The pathophysiology of edema formation in the nephrotic syndrome

The mechanism of edema formation in the nephrotic syndrome has long been a source of controversy. In this review, through the construct of Starling's forces, we examine the roles of albumin, intravascular volume, and neurohormones on edema formation and highlight the evolving literature on the role of primary sodium absorption in edema formation. We propose that a unifying mechanism of sodium retention is present in the nephrotic syndrome regardless of intravascular volume status and is due to the activation of epithelial sodium channel by serine proteases in the glomerular filtrate of nephrotic patients. Finally, we assert that mechanisms in addition to sodium retention are likely operant in the formation of nephrotic edema. The mechanism of edema formation in the nephrotic syndrome has long been a source of controversy. In this review, through the construct of Starling's forces, we examine the roles of albumin, intravascular volume, and neurohormones on edema formation and highlight the evolving literature on the role of primary sodium absorption in edema formation. We propose that a unifying mechanism of sodium retention is present in the nephrotic syndrome regardless of intravascular volume status and is due to the activation of epithelial sodium channel by serine proteases in the glomerular filtrate of nephrotic patients. Finally, we assert that mechanisms in addition to sodium retention are likely operant in the formation of nephrotic edema. Edema is the classic clinical presentation of the nephrotic syndrome. The mechanisms of edema formation in the nephrotic syndrome have long been a subject of investigation and are continually debated. The 'underfill' hypothesis states that a decrement in oncotic pressure leads to excess filtration of fluid from the intravascular space to the interstitial space, causing hypovolemia, renal hypoperfusion, activation of the renin–angiotensin–aldosterone system, and secondary renal sodium retention. The 'overfill' hypothesis states that the nephrotic syndrome causes primary renal sodium retention, leading to edema. The purpose of this review is to describe in detail the state of current knowledge in this area and ultimately to provide a unifying model of edema formation in the nephrotic syndrome. We will individually discuss the contribution of plasma oncotic pressure, the state of intravascular volume, perturbation in hormonal systems, and the role of primary sodium retention by the kidney using the framework provided by Starling: Jv=Kf([Pc–Pi]–σ[πc–πi]) •Jv is the net fluid movement between compartments.•[Pc-Pi]: Capillary-interstitial hydrostatic pressure•σ: reflection coefficient to proteins; which varies between 0 and 1 and reflects in this particular context some attribute of the permeability of capillaries to albumin and other large proteins•[πc-πi]: oncotic pressure (c is capillary and I is interstitial)•Kf=overall filtration permeability constant to volume flow (hydraulic conductivity and includes a term for surface area) Both Kf and σ are measures of vascular permeability. Kf, the product of hydraulic conductance and capillary surface area, is essentially a measure of capillary permeability to volume flow.1.Taylor A.E. Capillary fluid filtration. Starling forces and lymph flow.Circ Res. 1981; 49: 557-575Crossref PubMed Scopus (208) Google Scholar When the capillary is modeled as a surface with many pores, then its hydraulic conductance depends on the number of pores present, the radius of the pores, and the thickness of the capillary wall.1.Taylor A.E. Capillary fluid filtration. Starling forces and lymph flow.Circ Res. 1981; 49: 557-575Crossref PubMed Scopus (208) Google Scholar However, this parameter is not a true constant, rather it is known to increase in response to increases in intravascular pressure2.Baldwin A.L. Wilson L.M. Simon B.R. Effect of pressure on aortic hydraulic conductance.Arterioscler Thromb. 