New insights into the pathophysiology of oedema in nephrotic syndrome
Avances en la fisiopatología del edema en el síndrome nefrótico
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Valdivielso" "autores" => array:1 [ 0 => array:2 [ "Iniciales" => "J.M." "apellidos" => "Valdivielso" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "X0211699511051711" "doi" => "10.3265/Nefrologia.pre2010.Nov.10754" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0211699511051711?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251411051719?idApp=UINPBA000064" "url" => "/20132514/0000003100000002/v0_201502091641/X2013251411051719/v0_201502091641/en/main.assets" ] "en" => array:14 [ "idiomaDefecto" => true "titulo" => "New insights into the pathophysiology of oedema in nephrotic syndrome" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "148" "paginaFinal" => "154" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "H. Rondon-Berrios" "autores" => array:2 [ 0 => null 1 => array:4 [ "Iniciales" => "H." "apellidos" => "Rondon-Berrios" "email" => array:1 [ 0 => "hrondon@salud.unm.edu" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:3 [ "entidad" => "Division of Nephrology. Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, Nuevo México, EEUU, " "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Avances en la fisiopatología del edema en el síndrome nefrótico" ] ] "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">INTRODUCTION </span></p><p class="elsevierStylePara">Oedema is defined as the accumulation of fluid in the interstitial space and is a frequent clinical manifestation of nephrotic syndrome (NS). However, its pathophysiology has been under considerable debate for decades. The classic hypothesis, also called the <span class="elsevierStyleItalic">underfill </span>hypothesis, postulates that sodium retention in NS is secondary to decreased effective arterial blood volume, hence the term <span class="elsevierStyleItalic">underfill</span>. The hypothesis suggests the following sequence of events (Figure 1): urinary loss of proteins in NS, especially albumin, causing hypoalbuminaemia, which in turn causes a decrease in plasma oncotic pressure. This decrease in plasma oncotic pressure would then cause an imbalance in Starling forces, resulting in the movement of fluid from the intravascular space to the interstitial space, causing a decrease in effective arterial blood volume and consequently, relative hypovolaemia. This would then result in activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, increased antidiuretic hormone release and inhibition of atrial natriuretic peptide release. Activation of these systems would cause sodium and water retention in the kidneys, with subsequent oedema. However, several experimental and clinical observations made over the years do not support this hypothesis.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">EXPERIMENTAL AND CLINICAL OBSERVATIONS AGAINST THE UNDERFILL HYPOTHESIS</span><span class="elsevierStyleBold"><span class="elsevierStyleSup">1,2 </span></span>(Table 1)</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Patients and laboratory rats with low serum albumin levels do not develop oedema or sodium retention </span></p><p class="elsevierStylePara">Joles et al<span class="elsevierStyleSup">3 </span>measured the plasma and interstitial oncotic pressure of Nagase rats, which are mutant rats characterised by analbuminaemia. The researchers found no signs of sodium retention in those animals. Furthermore, Lecomte et al<span class="elsevierStyleSup">4 </span>carried out observations on patients with congenital analbuminaemia and found that most had no oedema. Many other published series of patients with congenital analbuminaemia do not report the appearance of oedema as the main symptom.<span class="elsevierStyleSup">5 </span>Steyl et al<span class="elsevierStyleSup">6 </span>studied 50 patients hospitalised in a general medical ward in South Africa and noted that 24 patients had a serum albumin level lower than 3.5g/dl, mostly associated with chronic inflammation (tuberculosis). Of these 24 patients, only six had oedema. These six patients with oedema had an alternative diagnosis that clearly explained the presence of oedema (<span class="elsevierStyleItalic">cor pulmonale</span>). During the study, they found some patients with serum albumin levels below 1.5g/dl, but none of them had oedema.