Albumin Clearance Research Articles

EVALUATION OF SERUM PERIOSTIN AND PIIINP AS BIOMARKERS OF RENAL FIBROSIS AND FUNCTION DECLINE IN RENAL TRANSPLANT PATIENTS

This study aimed to evaluate the potential of serum periostin and N-terminal propeptide of type III procollagen (PIIINP) as biomarkers for predicting renal fibrosis and functional decline in renal transplant patients. We conducted a two-visit observational study among 86 renal allograft patients, reduced to 35 at the two-year follow-up due to the COVID-19 pandemic. Blood samples were collected at baseline and follow-up, while urine samples were collected only at follow-up. Serum levels of PIIINP and periostin were measured using ELISA kits, and various renal function parameters were assessed. Serum PIIINP levels showed a significant decrease over two years (p<0.001, Wilcoxon test), while periostin levels significantly increased (p<0.001, Wilcoxon test). These changes correlated with declines in renal function, as indicated by decreased serum albumin and creatinine clearance levels, and increased serum creatinine levels. Significant correlations were found between changes in PIIINP and creatinine clearance (Spearman coefficient = 0.352, p<0.05), as well as between changes in periostin and creatinine clearance (Spearman coefficient = 0.626, p<0.001). Our findings suggest that serum periostin and PIIINP levels are valuable biomarkers for assessing renal fibrosis and functional decline in renal transplant patients. These biomarkers may provide insights into disease progression and guide therapeutic interventions.

Population pharmacokinetics and exposure-response analyses of safety (ARIA-E and isolated ARIA-H) of lecanemab in subjects with early Alzheimer's disease.

Lecanemab (Leqembi®) was recently approved by health authorities in the United States, Japan, and China to treat early Alzheimer's disease (AD), including patients with mild cognitive impairment (MCI) or mild dementia due to Alzheimer's disease upon confirmation of amyloid beta pathology. Extensively and sparsely sampled PK profiles from 1619 AD subjects and 21,929 serum lecanemab observations from two phase I, one phase II, and one phase III studies were well characterized using a two-compartment model with first-order elimination. The final PK model quantified covariate effects of body weight and sex on clearance and central volume of distribution, ADA-positive status, and albumin on clearance, and of Japanese ethnicity on central and peripheral volumes of distribution. Exposure to lecanemab was comparable between two lecanemab-manufacturing processes. However, none of the identified covariates in the model had a clinically relevant impact on model-predicted lecanemab Cmax or AUC at steady state following 10 mg/kg bi-weekly. Importantly, age, a well-recognized risk factor for AD, was not found to significantly affect lecanemab PK. The incidence of ARIA-E as a function of lecanemab exposure was modeled using a logit function with data pooled from 2641 subjects from the phase II and phase III studies, in which a total of 177 incidences of ARIA-E were observed. The probability of ARIA-E was significantly correlated with model-predicted Cmax and predicted to be higher in subjects homozygous for APOE4. The incidence of isolated ARIA-H was not associated with lecanemab exposure and was similar between placebo and lecanemab-treated subjects.

Development of a novel nomogram for predicting delayed methotrexate excretion following high-dose methotrexate in adult patients with hematologic malignancies.

