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Clinical and Molecular Hepatology Jan 2023The development of refractory ascites in approximately 10% of patients with decompensated cirrhosis heralds the progression to a more advanced stage of cirrhosis. Its... (Review)
Review
The development of refractory ascites in approximately 10% of patients with decompensated cirrhosis heralds the progression to a more advanced stage of cirrhosis. Its pathogenesis is related to significant hemodynamic changes, initiated by portal hypertension, but ultimately leading to renal hypoperfusion and avid sodium retention. Inflammation can also contribute to the pathogenesis of refractory ascites by causing portal microthrombi, perpetuating the portal hypertension. Many complications accompany the development of refractory ascites, but renal dysfunction is most common. Management starts with continuation of sodium restriction, which needs frequent reviews for adherence; and regular large volume paracentesis of 5 L or more with albumin infusions to prevent the development of paracentesisinduced circulatory dysfunction. Albumin infusions independent of paracentesis may have a role in the management of these patients. The insertion of a covered, smaller diameter, transjugular intrahepatic porto-systemic stent shunt (TIPS) in the appropriate patients with reasonable liver reserve can bring about improvement in quality of life and improved survival after ascites clearance. Devices such as an automated low-flow ascites pump may be available in the future for ascites treatment. Patients with refractory ascites should be referred for liver transplant, as their prognosis is poor. In patients with refractory ascites and concomitant chronic kidney disease of more than stage 3b, assessment should be referred for dual liver-kidney transplants. In patients with very advanced cirrhosis not suitable for any definitive treatment for ascites control, palliative care should be involved to improve the quality of life of these patients.
Topics: Humans; Ascites; Quality of Life; Liver Cirrhosis; Albumins; Hypertension, Portal; Sodium; Portasystemic Shunt, Transjugular Intrahepatic; Paracentesis
PubMed: 35676862
DOI: 10.3350/cmh.2022.0104 -
Journal of Nuclear Medicine : Official... Jun 2022Fibroblast activation protein (FAP) has become an attractive target for diagnosis and therapy, and a series of FAP inhibitor (FAPI)-based radiotracers has been developed...
Fibroblast activation protein (FAP) has become an attractive target for diagnosis and therapy, and a series of FAP inhibitor (FAPI)-based radiotracers has been developed and had excellent performance for diagnosis outcomes in clinical applications. Yet, their fast clearance and insufficient tumor retention have hampered their further clinical application in cancer treatment. In this study, we developed 2 albumin binder-conjugated FAPI radiotracers, TEFAPI-06 and TEFAPI-07. They were derived from FAPI-04 and were optimized by conjugating 2 types of well-studied albumin binders, 4-(-iodophenyl) butyric acid moiety (TEFAPI-06) and truncated Evans blue moiety (TEFAPI-07), to try to overcome the above limitations at the expense of prolonging the blood circulation. TEFAPI-06 and TEFAPI-07 were synthesized and labeled with Ga, Y, and Lu successfully. A series of cell assays was performed to identify the binding affinity and FAP specificity in vitro. PET imaging, SPECT imaging, and biodistribution studies were performed to evaluate the pharmacokinetics in pancreatic cancer patient-derived xenograft (PDX) animal models. The cancer treatment efficacy of Lu-TEFAPI-06 and Lu-TEFAPI-07 were evaluated in pancreatic cancer PDX-bearing mice. The binding affinities (dissociation constants) to FAP of Ga-TEFAPI-06 and Ga-TEFAPI-07 were 10.16 ± 2.56 nM and 7.81 ± 2.28 nM, respectively, which were comparable with that of Ga-FAPI-04. Comparative PET imaging of HT-1080-FAP and HT-1080 tumor-bearing mice and a blocking study showed the FAP-targeting ability in vivo of these 2 tracers. Compared with Lu-FAPI-04, PET imaging, SPECT imaging, and biodistribution studies of TEFAPI-06 and TEFAPI-07 demonstrated their remarkably enhanced tumor accumulation and retention, respectively. Notable tumor growth inhibition by Lu-TEFAPI-06 and Lu-TEFAPI-07 were observed, whereas the control group and the group treated by Lu-FAPI-04 showed a slight therapeutic effect. Two albumin binder-conjugated FAPI radiopharmaceuticals have been developed and evaluated in vitro and in vivo. Significantly improved tumor uptake and retention were observed, compared with the original FAPI tracer. Both Lu-TEFAPI-06 and Lu-TEFAPI-07 showed remarkable growth inhibition of PDX tumors, whereas the side effects were almost negligible, demonstrating that these radiopharmaceuticals are promising for further clinical translational studies.
