-
Annals of Biomedical Engineering Mar 2024Inadequate clearance of protein-bound uremic toxins (PBUTs) during dialysis is associated with morbidities in chronic kidney disease patients. The development of...
Inadequate clearance of protein-bound uremic toxins (PBUTs) during dialysis is associated with morbidities in chronic kidney disease patients. The development of high-permeance membranes made from materials such as graphene raises the question whether they could enable the design of dialyzers with improved PBUT clearance. Here, we develop device-level and multi-compartment (body) system-level models that account for PBUT-albumin binding (specifically indoxyl sulfate and p-cresyl sulfate) and diffusive and convective transport of toxins to investigate how the overall membrane permeance (or area) and system parameters including flow rates and ultrafiltration affect PBUT clearance in hemodialysis. Our simulation results indicate that, in contrast to urea clearance, PBUT clearance in current dialyzers is mass-transfer limited: Assuming that the membrane resistance is dominant, raising PBUT permeance from 3 × 10 to 10 m s (or equivalently, 3.3 × increase in membrane area from ~ 2 to ~ 6 m) increases PBUT removal by 48% (from 22 to 33%, i.e., ~ 0.15 to ~ 0.22 g per session), whereas increasing dialysate flow rates or adding adsorptive species have no substantial impact on PBUT removal unless permeance is above ~ 10 m s. Our results guide the future development of membranes, dialyzers, and operational parameters that could enhance PBUT clearance and improve patient outcomes.
Topics: Humans; Uremic Toxins; Uremia; Protein Binding; Renal Dialysis; Toxins, Biological
PubMed: 37993752
DOI: 10.1007/s10439-023-03397-6 -
Pakistan Journal of Medical Sciences 2023To compare the clinical effects of hemodialysis (HD) and peritoneal dialysis (PD) in the treatment of end-stage renal disease (ESRD) patients.
OBJECTIVE
To compare the clinical effects of hemodialysis (HD) and peritoneal dialysis (PD) in the treatment of end-stage renal disease (ESRD) patients.
METHODS
Clinical data of ESRD patients who received HD (n=74) and PD (n=77) for more than 12 months in the First People's Hospital of Tonglu County from October 2020 to November 2021 were retrospectively selected. Renal function indexes, blood pressure, and complication rates in the two groups before the first dialysis and at the end of the observation period were compared.
RESULTS
After the dialysis, the urea nitrogen (BUN) levels decreased in both groups, and were significantly lower in the PD group compared to the HD group. Urea clearance index (Kt/V) increased, and were significantly higher in the PD group compared to the HD group (<0.05). After the dialysis, albumin (ALB) and cardiac ejection fraction (EF) levels significantly increased, and ALB levels were significantly higher in the HD group while EF levels were significantly higher in the PD group (<0.05). Levels of whole parathyroid hormone (iPTH), systolic blood pressure, and diastolic blood pressure indicators in both groups decreased compared to before the dialysis, and were significantly lower in the PD group compared to the HD group of patients (<0.05). PD was associated with significantly lower total incidence of complications compared to HD (<0.05).
CONCLUSIONS
Peritoneal dialysis is more effective in maintaining the hemodynamic stability for ESRD patients, reducing blood pressure level, improving the clearance rate of molecular substances, and protecting the renal function of patients compared to hemodialysis.
PubMed: 37936738
DOI: 10.12669/pjms.39.6.8056 -
Medicine Nov 2023Diabetic nephropathy (DN) is a major microvascular complication of diabetes mellitus that leads to end-stage renal disease. Hyperglycemia triggers apoptosis and kidney...
BACKGROUND
Diabetic nephropathy (DN) is a major microvascular complication of diabetes mellitus that leads to end-stage renal disease. Hyperglycemia triggers apoptosis and kidney damage. Milk fat globule-epidermal growth factor 8 (MFG-E8) and TAM receptor tyrosine kinases, Tyro3, Axl, and Mer, are phagocytic receptors that mediate the clearance of apoptotic cells. This study aimed to identify the role of MFG-E8 and TAM receptors in the development of DN.
METHODS
A total of 146 patients with type 2 diabetes mellitus (T2DM), early stage DN, clinical DN and 48 healthy controls were employed to analyze the serum levels of MFG-E8, soluble Tyro3, Axl, Mer, and RAGE by enzyme-linked immunosorbent assay. The serum levels of CREA, hsCRP, CysC, and β2-microglobulin were measured by spectrophotometric analysis using a biochemical analyzer (AU5800).
