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.

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.

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).

The presence of a natriuretic factor in urine of patients with chronic uremia. The absence of the factor in nephrotic uremic patients.

A gel filtration fraction of serum from chronically uremic patients has been shown previously to produce natriuresis in the rat. In the present studies, the same fraction from urine of uremic patients and normal subjects was studied for its natriuretic activity. Urine samples were obtained from 17 chronically uremic patients (mean glomerular filtration rate [GFR], 8.7 ml/min; mean fractional sodium excretion [FE(Na)], 5.7%), and 14 normal subjects. The fraction from the uremic patients produced a significant increase in absolute sodium excretion (U(Na)V) and FE(Na); the fraction from normal subjects had no statistically significant effect on either U(Na)V or FE(Na); and the difference between the response to the uremic vs. normal fractions was highly significant for both parameters of sodium excretion. When a more concentrated urine fraction from uremic patients was administered, a striking natriuresis was observed with values for FE(Na) rising to levels as high as 12%. Studies also were performed on eight patients with far advanced chronic renal insufficiency and the nephrotic syndrome. The serum fraction was studied in each of these patients and the urine fraction in three. For the group, U(Na)V in the assay rats decreased by 0.87 mueq/min and FE(Na) decreased by 1.35% after infusion of the serum fraction. These results differ significantly from those of patients with chronic uremia without the nephrotic syndrome. The data are consistent with the view that the increased activity of the natriuretic factor in the serum of chronically uremic patients is not due to failure of excretion; rather it relates either to an increased rate of production and/or a decreased rate of degradation. The data also show that the inhibitor is detectable when FE(Na) is increased, but not when uremia is associated with a sodium-retaining state.

[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.

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.

Catecholamine excretion in "idiopathic" edema: decreased dopamine excretion, a pathogenic factor?

In 16 women with idiopathic edema, urinary dopamine excretion was decreased when compared to control women (146 +/- 13 SE ng/ml/m2 vs. 212 +/- 32, P less than 0.05 in the supine position and 140 +/- 9 vs. 199 +/- 20, P less than 0.005 combined values of supine and recumbent positions) and was also lower when pooled values for urinary dopamine excretions both before and after furosemide were compared in idiopathic edema patients and in control subjects (270 +/- 30 ng/ml vs. 480 +/- 70, P less than 0.05). These patients have lower basal sodium excretions, decreased tubular rejection fractions of sodium in the upright position and lower urinary sodium excretions following furosemide administration. The urinary sodium and dopamine excretions before and following furosemide are positively correlated in control (P less than 0.05), idiopathic edema patients (P less than 0.02) and in both groups combined (P less than 0.005). Idiopathic edema patients have normal urinary noradrenaline and adrenaline excretions but, as previously observed, elevated: 1) plasma renin activity while either recumbent or upright, and 2) plasma aldosterone concentrations while upright. These results suggest that a decrease in urinary dopamine, a catecholamine recently recognized to have natriuretic action, possibly reflects a suppression of the renal dopaminergic system and may contribute to the excessive sodium retention in idiopathic edema either directly or indirectly through the renin-aldosterone system.

Urinary and plasma cyclic adenosine 3',5'-monophosphate in patients with idiopathic edema.

Urinary excretion and plasma concentrations of adenosine 3',5'-monophosphate were determined in idiopathic edema patients both at rest and after assumption of the upright position. Patients and normal subjects responded similarly to upright posture with decreases in urinary volume and creatine excretion and their urinary excretion of cyclic AMP was not significantly different. The plasma concentration of cyclic AMP was high in patients, both in the recumbent and upright positions, and its renal clearance (unlike that of creatinine) was low. Plasma cyclic AMP increased in response to upright posture both in patients and normal subjects. Even if the significance of elevated plasma cyclic AMP is unknown, its presence without an increase in urinary cyclic AMP suggests that the renal handling of cyclic AMP is abnormal is idiopathic edema; this may be related to an excessive beta-adrenergic tone.

Effect of posture on plasma atrial natriuretic hormone and renal function during salt loading in patients with and without postural (idiopathic) edema.

The effect of posture on plasma atrial natriuretic hormone (ANH) and renal function was studied in subjects with idiopathic edema. Sixty-five subjects with edema but with no clinical evidence for cardiac, renal, or pulmonary diseases were studied after they had been off all medication for 1 week or more. They had nothing by mouth after midnight and were admitted to the Clinical Research Center at 0800 h. They voided, were weighed, and had their blood pressure and pulse measured in the recumbent and upright positions. A needle was inserted, and subjects were recumbent for 0.5 h, after which blood was drawn for measurement of plasma ANH, serum sodium, potassium, and (in 35 subjects) creatinine. They were then given 150 mL 0.14% sodium chloride solution to drink every 0.5 h for the next 6 h. Urine was collected every 0.5 h for measurement of sodium, potassium, and creatinine. After 4 h of recumbency repeat blood samples were drawn, subjects ambulated for 2 h, after which final repeat blood samples were drawn. Subjects were considered to have postural edema if their upright urinary sodium/previous 2-h urinary sodium was less than 33%, and to have a normal response if it was 33% or more. The clinical characteristics of the 34 patients with postural edema and 31 patients with a normal response were similar. Plasma ANH levels (initial, after oral saline, and after standing) were similar in the two groups, and there was no relationship between changes in ANH and urinary sodium with standing. In conclusion, under conditions of mild oral sodium chloride loading, changes in plasma ANH do not cause the abnormal sodium retention found in patients with postural edema.

