Clearance Values Research Articles

Evaluation of factors predicting the benefit from systemic oncological treatment for severely ill hospitalized patients: a retrospective study

BackgroundPatients with cancer in the disease’s end-stage with poor performance represent a challenging clinical scenario, as they have high chance of a fatal outcome due to clinical conditions, oncological emergencies, and/or metastatic disease. This study examines the factors predicting the potential benefit of “urgent” chemotherapy during hospitalization in this setting, thus addressing a research gap.MethodsThis retrospective observational study was conducted in the largest cancer center in the outskirts of São Paulo. It identified factors predicting the benefit from antineoplastic treatment in severe in-hospital patients admitted during 2019–2020, considering post-chemotherapy survival time as the main dependent variable. Data were retrieved from medical records. All patients aged ≥ 18 years, with an ECOG-PS score ≥ 2, and undergoing non-elective systemic cancer treatment were included.ResultsThis study evaluated 204 records, of which 89 were included in the final analysis. A statistically significant association with the worse outcome (death within 30 days of chemotherapy) was found with higher ECOG performance status; chemotherapy dose reduction; lower values of serum albumin, hemoglobin, and creatinine clearance; and higher values of leukocytes, neutrophils, direct bilirubin, urea, and C-reactive protein. In the multivariate analysis, only albumin remained statistically associated with the outcome (hazard ratio = 0.35; confidence interval: 0.14, 0.90; p = 0.034).ConclusionsSerum albumin and other clinical and laboratory variables might be associated with early post-treatment deaths in patients with cancer. The study data might help guide the decision to administer systemic treatment in this scenario and manage critically ill patients. This study adds to our knowledge of the factors predicting the objective benefits from “heroic” or “urgent” chemotherapy for hospitalized and severely ill patients with cancer.

Dosage optimization of tacrolimus based on the glucocorticoid dose and pharmacogenetics in adult patients with systemic lupus erythematosus

BackgroundThe purpose of the study was to develop a genotype-incorporated population pharmacokinetic (PPK) model of tacrolimus (TAC) in adults with systemic lupus erythematosus (SLE) to investigate the factors influencing TAC pharmacokinetics and to develop an individualized dosing regimen based on the model. In addition, a non-genotype-incorporated model was also established to assess its predictive performance compared to the genotype-incorporated model. MethodsA total of 365 trough concentrations from 133 adult SLE patients treated with TAC were collected to develop a genotype-incorporated PPK model and a non-genotype-incorporated PPK model of TAC using a nonlinear mixed-effects model (NONMEM). External validation of the two models was performed using data from an additional 29 patients. Goodness-of-fit diagnostic plots, bootstrap method, and normalized predictive distribution error test were used to validate the predictive performance and stability of the final models. The goodness-of-fit of the two final models was compared using the Akaike information criterion (AIC). The dosing regimen was optimized using Monte Carlo simulations based on the developed optimal model. ResultsThe typical value of the apparent clearance (CL/F) of TAC estimated in the final genotype-incorporated model was 14.3 L h−1 with inter-individual variability of 27.6%. CYP3A5 polymorphism and coadministered medication were significant factors affecting TAC-CL/F. CYP3A5 rs776746 GG genotype carriers had only 77.3% of the TAC-CL/F of AA or AG genotype carriers. Omeprazole reduced TAC-CL/F by 3.7 L h−1 when combined with TAC, while TAC-CL/F increased nonlinearly as glucocorticoid dose increased. Similar findings were demonstrated in the non-genotype-incorporated PPK model. Comparing these two models, the genotype-incorporated PPK model was superior to the non-genotype-incorporated PPK model (AIC = 643.19 vs. 657.425). Monte Carlo simulation based on the genotype-incorporated PPK model indicated that CYP3A5 rs776746 AA or AG genotype carriers required a 1/2–1 fold higher dose of TAC than GG genotype carriers to achieve the target concentration. And as the daily dose of prednisone increases, the dose of TAC required to reach the target concentration increases appropriately. ConclusionsWe developed the first pharmacogenetic-based PPK model of TAC in adult patients with SLE and proposed a dosing regimen based on glucocorticoid dose and CYP3A5 genotype according to the model, which could facilitate individualized dosing for TAC.

