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.

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.

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.

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.

Pre-operative serum albumin level substantially predicts post-operative morbidity and mortality among patients with colorectal cancer who undergo elective colectomy.

The quantitative relationship between serum albumin level and surgical outcomes has not been clearly established. This study included 3732 patients with colon cancer who underwent a potentially curative colectomy. Post-operative mortality and morbidity were analysed according to the patients' demographic data, pre-operative comorbidities, and tumour-related factors. Age, asthma, renal impairment, and albumin level were significantly associated with post-operative morbidity and mortality in the multivariate analyses. Logistic regression analysis revealed linear relationships of post-operative morbidity and mortality with albumin level. The morbidity and mortality rates decreased by 7.3% and 15.6%, respectively, for each 0.1 g/dL increase in albumin level. This finding remained significant in the hypoalbuminaemia subgroup but not in the normoalbuminaemia subgroup. That is, the morbidity and mortality rates significantly decreased by 8.7% and 17.7%, respectively (both P < 0.001), in the former group and decreased by 2.7% (P = 0.112) and 11.6% (P = 0.092), respectively, in the latter group. This study demonstrated that serum albumin level linearly predicted the post-operative morbidity and mortality among the colorectal cancer patients. Pre-operative serum albumin level may therefore be used as a continuous rather than a categorical marker of disease severity, especially among patients with hypoalbuminaemia.

Prognostic value of the Glasgow Prognostic Score in renal cell carcinoma: a meta-analysis.

PURPOSE: Glasgow Prognostic Score (GPS) has been reported to predict oncologic outcomes in various type of cancer. However, their prognostic value in patients with renal cell carcinoma (RCC) is unclear. In this meta-analysis, we evaluated the prognostic significance of GPS in RCC patients. METHODS: We performed comprehensive searches of electronic databases to identify studies that evaluated the prognostic impact of pretreatment GPS in RCC patients. The end points were cancer-specific survival (CSS), recurrence-free/disease-free survival (RFS/DFS). Meta-analysis using random-effects models was performed to calculate hazard ratios (HRs) or odds ratios with 95 % confidence intervals (CIs). RESULTS: Nine retrospective, observational, cohort studies involving 2096 patients were included. Seven studies evaluated CSS, and three evaluated RFS. Our results showed that higher GPS (0 vs. 1 vs. 2) was significantly predictive of poorer CSS (HR 3.68, 95 % CI 2.52-5.40, p < 0.001) and RFS/DFS (HR 2.83, 95 % CI 1.86-4.30, p < 0.001) in patients with RCC. These findings were robust when stratified by sample size, presence of metastasis, and study region. We also conducted subgroup analysis by assessment of Newcastle-Ottawa quality assessment scale (NOS) score, and the HRs were 2.708 (95 % CI 1.969, 3.725) in under 7 points group, 3.685 (95 % CI 2.516, 5.396) in over than 7 points group in CSS. Meta-regression analysis indicated that NOS score group had a significant difference in HRs (p = 0.032). CONCLUSIONS: Higher GPS is associated with tumor progression and is predictive of poorer survival in patients with RCC. Therefore, GPS may help to inform treatment decisions and predict treatment outcomes.

Simultaneous assessment of the synthesis rate and transcapillary escape rate of albumin in inflammation and surgery.

BACKGROUND: Better knowledge of albumin kinetics is needed to define the indications for albumin use in clinical practice. This study involved two approaches: the synthesis rate and transcapillary escape rate of albumin were measured simultaneously at different levels of plasma albumin concentration in relation to acute inflammation and surgery; and two different tracers were compared to determine plasma volume and the transcapillary escape rate. METHODS: Healthy volunteers (n = 10), patients with acute inflammatory abdominal disease (n = 10), and patients undergoing elective pancreatic resection (n = 10) were studied. The albumin synthesis rate was measured by the incorporation of deuterium-labeled phenylalanine. Plasma volume and the transcapillary escape rate were assessed using 123I-labeled and 125I-labeled albumin. RESULTS: A 50 % elevated de-novo albumin synthesis rate was seen in patients with acute inflammation and marked hypoalbuminemia, while patients with marginal hypoalbuminemia before the start of surgery had a normal albumin synthesis rate. The transcapillary escape rate was elevated intraoperatively during the reconstructive phase of pancreatic surgery, when plasma albumin was decreased but stable. In acute inflammation with marked hypoalbuminemia, the transcapillary escape rate was no different from normal. 123I-labeled and 125I-labeled albumin were found exchangeable for plasma volume determinations, but could be used only in groups of patients for the transcapillary escape rate. CONCLUSIONS: This observational study illustrates the limited information contained in albumin plasma concentrations to reflect albumin kinetics. On the contrary, single measurements of the synthesis rate and/or transcapillary escape rate of albumin obviously cannot explain the plasma level of albumin or the changes seen in plasma albumin concentration. TRIAL REGISTRATION: www.clinicaltrials.gov , study number NCT01686776 . Registered 13 September 2012.

