Hypertension and chronic kidney disease: controversies in pathogenesis and treatment.

The relationship between hypertension and chronic kidney disease (CKD) has long been the subject of controversy. The pathogenetic mechanisms of nephropathy in non-diabetic individuals with hypertension, as well as optimal hypertension treatment targets in populations with nephropathy remain important clinical concerns. This manuscript reviews breakthroughs in molecular genetics that have clarified the complex relationship between hypertension and kidney disease, answering the question of which factor comes first. An overview of the potential roles that hyperuricemia plays in the pathogenesis of hypertension and CKD and current blood pressure treatment guidelines in populations with CKD are discussed. The ongoing National Institutes of Health-sponsored Systolic Blood Pressure Intervention Trial (SPRINT) is underway to help answer these important questions. Enrollment of 9250 hypertensive SPRINT participants will be completed in 2013; important results on ideal blood pressure control targets for reducing nephropathy progression, cardiovascular disease end-points, and preserving cognitive function are expected. As such, many of the controversial aspects of hypertension management will likely be clarified in the near future.

The disposition and pharmacokinetics in humans of 5-azacytidine administered intravenously as a bolus or by continuous infusion.

The disposition of 5-[4-14C]azacytidine, administered i.v. as a bolus or continuous infusion, was studied in cancer patients. After bolus, plasma 14C levels exhibited as multiphasic disappearance pattern; half-life (t1/2, beta phase) = 3.4 to 6.2 hr. Of 14C in plasma, less than 2% was associated with 5-[4-14C]azacytidine 30 min after dose. The ratios of 14C levels were: red cells/plasma, approximately 0.8; leukocytes/plasma, 1.1 to 2.3; nucleic acids/leukocytes, 0.2 to 0.43; sputum/plasma, 0.05 to 0.17. Urinary excretion (3 days) accounted for 73 to 98% of 14C, LEss than 1% in feces. The relative concentration of 5-azacytidine in plasma with continuous infusion stayed higher than with bolus; urinary excretion was similar. Fewer side effects were observed with continuous infusion than with bolus. The stability of 5-azacytidine was determined in various media at several temperatures by thin layer chromatography and nuclear magnetic resonance. At 20 degrees in Ringer's lactate (pH 6.2), the t1/2 was 94 to 100 hr. Stability increased with lowering of temperature and pH. From our data we conclude that 5-azacytidine should be given by continuous infusion rather than as a bolus.

Using biological monitoring to assess human exposure to priority toxicants.

Scientifically valid exposure assessment is crucial to risk assessment, risk management, and prevention of environmental disease. Scientists have used three tools to assess exposure: exposure history/questionnaire, environmental monitoring (including personal monitoring), and biological monitoring. Combinations of these tools usually provide the exposure information needed to meet objectives of human studies evaluating the exposure-health effect relationship. Biological monitoring is a capable exposure assessment tool that has provided important information used in public health decisions. We briefly describe how risk assessment and risk management decisions for lead, dioxin, and volatile organic compounds have substantially benefited from exposure information obtained from biological monitoring.

The priority toxicant reference range study: interim report.

The relationship between human exposure to environmental toxicants and health effects is of utmost interest to public health scientists. To define this relationship, these scientists need accurate and precise methods for assessing human exposure and effects. One of the most accurate and precise means of assessing exposure is to measure the level of the toxicant or its primary metabolite in a biologic specimen; this has been defined as measuring the internal dose. This measurement must be quantitative to best study the dose-response relationship. Pertinent questions asked during an exposure assessment include "How do the levels of a given toxicant in a particular population compare with the levels of that toxicant in other populations?" and "What is the prevalence of exposure to that toxicant in other populations?" To answer these questions for two chemical classes of environmental toxicants, we developed state-of-the-art analytic methods and then applied them to measure the levels of 44 environmental toxicants in biologic specimens from 1000 United States residents who participated in the Third National Health and Nutrition Examination Survey (NHANES III). These 1000 people are a cross-sectional subset of the NHANES III population and were selected from urban and rural communities in four regions of the United States; all were between 20 and 59 years of age. This subset is not a probability-based sample.(ABSTRACT TRUNCATED AT 250 WORDS)

Exposure of the U.S. population to lead, 1991-1994.

