Diet and Other Modifiable Factors in Long-Term Decline of Kidney Function: Observational and Population-Based Cohort Study.

BACKGROUND: Lower physical activity, lower alcohol intake, higher protein intake, higher sodium intake, and lower potassium intake related to greater kidney function decline over time, according to previous studies. The present study aimed to analyze the cumulative effects of these factors. METHODS: This prospective, observational, population-based cohort study included 3039 adult examinees of the Gubbio study who participated in the baseline exam and 15-year follow-up exam. Kidney function was evaluated as estimated glomerular filtration rate (eGFR). Habitual physical activity in leisure time and habitual alcohol intake were assessed by questionnaires; dietary intakes of protein, sodium, and potassium were assessed by urinary markers. Based on previous reports, each one of the five modifiable factors was scored 0 for the tertile associated with smaller eGFR decline (low risk), 2 for the tertile associated with greater eGFR decline (high risk), and 1 for the intermediate tertile (intermediate risk). A cumulative score was calculated as the sum of the factor-specific scores and used as the main independent variable. RESULTS: The cumulative score ranged from 0 to 10, that is, from low risk for all factors to high risk for all factors (skewness = 0.032, mean ± SD = 5 ± 2). To avoid the bias of low-n analyses, score 0 was re-coded as 1 and score 10 was recoded as 9; after re-coding, the cumulative score ranged from 1 to 9 (skewness = 0.016, mean ± SD = 5 ± 2). The cumulative score related to annualized eGFR change in multi-variable linear regression (slope = -0.027, 95%CI = -0.039/-0.014, p < 0.001); findings were consistent in apparently healthy examinees and other subgroups. De novo incidence of eGFR < 60 mL/min × 1.73 m2 was higher along the cumulative score (p < 0.001). Compared to score 1 (n examinees = 35, adjusted incidence = 2.0%), incidence of low kidney function was 4.5 times higher in score 5 (n examinees = 624, adjusted incidence = 8.9%) and 6.5 times higher in score 9 (n examinees = 86, adjusted incidence = 12.9%). The cumulative score related to incidence of low kidney function in multi-variable logistic regression (odds ratio = 1.19, 95%CI = 1.08/1.32, p < 0.001). CONCLUSIONS: The combination of five modifiable factors predicted large differences in long-term incidence of low kidney function.

Marital status and long-term cardiovascular risk in general population (Gubbio, Italy).

To investigate whether marital status is associated to long-term major fatal and non-fatal cardiovascular events in men and women from the Gubbio Population Study. The incidence of cardiovascular disease (CVD), including stroke and coronary heart disease (CHD) and CVD death together with all-cause mortality were analyzed. The analysis included 2832 persons (44% men, 54 ± 11 years old). Marital status was defined at entry as married (married or living conjugally) versus unmarried subjects (widowed, separated, divorced or single). Married and unmarried subjects did not differ concerning socio-demographic, anthropometric and biological variables at baseline. Over 191 months median follow-up, the incidence of CHD was lower among married versus unmarried women [HR: 0.63 (95% CI 0.41-0.96)] only; the same was true for CHD mortality [HR: 0.43 (95% CI 0.22-0.84)] and all-cause mortality [HR: 0.75 (95% CI 0.59-0.96)] independently of traditional risk factors (age, SBP, total and HDL cholesterol, cigarette smoke and BMI). In men, marital status was not associated to any of the investigated outcomes. In primary care, marital status should be investigated as it can be associated with long-term CHD and all-cause incidence and mortality risks among women.

Relation of Alcohol Intake to Kidney Function and Mortality Observational, Population-Based, Cohort Study.

