Urine Albumin/Creatinine Ratio and Microvascular Disease in Elderly Hypertensive Patients without Comorbidities.

OBJECTIVES: A high urine albumin/creatinine ratio (UACR) is associated with microvascular disease in hypertensive patients. However, hypertensive patients frequently have other comorbidities. Thus, it is difficult to distinguish the role of UACR from that of comorbidities in microvascular disease. The aim of this study was to evaluate the association between UACR and microvascular disease in elderly hypertension patients without comorbidities. METHODS: A cross-sectional cohort study of 2252 essential hypertension patients aged 65-94 years without comorbidities between January 1, 2016, and December 31, 2017, was conducted. Microvascular disease was evaluated by hypertension retinopathy (HR). Multivariable adjusted odds of HR by UACR quartiles were determined using logistic regression. RESULTS: The HR prevalence was 22.1% (n = 472) among the cohort study and was significantly different among UACR quartiles (19.7%, 20.3%, 22.0%, and 26.4% in quartiles 1, 2, 3, and 4, respectively, P = 0.036). After adjustment for covariates, higher UACR (odds ratio (OR) = 1.42, 95% confidence interval (CI) 1.05-1.92, quartile 4 versus 1) were significantly associated with HR. Among male patients, higher UACR (OR = 1.65, 95% CI 1.07-2.55, quartile 4 versus 1) were significantly associated with HR after adjustment for covariates. Among female patients, however, 64% and 40% increased odds of HR were noted in the highest and lowest UACR (quartiles 4 and 1, respectively) compared to UACR quartile 2. CONCLUSIONS: Microvascular disease was associated with higher UACR in elderly male essential hypertension patients without comorbidities but was associated with lower and higher UACR in female patients without comorbidities.

Exaggerated blood pressure response to exercise is associated with subclinical vascular impairment in healthy normotensive individuals.

BACKGROUND: This study was designed to evaluate the possible association between an exaggerated blood pressure (BP) response to exercise and subclinical vascular impairment in normotensive individuals. METHODS: The study participants consisted of 92 untreated normotensive men (aged 42 ± 9 years) without a history of cardiovascular disease or stroke. A graded exercise test was conducted using a bicycle ergometer, and the mean arterial pressure (MAP) during submaximal exercise was evaluated. The brachial-ankle pulse wave velocity (baPWV) was measured as an index of arterial stiffness. The second peak of radial systolic BP (SBP2) was used as an estimate of central BP. The albumin-to-creatinine ratio (ACR) values were determined as the mean of two nonconsecutive spot urine specimens. RESULTS: Compared with individuals with a normal response (MAP z-score < +1.0, n = 60), those with an exaggerated BP response to exercise (MAP z-score ≥ +1.0, n = 32) exhibited significantly higher baPWV (1412 ± 158 vs. 1250 ± 140 cm/s), radial SBP2 (122 ± 11 vs. 106 ± 13 mmHg), and greater log-ACR (0.93 ± 0.30 vs. 0.59 ± 0.23 mg/gCre). Multiple regression analysis revealed that an exaggerated BP response to exercise was significantly associated with baPWV (ß = 0.198, P= .043), radial SBP2 (ß = 0.156, P = .049), and log-ACR (ß = 0.276, P = .006) independent of potential confounding factors. CONCLUSIONS: These results suggest that subclinical vascular impairment is associated with an exaggerated increase in BP during exercise even in the absence of clinical hypertension.

Arteriolar Hyalinosis Predicts Increase in Albuminuria and GFR Decline in Normo- and Microalbuminuric Japanese Patients With Type 2 Diabetes.