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Natriuresis in the recovery phase of nephrotic syndrome begins when proteinuria disappears but before serum albumin returns to normal levels</span><span class="elsevierStyleBold"><span class="elsevierStyleSup">7 </span></span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">The absolute decrease in plasma oncotic pressure does not affect the volume of the intravascular space in nephrotic syndrome </span></p><p class="elsevierStylePara">Studies performed on dogs suggest that the absolute decrease in plasma oncotic pressure would not affect plasma or blood volume.<span class="elsevierStyleSup">8 </span>Patients with NS caused by glomerulonephritis were studied by measuring their plasma and interstitial oncotic pressure: 12 patients in the active phase, 3 in complete remission and 3 in partial remission.<span class="elsevierStyleSup">9 </span>The researchers found that plasma and interstitial oncotic pressure were decreased in the active phase of NS but slowly returned to normal values during remission. During this time, the oncotic pressure gradient between plasma and interstitium was constant.<span class="elsevierStyleSup">9 </span>These studies show that it is the change in the oncotic pressure gradient between plasma and interstitium and not just the absolute decrease in plasma oncotic pressure that causes the movement of fluid from the intravascular to the interstitial space.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Plasma and blood volumes are normal or increased in nephrotic syndrome </span></p><p class="elsevierStylePara">Geers et al<span class="elsevierStyleSup">10 </span>measured plasma volumes in 88 patients with NS and in 51 controls. Plasma volume was measured by administration of radioactive albumin I.<span class="elsevierStyleSup">131 </span>Blood volume was calculated based on plasma volume and haematocrit. The plasma and blood volume of NS patients was found to be high in 14%, normal in 84% and low in only 2% of cases.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Intravascular space expansion with albumin does not increase natriuresis in patients with nephrotic syndrome </span></p><p class="elsevierStylePara">The effect of an intravenous infusion of hyperoncotic albumin (75g) was observed in patients with NS.<span class="elsevierStyleSup">11 </span>After the infusion, blood volume increased up to 120% of baseline. Plasma renin activity and serum aldosterone concentration decreased to the point of being suppressed. Urinary sodium excretion did not change significantly.</p><p class="elsevierStylePara"><span class="elsevierStyleBold">The activation of the renin-angiotensin-aldosterone system is not involved in the development of oedema in nephrotic syndrome </span></p><p class="elsevierStylePara">Brown et al<span class="elsevierStyleSup">12, </span>administered captopril to a group of NS patients and observed no change in sodium excretion despite suppressing serum aldosterone concentrations. In another study, Usberti et al<span class="elsevierStyleSup">13 </span>reported similar findings when using spironolactone.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Adrenalectomy does not prevent sodium retention and the development of ascites in nephrotic syndrome in laboratory rats </span></p><p class="elsevierStylePara">De Seigneux et al studied a group of rats from which they had removed both adrenal glands. The rats were administered dexamethasone to prevent adrenal failure.<span class="elsevierStyleSup">14 </span>The researchers induced NS in the rats by administering puromycin. The rats developed oedema and sodium retention despite having been adrenalectomised. These findings suggest that aldosterone does not play a major role in sodium retention that is characteristic of NS.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">ALTERNATIVE HYPOTHESIS OR </span><span class="elsevierStyleBold"><span class="elsevierStyleItalic">OVERFILL</span></span><span class="elsevierStyleBold">HYPOTHESIS OF OEDEMA FORMATION IN NEPHROTIC SYNDROME </span></p><p class="elsevierStylePara">Contrary to the classic hypothesis, the alternative hypothesis (also called the <span class="elsevierStyleItalic">overfill </span>hypothesis) postulates that sodium retention in many NS patients is a primary renal phenomenon and may be caused by an intrinsic renal defect in sodium excretion, which in turn causes an expansion in plasma volume (hence the term <span class="elsevierStyleItalic">overfill</span>). Although the molecular mechanism of sodium retention in the kidneys has not been clearly explained, there are a number of studies on this topic, which we describe below.