Prognostic significance of urinary protein and urinary ketone bodies in acute ischemic stroke.

BACKGROUND AND AIMS: Prior studies have shown an association between positive urinary protein and an elevated risk of long-term mortality in patients with acute ischemic stroke (AIS); however, data on the short-term prognostic significance of urinary protein and urinary ketone bodies in patients with AIS is sparse. METHODS AND RESULTS: A total of 2842 AIS patients enrolled from December 2013 to May 2014 across 22 hospitals in Suzhou city were included. Patients were divided into urinary protein positive and negative, urinary ketone bodies positive and negative by urine dipstick. Cox and logistic regression models were used to estimate the effect of urinary protein and urinary ketone bodies on all cause in-hospital mortality and poor outcome upon discharge (modified Rankin Scale score ≥3) in AIS patients. Patients with positive urinary protein was associated with a 2.74-fold and 1.62-fold increase in the risk of in-hospital mortality (adjusted HR 2.74; 95% CI, 1.54-4.89; P-value = 0.001) and poor outcome upon discharge (aOR, 1.62; 95% CI 1.26-2.08; P-value <0.001) in comparison to negative urinary protein after adjusting for potential covariates. Moreover, Patients with positive urinary ketone bodies was associated with 2.11-fold in the risk of poor outcome upon discharge (aOR 2.11; 95% CI 1.52-2.94; P-value <0.001) but not in-hospital mortality (P-value = 0.066) after adjusting for potential covariates. CONCLUSIONS: Urinary protein at admission was independently associated with in-hospital mortality and poor functional outcome at hospital discharge in acute stroke patients and urinary ketone bodies also associated with poor functional outcome at hospital discharge.

Urinary albumin-to-creatinine ratio is associated with white matter lesions severity in first-ever stroke patients.

BACKGROUND: The presence of white matter lesions (WML) is an indicator of small vessel disease; however, the underlying pathological mechanisms are still unclear. We aimed to investigate the association of estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) with WML severity in first-ever stroke patients. METHODS: We retrospectively enrolled 284 consecutive patients (177 male; median age 72years) admitted to our stroke center between May 2010 and January 2012. eGFR and UACR measurements were performed on admission. WML severity was assessed using the Fazekas classification. Severe WML was defined as a Fazekas grade of 2 or higher. The impact of eGFR and UACR on severe WML was evaluated using multiple logistic regression analysis. RESULTS: Age (P<0.0001), sex (P=0.0094), eGFR (P=0.0173), UACR (P=0.0001), hypertension (P=0.0436), and brain natriuretic peptide (P=0.0354) were significantly associated with severe WML. On multivariable logistic regression analysis, high UACR (≥39.6mg/g creatinine, P=0.039), but not low eGFR (≤74ml/min/1.73m2, P=0.3672), was independently associated with severe WML. Comparisons between the UACR levels showed that severe WML was more frequent in the UACR ≥300mg/g creatinine group than in the UACR <30.0mg/g creatinine group after multivariate adjustment (OR, 2.25; 95% CI, 1.04-5.00; P=0.039). However, there was no significant association between eGFR and severe WML. CONCLUSIONS: Our data suggest that high UACR, but not eGFR, is independently associated with severe WML.

Diagnostic Yield of Universal Urine Toxicology Screening in an Unselected Cohort of Stroke Patients.

BACKGROUND: Illicit drug use increases the risk of cerebrovascular events by a variety of mechanisms. A recent report suggested that universal urine toxicology (UTox) screening of patients with stroke may be warranted. We aimed to evaluate the diagnostic yield of urine drug screening among unselected patients admitted with acute stroke or transient ischemic attack (TIA). METHODS: Using a single-center prospective study design, we evaluated consecutive patients with acute ischemic stroke, TIA, intracerebral hemorrhage (ICH), or subarachnoid hemorrhage (SAH) over one year. Urine samples were collected within 48 hours of admission and analyzed for common classes of abused drugs. Prevalence of positive UTox screening was determined. We evaluated whether baseline demographics and clinical factors were associated with UTox results. RESULTS: Of 483 eligible patients (acute ischemic stroke 66.4%; TIA 18.8%; ICH 7.7%; SAH 7.0%), 414 (85.7%) completed UTox screening. The mean (standard deviation) age was 65.1 (15.6) years, 52.7% were male, and 64.3% were Caucasian. Twenty-two (4.6%) patients had positive screening-cannabinoids were detected in 13 cases (3.1%), cocaine in 5 cases (1.2%), amphetamines in 1 case, and phencyclidine in 1 case. The highest yield (14.1%) was observed in patients < 60 years old with history of tobacco use while it was < 5% in the remaining subgroups (p<0.01). CONCLUSIONS: Consistent with current guidelines, a selective approach to UTox screening should be pursued in acute stroke evaluation. The highest diagnostic yield is likely to be for cannabinoids and cocaine testing in younger patients with a history of concurrent tobacco use.

