Detection of circulating normal and tumor plasma cells in newly diagnosed patients of multiple myeloma and their associations with clinical and laboratory parameters.

INTRODUCTION: Circulating plasma cells (CPCs) are frequently noted in variable frequencies in the entire spectrum of plasma cells neoplasms. With advent of high sensitivity multi-parametric flow cytometry, it is not only possible to detect CPCs present in very low numbers, but also to categorise them into circulating tumor plasma cells (CTPCs) and circulating normal plasma cells (CNPCs), based on their marker-profile. This study used multi-colour flow cytometry to evaluate the load of both CTPCs & CNPCs at the time of diagnosis and at six months' time-point of therapy, and evaluated associations of both with clinical and laboratory parameters. METHODS: Twenty one newly diagnosed MM patients were enrolled. Six to nine millilitres of EDTA-anticoagulated peripheral blood sample was used for flow cytometry. A ten colour antibody panel was used for analysis of CPCs, which were categorised further into CTPCs and CNPCs. Approximately 4.8 million events were acquired for the analysis. The percentage &absolute numbers of CTPCs and CNPCs were noted and the proportion of CTPCs out of all CPCs (CTPCs + CNPCs) were also calculated for evaluating their statistical associations. RESULTS: All 21 patients of newly diagnosed MM showed presence of CPCs (CTPCs and/or CNPCs) at the time of diagnosis. The CTPCs were detected in 76 % of the study population. The median percentage and absolute counts of CTPCs were 0.52 % and 54.9 cells /µL, respectively. CNPCs were found in 95 % and the median percentage and absolute counts of CNPCs were 0.025 % and 2.66 cells/µL. After six months of therapy, CPCs (CTPCs and/or CNPCs) were found in all nine patients evaluated for this assay. CTPCs were found 33 %, with a median of 0.075 % and CNPCs were found in 89 % with a median of 0.01 %. Our study showed that the load of CTPCs was found to be higher in patients with presence of lytic bone lesions, plasmacytoma, presence of PCs on peripheral blood film by light microscopy, presence of Chr 1p32 deletion, expression of CD56 and CD81 on CTPCs, and in patients with absence of very good partial response (VGPR). Conversely, the load of CTPCs was significantly lower in patients with concomitant amyloidosis. Also, percentage of bone marrow plasma cells exhibited a significant positive correlation with the absolute count of CTPCs. We observed that the mean percentage of CNPCs was significantly higher in female patients. The load of CNPCs was lower in patients with thrombocytopenia and with hypoalbuminemia. CONCLUSION: Increased burden of CTPCs was associated with presence of lytic lesions, plasmacytomas, Chr 1p32 deletion, expression of CD56 and CD81 on tumor cells and with failure to achieve very good partial response. The CNPCs were lower in patients with thrombocytopenia and with hypoalbuminemia. To best ot our knowledge, this is the first study from India on the relevance of circulating tumor plasma cells and the first study in the world to analyse the associations of circulating normal plasma cells in newly diagnosed patients of multiple myeloma. The study also highlights the utility of multi-parametric flow cytometry in identification and enumeration of circulating plasma cells. MICRO ABSTRACT: Circulating plasma cells indicates poorer outcomes in patients of multiple myeloma. Twenty one newly diagnosed multiple myeloma patients were evaluated by flow cytometry to enumerate and characterise circulating tumor plasma cells (CTPCs) and circulating normal plasma cells (CNPCs). Higher load of CTPCs correlated with known poor prognostic markers and poor response to therapy.

The association between hypoalbuminemia and microcirculation, endothelium, and glycocalyx disorders in children with sepsis.

OBJECTIVE: The objective of this study was to evaluate the association between serum albumin levels and microcirculation changes, glycocalyx degradation, and the clinical outcomes of interest. METHODS: Observational, prospective study in children with sepsis. The primary outcome was the association between hypoalbuminemia and microcirculation disorders, endothelial activation and glycocalyx degradation using a perfused boundary region (PBR) (abnormal >2.0 µm on sublingual video microscopy) or plasma biomarkers (syndecan-1, angiopoietin-2). RESULTS: A total of 125 patients with sepsis were included. The median age was 2.0 years (IQR 0.5-12.5). Children with hypoalbuminemia had more abnormal microcirculation with a higher PBR (2.16 µm [IQR 2.03-2.47] vs. 1.92 [1.76-2.28]; p = .01) and more 4-6 µm capillaries recruited (60% vs. 40%; p = .04). The low albumin group that had the worst PBR had the most 4-6 µm capillaries recruited (rho 0.29; p < .01), 48% higher Ang-2 (p = .04), worse annexin A5 (p = 0.03) and no syndecan-1 abnormalities (p = .21). Children with hypoalbuminemia and a greater percentage of blood volume in their capillaries needed mechanical ventilation more often (56.3% vs. 43.7%; aOR 2.01 95% CI 1.38-3.10: p < .01). CONCLUSIONS: In children with sepsis, an association was found between hypoalbuminemia and microcirculation changes, vascular permeability, and greater endothelial glycocalyx degradation.