Data are conflicting about the effects of alcohol intake on kidney function. This population-based study investigated associations of alcohol intake with kidney function and mortality. The study cohort included adult participants in Exam-1, Exam-2 (6-year follow-up), and Exam-3 (20-year follow-up) of the Gubbio study. Kidney function was evaluated as estimated glomerular filtration rate (eGFR, CKD-Epi equation, mL/min × 1.73 m2). Daily habitual alcohol intake was assessed by questionnaires. Wine intake accounted for >94% of total alcohol intake at all exams. Alcohol intake significantly tracked over time (R > 0.66, p < 0.001). Alcohol intake distribution was skewed at all exams (skewness > 2) and was divided into four strata for analyses (g/day = 0, 1−24, 25−48, and >48). Strata of alcohol intake differed substantially for lab markers of alcohol intake (p < 0.001). In multivariable regression, strata of alcohol intake related cross-sectionally to eGFR at all exams (Exam-1: B = 1.70, p < 0.001; Exam-2: B = 1.03, p < 0.001; Exam-3: B = 0.55, p = 0.010) and related longitudinally to less negative eGFR change from Exam-1 to Exam-2 (B = 0.133, p = 0.002) and from Exam-2 to Exam-3 (B = 0.065, p = 0.004). In multivariable Cox models, compared to no intake, intakes > 24 g/day were not associated with different mortality while an intake of 1−24 g/day was associated with lower mortality in the whole cohort (HR = 0.77, p = 0.003) and in the subgroup with eGFR < 60 mL/min × 1.73 m2 (HR = 0.69, p = 0.033). These data indicate a positive independent association of alcohol intake with kidney function not due to a mortality-related selection.

Relationship of the Intake of Water and Other Beverages With Renal Endpoints: Cross-Sectional and Longitudinal Data-Observational, Population-Based Study.

OBJECTIVES: The relationship of water intake with kidney function in the population is uncertain. This study investigated cross-sectionally and longitudinally the relationship of the intake of water and other beverages with kidney function within an adult Italian population sample. METHODS: In 4,554 Gubbio Study examinees (54.4% women, age 18-95 years), data collection at baseline included demographics, anthropometry, questionnaires on habitual intakes of water and other beverages (non-water fluids), a timed overnight urine collection, estimated glomerular filtration rate (eGFR), decreased eGFR (<60 mL/minute/1.73 m2), and other variables including urinary markers of diet. At 15-year follow-up, the incidence of renal/kidney replacement therapy, the eGFR change from baseline, and the incidence of decreased eGFR were used as indices of kidney function change over time. RESULTS: In multivariable analyses, higher water intake is independently related to higher urine flow (beta = 0.163, P < .001), lower urine osmolality (beta = 0.184, P < .001), lower eGFR (beta = 0.030, P = .002), and higher prevalence of decreased eGFR (logistic coefficient ± standard error = 1.13 ± 0.32, P < .001). Water intake did not relate to kidney function change over time. Intake of non-water fluids did not independently relate to urinary indices nor to kidney function. CONCLUSIONS: In the general population, water intake relates cross-sectionally to urine flow, urine concentration, and kidney function but it does not relate to kidney function change over time. The intake of other beverages does not relate to urinary indices or kidney function. Results do not support a role of water intake in kidney function decline over time in the population.

Urinary Potassium and Kidney Function Decline in the Population-Observational Study.

Background-Some data suggest favorable effects of a high potassium intake on kidney function. The present population-based study investigated cross-sectional and longitudinal relations of urinary potassium with kidney function. Methods-Study cohort included 2027 Gubbio Study examinees (56.9% women) with age ≥ 18 years at exam-1 and with complete data on selected variables at exam-1 (1983-1985), exam-2 (1989-1992), and exam-3 (2001-2007). Urinary potassium as urinary potassium/creatinine ratio was measured in daytime spot samples at exam-1 and in overnight timed collections at exam-2. Estimated glomerular filtration rate (eGFR) was measured at all exams. Covariates in analyses included demographics, anthropometry, blood pressure, drug treatments, diabetes, smoking, alcohol intake, and urinary markers of dietary sodium and protein. Results-In multivariable regression, urinary potassium/creatinine ratio cross-sectionally related to eGFR neither at exam-1 (standardized coefficient and 95%CI = 0.020 and -0.059/0.019) nor at exam-2 (0.024 and -0.013/0.056). Exam-1 urinary potassium/creatinine ratio related to eGFR change from exam-1 to exam-2 (0.051 and 0.018/0.084). Exam-2 urinary potassium/creatinine ratio related to eGFR change from exam-2 to exam-3 (0.048 and 0.005/0.091). Mean of urinary potassium/creatinine ratio at exam-1 and exam-2 related to eGFR change from exam-1 to exam-3 (0.056 and 0.027/0.087) and to incidence of eGFR < 60 mL/min per 1.73 m2 from exam-1 to exam-3 (odds ratio and 95%CI = 0.78 and 0.61/0.98). Conclusion-In the population, urinary potassium did not relate cross-sectionally to eGFR but related to eGFR decline over time. Data support the existence of favorable effects of potassium intake on ageing-associated decline in kidney function.