Topics: Albumins; Animals; Cell Line, Tumor; Endopeptidases; Fibroblasts; Gallium Radioisotopes; Humans; Membrane Proteins; Mice; Pancreatic Neoplasms; Radiopharmaceuticals; Tissue Distribution
PubMed: 34593598
DOI: 10.2967/jnumed.121.262533 -
Antimicrobial Agents and Chemotherapy Jun 2022The objective of this study was to describe the total and unbound population pharmacokinetics of ceftriaxone in critically ill adult patients and to define optimized...
The objective of this study was to describe the total and unbound population pharmacokinetics of ceftriaxone in critically ill adult patients and to define optimized dosing regimens. Total and unbound ceftriaxone concentrations were obtained from two pharmacokinetic studies and from a therapeutic drug monitoring (TDM) program at a tertiary hospital intensive care unit. Population pharmacokinetic analysis and Monte Carlo simulations were used to assess the probability of achieving a free trough concentration/MIC ratio of ≥1 using Pmetrics for R. A total of 474 samples (267 total and 207 unbound) were available from 36 patients. A two-compartment model describing ceftriaxone-albumin binding with both nonrenal and renal elimination incorporating creatinine clearance to explain the between-patient variability best described the data. An albumin concentration of ≤20 g/L decreased the probability of target attainment (PTA) by up to 20% across different dosing regimens and simulated creatinine clearances. A ceftriaxone dose of 1 g twice daily is likely therapeutic in patients with creatinine clearance of <100 mL/min infected with susceptible isolates (PTA, ~90%). Higher doses administered as a continuous infusion (4 g/day) are needed in patients with augmented renal clearance (creatinine clearance, >130 mL/min) who are infected by pathogens with a MIC of ≥0.5 mg/L. The ceftriaxone dose should be based on the patient's renal function and albumin concentration, as well as the isolate MIC. Hypoalbuminemia decreases the PTA in patients receiving intermittent dosing by up to 20%.
Topics: Adult; Albumins; Anti-Bacterial Agents; Ceftriaxone; Creatinine; Critical Illness; Humans; Microbial Sensitivity Tests; Monte Carlo Method
PubMed: 35575578
DOI: 10.1128/aac.02189-21 -
Alzheimer's Research & Therapy Jan 2021Alzheimer's disease (AD) is an intractable neurodegenerative disorder in the elderly population, currently lacking a cure. Trichostatin A (TSA), a histone deacetylase...
BACKGROUND
Alzheimer's disease (AD) is an intractable neurodegenerative disorder in the elderly population, currently lacking a cure. Trichostatin A (TSA), a histone deacetylase inhibitor, showed some neuroprotective roles, but its pathology-improvement effects in AD are still uncertain, and the underlying mechanisms remain to be elucidated. The present study aims to examine the anti-AD effects of TSA, particularly investigating its underlying cellular and molecular mechanisms.
METHODS
Novel object recognition and Morris water maze tests were used to evaluate the memory-ameliorating effects of TSA in APP/PS1 transgenic mice. Immunofluorescence, Western blotting, Simoa assay, and transmission electron microscopy were utilized to examine the pathology-improvement effects of TSA. Microglial activity was assessed by Western blotting and transwell migration assay. Protein-protein interactions were analyzed by co-immunoprecipitation and LC-MS/MS.
RESULTS
TSA treatment not only reduced amyloid β (Aβ) plaques and soluble Aβ oligomers in the brain, but also effectively improved learning and memory behaviors of APP/PS1 mice. In vitro study suggested that the improvement of Aβ pathology by TSA was attributed to the enhancement of Aβ clearance, mainly by the phagocytosis of microglia, and the endocytosis and transport of microvascular endothelial cells. Notably, a meaningful discovery in the study was that TSA dramatically upregulated the expression level of albumin in cell culture, by which TSA inhibited Aβ aggregation and promoted the phagocytosis of Aβ oligomers.
CONCLUSIONS
These findings provide a new insight into the pathogenesis of AD and suggest TSA as a novel promising candidate for the AD treatment.