1992; 12: 163-171Crossref PubMed Scopus (53) Google Scholar,3.Knight A.D. Levick J.R. Effect of fluid pressure on the hydraulic conductance of interstitium and fenestrated endothelium in the rabbit knee.J Physiol. 1985; 360: 311-332Crossref PubMed Scopus (22) Google Scholar and hyperglycemia.4.Perrin R.M. Harper S.J. Corrall R. et al.Hyperglycemia stimulates a sustained increase in hydraulic conductivity in vivo without any change in reflection coefficient.Microcirculation. 2007; 14: 683-696Crossref PubMed Scopus (11) Google Scholar Also, σ is some measure of the permeability of the capillary to proteins. A σ value of 1 signifies that a capillary is completely impermeable to proteins, whereas a value of 0 signifies complete permeability to proteins.1.Taylor A.E. Capillary fluid filtration. Starling forces and lymph flow.Circ Res. 1981; 49: 557-575Crossref PubMed Scopus (208) Google Scholar This parameter has been shown to decrease in response to inflammatory mediators such as histamine and bradykinin.5.Carter R.D. Joyner W.L. Renkin E.M. Effects of histamine and some other substances on molecular selectivity of the capillary wall to plasma proteins and dextran.Microvasc Res. 1974; 7: 31-48Crossref PubMed Scopus (87) Google Scholar Although an increase in Kf does not necessarily produce a change in σ,4.Perrin R.M. Harper S.J. Corrall R. et al.Hyperglycemia stimulates a sustained increase in hydraulic conductivity in vivo without any change in reflection coefficient.Microcirculation. 2007; 14: 683-696Crossref PubMed Scopus (11) Google Scholar an decrease in σ (as with an increase in pore size) necessitates an increase in Kf. Further complicating matters is that vascular permeability is calculated rather than directly measured. It is therefore difficult to separate changes in permeability to different substances from current experiments in large part because of the lack of knowledge of the actual path that fluid flow takes across a complex biological structure such as a capillary. For this reason, for the remainder of the review, we will refer to Kf and σ under the general term of vascular permeability. A fundamental aspect of the 'underfill' theory is that a decrement in plasma albumin (and hence oncotic pressure) reduces the intravascular-to-interstitial albumin gradient producing an increase in the driving force for fluid filtration out of the intravascular space into the interstitial space. Several studies have addressed this important issue. Joles6.Joles J.A. Colloid osmotic pressure in young analbuminemic rats.Am J Physiol. 1989; 257: F23-F28PubMed Google Scholar showed that analbuminemic Nagase rats had no difference in transcapillary colloid osmotic pressure gradient when compared with Sprague-Dawley rats of similar age owing to increases in nonalbumin proteins in the Nagase rats. Fiorotto and Coward7.Fiorotto M. Coward W.A. Pathogenesis of oedema in protein-energy malnutrition: the significance of plasma colloid osmotic pressure.Br J Nutr. 1979; 42: 21-31Crossref PubMed Scopus (27) Google Scholar utilized a starvation model of hypoproteinemia to study the driving forces for edema formation in rats. The experiments showed that as serum oncotic pressure decreases there is a parallel decrease in interstitial oncotic pressure of greater magnitude (Figure 1). Also notable was that the normally negative interstitial hydrostatic pressure approached zero at the time of edema formation. For these reasons, despite the decrement in plasma oncotic pressure in the protein malnourished rats, the net driving force for edema formation was not significantly different from control rats. Preservation of the oncotic pressure gradient due to parallel decreases in serum and interstitial oncotic pressures has also been demonstrated in humans with the nephrotic syndrome.8.Koomans H.A. Kortlandt W. Geers A.B. et al.Lowered protein content of tissue fluid in patients with the nephrotic syndrome: observations during disease and recovery.Nephron. 1985; 40: 391-395Crossref PubMed Scopus (50) Google Scholar, 9.Koomans H.A. Geers A.B. Dorhout Mees E.J. et al.Lowered tissue-fluid oncotic pressure protects the blood volume in the nephrotic syndrome.Nephron. 