Renal function and ultrasound imaging in elderly subjects.
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ABSTRACT:
SUBMITTER: Zanoli L
PROVIDER: S-EPMC4274817 | biostudies-other | 2014
REPOSITORIES: biostudies-other
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Project description:The role of serum uric acid (SUA), an inflammatory agent and potential mediator of cardiovascular diseases, in endothelial function (EF) has been tested only in middle-aged subjects affected by specific diseases. Our aim was to assess the relationship between SUA and measures of EF in a cohort of elderly community-dwellers. This study involved 424 males and 426 females aged 70years from the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS), having complete data on SUA and EF assessed by flow-mediated vasodilation (FMD) and by intra-arterial infusion of acetylcholine (endothelium-dependent vasodilation, EDV) and sodium nitroprusside (endothelium-independent vasodilation, EIDV). Univariate and multivariate regression models obtained by backward selection from initial fully-adjusted models were built to assess the relationship between SUA and measures of EF in both genders. Cardiovascular risk factors, serum hormonal and metabolic mediators, and body composition were considered as potential confounders. In the univariate model, SUA was inversely associated in both genders with log(EDV) (?±SE males -0.39±0.17, p=0.03; females -0.57±0.19, p=0.003) and log(EIDV) (males -0.23±0.12, p=0.05; females -0.49±0.15, p=0.002), but not with log(FMD). After adjustment for BMI, only the association between SUA and log(EIDV) in females persisted, though attenuated (-0.32±0.16, p=0.049), and was no longer significant in the fully-adjusted multivariate model including waist/hip ratio. In conclusion, in older subjects, especially women, SUA is associated with EF not independently of a list of confounders including BMI and trunk fat mass, suggesting a role as surrogate metabolic marker rather than an active player in EF.
| S-EPMC5672624 | biostudies-literature
Project description:Delafloxacin, a fluoroquinolone, has activity against gram-positive organisms including methicillin-resistant Staphylococcus aureus and fluoroquinolone-susceptible and -resistant gram-negative organisms. This study was conducted to determine delafloxacin pharmacokinetics after a single intravenous infusion or oral dose administration in subjects with varying degrees of renal function. The study was an open-label, parallel-group crossover study in subjects with normal renal function or with mild, moderate, or severe renal impairment. Subjects received 300 mg delafloxacin intravenously, placebo intravenously, and 400 mg delafloxacin orally in 3 periods separated by ?14-day washouts. Blood and urine pharmacokinetic parameters were calculated using noncompartmental methods. Delafloxacin total clearance decreased with decreasing renal function, with a corresponding increase in AUC0-? . After intravenous administration, mean total clearance was 13.7 and 7.07 L/h, and mean AUC0-? was 22.6 and 45.0 ?g·h/mL in normal and severe renal subjects, respectively. Mean renal clearance as determined by urinary excretion was 6.03 and 0.44 L/h in normal and severe renal impairment subjects, respectively. Total clearance exhibited linear relationships to eGFR and CLCR . Similar observations were found after oral administration of delafloxacin. Single doses of delafloxacin 300 mg intravenously and 400 mg orally were well tolerated in all groups. In conclusion, renal insufficiency has an effect on delafloxacin clearance; a dosing adjustment for intravenous dosing is warranted for patients with severe renal impairment (eGFR < 30 mL/min).
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Project description:Background and aimThe Cockcroft-Gault (C-G) equation for estimation of creatinine clearance (CCr) is still used in a clinical setting for drug dosage adjustment. Because differences between measured and estimated CCr values have been reported, particularly for Japanese elderly people, the aim of this study was to improve the accuracy of CCr estimation equations, such as C-G and Orita-Horio, by fitting to newly obtained data. Also, glomerular filtration rate (GFR) estimation equations, such as the Modification of Diet in Renal Disease (MDRD), the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), and the eGFR equation for Japanese people, were studied to compare with measured CCr.MethodData from 313 subjects over the age of 40 years with laboratory data available were used for analysis in this study. Special attention was paid to elderly people, and approximately 70% of the subjects were over the age of 65 years.ResultsThe accuracy of estimation by the two conventional (C-G, Orita-Horio) CCr estimation equations was greatly improved by introducing adjusted body weight for which the degree of obesity is over 30% instead of measured body weight. By fitting the coefficients of the estimation equations to the present population, the mean error was reduced by almost half, particularly for people over the age of 75. Although all the values calculated by the GFR estimation equations were underestimated compared with measured CCr due to secretion, a coefficient of determination of above 0.65 was obtained for all GFR estimation equations.ConclusionsImprovement of the fitted CCr estimation equations suggests that reconstruction of renal function estimation equations is required, especially for old people. Further work is required to find optimal renal function (CCr and/or GFR) estimation equations for drug dosage adjustment.