Blood lead measurements were obtained on 13,642 persons aged 1 year and older who participated in Phase 2 of the Third National Health and Nutrition Examination Survey (NHANES III) from 1991 through 1994. NHANES III is a national representative survey of the civilian, noninstitutionalized U.S. population. The overall mean blood lead level for the U.S. population aged 1 year and older was 2.3 microgram/dl, with 2.2% of the population having levels >=10 microgram/dl, the level of health concern for children. Among U.S. children aged 1-5 years, the mean blood lead level was 2.7 microgram/dl, and 890,000 of these children (4.4%) had elevated blood lead levels. Sociodemographic factors associated with higher blood lead levels in children were non-Hispanic black race/ethnicity, low income, and residence in older housing. The prevalence of elevated blood lead levels was 21.9% among non-Hispanic black children living in homes built before 1946 and 16.4% among children in low-income families who lived in homes built before 1946. Blood lead levels continue to decline in the U.S. population, but 890,000 children still have elevated levels. Public health efforts have been successful in removing lead from population-wide sources such as gasoline and lead-soldered food and drink cans, but new efforts must address the difficult problem of leaded paint, especially in older houses, as well as lead in dust and soil. Lead poisoning prevention programs should target high-risk persons, such as children who live in old homes, children of minority groups, and children living in families with low income.

Levels of seven urinary phthalate metabolites in a human reference population.

Using a novel and highly selective technique, we measured monoester metabolites of seven commonly used phthalates in urine samples from a reference population of 289 adult humans. This analytical approach allowed us to directly measure the individual phthalate metabolites responsible for the animal reproductive and developmental toxicity while avoiding contamination from the ubiquitous parent compounds. The monoesters with the highest urinary levels found were monoethyl phthalate (95th percentile, 3,750 ppb, 2,610 microg/g creatinine), monobutyl phthalate (95th percentile, 294 ppb, 162 microg/g creatinine), and monobenzyl phthalate (95th percentile, 137 ppb, 92 microg/g creatinine), reflecting exposure to diethyl phthalate, dibutyl phthalate, and benzyl butyl phthalate. Women of reproductive age (20-40 years) were found to have significantly higher levels of monobutyl phthalate, a reproductive and developmental toxicant in rodents, than other age/gender groups (p < 0.005). Current scientific and regulatory attention on phthalates has focused almost exclusively on health risks from exposure to only two phthalates, di-(2-ethylhexyl) phthalate and di-isononyl phthalate. Our findings strongly suggest that health-risk assessments for phthalate exposure in humans should include diethyl, dibutyl, and benzyl butyl phthalates.

Role of solute in the early restitution of blood volume after hemorrhage.

We examined the putative roles of decreased capillary pressure and increased transcapillary osmolar gradient in mediation of the early restitution of blood volume after hemorrhage by comparing the degree of restitution of plasma volume and protein and comparing changes in capillary pressure and osmolality in awake dogs with those in dogs anesthetized with pentobarbital. Decreases in estimated capillary pressure and increases in plasma osmolality were greater in anesthetized than in awake dogs. However, early restitution of plasma volume and of protein was greater in awake animals. Analysis of the Starling forces indicated that interstitial hydrostatic pressure was greater in awake animals than in anesthetized animals, suggesting that interstitial volume increases more rapidly in awake animals. Selective venous sampling in anesthetized dogs indicated that the splanchnic and renal vascular beds release solute to the circulation following hemorrhage. However, rather than promoting the restitution of blood volume by production of a transcapillary osmolar gradient, the data suggest that the solute is delivered to the peripheral tissues, where it mediates the movement of water from cells to the interstitium more rapidly in awake than in anesthetized dogs. It thus appears that the early metabolic changes after hemorrhage, resulting in increased solute production, are important for the early restitution of blood volume and plasma protein.