OBJECTIVE: This study investigated the association between renal histology, as assessed by morphometric analysis using light (LM) and electron (EM) microscopy, and changes in urinary albumin excretion (UAE) and glomerular filtration rate (GFR) in Japanese people with type 2 diabetes in the early stages of diabetic nephropathy. RESEARCH DESIGN AND METHODS: We performed percutaneous renal biopsies in 29 patients with type 2 diabetes (22 men, mean ± SD age 49 ± 10 years and GFR 119 ± 27 mL/min/1.73 m2, with 15 normoalbuminuric [UAE <20 µg/min] and 14 microalbuminuric [UAE 20-200 µg/min]) to clarify which histological factors were associated with changes in UAE and GFR during 8.0 ± 3.5 years' follow-up. Glomerular structural changes including mesangial volume fraction [Vv(Mes/glom)] were estimated using EM, whereas the index of arteriolar hyalinosis (IAH) score was assessed by LM. Patients underwent annual measurement of GFR using iohexol injection with simultaneous urine collections for UAE. RESULTS: Vv(Mes/glom) was negatively correlated with baseline and follow-up GFR but not with UAE. The IAH score was positively correlated with UAE and negatively correlated with GFR at follow-up, but it was not correlated with either UAE or GFR at baseline. GFR at follow-up was significantly decreased from baseline in patients with IAH scores ≥2.0 and significantly lower than in patients with IAH scores <2.0. Patients with IAH scores <2.0 showed no significant change in GFR during follow-up. CONCLUSIONS: Arteriolar hyalinosis is an additional histological predictor for albuminuria increase and GFR decline in normo- and microalbuminuric Japanese people with type 2 diabetes.

The tryptophan/kynurenine pathway, systemic inflammation, and long-term outcome after kidney transplantation.

Tryptophan is metabolized along the kynurenine pathway, initially to kynurenine, and subsequently to cytotoxic 3-hydroxykynurenine. There is increasing interest in this pathway because of its proinflammatory nature, and drugs interfering in it have received increasing attention. We aimed to investigate whether serum and urinary parameters of the tryptophan/kynurenine pathway, and particularly cytotoxic 3-hydroxykynurenine, are associated with systemic inflammation and long-term outcome in renal transplant recipients (RTR). Data were collected in outpatient RTR with a functioning graft for >1 yr. Tryptophan, kynurenine, and 3-hydroxykynurenine in serum and urine were measured using LC-MS/MS. A total of 561 RTR (age: 51 ± 12 yr; 56% male) were included at a median of 6.0 (2.6-11.6) yr posttransplantation. Baseline median serum tryptophan was 40.0 (34.5-46.0) µmol/l, serum kynurenine was 1.8 (1.4-2.2) µmol/l, and serum 3-hydroxykynurenine was 42.2 (31.0-61.7) nmol/l. Serum kynurenine and 3-hydroxykynurenine were strongly associated with parameters of systemic inflammation. During follow-up for 7.0 (6.2-7.5) yr, 51 RTR (9%) developed graft failure and 120 RTR (21%) died. Both serum kynurenine and 3-hydroxykynurenine were independently associated with graft failure [HR 1.72 (1.23-2.41), P = 0.002; and HR 2.03 (1.42-2.90), P < 0.001]. Serum 3-hydroxykynurenine was also independently associated with mortality [HR 1.37 (1.08-1.73), P = 0.01], whereas serum kynurenine was not. Urinary tryptophan/kynurenine pathway parameters were not associated with outcome. Of tryptophan metabolites, serum 3-hydroxykynurenine is cross-sectionally most strongly and consistently associated with systemic inflammation and prospectively with adverse long-term outcome after kidney transplantation. Serum 3-hydroxykynurenine may be an interesting biomarker and target for the evaluation of drugs interfering in the tryptophan/kynurenine pathway.

Urine Arsenic and Arsenic Metabolites in U.S. Adults and Biomarkers of Inflammation, Oxidative Stress, and Endothelial Dysfunction: A Cross-Sectional Study.

