Bioimpedance spectroscopy for fluid status assessment in patients with decompensated liver cirrhosis: Implications for peritoneal dialysis.

Bioimpedance spectroscopy (BIS) is routinely used in peritoneal dialysis patients and might aid fluid status assessment in patients with liver cirrhosis, but the effect of ascites volume removal on BIS-readings is unknown. Here we determined changes in BIS-derived parameters and clinical signs of fluid overload from before to after abdominal paracentesis. Per our pre-specified sample size calculation, we studied 31 cirrhotic patients, analyzing demographics, labs and clinical parameters along with BIS results. Mean volume of the abdominal paracentesis was 7.8 ± 2.6 L. From pre-to post-paracentesis, extracellular volume (ECV) decreased (20.2 ± 5.2 L to 19.0 ± 4.8 L), total body volume decreased (39.8 ± 9.8 L to 37.8 ± 8.5 L) and adipose tissue mass decreased (38.4 ± 16.0 kg to 29.9 ± 12.9 kg; all p < 0.002). Correlation of BIS-derived parameters from pre to post-paracentesis ranged from R² = 0.26 for body cell mass to R² = 0.99 for ECV. Edema did not correlate with BIS-derived fluid overload (FO ≥ 15% ECV), which occurred in 16 patients (51.6%). In conclusion, BIS-derived information on fluid status did not coincide with clinical judgement. The changes in adipose tissue mass support the BIS-model assumption that fluid in the peritoneal cavity is not detectable, suggesting that ascites (or peritoneal dialysis fluid) mass should be subtracted from adipose tissue if BIS is used in patients with a full peritoneal cavity.

Mitochondrial dysfunction and oxidative stress are involved in the mechanism of methotrexate-induced renal injury and electrolytes imbalance.

Methotrexate is a folate analog used against a wide range of diseases including malignancies and autoimmune disorders. On the other hand, clinical use of the MTX is associated with kidney injury and renal failure. There is no clear mechanism for MTX-induced renal injury. The current investigation was designed to evaluate the role of mitochondrial dysfunction and oxidative stress in the pathogenesis of MTX-induced renal injury. Rats received MTX (a single dose of 20 or 30 mg/kg, i.p). Five days after MTX administration, serum biomarkers of kidney injury and tissue markers of oxidative stress were assessed. Moreover, kidney mitochondria were isolated, and several mitochondrial indices were determined. MTX-treated animals developed biochemical evidence of renal injury as judged by elevated serum blood urea nitrogen (BUN), creatinine (Cr) and along with hypokalemia, hypophosphatemia, hypocalcemia, and a decrease in serum glucose, and uric acid. Moreover, MTX caused an increase in kidney reactive oxygen species and lipid peroxidation. Renal glutathione reservoirs were also depleted, and tissue antioxidant capacity was decreased in MTX-treated animals. Kidney histopathological changes including interstitial inflammation, renal tubular degeneration, retraction glomeruli, and vascular congestion were also evident in MTX-treated rats. On the other hand, it was found that mitochondrial parameters including mitochondrial membrane potential, mitochondrial dehydrogenases activity, and mitochondrial glutathione and ATP content were decreased, while lipid peroxidation and mitochondrial permeabilization were increased with MTX treatment. These data suggest a role for mitochondrial dysfunction and oxidative stress in the mechanism of MTX nephrotoxicity.

Burden and correlates of readmissions related to pulmonary edema in US hemodialysis patients: a cohort study.