Hypoalbuminemia affects the spatio-temporal tissue distribution of ochratoxin A in liver and kidneys: consequences for organ toxicity.

Hypoalbuminemia (HA) is frequently observed in systemic inflammatory diseases and in liver disease. However, the influence of HA on the pharmacokinetics and toxicity of compounds with high plasma albumin binding remained insufficiently studied. The 'lack-of-delivery-concept' postulates that HA leads to less carrier mediated uptake of albumin bound substances into hepatocytes and to less glomerular filtration; in contrast, the 'concept-of-higher-free-fraction' argues that increased concentrations of non-albumin bound compounds facilitate hepatocellular uptake and enhance glomerular filtration. To address this question, we performed intravital imaging on livers and kidneys of anesthetized mice to quantify the spatio-temporal tissue distribution of the mycotoxin ochratoxin A (OTA) based on its auto-fluorescence in albumin knockout and wild-type mice. HA strongly enhanced the uptake of OTA from the sinusoidal blood into hepatocytes, followed by faster secretion into bile canaliculi. These toxicokinetic changes were associated with increased hepatotoxicity in heterozygous albumin knockout mice for which serum albumin was reduced to a similar extent as in patients with severe hypoalbuminemia. HA also led to a shorter half-life of OTA in renal capillaries, increased glomerular filtration, and to enhanced uptake of OTA into tubular epithelial cells. In conclusion, the results favor the 'concept-of-higher-free-fraction' in HA; accordingly, HA causes an increased tissue uptake of compounds with high albumin binding and increased organ toxicity. It should be studied if this concept can be generalized to all compounds with high plasma albumin binding that are substrates of hepatocyte and renal tubular epithelial cell carriers.

Variations in the Human Serum Albumin Gene: Molecular and Functional Aspects.

The human albumin gene, the most abundant serum protein, is located in the long arm of chromosome 4, near the centromere, position 4q11-3. It is divided by 14 intervening introns into 15 exons, the last of which is untranslated. To date, 74 nucleotide substitutions (mainly missense) have been reported, determining the circulating variants of albumin or pre-albumin. In a heterozygous state, this condition is known as alloalbuminaemia or bisalbuminaemia (OMIM # 103600). The genetic variants are not associated with disease, neither in the heterozygous nor in the homozygous form. Only the variants resulting in familial dysalbuminaemic hyperthyroxinaemia and hypertriiodothyroninaemia are of clinical relevance because affected individuals are at risk of inappropriate treatment or may have adverse drug effects. In 28 other cases, the pathogenic variants (mainly affecting splicing, nonsense, and deletions), mostly in the homozygous form, cause a premature stop in the synthesis of the protein and lead to the condition known as congenital analbuminaemia. In this review, we will summarize the current knowledge of genetic and molecular aspects, functional consequences and potential therapeutic uses of the variants. We will also discuss the molecular defects resulting in congenital analbuminaemia, as well as the biochemical and clinical features of this rare condition.

Serum Albumin and Bleeding Events After Percutaneous Coronary Intervention in Patients With Acute Myocardial Infarction (from the HAGAKURE-ACS Registry).