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Molecular mechanisms of sodium retention in nephrotic syndrome </span></p><p class="elsevierStylePara">The first observations supporting the <span class="elsevierStyleItalic">overfill </span>hypothesis were made by Chandra<span class="elsevierStyleSup">15 </span>and Ichikawa.<span class="elsevierStyleSup">16 </span>Most of our understanding of the molecular mechanisms of sodium retention in NS has come from the use of animal models that induced NS by puromycin aminonucleoside (PAN). When PAN is administered to rats, it causes massive proteinuria and sodium retention. The renal histopathology induced by PAN resembles minimal change disease.<span class="elsevierStyleSup">17-19 </span>Using the technique of selective unilateral perfusion through the left renal artery with PAN first described by Bricker in dogs<span class="elsevierStyleSup">20 </span>and later by Hoyer in rats,<span class="elsevierStyleSup">21 </span>Chandra<span class="elsevierStyleSup">15 </span>and Ichikawa<span class="elsevierStyleSup">16 </span>showed that proteinuria and sodium retention were confined to the kidney perfused with PAN. The unilateral NS model allows the study of a proteinuric kidney and a control kidney in the same animal. It must be emphasised that the sodium retention by the kidney perfused with PAN occurred without a reduction in plasma protein concentration, suggesting that the sodium retention observed in NS was due to an intrinsic renal defect in sodium excretion rather than due to extrinsic or systemic factors such as hypoalbuminaemia.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">The cortical collecting tubule is the reabsorption point for sodium in nephrotic syndrome </span></p><p class="elsevierStylePara">Ichikawa<span class="elsevierStyleSup">16 </span>also performed micropuncture studies of superficial nephron tubular segments in the unilateral NS model in rats, and showed that the amount of sodium at the end of the distal convoluted tubule is the same in the proteinuric kidney as in the normal kidney. The final urine of the nephrotic kidney, however, contained three times less sodium than the urine from the normal kidney, suggesting that stimulation of sodium reabsorption in the NS occurs in the cortical collecting tubule.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">The role of NHE3 in sodium retention in the NS </span></p><p class="elsevierStylePara">Despite the findings of Ichikawa et al, other studies have postulated that sodium retention in NS may occur in other nephron segments. Sixty-six percent of sodium filtered by the glomerulus is reabsorbed in the proximal tubule by the action of the Na-H cotransporter (NHE3). It would be reasonable then to assume that this segment would, at least in part, contribute to the sodium retention observed in NS. Besse-Eschmann et al<span class="elsevierStyleSup">22 </span>found that NHE3 activity (normalised to the amount of protein) was increased by 88% in rats treated with PAN, compared to control rats. NHE3 is present at two locations of the proximal tubular brush border, forming oligomers: <span class="elsevierStyleItalic">1) </span>in the intervillous space, where it is associated with the megalin receptor (a protein responsible for the reabsorption of albumin and other substances filtered by the glomerulus), representing the inactive form of NHE3, and <span class="elsevierStyleItalic">2) </span>in the microvillous space, where it is free and represents the active form of the transporter.<span class="elsevierStyleSup">23 </span>The researchers also found that in rats treated with PAN there was NHE3 movement from the intervillous space to the microvillus space.<span class="elsevierStyleSup">22 </span>They suggested that albumin filtered by the NS’s defective glomerular barrier could dissociate NHE3 from megalin and increase movement of NHE3 to the microvilli so that it might perform its sodium retention function from there.<span class="elsevierStyleSup">22 </span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">The role of the Na</span><span class="elsevierStyleBold"><span class="elsevierStyleSup">+</span></span><span class="elsevierStyleBold">/K</span><span class="elsevierStyleBold"><span class="elsevierStyleSup">+</span></span><span class="elsevierStyleBold">-ATPase pump in sodium retention in nephrotic syndrome </span></p><p class="elsevierStylePara">Another sodium transporter that has been reported to be involved in sodium retention in NS is the Na<span class="elsevierStyleSup">+</span>/K<span class="elsevierStyleSup">+</span>-ATPase pump. Deschenes et al<span class="elsevierStyleSup">24 </span>found that the activity of this pump was increased in rats treated with PAN when compared to control rats. These authors also observed that the increase in pump activity was confined to the cortical collecting tubule.