Association Between Biomarkers of Kidney Disorders and Atrial Fibrillation: A Literature Review

Kidney diseases and atrial fibrillation often occur together. Renal impairment increases the risk of developing incident atrial fibrillation (AF) and is linked to it in a bidirectional manner, making it a prothrombotic and pro-hemorrhagic condition. In Japanese patients with nonvalvular AF, lower creatinine clearance values were associated with thromboembolism, all-cause death, and cardiovascular death, but not with major haemorrhage. Older individuals with elevated serum levels of cystatin C had a significantly higher prevalence of AF. Moderate to severe chronic kidney disease individuals with increased levels of fibroblast growth factor-23 were independently associated with prevalent and incident AF. A higher baseline glomerular filtration rate was associated with an increased risk of AF. Elevated levels of insulin-like growth factor binding protein-7 were also observed in AF patients, while reduced circulating tissue inhibitor of metalloproteinase 2 levels were also associated with an increased risk of AF. Patients with AF had higher levels of non-esterified fatty acids and liver type fatty acid binding protein. Interleukin-18 levels in blood plasma were also found to be higher in AF patients. Furthermore, higher baseline urea/blood urea nitrogen levels were significantly associated with the incidence of AF in women and kidney disease in both men and women.

Novel Ferrocenyl-substituted Organometallics with Pyrimidine Moiety as Potent Antiprotozoal Agents: Synthesis, Characterization and in Silico Evaluation

Metallodrugs have been extensively used in modern research to design and synthesize new core drug molecules. In search of new leads in protozoal chemotherapy, we have synthesized novel ferrocene-substituted pyrimidine-based organometallic compounds and thoroughly investigated their ADMET [Absorption, distribution, metabolism, excretion and toxicity] and pharmacokinetic properties. The compounds exhibited excellent solubility potential, with favourable permeability and absorption characteristics. They demonstrated low toxicity, as indicated by clearance values and oral toxicity measurements. Molecular docking studies revealed strong interactions with the target site, surpassing the performance of reference drugs metronidazole and ornidazole. Overall, these organometallic compounds possess desirable ADMET profiles, meet Lipinski's criteria, and exhibit promising drug-likeness properties, positioning them as potential leads for the development of effective antiprotozoal agents.

Population Pharmacokinetic Analysis of Follicle-Stimulating Hormone During Ovarian Stimulation: Relation with Weight, Prolactin and Gene Polymorphism in THADA and ADIPOQ.

Personalisation strategies of ovarian stimulation for in vitro fertilisation (IVF)/ intracytoplasmic sperm injection (ICSI) treatments using exogenous follicle-stimulating hormone (FSH) have been extensively studied over the past 20 years. This research aimed to develop a FSH population pharmacokinetic (PPK) model taking into account the contribution of gene polymorphisms in Chinese reproductive-age women. Data from 173 patients undergoing GnRH agonist down-regulation long protocols of IVF/ICSI treatment were collected. PPK analysis was subsequently conducted using the nonlinear mixed-effect model (NONMEM) software. Several covariates, including 18 single nucleotide polymorphisms, demographic factors and biological characteristics, were evaluated. The final PPK model was extensively validated using bootstrapping and normalised prediction error distribution, as well as external validation on an independent group of 35 patients. FSH PPK was accurately described by a one-compartment model with first-order absorption. The typical population value of apparent clearance was estimated to be 0.81 L/h [relative standard errors (RSE) 5.3%] with an inter-individual variability (IIV) of 16.0%. The typical apparent distribution volume was 8.36 L (RSE 9.7%, 59.7% IIV), and the absorption rate constant was estimated to be 0.0444 h-1 (RSE 9.1%). Body weight, basal prolactin concentration and the gene ADIPOQ (rs1501299) showed a significant covariate effect on the FSH clearance rate and exposure concentration. Genotypes of THADA (rs12478601) significantly influenced the distribution volume. Simulation results indicated that patients with the TT genotype of THADA (rs12478601) required a longer time to reach steady state and had less fluctuation in FSH levels. Model evaluations showed that the final model accurately and precisely described the observed data and demonstrated effective prediction performance. PPK models of FSH have been developed, which could potentially be used for FSH dosage individualisation in the clinical setting. This study has been registered with the Chinese Clinical Trials Registry (ChiCTR2100049142).