BACKGROUND: Arsenic (As) exposure has been associated with increased risk for cardiovascular disease (CVD) and with biomarkers of potential CVD risk and inflammatory processes. However, few studies have evaluated the effects of As on such biomarkers in U.S. populations, which are typically exposed to low to moderate As concentrations. OBJECTIVES: We investigated associations between As exposures and biomarkers relevant to inflammation, oxidative stress, and CVD risk in a subset of participants from the New Hampshire Health Study, a population with low to moderate As exposure (n=418). METHODS: Associations between toenail As, total urine As (uAs), and %uAs metabolites [monomethyl (%uMMAV), dimethyl (%uDMAV), and inorganic (%iAs) species] and plasma biomarkers, including soluble plasma vascular and cellular adhesion molecules (VCAM-1 and ICAM-1, respectively), matrix metalloproteinase-9 (MMP-9), tumor necrosis factor-α, plasminogen activator inhibitor-1 (PAI-1), and urinary oxidative stress marker 15-F2t-isoprostane (15-F2t-IsoP), were evaluated using linear regression models. RESULTS: Covariate-adjusted estimates of associations with a doubling of urinary As suggested an 8.8% increase in 15-F2t-IsoP (95% CI: 3.2, 14.7), and a doubling of toenail As was associated with a 1.7% increase in VCAM-1 (95% CI: 0.2, 3.2). Additionally, a 5% increase in %uMMA was associated with a 7.9% increase in 15-F2t-IsoP (95% CI: 2.1, 14.1), and a 5% increase in %uDMA was associated with a 2.98% decrease in 15-F2t-IsoP [(95% CI: -6.1, 0.21); p=0.07]. However, in contrast with expectations, a doubling of toenail As was associated with a 2.3% decrease (95% CI: -4.3, -0.3) in MMP-9, and a 5% increase in %uMMA was associated with a 7.7% decrease (95% CI: -12.6, -2.5) in PAI-1. CONCLUSION: In a cross-sectional study of U.S. adults, we observed some positive associations of uAs and toenail As concentrations with biomarkers potentially relevant to CVD pathogenesis and inflammation, and evidence of a higher capacity to metabolize inorganic As was negatively associated with a marker of oxidative stress. https://doi.org/10.1289/EHP2062.

Effects of ambient coarse, fine, and ultrafine particles and their biological constituents on systemic biomarkers: a controlled human exposure study.

BACKGROUND: Ambient coarse, fine, and ultrafine particles have been associated with mortality and morbidity. Few studies have compared how various particle size fractions affect systemic biomarkers. OBJECTIVES: We examined changes of blood and urinary biomarkers following exposures to three particle sizes. METHODS: Fifty healthy nonsmoking volunteers, mean age of 28 years, were exposed to coarse (2.5-10 µm; mean, 213 µg/m3) and fine (0.15-2.5 µm; mean, 238 µg/m3) concentrated ambient particles (CAPs), and filtered ambient and/or medical air. Twenty-five participants were exposed to ultrafine CAP (< 0.3 µm; mean, 136 µg/m3) and filtered medical air. Exposures lasted 130 min, separated by ≥ 2 weeks. Blood/urine samples were collected preexposure and 1 hr and 21 hr postexposure to determine blood interleukin-6 and C-reactive protein (inflammation), endothelin-1 and vascular endothelial growth factor (VEGF; vascular mediators), and malondialdehyde (lipid peroxidation); as well as urinary VEGF, 8-hydroxy-deoxy-guanosine (DNA oxidation), and malondialdehyde. Mixed-model regressions assessed pre- and postexposure differences. RESULTS: One hour postexposure, for every 100-µg/m3 increase, coarse CAP was associated with increased blood VEGF (2.41 pg/mL; 95% CI: 0.41, 4.40) in models adjusted for O3, fine CAP with increased urinary malondialdehyde in single- (0.31 nmol/mg creatinine; 95% CI: 0.02, 0.60) and two-pollutant models, and ultrafine CAP with increased urinary 8-hydroxydeoxyguanosine in single- (0.69 ng/mg creatinine; 95% CI: 0.09, 1.29) and two-pollutant models, lasting < 21 hr. Endotoxin was significantly associated with biomarker changes similar to those found with CAPs. CONCLUSIONS: Ambient particles with various sizes/constituents may influence systemic biomarkers differently. Endotoxin in ambient particles may contribute to vascular mediator changes and oxidative stress.

Urinary adiponectin concentration is positively associated with micro- and macro-vascular complications.

BACKGROUND: A relationship between plasma adiponectin level and a number of metabolic conditions, including insulin resistance, obesity, and type 2 diabetes, has been reported. This study aimed to assess whether urinary adiponectin concentration is correlated with vascular complications. METHODS: The study comprised 708 subjects who enrolled in the Seoul Metro City Diabetes Prevention Program and were carefully monitored from September 2008 to December 2008. Levels of urinary adiponectin were measured using an enzyme linked immunosorbent assay (ELISA) kit (AdipoGen, Korea). Urinary albumin excretion was assessed by the ratio of urinary albumin to creatinine (A/C ratio). Participants were divided into three groups based on tertiles of urinary adiponectin concentration, and we investigated whether urinary adiponectin levels are associated with microalbuminuria and pulse wave velocity. RESULTS: Urinary adiponectin concentrations were significantly higher in subjects with microalbuminuria than subjects with normoalbuminuria (P < 0.001). Urinary adiponectin concentration was positively correlated with age, fasting plasma glucose level, HbA1C level, triglyceride level, HOMA-IR, systolic/diastolic blood pressure, and urinary A/C ratio (all P < 0.05). Subjects in the highest tertile of urinary adiponectin concentration had an increased likelihood of microalbuminuria than those in the lowest tertile (Odds ratio (OR), 6.437; 95% confidence interval (CI), 4.202 to 9.862; P < 0.001). After adjusting for age, sex, and estimated creatinine clearance rate (eCcr), the OR remained significant (OR, 5.607; 95% CI, 3.562 to 8.828; P < 0.001). Backward multiple linear regression analysis revealed urinary adiponectin concentration to be a significant determinant of mean brachial-ankle pulse wave velocity (baPWV). CONCLUSIONS: An increased urinary adiponectin concentration is significantly associated with microalbuminuria and increased mean baPWV. These results suggest that urinary adiponectin may play an important role as a biomarker for vascular dysfunction.

