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Journal of the American Society of... May 2014Cubilin is an endocytic receptor highly expressed in renal proximal tubules, where it mediates uptake of albumin and filtered forms of apoA-I/HDL. Cubilin deficiency...
Cubilin is an endocytic receptor highly expressed in renal proximal tubules, where it mediates uptake of albumin and filtered forms of apoA-I/HDL. Cubilin deficiency leads to urinary loss of albumin and apoA-I; however, the consequences of cubilin loss on the homeostasis of blood albumin and apoA-I/HDL have not been studied. Using mice heterozygous for cubilin gene deletion (cubilin HT mice), we show that cubilin haploinsufficiency leads to reduced renal proximal tubular uptake of albumin and apoA-I and significantly increased urinary loss of albumin and apoA-I. Moreover, cubilin HT mice displayed significantly decreased blood levels of albumin, apoA-I, and HDL. The levels of albumin and apoA-I protein or mRNA expressed in the liver, kidney, or intestine of cubilin HT mice did not change significantly. The clearance rate of small HDL3 particles (density>1.13 g/ml) from the blood increased significantly in cubilin HT mice. In contrast, the rate of clearance of larger HDL2 particles from the blood did not change significantly, indicating a decreased half-life for HDL particles capable of filtering through the glomerulus. On the basis of these findings, we conclude that cubilin deficiency reduces renal salvage and delivery back to the blood of albumin and apoA-I, which decreases blood levels of albumin and apoA-I/HDL. These findings raise the possibility that therapeutic increase of renal cubilin expression might reduce proteinuria and increase blood levels of albumin and HDL.
Topics: Albumins; Albuminuria; Animals; Apolipoprotein A-I; Gene Deletion; Genetic Carrier Screening; Humans; Kidney Glomerulus; Lipoproteins, HDL; Lipoproteins, HDL3; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Receptors, Cell Surface
PubMed: 24357674
DOI: 10.1681/ASN.2013060671 -
Clinical Pharmacokinetics Jun 2022Despite the surge in use of extracorporeal membrane oxygenation (ECMO) in the adult intensive care unit, little guidance is available on the appropriate dosing of...
BACKGROUND
Despite the surge in use of extracorporeal membrane oxygenation (ECMO) in the adult intensive care unit, little guidance is available on the appropriate dosing of antimicrobials in this setting. Ceftriaxone is an antimicrobial with a high affinity to plasma protein, a property identified in the literature as susceptible to sequestration into extracorporeal circuits and hypothesised to require dosage adjustments in this setting.
OBJECTIVE
The aim of this study was to describe the pharmacokinetics of ceftriaxone and identify the best dosing regimen for critically ill adult patients receiving ECMO.
METHODS
Serial blood samples were taken from patients receiving both ECMO and ceftriaxone. Total and unbound drug concentrations were measured in plasma by chromatographic assay and analysed using a population pharmacokinetic approach with Pmetrics. Dosing simulations were performed to identify the optimal dosing strategy: 60 and 100% of time with free (unbound) drug concentration exceeding the minimum inhibitory concentration (fT).
RESULTS
In total, 14 patients were enrolled, of which three were receiving renal replacement therapy (RRT). Total and unbound ceftriaxone was best described in a two-compartment model with total body weight, serum albumin concentrations, creatinine clearance (CrCL), and the presence of RRT included as significant predictors of pharmacokinetics. Patients not on RRT generated a mean renal clearance of 0.90 L/h, non-renal clearance of 0.33 L/h, and central volume of distribution of 7.94 L. Patients on RRT exhibited a mean total clearance of 1.18 L/h. ECMO variables were not significant predictors of ceftriaxone pharmacokinetics. Steady-state dosing simulations found that dosages of 1 g every 12 h and 2 g every 24 h achieved >90% probabilities of target attainment in patients with CrCL of 0 mL/min with RRT and 30 and 100 mL/min and various serum albumin concentrations (17 and 26 g/L).
CONCLUSIONS
Dosing recommendations for critically ill adult patients not on ECMO appear to be sufficient for patients on ECMO. Patients exhibiting augmented renal clearance (> 130 mL/min) or treatment of less susceptible pathogens may require higher doses, which requires further investigation.
