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Kidney360 Jun 2023Albumin kinetics not only reflected the pathophysiology of minimal change nephrotic syndrome but was also a predictor of relapse. The high estimated 24-hour albumin...
KEY POINTS
Albumin kinetics not only reflected the pathophysiology of minimal change nephrotic syndrome but was also a predictor of relapse. The high estimated 24-hour albumin clearance predicts the minimal change nephrotic syndrome relapse. The 24-hour albumin clearance can easily be calculated from only serum albumin and urinary protein excretion, which are routine laboratory measurements.
BACKGROUND
Although albuminuria leakage that occurs in minimal change nephrotic syndrome (MCNS) may be related to the disease state, albumin kinetics in MCNS has never been evaluated. In this study, we investigated albumin kinetics in adult Japanese patients with MCNS by the estimated 24-hour albumin clearance (eC) and examined the association between eC and relapse.
METHODS
We retrospectively identified 103 adult patients with a histological diagnosis of MCNS from four hospitals in Japan (2010–2020). The primary outcome is the first relapse in 2 years after complete remission after corticosteroid therapy. The eC [l/min] was defined as (2.71828 [g/24 hours])/(serum albumin [g/dl]×1440 [min/24 hours]) for women and (2.71828 [g/24 hours])/(serum albumin [g/dl]×1440 [min/24 hours]) for men.
RESULTS
Relapse was observed in 44 patients (103 kidney biopsy samples; 42.7%). The mean patient age was 41.0 years. Patients had an eGFR of 71.0 ml/min per 1.73 m, urinary protein excretion of 6.8 g/d, serum albumin of 1.4 g/dl, and eC of 2.27 l/min. eC was strongly associated with hypoalbuminemia, severe proteinuria, lipid abnormalities, and coagulopathy. In the multivariable analysis, a high eC was significantly associated with relapse after adjusting for age, eGFR, time to complete remission, and urinary protein excretion (adjusted hazard ratio, 5.027; 95% confidence interval, 1.88 to 13.47; = 0.001).
CONCLUSIONS
This study revealed that eC, which could substitute albumin kinetics, reflected the severity of MCNS, and a high eC was associated with recurrence.
Topics: Humans; Nephrosis, Lipoid; Kidney Function Tests; Nephrotic Syndrome; Chronic Disease; Albumins; Recurrence
PubMed: 37166949
DOI: 10.34067/KID.0000000000000143 -
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 Nuclear Medicine : Official... May 2023Fibroblast activation protein (FAP) has received increasing attention as an oncologic target because of its prominent expression in solid tumors but virtual absence from...
Fibroblast activation protein (FAP) has received increasing attention as an oncologic target because of its prominent expression in solid tumors but virtual absence from healthy tissues. Most radioligand therapies (RLTs) targeting FAP, however, suffer from inadequate tumor retention or clearance from healthy tissues. Herein we report a FAP-targeted RLT comprising an FAP6 ligand conjugated to DOTA and an albumin binder (4--iodophenylbutyric acid, or IP) for enhanced pharmacokinetics. We evaluated the performance of the resulting FAP6-IP-DOTA conjugate in 4 tumor models, 3 of which express FAP only on cancer-associated fibroblasts, that is, analogously to human tumors. Single-cell RNA-sequencing data were analyzed from 34 human breast, ovarian, colorectal, and lung cancers to quantify FAP-overexpressing cells. FAP6-DOTA conjugates were synthesized with or without an albumin binder (IP) and investigated for binding to human FAP-expressing cells. Accumulation of In- or Lu-labeled conjugates in KB, HT29, U87MG, and 4T1 murine tumors was also assessed by radioimaging or biodistribution analyses. Radiotherapeutic potency was quantitated by measuring tumor volumes versus time. Approximately 5% of all cells in human tumors overexpressed FAP (cancer-associated fibroblasts comprised ∼77% of this FAP-positive subpopulation, whereas ∼2% were cancer cells). FAP6 conjugates bound to FAP-expressing cells with high affinity (dissociation constant, ∼1 nM). Lu-FAP6-IP-DOTA achieved an 88-fold higher tumor dose than Lu-FAP6-DOTA and improved all tumor-to-healthy-organ ratios. Single doses of Lu-FAP6-IP-DOTA suppressed tumor growth by about 45% in all tested tumor models without causing reproducible toxicities. We conclude that Lu-FAP6-IP-DOTA constitutes a promising candidate for FAP-targeted RLT of solid tumors.