Measuring secondhand smoke exposure in babies: the reliability and validity of mother reports in a sample of low-income families.

The reliability and validity of mother's reports of their infants' exposure to secondhand smoke (SHS) were examined in an ethnically diverse sample of low-income, low-education families (N = 141 mothers). At baseline and posttest, smoking mothers reported about their infants' SHS exposure at different locations and by different sources during the previous week. Findings show that mothers can give reliable accounts of the degree to which they contribute to their babies' SHS exposure. Mothers are able to differentiate between their own smoking behavior and the extent to which they expose their infants. Consistent with the overall exposure pattern, exposure caused by the mother and exposure occurring at home showed the strongest associations with biological and environmental measures. These findings suggest that smoking mothers can provide reliable and valid reports of the degree to which their infants are exposed to SHS.

Current activities at the Centers for Disease Control and Prevention's National Diabetes Laboratory.

In 1997, the Centers for Disease Control and Prevention established the National Diabetes Laboratory in order to help prevent and treat type 1 diabetes. This state-of-the-art laboratory collaborates with research scientists and key national and international organizations throughout the world to identify and study risk factors for type 1 diabetes by developing measurements for glycosylated proteins, developing and evaluating technology for measuring genetic risk factors for the disease, and working to standardize autoantibody measurements. Developing improved technologies for diagnosing and managing diabetes and developing reference materials for properly calibrating and standardizing blood glucose meters are also critical aspects of the laboratory's work. In addition, the laboratory provides quality storage for valuable collections of biologics and other materials and facilitates sharing of specimens, associated epidemiologic data, and test results. Working with our partners in diabetes research, we are improving the diagnosis, treatment, and prevention of type 1 diabetes.

Role of cortisol in the restitution of blood volume after hemorrhage.

The restitution of blood volume and plasma protein after 10 per cent hemorrhage was studied in intact dogs and in dogs subjected to adrenalectomy and infused with cortisol at basal or physiologically increased rates. The results suggest that increased extracellular osmolality, mediated by an increased secretion of cortisol, mediates, in turn, the restitution of protein and plasma volume. The results are best explained by the hypothesis that after hemorrhage, as a direct result of an increased secretion of cortisol, extracellular osmolality increases. A shift of fluid from cells to interstitium follows, increasing the interstitial pressure. This latter increase leads to an increased return of protein through the lymphatics and to an increased return of fluid through both lymphatics and capillaries.

Improving exposure assessment by monitoring human tissues for toxic chemicals.

Typically, the availability of appropriate data to estimate human exposures to toxic chemicals is scarce. Consequently, exposure assessments are often based on indirect surrogates of exposure, such as a combination of questionnaire data on time-activities and concentrations of toxic chemicals measured in environmental media (e.g., air, water, food, soil, dust). Recent advances, however, make it technically feasible and relatively affordable to measure low levels of multiple toxic chemicals in accessible human tissues (e.g., blood, urine). The increasing availability of biological markers for exposure, along with improvements in pharmacokinetic understanding, present new opportunities to estimate exposure from human tissue measurements and from knowledge of intake and uptake parameters. Biological monitoring provides exposure information that is usually complementary to the type of exposure information obtained from environmental monitoring. Biological and environmental monitoring can be used separately or together in order to meet desired objectives. We present here a discussion of the value of biological monitoring for improving exposure assessment. We emphasize the role of biological monitoring in identifying high-priority exposures, evaluating the effectiveness of intervention and prevention efforts, identifying at-risk subpopulations, recognizing time trends in population exposures, establishing reference ranges of tissue concentrations, and providing integrated dose measurements.