Low serum albumin (SA) on admission in patients with acute myocardial infarction (AMI) has been reported to be associated with adverse cardiovascular events. The relation between low SA and post-AMI bleeding events is presently unknown. We analyzed 1,724 patients with AMI enrolled in the HAGAKURE-ACS registry who underwent primary percutaneous coronary intervention from January 2014 to December 2018. To assess the influence of low SA at admission, patients were divided into 3 groups according to the albumin tertiles: the low SA group (<3.8 g/100 ml), the middle SA (MSA) group (3.8 to 4.1 g/100 ml), and the normal SA (NSA) group (≥4.2 g/100 ml). The primary end point was the incidence of Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries moderate/severe bleeding. The cumulative 3-year incidence of the primary end point was significantly higher in the low SA group than in the MSA and NSA groups (30.8% and 11.9% vs 7.7%; p <0.001). In the landmark analysis at 30 days, the cumulative incidences of the primary end point were also significantly higher in the low SA group than in the MSA and NSA groups, both within and beyond 30 days (20.1% and 6.1% vs 3.5%; p <0.001, and 12.4% and 6.2% vs 4.5%; p <0.001, respectively). After adjusting for confounders, the low SA group showed excess risk of bleeding events relative to NSA (hazard ratio 1.56; 95% confidence interval 1.06 to 2.30; p = 0.026), whereas risk of bleeding was neutral in MSA relative to NSA (hazard ratio 0.94; 95% confidence interval 0.63 to 1.34; p = 0.752). In conclusion, low SA at admission was independently associated with higher risk for bleeding events in patients with AMI undergoing percutaneous coronary intervention.

Hypoalbuminemia as a prognostic biomarker for higher mortality and treatment complications in acute myeloid leukemia.

Older age and poor performance status lead to worse outcomes in acute myeloid leukemia (AML) patients. Hypoalbuminemia is a negative predictor of morbidity and mortality in several malignancies. We evaluated the relationship between baseline serum albumin levels on treatment-related complications, as well as short-term mortality and overall survival (OS) in 756 newly diagnosed AML patients. We conducted a retrospective multicenter study to examine treatment-related complications and OS according to pretreatment serum albumin levels: normal albumin ≥3.5 g/dl, marked hypoalbuminemia <2.5 g/dl, and hypoalbuminemia 2.5-3.4 g/dl. In an adjusted multivariate analysis, a lower baseline albumin was independently associated with a higher number of grade ≥3 complications when adjusting for age, secondary AML, sex and intensive treatment. When comparing normal to markedly low albumin levels, the estimated mean number of complications increases by a factor of 1.35. Patients who had a normal baseline albumin had a 30 day-mortality rate of 4.8%, which was significantly lower compared with patients with hypoalbuminemia (16.5%) and marked hypoalbuminemia (33.9%; p < 0.01). Similarly, 60-day mortality rate was significantly higher in the hypoalbuminemia group (24.0%) and marked hypoalbuminemia group (45%) compared with normal albumin group (8.3%; p < 0.01). Patients with lower baseline albumin levels have increased treatment-related morbidity and mortality, suggesting that pre-treatment serum albumin is an important independent prognostic marker.

Immunological abnormalities in patients with early-onset ataxia with ocular motor apraxia and hypoalbuminemia.

Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) is a neurodegenerative disorder caused by mutation in the aprataxin (APTX)-coding gene APTX, which is involved in DNA single-strand break repair (SSBR). The neurological abnormalities associated with EAOH are similar to those observed in patients with ataxia-telangiectasia. However, the immunological abnormalities in patients with EAOH have not been described. In this study, we report that EAOH patients have immunological abnormalities, including lymphopenia; decreased levels of CD4+ T-cells, CD8+ T-cells, and B-cells; hypogammaglobulinemia; low T-cell recombination excision circles and kappa-deleting element recombination circles; and oligoclonality of T-cell receptor ß-chain variable repertoire. These immunological abnormalities vary among the EAOH patients. Additionally, mild radiosensitivity in the lymphocytes obtained from the patients with EAOH was demonstrated. These findings suggested that the immunological abnormalities and mild radiosensitivity evident in patients with EAOH could be probably caused by the DNA repair defects.

Once-daily 1 g ceftriaxone optimizes exposure in patients with septic shock and hypoalbuminemia receiving continuous veno-venous hemodiafiltration.