1986; 42: 317-322Crossref PubMed Scopus (32) Google Scholar, 10.Fauchald P. Noddeland H. Norseth J. Interstitial fluid volume, plasma-volume and colloid osmotic-pressure in patients with nephrotic syndrome.Scand J Clin Lab Invest. 1984; 44: 661-667Crossref PubMed Google Scholar Finally, in a review of 21 cases of congenital analbuminemia by Russi and Weigand,11.Russi E. Weigand K. Analbuminemia.Klin Wochenschr. 1983; 61: 541-545Crossref PubMed Scopus (35) Google Scholar 43% had no edema, whereas 38% had only mild ankle edema. Hence, a reduction in the serum to interstitial oncotic pressure gradient due to hypoalbuminemia is not supported by existing data. It has been proposed by Aukland and Nicolaysen12.Aukland K. Nicolaysen G. Interstitial fluid volume: local regulatory mechanisms.Physiol Rev. 1981; 61: 556-643PubMed Google Scholar that two safety factors protect against edema formation in the presence of hypoalbuminemia. An increase in filtration of fluid from the intravascular space to the interstitial space will dilute or 'washdown' the interstitial protein concentration. In addition, an increase in fluid delivery to the interstitial space will produce an increase in lymphatic flow that will 'washout' interstitial proteins by bulk flow. Both washdown and washout, as may occur with loss of fluid from the intravascular to interstitial space in hypoproteinemia, serve to maintain the plasma to interstitial protein ratio close to normal and thus defend against edema. Edema formation would follow when the interstitial protein concentration was reduced to zero and no further reduction could occur in response to further intravascular protein decline. Koomans et al.13.Koomans H.A. Braam B. Geers A.B. et al.The importance of plasma protein for blood volume and blood pressure homeostasis.Kidney Int. 1986; 30: 730-735Abstract Full Text PDF PubMed Scopus (44) Google Scholar studied the influence of colloid osmotic pressure and plasma protein concentration on blood volume and blood pressure in nephrotic patients and those with chronic renal failure who were admitted to the hospital with extracellular fluid volume (ECFV) expansion. As compared with the chronic renal failure patients, the nephrotic patients had significantly lower plasma protein and oncotic pressures and higher hematocrits. An elevation of the ECFV to 300% of normal produced no significant change in blood volume compared with baseline in nephrotic patients; blood pressure similarly was not significantly different. In contrast, the blood volume and blood pressure were significantly elevated in the chronic renal failure patients at an ECFV of 200% above baseline. Thus, the ECFV excess expands both the intravascular and interstitial space in chronic renal failure, whereas the excess is largely confined to the interstitial space in nephrotic patients. The authors hypothesize that nephrotic patients have no edema despite marked hypoproteinemia at normal ECVF because of the protective effects of interstitial protein washdown and washout. They further hypothesize that expansion of the ECFV to 300% of normal does not raise the intravascular volume because the interstitial protein concentration is near zero and no further washdown or washout can occur. In some causes of nephrotic syndrome, particularly due to minimal change disease (MCD), the onset of nephrosis is abrupt and plasma protein levels can decline rapidly. A question then is what, if any, are the effects of acute reductions in plasma oncotic pressure on edema formation? Plasmapheresis with isotonic fluid replacement has been used to produce acute reductions in serum oncotic pressure in order to study the effect of plasma oncotic pressure on blood volume maintenance. Repeated episodes of plasmapheresis to produce moderate levels of hypoproteinemia in dogs (mean 4.6g/dl) led to increased ECFV, no change in blood volume, and stable renin and aldosterone levels, whereas plasmapheresis to severe hypoproteinemia (mean 2.4g/dl) produced a decrease in plasma volume and blood volume, an increase in renin and aldosterone, and a positive sodium balance.14.Manning Jr., R.D. Guyton A.C. Effects of hypoproteinemia on fluid volumes and arterial pressure.Am J Physiol. 