Cannabis, ischemic stroke, and transient ischemic attack: a case-control study.

BACKGROUND AND PURPOSE: There is a temporal relationship between cannabis use and stroke in case series and population-based studies. METHODS: Consecutive stroke patients, aged 18 to 55 years, who had urine screens for cannabis were compared with a cohort of control patients admitted to hospital without cardiovascular or neurological diagnoses. RESULTS: One hundred sixty of 218 (73%) ischemic stroke/transient ischemic attack patients had urine drug screens (100 men; mean [SD] age, 44.8 [8.7] years). Twenty-five (15.6%) patients had positive cannabis drug screens. These patients were more likely to be men (84% versus 59%; χ2: P=0.016) and tobacco smokers (88% versus 28%; χ2: P<0.001). Control urine samples were obtained from 160 patients matched for age, sex, and ethnicity. Thirteen (8.1%) control participants tested positive for cannabis. In a logistic regression analysis adjusted for age, sex, and ethnicity, cannabis use was associated with increased risk of ischemic stroke/transient ischemic attack (odds ratio, 2.30; 95% confidence interval, 1.08-5.08). However after adjusting for tobacco use, an association independent of tobacco could not be confirmed (odds ratio, 1.59; 95% confidence interval, 0.71-3.70). CONCLUSIONS: This study provides evidence of an association between a cannabis lifestyle that includes tobacco and ischemic stroke. Further research is required to clarify whether there is an association between cannabis and stroke independent of tobacco. CLINICAL TRIAL REGISTRATION URL: http://www.anzctr.org.au. Unique identifier: ACTRN12610000198022.

Urine toxicology screening in an urban stroke and TIA population.

OBJECTIVE: We sought to determine the rate of urine toxicology screening, differences in testing, and outcomes among patients with stroke and TIA presenting to a tertiary care emergency department. METHODS: In this retrospective cohort study, patients admitted with stroke or TIA to a single tertiary care stroke center between June 2005 and January 2007 were identified through a stroke database. Factors that predicted urine toxicology screening of patients and a positive test, and discharge outcomes of patients based on toxicology result were analyzed. Stroke severity, treatment with tissue plasminogen activator, discharge status, and stroke etiology were compared between toxicology positive and negative patients. RESULTS: A total of 1,024 patients were identified: 704 with ischemic stroke, 133 with intracerebral hemorrhage, and 205 with TIA. Urine toxicology screening was performed in 420 patients (40%); 11% of these studies were positive for cocaine (19% younger than 50 years and 9% 50 years or older). Factors that significantly predicted the performance of a urine toxicology screen were younger age (<50 years) and black race (<0.001). Positive toxicology screens occurred in a broad range of patients. There were no significant differences in admission NIH Stroke Scale score, stroke etiology, and discharge status between toxicology-positive and -negative patients. CONCLUSIONS: In this study, patients with stroke and TIA who were young and black were more likely to have urine toxicology screening. Eleven percent of all tested patients (and 9% of patients 50 years or older) were positive for cocaine. To avoid disparities, we suggest that all stroke and TIA patients be tested.

Multiple biomarkers and risk of clinical and subclinical vascular brain injury: the Framingham Offspring Study.