<span class="elsevierStyleSup">24 </span>However, many subsequent studies have shown that, in rats treated with PAN, the activity of this pump and other sodium transporters (such as NHE3) is decreased when compared to control rats.<span class="elsevierStyleSup">25 </span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">The role of ENaC in sodium retention in nephrotic syndrome </span></p><p class="elsevierStylePara">Another sodium transporter that has been reported to be strongly involved in sodium retention in NS is the epithelial sodium channel or amiloride-sensitive sodium channel (ENaC). ENaC is composed of three subunits: α, β, and γ. The first studies conducted on the role of ENaC in sodium retention in NS showed that there was no increase in protein expression (nor mRNA) of any of the three subunits of ENaC in rats treated with PAN when compared to control rats.<span class="elsevierStyleSup">26 </span>However, subsequent studies have shown an increase in protein expression of the three subunits of ENaC,<span class="elsevierStyleSup">14,25 </span>as well as an increase in the movement of these subunits from the cytosol to the apical plasma membrane.</p><p class="elsevierStylePara">ENaC is regulated by several factors, one of which is the enzyme 11-β-hydroxysteroid dehydrogenase type 2 (11βHSD2). Mineralocorticoid receptor activation causes an increase in ENaC activity by increasing expression of the gene that encodes the ENaC α subunit and a decrease in its intracellular recycling system mediated by the ubiquitin ligase Nedd4-2.<span class="elsevierStyleSup">27 </span>Cortisol has the same affinity as aldosterone to the mineralocorticoid receptor. However, aldosterone acts as the sole agonist of this receptor even though the concentration of cortisol in plasma is 100 times the concentration of aldosterone. The 11βHSD2 enzyme usually protects the mineralocorticoid receptor from cortisol activation by locally transforming it into cortisone, which is inactive on this receptor. Nevertheless, in pathological states such as in the syndrome of apparent mineralocorticoid excess, the activity of the 11βHSD2 enzyme is reduced, allowing the cortisol to activate the mineralocorticoid receptor and cause sodium retention.<span class="elsevierStyleSup">28 </span>A study by Kim et al<span class="elsevierStyleSup">29 </span>showed that the activity of the 11βHSD2 enzyme is reduced in rats with NS caused by mercuric chloride-induced membranous nephropathy when compared to control rats, which may explain the sodium retention in these animals. However, other studies have not confirmed these findings.<span class="elsevierStyleSup">14,30 </span></p><p class="elsevierStylePara">Another important factor in the regulation of ENaC is the group of serine proteases. These are a group of proteolytic enzymes that cleave the α and γ ENaC subunits in specific sites and thereby increase sodium conductance through the channel.<span class="elsevierStyleSup">31,32 </span>Under experimental conditions, sodium conductance is low in ENaC that has not been exposed to proteolysis by serine proteases. The first step in ENaC activation by serine proteases occurs in the Golgi complex, where a protease called furin cleaves the α subunit at the R205 and R231 sites (thus releasing an inhibitory peptide of 26 amino acids) and the γ subunit at the R143 site.<span class="elsevierStyleSup">33 </span>If this ENaC conductance were measured under experimental conditions, it would be intermediate. After this enzymatic process, the channel is assembled in the apical plasma membrane. For ENaC to be completely active and have high sodium conductance, it must be activated by a second protease (such as prostasin, neutrophil elastase or pancreatic elastase).<span class="elsevierStyleSup">34 </span></p><p class="elsevierStylePara">The first observations on ENaC activation by serine proteases in proteinuric states were made by Kastner et al.<span class="elsevierStyleSup">35 </span>Passero et al<span class="elsevierStyleSup">36 </span>found that ENaC currents increased when ENaC was exposed to plasmin, suggesting that plasmin acts as a second protease and is capable of activating ENaC. Passero<span class="elsevierStyleSup">36 </span>also discovered that plasmin activates ENaC by cleaving the γ subunit at the K194 site.