1983; 245: H284-H293PubMed Google Scholar, 15.Manning Jr., R.D. Effects of hypoproteinemia on renal hemodynamics, arterial pressure, and fluid volume.Am J Physiol. 1987; 252: F91-F98PubMed Google Scholar, 16.Joles J.A. Koomans H.A. Kortlandt W. et al.Hypoproteinemia and recovery from edema in dogs.Am J Physiol. 1988; 254: F887-F894PubMed Google Scholar Despite the significant decrease in blood and plasma volume, there was a significant increase in sodium space (indicating interstitial fluid volume expansion) in the dogs with severe hypoproteinemia. These studies suggest that severe acute hypoproteinemia can cause edema formation and intravascular volume depletion. It is not clear if the explosive onset of MCD in some patients could cause a similar reduction in intravascular volume with interstitial fluid volume expansion. The development of acute renal failure in a small subset of patients (typically with MCD) suggests that hypovolemia may play a role, but this cannot be conclusively proven without formal blood volume measurements.17.Jennette J.C. Falk R.J. Adult minimal change glomerulopathy with acute renal failure.Am J Kidney Dis. 1990; 16: 432-437Abstract Full Text PDF PubMed Scopus (108) Google Scholar, 18.Furuya R. Kumagai H. Ikegaya N. et al.Reversible acute renal failure in idiopathic nephrotic syndrome.Intern Med. 1993; 32: 31-35Crossref PubMed Scopus (20) Google Scholar, 19.Case records of the Massachusetts General Hospital Weekly clinicopathological exercise. Case 4-1982. Sudden onset of renal failure and the nephrotic syndrome in a middle-aged woman.N Engl J Med. 1982; 306: 221-231Crossref PubMed Scopus (8) Google Scholar, 20.Conolly M.E. Wrong O.M. Jones N.F. Reversible renal failure in idiopathic nephrotic syndrome with minimal glomerular changes.Lancet. 1968; 1: 665-668Abstract PubMed Google Scholar, 21.Hulter H.N. Bonner Jr., E.L. Lipoid nephrosis appearing as acute oliguric renal failure.Arch Intern Med. 1980; 140: 403-405Crossref PubMed Scopus (27) Google Scholar In a retrospective review of 95 cases of adult MCD at a single center, acute renal failure occurred in 24 patients. Those with acute renal failure were older, were hypertensive, and had lower serum albumin and more proteinuria compared with those who did not have acute renal failure.22.Waldman M. Crew R.J. Valeri A. et al.Adult minimal-change disease: clinical characteristics, treatment, and outcomes.Clin J Am Soc Nephrol. 2007; 2: 445-453Crossref PubMed Scopus (288) Google Scholar There are few studies on this subject and they assess different end points, which makes comparisons difficult. A significant issue in the consideration of this problem is the lack of a gold standard for the assessment of intravascular volume. At least three methods of intravascular volume assessment have been utilized in the nephrotic syndrome literature: neurohumoral hormone assays, blood volume measurement with radioactive labeling techniques, and presence or absence of hypovolemic symptoms and signs. This section will review some of the more important studies assessing blood volume in the nephrotic syndrome. Pioneering work on neurohumoral assessment of blood volume in the nephrotic syndrome was done by Meltzer et al.,23.Meltzer J.I. Keim H.J. Laragh J.H. et al.Nephrotic syndrome: vasoconstriction and hypervolemic types indicated by renin-sodium profiling.Ann Intern Med. 1979; 91: 688-696Crossref PubMed Scopus (131) Google Scholar who studied patients with untreated nephrotic syndrome and separated them into two groups by renin levels. Patients with high renin all had MCD and significantly higher aldosterone, higher creatinine clearance, lower urine sodium, and lower serum albumin than the low-renin group. There was a suggestion of low plasma volume as measured by 125I serum albumin in the high-renin group and elevated plasma volume in the low-renin group, but no definitive conclusions could be