Frequency and factors associated with increased small intestinal permeability in patients with portal hypertension.

AIM: Cirrhosis with portal hypertension (PHT) may be associated with increased small intestinal permeability (SIP), predisposing to malnutrition and bacterial translocation causing septicaemia, endotoxaemia and spontaneous bacterial peritonitis. However, data on SIP in extrahepatic portal venous obstruction (EHPVO), in which PHT occurs without hepatic dysfunction, are scanty. Such studies would help to know the effect of PHT on SIP independent of hepatic dysfunction; hence, we undertook this study. METHODS: A total of 96 patients with PHT (cirrhosis 71, EHPVO 25) underwent evaluation of SIP using urinary lactulose/mannitol excretion ratio over 6 hours after oral administration of 15 mL (10 g) lactulose and 5 g mannitol using 1H-NMR spectroscopy by a method described by us previously. RESULTS: Gender of patients with EHPVO and cirrhosis was comparable but patients with EHPVO were younger in age. The causes of cirrhosis were cryptogenic (n = 22), alcohol (n = 20), post-viral (n = 21) and others (n = 8). Twenty-seven (38%) patients with cirrhosis had ascites. Abnormal SIP was detected in 47 (49%) patients (40/71,56% with cirrhosis vs. 7/25, 28% with EHPVO, p = 0.01). Patients with cirrhosis had a higher urinary lactulose/mannitol excretion ratio than those with EHPVO (0.09, range 0-0.87 mmol vs. 0.05, 0-0.19 mmol; p = 0.008). Patients with abnormal SIP had a higher Child score, and more often had cirrhosis than EHPVO, ascites and deranged liver function. On multivariate analysis, presence of cirrhosis, ascites, high serum bilirubin level and prothrombin time were associated with abnormal SIP. CONCLUSIONS: Cirrhosis was associated with abnormal SIP, which was related to liver dysfunction. However, SIP was normal in patients with EHPVO.

Free hemoglobin induction of pulmonary vascular disease: evidence for an inflammatory mechanism.

Cell-free hemoglobin (Hb) exposure may be a pathogenic mediator in the development of pulmonary arterial hypertension (PAH), and when combined with chronic hypoxia the potential for exacerbation of PAH and vascular remodeling is likely more pronounced. We hypothesized that Hb may contribute to hypoxia-driven PAH collectively as a prooxidant, inflammatory, and nitric oxide (NO) scavenger. Using programmable micropump technology, we exposed male Sprague-Dawley rats housed under room air or hypoxia to 12 or 30 mg per day Hb for 3, 5, and 7 wk. Blood pressure, cardiac output, right ventricular hypertrophy, and indexes of pulmonary vascular remodeling were evaluated. Additionally, markers of oxidative stress, NO bioavailability and inflammation were determined. Hb increased pulmonary arterial (PA) pressure, pulmonary vessel wall stiffening, and right heart hypertrophy with temporal and dose dependence in both room air and hypoxic cohorts. Hb induced a modest increase in plasma oxidative stress markers (malondialdehyde and 4-hydroxynonenal), no change in NO bioavailability, and increased lung ICAM protein expression. Treatment with the antioxidant Tempol attenuated Hb-induced pulmonary arterial wall thickening, but not PA pressures or ICAM expression. Chronic exposure to low plasma Hb concentrations (range = 3-10 µM) lasting up to 7 wk in rodents induces pulmonary vascular disease via inflammation and to a lesser extent by Hb-mediated oxidation. Tempol demonstrated a modest effect on the attenuation of Hb-induced pulmonary vascular disease. NO bioavailability was found to be of minimal importance in this model.