An observational cohort study of histological screening for BK polyomavirus nephropathy following viral replication in plasma

Systematic screening for BKPyV-DNAemia has been advocated to aid prevention and treatment of polyomavirus associated nephropathy (PyVAN), an important cause of kidney graft failure. The added value of performing a biopsy at time of BKPyV-DNAemia, to distinguish presumptive PyVAN (negative SV40 immunohistochemistry) and proven PyVAN (positive SV40) has not been established. Therefore, we studied an unselected cohort of 950 transplantations, performed between 2008-2017. BKPyV-DNAemia was detected in 250 (26.3%) transplant recipients, and positive SV40 in 91 cases (9.6%). Among 209 patients with a concurrent biopsy at time of first BKPyV-DNAemia, 60 (28.7%) biopsies were SV40 positive. Plasma viral load showed high diagnostic value for concurrent SV40 positivity (ROC-AUC 0.950, 95% confidence interval 0.916-0.978) and the semiquantitatively scored percentage of tubules with evidence of polyomavirus replication (pvl score) (0.979, 0.968-0.988). SV40 positivity was highly unlikely when plasma viral load is below 4 log10 copies/ml (negative predictive value 0.989, 0.979-0.994). In SV40 positive patients, higher plasma BKPyV-DNA load and higher pvl scores were associated with slower viral clearance from the blood (hazard ratio 0.712, 95% confidence interval 0.604-0.839, and 0.327, 0.161-0.668, respectively), whereas the dichotomy positivity/negativity of SV40 immunohistochemistry did not predict viral clearance. Although the pvl score offers some prognostic value for viral clearance on top of plasma viral load, the latter provided good guidance for when a biopsy was unnecessary to exclude PyVAN. Thus, the distinction between presumptive and proven PyVAN, based on SV40 immunohistochemistry, has limited clinical value. Hence, management of BKPyV-DNAemia and immunosuppression reduction should be weighed against the risk of occurrence of rejection, or exacerbation of rejection observed concomitantly.

Population pharmacokinetics of polymyxin B in patients with liver dysfunction.

Polymyxin B (PMB) is widely used to treat infections caused by multidrug-resistant Gram-negative pathogens. Currently, the pharmacokinetic data of PMB in patients with liver dysfunction are limited. This study aimed to develop a population pharmacokinetic (PopPK) model of PMB in patients with liver dysfunction and identify the factors affecting PMB pharmacokinetics. We conducted a retrospective pharmacokinetic study involving 136 adults with different levels of liver function. Nonlinear mixed effects modelling was used to develop a PopPK model of PMB. Monte Carlo simulation was used to design PMB dosage schedules across various liver and renal functions. PMB pharmacokinetic analyses included 401 steady-state concentrations in 136 adult patients. A one-compartment pharmacokinetic model with first-order absorption and elimination was used to describe the data. The typical population value of PMB clearance was 2.43 L/h and the volume of distribution was 23.11 L. This study revealed that creatinine clearance (CrCL) and Child-Pugh class were significantly associated with PMB pharmacokinetic parameters; however, clinically relevant variations of dose-normalized drug exposure were not significant. For patients with a minimum inhibitory concentration of ≤0.5mg/L, the appropriate dose was 40-75 mg/12-h. When the dose exceeded 100 mg/12-h, the risk of nephrotoxicity increased significantly. This study provided PMB pharmacokinetic information for patients with liver dysfunction. Patients with renal and liver dysfunctions may not require an initial dose adjustment. Rather than PopPK-guided dose adjustment, therapeutic drug monitoring of PMB plays a more direct role in optimizing dosing regimens based on its therapeutic window.