Background: Pulmonary edema is prevalent and may be a common cause of hospital readmissions in hemodialysis patients. We aimed to estimate the national burden of, and identify correlates of, readmissions related to pulmonary edema among hemodialysis patients. Methods: In this retrospective cohort study using national registry data, we identified prevalent US hemodialysis patients (n = 215 251) with index admissions while under Medicare primary coverage in 2011-13. We defined readmissions as admissions occurring within 30 days of the index discharge and pulmonary edema-related readmissions as readmissions with discharge diagnoses of fluid overload, heart failure or pulmonary edema. Multivariable logistic regression models were used to determine odds ratios (ORs) for pulmonary edema-related readmissions by patient and index admission characteristics. Results: About one-quarter (23%) of index hospital admissions were followed by a readmission, with nearly half (44%) of the readmissions being associated with pulmonary edema. The strongest independent correlate of pulmonary edema-related readmission was a pulmonary edema-related index admission [OR = 2.32; 95% confidence interval (CI) 2.22-2.41]. With the exception of dialysis vintage <1 year (OR = 1.18; 95% CI 1.14-1.22), chronic obstructive pulmonary disease (OR = 1.34; 95% CI 1.29-1.38), dialysis non-compliance (OR = 1.53; 95% CI 1.41-1.64) and congestive heart failure (OR = 1.85; 95% CI 1.77-1.93), patient characteristics were not generally associated with higher risk of pulmonary edema-related readmission. Conclusions: Readmissions related to pulmonary edema are common in hemodialysis patients. Interventions aimed at preventing such readmissions could have a substantial impact on readmissions overall, particularly targeted at incident hemodialysis patients with a prior history of heart failure and patients initially admitted for pulmonary edema.

[Hyperosmolarity: Intracellular effects and implication in dry eye disease]. / Hyperosmolarité : effets intracellulaires et implication dans la sécheresse oculaire.

Dry eye disease is a multifactorial disease affecting the lacrimal functional unit and which has a significant impact on the quality of life of patients. This pathology works as a vicious circle at the ocular surface in which hyperosmolarity of the tear film plays a key role. This review intends to describe the different reported intracellular effects induced by hyperosmolarity in cells: alteration of cytoskeleton, cell cycle slowdown, adaptation mechanisms triggered as restoration of cell volume and accumulation of compatible osmolytes, the crucial role of the osmoprotectant factor Nuclear Factor of the Activated T cells-5 (NFAT5), apoptosis, as well as oxidative stress and inflammatory responses caused by this particular condition. Reported effects of hyperosmolarity in the experimental studies specific of dry eye disease concerning ocular surface cells will be described in parallel. Indeed, these data allow to understand a part of the pathophysiology of the disease, and specially the links between tear hyperosmolarity and inflammation of the ocular surface, the second key of the pathology phenomenon.

THE ROLE OF HISTAMINE IN THE MECHANISM OF ANTIBIOTIC-INDUCED CHANGES IN COLONIC ION AND WATER TRANSPORT.

The first time the role of histamine and H1-histamine receptors in the mechanisms of ceftriaxone-induced diarrhea in rats. Investigation of the flow of water and electrolytes through the epithelium of the colon performed male rats Wistar (180-250 g), isolated area by perfusion in vivo, for the actions of ceftriaxone (50 mg/kg intramuscularly), histamine (1,8; 3,6; 7,2 mg/ kg, introperytonealno, and 3,6 mg*kg-1 *h-1 intravenously) and loratadine (1,7 mg/kg, per os). Histamine intravenous administration, similar to ceftriaxone, makes a pro-secretory effect on the transport of water and sodium. Blockade of H1-histamine receptors loratadine prevents clinical signs ceftriaxone-induced diarrhea that accompanied the restoration of total water flow indicators and potassium through the epithelium of the colon of rats. Loratadine can be recommended for the prevention of diarrhea antybiotykasotsiyovanoyi not infectious etiology.

From cerebral salt wasting to diabetes insipidus with adipsia: case report of a child with craniopharyngioma.

UNLABELLED: Craniopharyngioma is associated with a wide and interesting variety of sodium states both by itself and following surgical resection. These are often challenging to diagnose, especially given their dynamic nature during the perioperative course. We present the case of a boy with craniopharyngioma who had hyponatremia due to cerebral salt wasting preoperatively, developed diabetes insipidus (DI) intraoperatively and proceeded to develop hypernatremia with adipsic DI. CONCLUSION: Cerebral salt wasting is a rare presenting feature of craniopharyngioma. Postoperative DI can be associated with thirst abnormalities including adipsia due to hypothalamic damage; careful monitoring and a high index of suspicion are required for its detection. Adipsic DI is a difficult condition to manage; hence a conservative surgical approach is suggested.

Dynamic changes in bioelectrical impedance vector analysis and phase angle in acute decompensated heart failure.