High-dose methotrexate (HDMTX) is integral in treating hematologic malignancies but carries risks of severe toxicities due to prolonged MTX exposure. However, knowledge of delayed MTX excretion is primarily derived from pediatric and adolescent cohorts, with the reported predictors being presented as rough dichotomous values. This study aimed to identify risk factors for delayed MTX excretion exclusively in adult patients with hematologic malignancies and develop a more applicable predictive nomogram based on continuous clinical and laboratory variables. 517 HDMTX cycles in 194 patients were retrospectively analyzed. Delayed MTX excretion was defined as either MTX concentration ≥ 1.0 µmol/L at 48h or ≥ 0.1 µmol/L at 72h after HDMTX initiation. Multivariate logistic regression analysis was used to construct the nomogram internally validated with the bootstrap method. Delayed MTX excretion was observed in 24.0% of cycles. Six significant predictors were identified: relapsed/refractory disease (Odds ratio [OR] 2.03), fewer HDMTX cycles (OR 0.771), treatment intent (OR 2.13), lower albumin (OR 0.563) and creatinine clearance levels (OR 0.993), and increased γ-glutamyl transpeptidase levels (OR 1.004, all P < 0.05). These were incorporated into a web-based nomogram as continuous variables with good prediction accuracy (area under the curve, 0.73) and without significant overfitting. Delayed MTX excretion increased risks of developing acute kidney injury, even solely at the 72h timepoint (OR 2.57, P = 0.025), without providing any benefit of clinical outcomes. This study comprehensively characterized MTX elimination failure following HDMTX in adult patients and could pave the way for individualized risk prediction.

Elimination of Medium/High Molecular Weight Solutes. Comparison of High Flow Hemodialysis with Extended Hemodialysis

Introduction: Post-dilution online hemodiafiltration is the most efficient extracorporeal depurative treatment of CKD. Recently a new type of membrane has been developed, with a higher cut-off point also called a medium cut-off point, which has the capacity to eliminate higher molecular weight molecules in hemodialysis. The hemodialysis performed with these membranes has been called “Expanded Hemodialysis”. Objective: Compare the purifying efficacy of medium and high molecular weight molecules in patients dialyzed with high-flux hemodialysis, VitaPES 210HF, and with patients treated with expanded hemodialysis with the medium cut-off dialyzer, Elisio-HX. We also assessed the effect that the increased removal of inflammatory mediators by MCO hemodialysis had on fecal Calprotectin levels. Patients and methods: This is a prospective observational cross-over study in which 8 prevalent hemodialysis patients were followed for two months. Blood levels of IL-6, C-reactive protein (CRP), β2-microglobulin, Kappa and Lambda immunoglobulin light chains, and serum albumin were determined before and after each hemodialysis session. Results: The percentage of reduction of medium and higher molecular weight molecules: β2microglobulin, IL-6, Kappa and Lambda chains and CRP were higher with the Elisio-21HX dialyzer compared to the VitaPES 210HF dialyzer. There was no difference in albumin clearance between the two dialyzers. Fecal calprotectin levels were lower in patients dialyzed with Elisio-21HX. Conclusion: The medium cutoff dialyzer, Elisio-HX, is more efficient in the elimination of medium/high molecular weight molecules than the VitaPES HF high-flux dialyzer, with the same albumin elimination. Improving inflammation at the local intestinal level with lower levels of fecal Calprotectin.

Characterizing Glomerular Barrier Dysfunction with Patient-Derived Serum in Glomerulus-on-a-Chip Models: Unveiling New Insights into Glomerulonephritis.

Glomerulonephritis (GN) is characterized by podocyte injury or glomerular filtration dysfunction, which results in proteinuria and eventual loss of kidney function. Progress in studying the mechanism of GN, and developing an effective therapy, has been limited by the absence of suitable in vitro models that can closely recapitulate human physiological responses. We developed a microfluidic glomerulus-on-a-chip device that can recapitulate the physiological environment to construct a functional filtration barrier, with which we investigated biological changes in podocytes and dynamic alterations in the permeability of the glomerular filtration barrier (GFB) on a chip. We also evaluated the potential of GN-mimicking devices as a model for predicting responses to human GN. Glomerular endothelial cells and podocytes successfully formed intact monolayers on opposite sides of the membrane in our chip device. Permselectivity analysis confirmed that the chip was constituted by a functional GFB that could accurately perform differential clearance of albumin and dextran. Reduction in cell viability resulting from damage was observed in all serum-induced GN models. The expression of podocyte-specific marker WT1 was also decreased. Albumin permeability was increased in most models of serum-induced IgA nephropathy (IgAN) and membranous nephropathy (MN). However, sera from patients with minimal change disease (MCD) or lupus nephritis (LN) did not induce a loss of permeability. This glomerulus-on-a-chip system may provide a platform of glomerular cell culture for in vitro GFB in formation of a functional three-dimensional glomerular structure. Establishing a disease model of GN on a chip could accelerate our understanding of pathophysiological mechanisms of glomerulopathy.