Computational Investigation of Effect of Tip Clearance in an Annular Turbine Rotor Impulse Cascade

This paper describes three dimensional computational investigations of the effect of the tip clearance on the secondary and tip clearance flows in an annular turbine rotor cascade with non uniform inlet flow. In the actual turbine, the flow at inlet of the rotor is non uniform due to radial pressure gradient acting from the hub to casing. To provide non uniformity at the rotor cascade inlet, an annular nozzle cascade is provided at the upstream. The studies are carried out with the help of a commercially available CFD package. The studies have been carried out for four values of clearance, i.e. 0%, 1%, 3% and 5% of chord. Detailed comparison of the leakage flow direction, pressure gradient, and leakage vortex size, losses, location and interaction with other flow features is carried out. The results are presented in terms of static pressure coefficient distribution on the blade surfaces and total pressure loss coefficient contours in the passage. Spanwise distributions of the circumferentially averaged loss coefficient and flow angle are presented. The extent of losses in the circumferential direction is increased with the increase in the height of the tip clearance but reduced in the spanwise direction. The mass averaged loss coefficient increases rapidly from 0.24 at zero clearance to 0.42 at 1% tip clearance. As the tip clearance is further increased, the losses increase slowly (0.54 at 3% tip clearance to 0.58 at 5% tip clearance). The mass averaged flow angle decreases from 66.3° at zero clearance to 63.7° at 1% clearance to 60.1° at 3% clearance and to 57.3° at 5% clearance.

Prevention of contrast induced-acute kidney injury using coenzyme Q10 in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.

We assessed the potential effect of CoQ10 administration for the prevention of contrast induced-acute kidney injury (CI-AKI) in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). One hundred fifty STEMI patients who were candidates for primary PCI, along with intravenous saline hydration, randomly received a placebo or CoQ10. CoQ10 was administrated orally, 400 mg before the procedure and 200 mg twice daily after the procedure for three consecutive days. Serum creatinine concentration and corresponding creatinine clearance (estimated by the CKD Epidemiology Collaboration (CKD-EPI) creatinine equation) were measured at baseline and 24, 48, and 72 h after primary PCI. Furthermore, the serum level of superoxide dismutase (SOD), total antioxidant capacity (TAC), and malondialdehyde (MDA) was measured before and 72 h after primary PCI. The mean serum creatinine concentration before contrast administration was similar in the two groups (0.98 ± 0.08 versus 0.99 ± 0.09mg/dL). While in both study groups, compared to baseline, the mean serum creatinine concentration increased at 48 and 72 h after contrast exposure, the CoQ10 group showed a lower serum creatinine concentration than the placebo group (P-value = 0.017 and 0.004, respectively). However, comparing the mean values of creatinine clearance between the groups at the study time points did not demonstrate a statistically significant difference. CI-AKI, defined as a > 25% or 0.5 mg/dL increase in baseline serum creatinine concentration, occurred in 8.00% of the cases in the CoQ10 group versus 20.00% in the placebo group (P-value = 0.034). Furthermore, at 72 h, the CoQ10-treated group exhibited higher serum levels of SOD and TAC and a lower MDA level than the placebo-treated group. Our research's findings proposed CoQ10 supplementation as an adjuvant to saline hydration as a preventive approach against CI-AKI. The trial was registered at Iranian Registry of Clinical Trials ( https://www.irct.ir/trial/60435 , identifier code: IRCT20120215009014N414). Registration date: 2021-12-29.

Initial dosage optimisation of cyclosporine in Chinese paediatric patients undergoing allogeneic haematopoietic stem cell transplantation based on population pharmacokinetics: a retrospective study

ObjectiveImproved understanding of cyclosporine A (CsA) pharmacokinetics in children undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT) is crucial for effective prevention of acute graft-versus-host disease and medication safety. The aim...

Design of Z Profile Roller Tooling and Research on Roller Clearance

In metal processing, bending forming is widely applied in various fields. To prevent excessive surface scratching and heavy indentation on the profiles, which can negatively affect the surface quality, it is often necessary to determine the clearances between the rollers and the upper and lower surfaces of the profiles using experimental methods. However, this experimental approach not only results in material waste but also fails to determine the optimal clearance value. Therefore, orthogonal experiments were conducted to design different clearances between the rollers and the upper and lower surfaces of the profiles to mitigate the issues of excessive surface scratching and poor surface quality during the bending forming process of large-section Z-profiles. Finite element simulation was employed to simulate the different experiments, and a range analysis was performed on the experimental results to obtain the optimal clearance value. The obtained results fall within the range of results obtained from traditional experimental methods, indicating its consistency with actual practice, higher accuracy, and scientific rigor compared with experimental methods. Furthermore, the roller tooling design was revised based on the optimal clearance value for the profile processing. The experimental results demonstrate that the surface quality of the profiles processed with optimal clearance is superior to those processed without it. Additionally, this study presents a comprehensive methodology for roller tooling design and investigates the influence of different loading modes on the local wrinkling deformation of the profiles.