RESULTS
Our results showed that the serum levels of MFG-E8 were elevated in patients with T2DM compared with healthy controls; however, it decreased gradually in patients with DN with the severity of kidney injury, especially in the clinical DN group. Moreover, the levels of sTyro3, sAxl, and sMer were reduced in patients with T2DM and DN compared to healthy controls, particularly in patients with DN. The levels of MFG-E8, sTyro3, sAxl, and sMer were negatively correlated with UAER at 24 hours, CREA, hsCRP, CysC, β2-microglobulin, and RAGE, respectively. In addition, TAM receptors had significantly higher predictive and diagnostic values for early stage DN from T2DM than hsCRP, β2-microglobulin, and CysC, which are also predictive biomarkers of early stage DN from clinical DN.
CONCLUSIONS
Decreased MFG-E8 and TAM receptor expression is associated with an increased risk of microvascular complications in patients with T2DM, which plays a critical role in the diagnosis of diabetic patients with microvascular complications, especially early stage DN, and in monitoring the development of DN.
Topics: Humans; Antigens, Surface; C-Reactive Protein; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Receptor Protein-Tyrosine Kinases
PubMed: 37933040
DOI: 10.1097/MD.0000000000035788 -
Annals of Gastroenterological Surgery Nov 2023Liver resection is an effective therapeutic option for patients with hepatocellular carcinoma. However, posthepatectomy liver failure (PHLF) remains a major cause of... (Review)
Review
Liver resection is an effective therapeutic option for patients with hepatocellular carcinoma. However, posthepatectomy liver failure (PHLF) remains a major cause of hepatectomy-related mortality, and the accurate prediction of PHLF based on preoperative assessment of liver functional reserve is a critical issue. The definition of PHLF proposed by the International Study Group for Liver Surgery has gained acceptance as a standard grading criterion. Liver function can be estimated using a variety of parameters, including routine blood biochemical examinations, clinical scoring systems, dynamic liver function tests, liver stiffness and fibrosis markers, and imaging studies. The Child-Pugh score and model for end-stage liver disease scores are conventionally used for estimating liver decompensation, although the alternatively developed albumin-bilirubin score shows superior performance for predicting hepatic dysfunction. Indocyanine green clearance, a dynamic liver function test mostly used in Japan and other Asian countries, serves as a quantitative estimation of liver function reserve and helps determine indications for surgical procedures according to the estimated risk of PHLF. In an attempt to improve predictive accuracy, specific evaluation of liver fibrosis and portal hypertension has gained popularity, including liver stiffness measurements using ultrasonography or magnetic resonance elastography, as well as noninvasive fibrosis markers. Imaging modalities, including Tc-99m-labeled galactosyl serum albumin scintigraphy and gadolinium-enhanced magnetic resonance imaging, are used for preoperative evaluation in combination with liver volume. This review aims to provide an overview of the usefulness of current options for the preoperative assessment of liver function in predicting PHLF.
PubMed: 37927928
DOI: 10.1002/ags3.12692 -
Scientific Reports Nov 2023Oxidized albumin (oxHSA) is elevated in several pathological conditions, such as decompensated cirrhosis, acute on chronic liver failure and liver mediated renal...
Oxidized albumin (oxHSA) is elevated in several pathological conditions, such as decompensated cirrhosis, acute on chronic liver failure and liver mediated renal failure. Patient derived oxidized albumin was previously shown to be an inflammatory mediator, and in normal serum levels of oxHSA are low. The removal from circulation of oxidized albumins is therefore likely required for maintenance of homeostasis. Liver sinusoidal endothelial cells (LSEC) are prominent scavenger cells specialized in removal of macromolecular waste. Given that oxidized albumin is mainly cleared by the liver, we hypothesized the LSEC are the site of uptake in the liver. In vivo oxHSA was cleared rapidly by the liver and distributed to mainly the LSEC. In in vitro studies LSEC endocytosed oxHSA much more than other cell populations isolated from the liver. Furthermore, it was shown that the uptake was mediated by the stabilins, by affinity chromatography-mass spectrometry, inhibiting uptake in LSEC with other stabilin ligands and showing uptake in HEK cells overexpressing stabilin-1 or -2. oxHSA also inhibited the uptake of other stabilin ligands, and a 2-h challenge with 100 µg/mL oxHSA reduced LSEC endocytosis by 60% up to 12 h after. Thus the LSEC and their stabilins mediate clearance of highly oxidized albumin, and oxidized albumin can downregulate their endocytic capacity in turn.
Topics: Humans; Albumins; Endothelial Cells; Endothelium; Hepatocytes; Ligands; Liver
PubMed: 37926735
DOI: 10.1038/s41598-023-46462-9 -
Biological & Pharmaceutical Bulletin 2023The modified Cockcroft-Gault (CG) equation, previously developed for an aged-oriented cohort, was validated in a newly obtained dataset. Estimates of creatinine...