Serum albumin perturbations in cyanotics after cardiac surgery: Patterns and predictions.

INTRODUCTION: Hypoalbuminemia is a well-recognized predictor of general surgical risk and frequently occurs in patients with cyanotic congenital heart disease (CCHD). Moreover, cardiopulmonary bypass (CPB)-induced an inflammatory response, and the overall surgical stress can effect albumin concentration greatly. The objective of his study was to track CPB-induced changes in albumin concentration in patients with CCHD and to determine the effect of hypoalbuminemia on postoperative outcomes. MATERIALS AND METHODS: Prospective observational study conducted in 150 patients, Group 1 ≤18 years (n = 75) and Group 2 >18 years (n = 75) of age. Albumin levels were measured preoperatively (T1), after termination of CPB (T2) and 48 h post-CPB (T3). Primary parameters (mortality, duration of postoperative ventilation, duration of inotropes and duration of Intensive Care Unit [ICU] stay) and secondary parameters (urine output, oliguria, arrhythmias, and hemodynamic parameters) were recorded. RESULTS: The albumin levels in Group 1 at T1, T2, and T3 were 3.8 ± 0.48, 3.2 ± 0.45 and 2.6 ± 0.71 mg/dL; and in Group 2 were 3.7 ± 0.50, 3.2 ± 0.49 and 2.7 ± 0.62 mg/dL respectively. All patients showed a significant decrease in albumin concentration 48 h after surgery (P < 0.01). Analysis between the groups, however, showed no statistical difference. Eleven patients expired during the study period, and nonsurvivors showed significantly lower serum albumin concentration 48 h after surgery 2.3 ± 0.62 mg/dL versus 3.7 ± 0.56 mg/dL in the survivors (P < 0.05). Receiver operating characteristic curve showed that a baseline albumin cut-off value of 3.3 g/dL predicts mortality with a positive predictive value 47.6% and a negative predictive value of 99.2% (P < 0.05). A strong correlation was seen between albumin levels at 48 h with duration of CPB (r2 = 0.6321), ICU stay (r2 = 0.7447) and incidence of oliguria (r2 = 0.8803). CONCLUSIONS: The study demonstrated similar fall in albumin concentration in cyanotic patients (both adult and pediatric) in response to CPB. Low preoperative serum albumin concentrations (<3.3 g/dL) can be used to identify and prognosticate subset of cyanotics predisposed to additional surgical risk.

Effects of mild hypoalbuminemia on the pharmacokinetics and pharmacodynamics of dexmedetomidine in patients after major abdominal or thoracic surgery.

STUDY OBJECTIVE: To explore the effects of mild hypoalbuminemia on pharmacokinetics and pharmacodynamics of dexmedetomidine in patients after major abdominal or thoracic surgery. DESIGN: A prospective cohort study. SETTING: University-affiliated teaching hospital. PATIENTS: The study was performed in 30 consecutive patients undergoing major abdominal or thoracic surgery. They were aged 18 to 65 years and graded as American Society of Anesthesiologists physical status I and II. All patients were scheduled to require more than 6 hours of postoperative sedation and mechanical ventilation. Nine of the patients had low plasma albumin levels (<35 g/L but >24 g/L; male/female, 6/3) after the operation, who were assigned to hypoalbuminemia group, and the remainder with normoalbuminemia (>35 g/L; male/female, 15/6) were assigned to normoalbuminemia group. INTERVENTIONS: All patients were administered a loading dose of dexmedetomidine 1.0 µg/kg infused over 10 minutes after admitted into intensive care unit and a maintenance dose of 0.4 µg/kg per hour followed for 6 hours. MEASUREMENTS: Plasma dexmedetomidine levels were determined by high performance liquid chromatography - mass spectrum. Sedation was evaluated using Ramsay sedation score. Heart rate and arterial pressures were monitored. Adverse events were recorded. MAIN RESULTS: Compared with patients with normoalbuminemia, maximum plasma concentration of dexmedetomidine decreased by 21.2% in patients with hypoalbuminemia (P < .01). Its volume of distribution at steady state increased by 40.5%; elimination half-life decreased by 33.5% (P < .01). However, heart rates, arterial pressures, and Ramsay sedation scores did not differ significantly between the 2 groups. No serious adverse events occurred in either the patients with hypoalbuminemia or normoalbuminemia. CONCLUSIONS: Sedation and adverse reactions of dexmedetomidine infusion did not differ significantly between patients with mild hypoalbuminemia and normoalbuminemia, although its volume of distribution at steady state increased and elimination half-life shortened in patients with hypoalbuminemia. This suggests that dexmedetomidine infusion can safely be used in mild hypoalbuminemia patients after major abdominal or thoracic surgery.