Topics: Humans; Animals; Mice; Tissue Distribution; Cell Line, Tumor; Albumins; Fibroblasts
PubMed: 37116911
DOI: 10.2967/jnumed.122.264494 -
Mathematical Biosciences and... Oct 2023Human immunodeficiency virus (HIV) infection is a major public health concern with 1.2 million people living with HIV in the United States. The role of nutrition in...
Human immunodeficiency virus (HIV) infection is a major public health concern with 1.2 million people living with HIV in the United States. The role of nutrition in general, and albumin/globulin in particular in HIV progression has long been recognized. However, no mathematical models exist to describe the interplay between HIV and albumin/globulin. In this paper, we present a family of models of HIV and the two protein components albumin and globulin. We use albumin, globulin, viral load and target cell data from simian immunodeficiency virus (SIV)-infected monkeys to perform model selection on the family of models. We discover that the simplest model accurately and uniquely describes the data. The selection of the simplest model leads to the observation that albumin and globulin do not impact the infection rate of target cells by the virus and the clearance of the infected target cells by the immune system. Moreover, the recruitment of target cells and immune cells are modeled independently of globulin in the selected model. Mathematical analysis of the selected model reveals that the model has an infection-free equilibrium and a unique infected equilibrium when the immunological reproduction number is above one. The infection-free equilibrium is locally stable when the immunological reproduction number is below one, and unstable when the immunological reproduction number is greater than one. The infection equilibrium is locally stable whenever it exists. To determine the parameters of the best fitted model we perform structural and practical identifiability analysis. The structural identifiability analysis reveals that the model is identifiable when the immune cell infection rate is fixed at a value obtained from the literature. Practical identifiability reveals that only seven of the sixteen parameters are practically identifiable with the given data. Practical identifiability of parameters performed with synthetic data sampled a lot more frequently reveals that only two parameters are practically unidentifiable. We conclude that experiments that will improve the quality of the data can help improve the parameter estimates and lead to better understanding of the interplay of HIV and albumin-globulin metabolism.
Topics: Animals; Humans; HIV Infections; Models, Theoretical; Simian Immunodeficiency Virus; Albumins
PubMed: 38052613
DOI: 10.3934/mbe.2023865 -
World Journal of Gastroenterology Oct 2022Estimation of the functional reserve of the remnant liver is important to reduce morbidity and mortality. (Review)
Review
BACKGROUND
Estimation of the functional reserve of the remnant liver is important to reduce morbidity and mortality.
AIM
To estimate the functional reserve of the remnant liver in patients with hepatocellular carcinoma (HCC).
METHODS
We reviewed the medical records of 199 patients who underwent resection of HCC. Hepatic clearance of the remnant liver was calculated using fusion images of Tc-labelled galactosyl-human serum albumin liver scintigraphy and computed tomography. Posthepatectomy liver failure (PHLF) was classified according to the International Study Group of Liver Surgery. Complications was classified according to Clavien-Dindo classification. We analyzed by the risk factors for PHLF, morbidity and mortality with multivariate analysis.
RESULTS
Twenty-seven (30%) patients had major complications and 23 (12%) developed PHLF. The incidence of major complications increased with increasing albumin-bilirubin (ALBI) grade. The area under the curve values for hepatic clearance of the remnant liver, liver to heart-plus-liver radioactivity at 15 min (LHL15), and ALBI score predicting PHLF were 0.868, 0.629, and 0.655, respectively. The area under the curve for hepatic clearance of the remnant liver, LHL15, and ALBI score predicting major complications were 0.758, 0.594, and 0.647, respectively. The risk factors for PHLF and major complications were hepatic clearance of the remnant liver and intraoperative bleeding.
CONCLUSION
The measurement of hepatic clearance may predict PHLF and major complications for patients undergoing resection of HCC.
