a mean follow-up of 45 months, 429 (4.1%) of 10 420 patients with hypertension developed CKD. In multivariate models, factors that independently predicted incident CKD were baseline age [odds ratio (OR) 1.13 per 10 years, 95% confidence interval (CI), 1.03–1.24], baseline eGFR (OR 0.69 per 10 units, 95% CI 0.65–0.73), diabetes (OR 3.66, 95% CI 2.97–4.51) and vascular disease (OR 1.67, 95% CI 1.32–2.10). We found no independent association between age, gender or race/ethnicity and eGFR slope. In patients who did not have diabetes or vascular disease, eGFR declined at 1.5 mL/min/1.73 m2 per year. Diabetes at baseline was associated with an additional decline of 1.38 mL/min/1.73 m2.
Conclusions. Diabetes was the strongest predictor of both incident CKD as well as eGFR slope. Rates of incident CKD or in decline of kidney function did not differ by race or ethnicity in this cohort.
chronic kidney disease; hypertension; progression
Some experimental evidence suggests that uric acid impairs endothelial function. It is controversial if high uric acid levels and impaired endothelial function are related in healthy adults. In addition, the effect of uric acid on endothelial cells (ECs) of humans is unexplored.
Data of 107 healthy adult volunteers were analyzed. The association between serum uric acid and endothelial-dependant dilation (EDD) and endothelial-independent dilation (EID) was evaluated by linear regression models. We also examined the relations between uric acid and systemic and cellular markers of inflammation and oxidative stress in all or subsets of participants.
Uric acid levels and EDD were not related in unadjusted or adjusted models. There was a significant negative correlation between uric acid and EID in the pooled sample (r = −0.34, P = 0.005). This correlation remained significant after adjusting for demographics (P = 0.04) and was attenuated after adjusting for other cardiac risk factors (P = 0.12). Higher serum uric acid levels were found to correlate significantly with C-reactive protein (CRP) (r = 0.31, P = 0.002). Serum uric acid levels were not associated with brachial artery EC nuclear factor-κB (NF-κB) p65 or NADPH oxidase p47phox expression or with nitrotyrosine staining, but were inversely associated with EC manganese superoxide dismutase (MnSOD) expression (r = −0.5, P = 0.01, n = 25).
Elevated serum uric acid is not associated with endothelial dysfunction among healthy adults, but is inversely related to EID and EC MnSOD, and positively related to systemic inflammation. These findings may have implications for cardiovascular risk in healthy adults.
blood pressure; endothelium; hypertension; inflammation; uric acid