Inflammation-based prognostic score is a useful predictor of postoperative outcome in patients with extrahepatic cholangiocarcinoma.

BACKGROUND/PURPOSE: Recent studies have revealed that the Glasgow prognostic score (GPS), an inflammation-based prognostic score, is useful for predicting outcome in a variety of cancers. This study sought to investigate the significance of GPS for prognostication of patients who underwent surgery with extrahepatic cholangiocarcinoma. METHODS: We retrospectively analyzed a total of 62 patients who underwent resection for extrahepatic cholangiocarcinoma. We calculated the GPS as follows: patients with both an elevated C-reactive protein (>10 mg/L) and hypoalbuminemia (<35 g/L) were allocated a score of 2; patients with one or none of these abnormalities were allocated a s ore of 1 or 0, respectively. Prognostic significance was analyzed by the log-rank test and a Cox proportional hazards model. RESULTS: Overall survival rate was 25.5 % at 5 years for all 62 patients. Venous invasion (p = 0.01), pathological primary tumor category (p = 0.013), lymph node metastasis category (p < 0.001), TNM stage (p < 0.001), and GPS (p = 0.008) were significantly associated with survival by univariate analysis. A Cox model demonstrated that increased GPS was an independent predictive factor with poor prognosis. CONCLUSIONS: The preoperative GPS is a useful predictor of postoperative outcome in patients with extrahepatic cholangiocarcinoma.

Cyclosporin a inhibits albumin synthesis in Huh7 cells.

BACKGROUND/AIMS: Hypoalbuminemia occurs frequently in renal transplant recipients immediately after renal transplantation. We studied the regulation of hepatic albumin synthesis by cyclosporin A (CsA) in Huh7 cells. METHODS: Huh7 cells were incubated with various concentrations of CsA for 4, 8, 16, and 24 hours. Albumin was measured in Huh7 cell-conditioned medium by sandwich enzyme-linked immunosorbent assay and Western blot. Albumin mRNA expression was analyzed by Northern blotting in CsA-treated cells. RESULTS: CsA (10(-7)-10(-4) M) inhibited albumin synthesis in Huh7 cells in a dose- dependent manner. A Western blot analysis for albumin in the conditioned medium released from CsA-treated (10(-7)-10(-5) M) cells also showed significant inhibition of albumin synthesis in a dose-dependent manner. Vehicle (olive oil) did not affect albumin synthesis. In contrast, a Northern blot analysis revealed no inhibition of albumin mRNA expression by CsA at any time point from 1-24 hours, indicating that the inhibition of albumin synthesis occurred at the translational level. CONCLUSIONS: Our results suggest that inhibition of hepatic albumin synthesis by high dose CsA contributes to the hypoalbuminemia in renal transplant recipients.

Two unrelated patients with MRE11A mutations and Nijmegen breakage syndrome-like severe microcephaly.

MRE11 and NBS1 function together as components of a MRE11/RAD50/NBS1 protein complex, however deficiency of either protein does not result in the same clinical features. Mutations in the NBN gene underlie Nijmegen breakage syndrome (NBS), a chromosomal instability syndrome characterized by microcephaly, bird-like faces, growth and mental retardation, and cellular radiosensitivity. Additionally, mutations in the MRE11A gene are known to lead to an ataxia-telangiectasia-like disorder (ATLD), a late-onset, slowly progressive variant of ataxia-telangiectasia without microcephaly. Here we describe two unrelated patients with NBS-like severe microcephaly (head circumference -10.2 SD and -12.8 SD) and mutations in the MRE11A gene. Both patients were compound heterozygotes for a truncating or missense mutation and carried a translationally silent mutation. The truncating and missense mutations were assumed to be functionally debilitating. The translationally silent mutation common to both patients had an effect on splicing efficiency resulting in reduced but normal MRE11 protein. Their levels of radiation-induced activation of ATM were higher than those in ATLD cells.

OPPORTUNITY: a randomized clinical trial of growth hormone on outcome in hemodialysis patients.