made because not all subjects had their plasma volume measured. In one of the largest studies of nephrotic patients, Geers et al.24.Geers A.B. Koomans H.A. Roos J.C. et al.Functional relationships in the nephrotic syndrome.Kidney Int. 1984; 26: 324-330Abstract Full Text PDF PubMed Scopus (65) Google Scholar compared 28 patients with MCD and 24 with nephrotic syndrome due to other histologic lesions; patients included all had a low fractional excretion of sodium. The group with MCD had significantly lower plasma volume as assessed by 131I-albumin, higher plasma aldosterone, and lower serum albumin (1.5 vs. 2.1g/dl) than the other histologic lesion group, but blood volume was not significantly different. There was no correlation between blood volume and plasma renin activity (PRA) or serum albumin and blood volume. In a study of 88 patients with the nephrotic syndrome, 33 of whom had MCD, it was found that plasma and blood volumes as assessed by 131I-albumin were no different than those of healthy controls.25.Geers A.B. Koomans H.A. Boer P. et al.Plasma and blood volumes in patients with the nephrotic syndrome.Nephron. 1984; 38: 170-173Crossref PubMed Scopus (88) Google Scholar Other studies have also found that patients with the nephrotic syndrome have normal or expanded blood volumes.24.Geers A.B. Koomans H.A. Roos J.C. et al.Functional relationships in the nephrotic syndrome.Kidney Int. 1984; 26: 324-330Abstract Full Text PDF PubMed Scopus (65) Google Scholar, 26.Geers A.B. Koomans H.A. Roos J.C. et al.Preservation of blood volume during edema removal in nephrotic subjects.Kidney Int. 1985; 28: 652-657Abstract Full Text PDF PubMed Scopus (29) Google Scholar, 27.Vande Walle J. Donckerwolcke R. Boer P. et al.Blood volume, colloid osmotic pressure and F-cell ratio in children with the nephrotic syndrome.Kidney Int. 1996; 49: 1471-1477Abstract Full Text PDF PubMed Scopus (39) Google Scholar Conversely, there are also studies supporting the presence of hypovolemia in the nephrotic syndrome. Vande Walle et al.28.Vande Walle J.G. Donckerwolcke R.A. Koomans H.A. Pathophysiology of edema formation in children with nephrotic syndrome not due to minimal change disease.J Am Soc Nephrol. 1999; 10: 323-331PubMed Google Scholar compared children with nephrotic syndrome due to MCD with those with non-MCD and further divided each group by the presence or absence of symptoms or signs of hypovolemia. Patients in both groups with hypovolemic symptoms had significantly higher levels of norepinephrine, PRA, and aldosterone, and lower fractional excretion of sodium than their nonsymptomatic counterparts. When considering only the group with hypovolemic symptoms, the non-MCD group (comprising mostly Finnish type nephrotic syndrome patients) had a lower albumin (0.8g/dl) and greater elevation in norepinephrine, PRA, and aldosterone than did the MCD group whose albumin was 1.5g/dl. When analyzing the entire cohort, it was found that there was a significant negative correlation between aldosterone and both serum colloid osmotic pressure and fractional excretion of sodium. Thus, neurohumoral activation was associated with hypovolemic symptoms and those with the most severe neurohumoral activation had the lowest serum albumin. These data suggest that severe hypoalbuminemia is associated with hypovolemia. Usberti et al.29.Usberti M. Federico S. Meccariello S. et al.Role of plasma vasopressin in the impairment of water excretion in nephrotic syndrome.Kidney Int. 1984; 25: 422-429Abstract Full Text PDF PubMed Scopus (71) Google Scholar subjected nephrotic patients and control patients with glomerulonephritis or hematuria to water loading. The nephrotic patients (8/16 with MCD) had a significantly lower blood volume and serum albumin than controls (1.5 vs. 4.0g/dl). In response to water loading, a significant direct correlation between plasma osmolality and arginine vasopressin (AVP) levels was seen in control, but not in nephrotic patients. In contrast, a significant negative correlation was seen between blood volume and plasma AVP in nephrotic but not in control patients. This suggests that a volume-mediated stimulus was driving vasopressin release in nephrotic patients. In 1995, Usberti et al.30.Usberti M. Gazzotti R.M. Poiesi C. et al.Considerations on the sodium retention in nephrotic syndrome.Am J Nephrol. 