Topics: Adult; Anti-Bacterial Agents; Ceftriaxone; Critical Illness; Extracorporeal Membrane Oxygenation; Humans; Microbial Sensitivity Tests; Serum Albumin
PubMed: 35253107
DOI: 10.1007/s40262-021-01106-x -
Journal of Pharmacy & Pharmaceutical... 2018Alveolar clearance of proteins, such as albumin, plays an essential role in recovery from lung injuries. Albumin is known to be oxidized by reactive oxygen species...
PURPOSE
Alveolar clearance of proteins, such as albumin, plays an essential role in recovery from lung injuries. Albumin is known to be oxidized by reactive oxygen species (ROS), leading to generation of advanced oxidation protein products (AOPP)-albumin in the alveolar lining fluid. In this study, we aimed to characterize the uptake of FITC-labeled AOPP-albumin (FITC-AOPP-albumin) into human alveolar epithelial cell line, A549.
METHODS
FITC-AOPP-albumin uptake into A549 cells and its effect of ROS generation was evaluated using fluorescence spectrometer and flow cytometry, respectively.
RESULTS
FITC-AOPP-albumin was taken up by A549 cells in a time- and temperature-dependent fashion, and showed saturation kinetics with a Km value of 0.37 mg/mL. The uptake of FITC-AOPP-albumin was suppressed by phenylarsine oxide, a clathrin-mediated endocytosis inhibitor, but not by indomethacin and nystatin, caveolae-mediated endocytosis inhibitors, or 5-(N-ethyl-N-isopropyl) amiloride, a macropinocytosis inhibitor. AOPP-albumin induced ROS generation in A549 cells, suggesting that alveolar clearance of AOPP-albumin should be important to prevent further ROS generation.
CONCLUSION
AOPP-albumin is transported into alveolar epithelial cells through clathrin-mediated endocytosis, which may be important to prevent further ROS generation. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
Topics: A549 Cells; Advanced Oxidation Protein Products; Alveolar Epithelial Cells; Flow Cytometry; Fluorescein-5-isothiocyanate; Humans; Reactive Oxygen Species; Serum Albumin; Temperature; Time Factors
PubMed: 29975628
DOI: 10.18433/jpps29905 -
The Journal of Cell Biology Nov 1983The intra- and transcellular transports of hepatic secretory and membrane proteins were studied in rats in vivo using [3H]fucose and [35S]cysteine as metabolic...
The intra- and transcellular transports of hepatic secretory and membrane proteins were studied in rats in vivo using [3H]fucose and [35S]cysteine as metabolic precursors. Incorporated radioactivity in plasma, bile, and liver subcellular fractions was measured and the labeled proteins of the Golgi complex, bile, and plasma were separated by SDS PAGE and identified by fluorography. 3H-radioactivity in Golgi fractions peaked at 10 min postinjection (p.i.) and then declined concomitantly with the appearance of labeled glycoproteins in plasma. Maximal secretion of secretory fucoproteins from Golgi occurred between 10 and 20 min p.i. In contrast, the clearance of labeled proteins from Golgi membrane subfractions occurred past 30 min p.i., indicating that membrane proteins leave the Golgi complex at least 30 min later than the bulk of content proteins. A major 80,000-dalton form of secretory component (SC) was identified in the bile by co-precipitation with (IgA)2 by an anti-IgA antibody. An antibody (raised in rabbit) against the biliary 80,000-dalton peptide recognized two larger forms (116,000 and 94,000 dalton), presumably precursors, in Golgi membranes. A comparative study of kinetics of transport of 35S-SC and 35S-albumin showed that albumin peaked in bile at approximately 45 min p.i., whereas the SC peak occurred at 80 min p.i., suggesting that the transit time differs for plasma and membrane proteins that are delivered to the bile canaliculus.