A report on the Gubbio Study thirty-eight years after its inception.

BACKGROUND: The Gubbio Population Study (Gubbio Study) is a prospective epidemiological study carried out on the resident population of the city of Gubbio, Perugia, Italy. The study's objectives were both of public health nature (the control and awareness of hypertension), and experimental (the role of electrolyte handling at the cellular membrane level and its relation to hypertension). Additional objectives were addressed during the 30+ year activity of the study, in particular the role of kidney dysfunction. METHODS: Three active screenings (exams) were performed beginning 38 years ago: the first (Exam 1) in 1983-1986 (5376 individuals - response rate 92%) and two follow-up exams, were completed between 1989-92 (Exam 2) and 2001-2007 (Exam 3). Data collected include demographics, personal and family medical history, lifestyle (smoking, alcohol, diet and physical activity), education, type of work, anthropometry, blood pressure, pulse rate, blood biochemistry, urine biochemistry and special investigations on cellular electrolyte handling. Additional measurements were performed in selected subgroups of participants. Data on hospitalizations, mortality and causes of death were collected after the completion of Exam 1. RESULTS: The main results of the study, presented in this paper, identify new variables to consider in screening for cardiovascular risk factors, and show the impact that the focused and coordinated effort of a longitudinal program can have on a free-living population'. CONCLUSIONS: The data are of relevance to Public Health and to experimental medicine alike and vouch to the importance of the control of risk factors at the community level.

Sodium intake and kidney function in the general population: an observational, population-based study.

BACKGROUND: The relationships of sodium intake to kidney function within the population have been poorly investigated and are the objective of the study. METHODS: This observational, population-based, cross-sectional and longitudinal study targeted 4595 adult participants of the Gubbio study with complete data at baseline exam. Of these participants, 3016 participated in the 15-year follow-up (mortality-corrected response rate 78.4%). Baseline measures included sodium:creatinine ratio in timed overnight urine collection, used as an index of sodium intake, together with serum creatinine, sex, age and other variables. Follow-up measures included serum creatinine and other variables. Estimated glomerular filtration rate (eGFR, mL/min/1.73 m2) was calculated using serum creatinine, sex and age and was taken as an index of kidney function. RESULTS: The study cohort was stratified in sex- and age-controlled quintiles of baseline urine sodium:creatinine ratio. A higher quintile associated with higher baseline eGFR (P < 0.001). In multivariable analysis, the odds ratio (OR) of Stage1 kidney function (eGFR ≥90 mL/min/1.73 m2) was 1.98 times higher in Quintile 5 compared with Quintile 1 [95% confidence interval (CI) 1.50-2.59, P < 0.001]. The time from baseline to follow-up was 14.1 ± 2.5 years. Baseline to follow-up, the eGFR change was more negative along quintiles (P < 0.001). In multivariable analysis, the OR in Quintile 5 compared with Quintile 1 was 2.21 for eGFR decline ≥30% (1.18-4.13, P = 0.001) and 1.38 for worsened stage of kidney function (1.05-1.82, P = 0.006). Findings were consistent within subgroups. CONCLUSIONS: Within the general population, an index of higher sodium intake associated cross-sectionally with higher kidney function but longitudinally with greater kidney function decline.

Impact of Sex on Office White Coat Effect Tail: Investigating Two Italian Residential Cohorts.