1995; 15: 38-47Crossref PubMed Scopus (39) Google Scholar studied two groups of nephrotic patients with normal renal function, one who had a positive sodium balance and the other in sodium balance. The group in positive sodium balance (7/12 with MCD) had significantly lower measured blood volume, lower serum albumin (1.4 vs. 2.2g/dl), and higher renin, angiotensin II, and aldosterone than the group in sodium balance. In both groups there was a direct relationship between serum albumin and blood volume. As discussed above, this finding is at odds with other studies. In summary, most edematous patients with the nephrotic syndrome have a normal to expanded intravascular volume, whereas a minority of patients have a depleted intravascular volume. Those patients with intravascular volume depletion typically have MCD and more severe hypoalbuminemia. It is worth noting that although MCD and severe hypoalbuminemia are associated with intravascular volume depletion in some studies, most patients with MCD and significant hypoalbuminemia do not show evidence of intravascular volume depletion. The renin, angiotensin II, and aldosterone system has frequently been implicated as a cause of sodium retention in the nephrotic syndrome, particularly in patients who have intravascular volume depletion. Although Geers et al.24.Geers A.B. Koomans H.A. Roos J.C. et al.Functional relationships in the nephrotic syndrome.Kidney Int. 1984; 26: 324-330Abstract Full Text PDF PubMed Scopus (65) Google Scholar found no correlation between PRA and blood volume in their large study of nephrotic patients,24.Geers A.B. Koomans H.A. Roos J.C. et al.Functional relationships in the nephrotic syndrome.Kidney Int. 1984; 26: 324-330Abstract Full Text PDF PubMed Scopus (65) Google Scholar significant negative correlations have been found between ECFV and log PRA,13.Koomans H.A. Braam B. Geers A.B. et al.The importance of plasma protein for blood volume and blood pressure homeostasis.Kidney Int. 1986; 30: 730-735Abstract Full Text PDF PubMed Scopus (44) Google Scholar plasma volume and PRA,31.Kumagai H. Onoyama K. Iseki K. et al.Role of renin angiotensin aldosterone on minimal change nephrotic syndrome.Clin Nephrol. 1985; 23: 229-235PubMed Google Scholar and blood volume and PRA.30.Usberti M. Gazzotti R.M. Poiesi C. et al.Considerations on the sodium retention in nephrotic syndrome.Am J Nephrol. 1995; 15: 38-47Crossref PubMed Scopus (39) Google Scholar In a study of nephrotic patients with active sodium retention with high plasma renin, ACE inhibition with captopril did not lead to negative sodium balance or weight loss despite a reduction in plasma aldosterone.32.Brown E.A. Markandu N.D. Sagnella G.A. et al.Evidence that some mechanism other than the renin system causes sodium retention in nephrotic syndrome.Lancet. 1982; 2: 1237-1240Abstract PubMed Scopus (59) Google Scholar In a similar study of nephrotic patients with low and high renin, captopril failed to produce negative sodium balance despite a decline in aldosterone levels.33.Brown E.A. Markandu N.D. Sagnella G.A. et al.Lack of effect of captopril on the sodium retention of the nephrotic syndrome.Nephron. 1984; 37: 43-48Crossref PubMed Scopus (41) Google Scholar Several studies have shown that patients with MCD have higher renin or renin activity and aldosterone levels than those with other histologic lesions despite similar blood volumes.23.Meltzer J.I. Keim H.J. Laragh J.H. et al.Nephrotic syndrome: vasoconstriction and hypervolemic types indicated by renin-sodium profiling.Ann Intern Med. 1979; 91: 688-696Crossref PubMed Scopus (131) Google Scholar,34.Hammond T.G. Whitworth J.A. Saines D. et al.Renin-angiotensin-aldosterone system in nephrotic syndrome.Am J Kidney Dis. 1984; 4: 18-23Abstract Full Text PDF PubMed Scopus (18) Google