BACKGROUND: Several biomarkers have been individually associated with vascular brain injury, but no prior study has explored the simultaneous association of a biologically plausible panel of biomarkers with the incidence of stroke/transient ischemic attack and the prevalence of subclinical brain injury. METHODS AND RESULTS: In 3127 stroke-free Framingham offspring (age, 59±10 years; 54% female), we related a panel of 8 biomarkers assessing inflammation (C-reactive protein), hemostasis (D-dimer and plasminogen activator inhibitor-1), neurohormonal activity (aldosterone-to-renin ratio, B-type natriuretic peptide, and N-terminal proatrial natriuretic peptides), and endothelial function (homocysteine and urinary albumin/creatinine ratio) measured at the sixth examination (1995-1998) to risk of incident stroke/transient ischemic attack. In a subset of 1901 participants with available brain magnetic resonance imaging (1999-2005), we further related these biomarkers to total cerebral brain volume, covert brain infarcts, and large white-matter hyperintensity volume. During a median follow-up of 9.2 years, 130 participants experienced incident stroke/transient ischemic attack. In multivariable analyses adjusted for stroke risk factors, the biomarker panel was associated with incident stroke/transient ischemic attack and with total cerebral brain volume (P<0.05 for both) but not with covert brain infarcts or white-matter hyperintensity volume (P>0.05). In backward elimination analyses, higher log-B-type natriuretic peptide (hazard ratio, 1.39 per 1-SD increment; P=0.002) and log-urinary albumin/creatinine ratio (hazard ratio, 1.31 per 1-SD increment; P=0.004) were associated with increased risk of stroke/transient ischemic attack and improved risk prediction compared with the Framingham Stroke Risk Profile alone; when the <5%, 5% to 15%, or >15% 10-year risk category was used, the net reclassification index was 0.109 (P=0.037). Higher C-reactive protein (ß=-0.21 per 1-SD increment; P=0.008), D-dimer (ß=-0.18 per 1-SD increment; P=0.041), total homocysteine (ß=-0.21 per 1-SD increment; P=0.005), and urinary albumin/creatinine ratio (ß=-0.15 per 1-SD increment; P=0.042) were associated with lower total cerebral brain volume. CONCLUSION: In a middle-aged community sample, we identified multiple biomarkers that were associated with clinical and subclinical vascular brain injury and could improve risk stratification.

Strong independent correlation of proteinuria with cerebral microbleeds in patients with stroke and transient ischemic attack.

OBJECTIVE: To assess the association of proteinuria with the frequency and number of cerebral microbleeds (CMB), a harbinger of future hemorrhagic stroke. DESIGN: Cross-sectional analysis. Patients Patients with consecutive ischemic stroke and transient ischemic attack admitted to a university hospital during a 22-month period. INTERVENTIONS: Presence and number of CMB were evaluated using gradient-echo T2*-weighted magnetic resonance imaging. Multivariable models were generated to determine the contribution of proteinuria to the frequency and number of CMB after adjusting for confounders. RESULTS: Of 236 patients (mean age, 70 years; 53% female), 72 (31%) had CMB present on gradient-echo imaging and 89 (38%) had evidence of proteinuria. In multivariable analyses with presence of CMB as the outcome, higher urinary protein (odds ratio [OR], 2.33; 95% confidence interval [CI], 1.10-4.95), being female (OR, 2.29; 95% CI, 1.19-4.49), history of atrial fibrillation (OR, 2.49; 95% CI, 1.14-5.44), elevated serum homocysteine (OR, 1.19; 95% CI, 1.09-1.29), and small-vessel disease subtype (OR, 2.95 95% CI, 1.43-6.10) were all significantly associated with presence of CMB. Logistic regression analysis by number of CMB showed similar findings. CONCLUSIONS: Proteinuria is strongly associated with both the frequency and number of CMB in patients with recent cerebral ischemia. Urinary protein excretion may be a CMB risk marker or potential therapeutic target for mitigating the untoward clinical sequela of CMB.

Raised erythrocyte polyamine levels in non-insulin-dependent diabetes mellitus with great vessel disease and albuminuria.