To assess the impact of sex on office white-coat effect tail (OWCET), the waning of systolic blood pressure (SBP) after its waxing during office visit, on the incidence of long-term major fatal and non-fatal events in two Italian residential cohorts [from the Gubbio Study and the Italian Rural Areas of the Seven Countries Study (IRA)]. There were 3565 persons (92 with missing data, 44% men, 54 ± 11 years) included in the Gubbio and 1712 men (49 ± 5 years) in the IRA studies. OWCET was defined as a decrease of ≥10 mmHg in SBP between successive measurements with slight measurement differences between the two cohorts. Cardiovascular (CVD), coronary heart disease (CHD) and stroke (STR) incidences were considered. Over an approximately 20-year follow-up, women with OWCET had an increased risk of CVD [HR: 1.591 (95%CI: 1.204-2.103)], CHD [HR: 1.614 (95%CI: 1.037-2.512)] and STR [HR: 1.696 (95%CI: 1.123-2.563)] events independently of age, serum and HDL cholesterol, cigarettes, BMI and SBP in the Gubbio study. However, there was no increased risk of CVD, CHD or STR in men with OWCET neither in the Gubbio 20-year follow-up nor in the IRA 50-year follow-up. These results were not modified significantly by the correction of the regression dilutions bias between the first and the subsequent SBP measurements. Thus, in primary care, OWCET should be actively evaluated in women as it can improve stratification of long-term CVD, CHD and STR risks.

Estimation of metabolic syndrome heritability in three large populations including full pedigree and genomic information.

Metabolic syndrome is a complex human disorder characterized by a cluster of conditions (increased blood pressure, hyperglycemia, excessive body fat around the waist, and abnormal cholesterol or triglyceride levels). Any of these conditions increases the risk of serious disorders such as diabetes or cardiovascular disease. Currently, the degree of genetic regulation of this syndrome is under debate and partially unknown. The principal aim of this study was to estimate the genetic component and the common environmental effects in different populations using full pedigree and genomic information. We used three large populations (Gubbio, ARIC, and Ogliastra cohorts) to estimate the heritability of metabolic syndrome. Due to both pedigree and genotyped data, different approaches were applied to summarize relatedness conditions. Linear mixed models (LLM) using average information restricted maximum likelihood (AIREML) algorithm were applied to partition the variances and estimate heritability (h2) and common sib-household effect (c2). Globally, results obtained from pedigree information showed a significant heritability (h2: 0.286 and 0.271 in Gubbio and Ogliastra, respectively), whereas a lower, but still significant heritability was found using SNPs data ([Formula: see text]: 0.167 and 0.254 in ARIC and Ogliastra). The remaining heritability between h2 and [Formula: see text] ranged between 0.031 and 0.237. Finally, the common environmental c2 in Gubbio and Ogliastra were also significant accounting for about 11% of the phenotypic variance. Availability of different kinds of populations and data helped us to better understand what happened when heritability of metabolic syndrome is estimated and account for different possible confounding. Furthermore, the opportunity of comparing different results provided more precise and less biased estimation of heritability.

Low Protein Intake in the Population: Low Risk of Kidney Function Decline but High Risk of Mortality.

OBJECTIVE: This population-based study investigated low protein intake, mortality, and kidney function decline. DESIGN: Observational longitudinal cohort study. SUBJECTS: Target cohort consisted of 4,679 adults participating in 1988-1992 and 2001-2007 examinations of the Gubbio Study (baseline and follow-up). Data collection included overnight urine urea nitrogen (UUN) and other variables at baseline, serum creatinine at baseline and follow-up, and mortality from baseline to follow-up. Three hundred seventy-two persons were excluded for missing data. UUN in the lowest 20% of the distribution was defined as low and used as index of low protein intake. Estimated glomerular filtration rate (eGFR, mL/minute × 1.73 m2) was used as kidney function index. INTERVENTION: None (observational study). MAIN OUTCOME MEASURE: Mortality and eGFR decline are the main outcome measures, and eGFR decline was defined as eGFR change from baseline to follow-up ≤ mean-1 standard deviation (Z-score ≤ -1). RESULTS: Eight hundred seventy-one deaths occurred over 15.9 ± 4.0 years of observation (417 from cardiovascular disease and 276 from neoplastic disease). Low UUN associated with mortality (hazard ratio, HR = 1.31, 95% confidence interval, CI = 1.12/1.53) due to association with mortality from neoplastic disease (HR = 1.33, 95% CI = 1.02/1.76). Mortality-corrected follow-up response rate was 79.9% (n = 2845). Baseline to follow-up eGFR change was -9.9 ± 10.1, and eGFR decline was found in 454 examinees. Low UUN associated with eGFR decline only in subgroup with baseline eGFR <90 (n = 1441, odds ratio = 0.44, 95% CI = 0.22/0.85). Low baseline eGFR interacted with the association between low UUN and eGFR decline (P = .024). CONCLUSION: Low protein intake predicted higher mortality in the whole population and lower incidence of eGFR decline only in subgroup with reduced kidney function.