Glycated serum proteins and albumin but not glycated albumin show negative correlation with BMI in an overweight/obese, diabetic population from the United States

Background and aimsMultiple 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/m2. 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.

Evaluation of factors predicting the benefit from systemic oncological treatment for severely ill hospitalized patients: a retrospective study

BackgroundPatients with cancer in the disease’s end-stage with poor performance represent a challenging clinical scenario, as they have high chance of a fatal outcome due to clinical conditions, oncological emergencies, and/or metastatic disease. This study examines the factors predicting the potential benefit of “urgent” chemotherapy during hospitalization in this setting, thus addressing a research gap.MethodsThis retrospective observational study was conducted in the largest cancer center in the outskirts of São Paulo. It identified factors predicting the benefit from antineoplastic treatment in severe in-hospital patients admitted during 2019–2020, considering post-chemotherapy survival time as the main dependent variable. Data were retrieved from medical records. All patients aged ≥ 18 years, with an ECOG-PS score ≥ 2, and undergoing non-elective systemic cancer treatment were included.ResultsThis study evaluated 204 records, of which 89 were included in the final analysis. A statistically significant association with the worse outcome (death within 30 days of chemotherapy) was found with higher ECOG performance status; chemotherapy dose reduction; lower values of serum albumin, hemoglobin, and creatinine clearance; and higher values of leukocytes, neutrophils, direct bilirubin, urea, and C-reactive protein. In the multivariate analysis, only albumin remained statistically associated with the outcome (hazard ratio = 0.35; confidence interval: 0.14, 0.90; p = 0.034).ConclusionsSerum albumin and other clinical and laboratory variables might be associated with early post-treatment deaths in patients with cancer. The study data might help guide the decision to administer systemic treatment in this scenario and manage critically ill patients. This study adds to our knowledge of the factors predicting the objective benefits from “heroic” or “urgent” chemotherapy for hospitalized and severely ill patients with cancer.

A risk prediction model for cisplatin-induced acute kidney injury in patients with head and neck cancer who receive chemoradiotherapy: A supplement analysis of a phase II/III trial of JCOG1008.