OBJECTIVES: To evaluate whether changes in hydration status (reflecting fluid retention) would be detected by bioelectrical impedance vector analysis (BIVA) and phase angle during hospitalization for acute decompensated heart failure (ADHF) and after clinical stabilization. METHODS: Patients admitted to ADHF were evaluated at admission, discharge and after clinical stabilization (3 mo after discharge) for dyspnea, weight, brain natriuretic peptide, bioelectrical impedance resistance, reactance, and phase angle. Generalized estimating equations and chi-square detected variations among the three time points of evaluation. RESULTS: Were included 57 patients: Mean age was 61 ± 13 y, 65% were male, LVEF was 25 ± 8%. During hospitalization there were improvements in clinical parameters and increase in resistance/height (from 250 ± 72 to 302 ± 59 Ohms/m, P < 0.001), reactance/height (from 24 ± 10 to 31 ± 9 Ohms/m, P < 0.001), and phase angle (from 5.3 ± 1.6 to 6 ± 1.6°, P = 0.007). From discharge to chronic stability, both clinical and BIVA parameters remained stable. At admission, 61% of patients had significant congestion by BIVA, and they lost more weight and had higher improvement in dyspnea during hospitalization (P < 0.05). At discharge, more patients were in the upper half of the graph (characterizing some degree of dehydration) while at chronic stability normal hydration status was more prevalent (P < 0.001). CONCLUSIONS: BIVA and phase angle were able to detect significant changes in hydration status during ADHF, which paralleled the clinical course of recompensation, both acutely and chronically. The classification of congestion by BIVA at admission identified patients with more pronounced changes in weight and dyspnea during compensation.

TMPRSS13 deficiency impairs stratum corneum formation and epidermal barrier acquisition.

Membrane-anchored serine proteases serve as important regulators of multiple developmental and homoeostatic processes in mammals. TMPRSS13 (transmembrane protease, serine 13; also known as mosaic serine protease large-form, MSPL) is a membrane-anchored serine protease with unknown biological functions. In the present study, we used mice with the Tmprss13 gene disrupted by a ß-galactosidase-neomycin fusion gene insertion to study the expression and function of the membrane-anchored serine protease. High levels of Tmprss13 expression were found in the epithelia of the oral cavity, upper digestive tract and skin. Compatible with this expression pattern, Tmprss13-deficient mice displayed abnormal skin development, leading to a compromised barrier function, as measured by the transepidermal fluid loss rate of newborn mice. The present study provides the first biological function for the transmembrane serine protease TMPRSS13.

Brain cell swelling during hypocapnia increases with hyperglycemia or ketosis.

BACKGROUND: Severe hypocapnia reduces cerebral blood flow (CBF) and is known to be a risk factor for diabetic ketoacidosis (DKA)-related cerebral edema and cerebral injury in children. Reductions in CBF resulting from hypocapnia alone, however, would not be expected to cause substantial cerebral injury. We hypothesized that either hyperglycemia or ketosis might alter the effects of hypocapnia on CBF and/or cerebral edema associated with CBF reduction. METHODS: We induced hypocapnia (pCO2 20 ± 3 mmHg) via mechanical ventilation in three groups of juvenile rats: 25 controls, 22 hyperglycemic rats (serum glucose 451 ± 78 mg/dL), and 15 ketotic rats (ß-hydroxy butyrate 3.0 ± 1.0 mmol/L). We used magnetic resonance imaging to measure CBF and apparent diffusion coefficient (ADC) values in these groups and in 17 ventilated rats with normal pCO2 (40 ± 3 mmHg). In a subset (n = 35), after 2 h of hypocapnia, pCO2 levels were normalized (40 ± 3 mmHg) and ADC and CBF measurements were repeated. RESULTS: Declines in CBF with hypocapnia occurred in all groups. Normalization of pCO2 after hypocapnia resulted in hyperemia in the striatum. These effects were not substantially altered by hyperglycemia or ketosis. Declines in ADC (suggesting brain cell swelling) during hypocapnia, however, were greater during both hyperglycemia and ketosis. CONCLUSIONS: We conclude that brain cell swelling associated with hypocapnia is increased by both hyperglycemia and ketosis, suggesting that these metabolic conditions may make the brain more vulnerable to injury during hypocapnia.

Early factors associated with fluid sequestration and outcomes of patients with acute pancreatitis.