</p><p class="elsevierStylePara">Perhaps the most convincing evidence to date about the role of serine proteases in ENaC activation in NS is the recently published report by Svenningsen et al.<span class="elsevierStyleSup">37 </span>They found that urine in nephrotic rats treated with PAN increased the ENaC currents and that amiloride abolished them. Svenningsen et al investigated why the urine of these nephrotic rats activated ENaC and found that the ENaC currents were abolished when ENaC was exposed to aprotinin, a known inhibitor of serine proteases. Another important observation was that the urine of nephrotic rats did not increase ENaC currents when subjected to heat. When serine protease activity in this urine was measured, it was found to be high. All these findings suggest that the urine of nephrotic rats contains a serine protease capable of activating ENaC.<span class="elsevierStyleSup">37 </span>Several previous studies performed on NS patients have documented the presence of plasminogen in the urine of these patients.<span class="elsevierStyleSup">38,39 </span>After several purification steps and mass spectrometry (MALDI-TOF), Svenningsen et al found that plasminogen and/or plasmin were the serine proteases responsible for ENaC activation in the urine of nephrotic rats. The urine of nephrotic rats contained both substances, but the plasma from these animals only contained plasminogen, suggesting that plasmin was formed in the urine <span class="elsevierStyleItalic">in situ </span>and was not filtered out of the plasma.<span class="elsevierStyleSup">37 </span>Plasmin is known to come from the activation of plasminogen through the enzymatic action of urokinase, which is normally present in the collecting tubule.<span class="elsevierStyleSup">40 </span>Svenningsen et al<span class="elsevierStyleSup">37 </span>observed that the cortical collecting tubule cells of nephrotic rats had urokinase activity. They also observed that while the combination of plasminogen and urokinase increased ENaC currents in oocytes, plasminogen and urokinase were incapable of doing so in isolation.<span class="elsevierStyleSup">37 </span>Another important finding was that amiloride not only blocks ENaC but also blocks the urokinase enzyme responsible for converting plasminogen into plasmin.<span class="elsevierStyleSup">37 </span>Significantly, Svenningsen et al<span class="elsevierStyleSup">37 </span>were able to reproduce all of the previously described results with urine from NS patients. To summarise, the plasminogen present in plasma is probably filtered through NS’s own defective glomerular barrier and is then converted into plasmin by the action of urokinase present in the collecting tubule. Plasmin would then activate ENaC, resulting in sodium retention with the subsequent appearance of oedema (Figure 2).</p><p class="elsevierStylePara"><span class="elsevierStyleBold">The use of amiloride to treat nephrotic oedema </span></p><p class="elsevierStylePara">Treatment of oedema in NS is traditionally based on a low sodium diet (2.3g of sodium a day or 6g of sodium chloride a day) and the use of loop diuretics. Amiloride is a potassium-sparing diuretic and its use has traditionally been restricted to the prevention of hypopotassaemia associated with the use of loop diuretics. However, according to the findings described above, the use of amiloride may play an important role in the treatment of oedema in NS. In our clinical experience, the use of amiloride enhances diuresis caused by loop diuretics. This has been reproduced experimentally<span class="elsevierStyleSup">41 </span>and has also been reported in other clinical studies.<span class="elsevierStyleSup">42 </span>We usually start treatment of nephrotic oedema with a 1mg dose of bumetanide orally twice a day and a 5mg dose of amiloride orally once a day. Amiloride should not be used in isolation but rather in combination with loop diuretics, given that although the collecting tubule plays a key role in sodium retention in NS, in absolute terms it only contributes 4% of total filtered sodium reabsorption.