PURPOSE: Ceftriaxone total and unbound pharmacokinetics (PK) can be altered in critically ill patients with septic shock and hypoalbuminemia receiving continuous veno-venous hemodiafiltration (CVVHDF). The objective of this study was to determine the dosing strategy of ceftriaxone that maximizes the probability of maintaining the concentration above the MIC of the susceptible bacteria (≤2 mg/L by the EUCAST) for a 100% of the dosing interval (100% ƒuT>MIC). METHODS: In a prospective PK study in the intensive care units of two tertiary Spanish hospitals, six timed blood samples were collected per patient; for each sample, ceftriaxone total and unbound concentrations were measured using a liquid chromatography coupled to tandem mass spectrometry method. Population PK analysis and Monte-Carlo simulations were performed using NONMEMv.7.3®. RESULTS: We enrolled 8 critically ill patients that met the inclusion criteria (47 blood samples). Median age (range) was 70 years (47-85), weight 72.5 kg (40-95), albumin concentration 24.2 g/L (22-34), APACHE II score at admission 26 (17-36), and SOFA score on the day of study 12 (9-15). The unbound fraction (ƒu) of ceftriaxone was 44%, and total CL was 1.27 L/h, 25-30% higher than the CL reported in septic critically ill patients not receiving renal replacement therapies, and dependent on albumin concentration and weight. Despite this increment in ƒu and CL, Monte-Carlo simulations showed that a dose of 1 g once-daily ceftriaxone is sufficient to achieve a 100% ƒuT>MIC for MICs ≤2 mg/L for any range of weight and albumin concentration. CONCLUSION: Once-daily 1 g ceftriaxone provides optimal exposure in critically ill patients with septic shock and hypoalbuminemia receiving CVVHDF.

Janus Kinase Inhibitors Ameliorated Gastrointestinal Amyloidosis and Hypoalbuminemia in Persistent Dermatitis Mouse Model.

Malnutrition is not only regarded as a complication of rheumatoid arthritis and inflammatory bowel disease but also that of inflammatory skin disease; however, the mechanisms and efficacy of its treatment have not been elucidated. Using a mouse model of dermatitis, we investigated the pathophysiology of malnutrition in inflammatory skin conditions and efficacy of its treatment. We employed spontaneous skin inflammation mice models overexpressing human caspase-1 in the epidermal keratinocytes. Body weight, nutrition level, and α1-antitrypsin fecal concentration were measured. The gastrointestinal tract was histologically and functionally investigated. Fluorescein isothiocyanate (FITC)-dextran was forcibly fed on an empty stomach, and plasma FITC-dextran was measured. The treatment efficacy of antibodies against tumor necrosis factor-α (TNF-α) and interleukin (IL)-α/ß as well as Janus kinase (JAK) inhibitors was investigated. Compared with wild-type littermates, the inflammatory skin mice models showed a lowered body weight, reduction of serum albumin level, amyloid deposition in the stomach, small intestine, and large intestine, and increased α1-antitrypsin fecal concentration. However, the plasma FITC-dextran was unchanged between the dermatitis models and wild-type littermates. The over-produced serum amyloid A1 in the liver was detected in the plasma in the dermatitis model. Antibodies against TNF-α and IL-α/ß showed partial effects on amyloid deposition; however, JAK inhibitors improved gastrointestinal amyloidosis with the improvement of skin symptoms. Chronic dermatitis is closely related to secondary amyloidosis in the gastrointestinal tract, resulting in hypoalbuminemia. Therefore, active control of skin inflammation is essential for preventing gastrointestinal complications.

DGAT1 mutations leading to delayed chronic diarrhoea: a case report.

BACKGROUND: Early-onset chronic diarrhoea often indicates a congenital disorder. Mutation in diacylglycerol o-acyltransferase 1 (DGAT1) has recently been linked to early-onset chronic diarrhoea. To date, only a few cases of DGAT1 deficiency have been reported. Diarrhoea in those cases was severe and developed in the neonatal period or within 2 months after birth. CASE PRESENTATION: Here, we report a female patient with DGAT1 mutations with delayed-onset chronic diarrhoea. The patient had vomiting, hypoalbuminemia, hypertriglyceridemia, and failure to thrive at early infancy. Her intractable chronic diarrhoea occurred until she was 8 months of age. A compound heterozygous DGAT1 mutation was found in the patient, which was first found in the Chinese population. Her symptoms and nutrition status improved after nutritional therapy, including a fat restriction diet. CONCLUSIONS: This case expanded our knowledge of the clinical features of patients with DGAT1 mutations. Intractable diarrhoea with delayed onset could also be a congenital disorder.

Arrhythmias in Relation to Mortality After Transcatheter Aortic Valve Replacement.