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Project description:PURPOSE:This single-dose, randomized, open-label, parallel-group, and crossover study assessed pharmacokinetics (PK), pharmacodynamics (PD), and safety of ticagrelor in subjects on hemodialysis versus healthy subjects. METHODS:Hemodialysis subjects were randomized, receiving a single ticagrelor 90-mg dose 1 day post-hemodialysis or just before hemodialysis, with an intervening washout of ??7 days. Healthy subjects (creatinine clearance ??90 mL/min) received a single ticagrelor 90-mg dose. PK, PD (P2Y12 reaction units [PRU], inhibition of platelet aggregation [IPA]), and safety were evaluated. RESULTS:Twenty-seven subjects (14 hemodialysis, 13 healthy) received ticagrelor. The mean maximum plasma concentration (Cmax) and area under the plasma concentration curve from time zero to infinity (AUC0-?) of ticagrelor were 598.4 ng/mL and 3256.1 ng·h/mL, respectively, in pre-hemodialysis subjects; 560.3 ng/mL and 3015.1 ng·h/mL, respectively, in post-hemodialysis subjects; and 370.8 ng/mL and 2188.8 ng·h/mL, respectively, in healthy subjects. Cmax and AUC0-? of AR-C124910XX, the active metabolite, were 152.3 ng/mL and 1144.2 ng·h/mL, respectively, in pre-hemodialysis subjects; 130.8 ng/mL and 1127.8 ng·h/mL, respectively, in post-hemodialysis subjects; and 111.7 ng/mL and 1000.4 ng·h/mL, respectively, in healthy subjects. Mean IPA time curves over 24 h post-dose were almost indistinguishable for all three treatments. The greatest reduction in mean PRU occurred approximately 2 h post-dose for all three treatments. No safety or tolerability issues were identified. CONCLUSION:Hemodialysis resulted in modestly higher exposure to ticagrelor and AR-C124910XX, with no clinically significant effect on PD or tolerability. Accordingly, no dose adjustment is required for hemodialysis patients. Timing of hemodialysis has little impact on ticagrelor PK, or the effect of ticagrelor on IPA.
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Project description:Many antibiotics require dose adjustments in patients with renal impairment and/or in those undergoing hemodialysis. Omadacycline, the first aminomethylcycline antibiotic in late-stage clinical development, displays activity against a broad spectrum of bacterial pathogens, including drug-resistant strains. Data from completed phase 3 studies of omadacycline for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) showed intravenous (i.v.) to once-daily oral omadacycline to be clinically effective and well tolerated. To determine if the dosing of omadacycline should be adjusted in patients with impaired renal function, a phase 1 study examining the pharmacokinetics (PK) and safety of i.v. omadacycline (100 mg) was conducted in subjects with end-stage renal disease (ESRD) on stable hemodialysis (n = 8) and in matched healthy subjects (n = 8). i.v. administration of omadacycline produced similar plasma concentration-time profiles in subjects with ESRD and healthy subjects. Further, in subjects with ESRD, similar values of the PK parameters were observed when omadacycline was administered i.v. after or before dialysis. The mean area under the concentration-time curve from time zero extrapolated to infinity in plasma was 10.30 ?g · h/ml when omadacycline was administered to ESRD subjects after dialysis, 10.20 ?g · h/ml when omadacycline was administered to ESRD subjects before dialysis, and 9.76 ?g · h/ml when omadacycline was administered to healthy subjects. The mean maximum observed concentration of omadacycline in plasma in ESRD subjects was 1.88 ?g/ml when it was administered after dialysis and 2.33 ?g/ml when it was administered before dialysis, and in healthy subjects it was 1.92 ?g/ml. The 100-mg i.v. dose of omadacycline was generally safe and well tolerated in both ESRD and healthy subjects. This study demonstrates that no dose adjustment is necessary for omadacycline in patients with impaired renal function or on days when patients are receiving hemodialysis.
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Project description:BackgroundChronic kidney disease is an important concern in preventive medicine, but the rate of decline in renal function in healthy population is not well defined. The purpose of this study was to determine reference values for the estimated glomerular filtration rate (eGFR) and rate of decline of eGFR in healthy subjects and to evaluate factors associated with this decline using a large cohort in Japan.MethodsRetrospective cross-sectional and longitudinal studies were performed with healthy subjects aged ?18 years old who received a medical checkup. Reference values for eGFR were obtained using a nonparametric method and those for decline of eGFR were calculated by mixed model analysis. Relationships of eGFR decline rate with baseline variables were examined using a linear least-squares method.ResultsIn the cross-sectional study, reference values for eGFR were obtained by gender and age in 72,521 healthy subjects. The mean (±SD) eGFR was 83.7±14.7 ml/min/1.73 m2. In the longitudinal study, reference values for eGFR decline rate were obtained by gender, age, and renal stage in 45,586 healthy subjects. In the same renal stage, there was little difference in the rate of decline regardless of age. The decline in eGFR depended on the renal stage and was strongly related to baseline eGFR, with a faster decline with a higher baseline eGFR and a slower decline with a lower baseline eGFR. The mean (±SD) eGFR decline rate was ?1.07±0.42 ml/min/1.73 m2/year (?1.29±0.41%/year) in subjects with a mean eGFR of 81.5±11.6 ml/min/1.73 m2.ConclusionsThe present study clarified for the first time the reference values for the rate of eGFR decline stratified by gender, age, and renal stage in healthy subjects. The rate of eGFR decline depended mainly on baseline eGFR, but not on age, with a slower decline with a lower baseline eGFR.