12104 Background: Cisplatin-induced acute kidney injury (C-AKI) is a common reason for treatment interruption in head and neck cancer patients who receive chemoradiotherapy (CRT). We developed a risk prediction model for C-AKI in patients from a randomized phase II/III trial of JCOG1008, which demonstrated that CRT with weekly cisplatin at 40 mg/m2 (weekly arm) was noninferior to 3-weekly cisplatin at 100 mg/m2 (3-weekly arm) in terms of overall survival for postoperative high-risk head and neck cancer ( J Clin Oncol 2022; 40: 1980-90). Methods: Two hundred fifty-one patients received RT with a total of 66 Gy/33 fr concurrently with 3-weekly or weekly cisplatin. AKI was defined using the AKI Network classification/staging system as an increase in serum creatinine of ≥0.3 mg/dL or a 1.5-fold or greater increase from baseline (≥ stage I) by 30 days after the completion of CRT. AKI risk prediction models were developed by combining explanatory variables which were expected to contribute, including age, sex, ECOG performance status, primary site, pathological stage, diabetes mellites, hypertension, main nutritional method, treatment arm, serum albumin, serum magnesium, and creatinine clearance (CCr) at registration. A logistic regression model with the Akaike information criterion was used to explore the optimal model. Results: Ninety-four of 251 (37.5%) patients developed C-AKI in this study. The optimal C-AKI risk prediction model was composed of four factors, including a primary site (hypopharynx/larynx or oral cavity/oropharynx, odds ratio [OR] 1.92 [95% CI, 1.10 to 3.30]), treatment arm (3-weekly arm or weekly arm, OR 1.75 [95% CI, 1.02 to 3.00]), serum albumin (≤ 3.5 g/dL or &gt; 3.5 g/dL, OR 2.06 [95% CI, 1.11 to 3.87]) and CCr ( &lt; 90 mL/min or ≥ 90 mL/min, OR 1.85 [95% CI, 1.05 to 3.26]). The incidence of C-AKI increased in accordance with a total count of the four factors (Table): with a total count of 0-1, 2 and 3-4, the incidence of clinically relevant stage II/III C-AKI was 2.9%, 11.5%, and 22.6%, respectively. When total count was ≤1, the positive and negative predictive values for stage II/III C-AKI development were 16.1% and 97.0%, respectively. Conclusions: We developed a risk prediction model for C-AKI in head and neck cancer patients who receive CRT using primary site, cisplatin administration method, serum albumin, and CCr. The high negative predictive value of this prediction model may help rule out the development of moderate to severe C-AKI. Clinical trial information: jRCTs031180135 . [Table: see text]

High Albumin Clearance Predicts the Minimal Change Nephrotic Syndrome Relapse.

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-h albumin clearance (eCALB) and examined the association between eCALB and relapse. 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 (CR) following corticosteroid therapy. The estimated 24-h albumin clearance (eCALB) [µL/min] was defined as (2.71828log(0.0445 + 0.9488*log(urinary protein) [g/24h]/(serum albumin [g/dL] × 1440 [min/24 h]) for women and (2.71828log(-0.1522 + 0.9742*log(urinary protein) [g/24h]/(serum albumin [g/dL] × 1440 [min/24 h]) for men. Relapse was observed in 44 patients (103 kidney biopsy samples; 42.7%). The mean patient age was 41.0 years. Patients had an estimated glomerular filtration rate (eGFR) of 71.0 mL/min/1.73 m2, urinary protein excretion (UPE) of 6.8 g/day, serum albumin of 1.4 g/dL, and eCALB of 2.27 μL/min. eCALB was strongly associated with hypoalbuminemia, severe proteinuria, lipid abnormalities, and coagulopathy. In the multivariable analysis, a high eCALB was significantly associated with relapse after adjusting for age, eGFR, time to CR, and UPE (adjusted hazard ratio = 5.027, 95% confidence interval 1.88-13.47, P = 0.001). This study revealed that eCALB, which could substitute albumin kinetics, reflected the severity of MCNS, and a high eCALB was associated with recurrence.

Time of Day Influences Concentrations of Total Protein and Albumin in Cerebrospinal Fluid in HIV.

The accumulation of soluble proteins and metabolites during wakefulness and their clearance during sleep via the glymphatic system occurs in healthy adults and is disturbed in some neurological conditions. Such diurnal variations in the cerebrospinal fluid (CSF) proteins produced outside the central nervous system and entering via the blood-brain barrier (BBB) have not been evaluated in people with HIV (PWH). CSF and blood were collected in 165 PWH at six US centers between 2003 and 2007. The time of collection was compared to CSF albumin, globulin, and total protein concentrations using bivariate and multivariate regression. Participants all took antiretroviral therapy (ART) and were mostly middle-aged (median age 44.0 years) men (78.8%), with AIDS (77.0%), plasma HIV RNA ≤ 200 copies/mL (75.8%), and immune recovery (median CD4+ T-cell count 414/µL). CSF was collected at median 1:10 p.m. (range 9:00 a.m. to 5:20 p.m.) and within a median of 15 min of blood collection. A later time of CSF collection was associated with higher total protein (p = 0.0077) and albumin (p = 0.057) in CSF but not in serum, and was additionally associated with higher CSF globulin (p = 0.013). The glymphatic clearance of albumin, globulin, and total protein is preserved in PWH. The analyses of soluble biomarkers in CSF should account for the time of collection.