BACKGROUND & AIMS: Predicting level of fluid sequestration could help identify patients with acute pancreatitis (AP) who need more or less aggressive fluid resuscitation. We investigated factors associated with level of fluid sequestration in the first 48 hours after hospital admission in patients with AP and effects on outcome. METHODS: We analyzed data from consecutive adult patients with AP admitted to the Brigham and Women's Hospital in Boston, Massachusetts, from June 2005 to December 2007 (n = 266) or the Alicante University General Hospital in Spain from September 2010 to December 2012 (n = 137). Level of fluid sequestration in the first 48 hours after hospital admission was calculated by subtracting the total amount of fluid administered and lost in the first 48 hours of hospitalization. Demographic and clinical variables obtained in the emergency department were analyzed to identify factors associated with level of fluid sequestration in the first 48 hours after hospital admission. Outcome assessed included length of hospital stay, acute fluid collection(s), pancreatic necrosis, persistent organ failure, and mortality. RESULTS: The median level of fluid sequestration in the first 48 hours after hospital admission was 3.2 L (1.4-5 L). The simple and multiple linear regression models showed that younger age, alcohol etiology, hematocrit, glucose, and systemic inflammatory response syndrome were significantly associated with increased levels of fluid sequestration in the first 48 hours after hospital admission. Increased level of fluid sequestration in the first 48 hours was significantly associated with longer hospital stays and higher rates of acute fluid collection, pancreatic necrosis, and persistent organ failure. There was a nonsignificant trend toward a higher level of fluid sequestration in the first 48 hours among patients who died. CONCLUSION: Age, alcoholic etiology of AP, hematocrit, glucose, and presence of systemic inflammatory response syndrome in the emergency department were independent predictors of increased levels of fluid sequestration in the first 48 hours after hospital admission. These patients have higher risks of local and systemic complications and longer hospital stays.

KSHV/HHV8-negative effusion-based lymphoma, a distinct entity associated with fluid overload states.

Human herpesvirus-8 (HHV8)-positive effusion-based lymphomas have been termed primary effusion lymphoma (PEL) in the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Kaposi sarcoma herpesvirus (KSHV)/HHV8-negative effusion-based lymphomas (KSHV/HHV8-negative EBLs) resembling PELs have been reported in the literature and in many cases have been (mis)classified as PEL-like lymphomas. Herein, we present a series of cases and a review of KSHV/HHV8-negative EBLs. This lymphoma, although cytomorphologically resembling PEL, is a distinct entity with characteristic clinical and pathologic features. Patients are older, generally human immunodeficiency virus negative and not immunosuppressed, frequently hepatitis C positive compared with the population baseline, and often have an underlying medical condition leading to fluid overload. The lymphoma cells express pan-B-cell antigens in 86.7%, and CD20 is expressed in 71.1% of the cases. The lymphoma is often of germinal center B or mixed germinal center B/activated B-cell signature with the Hans classifier, and Epstein-Barr virus is positive in nearly 30% of cases. Rare T-cell lymphomas were also reported. Clinical outcomes and response to therapy, including isolated aspiration, are relatively favorable compared with cases of PEL. We suggest that HHV8-negative effusion-based lymphoma is a distinct entity associated with fluid overload states.

Aqp2-expressing cells give rise to renal intercalated cells.

The mammalian collecting duct comprises principal and intercalated cells, which maintain sodium/water and acid/base balance, respectively, but the epigenetic contributors to the differentiation of these cell types remain unknown. Here, we investigated whether the histone H3 K79 methyltransferase Dot1l, which is highly expressed in principal cells, participates in this process. Taking advantage of the distribution of aquaporin 2 (Aqp2), which localizes to principal cells of the collecting duct, we developed mice lacking Dot1l in Aqp2-expressing cells (Dot1l(AC)) and found that these mice had approximately 20% fewer principal cells and 13%-16% more intercalated cells than control mice. This deletion of Dot1l in principal cells abolished histone H3 K79 methylation in these cells, but unexpectedly, most intercalated cells also had undetectable di-methyl K79, suggesting that Aqp2(+) cells give rise to intercalated cells. These Aqp2(+) cell-derived intercalated cells were present in both developing and mature kidneys. Furthermore, compared with control mice, Dot1l(AC) mice had 40% higher urine volume and 18% lower urine osmolarity with relatively normal electrolyte and acid-base homeostasis. In conclusion, these data suggest that Dot1l deletion facilitates the differentiation of some α- and ß-intercalated cells from Aqp2-expressing progenitor cells or mature principal cells.