Effects of measurement error on estimating biological half-life.

Direct computation of the observed biological half-life of a toxic compound in a person can lead to an undefined estimate when subsequent concentration measurements are greater than or equal to previous measurements. The likelihood of such an occurrence depends upon the length of time between measurements and the variance (intra-subject biological and inter-sample analytical) associated with the measurements. If the compound is lipophilic the subject's percentage of body fat at the times of measurement can also affect this likelihood. We present formulas for computing a model-predicted half-life estimate and its variance; and we derive expressions for the effect of sample size, measurement error, time between measurements, and any relevant covariates on the variability in model-predicted half-life estimates. We also use statistical modeling to estimate the probability of obtaining an undefined half-life estimate and to compute the expected number of undefined half-life estimates for a sample from a study population. Finally, we illustrate our methods using data from a study of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure among 36 members of Operation Ranch Hand, the Air Force unit responsible for the aerial spraying of Agent Orange in Vietnam.

Indices of TCDD exposure and TCDD body burden in veterans of Operation Ranch Hand.

Using responses from a questionnaire detailing herbicide exposure during service in Vietnam and information on job classifications, we investigated the relationship between 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) body burden and self-reported exposure in enlisted members of Operation Ranch Hand, the United States Air Force herbicide spraying mission in Vietnam. We constructed three TCDD exposure indices from the questionnaire data: the number of days of skin exposure (DAYS), the percentage of skin area exposed (PCNT), and a combined index (SRI) which was the product of these and the concentration of TCDD in the herbicide. A fourth index (AFI) based on gallons of herbicide sprayed and the number of men on the job was also studied. The regression model most predictive of TCDD levels (R2 = 0.61) included job classification (divided into four categories), the number of days of skin exposure, percent body fat during the tour of duty, and relative change in body fat. A model with job classification alone had an R2 of 0.60. The four exposure indices were constructed to further explain TCDD exposure in the job classifications with the highest potential for exposure: Ranch Hand flight engineers and ground crew. In these two groups, days of skin exposure was the index most significantly associated with TCDD levels. Overall, the best index of exposure was the number of days of skin exposure to herbicide.

The reliability of the serum dioxin measurement in veterans of Operation Ranch Hand.

A study was conducted on the reliability of the serum dioxin measurement of enlisted Ranch Hands veterans participating in the Air Force Health Study using paired serum dioxin measurements. The 46 veterans were not randomly selected, but their demographic characteristics, health, and dioxin levels were similar to those of 404 other enlisted Ranch Hand veterans who had a single dioxin measurement made in 1987. The average time between the measurements was 0.61 years, the first measurement made from blood drawn on 10 April 1987 and the second from blood collected at a subsequent physical examination. In original unit, the coefficient of reliability was 0.87 (95% confidence interval: 0.76, 0.94) when the first measurement was at or below 50 parts per trillion. The measurement had no reliability in original units when the first measurement was greater than 50 parts per trillion. After a logarithmic transformation, the coefficient of reliability was 0.96 (95% confidence interval: 0.93 to 0.98). These results suggest that the serum dioxin measurement should not be used in original units for any purpose when the value exceeds 50 parts per trillion. The measurement is, however, highly reliable after a logarithmic transformation over the entire range of concentrations. Other studies using the same analytical method to measure dioxin in serum could similarly benefit if the measurement used is on the natural logarithm scale.

Reference range concentrations of N-acetyl-S-(2-hydroxyethyl)-L-cysteine, a common metabolite of several volatile organic compounds, in the urine of adults in the United States.