Topics: Albumins; Animals; Bile; Cysteine; Fucose; Golgi Apparatus; Immunoglobulin Fragments; Liver; Male; Membrane Proteins; Molecular Weight; Rats; Rats, Inbred Strains; Secretory Component
PubMed: 6630294
DOI: 10.1083/jcb.97.5.1582 -
Nephrology (Carlton, Vic.) Jun 2022To compare small, middle and large-middle molecule clearance; and expression of markers of inflammation, between Solacea-190H (asymmetric cellulose triacetate [ATA]) and... (Randomized Controlled Trial)
Randomized Controlled Trial
A pilot study comparing the efficiency of a novel asymmetric cellulose triacetate (ATA) dialyser membrane (Solacea-190H) to a standard high flux polysulfone dialyser membrane (FX-80) in the setting of extended hours haemodialysis.
AIM
To compare small, middle and large-middle molecule clearance; and expression of markers of inflammation, between Solacea-190H (asymmetric cellulose triacetate [ATA]) and FX-80 dialysers in long-hour haemodialysis patients.
METHODS
This pilot, randomized cross-over trial recruited 10 home haemodialysis patients. The total study duration was 8 weeks, using each dialyser for 4 weeks. Removal of small (urea, phosphate, creatinine and indoxyl sulfate [IS]), middle and large-middle molecules (beta-2 microglobulin [β2M], albumin), markers of inflammation (interleukin-6 [IL-6], malondialdehyde-modified low density lipoprotein [MDA-LDL] and alpha-1 microglobulin [α1M]), was evaluated in serum and dialysate samples.
RESULTS
Reduction ratios [RR] were calculated for variables at the fourth week of each dialyzer sequence and results expressed as difference in mean RR between dialyzers. There was no difference in clearance of small molecules, with difference in mean RR for urea -2.43 (95% CI -6.44, 1.57; p = .19), creatinine -1.82 (95% CI -5.50, 1.85; p = .28) and phosphate -2.61 (95% CI -12.45, 7.23; p = .55); clearance of middle and large-middle molecules with difference in mean RR (range) for β2M 2.2 (95% CI -3.2, 7.7; p = .35), IS 1.8 (95% CI -9.5, 13; p = .72) and albumin -0.6 (95% CI -5.5, 4.2; p = .77). There was lack of induction of markers of inflammation, including IL-6 15.2 (95% CI -31.9, 62.2; p = .47), MDA-LDL -8.1 (95% CI -22.1, 5.8; p = .21) and α1M -3.50 (95% CI -29.2, 22.2; p = .76). Dialysate removal results were concurrent.
CONCLUSION
This study showed no difference in clearance of small, middle and large-middle molecules, nor expression of markers of inflammation between dialysers.
Topics: Albumins; Cellulose; Creatinine; Dialysis Solutions; Fluorocarbons; Furans; Humans; Inflammation; Interleukin-6; Membranes, Artificial; Phosphates; Pilot Projects; Polymers; Renal Dialysis; Sulfones; Urea; beta 2-Microglobulin
PubMed: 35195932
DOI: 10.1111/nep.14030 -
International Journal of Molecular... Jan 2023Cadmium (Cd) is a toxic metal that accumulates in kidneys, especially in the proximal tubular epithelial cells, where virtually all proteins in the glomerular...
Cadmium (Cd) is a toxic metal that accumulates in kidneys, especially in the proximal tubular epithelial cells, where virtually all proteins in the glomerular ultrafiltrate are reabsorbed. Here, we analyzed archived data on the estimated glomerular filtration rate (eGFR) and excretion rates of Cd (E), total protein (E), albumin (E), β-microglobulin (E), and α1-microglobulin (E), which were recorded for residents of a Cd contamination area and a low-exposure control area of Thailand. Excretion of Cd and all proteins were normalized to creatinine clearance (C) as E/C and E/C to correct for differences among subjects in the number of surviving nephrons. Low eGFR was defined as eGFR ≤ 60 mL/min/1.73 m, while proteinuria was indicted by E/C ≥ 20 mg/L of filtrate. E/C varied directly with E/C (β = 0.263, < 0.001) and age (β = 0.252, < 0.001). In contrast, eGFR values were inversely associated with E/C (β = -0.266, < 0.001) and age (β = -0.558, < 0.001). At E/C > 8.28 ng/L of filtrate, the prevalence odds ratios for proteinuria and low eGFR were increased 4.6- and 5.1-fold, respectively ( < 0.001 for both parameters). Thus, the eGFR and tubular protein retrieval were both simultaneously diminished by Cd exposure. Of interest, E/C was more closely correlated with E/C ( = 0.507), E ( = 0.430), and E/C ( = 0.364) than with E/C ( = 0.152). These data suggest that Cd may differentially reduce the ability of tubular epithelial cells to reclaim proteins, resulting in preferential reabsorption of albumin.