Increased interstitial protein because of impaired lymph drainage does not induce fibrosis and inflammation in lymphedema.

OBJECTIVE: The pathophysiology of lymphedema is incompletely understood. We asked how transcapillary fluid balance parameters and lymph flow are affected in a transgenic mouse model of primary lymphedema, which due to an inhibition of vascular endothelial growth factor receptor-3 (VEGFR-3) signaling lacks dermal lymphatics, and whether protein accumulation in the interstitium occurring in lymphedema results in inflammation. METHODS AND RESULTS: As estimated using a new optical-imaging technique, we found that this signaling defect resulted in lymph drainage in hind limb skin of K14-VEGFR-3-Ig mice that was 34% of the corresponding value in wild-type. The interstitial fluid pressure and tissue fluid volumes were significantly increased in the areas of visible swelling only, whereas the colloid osmotic pressure in plasma, and thus the colloid osmotic pressure gradient, was reduced compared to wild-type mice. An acute volume load resulted in an exaggerated interstitial fluid pressure response in transgenic mice. There was no accumulation of collagen or lipid in skin, suggesting that chronic edema presented in the K14-VEGFR-3-Ig mouse was not sufficient to induce changes in tissue composition. Proinflammatory cytokines (interleukin-2, interleukin-6, interleukin-12) in subcutaneous interstitial fluid and macrophage infiltration in skin of the paw were lower, whereas the monocyte/macrophage cell fraction in blood and spleen was higher in transgenic compared with wild-type mice. CONCLUSIONS: Our data suggest that a high interstitial protein concentration and longstanding edema is not sufficient to induce fibrosis and inflammation characteristic for the human condition and may have implications for our understanding of the pathophysiology of this condition.

Hemodynamic and biochemical benefits of the objective measurement of fluid status in hemodialysis patients.

Subtle fluid imbalance can cause poor clinical outcomes among hemodialysis patients. However, the traditional subjective assessment of fluid status may be inadequate. We evaluated whether the objective measurement and optimization of fluid status could be beneficial for hemodynamic and biochemical parameters in hemodialysis patients. We enrolled 120 hemodialysis patients, who were clinically euvolemic for at least 3 months. Based on the results of a body composition monitor, we divided the patients into the following two groups: the hyperhydrated group (post hemodialysis fluid overload ≥ 1.1 L) and the dehydrated group (post hemodialysis fluid overload < -1.1 L). We reduced the patient's body weight in the hyperhydrated group and raised the body weight in the dehydrated group towards normohydration (-1.1 L ≤ fluid overload < 1.1 L) for 16 weeks. Forty-four of 120 patients were in the hyperhydrated group, and 18 of 120 patients in the dehydrated group. After 16 weeks, systolic blood pressure and pulse pressure decreased in the hyperhydrated group, while there was no increase in blood pressure in the dehydrated group after the intervention. Serum levels of monocyte chemotactic protein-1, an inflammatory marker, gradually decreased in the hyperhydrated group, and serum adiponectin levels, an anti-atherogenic biomarker, increased in the two groups. We found that hyperhydrated patients contributed over 1/3 of the participants despite enrolling clinically euvolemic patients and that body composition monitor-guided optimization of body fluid status may lead to improvement of inflammatory markers and anti-atherogenic adipokines as well as hemodynamic parameters in hemodialysis patients.

Brain water channel proteins in health and disease.

The aim of this article is to describe the roles of water channel proteins (WCPs) in brain functionality. The fluid compartments of the brain, which include the brain parenchyma (with intracellular and extracellular spaces), the intravascular and the cerebrospinal fluid compartments are presented. Then the localization and functional roles of WCPs found in the brain are described: AQP1, AQP2, AQP3, AQP4, AQP5, AQP7, AQP8, AQP9 and AQP11. In subsequent chapters the involvement of brain WCPs in pathologies are discussed: brain edema, brain trauma, brain tumors, stroke, dementia (Alzheimer's disease, human immunodeficiency virus--HIV-dementia), autism, pain signal transduction and migraine, hydrocephalus and other pathologies with neurological implications: eclampsia, uremia. New WCP ligands for brain imaging are also discussed.

