Efficacy of furosemide-albumin compared with furosemide in critically ill hypoalbuminemia patients admitted to intensive care unit: a prospective randomized clinical trial.

BACKGROUND: Some physicians co-administer albumin with loop diuretics to overcome diuretic resistance in critically ill hypoalbuminemia patients, though previous studies have reported conflicting results on this matter. OBJECTIVE: The effects of adding albumin to furosemide to enhance its efficacy in critically ill hypoalbuminemia patients are evaluated. METHODS: This was a non-blinded randomized trial. 49 adult critically ill patients with hypoalbuminemia and generalized edema who received randomly furosemide and furosemide/albumin complex were enrolled. The patients' urine was collected at intervals of 2, 4, 6 and 8 h after initiation of the furosemide treatment, and the urine output and urinary excretion of furosemide and sodium were measured. The urinary excretion of furosemide was considered an indicator of drug efficacy. RESULTS: The amount of sodium and furosemide excreted in urine showed no significant differences between the two groups; however, the mean of the urinary excretion of furosemide in the first 2 h after drug infusion was significantly higher (p = 0.03) in the furosemide/albumin group. No significant correlation between APACHE II scores and serum albumin levels and the urinary excretion of furosemide was seen. CONCLUSION: The results indicated that there is not statistically significant differences between groups with furosemide alone and combined with albumin in urinary furosemide excretion. It seems that adding albumin for furosemide pharmacotherapy regime is not recommended as an intervention to increase furosemide efficacy in critically ill hypoalbuminemia patients. TRIAL REGISTRATION: IRCT with the registration number IRCT201412132582N12 in 23 February 2015; https://en.irct.ir/trial/2356 Graphical abstract.

Urinary Organic Acids Increase After Clinical Stabilization of Hospitalized Children With Severe Acute Malnutrition.

BACKGROUND: Despite a reduction of child mortality in low-income countries, acutely ill undernourished children still have an elevated risk of death. Those at highest risk are children with severe acute malnutrition (SAM) who often show metabolic dysregulation that remains poorly understood. OBJECTIVE: We performed a pilot study to examine changes in urinary organic acids during nutritional rehabilitation of children with SAM, and to identify metabolites associated with the presence of edema or with mortality. METHODS: This study included 76 children aged between 6 and 60 months, hospitalized for SAM at the Moyo Nutritional Rehabilitation and Research Unit in Blantyre, Malawi. Urine was collected at admission and 3 days after clinical stabilization and metabolomics were performed using gas chromatography-mass spectrometry. Metabolite concentrations were evaluated with both uni- and multivariate approaches. RESULTS: Most metabolites increased 3 days after clinical stabilization, and total urinary concentration changed from 1.2 mM (interquartile range [IQR], 0.78-1.7) at admission to 3.8 mM (IQR, 2.1-6.6) after stabilization (P < .0001). In particular, 6 metabolites showed increases: 3-hydroxybutyric, 4-hydroxyhippuric, p-hydroxyphenylacetic, oxoglutaric, succinic, and lactic acids. Urinary creatinine was low at both time points, but levels did increase from 0.63 mM (IQR, 0.2-1.2) to 2.6 mM (IQR,1.6-4.4; P < .0001). No differences in urinary profiles were found between children who died versus those who survived, nor between children with severe wasting or edematous SAM. CONCLUSIONS: Total urinary metabolites and creatinine increase after stabilization and may reflect partial recovery of overall metabolism linked to refeeding. The use of urinary metabolites for risk assessment should be furthered explored. TRIAL REGISTRATION: TranSAM study (ISRCTN13916953).

Association of Urinary Plasminogen-Plasmin with Edema and Epithelial Sodium Channel Activation in Patients with Nephrotic Syndrome.