BACKGROUND: The purpose of this study was to identify predictors of mortality and potentially modifiable factors related to arrhythmias in patients that undergo transcatheter aortic valve replacement (TAVR). Patients that undergo TAVR are at risk for complete heart block requiring pacemaker implant. Additionally, other arrhythmias, specifically atrial fibrillation (AF), are common in this population. It is unclear how arrhythmias and their management contribute to mortality risk. METHODS: The study analyzed 176 patients who underwent TAVR at a single center. Factors associated with pacemaker implantation within 30 days were analyzed by logistic regression. Factors associated with mortality were analyzed by Kaplan-Meier and Cox regression analyses. RESULTS: Mean age was 80 ± 8.5 years. AF was present in 69 patients, and 39 received anticoagulation. Post-TAVR, a pacemaker was implanted in 25 patients within 30 days. Over a follow up of 566 ± 496 days, 49 patients died. In multivariable analysis, right bundle branch block remained significant (odds ratio 4.212, P = 0.012) for pacemaker implant within 30 days. The AF (hazard ratio [HR] 3.905, P = 0.001), albumin level (HR 0.316, P = 0.034), and diabetes (HR 2.323, P = 0.027) were predictors of death in a multivariate analysis, while pacemaker implant within 30 days was not. Patients with AF who were anticoagulated had improved survival in a stratified Kaplan-Meier analysis compared with those who were not anticoagulated (P = 0.0001). CONCLUSION: AF, diabetes, and low albumin levels are independently associated with mortality after TAVR. In particular, patients with AF who are not anticoagulated are at highest risk for death. Efforts to identify AF and consider anticoagulation should be emphasized.

Prediction of Serum-Free and Cerebrospinal Fluid Valproic Acid Levels in Patients With Hypoalbuminemia After Craniotomy.

BACKGROUND: In patients with hypoalbuminemia after craniotomy, total serum concentrations of valproic acid (VPA) may provide poor clinical insights, owing to saturated protein binding and increased unbound fractions. However, very few clinical laboratories routinely analyze free concentrations of the drug. The aim of this study was to develop a model to predict serum-free and cerebrospinal fluid (CSF) levels of VPA based on its total concentration and to investigate the model's applicability. METHODS: Total serum and CSF concentrations of VPA in 79 patients were measured using a validated immunoassay between January 2015 and December 2015. The demographic, clinical, and laboratory information of patients were retrieved from medical records. A multiple linear regression analysis was adopted to determine the potential variations and establish the functional relationship between CSF concentration and significant clinical factors. RESULTS: Based on the stepwise multiple linear regression analysis performed using the natural logarithm of the concentration of VPA in the CSF as the dependent variable, serum concentrations of VPA (X1, ß' = 0.844), serum albumin concentration (X2, ß' = -0.393), and CSF protein concentration (X3, ß' = 0.098) were identified as the 3 variables that significantly predicted the dependent variable: (Equation is included in full-text article.), with a coefficient of determination (R) of 0.874. As the CSF protein level is often unavailable, the model was redefined to include 2 variables-serum concentrations of VPA (X1, ß' = 0.840) and serum albumin concentration (X2, ß' = -0.359): (Equation is included in full-text article.), with R = 0.813. CONCLUSIONS: Based on total VPA and serum albumin concentrations, we developed a model to predict serum-free and CSF levels of VPA. This model is useful for correcting dose adjustment in patients with hypoalbuminemia after craniotomy.

Congenital Analbuminemia in a Korean Male Diagnosed with Single Nucleotide Polymorphism in the ALB Gene: The First Case Reported in Korea.

Congenital analbuminemia (CAA) is an autosomal recessive disease characterized by extremely low serum levels of albumin. CAA is caused by various homozygous or heterozygous mutations of the ALB gene. Patients often exhibit no clinical symptoms, aside from rare accompanying conditions, such as fatigue, ankle edema, and hypotension. This case report describes the case of a 28-year-old asymptomatic Korean male referred to our center with hypocalcemia, vitamin D deficiency, and hypoalbuminemia who was diagnosed with CAA. To determine the cause of hypoalbuminemia in the patient, laboratory tests, radiological examination, and DNA sequencing were performed. The patient was confirmed to not exhibit any other clinical conditions that can induce hypoalbuminemia and was diagnosed with CAA using DNA sequencing. The present case of CAA is the first to be reported in Korea.

Serum albumin and hospitalization among pediatric patients with end-stage renal disease who started dialysis therapy.