Clathrin-Mediated Albumin Clearance in Alveolar Epithelial Cells of Murine Precision-Cut Lung Slices.

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 SftpcCreERT2/+: tdTomatoflox/flox mouse strain (defined as EpCAM+CD31-CD45-tdTomatoSPC-T1α+ for ATI and EpCAM+CD31-CD45-tdTomatoSPC+T1α- 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.

Cabozantinib exposure–response analysis for the phase 3 CheckMate 9ER trial of nivolumab plus cabozantinib versus sunitinib in first-line advanced renal cell carcinoma

PurposeIn the phase 3 CheckMate 9ER trial, intravenous nivolumab (240 mg every 2 weeks) plus oral cabozantinib (40 mg/day) improved progression-free survival (PFS) versus sunitinib as first-line therapy for advanced renal cell carcinoma (RCC). To support cabozantinib dosing with the combination, this exposure–response analysis characterized the relationship of cabozantinib exposure with clinical endpoints.MethodsDose modification was allowed with cabozantinib (holds and reductions) to manage adverse events (AEs). The population pharmacokinetics analysis was updated and used to generate individual predicted cabozantinib exposure measures. Kaplan–Meier plots and time-to-event Cox proportional hazard (CPH) exposure–response models characterized the relationship of cabozantinib exposure with PFS, dose modifications, and selected AEs.ResultsKaplan–Meier plots showed no clear difference in PFS across cabozantinib exposure quartiles. Cabozantinib exposure did not significantly affect the hazard of PFS in the CPH base model nor in the final model. In contrast, baseline albumin and nivolumab clearance had a significant effect on PFS. There was no significant relationship between cabozantinib clearance and risk of dose modification, but a significant relationship was identified between cabozantinib exposure and Grade ≥ 1 palmar-plantar-erythrodysesthesia and Grade ≥ 3 diarrhea in the exposure–response analysis.ConclusionTo optimize individual cabozantinib exposure, these data support the dose modification strategies in CheckMate 9ER for cabozantinib in patients with advanced RCC when combined with nivolumab.

Mitigation of cisplatin induced nephrotoxicity by casticin in male albino rats.

Cisplatin (CP) is a commonly used, powerful antineoplastic drug, having numerous side effects. Casticin (CAS) is considered as a free radical scavenger and a potent antioxidant. The present research was planned to assess the curative potential of CAS on CP persuaded renal injury in male albino rats. Twenty four male albino rats were distributed into four equal groups. Group-1 was considered as a control group. Animals of Group-2 were injected with 5mg/kg of CP intraperitoneally. Group-3 was co-treated with CAS (50mg/kg) orally and injection of CP (5mg/kg). Group-4 was treated with CAS (50mg/kg) orally throughout the experiment. CP administration substantially reduced the activities of catalase (CAT), superoxide dismutase (SOD), peroxidase (POD), glutathione S-transferase (GST), glutathione reductase (GSR), glutathione (GSH) content while increased thiobarbituric acid reactive substances (TBARS), and hydrogen peroxide (H2O2) levels. Urea, urinary creatinine, urobilinogen, urinary proteins, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) levels were substantially increased. In contrast, albumin and creatinine clearance was significantly reduced in CP treated group. The results demonstrated that CP significantly increased the inflammation indicators including nuclear factor kappa-B (NF-κB), tumor necrosis factor-α (TNF-α), Interleukin-1β (IL-1β), Interleukin-6 (IL-6) levels and cyclooxygenase-2 (COX-2) activity and histopathological damages. However, the administration of CAS displayed a palliative effect against CP-generated renal toxicity and recovered all parameters by bringing them to a normal level. These results revealed that the CAS is an effective compound having the curative potential to counter the CP-induced renal damage.