Topics: Humans; Cadmium; Proteinuria; Kidney; Kidney Glomerulus; Glomerular Filtration Rate; beta 2-Microglobulin; Albumins; Creatinine
PubMed: 36768208
DOI: 10.3390/ijms24031893 -
The International Journal of Artificial... Sep 2023Besides standard medical therapy and critical care monitoring, extracorporeal liver support may provide a therapeutic option in patients with liver failure. However,...
BACKGROUND
Besides standard medical therapy and critical care monitoring, extracorporeal liver support may provide a therapeutic option in patients with liver failure. However, little is known about detoxification capabilities, efficacy, and efficiency among different devices.
METHODS
Retrospective single-center analysis of patients treated with extracorporeal albumin dialysis. Generalized Estimating Equations with robust variance estimator were used to account for repeated measurements of several cycles and devices per patient.
RESULTS
Between 2015 and 2021 = 341 cycles in = 96 patients were eligible for evaluation, thereof = 54 (15.8%) treatments with Molecular Adsorbent Recirculating System, = 64 (18.7%) with OpenAlbumin, = 167 (48.8%) Advanced Organ Support treatments, and = 56 (16.4%) using Single Pass Albumin Dialysis. Albumin dialysis resulted in significant bilirubin reduction without differences between the devices. However, ammonia levels only declined significantly in ADVOS and OPAL. First ECAD cycle was associated with highest percentage reduction in serum bilirubin. With the exception of SPAD all devices were able to remove the water-soluble substances creatinine and urea and stabilized metabolic dysfunction by increasing pH and negative base excess values. Platelets and fibrinogen levels frequently declined during treatment. Periprocedural bleeding and transfusion of red blood cells were common findings in these patients.
CONCLUSIONS
From this clinical perspective ADVOS and OPAL may provide higher reduction capabilities of liver solutes (i.e. bilirubin and ammonia) in comparison to MARS and SPAD. However, further prospective studies comparing the effectiveness of the devices to support liver impairment (i.e. bile acid clearance or albumin binding capacity) as well as markers of renal recovery are warranted.
Topics: Humans; Ammonia; Critical Illness; Prospective Studies; Retrospective Studies; Renal Dialysis; Liver Failure; Albumins; Bilirubin
PubMed: 37609875
DOI: 10.1177/03913988231191952 -
International Journal of Molecular... Dec 2023Small molecule fluorophores often face challenges such as short blood half-life, limited physicochemical and optical stability, and poor pharmacokinetics. To overcome...
Small molecule fluorophores often face challenges such as short blood half-life, limited physicochemical and optical stability, and poor pharmacokinetics. To overcome these limitations, we conjugated the zwitterionic near-infrared fluorophore ZW800-PEG to human serum albumin (HSA), creating HSA-ZW800-PEG. This conjugation notably improves chemical, physical, and optical stability under physiological conditions, addressing issues commonly encountered with small molecules in biological applications. Additionally, the high molecular weight and extinction coefficient of HSA-ZW800-PEG enhances biodistribution and tumor targeting through the enhanced permeability and retention effect. The unique distribution and elimination dynamics, along with the significantly extended blood half-life of HSA-ZW800-PEG, contribute to improved tumor targetability in both subcutaneous and orthotopic xenograft tumor-bearing animal models. This modification not only influences the pharmacokinetic profile, affecting retention time and clearance patterns, but also enhances bioavailability for targeting tissues. Our study guides further development and optimization of targeted imaging agents and drug-delivery systems.