BACKGROUND: Previous animal experiments and small human studies suggest that urinary plasmin can activate the epithelial sodium channel (ENaC) and contribute to sodium retention in nephrotic syndrome (NS), but this however is not well studied in clinical settings, and its relevance to edema formation is not well characterized in humans. We have investigated the association between urinary plasmin and clinical phenotypes in a large group of patients with NS from multiple etiologies, aiming to assess the role of urinary plasmin in sodium handling and edema formation. METHODS: Two hundred and three NS patients with urine and blood samples were divided into mild and severe symptom groups based on their edema severity. Twenty six of them had serial samples collected during the course of immunosuppressive therapy. The plasminogen-plasmin level and other key parameters were assayed, and their association with clinical manifestations were analyzed. RESULTS: One hundred and one of the 203 patients had renal biopsies performed, the results of which had included all the common types of primary NS and various types of secondary NS. Quantitative comparison and multivariate logistic regression analysis identified urinary plasminogen-plasmin to creatinine ratio (uPLG-PL/C), serum albumin, D-Dimer, and cardiac dysfunction history, but not albuminuria or 24-h urine protein, as independent risk factors for edema (p < 0.01). In patients who were treated and had serial samples, a decrease in uPLG-PL/C was identified as an independent influencing factor of edema remission (p < 0.01). Finally, the urinary fractional excretion of sodium (FENa) in patients was inversely correlated with the fractional excretion of potassium (FEK; p< 0.001), and FEK/FENa ratio was positively correlated with uPLG-PL/C (p < 0.001), suggesting a close association between uPLG-PL and ENaC activation. CONCLUSIONS: Our study identifies uPLG-PL abundance as an independent influencing factor of edema in adult NS patients, and supports the conclusion that plasmin-dependent ENaC activation is an important pathophysiological mechanism of sodium retention and edema formation in humans with NS.

Expression pattern of aquaporins in patients with primary nephrotic syndrome with edema.

The association between the expression of aquaporins (AQPs) in kidney tissues and the occurrence of edema in nephrotic syndrome (NS) remains unclear. The current study aimed to investigate this association. A total of 54 patients with primary glomerular disease, diagnosed by renal biopsy, were divided into three groups: Control, NS without edema and NS with edema. The expression of AQP1, AQP2, AQP3 and AQP4 in kidney tissues from these patients was assessed using immunohistochemistry, and urinary AQP concentrations were quantified by ELISA. Comparison of the three groups was conducted using one way analysis of variance, independent samples t­test or the Chi­square test. AQP1 was strongly expressed in the proximal tubules. The proportion of the AQP1­positive area in kidney tissues from patients with NS with edema was significantly reduced, in comparison with the other two groups. By contrast, the proportion of the AQP2­positive area in the NS with edema group was significantly higher than that of the other two groups; significant differences were also observed between the control and NS without edema groups for this parameter. Urinary AQP2 concentrations in patients with NS (with and without edema) were significantly higher than that of the control group, and exhibited a significant positive correlation with kidney tissue AQP2 concentrations. The present study demonstrated the abnormal expression pattern of AQP1­AQP4 in the kidney tissues of patients with NS, providing a basis for an improved understanding of the role of AQP in the pathogenesis of NS.

Anti-edematous effects of tolvaptan in experimental rodent models.

PURPOSE: The aim of this study was to evaluate the therapeutic efficacy of tolvaptan, a vasopressin V(2) receptor antagonist, on edema in two rat models: 1) histamine-induced vascular hyperpermeability of the dorsal skin and 2) carrageenan-induced paw edema. METHODS: In the skin vascular hyperpermeability model, 3 h after oral administration of tolvaptan or the natriuretic agent furosemide, rats were intravenously injected with Evans Blue (EB), followed by intradermal injection of 10 µg of histamine into the dorsal skin. One hour later, blood was collected to measure serum parameters. EB leakage area into the dorsal skin was also measured. Urine was collected for 4 h to determine urine parameters. In the paw edema model, edema was induced by injecting 1% w/v carrageenan into the right hind paw. Paw volume was measured hourly for 5 h. Tolvaptan or furosemide was orally administered 1 h before carrageenan injection. RESULTS: A single oral dose of tolvaptan (1-10 mg/kg) elicited marked and dose-dependent aquaresis, and improvements in edema. Similar effects were observed with furosemide (30 mg/kg). Tolvaptan tended to elevate the serum sodium level while furosemide caused a significant decrease. CONCLUSION: Tolvaptan had anti-edematous effects in two different rat models. By increasing free water excretion, tolvaptan may be more advantageous for certain patients than loop diuretics because it does not cause electrolyte loss, and may prevent electrolyte abnormities, such as hyponatremia. These results suggest that tolvaptan has potential clinical benefits for the treatment of edema.