Analytical and Experimental Investigation of Product Geometry and Dimensional Accuracy in the Punching Process of AA 1050 and AA 1070 Sheets

Punching is a widely used and economic manufacturing method that needs to be addressed. Especially the forces that occurred during punching and the dimensions of the parts obtained from punching are important in manufacturing processes. This study aimed to examine the cutting forces that occur in the punching process and the dimensional accuracy of the parts. AA 1050 and AA 1070 sheet materials were used in the experimental studies. Five punches with different tip geometries were used in the punching processes. Punching operations were carried out at a constant clearance value and press speed. The geometries of the specimens obtained from the experimental studies were examined using stereo and shuttle-pix microscopes. In addition, punching processes were also investigated using the finite element method. The consistency of the finite element model was analyzed by comparing experimental and numerical studies. The highest cutting force occurred in the use of the flat punch geometry. The lowest cutting force was obtained by using the largest angled punch geometry. It has been determined that the dimensional accuracy of not only the blank but the falling part is better in the use of the flat punch geometry comparing the other punches used. In addition, it was observed that experimental and theoretical studies are compatible with each other. It is thought that finite element software can provide time and cost savings in determining the cutting force of materials.

Limited Sampling Strategy Using End of Infusion and Six-Hour Concentrations Overestimates Intravenous Busulfan Clearance Compared With Standard Six-Point Sampling in Hematopoietic Stem Cell Transplant Patients.

Therapeutic drug monitoring for busulfan (Bu) is important to improve outcomes of hematopoietic stem cell transplantation. However, standard therapeutic drug monitoring requires multiple samples and is inconvenient, labor-intensive, and costly. Accordingly, a limited sampling strategy (LSS) was evaluated, using 2-point sampling at end of infusion and at 6 hours, and the area-under-the-curve and Bu clearances (CLs) were compared with the results obtained from the standard sampling strategy (SSS) using 5-6 samples. The analysis was based on retrospective clinical data from 202 patients receiving intravenous Bu before hematopoietic stem cell transplantation for malignant or nonmalignant conditions. Bu plasma concentrations were measured via liquid chromatography tandem-mass spectrometry, and pharmacokinetic parameters were calculated using the PKCNA package in R program. A total of 502 doses were analyzed by applying SSS and LSS. Using the modified Bland-Altman plot, the mean percentage difference in CL between the SSS and LSS estimates of Bu 6-hourly regimen was -41% (Limits: -53% and -30%). In the once daily regimen, the mean difference in CL between the 2 strategies on the modified Bland-Altman plot was -22% (Limits: -66% and +22%). The Bu CL values estimated based on the BU concentration at end of infusion and at 6 hours postinfusion were significantly higher than the values obtained via the SSS.

Studying the system of diagnostic parameters of the hydraulic drive taking into account the measurement error

Problem. The article considers a methodology for improving the efficiency of operational performance of mobile machines due to the perfection of the hydraulic drive diagnostic system, which is determined by the improvement of design, manufacture, and operation. Goal. The modern development of diagnostic methods is carried out through the use of more accurate or non-contact measuring instruments, and the technical condition of most hydraulic units is determined by the size of the gaps in the joints of their parts. Methodology. The study of the relationship between structural and diagnostic parameters based on the mathematical model of the hydraulic drive made it possible to develop diagnostics of hydraulic units of mobile machines by measuring the determining diagnostic parameter (performance or pressure) at one point of the hydraulic drive, as well as to establish analytical dependencies that determine the error of diagnosing hydraulic units and its components under uncertainty of the values of the gaps in these hydraulic units. Results. The presented work continues research in this direction and establishes the properties of the system of diagnostic parameters, in which the pump speed is the determining parameter. Originality. The properties of the system of diagnostic parameters, in which the pump speed is the determining parameter, are established. The relationship between the standard and the investigated systems of diagnostic parameters is established. Practical value. The equations are obtained and the diagnostic errors of hydraulic units and the components of these errors are determined using these equations when diagnosing by pump speed under the condition of uncertainty in the values of pump clearances. The results are compared with a standard diagnostic system.