Erythrocyte content of polyamines has been previously found increased in insulin-dependent diabetes mellitus with microalbuminuria. Since increased urinary albumin excretion (AER) is associated with the presence of vascular diseases in non-insulin-dependent diabetes mellitus (NIDDM) the aim of this study was to verify the hypothesis that the presence of increased urinary albumin excretion (AER), and of macroangiopathy in NIDDM would be related to a significant modification in polyamine erythrocyte levels. The erythrocyte content of spermine and spermidine was measured by a HPLC method in 39 patients affected with NIDDM and in 24 age- and sex-matched healthy control subjects, evaluating the relationship between erythrocyte polyamines of NIDDM patients with the presence of macroangiopathy as well as with retinopathy or increased AER (> or = 20 micrograms/ml). Both spermidine and spermine were not modified in the group of NIDDM patients while the presence of raised urinary AER was characterised by an increase in erythrocyte spermine (11 +/- 1.7 vs. 7.7 +/- 1.7 nmol/ml packed erythrocytes; P = 0.04) and spermidine (18.9 +/- 1.7 vs. 12.6 +/- 1.5 nmol/ml packed erythrocytes; P = 0.02), being both polyamines significantly related to AER and to metabolic control. Erythrocyte spermidine and spermine were moreover significantly higher in the group of patients with macroangiopathy (22.8 +/- 1.5 vs. 12.3 +/- 1.5 nmol/ml; P = 0.0001 and 11.5 +/- 1.7 vs. 7.8 +/- 1.7 nmol/l packed erythrocytes; P = 0.04) and being, moreover, erythrocyte spermidine augmented in patients with retinopathy (24.2 +/- 1.5 vs. 12.2 +/- 1.5 nmol/ml packed erythrocytes; P = 0.009). In conclusion the levels of erythrocyte spermine and spermidine are both associated with the presence of albuminuria and macroangiopathy in NIDDM, while spermidine is on the average increased in the group of diabetic patients with retinopathy.

[The effect of intravenous ascorbic acid on urinary 17-hydroxysteroid excretion at an early stage of cerebral stroke]. / Wplyw dozylnego podawania kwasu askorbinowego na wydalanie 17-hydroksysterydów w moczu u chorych z udarem mózgu we wczesnym okresie choroby.

The main symptoms of stroke such as a displacement of intracranial structures, changes in spatial relations, secondary hemorrhagic and ischemic foci, oedema and metabolic disturbances are the cause of the disorders of hypothalamus-hypophysis system leading to increased secretion of corticosteroids including 17-hydroxyketosteroids (17-OHKS). Steroidogenesis in inhibited by high concentrations of ascorbic acid. Intravenous injections of ascorbic acid 0.5 g were given to the patients with stroke and their urine was analysed daily to examine the secretion of 17-OHKS. A slight increase in 17-OHKS secretion was found on 1 and 2 days of the disease in patients suffering from TIA and a significant increase in 17-OHKS secretion was detected in patients with cerebral ischaemia (ischemic stroke) and cerebral hemorrhage and persisted for 3-4 days of the illness. One can presume that the disorders of hypothalamus-hypophysis-adrenal system contributes much more to the decrease in 17 OHKS secretion on successive days of stroke than the administration of ascorbic acid.

Increased thromboxane biosynthesis in patients with acute cerebral ischemia.

BACKGROUND AND PURPOSE: Clinical and experimental studies suggest that platelets have a major role in the pathogenesis of cerebral ischemia. However, ex vivo both platelet aggregation studies and measurements of platelet-derived products in patients with cerebral ischemia have shown inconsistent results. The present study was designed to resolve this inconsistency. METHODS: We have measured the urinary excretion of a thromboxane metabolite, 11-dehydro-thromboxane B2, by a previously validated radioimmunoassay technique in 51 patients with acute cerebral ischemia who had experienced either a transient ischemic attack (14 patients) or an ischemic stroke (37 patients) and in 20 control patients with nonvascular neurological disorders. The median time between the onset of symptoms and urine sampling was 24 hours (range, from 2 hours to 8 days). RESULTS: The excretion rate of immunoreactive 11-dehydro-thromboxane B2 ranged between 39 and 478 pmol/mmol creatinine in patients with a transient ischemic attack and between 23 and 5,916 pmol/mmol creatinine in stroke patients, with 29% (p = 0.18) and 51% (p = 0.004) of the urine samples, respectively, exceeding the upper limit of the control samples (251 pmol/mmol creatinine [mean +/- 2 SD]) (p = 0.01). In stroke patients, metabolite excretion was not related to the type (cortical or "lacunar") or site of cerebral infarction. Low-dose aspirin (50 mg per day for 7 days) reduced the urinary excretion by approximately 85% in 11 consecutive stroke patients. CONCLUSIONS: We conclude that 1) episodes of enhanced thromboxane biosynthesis are detected infrequently in patients with a transient ischemic attack, 2) aspirin-suppressible episodes of increased thromboxane formation can be detected during the early phase of acute ischemic stroke, and 3) this finding may provide a rationale for testing the efficacy and safety of this drug in this setting.