BACKGROUND: Hypoalbuminemia is a strong predictor of hospitalization and mortality among adult dialysis patients. However, data are scant on the association between serum albumin and hospitalization among children new to dialysis. METHODS: In a retrospective cohort study of children 1-17 years old with end-stage renal disease receiving dialysis therapy in a large US dialysis organization 2007-2011, we examined the association of serum albumin with hospitalization frequency and total hospitalization days using a negative binomial regression model. RESULTS: Among 416 eligible patients, median (interquartile range) age was 14 (10-16) years and mean ± SD baseline serum albumin level was 3.7 ± 0.8 g/dL. Two hundred sixty-six patients (64%) were hospitalized during follow-up with an incidence rate of 2.2 (95%CI, 1.9-2.4) admissions per patient-year. There was a U-shaped association between serum albumin and hospitalization frequency; hospitalization rates (95%CI) were 2.7 (2.2-3.2), 1.9 (1.5-2.4), 1.6 (1.3-1.9), and 2.7 (1.7-3.6) per patient-year among patients with serum albumin levels < 3.5, 3.5- < 4.0, 4.0- < 4.5, and ≥ 4.5 g/dL, respectively. Case mix-adjusted hospitalization incidence rate ratios (IRRs) (95%CI) were 1.63 (1.24-2.13), 1.32 (1.10-1.58), and 1.25 (1.06-1.49) at serum albumin levels 3.0, 3.5, and 4.5 g/dL, respectively (reference: 4.0 g/dL). Similar trends were observed in hospitalization days. These associations remained robust against further adjustment for laboratory variables associated with malnutrition and inflammation. CONCLUSIONS: Both high and low serum albumin were associated with higher hospitalization in children starting dialysis. Because the observed association is novel and not fully explainable especially for high serum albumin levels, interpreting the results requires caution and further studies are needed to confirm and elucidate this association before clinical recommendations are made.

A reduced liver 18F-FDG uptake may be related to hypoalbuminemia in patients with malnutrition.

OBJECTIVE: 18F-FDG PET/CT is a hybrid imaging method widely used as a useful, noninvasive imaging modality for evaluating various neoplastic diseases. When assessing the tumor uptake, the liver and the mediastinal blood pool are often used as a reference region. In daily clinical practice, the 18F-FDG uptake in the liver sometimes appears to decrease on PET images of patients with malnutrition. The purpose of this study was to investigate whether or not the liver 18F-FDG uptake is decreased in patients with malnutrition. METHODS: We retrospectively analyzed 246 patients who underwent 18F-FDG PET/CT from January 2018 to June 2018 and whose blood serum albumin was measured within 1 month of PET/CT. We compared the liver uptake and mediastinal blood uptake of patients with low serum albumin level (< 4.0 g/dl) and hypoalbuminemia (< 3.5 g/dl) with those with a normal serum albumin level (≥ 4.0 g/dl). Correlations between the liver and mediastinal blood uptake and the serum albumin level were also calculated. RESULTS: The maximum standardized uptake value (SUVmax) and mean standardized uptake value (SUVmean) of the liver in 117 patients with low serum albumin were 3.1 ± 0.5 and 2.3 ± 0.3, respectively, while they were 2.9 ± 0.4, 2.0 ± 0.3 in 29 patients with hypoalbuminemia; these values were all significantly lower than the respective ones (3.4 ± 0.5, 2.5 ± 0.4) in 129 patients with normal serum albumin (all p < 0.001). The SUVmean of the mediastinal blood uptake in patients with hypoalbuminemia and normal serum albumin were 1.6 ± 0.2 and 1.7 ± 0.3, respectively (p = 0.053). The serum albumin level demonstrated a significantly positive, moderate correlation with the liver SUVmean, showing a regression line of y = 0.31x + 1.1 (r = 0.41, p < 0.001). CONCLUSION: The liver 18F-FDG uptake tended to decrease in patients with hypoalbuminemia. In the patients with malnutrition, the mediastinal blood pool may be a more stable reference than the liver for evaluating the tumor activity because hypoalbuminemia is considered to less strongly influence the mediastinal blood pool than that in the liver.

Pharmacokinetics of Caspofungin in Critically Ill Patients in Relation to Liver Dysfunction: Differential Impact of Plasma Albumin and Bilirubin Levels.