Co-administration of albumin-furosemide in patients with the nephrotic syndrome.

Generalized edema is one of the most important complications in patients with nephrotic syndrome. Diuretics like furosemide are the first choice for reducing the edema. Hypo-albuminemia reduces the effect of furosemide, and thus, this drug is co-administered with albumin to reinforce the therapeutic effect and for the correction of reduced oncotic pressure. The aim of this study was to compare urine volume and 24-hour sodium levels after using furosemide alone versus using furosemide along with albumin in patients with nephrotic syndrome. In a randomized clinical trial, ten patients with nephrotic syndrome were chosen and were randomly allocated into four groups. Three therapeutic protocols were chosen, and at the end, each patient had received all three protocols randomly. Data were gathered and analyzed using non-parametric tests in SPSS software. The average urine volume after receiving albumin alone, furosemide alone and albumin plus furosemide were 742 mL (SD = 528), 1707 mL (SD = 745) and 2175 mL (SD = 971), respectively (P = 0.015); the fractional excretion of sodium was 1.96 (SD = 0.251), 3.18 (SD = 0.25), and 4.77 (SD = 8.45), respectively (P = 0.000); the 24-hour urinary sodium levels were 18.3 (SD = 6.68), 208.4 (SD = 5.27) and 206 (SD = 8.45), respectively; while the glomerular filtration rate (GFR) was 104.5, 96.6 and 106.6 (P = 0.021), respectively, in the three therapy groups. Our study shows that albumin administration alone and with furosemide in patients with nephrotic syndrome who had normal kidney function, results in different urine volumes and sodium levels. Co-administration of albumin and furosemide increased the urine volume and sodium level, which is due to increase in the GFR as well as the diuretic effects of furosemide.

Ratio of urinary potassium to urinary sodium and the potassium and edema status in nephrotic syndrome.

OBJECTIVE: This study aimed to evaluate the relevance of ratios of urinary potassium to urinary sodium + potassium (U(K)/U(Na + K)) to edema status in minimal-change nephrotic syndrome (MCNS). METHODS: We retrospectively studied 26 adults with newly diagnosed MCNS with significant pitting edema. On the basis of mean value (0.46±0.21) of U(K)/U(Na + K) determined from spot urine samples on admission, patients were classified into 2 groups. RESULTS: On admission, 12 of 26 patients had U(K)/U(Na + K) >0.46 (0.65±0.16, Group H), 14 patients had U(K)/U(Na + K) <0.46 (0.29±0.08, Group L). The level of serum albumin was similarly decreased in these 2 groups. Noteworthy were lower urine volume, fractional excretion of sodium (FENa), serum sodium, and higher hematocrit in the group H as compared with the group L. The group H had a shorter mean time required from onset of edema to hospitalization, and tended to have a longer mean time to complete remission than group L. High U(K)/U(Na + K) levels in group H decreased significantly after remission, eventually becoming equal to those of group L (0.24±0.05 vs. 0.25±0.05). CONCLUSION: U(K)/U(Na + K) determined from spot urine sample on admission relates to laboratory or clinical indices to distinguish edema status in adult patients with MCNS.

Renal Behçet's disease: an update.

OBJECTIVE: The aims of this study are (1) to report 33 patients with Behçet's disease (BD) having various renal manifestations, and (2) to update current data using our patients and published papers about BD and renal manifestations. METHODS: The PubMed database was searched using the terms BD or Behçet's syndrome. We found reports of 94 patients (including ours) with BD and specific renal diseases (amyloidosis, 39; glomerulonephritis [GN], 37; renal vascular disease, 19; interstitial nephritis, 1). RESULTS: The presentation of renal disease was edema/nephrotic syndrome in 12 patients (36%). Renal disease was incidentally diagnosed by routine urine analysis and measurement of serum creatinine level in 20 patients (61%). Renal failure was present in 23 patients (70%) and 5 of them have had cyclosporine treatment. The frequency of renal disease among BD patients has been reported to vary from less than 1 to 29%. CONCLUSIONS: The clinical spectrum of renal BD shows a wide variation. Amyloidosis (AA type), GN, and macroscopic/microscopic vascular disease are the main causes of renal BD. Patients with vascular involvement have a high risk of amyloidosis and amyloidosis is the most common cause of renal failure in BD. Several types of glomerular lesions are seen in BD. Current treatment options for renal BD are not evidence based. Radiological vascular intervention combined with immunosuppressive drugs can be useful in selected cases. Routine urine analysis and measurement of serum creatinine level are needed for early diagnosis of renal BD.