The contrasting relationships between betaine and homocysteine in two clinical cohorts are associated with plasma lipids and drug treatments.

BACKGROUND: Urinary betaine excretion positively correlated with plasma homocysteine in outpatients attending a lipid disorders clinic (lipid clinic study). We aimed to confirm this in subjects with established vascular disease. METHODS: The correlation between betaine excretion and homocysteine was compared in samples collected from subjects 4 months after hospitalization for an acute coronary episode (ACS study, 415 urine samples) and from 158 sequential patients visiting a lipid disorders clinic. PRINCIPAL FINDINGS: In contrast to the lipid clinic study, betaine excretion and plasma homocysteine did not correlate in the total ACS cohort. Differences between the patient groups included age, non-HDL cholesterol and medication. In ACS subjects with below median betaine excretion, excretion correlated (using log transformed data) negatively with plasma homocysteine (r = -0.17, p = 0.019, n = 199), with no correlation in the corresponding subset of the lipid clinic subjects. In ACS subjects with above median betaine excretion a positive trend (r = +0.10) between betaine excretion and homocysteine was not significant; the corresponding correlation in lipid clinic subjects was r = +0.42 (p = 0.0001). In ACS subjects, correlations were stronger when plasma non-HDL cholesterol and betaine excretion were above the median, r = +0.20 (p = 0.045); in subjects above median non-HDL cholesterol and below median betaine excretion, r = -0.26 (p = 0.012). ACS subjects taking diuretics or proton pump inhibitors had stronger correlations, negative with lower betaine excretion and positive with higher betaine excretion. CONCLUSIONS: Betaine excretion correlates with homocysteine in subjects with elevated blood lipids.

Changes in albuminuria predict mortality and morbidity in patients with vascular disease.

The degree of albuminuria predicts cardiovascular and renal outcomes, but it is not known whether changes in albuminuria also predict similar outcomes. In two multicenter, multinational, prospective observational studies, a central laboratory measured albuminuria in 23,480 patients with vascular disease or high-risk diabetes. We quantified the association between a greater than or equal to twofold change in albuminuria in spot urine from baseline to 2 years and the incidence of cardiovascular and renal outcomes and all-cause mortality during the subsequent 32 months. A greater than or equal to twofold increase in albuminuria from baseline to 2 years, observed in 28%, associated with nearly 50% higher mortality (HR 1.48; 95% CI 1.32 to 1.66), and a greater than or equal to twofold decrease in albuminuria, observed in 21%, associated with 15% lower mortality (HR 0.85; 95% CI 0.74 to 0.98) compared with those with lesser changes in albuminuria, after adjustment for baseline albuminuria, BP, and other potential confounders. Increases in albuminuria also significantly associated with cardiovascular death, composite cardiovascular outcomes (cardiovascular death, myocardial infarction, stroke, and hospitalization for heart failure), and renal outcomes including dialysis or doubling of serum creatinine (adjusted HR 1.40; 95% CI 1.11 to 1.78). In conclusion, in patients with vascular disease, changes in albuminuria predict mortality and cardiovascular and renal outcomes, independent of baseline albuminuria. This suggests that monitoring albuminuria is a useful strategy to help predict cardiovascular risk.

Urinary cysteinyl leukotriene E(4) is associated with increased risk for pain and acute chest syndrome in adults with sickle cell disease.

Leukotriene E(4) (LTE(4)) levels are associated with rate of pain episodes in children with sickle cell disease (SCD). Because complications of SCD manifest differently in adults than children, we examined a cohort of adults with SCD to determine the relationship between baseline LTE(4) and SCD-related morbidity. Baseline LTE(4) levels were associated with increased rates of pain and acute chest syndrome (ACS) episodes, when those with LTE(4) values in the highest tertile were compared with those in the lowest tertile (pain: risk ratio 7.1, 95% CI 1.8-27.5, P = 0.005; ACS: risk ratio 12.2, 95% CI 2.1-69.8, P = 0.005).

Changes in albumin excretion in the diabetes prevention program.