Caspofungin has a liver-dependent metabolism. Reduction of the dose is recommended based on Child-Pugh (C-P) score. In critically ill patients, drug pharmacokinetics (PK) may be altered. The aim of this study was to investigate the prevalence of abnormal liver function tests, increased C-P scores, their effects on caspofungin PK, and whether pharmacokinetic-pharmacodynamic (PK/PD) targets were attained in patients with suspected candidiasis. Intensive care unit patients receiving caspofungin were prospectively included. PK parameters were determined on days 2, 5, and 10, and their correlations to the individual liver function tests and the C-P score were analyzed. Forty-six patients were included with C-P class A (n = 5), B (n = 40), and C (n = 1). On day 5 (steady state), the median and interquartile range for area under the curve from 0 to 24 h (AUC0-24), clearance (CL), and central volume of distribution (V1) were 57.8 (51.6 to 69.8) mg·h/liter, 0.88 (0.78 to 1.04) liters/h, and 11.9 (9.6 to 13.1) liters, respectively. The C-P score did not correlate with AUC0-24 (r = 0.03; P = 0.84), CL (r = -0.07; P = 0.68), or V1 (r = 0.19; P = 0.26), but there was a bilirubin-driven negative correlation with the elimination rate constant (r = -0.46; P = 0.004). Hypoalbuminemia correlated with low AUC0-24 (r = 0.45; P = 0.005) and was associated with higher clearance (r = -0.31; P = 0.062) and somewhat higher V1 (r = -0.15; P = 0.37), resulting in a negative correlation with the elimination rate constant (r = -0.34; P = 0.042). For Candida strains with minimal inhibitory concentrations of ≥0.064 µg/ml, PK/PD targets were not attained in all patients. The caspofungin dose should not be reduced in critically ill patients in the absence of cirrhosis, and we advise against the use of the C-P score in patients with trauma- or sepsis-induced liver injury.

Clinical Features of Nephrotic Syndrome with Cerebral Hemorrhage.

BACKGROUND Cerebral hemorrhage has been increasingly reported in patients with nephrotic syndrome (NS). However, the clinical features and pathogenesis of NS patients with cerebral hemorrhage remain unclear. MATERIAL AND METHODS From January 2007 to August 2017, continuous NS patients with cerebral hemorrhage at the First Affiliated Hospital of Guangxi Medical University were selected. The clinical manifestations, laboratory measurements, and neurological images of these patients were collected and analyzed. RESULTS Acute cerebral hemorrhage was recorded in 15 of 10 461 NS patients. The average age of these 15 patients (9 males and 6 females) was 50.87±23.27 years old. Among these 15 patients, conventional vascular risk factors were identified in 8 patients, hypoalbuminemia and proteinuria were recorded in all 15 patients, coagulopathy was observed in 9 patients, increased D-dimer level was recorded in 13 patients, hyperlipidemia was recorded in 11 patients, and impaired renal function was recorded in 9 patients. The hemorrhage developed in the lobe (n=9), basal ganglia (n=3), cerebellum (n=2), and cerebral hemisphere (n=1). Eight patients were in a coma on the day the cerebral hemorrhage occurred, while 12 patients had a poor prognosis after 30 days of hemorrhage onset. CONCLUSIONS Poor prognosis was recorded in NS patients with cerebral hemorrhage. Although conventional vascular risk factors have only been identified in 8 patients, biochemical abnormalities (hypoalbuminemia, proteinuria, elevated D-dimer, and hyperlipidemia) were recorded in the majority of these 15 patients. Furthermore, most of the hemorrhages developed in the lobes. Coagulopathy might be the potential pathogenesis of cerebral hemorrhage in NS patients.

Retinal and choroidal thickness in paediatric patients with hypoalbuminaemia caused by nephrotic syndrome.