N-acetyl-S-(2-hydroxyethyl)-L-cysteine (2-hydroxyethyl mercapturic acid, HEMA) is a urinary metabolite of several hazardous chemicals, including vinyl chloride (VC), ethylene oxide (EO), and ethylene dibromide (EDB). Information about the levels of HEMA in the general population is useful for assessing human exposures to HEMA parent compounds, including VC, EO, and EDB. To establish reference range concentrations for HEMA, we analyzed urine samples from 412 adult participants in the Third National Health and Nutrition Examination Survey (NHANES II) by using isotope-dilution high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). HEMA was detected in 71% of the samples examined. Creatinine-corrected concentrations ranged from less than 0.68 microg/g creatinine to 58.7 microg/g creatinine; the 95th percentile concentration was 11.2 microg/g creatinine; and the geometric mean and median creatinine-corrected concentrations were both 1.6 microg/g creatinine. We observed a statistically significant difference (P=0.0001) in the creatinine-corrected geometric mean concentration values of HEMA between smokers (2.8 microg/g creatinine) and nonsmokers (1.1 microg/g creatinine). The high levels of HEMA seen among smokers likely originated from HEMA-producing chemicals known to be present in tobacco smoke.

Exposure of casino employees to environmental tobacco smoke.

Environmental and medical evaluations were performed to evaluate occupational exposure to environmental tobacco smoke (ETS) among casino employees. Air concentrations of both nicotine and respirable dust were similar to those published in the literature for other non-industrial indoor environments. The geometric mean serum cotinine level of the 27 participants who provided serum samples was 1.34 nanograms per milliliter (ng/mL) (pre-shift) and 1.85 ng/mL (post-shift). Both measurements greatly exceeded the geometric mean value of 0.65 ng/mL for participants in the Third National Health and Nutrition Examination Survey (NHANES III) who reported exposure to ETS at work. This evaluation demonstrates that a sample of employees working in a casino gaming area were exposed to ETS at levels greater than those observed in a representative sample of the US population, and that the serum and urine cotinine of these employees increased during the workshift.

Blood lead levels of 4-11-year-old Mexican American, Puerto Rican, and Cuban children.

Data from the Hispanic Health and Nutrition Examination Survey were used to estimate arithmetic mean blood lead and percent with elevated blood lead [25 micrograms per deciliter (micrograms per dl) or greater] for 4-11-year-old Mexican American, Puerto Rican, and Cuban children. The sample size was 1,390 for Mexican American children, 397 for Puerto Rican children, and 114 for Cuban children. Puerto Rican children had the highest mean blood lead levels (11.5 micrograms per dl), followed by Mexican American children (10.4 micrograms per dl) and Cuban children (8.6 micrograms per dl, P less than .05). Puerto Rican children had the highest percent with elevated blood lead (2.7 percent); 1.6 percent of Mexican American children had elevated blood lead; less than 1 percent (0.9 percent) of the Cuban children had elevated blood lead (P less than .05). Mexican American girls had a lower mean blood lead level than did boys: 9.7 micrograms per dl versus 11.0 micrograms per dl (P less than .05). For both Puerto Rican and Mexican American children, younger age indicated a higher risk of having elevated blood lead levels. Mexican American children who lived in poverty had higher mean blood lead levels than did Mexican American children who did not live in poverty--11.6 micrograms per dl versus 9.6 micrograms per dl (P less than .05). Despite advances in primary prevention of lead toxicity in children during the past 10 years, many Hispanic children are at risk of lead toxicity. Approximately 19,000 Mexican American 4-11-year-old children living in the Southwest and approximately 8,000 Puerto Rican children living in the New York City area had elevated blood lead levels (greater than or equal to 25 micrograms per dl) during 1982-84.

Evaluation of four maternal smoking questions.