Osmotic indices and kidney concentrating activity: population-based data on correlates and prognostic power.

Background: Research data are limited on indices of osmotic equilibrium and of kidney concentrating activity (KCA). This study investigated correlates and prognostic power of these indices in a sample of the general population. Methods: Urine osmolality (U-osm), plasma osmolality (P-osm), plasma creatinine and other variables were measured by the Gubbio Study for the 1988-92 exam (baseline). Plasma creatinine and other variables were re-measured in the 2001-07 exam (follow-up). KCA was assessed as the U-osm/P-osm ratio and kidney function as estimated glomerular filtration rate (eGFR). Results: Baseline data were complete in 4220 adults, of whom 852 died before follow-up and 2795 participated in the follow-up. At baseline, the following independent cross-sectional associations were identified: female sex and higher urine flow with lower values of U-osm, P-osm and U-osm/P-osm ratio (P < 0.01); obesity with higher values of U-osm, P-osm and U-osm/P-osm ratio (P < 0.01); older age and lower eGFR with lower U-osm, lower U-osm/P-osm ratio and higher P-osm (P < 0.05); hypertension and smoking with lower U-osm and lower U-osm/P-osm ratio (P < 0.05) but not with P-osm. From baseline to follow-up, the annualized rate was 1.26% for mortality and -0.74 ± 0.76 mL/min × 1.73 m2 for eGFR change. Mortality was independently predicted by baseline U-osm and baseline U-osm/P-osm ratio (hazard ratio for one higher standard deviation was ≤0.91, 95% confidence interval was ≤0.97, P < 0.01), but not by baseline P-osm. The eGFR change was not independently predicted by baseline values of U-osm, P-osm and U-osm/P-osm ratio (P ≥ 0.4). Conclusions: Sex, age, obesity, eGFR, urine flow, hypertension and smoking independently associated with U-osm and KCA. U-osm and KCA independently predicted mortality, but not kidney function change over time.

Antihypertensive treatment is not a risk factor for major cardiovascular events in the Gubbio residential cohort study.

BACKGROUND AND OBJECTIVES: Demonstration of antihypertensive beneficial role in population settings is difficult. Relationships of antihypertensive treatment, blood pressure control, risk factors and cardiovascular outcomes were investigated in the Gubbio study. MATERIAL AND METHODS: Among 2248 cardiovascular disease-free men and women aged 35-74 years, individuals were classified as nonhypertensive, controlled hypertensive, uncontrolled hypertensive and untreated hypertensive based on cut-off limits of 140/90  mmHg for SBP/DBP and/or the use of antihypertensive drugs. End-point was the first major coronary, cerebrovascular or peripheral hard event [cardiovascular disease (CVD)] during a 15-year average. Univariate and multivariate analyses were run. RESULTS: Nonhypertensive individuals were about 10 years younger and had lower risk factor levels than the other categories. The relative risk (and 95% confidence interval) for CVD versus nonhypertension was 1.78 (1.02-3.10) for controlled hypertension, 3.76 (2.79-5.06) for uncontrolled hypertension and 3.30 (2.59-4.21) for untreated hypertension (UTH). After adjusting for covariates, such as sex, age, achieved blood pressure and other risk factors, the CVD risk of controlled hypertension was practically equal to that of nonhypertension, and remained unchanged even when blood pressure was excluded from the model (1.03, 0.58-1.82). The higher cardiovascular risk of uncontrolled hypertension and UTH was reduced after adjusting for covariates, but remained significantly higher than in nonhypertension, with no significant differences between uncontrolled hypertension and UTH. CONCLUSIONS: A higher level of baseline risk is not due to treatment per se, the risk being similar in uncontrolled hypertension and UTH. Adjustment for risk factors reduces the risk only in controlled hypertension, suggesting that there may be structural alterations scarcely reversible by antihypertensive treatment.

