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New insights into the pathophysiology of oedema in nephrotic syndrome

New insights into the pathophysiology of oedema in nephrotic syndrome

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11/05/2012

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short reviews
148
http://www.revistanefrologia.com
 © 2011 Revista Nefrología. Official Publication of the Spanish Nephrology Society
New insights into the pathophysiology of oedemain nephrotic syndrome
H. Rondon-Berrios
Division of Nephrology. Department of Internal Medicine. University of New Mexico School of Medicine.Albuquerque, New Mexico (USA)
Nefrologia 2011;31(2):148-54
doi:10.3265/Nefrologia.pre2010.Nov.10724
Correspondence:
Helbert Rondon-Berrios
Division of Nephrology. Department of Internal Medicine.University of New Mexico School of Medicine, ACC 5. MSC10 5550.1 University of New Mexico, 87131-0001.Albuquerque, New Mexico, USA.HRondon@salud.unm.edu
Avances en la fisiopatología del edema en el síndrome nefrótico RESUMEN 
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 underfill 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 independientde 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. Lactivación 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.
Palabras clave: 
Edema. Síndrome nefrótico. Hipoalbuminemia.Canal epitelial de sodio. Plasmina.
ABSTRACT
Oedema is a common clinical manifestation of nephroticsyndrome. However, the pathophysiological mechanism ofsodium retention in nephrotic syndrome has been intenselydebated for decades. Several clinical and experimental obser-vations argue against the classic or "underfill" hypothesis ofoedema formation in nephrotic syndrome. In many patients,oedema formation in nephrotic syndrome is due to the kid-ney being intrinsically unable to excrete salt and is unrelatedto systemic factors (i.e. hypoalbuminaemia, decreased “effec-tivearterial blood volume, and secondary hyperaldostero-nism). The cortical collecting duct is the nephron site of so-dium retention in nephrotic syndrome. Activation of theepithelial sodium channel in the cortical collecting duct is res-ponsible for sodium retention in nephrotic syndrome. Innephrotic syndrome, a defective glomerular filtration barrierallows the passage of proteolytic enzymes or their precursors,which have the ability to activate the epithelial sodium chan-nel, thereby causing the the subsequent sodium retentionand oedema.
Keywords:
Oedema. Nephrotic syndrome. Hypoalbuminemia.Epithelial sodium channel. Plasmin
INTRODUCTION
Oedema isdefined as the accumulation of fluid in theinterstitial space and is a frequent clinical manifestation of nephrotic syndrome (NS). However, its pathophysiologyhas been under considerable debate for decades. Theclassic hypothesis, also called the
underfill
hypothesis,postulates that sodium retention in NS is secondary todecreased effective arterial blood volume, hence the term
underfill
. The hypothesis suggests the following sequenceof events (Figure 1): urinary loss of proteins in NS,especially albumin, causing hypoalbuminaemia, whichin turn causes a decrease in plasma oncotic pressure.This decrease in plasma oncotic pressure would thencause an imbalance in Starling forces, resulting in the
 
short reviews
149
H. Rondon-Berrios.Oedema in nephrotic syndrome
Nefrologia 2011;31(2):148-54
movement of fluid from the intravascular space to theinterstitial space, causing a decrease in effective arterialblood volume and consequently, relative hypovolaemia.This would then result in activation of the renin-angiotensin-aldosterone and sympathetic nervoussystems, increased antidiuretic hormone release andinhibition of atrial natriuretic peptide release. Activationof these systems would cause sodium and waterretention in the kidneys, with subsequent oedema.However, several experimental and clinical observationsmade over the years do not support this hypothesis.
EXPERIMENTAL AND CLINICAL OBSERVATIONSAGAINST THE UNDERFILL HYPOTHESIS
1,2
(Table 1)
Patients and laboratory rats with low serumalbumin levels do not develop oedema or sodiumretention
Joles et al
3
measured the plasma and interstitial oncoticpressure of Nagase rats, which are mutant ratscharacterised by analbuminaemia. The researchers foundno signs of sodium retention in those animals.Furthermore, Lecomte et al
4
carried out observations onpatients with congenital analbuminaemia and found thatmost had no oedema. Many other published series of patients with congenital analbuminaemia do not report theappearance of oedema as the main symptom.
5
Steyl et al
6
studied 50 patients hospitalised in a general medical wardin South Africa and noted that 24 patients had a serumalbumin level lower than 3.5g/dl, mostly associated withchronic inflammation (tuberculosis). Of these 24 patients,
Figure 1.
Classic or underfill hypothesis of oedema formationin nephrotic syndrome.
Table 1.
Arguments against the underfill hypothesisofoedema formation in nephrotic syndrome
1.Patients and laboratory rats with low serum albumin levelsdo not develop oedema or sodium retention.2.Natriuresis in the recovery phase of nephrotic syndromebegins when proteinuria disappears but before serumalbumin returns to normal levels.3.The absolute decrease in plasma oncotic pressure does notaffect the volume of the intravascular space in nephroticsyndrome.4.Plasma and blood volumes are normal or increased innephrotic syndrome.5.Intravascular space expansion with albumin does notincrease natriuresis in patients with nephrotic syndrome.6.The activation of the renin-angiotensin-aldosterone systemis not involved in the development of oedema in nephroticsyndrome.7.Bilateral adrenalectomy does not prevent sodium retentionin nephrotic syndrome in laboratory rats.Nephrotic syndromeAlbuminuriaHypoalbuminaemiaReduction in plasma oncotic pressureTranslocation of fluid from the intravascular spaceto the interstitial spaceDecrease in effective arterial blood volume
Renin-angiotensin-aldosterone system
Sympathetic nervous system
Arginine-vasopressin
Atrial natriuretic peptideSodium and water retention by the kidneyOedema
 