Intelligent Diagnostics of Radial Internal Clearance in Ball Bearings with Machine Learning Methods

This article classifies the dynamic response of rolling bearings in terms of radial internal clearance values. The value of the radial internal clearance in rolling-element bearings cannot be described in a deterministic manner, which shows the challenge of its detection through the analysis of the bearing’s dynamics. In this article, we show the original approach to its intelligent detection through the analysis of short-time intervals and the calculation of chosen indicators, which can be assigned to the specific clearance class. The tests were carried out on a set of 10 brand new bearings of the same type (double row self-aligning ball bearing NTN 2309SK) with different radial internal clearances corresponding to individual classes of the ISO-1132 standard. The classification was carried out based on the time series of vibrations recorded by the accelerometer and then digitally processed. Window statistical indicators widely used in the diagnosis of rolling bearings, which served as features for the machine learning models, were calculated. The accuracy of the classification turned out to be unsatisfactory; therefore, it was decided to use a more advanced method of time series processing, which allows for the extraction of subsequent dominant frequencies into experimental modes (Variational Mode Decomposition (VMD)). Applying the same statistical indicators to the modes allowed for an increase in classification accuracy to over 90%.

The influence of shoulder-workpiece clearance on channel formation during friction stir channeling at low and high heat inputs

Friction stir channeling (FSC) is a newly developed manufacturing process that can replace the traditional fabrication processes of cooling channels for heat exchangers. Regardless of its application, the size and shape of a cooling channel are fundamental to its efficiency. In FSC, clearance between the shoulder of the tool and the workpiece top surface is a prime factor that significantly influences channel size and shape. This study examined the effect of clearance on channel characteristics using two different clearance values, 0.8 mm and 1.2 mm, respectively. The process parameters are chosen in such a way that the effect of clearance can be understood under low and high heat input conditions on several characteristics. These include channel geometry, dimensions, roof thickness, the roughness of the internal surface of the channel walls, and their topography. A rectangular channel geometry with a larger height and width was found to form at 1.2 mm clearance with high heat input parameters. Lower clearance at low heat input resulted in a successful channel, but a higher clearance value produced a defective channel for the same parameters. In conclusion, the results demonstrate how clearance and the amount of heat input are co-dependent to produce a channel with enhanced characteristics that may directly influence the performance of a cooling channel in various heat exchanger applications.

Clinical significance of serum urea-to-creatinine ratio in patients undergoing peritoneal dialysis.

We aimed to determine the correlation between the serum urea-to-creatinine ratio and residual kidney function (RKF) in patients undergoing peritoneal dialysis (PD), as well as its predictive value for PD-related outcomes. This study included a cross-sectional study to assess the correlation between serum urea-to-creatinine ratio and RKF in 50 patients on PD and a retrospective cohort study to assess the association between serum urea-to-creatinine ratio and PD-related outcomes in 122 patients who initiated PD. Serum urea-to-creatinine ratios had significant positive correlations with renal Kt/V and creatinine clearance values (r = 0.60, p < 0.001 and r = 0.61, p < 0.001, respectively). Additionally, serum urea-to-creatinine ratio was significantly associated with a lower risk of transfer to hemodialysis or PD/hemodialysis hybrid therapy (hazard ratio: 0.84, 95% confidence interval: 0.75-0.95). The serum urea-to-creatinine ratio can be an indicator of RKF and a prognostic factor in patients undergoing PD.

Establishing Population Pharmacokinetic Model for Ethambutol on Pulmonary Tuberculosis Patients

The population pharmacokinetic model of ethambutol with covariates was built from data from 136 pulmonary tuberculosis patients recruited from 3 hospitals: Hanoi Lung Hospital, Central Hospital 74, and Central Lung Hospital. Blood samples were obtained on the 10-14th day after initiation of treatment for plasma drug analysis by LC-MS/MS method. Time - concentration data were processed by the method of non-linear mixed effect modeling on MONOLIX 2021R1 software. The final population pharmacokinetic model is a two-compartment model, sequential zero (with prior lag time Tk01) followed by first-order absorption, and linear elimination. The volumes of distribution of the central and peripheral compartments were respectively 6.73 L and 1250 L; the clearance value Cl was 45.8 L/h. Janmahasatian’s Fat-free mass and age were found to be influential to the inter-individual variability of clearance.