Topics: Aged; Albumins; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Chromatography, Liquid; Cognition; Disease Models, Animal; Endothelial Cells; Humans; Hydroxamic Acids; Mice; Mice, Transgenic; Presenilin-1; Tandem Mass Spectrometry
PubMed: 33397436
DOI: 10.1186/s13195-020-00746-8 -
Gastroenterology Oct 2023Although transient bacteremia is common during dental and endoscopic procedures, infections developing during sterile diseases like acute pancreatitis (AP) can have...
BACKGROUND & AIMS
Although transient bacteremia is common during dental and endoscopic procedures, infections developing during sterile diseases like acute pancreatitis (AP) can have grave consequences. We examined how impaired bacterial clearance may cause this transition.
METHODS
Blood samples from patients with AP, normal controls, and rodents with pancreatitis or those administered different nonesterified fatty acids (NEFAs) were analyzed for albumin-unbound NEFAs, microbiome, and inflammatory cell injury. Macrophage uptake of unbound NEFAs using a novel coumarin tracer were done and the downstream effects-NEFA-membrane phospholipid (phosphatidylcholine) interactions-were studied on isothermal titration calorimetry.
RESULTS
Patients with infected AP had higher circulating unsaturated NEFAs; unbound NEFAs, including linoleic acid (LA) and oleic acid (OA); higher bacterial 16S DNA; mitochondrial DNA; altered β-diversity; enrichment in Pseudomonadales; and increased annexin V-positive myeloid (CD14) and CD3-positive T cells on admission. These, and increased circulating dead inflammatory cells, were also noted in rodents with unbound, unsaturated NEFAs. Isothermal titration calorimetry showed progressively stronger unbound LA interactions with aqueous media, phosphatidylcholine, cardiolipin, and albumin. Unbound NEFAs were taken into protein-free membranes, cells, and mitochondria, inducing voltage-dependent anion channel oligomerization, reducing ATP, and impairing phagocytosis. These were reversed by albumin. In vivo, unbound LA and OA increased bacterial loads and impaired phagocytosis, causing infection. LA and OA were more potent for these amphipathic interactions than the hydrophobic palmitic acid.
CONCLUSIONS
Release of stored LA and OA can increase their circulating unbound levels and cause amphipathic liponecrosis of immune cells via uptake by membrane phospholipids. This impairs bacterial clearance and causes infection during sterile inflammation.
Topics: Humans; Acute Disease; Pancreatitis; Fatty Acids, Nonesterified; Oleic Acid; Inflammation; Albumins; Phosphatidylcholines
PubMed: 37263302
DOI: 10.1053/j.gastro.2023.05.034 -
American Journal of Kidney Diseases :... May 2022Tubular secretion plays an important role in the efficient elimination of endogenous solutes and medications, and lower secretory clearance is associated with risk of...
RATIONALE & OBJECTIVE
Tubular secretion plays an important role in the efficient elimination of endogenous solutes and medications, and lower secretory clearance is associated with risk of kidney function decline. We evaluated whether histopathologic quantification of interstitial fibrosis and tubular atrophy (IFTA) is associated with lower tubular secretory clearance in persons undergoing kidney biopsy.
STUDY DESIGN
Cross-sectional.
SETTINGS & PARTICIPANTS
The Boston Kidney Biopsy Cohort is a study of persons undergoing native kidney biopsies for clinical indications.
EXPOSURES
Semiquantitative score of IFTA reported by 2 trained pathologists.
OUTCOMES
We measured plasma and urine concentrations of 9 endogenous secretory solutes using a targeted liquid chromatography/mass spectrometry assay. We used linear regression to test associations of urine-to-plasma ratios (UPRs) of these solutes with IFTA score after controlling for estimated glomerular filtration rate (eGFR) and albuminuria.
RESULTS
Among 418 participants, mean age was 53 years, 51% were women, 64% were White, and 18% were Black. Mean eGFR was 50mL/min/1.73m, and median urinary albumin-creatinine ratio was 819mg/g. Compared with individuals with≤25% IFTA, those with>50% IFTA had 12%-37% lower UPRs for all 9 secretory solutes. Adjusting for age, sex, race, eGFR, and urine albumin and creatinine levels attenuated the associations, yet a trend of lower secretion across groups remained statistically significant (P<0.05 for trend) for 7 of 9 solutes. A standardized composite secretory score incorporating UPR for all 9 secretory solutes using the min-max method showed similar results (P<0.05 for trend).