The modified Cockcroft-Gault (CG) equation, previously developed for an aged-oriented cohort, was validated in a newly obtained dataset. Estimates of creatinine clearance (CCr) using this equation were found to be more accurate than those determined using the conventional CG equation, particularly for patients exceeding 65 years of age. We identified a subset of patients in this cohort whose estimates were inadequate. Using statistical analysis, we found that the deviation from estimates was attributed to a decreased albumin level. In addition, we determined a reduced albumin cutoff value for the modified CG equation to obtain a good estimate. Univariate linear regression analysis was applied to measure the CCr in this cohort and identify parameters related to body composition, and we found that extracellular water (ECW)/total body water (TBW) and body fat (%) were relevant. Using measured values of ECW/TBW and body fat (%), a multivariate linear regression (MLR) estimating equation was developed based on the modified CG equation. This equation was applied to a cohort over 65 years of age, and it was found that a good estimate was obtained for older patients with low albumin levels. Thus, we propose a flow diagram that illustrates conditions for selecting an appropriate estimating equation from among the CG, modified CG, and MLR equations.
Topics: Humans; Aged; Glomerular Filtration Rate; Creatinine; Kidney; Body Composition; Albumins
PubMed: 37914363
DOI: 10.1248/bpb.b23-00466 -
PloS One 2023Liver sinusoidal endothelial cells (LSECs) are fenestrated endothelial cells with a unique, high endocytic clearance capacity for blood-borne waste macromolecules and...
Liver sinusoidal endothelial cells show reduced scavenger function and downregulation of Fc gamma receptor IIb, yet maintain a preserved fenestration in the Glmpgt/gt mouse model of slowly progressing liver fibrosis.
Liver sinusoidal endothelial cells (LSECs) are fenestrated endothelial cells with a unique, high endocytic clearance capacity for blood-borne waste macromolecules and colloids. This LSEC scavenger function has been insufficiently characterized in liver disease. The Glmpgt/gt mouse lacks expression of a subunit of the MFSD1/GLMP lysosomal membrane protein transporter complex, is born normal, but soon develops chronic, mild hepatocyte injury, leading to slowly progressing periportal liver fibrosis, and splenomegaly. This study examined how LSEC scavenger function and morphology are affected in the Glmpgt/gt model. FITC-labelled formaldehyde-treated serum albumin (FITC-FSA), a model ligand for LSEC scavenger receptors was administered intravenously into Glmpgt/gt mice, aged 4 months (peak of liver inflammation), 9-10 month, and age-matched Glmpwt/wt mice. Organs were harvested for light and electron microscopy, quantitative image analysis of ligand uptake, collagen accumulation, LSEC ultrastructure, and endocytosis receptor expression (also examined by qPCR and western blot). In both age groups, the Glmpgt/gt mice showed multifocal liver injury and fibrosis. The uptake of FITC-FSA in LSECs was significantly reduced in Glmpgt/gt compared to wild-type mice. Expression of LSEC receptors stabilin-1 (Stab1), and mannose receptor (Mcr1) was almost similar in liver of Glmpgt/gt mice and age-matched controls. At the same time, immunostaining revealed differences in the stabilin-1 expression pattern in sinusoids and accumulation of stabilin-1-positive macrophages in Glmpgt/gt liver. FcγRIIb (Fcgr2b), which mediates LSEC endocytosis of soluble immune complexes was widely and significantly downregulated in Glmpgt/gt liver. Despite increased collagen in space of Disse, LSECs of Glmpgt/gt mice showed well-preserved fenestrae organized in sieve plates but the frequency of holes >400 nm in diameter was increased, especially in areas with hepatocyte damage. In both genotypes, FITC-FSA also distributed to endothelial cells of spleen and bone marrow sinusoids, suggesting that these locations may function as possible compensatory sites of clearance of blood-borne scavenger receptor ligands in liver fibrosis.
Topics: Mice; Animals; Endothelial Cells; Ligands; Down-Regulation; Fluorescein-5-isothiocyanate; Liver; Liver Cirrhosis; Hepatocytes; Disease Models, Animal; Collagen; Membrane Transport Proteins; Cell Adhesion Molecules, Neuronal
PubMed: 37910485
DOI: 10.1371/journal.pone.0293526 -
Pharmaceutics Oct 2023Free drug concentrations are generally considered the pharmacologically active moiety and are important for cellular diffusion and distribution. Pregnancy-related...
Total and Free Blood and Plasma Concentration Changes in Pregnancy for Medicines Highly Bound to Plasma Proteins: Application of Physiologically Based Pharmacokinetic Modelling to Understand the Impact on Efficacy.