[Diuretic effect of injecting furosemide into low hydraulic resistance point Shuifen along the conception meridian in pigs with acute edema].

OBJECTIVE: To observe whether injection of medicine into low hydraulic resistance point along meridian brings about higher medicinal effect and to explore the efficacy of the theory that meridians are made up of channels featuring low hydraulic resistance by observing the diuretic effect of injecting furosemide or saline into the low hydraulic resistance point Shuifen (CV 9), vein and Zusanli (St 36) respectively. METHODS: Acute edema was induced in pigs by rapid intravenous injection of 2 000 ml normal saline. The pigs were divided into four groups: Shuifen (CV 9) injection of half dose furosemide group (SFF group), intravenous injection of full dose furosemide group (VF group), Zusanli (St 36) injection of full dose furosemide group (ZSLF group), and Shuifen (CV 9) injection of half dose normal saline group (SFS group). The accumulated urine quantity and the urine quantity generated in every 15-minute period were measured in each group respectively, every 15 minutes after injection, and the measurement lasted for two hours at one experiment. Each group involved eight times of experiments with one pig used for one experiment, which means the whole observation involved 32 times of experiments. RESULTS: The accumulated urine quantities observed in both SFF group and VF group were higher than those in the ZSLF group and the SFS group all through the measurement, showing significant differences during the period from the 15th minute to the 45th minute (P<0.05). But no significant difference was observed between the SFF group and the VF group during the whole 2-hour measurement (P>0.05). Analysis of urine quantity generated in every 15-minute period showed that diuretic effect climaxed during the 15th minute to the 30th minute in both SFF group and VF group. By contrast, ZSLF group reached diuresis climax during the 45th minute to 60th minute and no diuresis climax was observed in the SFS group all through the measurement. CONCLUSION: Injection of medicine into low hydraulic resistance point along meridian generates faster and more powerful medicinal potency, and this is likely to be applied to clinical practice. The theory that meridians are channels featuring low hydraulic resistance is important to the elucidation of meridians.

Oedema with proteinuria in Gambian children--a descriptive study.

The clinical syndrome of oedema with proteinuria is an important cause of paediatric morbidity in sub-Saharan Africa. The aim of this study was to assess its prevalence, clinical presentation and outcome in The Gambia, where the syndrome is perceived to be common but has not previously been studied. All children admitted with oedema and proteinuria to three hospitals in the Western region of The Gambia between January 1995 and June 1998 were identified retrospectively. Hospital records were retrieved to assess admission characteristics. All traceable children were clinically reviewed, and urinalysis was performed between 3 months and 4 years after admission. Two hundred and two children who presented with proteinuria and oedema were identified, accounting for 1.2% of paediatric hospital admissions in The Gambia. Haematuria on dipstick testing was common (76.5%). Of 39 children who were traced, four (10.3%) were dead. Eighteen of the remaining 35 (51.4%) had proteinuria at follow up. Older age at first presentation was significantly associated with increased long-term morbidity. These preliminary data suggest that oedema with proteinuria may be common and could cause long-term morbidity and mortality in Gambian children. Further studies on its aetiology and treatment are warranted.

The Na+-excreting efficacy of indapamide in combination with furosemide in massive edema.