OBJECTIVE: Increased urinary albumin excretion rates have been linked to nephropathy and macrovascular disease. We here describe the baseline prevalence and effect of Diabetes Prevention Program (DPP) interventions on the development and reversal of elevated albumin excretion. RESEARCH DESIGN AND METHODS: Urine albumin-to-creatinine ratios (ACRs) were calculated from untimed urine collections. Analyses compared participants by treatment group, diabetes and hypertension status, and use of ACE inhibitors or angiotensin II receptor blockers (ARBs). RESULTS: Elevated ACR levels (>or=30 mg/g creatinine) were present at baseline in 198 (6.2%) of 3,188 participants: placebo 5.3%, metformin 6.5%, and intensive lifestyle (ILS) 6.8%. Of the 2,802 with ACR measurements at baseline and at the end of the study, the percentage with elevated levels declined (incident and regression) from 6.2 to 6.1%, with no significant differences between the groups even with adjustment for ACE inhibitor and ARB use. The odds of developing an elevated ACR were 59% higher for a participant who developed diabetes compared with one who did not. CONCLUSIONS: At entry into the DPP, an elevated ACR was present in 6.2%. Despite the marked decrease in progression to diabetes and the improvement in insulin resistance and other cardiovascular risk markers in the ILS and metformin groups, there was no improvement in ACR, on average, in those two groups. However, the frequency of an elevated ACR was higher in participants who developed diabetes. An increased ACR may have multiple causes, thus obscuring the improvements that might have been expected with the reduction in insulin resistance seen in the DPP.

Increased expression of urinary matrix metalloproteinases parallels the extent and activity of vascular anomalies.

OBJECTIVE: Matrix metalloproteinases (MMPs) and the angiogenic proteins basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) have been implicated in mechanisms of human cancer and metastasis. Assays were conducted on the urine of patients with vascular anomalies (tumors and malformations), relatively common and occasionally life-threatening disorders for which few therapies exist. We sought to determine whether these angiogenesis modulators are present in the urine and whether their expression is associated with the extent and clinical course of the vascular lesion. METHODS: A total of 217 patients with vascular anomalies and 74 age-matched control subjects participated. Urinary MMP expression was determined by substrate gel electrophoresis. Urinary bFGF and VEGF levels were measured by enzyme-linked immunosorbent assay. Each patient was assigned to 1 of 2 categories (tumor or malformation) and 1 of 9 specific groups. Extent of the vascular lesion and activity were scored by a blinded clinician. RESULTS: Urinary high molecular weight (hMW) MMPs and bFGF were significantly increased in patients with vascular tumors (53%) and vascular malformations (41%), compared with control subjects (22%). These percentages increased as a function of extent of the lesion and disease activity. hMW MMPs were increased in 4 groups: infantile hemangioma, other vascular neoplasms, lymphatic malformation and capillary-lymphaticovenous malformations, and extensive and unremitting capillary malformation and arteriovenous malformation. No significant differences among the groups were detected for low molecular weight MMPs or VEGF. CONCLUSIONS: Expression patterns of hMW MMPs and bFGF in the urine of patients with tumors and malformations are consistent with their different clinical behavior. These data represent the first evidence that MMPs are elevated in the urine of children with vascular anomalies. These data also suggest that the increased expression of urinary MMPs parallels the extent and activity of vascular anomalies in children. In addition to tumors, vascular malformations are angiogenesis dependent, suggesting that progression of a vascular malformation might be suppressed by angiogenic inhibitors, which would target bFGF and MMPs.

C-reactive protein and microalbuminuria differ in their associations with various domains of vascular disease.

C-reactive protein (CRP) and microalbuminuria (MA) have been identified as risk markers for cardiovascular disease (CVD). We questioned whether CRP and MA are similar markers of vascular disease in different regions of the vascular tree like the heart, kidneys and extremities or if they differ in their relationships with these vascular beds. Baseline levels of CRP and urinary albumin were measured in 6669 non-diabetic participants in the Prevention of Renal and Vascular ENdstage Disease (PREVEND) study, a Dutch cohort derived from the general population. We defined three domains of vascular disease; coronary heart disease (myocardial infarction or infarct pattern on the ECG), renal insufficiency (creatinine clearance <60 ml min(-1)) and peripheral artery disease (ankle brachial index <0.9 or lower limb revascularisation). The prevalence of an elevated CRP (27.7 vs. 17.9%) and MA (17.5 vs. 10.4%) were increased in subjects with vascular disease as compared with subjects without CVD. The prevalence of an elevated CRP was equal in subjects with either coronary heart disease, renal insufficiency or peripheral artery disease (28.4 vs. 29.5 vs. 26.0%, NS), whereas MA was most prevalent in subjects with coronary heart disease (22.5 vs. 12.8 vs. 14.9%, P<0.05). Using multivariate analyses, CRP was independently associated with all three domains of vascular disease, whereas MA was independently associated with coronary heart disease only. In addition, we found synergistic contributions of an elevated CRP and older age to the risk of vascular disease in all three domains. Thus, CRP and MA are risk markers for vascular disease, each showing a different risk profiling for different vascular beds.