Heritability of blood pressure through latent curve trajectories in families from the Gubbio population study.

BACKGROUND AND OBJECTIVES: Prospective investigations on cardiovascular risk factors in populations provide a unique opportunity to dissect time-dependent quantitative complex traits, such as arterial blood pressure (BP), into their polygenic and environmental components. BP heritability analyses were carried out on 2620 patients belonging to 711 nuclear pedigrees that could be followed up throughout 25 years in the Gubbio Population Study. METHODS: Each patient's BP serial measurements were summarized into individual intercepts (expected values at baseline) and slopes (time-related changes), which were predicted through latent curve models. These models considered either age in years or waves (times from the first survey) as time axis and were linked at a family level in the heritability analyses using additive polygenic-common environment-unique error models adjusted for sex, age and clinical variables. RESULTS: The additive genetic effect explained 32-49% of the variance of SBP values at baseline, the wave-dependent analysis with nuclear pedigrees and the sibs-household matrix accounting for higher heritability values. Heritability of DBP baseline value was lower than that of SBP in analyses by age (5-15%), but fell in the same heritability range as SBP on the analysis by waves (36-37%). The BP variation over time (slope) explained by an additive genetic effect ranged from 33 to 43% and from 24 to 25% for SBP and DBP, respectively, in the analysis by age. Shared environment also exerted a significant influence, but explained a smaller portion of the variances (4-17%) for both traits. CONCLUSION: Longitudinal data from the Gubbio population show strong to moderate genetic influences on SBP and DBP baseline values and changes over time with a smaller, though significant, effect of environment.

Cohort profile: The Gubbio Population Study.

The Gubbio Study is a prospective epidemiological study on the population residing in the city of Gubbio, Italy. Original objectives of the study were the control of hypertension and the role of cellular electrolyte handling in hypertension. Other objectives were added during the 30-year activity of the study. The original target cohort consists of individuals aged ≥5 years residing within the medieval walls of the city. To complete family genealogies, individuals residing outside the city were also included. Three active screenings (exams) were conducted. A total of 5376 individuals (response rate 92%) participated in Exam 1 which was performed in 1983-86. Follow-up exams were completed between 1989-92 and 2001-2007. Data categories included demographics, personal and family medical history, lifestyle habits, education, type of work, anthropometry, blood pressure, pulse rate, blood biochemistry, urine biochemistry and special investigations on cellular electrolyte handling. Electrocardiogram, echocardiogram, 24-h ambulatory blood pressure and uroflowmetry were performed in selected subgroups defined by age and/or sex. Data about hospitalizations, mortality and causes of death were collected starting from completion of Exam 1. The study shared the data with other studies.

Early bactericidal activity and pharmacokinetics of PA-824 in smear-positive tuberculosis patients.