BACKGROUND: Massive systemic edema is often observed in patients with severe nephrotic syndrome, including diabetic nephropathy. Although furosemide, a loop diuretic, is often administered to these patients, some patients do not respond to this treatment, still showing massive edema. METHODS: The efficacy of indapamide which has a thiazide-like effect on distal convoluted tubules in combination with furosemide, was evaluated in eight patients with massive edema, in regard to both Na+ excretion and diuresis. Indapamide 2 mg was administered once a day, in the morning, to patients in whom it was considered that furosemide treatment of 40-120 mg a day for 1 week was ineffective. RESULTS: Urinary Na+ excretion was markedly increased, from 83.7 +/- 82.2 mEq/day to 140.7 +/- 33.8 mEq/day after 1 week of the combination therapy compared with furosemide alone (P < 0.01); urine volume was also increased, from 1070 +/- 230 ml to 1359 +/- 296 ml after 1 week of the combination therapy (P < 0.05). In this context, body weight was significantly decreased, from 57.2 +/- 12.3 kg to 53.4 +/- 12.8 kg, after the combination therapy (P = 0.01). Indapamide in combination with furosemide was well tolerated, and no significant changes in serum levels of creatinine and potassium were observed. CONCLUSIONS: This combination therapy appears to be effective in patients with massive edema, as it increased diuresis, and achieved potent Na+ excretion.

A whitened face woman with nephrotic syndrome.

Skin whitening cream from developing countries is a recognized source of chronic mercury poisoning. The authors report on a 34-year-old Indonesian domestic helper who presented with nephrotic syndrome secondary to membranous nephropathy. It was subsequently found that she used a skin whitening cream regularly that was found to contain a mercury level of almost 2,000 times above the allowable limit. Her blood and urinary mercury levels were both grossly elevated. Her symptoms improved after she stopped using the cream. However, she returned to her home country before chelating therapy could be arranged. Because mercury-containing skin products are still widely available in developing countries, the use of these products should be considered a possible cause of membranous nephropathy in immigrants from those countries.

Epidemic dropsy: observations on pathophysiology and clinical features during the Delhi epidemic of 1998.

Epidemic dropsy results from the consumption of edible oils adulterated with Argemone mexicana oil by unscrupulous traders. Twenty consecutive 'in-door' patients of dropsy were intensively studied during the recent Delhi epidemic. Samples of edible oil used by them, their urine and their serum samples tested positive for sanguinarine on thin layer chromatography. The illness starts as a gastro-enteric illness followed by oliguria and pedal oedema. The following are often observed: cutaneous erythema with blanching and tenderness on pressure; violacious pigmentation of the skin; shortness of breath with orthopnoea; right-sided heart failure with normal left ventricle (LV) functions; as well as severe anaemia and hypoalbuminaemia. Renal function tests showed: bland urinary sediments; decreased glomerular filtration rate (GFR); mild to moderate azotaemia; acute tubular necrosis; patchy pneumonitis; moderate hypoxia with respiratory alkalosis; and restrictive ventilatory defects on blood gas analysis; and spirometry suggestive of interstitial pulmonary oedema of non-cardiogenic origin. 99mTc colloid sulphur liver scans showed colloid shift. There was marked dilatation and proliferation of dermal capillaries in the absence of significant inflammation in the biopsy specimens. Toxic alkaloids of Argemone mexicana oil induce widespread capillary dilatation and permeability causing leakage of protein rich plasma into the interstitial tissues of various organs. A hypovolaemic state is thus induced producing renal hypoperfusion which may progress to acute tubular necrosis. Interstitial fluid in alveoli causes restrictive ventilatory dysfunction with hypertension and right-sided failure with well-preserved LV function. The hepatic venous congestion induces Kupffer's cell dysfunction, which results in colloid shift on a radionuclide liver scan.

Pharmacokinetics and pharmacodynamics of bumetanide in critically ill pediatric patients.

This prospective, open-label, clinical trial was conducted to describe the pharmacology of bumetanide in pediatric patients with edema. Nine infants, children, and young adults with edema who were selected for diuretic therapy were studied. After a brief baseline period, each patient received parenteral bumetanide 0.2 mg/kg divided into two equal doses and administered every 12 hours. Urine excretion rate, fractional and total excretion of Na+, Cl-, and K+, creatinine clearance, and plasma and urine concentrations of bumetanide were measured at multiple intervals after drug administration. Bumetanide caused significant increases in the excretion rate of urine and each measured electrolyte. Unexpectedly, creatinine clearance increased dramatically after each dose. Adverse effects, including hypokalemia and hypochloremic metabolic alkalosis, were evident by the end of the treatment period. The plasma pharmacokinetics of bumetanide revealed mean +/- standard deviation values for total clearance and apparent volume of distribution of 3.9 +/- 2.4 mL/min/kg and 0.74 +/- 0.54 L/kg, respectively. Patients excreted an average of 34% of each dose unchanged in the urine over 12 hours. Plasma concentrations of bumetanide accurately predicted several renal effects using a link model with similar pharmacodynamic parameters in each case. Parenteral bumetanide 0.1 mg/kg administered every 12 hours produced significant beneficial and adverse effects in these critically ill pediatric patients with edema. Pharmacokinetic parameters are similar to those previously reported for infants. Plasma concentrations of bumetanide can predict effect-compartment pharmacodynamics.