OBJECTIVE: The authors evaluated four questions about maternal smoking during pregnancy for use on birth certificates. METHODS: Question 1 (yes/no format) and Question 2 (trimester-specific design) were tested among 1171 women who delivered at two Kaiser Permanente medical centers in northern California. Responses to Questions 1 and 2 were compared with smoking information provided by participants in telephone interviews conducted during pregnancy. Question 3 (multiple choice format) and Question 4 (month- and grouped month-specific design) were tested among 900 women who enrolled in a statewide prenatal screening program and who delivered in 20 hospitals in four Central Valley counties. Responses to Questions 3 and 4 were compared with mid-pregnancy serum cotinine levels. The authors evaluated the four questions in terms of conciseness, response rate, data accuracy, and type of data requested. RESULTS: Questions 1 and 2 were the most concise. Response rates could not be calculated for Questions 1 and 2. Response rates were 86.0% for Question 3 and 74.2% for Question 4. Sensitivity was 47.3% for Question 1, 62.1% for Question 2, 83.8% for Question 3, and 86.7% for Question 4. The types of data requested by Questions 2 and 4 seem to best satisfy the needs of the broad audience of birth certificate users. CONCLUSIONS: No single question was clearly superior. The authors propose a combination of Questions 2 and 4, which asks about average number of cigarettes smoked per day in the three months before pregnancy and in each trimester of pregnancy.

Comparison of serum and salivary cotinine measurements by a sensitive high-performance liquid chromatography-tandem mass spectrometry method as an indicator of exposure to tobacco smoke among smokers and nonsmokers.

Exposure to tobacco smoke, both from active smoking and from passive exposure to environmental tobacco smoke, can be monitored by measuring cotinine, a metabolite of nicotine, in a variety of biological sources including blood, urine, and saliva. Previously, a sensitive atmospheric-pressure ionization, tandem mass spectrometric (LC-API-MS-MS) method for cotinine measurements in serum was developed in support of a large, recurrent national epidemiologic investigation. The current study examined the application of this LC-API-MS-MS method to both serum and saliva cotinine measurements in a group of 200 healthy adults, including both smokers and nonsmokers. The primary objective of this study was to evaluate the relationship between serum and saliva cotinine concentrations to facilitate the linking of results from epidemiologic studies using salivary cotinine measurements to existing national data based on serum cotinine analyses. The results indicate that a simple, linear relationship can be developed to describe serum and saliva cotinine concentrations in an individual, and the expression describing this relationship can be used to estimate with reasonable accuracy (approximately +/- 10%) the serum cotinine concentration in an individual given his or her salivary cotinine result. It was further confirmed that saliva cotinine samples are generally quite stable during storage after collection, even at ambient temperatures, and this sample matrix appears to be well-suited to the requirements of many epidemiologic investigations.

p-Dichlorobenzene exposure among 1,000 adults in the United States.

p-Dichlorobenzene is used widely in the United States as a room deodorizer, a moth repellent, and a precursor for a polymer. In a previous study of selected children in Arkansas, we found that 96% of the children had detectable urinary concentrations of 2,5-dichlorophenol, the metabolite of p-dichlorobenzene. In the current study, we found that, in a sample of 1,000 adults who lived throughout the United States, 98% had detectable levels of 2,5-dichlorophenol in their urine, and 96% had detectable levels of p-dichlorobenzene in their blood. Urinary 2,5-dichlorophenol concentrations ranged up to 8,700 micrograms/l (median and mean concentrations of 30 micrograms/l and 200 micrograms/l, respectively). p-Dichlorobenzene blood concentrations ranged up to 49 micrograms/l, with median and mean concentrations of 0.33 micrograms/l and 2.1 micrograms/l, respectively. The Pearson correlation coefficient for 2,5-dichlorophenol in urine and p-dichlorobenzene in blood was .82 (p < .0001), thus demonstrating a strong association between these exposure measurements. Neither age nor gender was related to urinary 2,5-dichlorophenol or blood p-dichlorobenzene concentrations (p > .40). When these results are viewed with data from other studies, the collective data show that p-dichlorobenzene is a common, worldwide contaminant. The high prevalence of exposure to p-dichlorobenzene, coupled with its potential for adverse health effects, indicate the need for more detailed studies, including studies of long-term health effects on exposed populations.