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Project description:Brain changes reminiscent of Alzheimer disease (AD) have been previously reported in a substantial portion of elderly cognitive healthy (HC) subjects. The major aim was to evaluate the accuracy of MRI assessed regional gray matter (GM) volume, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), and neuropsychological test scores to identify those HC subjects who subsequently convert to mild cognitive impairment (MCI) or AD dementia. We obtained in 54 healthy control (HC) subjects a priori defined region of interest (ROI) values of medial temporal and parietal FDG-PET and medial temporal GM volume. In logistic regression analyses, these ROI values were tested together with neuropsychological test scores (free recall, trail making test B (TMT-B)) as predictors of HC conversion during a clinical follow-up between 3 and 4 years. In voxel-based analyses, FDG-PET and MRI GM maps were compared between HC converters and HC non-converters. Out of the 54 HC subjects, 11 subjects converted to MCI or AD dementia. Lower FDG-PET ROI values were associated with higher likelihood of conversion (p = 0.004), with the area under the curve (AUC) yielding 82.0% (95% CI = (95.5%, 68.5%)). The GM volume ROI was not a significant predictor (p = 0.07). TMT-B but not the free recall tests were a significant predictor (AUC = 71% (95% CI = 50.4%, 91.7%)). For the combination of FDG-PET and TMT-B, the AUC was 93.4% (sensitivity = 82%, specificity = 93%). Voxel-based group comparison showed reduced FDG-PET metabolism within the temporo-parietal and prefrontal cortex in HC converters. In conclusion, medial temporal and-parietal FDG-PET and executive function show a clinically acceptable accuracy for predicting clinical progression in elderly HC subjects.
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Project description:Apolipoprotein E (APOE) is the major genetic risk factor for late-onset Alzheimer's disease (AD). Inconsistent results about the role of APOE ε4 alleles on cognitive decline of community non-dementia elderly have been reported. This study aimed to examine the relationship between APOE ε4 allele and cognitive abilities in the subjects aged 60 years or above from a community in Shanghai, China. A total of 1445 participants voluntarily accepted the analysis of APOE genotype and global cognitive assay using the Mini Mental Status Evaluation (MMSE). There were no significant differences in total MMSE scores between APOE ε4 carriers and non-carriers. In addition, the performances of orientation, registration, attention, calculation, and language had no significant differences between subjects with and without APOE ε4 allele. However, stratified analysis showed that the performance of delayed recall in subjects with APOE ε4 allele was inferior to that in non-ε4 carriers (p = 0.041). Further, the multiple linear regression analysis showed the significant correlations between the presence of APOE ε4 allele and the scores of the delayed memory subdomain if age, gender, and education were adjusted but no significant correlations if the related factors were not adjusted. The results indicate that significant impact of APOE ε4 allele only on the delay memory but not on global or other sub-domains of cognitive abilities.
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Project description:Purpose:Revefenacin, a long-acting muscarinic antagonist for nebulization, has been shown to improve lung function in patients with chronic obstructive pulmonary disease. Here we report pharmacokinetic (PK) and safety results from two multicenter, open-label, single-dose trials evaluating revefenacin in subjects with severe renal impairment (NCT02578082) and moderate hepatic impairment (NCT02581592). Subjects and methods:The renal impairment trial enrolled subjects with normal renal function and severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2). The hepatic impairment trial enrolled subjects with normal hepatic function and moderate hepatic impairment (Child-Pugh class B). Subjects received a single 175-µg dose of revefenacin through nebulization. PK plasma samples and urine collections were obtained at multiple time points for 5 days following treatment; all subjects were monitored for adverse events. Results:In the renal impairment study, the maximum observed plasma revefenacin concentration (Cmax) was up to 2.3-fold higher and area under the concentration-time curve from time 0 to infinity (AUCinf) was up to 2.4-fold higher in subjects with severe renal impairment compared with those with normal renal function. For THRX-195518, the major metabolite of revefenacin, the corresponding changes in Cmax and AUCinf were 1.8- and 2.7-fold higher, respectively. In the hepatic impairment study, revefenacin Cmax and AUCinf were 1.03- and 1.18-fold higher, respectively, in subjects with moderate hepatic impairment compared with those with normal hepatic function. The corresponding changes in THRX-195518 Cmax and AUCinf were 1.5- and 2.8-fold higher, respectively. Conclusion:Systemic exposure to revefenacin increased modestly in subjects with severe renal impairment but was similar between subjects with moderate hepatic impairment and normal hepatic function. The increase in plasma exposure to THRX-195518 in subjects with severe renal or moderate hepatic impairment is unlikely to be of clinical consequence given its low antimuscarinic potency, low systemic levels after inhaled revefenacin administration, and favorable safety profile.
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