Idiopathic intracranial hypertension and orthostatic edema may share a common pathogenesis.

Our aim was to determine the frequency of orthostatic edema (OE) in patients with idiopathic intracranial hypertension (IIH). We evaluated 30 women with IIH for evidence of OE by comparing sodium and water excretion in the recumbent and standing postures and morning and evening body weights. Data were compared with findings in 30 women with OE, 22 weight-matched obese normal subjects, and 20 lean normal subjects. The effect of treatment with diuretics or diuretics plus sympathomimetic agents was compared. Seventy-seven percent of IIH patients had evidence of peripheral edema and 80% had significant orthostatic retention of sodium or water. Excretion of a standard saline load and of a tap water load was significantly impaired in the upright posture in the IIH and OE patients compared with the lean and obese normal subjects. Diuretic therapy induced weight loss (up to 9 kg) and decreased mean weight gain from morning to evening in 5 of 12 patients treated. In seven patients also treated with diuretics plus sympathomimetic drugs, the diuretic-induced morning weight loss and morning to evening weight gain were both significantly improved with the addition of sympathomimetic agents. Therapy reduced the frequency or severity of headaches in seven patients and reduced papilledema in four patients who received no other concurrent treatment for IIH. The orthostatic retention of sodium and water and the consequent edema is very similar in IIH and OE patients, suggesting a common pathogenesis for both disorders. Diuretic therapy, dietary salt and water restriction, and planned periods of recumbency merit study as a treatment for these patients.

Renal sodium excretion and edematous disorders.

Body sodium and water homeostasis is regulated by multifactorial renal and extrarenal systems. Following a description of these systems, four common edema states are reviewed, with special emphasis on the pathophysiologic mechanisms leading to sodium and water retention.

Assay of trypsinogen activation in the cat experimental model of acute pancreatitis.

An enzyme-linked immunosorbent assay for trypsinogen activation peptide (TAP) was used to measure urinary TAP levels in standard feline models of acute oedematous pancreatitis and acute haemorrhagic pancreatitis. It has been shown that the extent of pancreatic damage as assessed histologically is significantly greater in the model of acute haemorrhagic pancreatitis. This increase in damage has been found to be associated with a significantly greater increase in the excretion of urinary TAP.

Effect of daily immersion on the edema of pregnancy.

To evaluate whether pregnant women become refractory to the effects of immersion, we studied 11 healthy women from 26 to 38 weeks' gestation, immersed in 34 degrees C shoulder-deep water for 4 or 5 consecutive days. The daily immersion diuresis showed no change throughout the study (p = 0.98: mean, 145 ml, 159 ml, 159 ml, 173 ml, 184 ml, day 1 through day 5, respectively). The range of urine volumes was broad, 35 to 675 ml, depending on the subject's degree of edema. Immersion produced a significantly larger diuresis compared with preimmersion values, 162 ml versus 110 ml. Maternal blood pressure and heart rate consistently fell during immersion, and this effect was maintained for each day studied. The subjects' hematocrit, hemoglobin, and total protein were unchanged from a preimmersion sample on day 1 to a postimmersion sample on the last day of the study. The results of this study indicate that pregnant women do not become refractory to the hemodynamic and diuretic effects of immersion.

Malacoplaquia intestinal en pediatría: A propósito de un caso y revisión de la literatura / Intestinal Malacoplaquia

Se inform del caso de un niño de 13 años de edad hospitalizado en el Instituto Nacional de Salud del Niño, que ingresó con edema generalizado, diarrea crónica y hematoquezia. La biopsia de intestino estableció el diagnóstico de Malacoplaquia. A pesar del tratamiento instaurado la evolución clínica fué tórpida. Se revisa la literatura médica principalmente la relacionada al grupo pediátrico