Long term monitoring of immunoreactive endothelin-1 and endothelin-3 in ventricular cerebrospinal fluid, plasma, and 24-h urine of patients with subarachnoid hemorrhage.

Endothelins (ETs), peptides that were originally isolated from endothelial cells, have extremely potent and long-lasting vasoconstricting effects on cerebral vessels in vitro and in vivo. Observations that astrocytes produce these peptides and that their ET production can be stimulated, e.g. by thrombin, and potentiated via a self-enhancing autoregulatory mechanism may have shed new light upon the pathogenesis of cerebrovasospasm (CVS). ETs are present at low levels in normal human cerebrospinal fluid (CSF). Few and contradictory reports exist on ET levels in subarachnoid hemorrhage (SAH)-associated CVS. We monitored ventricular CSF, plasma, and 24-h urine levels of immunoreactive endothelin-1 (ET-1) and endothelin-3 (ET-3) in seven patients with SAH, who did (five) or did not (two) develop CVS in the course of their disease, as well as in two patients with different conditions (acoustic neuroma/postoperative meningitis; hydro-/hematocephalus) over 7-19 days. A distinct peak of both ET-1 and ET-3 in CSF of patients with SAH coincided with clinically documented signs of CVS and was absent in CSF of patients with SAH but no CVS. CSF levels of ET-1 and ET-3 displayed a striking parallelism in all subjects. Plasma ET-1 levels were essentially in the normal range. ET-3 was not detectable in plasma under our assay conditions. The excretion profiles of ET-1 and ET-3 in 24-h urine revealed again a predominantly parallel behavior of the two peptides. Interestingly, patients with high ET levels in CSF showed simultaneous peaks in urinary ET excretion, expressed as nanograms per gram of creatinine. Our findings support an association of ETs with the pathogenic events following SAH. The well-documented effects of these peptides on cerebral vessels suggest they are mediators rather than markers of disease.

[Hydroxyproline and acid glycosaminoglycans in acute cerebral circulatory disorders]. / Oksiprolin i kislye glikozaminoglikany pri ostrykh narusheniiakh mozgovogo krovoobrashcheniia.

In patients with acute disorders of cerebral circulation dynamic examinations of hydroxyproline excretion, total content of glycosamineglycans (GAGs) and content of the latters' fractions were carried out. During the first week of the disease the total content of the GAGs in the urine daily portion was found to be increased, this increase being statistically significant and correlating with the size of the expected brain lesion. The fractional spectrum of the GAGs changed towards greater content of sulphonated fractions. By the 3d--5th week of the disease the hydroxyproline concentration in the urine sharply rose, an evidence of the intense organizational processes within the ischemic focus by that time.

[Sulfur-containing substances in the urine and blood of patients with cerebral circulatory disorders]. / Serosoderzhashchie veshchestva v moche i krovi u bol'nykh s rasstroistvami mozgovogo krovoobrashcheniia.

In 138 patients (87 males and 51 females) with hypertensive disease (90 cases) and atherosclerosis (48 cases) the authors studied the content of sulfur and its fractions in the blood and the level of excretion with urine in disturbances of cerebral circulation. In hypertensive disease and cerebral atherosclerosis, complicated by disturbances of cerebral circulation, there were quantitative changes in the level of sulfur-containing substances both in the blood serum and urine. Disorders in the sulfur metabolism indicate a drop of the autotoxic function in the liver, quite possibly related to the influence of pathological changes proceeding in the central nervous system.