Free drug concentrations are generally considered the pharmacologically active moiety and are important for cellular diffusion and distribution. Pregnancy-related changes in plasma protein binding and blood partitioning are due to decreases in plasma albumin, alpha-1-acid glycoprotein, and haematocrit; this may lead to increased free concentrations, tissue distribution, and clearance during pregnancy. In this paper we highlight the importance and challenges of considering changes in total and free concentrations during pregnancy. For medicines highly bound to plasma proteins, such as tacrolimus, efavirenz, clindamycin, phenytoin, and carbamazepine, differential changes in concentrations of free drug during pregnancy may be clinically significant and have important implications for dose adjustment. Therapeutic drug monitoring usually relies on the measurement of total concentrations; this can result in dose adjustments that are not necessary when changes in free concentrations are considered. We explore the potential of physiologically based pharmacokinetic (PBPK) models to support the understanding of the changes in plasma proteins binding, using tacrolimus and efavirenz as example drug models. The exposure to either drug was predicted to be reduced during pregnancy; however, the decrease in the exposure to the total tacrolimus and efavirenz were significantly larger than the reduction in the exposure to the free drug. These data show that PBPK modelling can support the impact of the changes in plasma protein binding and may be used for the simulation of free concentrations in pregnancy to support dosing decisions.
PubMed: 37896215
DOI: 10.3390/pharmaceutics15102455 -
Biomedicines Oct 2023Adalimumab is a fully human monoclonal antibody used for the treatment of inflammatory bowel disease (IBD). Due to its considerably variable pharmacokinetics and the...
Adalimumab is a fully human monoclonal antibody used for the treatment of inflammatory bowel disease (IBD). Due to its considerably variable pharmacokinetics and the risk of developing antibodies against adalimumab, it is highly recommended to use a model-informed precision dosing approach. The aim of this study is to develop a population pharmacokinetic (PopPK) model of adalimumab for patients with IBD based on a literature model (reference model) to be used in the clinical setting. A retrospective observational study with 54 IBD patients was used to develop two different PopPK models based on the reference model. One of the developed models estimated the pharmacokinetic population parameters (estimated model), and the other model incorporated informative priors (prior model). The models were evaluated with bias and imprecision. Clinical impact was also assessed, evaluating the differences in dose interventions. The developed models included the albumin as a continuous covariate on apparent clearance. The prior model was superior to the estimated model in terms of bias, imprecision and clinical impact on the target population. In conclusion, the prior model adequately characterized adalimumab PK in the studied population and was better than the reference model in terms of predictive performance and clinical impact.
PubMed: 37893195
DOI: 10.3390/biomedicines11102822 -
CPT: Pharmacometrics & Systems... Jan 2024APX3330 ((2E)-2-[(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)methylene]-undecanoic acid), a selective inhibitor of APE1/Ref-1, has been investigated in...
APX3330 ((2E)-2-[(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)methylene]-undecanoic acid), a selective inhibitor of APE1/Ref-1, has been investigated in treatment of hepatitis, cancer, diabetic retinopathy, and macular edema. APX3330 is administered orally as a quinone but is rapidly converted to the hydroquinone form. This study describes the pharmacokinetics of APX3330 and explores effect of food on absorption. Total plasma quinone concentrations of APX3330 were obtained following oral administration from studies in healthy Japanese male subjects (single dose-escalation; multiple-dose; food-effect) and patients with cancer patients. Nonlinear mixed effects modeling was performed using Monolix to estimate pharmacokinetic parameters and assess covariate effects. To further evaluate the effect of food on absorption, a semi-physiologic pharmacokinetic model was developed in Gastroplus to delineate effects of food on dissolution and absorption. A two-compartment, first order absorption model with lag time best described plasma concentration-time profiles from 49 healthy Japanese males. Weight was positively correlated with apparent clearance (CL/F) and volume. Administration with food led to an 80% higher lag time. CL/F was 41% higher in the cancer population. The semi-physiologic model indicates a switch from dissolution-rate control of absorption in the fasted-state to gastric emptying rate determining absorption rate in the fed-state. Oral clearance of APX3330 is higher in patients with cancer than healthy Japanese males, possibly due to reduced serum albumin in patients with cancer. Delayed APX3330 absorption with food may be related to higher conversion to the more soluble but less permeable hydroquinone form in the gastrointestinal tract. Future work should address pharmacokinetic differences between APX3330 quinone and hydroquinone forms.
Topics: Humans; Male; Hydroquinones; Neoplasms; Administration, Oral; Angiogenesis Inhibitors; Quinones
PubMed: 37884051
DOI: 10.1002/psp4.13061