</p><p class="elsevierStylePara"><a href="10724_16025_13031_en_w477710811810724_table_1_engb_js.doc" class="elsevierStyleCrossRefs">10724_16025_13031_en_w477710811810724_table_1_engb_js.doc</a></p><p class="elsevierStylePara">Table 1. Arguments against the hypothesis of underfill oedema formation in nephrotic syndrome</p><p class="elsevierStylePara"><a href="10724_16025_13032_en_w47771081210724_figura_1_en_gb_js.doc" class="elsevierStyleCrossRefs">10724_16025_13032_en_w47771081210724_figura_1_en_gb_js.doc</a></p><p class="elsevierStylePara">Figure 1. Classic or underfill hypothesis of oedema formation in nephrotic syndrome</p><p class="elsevierStylePara"><a href="10724_16025_13034_en_w4777108111010724_figure_2_en_gb_js.doc" class="elsevierStyleCrossRefs">10724_16025_13034_en_w4777108111010724_figure_2_en_gb_js.doc</a></p><p class="elsevierStylePara">Figure 2. Plasmin in the cortical collecting duct activates ENaC</p>" "pdfFichero" => "P1-E518-S2894-A10724-EN.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:5 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441239" "palabras" => array:1 [ 0 => "Plasmin" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441241" "palabras" => array:1 [ 0 => "Epithelial sodium channel" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441243" "palabras" => array:1 [ 0 => "Hypoalbuminemia" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441245" "palabras" => array:1 [ 0 => "Nephrotic syndrome" ] ] 4 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441247" "palabras" => array:1 [ 0 => "Edema" ] ] ] "es" => array:5 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec441240" "palabras" => array:1 [ 0 => "Canal epitelial de sodio" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec441242" "palabras" => array:1 [ 0 => "Hipoalbuminemia" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec441244" "palabras" => array:1 [ 0 => "Síndrome nefrótico" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec441246" "palabras" => array:1 [ 0 => "Edema" ] ] 4 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec441248" "palabras" => array:1 [ 0 => "Plasmina" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:1 [ "resumen" => "<p class="elsevierStylePara">Oedema is a common clinical manifestation of nephrotic syndrome. However, the pathophysiological mechanism of sodium retention in nephrotic syndrome has been intensely debated for decades. Several clinical and experimental observations argue against the classic or "underfill" hypothesis of oedema formation in nephrotic syndrome. In many patients, oedema formation in nephrotic syndrome is due to the kidney being intrinsically unable to excrete salt and is unrelated to systemic factors (i.e. hypoalbuminaemia, decreased “effective” arterial blood volume, and secondary hyperaldosteronism). The cortical collecting duct is the nephron site of sodium retention in nephrotic syndrome. Activation of the epithelial sodium channel in the cortical collecting duct is responsible for sodium retention in nephrotic syndrome. In nephrotic syndrome, a defective glomerular filtration barrier allows the passage of proteolytic enzymes or their precursors, which have the ability to activate the epithelial sodium channel, thereby causing the the subsequent sodium retention and oedema.</p>" ] "es" => array:1 [ "resumen" => "<p class="elsevierStylePara">El edema es una manifestación clínica frecuente del síndrome nefrótico (SN); sin embargo, el mecanismo fisiopatológico responsable de la retención de sodio ha sido un tema de intenso debate durante décadas. Muchas observaciones clínicas y experimentales no apoyan a la hipótesis clásica o del <span class="elsevierStyleItalic">underfill</span> en la formación del edema nefrótico. En numerosos pacientes, el edema propio del SN se produce por un defecto renal intrínseco en la excreción de sodio y es independiente de factores sistémicos (p. ej., hipoalbuminemia, disminución del volumen arterial efectivo o hiperaldosteronismo secundario). El punto de la nefrona donde se produce la retención de sodio en el SN es el túbulo colector cortical. La activación del canal de sodio epitelial a ese nivel es responsable de la retención de sodio en la patología que nos ocupa. Una barrera glomerular defectuosa propia del SN permitiría el paso de enzimas proteolíticas o sus precursores que a su vez activarían el canal de sodio epitelial causando de esa manera su retención y consiguiente edema.