short reviews
150
H. Rondon-Berrios.Oedema in nephrotic syndrome
Nefrologia 2011;31(2):148-54
only six had oedema. These six patients with oedema hadan alternative diagnosis that clearly explained the presenceof oedema (
cor pulmonale
). During the study, they foundsome patients with serum albumin levels below 1.5g/dl,but none of them had oedema.
Natriuresis in the recovery phase of nephroticsyndrome begins when proteinuria disappears butbefore serum albumin returns to normal levels
7
The absolute decrease in plasma oncotic pressuredoes not affect the volume of the intravascularspace in nephrotic syndrome
Studies performed on dogs suggest that the absolutedecrease in plasma oncotic pressure would not affectplasma or blood volume.
8
Patients with NS caused byglomerulonephritis were studied by measuring theirplasma and interstitial oncotic pressure: 12 patients in theactive phase, 3 in complete remission and 3 in partialremission.
9
The researchers found that plasma andinterstitial oncotic pressure were decreased in the activephase of NS but slowly returned to normal values duringremission. During this time, the oncotic pressure gradientbetween plasma and interstitium was constant.
9
Thesestudies show that it is the change in the oncotic pressuregradient between plasma and interstitium and not just theabsolute decrease in plasma oncotic pressure that causesthe movement of fluid from the intravascular to theinterstitial space.
Plasma and blood volumes are normal or increasedin nephrotic syndrome
Geers et al
10
measured plasma volumes in 88 patients withNS and in 51 controls. Plasma volume was measured byadministration of radioactive albumin I.
131
Blood volumewas calculated based on plasma volume and haematocrit.The plasma and blood volume of NS patients was foundto be high in 14%, normal in 84% and low in only 2% of cases.
Intravascular space expansion with albumin doesnot increase natriuresis in patients with nephroticsyndrome
The effect of an intravenous infusion of hyperoncoticalbumin (75g) was observed in patients with NS.
11
Afterthe infusion, blood volume increased up to 120% of baseline. Plasma renin activity and serum aldosteroneconcentration decreased to the point of beingsuppressed. Urinary sodium excretion did not changesignificantly.
The activation of the renin-angiotensin-aldosteronesystem is not involved in the development ofoedema in nephrotic syndrome
Brown et al
12,
administered captopril to a group of NSpatients and observed no change in sodium excretion despitesuppressing serum aldosterone concentrations. In anotherstudy, Usberti et al
13
reported similar findings when usingspironolactone.
Adrenalectomy does not prevent sodium retentionand the development of ascites in nephroticsyndrome in laboratory rats
De Seigneux et al studied a group of rats from which theyhad removed both adrenal glands. The rats wereadministered dexamethasone to prevent adrenal failure.
14
Theresearchers induced NS in the rats by administeringpuromycin. The rats developed oedema and sodium retentiondespite having been adrenalectomised. These findingssuggest that aldosterone does not play a major role in sodiumretention that is characteristic of NS.
ALTERNATIVE HYPOTHESIS OR
OVERFILL
HYPOTHESIS OF OEDEMA FORMATION INNEPHROTIC SYNDROME
Contrary to the classic hypothesis, the alternative hypothesis(also called the
overfill
hypothesis) postulates that sodiumretention in many NS patients is a primary renalphenomenon and may be caused by an intrinsic renal defectin sodium excretion, which in turn causes an expansion inplasma volume (hence the term
overfill
). Although themolecular mechanism of sodium retention in the kidneys hasnot been clearly explained, there are a number of studies onthis topic, which we describe below.
Molecular mechanisms of sodium retentionin nephrotic syndrome
The first observations supporting the
overfill
hypothesiswere made by Chandra
15
and Ichikawa.
16
Most of ourunderstanding of the molecular mechanisms of sodiumretention in NS has come from the use of animal models thatinduced NS by puromycin aminonucleoside (PAN). WhenPAN is administered to rats, it causes massive proteinuriaand sodium retention. The renal histopathology induced byPAN resembles minimal change disease.
17-19
Using thetechnique of selective unilateral perfusion through the leftrenal artery with PAN first described by Bricker in dogs
20
and later by Hoyer in rats,
21
Chandra
15
and Ichikawa
16
showedthat proteinuria and sodium retention were confined to thekidney perfused with PAN. The unilateral NS model allows

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