BACKGROUND: The mortality rate of maintenance hemodialysis (MHD) patients remains high. Measures of protein-energy wasting, including hypoalbuminemia, are strongly associated with their high mortality. Growth hormone (GH) may improve lean body mass (LBM) and serum albumin levels, and health-related quality of life (HRQoL), which are significantly and positively associated with survival in MHD patients. The OPPORTUNITY Trial will examine whether GH reduces mortality and morbidity and improves overall health in hypoalbuminemic MHD patients. HYPOTHESIS: The primary hypothesis is that daily recombinant human GH injections, compared with placebo, improve survival in hypoalbuminemic MHD patients. Secondary hypotheses are that GH improves morbidity and health, including number of hospitalized days, time to cardiovascular events, LBM, serum protein and inflammatory marker levels, exercise capacity, and HRQoL, and has a favorable safety profile. DESIGN/MEASUREMENTS: This is a prospective, double-blind, multicenter, randomized clinical trial involving 2500 MHD patients, up to 50% with diabetes mellitus, from 22 countries. Patients are randomized in a 1:1 ratio to receive daily injections of GH (20 microg/kg per day) or placebo for 104 weeks. Key inclusion criteria include clinically stable and well-dialyzed (Kt/V > or =1.2) adult MHD patients with serum albumin <4.0 g/dl. Exclusion criteria include active malignancy, active proliferative or severe nonproliferative diabetic retinopathy, uncontrolled hypertension, chronic use of high-dose glucocorticoids, or immunosuppressive agents and pregnancy. CONCLUSIONS: The OPPORTUNITY Trial is the first large-scale randomized clinical trial in adult MHD patients evaluating the response to GH of such clinical endpoints as mortality, morbidity, markers of body protein mass, inflammation, exercise capacity, and HRQoL.

Putative role of endothelial lipase in dialysis patients with hypoalbuminemia and inflammation.

BACKGROUND/AIMS: A recent study suggests that inflammation and malnutrition are strongly associated with cardiovascular disease in dialysis patients. Endothelial lipase (EL) is a newly cloned physiological regulator of high-density lipoprotein cholesterol (HDL), which is associated with the progression of atherosclerosis. To clarify the role of EL in dialysis patients, we evaluated serum markers on the basis of the presence of hypoalbuminemia and inflammation. METHODS: We divided the 97 study patients into two groups on the basis of serum albumin (Alb) and high-sensitive C-reactive protein (hsCRP) levels, and measured serum EL levels. Serum EL levels were significantly correlated with Alb, cholinesterase, log hsCRP, and log tumor necrosis factor-alpha. They were also assigned to one of three groups on the basis of hypoalbuminemia and inflammatory status. RESULTS: Serum EL levels were significantly higher and serum HDL levels were lower in patients with low serum Alb and/or high hsCRP levels than in those without these abnormalities. Furthermore, when patients were classified into two groups on the basis of the EL levels measured, cardiovascular disease events during the 2-year follow-up period were significantly greater in the group with higher EL levels. CONCLUSIONS: Our findings suggest that the link between EL, hypoalbuminemia and inflammation may play an important role in atherogenesis in dialysis patients.

Mechanism of hypoalbuminemia in rodents.

Normal albumin loss from the plasma is thought to be minimized by a number of mechanisms, including charge repulsion with the capillary wall and an intracellular rescue pathway involving the major histocompatibility complex-related Fc receptor (FcRn)-mediated mechanism. This study investigates how these factors may influence the mechanism of hypoalbuminemia. Hypoalbuminemia in rats was induced by treatment with puromycin aminonucleoside (PA). To test the effects of PA on capillary wall permeability, plasma elimination rates were determined for tritium-labeled tracers of different-sized Ficolls, negatively charged Ficolls, and (14)C-labeled tracer of albumin in control and PA-treated Sprague-Dawley rats. Urinary excretion and tissue uptake were also measured. Hypoalbuminemia was also examined in two strains of FcRn-deficient mice: beta(2)-microglobulin (beta(2)M) knockout (KO) mice and FcRn alpha-chain KO mice. The excretion rates of albumin and albumin-derived fragments were measured. PA-induced hypoalbuminemia was associated with a 2.5-fold increase in the plasma elimination rate of albumin. This increase could be completely accounted for by the increase in urinary albumin excretion. Changes in the permeability of the capillary wall were not apparent, inasmuch as there was no comparable increase in the plasma elimination rate of 36- to 85-A Ficoll or negatively charged 50- to 80-A Ficoll. In contrast, hypoalbuminemic states in beta(2)M and FcRn KO mice were associated with decreases in excretion of albumin and albumin-derived fragments. This demonstrates that the mechanism of hypoalbuminemia consists of at least two distinct forms: one specifically associated with the renal handling of albumin and the other mediated by systemic processes.