PS-B07-2: EXERCISE TRAINING PREVENTS HIGH FRUCTOSE-INDUCED HYPERTENSION AND RENAL DAMAGES IN DAHL SALT-SENSITIVE RATS

Background: High fructose diet (HFr) causes metabolic syndrome, and HFr-induced hypertension and renal damage are exaggerated in Dahl salt-sensitive (DS) rats. Exercise training (Ex) have antihypertensive and renal protective effects in rats fed HFr, but these effects of Ex are weak in DS rats fed a high-salt diet. This study thus examined the effects of Ex on DS rats fed HFr. Methods: Male DS rats were divided into three groups. The control group was fed a control diet, both the HFr group and the HFr-Ex group were fed a HFr (60% fructose). The HFr-Ex group also underwent treadmill running (20 m/min, 60 min/day, 5 day/ week). After 12 weeks, renal function, histology, and renin-angiotensin system (RAS) were examined. Results: HFr increased blood pressure, urinary albumin, and creatinine clearance, and Ex inhibited these increases. HFr induced glomerular sclerosis, podocyte injury, afferent arteriole thickening, and renal interstitial fibrosis, and Ex ameliorated them. HFr reduced plasma renin activity, and Ex further reduced the activity. HFr also increased the expression of angiotensinogen, renin, angiotensin converting enzyme (ACE), and angiotensin II type1 receptor (AT1R), and Ex restored the ACE expression to the control levels. HFr decreased the expression of ACE2, angiotensin II type2 receptor (AT2R), and Mas receptor (MasR), and Ex restored the ACE2 and MasR expressions to the control levels and further decreased the AT2R expression. HFr increased the ACE activity and decreased the ACE2 activity, and Ex restored these activities to the control levels. Conclusion: Ex prevents HFr-induced hypertension and renal damages in DS rats. The changes in renal RAS may be involved in the mechanism of the antihypertensive and renal protective effects of Ex.

Toxicological effects of thimerosal on rat kidney: a histological and biochemical study.

Thimerosal is an organomercurial compound, which is used in the preparation of intramuscular immunoglobulin, antivenoms, tattoo inks, skin test antigens, nasal products, ophthalmic drops, and vaccines as a preservative. In most of animal species and humans, the kidney is one of the main sites for mercurial compounds deposition and target organs for toxicity. So, the current research was intended to assess the thimerosal induced nephrotoxicity in male rats. Twenty-four adult male albino rats were categorized into four groups. The first group was a control group. Rats of Group-II, Group-III, and Group-IV were administered with 0.5µg/kg, 10µg/kg, and 50µg/kg of thimerosal once a day, respectively. Thimerosal administration significantly decreased the activities of catalase (CAT), superoxide dismutase (SOD), peroxidase (POD), glutathione reductase (GR), glutathione (GSH), and protein content while increased the thiobarbituric acid reactive substances (TBARS) and hydrogen peroxide (H2O2) levels dose-dependently. Blood urea nitrogen (BUN), creatinine, urobilinogen, urinary proteins, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) levels were substantially increased. In contrast, urinary albumin and creatinine clearance was reduced dose-dependently in thimerosal treated groups. The results demonstrated that thimerosal significantly increased the inflammation indicators including nuclear factor kappaB (NF-κB), tumor necrosis factor-α (TNF-α), Interleukin-1β (IL-1β), Interleukin-6 (IL-6) levels and cyclooxygenase-2 (COX-2) activities, DNA and histopathological damages dose-dependently. So, the present findings ascertained that thimerosal exerted nephrotoxicity in male albino rats.

Exercise Training Prevents High Fructose-Induced Hypertension and Renal Damages in Male Dahl Salt-Sensitive Rats.