The effect of glycine on oxidative stress, inflammation and renin-angiotensin system in kidneys and aorta of cyclosporine-administered rats

Cyclosporine A (CsA) is an immunosuppressive drug, used in organ transplantations. Oxidative stress, inflammation and renin-angiotensin system (RAS) activation play an important role in CsA-toxicity. Glycine (Gly) has antioxidant and anti-inflammatory effects. In this study, Gly was investigated for its protective role against CsA-induced toxicity. CsA (20 mg/kg/day; subcutaneously) was administered to rats along with Gly injection (250 or 1000 mg/kg; intraperitoneally) for 21 days. Renal function markers [serum urea and creatinine and urinary protein and kidney injury molecule levels and creatinine clearance values] together with histopathological examinations were performed. Oxidative stress (reactive oxygen species, thiobarbutiric acid reactive substances, advanced oxidation products of protein, glutathione, ferric reducing anti-oxidant power and 4-hydroxynonenal levels), and inflammation (myeloperoxidase activity) were determined in kidney tissue. The RAS system [angiotensin II (Ang II) levels, and mRNA expressions of angiotensin converting enzyme (ACE), angiotensin II type-I receptor (AT1R)] and NADPH-oxidase 4 (NOX4) were measured in kidney and aorta. CsA caused significant disturbances in renal function markers, increases in oxidative stress and inflammation parameters and renal damage. Serum angiotensin II levels and mRNA expressions of ACE, AT1R and NOX4 elevated in the aorta and kidney of CsA-rats. Gly, especially its high-dose, alleviated renal function markers, oxidative stress, inflammation and renal damage in CsA-rats. Moreover, serum Ang II levels and mRNA expressions of ACE, AT1R and NOX4 decreased significantly in aorta and kidney in CsA-rats due to Gly treatment. Our results indicate that Gly may be useful for the prevention of CsA-induced renal and vascular toxicity.

#4905 PERITONEAL CLEARANCE OF TRACE ELEMENTS IN PERITONEAL DIALYSIS PATIENTS

Abstract Background and Aims Both accumulations and deficiencies of trace elements (TE) could be seen in peritoneal dialysis (PD) patients. Peritoneal clearance remains major route of elimination for many solutes including TE, in PD patients. Imbalances of TE may have deleterious effects on the patients. Data on TE balances in PD patients are inadequate. Here, we present some data from a larger study. We aimed to analyze peritoneal clearance of Boron (B), Cupper (Cu), Zinc (Zn), Selenium (Se), Strontium (Sr) and Molybdenum (Mo) in a cohort of PD patients. Method This cross-sectional study included three female and five male PD patients giving consent for the study. Mean age was 43,6±5,6 and patients were on continuous ambulatory PD for at least three months. Patients with recent peritonitis were excluded. Peritoneal solutions were individualized, so had different osmolarities. A sample of plasma and 24-hour spent dialysate was analyzed by inductively coupled plasma mass spectrometry (ICP-MS) (Thermo Scientific™ iCAP Q ICP-MS, USA). Sensitivity was on the order of ppb (μg/L). A control group (CG) with glomerular filtration rate ≥ 90 ml/min were used for comparison of plasma levels of TE. Peritoneal clearances were calculated by the following formula: ${{24 \!-\! hour \, spent\, dialysate\, volume \!\times\! \displaystyle\frac{{dialysate\ concentration\ of\ the\ trace\ element}}{{plasma\ concentration\ of\ the\ trace\ element}}}}$ Results Data on plasma levels, clearances and daily loss of TE are shown in the Table 1. The clearances were ordered from smallest to largest as follows: Zn, Cu, Se, Sr, Mo, Ni, B. On the other hand, spent dialysate daily element losses were ordered from smallest to highest as follows: Cr, Ni, Se, Mo, Cu, Sr, Zn, B Conclusion Our study provides data on elimination of some trace elements, which may help to better understand the TE balance in PD patients. Data suggest that B has the highest and Zn the lowest peritoneal clearance values.