Aspirin dosage and thromboxane synthesis in patients with vascular disease.

STUDY OBJECTIVE: To determine whether urinary 11-dehydrothromboxane B2 (d-TXB2) is a marker of aspirin resistance and define the relationship between aspirin dosage and concentrations of this thromboxane metabolite. DESIGN: Randomized, crossover study. SETTING: Two outpatient clinical centers. PATIENTS: Forty-eight patients (mean age 70 yrs) with vascular disease (52% clinical coronary artery disease, 29% cerebrovascular disease, 46% atrial fibrillation). INTERVENTION: Levels of serum thromboxane B2 and d-TXB2 were measured after patients were treated initially with aspirin 325 mg/day for 4 weeks, then again after random assignment to receive aspirin 81, 325, or 1300 mg/day for 4 weeks, and then again after resumption of 325 mg/day for 4 weeks. MEASUREMENTS AND MAIN RESULTS: During treatment with aspirin 325 mg/day, the mean +/- SD serum thromboxane B2 level was 0.9 +/- 1.2 ng/ml and median (interquartile range) was 0.4 (0.2-0.9) ng/ml. Mean urinary d-TXB2 was 16 +/- 7.9 ng/mmol creatinine, with a median of 15 (9.9-23) ng/mmol creatinine with aspirin 325 mg/day. After 4 weeks of aspirin 81 mg/day, levels of serum thromboxane B2 (p<0.01) and urinary d-TXB2 (p=0.04) were both significantly higher compared with aspirin 325 mg/day; for urinary d-TXB2, the median increase was 3.0 ng/mmol creatinine. After 4 weeks of treatment with aspirin 1300 mg/day, levels of serum thromboxane B2 (p<0.01) and urinary d-TXB2 (p<0.01) were both significantly lower compared with aspirin 325 mg/day; the median decrease in urinary d-TXB2 was 4.4 ng/mmol creatinine. CONCLUSION: Different aspirin dosages significantly affect serum and urinary markers of thromboxane synthesis.

Diagnosis of nut-cracker phenomenon using renal Doppler ultrasound in orthostatic proteinuria.

BACKGROUND: We evaluated the efficacy of non-invasive renal Doppler ultrasound (US) to detect the nut-cracker phenomenon (NCP) and we studied the prevalence of NCP in children with orthostatic proteinuria. METHODS: Among a total 66 cases of orthostatic proteinuria, 39 cases of NCP were found, with 27 cases being detected in a normal control group. Using Doppler US, the anteroposterior (AP) diameter and peak velocity (PV) of the left renal vein (LRV) were measured at the hilar and aortomesenteric portion. We calculated the ratio of AP and PV diameters between the two portions. The parameters were analysed using Student's t-test. RESULTS: The AP diameters and the ratio in the hilar and narrow portions were all significantly different between the two groups (P<0.01). The PV in the narrow portion and the ratio of PV were significantly different (P<0.01), but the PV in the hilar portion was not statistically different between the two groups (P>0.05). If the diagnostic criteria for NCP was that the ratio of PV was more than 5, then 22 subjects (56.4%) in the orthostatic proteinuria group and none in the control group could be diagnosed as NCP. If, however, the cut-off values for the diagnosis of NCP were set at the mean+/-2 SD of the ratio (PV ratio 3.98 and size ratio 4.16), then the orthostatic proteinuria group showed abnormal AP diameter in 25 (64.1%), peak velocity in 28 (71.8%), and both in 21 patients (53.8%), and the control group showed an abnormal AP diameter in one subject (3.7%). CONCLUSIONS: NCP may be one of the leading causes of orthostatic proteinuria, and non-invasive renal Doppler US may be a useful diagnostic tool in the screening of NCP. In the future, the diagnostic criteria of NCP must be redefined in children.