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.

Differential effect of swelling and anoxia on kidney function and its consequences on the mechanism of action of intracellular organ preservation solutions.

In order to differentiate the effects of swelling and anoxia on kidney function, a canine experimental model is used. After complete liberation of kidneys and their vessels from adjacent tissues, each kidney is submitted to 10 min of hypotonic flushing, or to 60 min of normothermic anoxia. Swelling resulting from these two procedures are equal and permit the study of the consequences of anoxia independently from swelling. Edema is determined by water content and renal blood flow is measured. Kidney function is studied by time of restoration of urinary flow, creatinine, and inulin clearances and fractional water reabsorption. The results show that nonanoxic edema is much less damaging than anoxic edema and consequently that anoxic injury is not the simple consequence of spatial disruption of cell architecture. Since many works have shown the beneficial effects of intracellular organ preservation solutions and consequently that anoxia is better tolerated in the absence of swelling, it can be deduced that injuries induced by anoxia and by swelling are cumulative and that the efficiency of intracellular solutions cannot be attributed solely to the preventive effect on swelling, considered as lethal for the cell.

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.

The use of furosemide in the treatment of edema in infants and children.

One hundred thirty-seven courses of furosemide therapy were given to 106 hospitalized pediatric patients with salt and water retention associated with cardiac or renal disease. The diuretic was effective and safe in the pediatric age group when administered acutely as a parenteral medication and over a long-term course by the oral route in the doses and at the time intervals used in this study. On the basis of each kilogram of body weight, the infants with edema as a result of cardiac failure and the children with edema secondary to renal disease responded equally well to furosemide therapy.

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.

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.

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.

The mass spectrometric identification of dipeptides in the urine of a patient suffering from chronic skin ulceration and oedema.

The identification of a complex ninhydrin positive mixture present in the urine of a child suffering from chronic skin ulceration and oedema by direct chemical ionisation mass spectrometric analysis is described. The compounds were shown to be dipeptides, of which glycylproline was the major constituent. At least 15 dipeptides were identified in the urine, most of which contained proline or hydroxyproline in the carboxy terminal position. The results suggested that the patient suffered from a defect in collagen metabolism. This hypothesis was subsequently confirmed by a grossly diminished level of prolidase in cultured fibroblasts and erythrocytes.

Influence of cardiac function on the diuretic and hemodynamic effects of the loop diuretic piretanide.

The influence of cardiac function on the diuretic and hemodynamic effects of the loop diuretic piretanide was investigated in nine patients with congestive heart failure. The diuretic response to piretanide correlated significantly with the pretreatment cardiac index (r = 0.90). Furthermore, a significant correlation was found between the pretreatment fractional sodium excretion and the cardiac index (r = 0.85). The fractional sodium excretion is reciprocal to the renal sodium and water reabsorption. No change in the hemodynamics was observed prior to the onset of diuresis. At 120 minutes after administration of piretanide, the reduction of mean pulmonary capillary wedge pressure (r = 0.88) and mean right atrial pressure (r = 0.80) was significantly related to the diuretic response. We conclude that the reduced diuretic response to piretanide in patients with low cardiac index is due to increased renal sodium and water reabsorption. The hemodynamic changes following the administration of piretanide are dependent on the diuresis.

Udder edema in cattle: effects of diuretics (furosemide, hydrochlorothiazide, acetazolamide, and 50% dextrose) on serum and urine electrolytes.

Blood and urine chemical values at parturition in clinically normal Holstein cows (n = 12) were compared with the same values in Holstein cows developing udder edema (n = 12). There was no statistically significant mean difference between the 2 groups for the serum and urine chemical data. Furosemide (500 mg) given IV caused a significant increase in serum calcium and sodium, urine chloride, potassium, and sodium, and fractional excretional ratio of chloride, potassium, and sodium. There was a significant mean decrease in the serum potassium, urine creatinine, osmolality, pH, and specific gravity. Hydrochlorothiazide (250 mg) given IV caused a significant mean increase in serum chloride, urine chloride, potassium, and sodium, and fractional excretion ratio of chloride, potassium, and sodium. There was a significant mean decrease in serum potassium and sodium, urine osmolality, pH, and specific gravity. Acetazolamide (500 mg) given IV caused a significant mean increase in blood urea nitrogen, serum chloride and glucose, urine sodium, and fractional excretion ratio of sodium, while causing a significant mean decrease in serum potassium, sodium, and phosphorus, and urine creatinine. Dextrose (500 g) given IV as a 50% solution caused a statistical mean increase in serum glucose, urine chloride, potassium, and sodium, and fractional excretion ratio of chloride and potassium. A statistical mean decrease occurred in the packed cell volume, blood urea nitrogen, serum calcium, potassium, sodium, and phosphorus, urine creatinine, osmolality, and pH.