Topics: Humans; Carcinoma, Hepatocellular; Hepatectomy; Liver Neoplasms; Retrospective Studies; Liver Failure; Bilirubin; Albumins; Postoperative Complications
PubMed: 36304091
DOI: 10.3748/wjg.v28.i38.5614 -
Kidney360 Jun 2023
Topics: Adult; Humans; Nephrosis, Lipoid; Chronic Disease; Recurrence; Albumins
PubMed: 37384885
DOI: 10.34067/KID.0000000000000169 -
Journal of Clinical Pharmacology Feb 2021Treatment of patients with biologics such as infliximab may trigger development of antidrug antibodies, which are associated with faster drug clearance, reduced... (Randomized Controlled Trial)
Randomized Controlled Trial
Treatment of patients with biologics such as infliximab may trigger development of antidrug antibodies, which are associated with faster drug clearance, reduced treatment efficacy, and increased risk of infusion-related reactions. The aim of this study was to identify predictors of baseline infliximab clearance and early antidrug antibody formation. Pharmacokinetic and pharmacokinetic/pharmacodynamic models for infliximab were developed using 21 178 observations from 859 patients from the PLANETRA (ClinicalTrials.gov identifier: NCT01217086) and PLANETAS (NCT01220518) studies in rheumatoid arthritis and ankylosing spondylitis, respectively, to address the specified aims. Infliximab pharmacokinetics were well described by a 2-compartment model with linear mean estimated baseline clearance of 0.26 L/day. Alongside increased body weight, serum C-reactive protein, and antidrug antibody concentrations and decreased serum albumin, elevated serum glucose levels predicted higher clearance. In patients with rheumatoid arthritis, baseline infliximab clearance and body weight were the only identified predictors of early antidrug antibody detection. The odds ratio for antidrug antibody detection for each 0.1 L/day increase in baseline infliximab clearance was 1.78 (95% confidence interval, 1.50-2.12); for each 10-kg increase in body weight, this was 1.19 (1.06-1.33). Here we describe increased serum glucose levels as a novel independent predictor of baseline infliximab clearance. Estimates of baseline infliximab clearance should be incorporated to guide dosing modifications and/or antidrug antibody prophylaxis in clinical practice.
Topics: Adolescent; Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Blood Glucose; Body Weight; C-Reactive Protein; Double-Blind Method; Female; Humans; Infliximab; Male; Metabolic Clearance Rate; Middle Aged; Serum Albumin; Spondylitis, Ankylosing; Young Adult
PubMed: 32905628
DOI: 10.1002/jcph.1732 -
International Journal of Molecular... Jan 2023A hallmark of acute respiratory distress syndrome (ARDS) is an accumulation of protein-rich alveolar edema that impairs gas exchange and leads to worse outcomes. Thus,...
A hallmark of acute respiratory distress syndrome (ARDS) is an accumulation of protein-rich alveolar edema that impairs gas exchange and leads to worse outcomes. Thus, understanding the mechanisms of alveolar albumin clearance is of high clinical relevance. Here, we investigated the mechanisms of the cellular albumin uptake in a three-dimensional culture of precision-cut lung slices (PCLS). We found that up to 60% of PCLS cells incorporated labeled albumin in a time- and concentration-dependent manner, whereas virtually no uptake of labeled dextran was observed. Of note, at a low temperature (4 °C), saturating albumin receptors with unlabeled albumin and an inhibition of clathrin-mediated endocytosis markedly decreased the endocytic uptake of the labeled protein, implicating a receptor-driven internalization process. Importantly, uptake rates of albumin were comparable in alveolar epithelial type I (ATI) and type II (ATII) cells, as assessed in PCLS from a SftpcCre: tdTomato mouse strain (defined as EpCAMCD31CD45tdTomatoSPCT1α for ATI and EpCAMCD31CD45tdTomatoSPCT1α for ATII cells). Once internalized, albumin was found in the early and recycling endosomes of the alveolar epithelium as well as in endothelial, mesenchymal, and hematopoietic cell populations, which might indicate transcytosis of the protein. In summary, we characterize albumin uptake in alveolar epithelial cells in the complex setting of PCLS. These findings may open new possibilities for pulmonary drug delivery that may improve the outcomes for patients with respiratory failure.