Topics: Animals; Humans; Serum Albumin, Human; Tissue Distribution; Neoplasms; Biological Availability; Drug Delivery Systems; Fluorescent Dyes; Ionophores
PubMed: 38203730
DOI: 10.3390/ijms25010559 -
Renal Failure Dec 2022Expanded hemodialysis (HDx) is a new dialysis modality, but a systematic review of the clinical effects of using HDx is lacking. This systematic review and meta-analysis... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Expanded hemodialysis (HDx) is a new dialysis modality, but a systematic review of the clinical effects of using HDx is lacking. This systematic review and meta-analysis aimed to assess the efficacy and safety of HDx for hemodialysis (HD) patients.
METHODS
PubMed, the Cochrane library, and EMBASE databases were systematically searched for prospective interventional studies comparing the efficacy and safety of HDx with those of high flux HD or HDF in HD patients.
RESULTS
Eighteen trials including a total of 853 HD patients were enrolled. HDx increased the reduction ratio (RR) of β2-microglobulin (SMD 6.28%, 95% CI 0.83, 1.73, = .02), κFLC (SMD 15.86%, 95% CI 6.96, 24.76, = .0005), and λFLC (SMD 22.42%, 95% CI, 17.95, 26.88, < .0001) compared with high flux HD. The RR of β2-microglobulin in the HDx group was lower than that in the HDF group (SMD -3.53%, 95% CI -1.16, -1.9, < .0001). HDx increased the RRs of κFLC (SMD 1.34%, 95% CI 0.52, 2.16, = .001) and λFLC (SMD 7.28%, 95% CI 1.08, 13.48, = .02) compared to HDF. There was no significant difference in albumin loss into the dialysate between the HDx and HDF groups (SMD 0.35 g/session, 95% CI -2.38, 3.09, = .8).
CONCLUSIONS
This meta-analysis indicated that compared with high-flux HD and HDF, HDx can increase the clearance of medium and large-molecular-weight uremic toxins. And it does not increase the loss of albumin compared with HDF.
Topics: Albumins; Dialysis Solutions; Humans; Prospective Studies; Renal Dialysis
PubMed: 35343378
DOI: 10.1080/0886022X.2022.2048855 -
British Journal of Clinical Pharmacology Feb 2023To describe the pharmacokinetics (PK) of cefotaxime as pre-emptive treatment in critically ill adult patients, including covariates and to determine the probability of...
AIMS
To describe the pharmacokinetics (PK) of cefotaxime as pre-emptive treatment in critically ill adult patients, including covariates and to determine the probability of target attainment (PTA) of different dosage regimens for Enterobacterales and Staphylococcus aureus.
METHODS
Five samples were drawn during 1 dosage interval in critically ill patients treated with cefotaxime 1 g q6h or q4h. PK parameters were estimated using NONMEM (v7.4.2). The percentage of patients reaching 100% fT>MIC was used to compare different dosage regimens for Enterobacterales and S. aureus.
RESULTS
This study included 92 patients (437 samples). The best structural model was a 2-compartment model with a combined error, interindividual variability on clearance, central volume and intercompartmental clearance. Correlations between interindividual variability were included. Clearance increased with higher estimated glomerular filtration rate (eGFR; creatinine clearance) and albumin concentration. For Enterobacterales, 1 g q8h reached 95% PTA and continuous infusion (CI) of 4 g 24 h 100% PTA at the highest eGFR and albumin concentration. For S. aureus the predefined target of 95% PTA was not reached with higher eGFR and/or albumin concentrations. CI of 6 g 24 h for S. aureus resulted in a minimum of 99% PTA.
CONCLUSION
Cefotaxime PK in critically ill patients was best described by a 2-compartment model with eGFR and albumin concentration as covariates influencing clearance. For Enterobacterales 1 g q8h or CI of 4 g 24 h was adequate for all combinations of eGFR and albumin concentration. For S. aureus CI of 6 g 24 h would be preferred if eGFR and albumin concentration exceed 80 mL min and 40 g L respectively.
Topics: Humans; Adult; Anti-Bacterial Agents; Cefotaxime; Critical Illness; Staphylococcus aureus; Albumins; Microbial Sensitivity Tests; Monte Carlo Method
PubMed: 35942921
DOI: 10.1111/bcp.15487