PA-824 is a novel nitroimidazo-oxazine being evaluated for its potential to improve tuberculosis (TB) therapy. This randomized study evaluated safety, tolerability, pharmacokinetics, and extended early bactericidal activity of PA-824 in drug-sensitive, sputum smear-positive, adult pulmonary tuberculosis patients. Fifteen patients per cohort received 1 of 4 doses of oral PA-824: 200, 600, 1,000, or 1,200 mg per day for 14 days. Eight subjects received once daily standard antituberculosis treatment as positive control. The primary efficacy endpoint was the mean rate of change in log CFU of Mycobacterium tuberculosis in sputum incubated on agar plates from serial overnight sputum collections, expressed as log10 CFU/day/ml (+/-standard deviation [SD]). The drug demonstrated increases that were dose linear but less than dose proportional in serum concentrations in doses from 200 to 1,000 mg daily. Dosing of 1,200 mg gave no additional exposure compared to 1,000 mg daily. The mean daily CFU fall under standard treatment was 0.148 (+/-0.055), consistent with that found in previous studies. The mean daily fall under PA-824 was 0.098 (+/-0.072) and was equivalent for all four dosages. PA-824 appeared safe and well tolerated; the incidence of adverse events potentially related to PA-824 appeared dose related. We conclude that PA-824 demonstrated bactericidal activity over the dose range of 200 to 1,200 mg daily over 14 days. Because maximum efficacy was unexpectedly achieved at the lowest dosage tested, the activity of lower dosages should now be explored.

Safety, tolerability, and pharmacokinetics of PA-824 in healthy subjects.

PA-824 is a novel antibacterial agent that has shown in vitro activity against both drug-sensitive and drug-resistant Mycobacterium tuberculosis. The compound's MIC is between 0.015 and 0.25 microg/ml for drug-sensitive strains and between 0.03 and 0.53 microg/ml for drug-resistant strains. In addition, it is active against nonreplicating anaerobic Mycobacterium tuberculosis. The safety, tolerability, and pharmacokinetics of PA-824 were evaluated in two escalating-dose clinical studies, one a single-dose study and the other a multiple-dose study (up to 7 days of daily dosing). In 58 healthy subjects dosed with PA-824 in these studies, the drug candidate was well tolerated, with no significant or serious adverse events. In both studies, following oral administration PA-824 reached maximal plasma levels in 4 to 5 h independently of the dose. Maximal blood levels averaged approximately 3 microg/ml (1,500-mg dose) in the single-dose study and 3.8 microg/ml (600-mg dose) in the multiple-dose study. Steady state was achieved after 5 to 6 days of daily dosing, with an accumulation ratio of approximately 2. The elimination half-life averaged 16 to 20 h. Overall, PA-824 was well tolerated following oral doses once daily for up to 7 days, and pharmacokinetic parameters were consistent with a once-a-day regimen. The results of these studies, combined with the demonstrated activity of PA-824 against drug-sensitive and multidrug-resistant Mycobacterium tuberculosis, support the investigation of this novel compound for the treatment of tuberculosis.

Assessment of the effects of the nitroimidazo-oxazine PA-824 on renal function in healthy subjects.

The mechanism underlying a dose-dependent, reversible increase in serum creatinine (SC) caused by the administration of PA-824, a novel nitroimidazo-oxazine, was evaluated in 47 healthy male and female volunteers. Subjects were administered either 800 or 1,000 mg PA-824 or matching placebo once daily for 8 days. The following renal function parameters were determined before and during dosing and after a 7-day washout: SC, glomerular filtration rate (GFR; measured as the iohexol clearance), effective renal plasma flow (ERPF; measured as the para-amino hippurate clearance), filtration fraction (FF), creatinine clearance (CrCl), extraglomerular creatinine excretion (EGCE; defined as CrCl minus GFR), blood urea nitrogen (BUN), and uric acid (UA) levels. Eight days' administration of 800 or 1,000 mg PA-824 was associated with increased SC and a trend toward decreased CrCl and EGCE. SC, CrCl, and EGCE values returned to normal/baseline within 1 week's washout. GFR, ERPF, FF, BUN, and UA values were similar across groups during treatment and washout. The reversible increase in SC observed in this and earlier trials of PA-824, thus, did not appear to be the result of a pathological effect on renal function (as measured by GFR, ERPF, FF, BUN, or UA). Pharmacokinetic analyses confirmed that PA-824 exposures were similar to those in previous healthy-volunteer clinical studies. That EGCE declined maximally when drug levels were highest suggests that PA-824 causes creatinine levels to rise by inhibiting renal tubular creatinine secretion. Such an effect, considered clinically benign, has been described for several marketed drugs.