Topics: Mice; Animals; Alveolar Epithelial Cells; Epithelial Cell Adhesion Molecule; Clathrin; Lung; Epithelial Cells; Serum Albumin; Pulmonary Alveoli
PubMed: 36768968
DOI: 10.3390/ijms24032644 -
Clinical Biochemistry Oct 2023Multiple previously published studies have shown a weak to medium, negative correlation between BMI and glycated albumin (GA). However, many of these studies were in...
BACKGROUND AND AIMS
Multiple previously published studies have shown a weak to medium, negative correlation between BMI and glycated albumin (GA). However, many of these studies were in populations with a narrow range of BMI. It is unknown whether this trend exists if a wider BMI range is used. This is an important question for proper interpretation of GA levels in obese populations.
MATERIALS AND METHODS
A retrospective analysis of clinical trial data (NCT02519309) was performed. After appropriate exclusions, 334 subjects remained. These included 73.7% with type 2 diabetes (T2D) diagnosis and 26.3% with prediabetes. BMI ranged from 24.8-86.9 kg/m. Laboratory data were measured in a CLIA-certified laboratory using commercially available, automated methods.
RESULTS
No significant, negative correlation was seen between GA and BMI. However, individual components (glycated serum proteins and albumin) as well as the GA/HbA1c ratio show a weak, negative correlation with BMI for all subjects and those with T2D. The strongest negative correlation was with albumin. Examination by traditional BMI subgroups also showed statistically significant differences for those with T2D, but not for the prediabetic cohort. Correlations between BMI and C-reactive protein were similar in those with diabetes and prediabetes; however, correlation between BMI and insulin was stronger in those with diabetes.
CONCLUSION
Negative correlations between BMI and albumin or BMI and glycated serum proteins persist in diabetic populations that are obese and overweight, even when a statistically significant negative correlation is not observed between BMI and GA. Inflammation or insulin-mediated changes in protein synthesis could be contributors to these negative correlations, but BMI-related changes to the glomerulus could also affect clearance of albumin or glycated proteins and should be examined.
Topics: Humans; United States; Diabetes Mellitus, Type 2; Glycated Serum Albumin; Prediabetic State; Glycated Serum Proteins; Overweight; Body Mass Index; Retrospective Studies; Glycated Hemoglobin; Glycation End Products, Advanced; Serum Albumin; Obesity; Insulin; Blood Glucose
PubMed: 37757966
DOI: 10.1016/j.clinbiochem.2023.110654 -
Revista Espanola de Quimioterapia :... Sep 2022Cefiderocol is a new cephalosporin with a catechol in its chemical structure faciliting its access to the interior of bacteria through iron channels. In addition, it is... (Review)
Review
Cefiderocol is a new cephalosporin with a catechol in its chemical structure faciliting its access to the interior of bacteria through iron channels. In addition, it is broadly stable to beta-lactamases. The pharmacokinetic profile is a beta-lactam one: no oral absorption, and with a wide distribution within the vascular space and the interstitial fluid of well vascularized tissues, reaching therapeutic concentrations in the alveolar lavage fluid and within the macrophage. The binding of cefiderocol to human plasma proteins, primarily albumin, is moderate (range 40-60%). The terminal elimination half-life in healthy adult subjects was 2 to 3 hours. Cefiderocol is mainly renally eliminated, so dose adjustments are recommended in subjects with moderate / severe renal impairment, in case of dialysis, and probably in patients with external clearance. Like other beta-lactams, the PK / PD parameter that has been shown to best correlate with efficacy is the efficacy time of unbound plasma concentrations (%fT>MIC), which must be close to 100% to achieve a bactericidal effect. This is possible with 2 g in a 3-hour infusion every 8 hours. In controlled trials appears to be well tolerated, similar to comparators: meropenem or imipenem-cilastatin. Cefiderocol has no apparent clinically significant effect on ECG parameters nor on plasma iron values.
Topics: Adult; Albumins; Anti-Bacterial Agents; Blood Proteins; Catechols; Cephalosporins; Cilastatin, Imipenem Drug Combination; Humans; Iron; Meropenem; beta-Lactamases; beta-Lactams; Cefiderocol
PubMed: 36193982
DOI: 10.37201/req/s02.04.2022