</p>" ] ] "multimedia" => array:3 [ 0 => array:8 [ "identificador" => "mmc1" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "Ecomponente" => array:2 [ "fichero" => "10724_16025_13031_en_w477710811810724_table_1_engb_js.doc" "ficheroTamanyo" => 30720 ] "descripcion" => array:1 [ "en" => "Arguments against the hypothesis of underfill oedema formation in nephrotic syndrome" ] ] 1 => array:8 [ "identificador" => "mmc2" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "Ecomponente" => array:2 [ "fichero" => "10724_16025_13032_en_w47771081210724_figura_1_en_gb_js.doc" "ficheroTamanyo" => 24064 ] "descripcion" => array:1 [ "en" => "Classic or underfill hypothesis of oedema formation in nephrotic syndrome" ] ] 2 => array:8 [ "identificador" => "mmc3" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "Ecomponente" => array:2 [ "fichero" => "10724_16025_13034_en_w4777108111010724_figure_2_en_gb_js.doc" "ficheroTamanyo" => 599040 ] "descripcion" => array:1 [ "en" => "Plasmin in the cortical collecting duct activates ENaC" ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:43 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "\u{A0}" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 1 => array:3 [ "identificador" => "bib2" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Deschenes G, Guigonis V, Doucet A. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 45 | 11 | 56 |
| 2024 October | 367 | 129 | 496 |
| 2024 September | 491 | 116 | 607 |
| 2024 August | 472 | 137 | 609 |
| 2024 July | 496 | 62 | 558 |
| 2024 June | 431 | 109 | 540 |
| 2024 May | 378 | 103 | 481 |
| 2024 April | 371 | 67 | 438 |
| 2024 March | 351 | 70 | 421 |
| 2024 February | 223 | 43 | 266 |
| 2024 January | 296 | 40 | 336 |
| 2023 December | 299 | 46 | 345 |
| 2023 November | 393 | 53 | 446 |
| 2023 October | 474 | 109 | 583 |
| 2023 September | 369 | 80 | 449 |
| 2023 August | 259 | 92 | 351 |
| 2023 July | 304 | 65 | 369 |
| 2023 June | 322 | 81 | 403 |
| 2023 May | 333 | 102 | 435 |
| 2023 April | 175 | 68 | 243 |
| 2023 March | 256 | 41 | 297 |
| 2023 February | 268 | 50 | 318 |
| 2023 January | 157 | 77 | 234 |
| 2022 December | 196 | 53 | 249 |
| 2022 November | 281 | 57 | 338 |
| 2022 October | 255 | 87 | 342 |
| 2022 September | 213 | 68 | 281 |
| 2022 August | 272 | 94 | 366 |
| 2022 July | 224 | 80 | 304 |
| 2022 June | 254 | 60 | 314 |
| 2022 May | 356 | 64 | 420 |
| 2022 April | 348 | 76 | 424 |
| 2022 March | 315 | 85 | 400 |
| 2022 February | 241 | 57 | 298 |
| 2022 January | 251 | 50 | 301 |
| 2021 December | 185 | 50 | 235 |
| 2021 November | 246 | 60 | 306 |
| 2021 October | 206 | 60 | 266 |
| 2021 September | 153 | 53 | 206 |
| 2021 August | 191 | 48 | 239 |
| 2021 July | 150 | 40 | 190 |
| 2021 June | 134 | 34 | 168 |
| 2021 May | 180 | 52 | 232 |
| 2021 April | 406 | 64 | 470 |
| 2021 March | 299 | 65 | 364 |
| 2021 February | 166 | 33 | 199 |
| 2021 January | 150 | 28 | 178 |
| 2020 December | 189 | 31 | 220 |
| 2020 November | 160 | 19 | 179 |
| 2020 October | 77 | 30 | 107 |
| 2020 September | 147 | 13 | 160 |
| 2020 August | 78 | 39 | 117 |
| 2020 July | 103 | 15 | 118 |
| 2020 June | 147 | 17 | 164 |
| 2020 May | 148 | 20 | 168 |
| 2020 April | 243 | 46 | 289 |
| 2020 March | 206 | 27 | 233 |
| 2020 February | 209 | 40 | 249 |
| 2020 January | 201 | 33 | 234 |
| 2019 December | 241 | 49 | 290 |
| 2019 November | 308 | 47 | 355 |
| 2019 October | 256 | 37 | 293 |
| 2019 September | 316 | 35 | 351 |
| 2019 August | 243 | 45 | 288 |
| 2019 July | 187 | 32 | 219 |
| 2019 June | 253 | 20 | 273 |
| 2019 May | 221 | 27 | 248 |
| 2019 April | 308 | 77 | 385 |
| 2019 March | 194 | 46 | 240 |
| 2019 February | 113 | 36 | 149 |
| 2019 January | 113 | 44 | 157 |
| 2018 December | 197 | 69 | 266 |
| 2018 November | 180 | 61 | 241 |
| 2018 October | 169 | 42 | 211 |
| 2018 September | 127 | 38 | 165 |
| 2018 August | 78 | 27 | 105 |
| 2018 July | 78 | 13 | 91 |
| 2018 June | 74 | 17 | 91 |
| 2018 May | 68 | 17 | 85 |
| 2018 April | 93 | 12 | 105 |
| 2018 March | 62 | 11 | 73 |
| 2018 February | 73 | 6 | 79 |
| 2018 January | 59 | 17 | 76 |
| 2017 December | 70 | 12 | 82 |
| 2017 November | 82 | 17 | 99 |
| 2017 October | 81 | 19 | 100 |
| 2017 September | 74 | 18 | 92 |
| 2017 August | 86 | 25 | 111 |
| 2017 July | 61 | 14 | 75 |
| 2017 June | 81 | 16 | 97 |
| 2017 May | 94 | 20 | 114 |
| 2017 April | 59 | 30 | 89 |
| 2017 March | 62 | 14 | 76 |
| 2017 February | 59 | 13 | 72 |
| 2017 January | 64 | 7 | 71 |
| 2016 December | 119 | 14 | 133 |
| 2016 November | 178 | 18 | 196 |
| 2016 October | 177 | 8 | 185 |
| 2016 September | 190 | 17 | 207 |
| 2016 August | 312 | 12 | 324 |
| 2016 July | 216 | 24 | 240 |
| 2016 June | 157 | 0 | 157 |
| 2016 May | 181 | 0 | 181 |
| 2016 April | 110 | 0 | 110 |
| 2016 March | 112 | 0 | 112 |
| 2016 February | 131 | 0 | 131 |
| 2016 January | 134 | 0 | 134 |
| 2015 December | 126 | 0 | 126 |
| 2015 November | 126 | 0 | 126 |
| 2015 October | 109 | 0 | 109 |
| 2015 September | 98 | 0 | 98 |
| 2015 August | 106 | 0 | 106 |
| 2015 July | 117 | 0 | 117 |
| 2015 June | 80 | 0 | 80 |
| 2015 May | 73 | 0 | 73 |
| 2015 April | 11 | 0 | 11 |
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