High-fructose diet (HFr) causes metabolic syndrome, and HFr-induced hypertension and renal damage are exaggerated in Dahl salt-sensitive (DS) rats. Exercise training (Ex) has antihypertensive and renal protective effects in rats fed HFr; however, there has been little discussion about the DS rats, which exhibit metabolic disturbances. This study thus examined the effects of Ex on DS rats fed HFr. Male DS rats were divided into three groups. The control group was fed a control diet, and both the HFr group and the HFr-Ex group were fed an HFr (60% fructose). The HFr-Ex group also underwent treadmill running (20 m·min -1 , 60 min·d -1 , 5 d·wk -1 ). After 12 wk, renal function, histology, and renin-angiotensin system were examined. HFr increased blood pressure, urinary albumin, and creatinine clearance, and Ex inhibited these increases. HFr induced glomerular sclerosis, podocyte injury, afferent arteriole thickening, and renal interstitial fibrosis, and Ex ameliorated them. HFr reduced plasma renin activity, and Ex further reduced the activity. HFr also increased the expression of angiotensinogen, renin, angiotensin-converting enzyme (ACE), and angiotensin II type 1 receptor, and Ex restored the ACE expression to the control levels. HFr decreased the expression of ACE2, angiotensin II type 2 receptor, and Mas receptor, and Ex restored the ACE2 and Mas receptor expressions to the control levels and further decreased the angiotensin II type 2 receptor expression. HFr increased the ACE activity and decreased the ACE2 activity, and Ex restored these activities to the control levels. Ex prevents HFr-induced hypertension and renal damages in DS rats. The changes in renal renin-angiotensin system may be involved in the mechanism of the antihypertensive and renal protective effects of Ex.

Serum cystatin C is an early renal dysfunction biomarker in patients with hepatitis C virus

BackgroundHepatitis C virus (HCV) may induce extrahepatic manifestations as acute or chronic renal dysfunction. The aim was to evaluate the diagnostic role of some biomarkers as cystatin C, cryoglobulins, rheumatoid factor (RF), and complement C3 for extrahepatic renal affection in newly diagnosed patients with HCV infection.MethodsBlood and urine were collected from randomized individuals screened for new HCV infection (n=400). The studied populations were divided into 3 groups: control group I: thirty healthy individuals not suffering from either liver or kidney diseases, group IIa: thirty HCV patients who have positive HCV antibody test but showed negative PCR test, and group IIb: thirty HCV patients who showed positive results for both HCV antibody and PCR tests.ResultsIn HCV group IIb, levels of serum total bilirubin, AST and ALT, and urine albumin/creatinine ratio were increased whereas serum albumin and creatinine clearance were decreased versus other groups. However, the levels of blood urea nitrogen and serum creatinine were still within the normal range in all groups. In HCV group IIb, cystatin C, cryoglobulins, and RF levels were increased; meanwhile, serum creatinine/cystatin C ratio and complement 3 levels were decreased compared to the other groups. HCV-infected patients significantly had higher serum cystatin C (>1.24 mg/L, P<0.001) and lower creatinine/cystatin C ratio (<70.1μMol/mg, P=0.002), and cystatin C was significantly correlated with liver and kidney parameters.ConclusionHigh serum cystatin C and low creatinine/cystatin C ratio may be early indicators of mild renal dysfunction with normal serum levels of creatinine in HCV-infected individuals.

Protein-losing Enteropathy as a Complication and/or Differential Diagnosis of Common Variable Immunodeficiency.