LIMITATIONS
Single time point and spot measures of secretory solutes.
CONCLUSIONS
Greater IFTA severity is associated with lower clearance of endogenous secretory solutes even after adjusting for eGFR and albuminuria.
Topics: Albumins; Albuminuria; Creatinine; Cross-Sectional Studies; Female; Fibrosis; Glomerular Filtration Rate; Humans; Kidney; Kidney Diseases; Kidney Tubules; Male; Middle Aged
PubMed: 34571064
DOI: 10.1053/j.ajkd.2021.08.015 -
Frontiers in Immunology 2023Acute respiratory distress syndrome (ARDS) is a common complication of influenza virus (IV) infection. During ARDS, alveolar protein concentrations often reach 40-90% of...
INTRODUCTION
Acute respiratory distress syndrome (ARDS) is a common complication of influenza virus (IV) infection. During ARDS, alveolar protein concentrations often reach 40-90% of plasma levels, causing severe impairment of gas exchange and promoting deleterious alveolar remodeling. Protein clearance from the alveolar space is at least in part facilitated by the multi-ligand receptor megalin through clathrin-mediated endocytosis.
METHODS
To investigate whether IV infection impairs alveolar protein clearance, we examined albumin uptake and megalin expression in MLE-12 cells and alveolar epithelial cells (AEC) from murine precision-cut lung slices (PCLS) and in vivo, under IV infection conditions by flow cytometry and western blot. Transcriptional levels from AEC and broncho-alveolar lavage (BAL) cells were analyzed in an in-vivo mouse model by RNAseq.
RESULTS
IV significantly downregulated albumin uptake, independently of activation of the TGF-β1/GSK3β axis that has been previously implicated in the regulation of megalin function. Decreased plasma membrane abundance, total protein levels, and mRNA expression of megalin were associated with this phenotype. In IV-infected mice, we identified a significant upregulation of matrix metalloproteinase (MMP)-14 in BAL fluid cells. Furthermore, the inhibition of this protease partially recovered total megalin levels and albumin uptake.
DISCUSSION
Our results suggest that the previously described MMP-driven shedding mechanisms are potentially involved in downregulation of megalin cell surface abundance and clearance of excess alveolar protein. As lower alveolar edema protein concentrations are associated with better outcomes in respiratory failure, our findings highlight the therapeutic potential of a timely MMP inhibition in the treatment of IV-induced ARDS.
Topics: Animals; Mice; Alveolar Epithelial Cells; Low Density Lipoprotein Receptor-Related Protein-2; Biological Transport; Albumins; Orthomyxoviridae Infections; Orthomyxoviridae
PubMed: 37727782
DOI: 10.3389/fimmu.2023.1260973 -
Critical Care (London, England) Dec 2021The measurement of circulating substrate concentrations does not provide information about substrate kinetics. It, therefore, remains unclear if a decrease in plasma... (Observational Study)
Observational Study
BACKGROUND
The measurement of circulating substrate concentrations does not provide information about substrate kinetics. It, therefore, remains unclear if a decrease in plasma concentration of albumin, as seen during critical illness, is a consequence of suppressed production in the liver or increased peripheral clearance. In this study, using stable isotope tracer infusions, we measured albumin and fibrinogen kinetics in septic patients and in a control group of non-septic subjects.
METHODS
With the approval from the institutional Research Ethics Board and after obtaining written informed consent from patients or their substitute decision maker, mechanically ventilated patients with sepsis and patients scheduled for elective coronary artery bypass grafting were enrolled. Patients in the non-sepsis group were studied on the day before surgery. The stable isotope L-[ring-H]phenylalanine was used to measure absolute synthesis rates (ASR) of albumin and fibrinogen. A priming dose of L-[ring-H]phenylalanine (4 µmol/kg) was given followed by a six-hour infusion at a rate of 0.15 µmol/kg/min. At baseline and hourly thereafter, blood was drawn to measure isotope enrichments by gas chromatography/mass spectrometry. Very low density lipoprotein apolipoprotein-B 100 isotopic enrichment was used to represent the isotopic enrichment of the phenylalanine precursor pool from which the liver synthesizes proteins. Plasma albumin and fibrinogen concentrations were also measured.