The disturbed blood-brain barrier in human glioblastoma.

The aim of this article is to describe alterations of the blood-brain barrier (BBB) in gliomas. The main clinical problem of human gliomas is the edematous swelling and the dramatic increase of intracerebral pressure, also compromising healthy areas of the brain. According to our concept, one of the main reasons on the cellular level for these clinical problems is the loss or reduction of astroglial polarity. Astroglial polarity means the specific accumulation of potassium and water channels in the superficial and perivascular astroglial endfeet membranes. The most important water channel in the CNS is the astroglial water channel protein aquaporin-4 (AQP4) which is arranged in a morphologically spectacular way, the so-called orthogonal arrays of particles (OAPs) to be observed in freeze-fracture replicas. In brain tumors, but also under conditions of trauma or inflammation, these OAPs are redistributed to membrane domains apart from endfeet areas. Probably, this dislocation might be due to the degradation of the proteoglycan agrin by the matrix metalloproteinase 3 (MMP3). Agrin binds to the dystrophin-dystroglycan-complex (DDC), which in turn is connected to AQP4. As a consequence, agrin loss may lead to a redistribution of AQP4 and a compromised directionality of water transport out of the cell, finally to cytotoxic edema. This in turn is hypothesized to lead to a breakdown of the BBB characterized by disturbed tight junctions, and thus to the development of vasogenic edema. However, the mechanism how the loss of polarity is related to the disturbance of microvascular tight junctions is completely unknown so far.

Aquaporins in drug discovery and pharmacotherapy.

Identification of the aquaporin (AQP) protein family more than twenty years ago has ushered in an era where water and neutral solute trafficking is considered a prime target for pharmacological intervention. Using AQP modulation as a basis for the treatment of human disorders has been suggested by phenotype analysis involving specific AQP-null animals, as well as by pathohistological studies. Based on those reports, a wide variety of disorders, such as cerebral edema, cancer and malaria, are considered indications for AQP modulators. Recent studies have also identified several small molecule AQP modulators that can be used to test those hypotheses in disease models. We believe these studies and compounds form the basis from which future treatments and diagnostic protocols of aquaporin-based disorders will be developed.

Protean presentation and multiple challenges of nephrocalcinosis in pregnancy (six pregnancies in four patients).

BACKGROUND: Nephrocalcinosis is an umbrella term covering increased content of calcium salts in the renal parenchyma, interstitial damage and potential evolution towards renal failure. Pregnancy is often the first occasion for biochemical or imaging tests in young women and may allow early diagnosis. Conversely, even mild kidney disease may represent a challenge in pregnancy. AIM: The aim of this study was to report on four patients in whom nephrocalcinosis was first diagnosed during pregnancy, exemplifying the protean presentation and multiple challenges of nephrocalcinosis in pregnancy. METHODS: This is a case series study including data on all pregnancies prospectively gathered in the Nephrological-Obstetric Unit dedicated to pregnancy and kidney diseases (2000-11). RESULTS: Six pregnancies were observed in four patients (31-35 years; one twin pregnancy, one ongoing, one patient with three pregnancies). Symptoms were oedema in two (later developed in a further patient), renal functional impairment and electrolyte imbalance in two each. Two patients developed hypertension late in pregnancy. Electrolyte imbalance was life-threatening in one patient (severe acidosis, severe hyperkalaemia: 7.5 mEq/L). Delivery was by Caesarean section in three patients, preterm in one. Multiple or long hospitalizations for metabolic reasons were needed in three patients, the fourth was hospitalized for obstetric reasons. In all patients, diagnosis of nephrocalcinosis was made at ultrasounds during basic nephrological evaluation, confirmed at computerized tomography scan in three. The pathogenesis was linked to diuretic abuse in one case and to collagen disease, inborn errors and prematurity, possibly associated with diuretic misuse, in the others. CONCLUSION: Nephrocalcinosis may have protean presentations in pregnancy. The risk of severe electrolyte derangements, oedema and hypertension warrants strict clinical surveillance.