As protein-losing enteropathy (PLE) can lead to hypogammaglobulinemia and lymphopenia, and since common variable immunodeficiency (CVID) is associated with digestive complications, we wondered if (1) PLE could occur during CVID and (2) specific features could help determine whether a patient with antibody deficiency has CVID, PLE, or both. Eligible patients were thus classified in 3 groups: CVID + PLE (n = 8), CVID-only (= 19), and PLE-only (n = 13). PLE was diagnosed using fecal clearance of α1-antitrypsin or 111In-labeled albumin. Immunoglobulin (Ig) A, G, and M, naive/memory B and T cell subsets were compared between each group. CVID + PLE patients had multiple causes of PLE: duodenal villous atrophy (5/8), nodular follicular hyperplasia (4/8), inflammatory bowel disease-like (4/8), portal hypertension (4/8), giardiasis (3/8), and pernicious anemia (1/8). Compared to the CVID-only group, CVID + PLE patients had similar serum Ig levels, B cell subset counts, but lower naive T cell proportion and IgG replacement efficiency index. Compared to the CVID-only group, PLE-only patients did not develop infections but had higher serum levels of IgG (p = 0.03), IgA (p < 0.0001), and switched memory B cells (p = 0.001); and decreased naive T cells (CD4+: p = 0.005; CD8+: p < 0.0001). Compared to the PLE-only group, CVID + PLE patients had higher infection rates (p = 0.0003), and lower serum Ig (especially IgA: p < 0.001) and switched memory B cells levels. In conclusion, PLE can occur during CVID and requires higher IgG replacement therapy dosage. PLE can also mimic CVID and is associated with milder immunological abnormalities, notably mildly decreased to normal serum IgA and switched memory B cell levels.

Kidney functions adaptations of professional soccer players in response to an entire game season.

This study investigated the renal function of soccer players after an entire game-season. Thirty-five athletes recruited to play for the Macae Futebol Clube were invited for this study, of which 18 athletes completed the entire game season. Blood and 24-hour urine were collected at the beginning (Pre-Season) and the end of the game season (Post-Season). Kidney functions were assessed by calculating the urinary excretion, clearance, and fractional excretion of the selected solutes. Plasma creatinine, sodium, total protein, and osmolality were lower in the Post-Season . In contrast, plasma urea was higher in the Post-Season period. Urinary excretion of urea was reduced while albumin excretion was higher in comparison to Pre-Season. The clearances of creatinine, total proteins, and albumin were higher in the Post-Season period. In accordance, the fractional excretion of albumin increased. On the other hand, the clearance and fractional excretion of urea was lower in the Post-Season period. These results show that soccer-associated exercise throughout the entire game-season induces kidney functions adaptations that may prevent dehydration in these athletes through increased urea reabsorption to conserve water. In addition, this data corroborates to increased glomerular permeability to plasma proteins, such as albumin, that soccer players may experience.

An exploratory study of the relationship between systemic microcirculatory function and small solute transport in incident peritoneal dialysis patients.

The peritoneal capillary endothelium is widely considered to be the most influential structure in dictating the rate of small solute transport (SST) during peritoneal dialysis (PD). PD patients are at significant risk of systemic microcirculatory dysfunction. The relationship between peritoneal and systemic microcirculations in patients new to PD has not been well studied. We hypothesised that for patients on PD for less than 6 months, dysfunction in the systemic microcirculation would be reflected in the rate of SST. We recruited 29 patients to a cross-sectional, observational study. Rate of SST was measured using a standard peritoneal equilibration test. Laser Doppler Flowmetry was used to measure response to physical and pharmacological challenge (post-occlusive hyperaemic response and iontophoretic application of vasodilators) in the cutaneous microcirculation. Sidestream Darkfield imaging was used to assess sublingual microvascular density, flow and endothelial barrier properties. We found no moderate or strong correlations between any of the measures of systemic microcirculatory function and rate of SST or albumin clearance. There was however a significant correlation between dialysate interleukin-6 concentrations and both SST (rs = 0.758 p ≤ 0.0001) and albumin clearance (rs = 0.53, p = 0.01). In this study, systemic microvascular dysfunction did not significantly influence the rate of SST even early in patients PD careers. In conclusion, this study demonstrates that intraperitoneal factors particularly inflammation have a far greater impact on rate of SST than systemic factors.