BACKGROUND: A study was conducted to evaluate the choroidal thickness (CT) and retinal thickness (RT) in paediatric patients with hypoalbuminaemia caused by nephrotic syndrome (NS). We also studied the correlation between the subfoveal choroidal thickness (SFCT) and serum protein concentration. METHODS: This was a cross-sectional study. Fifty-one paediatric patients with hypoalbuminaemia caused by NS and 41 normal subjects were included in the study. Enhanced depth imaging optical coherence tomography (EDI-OCT) was performed to measure the RT and CT. The RT and CT were measured manually at intervals of 0.5 mm along a horizontal line through the macular fovea between 2.5 mm nasal and 2.5 mm temporal to the fovea. Clinical data including measurements of serum proteins were obtained. RESULTS: The mean RTs at the T2.5, T2, N1.5, N2, and N2.5 locations and the average macular horizontal RT were slightly greater in the NS group than those in the control group. The mean CTs at all locations were significantly greater in the NS group than those in the control group; the difference was most significant at the fovea (373.8 ± 74.9 µm vs. 280.2 ± 57.1; p < 0.001). The SFCT in patients with NS was correlated with age (r = - 0.307, p = 0.003), body height (r = - 0.320, p = 0.022), body weight (r = - 0.343, p = 0.014), axial length (AL, r = - 0.237, p = 0.023), total protein (TP, r = - 0.302, p = 0.031), albumin (ALB, r = - 0.285, p = 0.042), prealbumin (PA, r = - 0.303, p = 0.033) and 24-h urine volume (UV, r = - 0.298, p = 0.034). Multiple linear regression analysis showed that the TP concentration and body weight had the highest correlation with the SFCT (R2 = 0.220, p < 0.05). CONCLUSIONS: The macular RT is slightly increased and the macular CT is significantly increased in paediatric patients with hypoalbuminaemia caused by NS, indicating fluid accumulation in the retina and choroid. There is a negative correlation between the SFCT and serum TP concentration. Thus, the serum TP concentration is an important indicator of CT in patients with hypoalbuminaemia.

Body Fluids in End-Stage Renal Disease: Statics and Dynamics.

BACKGROUND: Abnormalities in fluid status in hemodialysis (HD) patients are highly prevalent and are related to adverse outcomes. SUMMARY: The inherent discontinuity of the HD procedure in combination with an often compromised cardiovascular response is a major contributor to this phenomenon. In addition, systemic inflammation and endothelial dysfunction are related to extracellular fluid overload (FO). Underlying this relation may be factors such as hypoalbuminemia and an increased capillary permeability, leading to an altered fluid distribution between the blood volume (BV) and the interstitial fluid compartments, compromising fluid removal during dialysis. Indeed, whereas estimates of extracellular volume by bioimpedance spectroscopy are highly predictive of mortality, absolute BV assessed by the saline dilution technique was predictive of intra-dialytic morbidity. Changes in relative BV during HD are positively related to ultrafiltration rate (UFR) and, at least in some studies, negatively to FO. High UFR is also related to changes in central venous oxygen saturation (ScvO2), a marker for tissue perfusion. On the one hand, high UFR and more pronounced declines in ScvO2, but on the other hand, flat relative BV curves are also predictive of mortality; the relation between outcome which statics and dynamics of fluid status appears to be complex. Key Message: While technological developments enable the clinician to monitor statics and dynamics of fluid status and hemodynamics during HD in an accessible way, the role of technology-based interventions needs further study.

A Physiologically Based Pharmacokinetic Perspective on the Clinical Utility of Albumin-Based Dose Adjustments in Critically Ill Patients.

INTRODUCTION: In hypo-albuminemia, the extent of albumin binding of a drug decreases. The resulting change in plasma protein binding only rarely leads to clinically relevant changes in unbound drug exposure. Nevertheless, in the critically ill, a tendency to increase dosing of anti-infective therapy is seen in patients experiencing hypo-albuminemia. To reconcile basic pharmacological principles with current clinical practice, this work presents a pharmacologically-based pharmacokinetic simulation study to emphasize the (lack of) effect of altered plasma protein binding on a drug's concentration-time profile and associated pharmacokinetic parameters. METHODS: Four virtual compounds, representing a broad chemical space (low/high clearance/volume of distribution), were created and administered to a virtual population of normal patients and three types of hypo-albuminemic patients in Simcyp®. The influence of decreased plasma protein binding in hypoalbuminemia on the pharmacokinetic parameters and profiles of these four compounds was investigated. RESULTS: Simulation results showed that while high-clearance compounds suffer from increased unbound exposure with decreased plasma protein binding, the unbound exposure of low-clearance compounds was unaffected. However, for the subset of low-clearance compounds with a small volume of distribution, it appeared that there were still alterations in their plasma concentration-time profiles. Since this may lead to different times above a minimum inhibitory concentration value, this might affect the bacterial killing for some anti-infective drugs. Overall, for any compound involved in the simulations, the unbound exposure did not decrease in plasma protein binding subjects relative to normal plasma protein binding subjects. DISCUSSION: This finding is in line with the few case-controlled studies in the literature. Hence, increasing the dose/dosing frequency seems futile and might reduce the benefit-risk ratio for narrow therapeutic index drugs. Moreover, these simulations indicate that when only total plasma concentrations and derived pharmacokinetic parameters are considered, incorrect conclusions will be drawn.