RESULTS
Mean plasma albumin in septic patients was decreased when compared to non-septic patients, while synthesis rates were comparable. Mean plasma fibrinogen and ASR in septic patients was increased when compared to non-septic patients. In non-septic patients, no statistically significant correlation between plasma albumin and ASR was observed but plasma fibrinogen significantly correlated with ASR. In septic patients, plasma albumin and fibrinogen significantly correlated with ASR.
CONCLUSIONS
While septic patients showed lower plasma albumin levels than non-septic patients, albumin synthesis was similar in the two groups suggesting that hypoalbuminemia during sepsis was not caused by suppressed hepatic production but a result of enhanced clearance from the circulation. Hyperfibrinogenemia in septic patients was a consequence of increased fibrinogen production.
TRIAL REGISTRATION
ClinicalTrials.gov: NCT02865408 (registered on August 12, 2016) and ClinicalTrials.gov: NCT02549443 (registered on September 15, 2015).
Topics: Fibrinogen; Humans; Hypoalbuminemia; Kinetics; Sepsis; Serum Albumin
PubMed: 34920728
DOI: 10.1186/s13054-021-03860-7 -
Journal of Hepatology Aug 2014Human serum albumin (HSA) is one of the most frequent treatments in patients with decompensated cirrhosis. Prevention of paracentesis-induced circulatory dysfunction,... (Review)
Review
Human serum albumin (HSA) is one of the most frequent treatments in patients with decompensated cirrhosis. Prevention of paracentesis-induced circulatory dysfunction, prevention of type-1 HRS associated with bacterial infections, and treatment of type-1 hepatorenal syndrome are the main indications. In these indications treatment with HSA is associated with improvement in survival. Albumin is a stable and very flexible molecule with a heart shape, 585 residues, and three domains of similar size, each one containing two sub-domains. Many of the physiological functions of HSA rely on its ability to bind an extremely wide range of endogenous and exogenous ligands, to increase their solubility in plasma, to transport them to specific tissues and organs, or to dispose of them when they are toxic. The chemical structure of albumin can be altered by some specific processes (oxidation, glycation) leading to rapid clearance and catabolism. An outstanding feature of HSA is its capacity to bind lipopolysaccharide and other bacterial products (lipoteichoic acid and peptidoglycan), reactive oxygen species, nitric oxide and other nitrogen reactive species, and prostaglandins. Binding to NO and prostaglandins are reversible, so they can be transferred to other molecules at different sites from their synthesis. Through these functions, HSA modulates the inflammatory reaction. Decompensated cirrhosis is a disease associated systemic inflammation, which plays an important role in the pathogenesis of organ or system dysfunction/failure. Although, the beneficial effects of HAS have been traditionally attributed to plasma volume expansion, they could also relate to its effects modulating systemic and organ inflammation.
Topics: Hepatorenal Syndrome; Humans; Inflammation; Liver Cirrhosis; Peritonitis; Serum Albumin
PubMed: 24751830
DOI: 10.1016/j.jhep.2014.04.012 -
Current Opinion in Chemical Biology Aug 2021The field of nuclear imaging and therapy is rapidly progressing with the development of targeted radiopharmaceuticals that show rapid targeting and rapid clearance with... (Review)
Review
The field of nuclear imaging and therapy is rapidly progressing with the development of targeted radiopharmaceuticals that show rapid targeting and rapid clearance with minimal background. Unfortunately, they are often reabsorbed in the kidneys, leading to possible nephrotoxicity, limiting the therapeutic dose, and/or reducing imaging quality. The blocking of endocytic receptors has been extensively used as a strategy to reduce kidney radiation. Alternatively, the physicochemical properties of radiotracers can be modulated to either prevent their reuptake or promote the excretion of radiometabolites. Other interesting strategies focus on the insertion of a cleavable linker between the radiolabel and the targeting moiety or pretargeting approaches in which the targeting moiety and radiolabel are administered separately. In the context of this review, we will discuss the latest advances and insights on strategies used to reduce renal retention of low- to moderate-molecular-weight radiopharmaceuticals.
Topics: Albumins; Animals; Contrast Media; Dose-Response Relationship, Radiation; Humans; Kidney; Molecular Weight; Radioisotopes; Radiopharmaceuticals; Single Photon Emission Computed Tomography Computed Tomography; Structure-Activity Relationship
PubMed: 34325089
DOI: 10.1016/j.cbpa.2021.06.008