Scholar A large study of nephrotic patients failed to show a difference in PRA in patients with MCD vs. those with histologic lesions, although those with MCD did have significantly higher aldosterone concentrations.24.Geers A.B. Koomans H.A. Roos J.C. et al.Functional relationships in the nephrotic syndrome.Kidney Int. 1984; 26: 324-330Abstract Full Text PDF PubMed Scopus (65) Google Scholar Studies of children with the nephrotic syndrome showed that patients with hypovolemic symptoms had greater elevations in renin activity and aldosterone, despite similar measured blood volumes.27.Vande Walle J. Donckerwolcke R. Boer P. et al.Blood volume, colloid osmotic pressure and F-cell ratio in children with the nephrotic syndrome.Kidney Int. 1996; 49: 1471-1477Abstract Full Text PDF PubMed Scopus (39) Google Scholar, 28.Vande Walle J.G. Donckerwolcke R.A. Koomans H.A. Pathophysiology of edema formation in children with nephrotic syndrome not due to minimal change disease.J Am Soc Nephrol. 1999; 10: 323-331PubMed Google Scholar, 35.Vande Walle J.G. Donckerwolcke R.A. van Isselt J.W. et al.Volume regulation in children with early relapse of minimal-change nephrosis with or without hypovolaemic symptoms.Lancet. 1995; 346: 148-152Abstract PubMed Scopus (0) Google Scholar Blockade of aldosterone in a small group of nephrotic patients who were retaining sodium and who were fed a high salt diet resulted in marginal negative sodium balance.36.Shapiro M.D. Hasbargen J. Hensen J. et al.Role of aldosterone in the sodium retention of patients with nephrotic syndrome.Am J Nephrol. 1990; 10: 44-48Crossref PubMed Scopus (32) Google Scholar This study did not, however, control for the degree of proteinuria reduction caused by aldosterone blockade. An inverse relationship has been shown between plasma aldosterone and urinary sodium excretion by several investigators,28.Vande Walle J.G. Donckerwolcke R.A. Koomans H.A. Pathophysiology of edema formation in children with nephrotic syndrome not due to minimal change disease.J Am Soc Nephrol. 1999; 10: 323-331PubMed Google Scholar, 31.Kumagai H. Onoyama K. Iseki K. et al.Role of renin angiotensin aldosterone on minimal change nephrotic syndrome.Clin Nephrol. 1985; 23: 229-235PubMed Google Scholar, 37.Reubi F.C. Weidmann P. Gluck Z. Interrelationships between sodium clearance, plasma aldosterone, plasma renin activity, renal hemodynamics and blood pressure in renal disease.Klin Wochenschr. 1979; 57: 1273-1285Crossref PubMed Scopus (9) Google Scholar, 38.Oliver W.J. Owings C.L. Sodium excretion in the nephrotic syndrome. Relation to serum albumin concentration, glomerular filtration rate, and aldosterone excretion rate.Am J Dis Child. 1967; 113: 352-362Crossref PubMed Scopus (14) Google Scholar whereas other investigators have found no relation.39.Bohlin A.B. Berg U. Renal sodium handling in minimal change nephrotic syndrome.Arch Dis Child. 1984; 59: 825-830Crossref PubMed Google Scholar It is noteworthy that in several studies the development of edema occurred without significant elevations in serum aldosterone levels.24.Geers A.B. Koomans H.A. Roos J.C. et al.Functional relationships in the nephrotic syndrome.Kidney Int. 1984; 26: 324-330Abstract Full Text PDF PubMed Scopus (65) Google Scholar, 28.Vande Walle J.G. Donckerwolcke R.A. Koomans H.A. Pathophysiology of edema formation in children with nephrotic syndrome not due to minimal change disease.J Am Soc Nephrol. 1999; 10: 323-331PubMed Google Scholar, 40.Usberti M. Gazzotti R.M. Hyporeninemic hypoaldosteronism in patients with nephrotic syndrome.Am J Nephrol. 1998; 18: 251-255Crossref PubMed Scopus (23) Google Scholar The above suggest that renin–angiotensin–aldosterone system is not a major mechanism of sodium retention in the nephrotic syndrome. MCD is phenotypically associated with elevated PRA and aldosterone, although in most cases the blood volume is not different from those who have other histologic lesions and normal PRA and aldosterone. It is not clear if this MCD phenotype suggests an alternate pathophysiology. The renal vasculature, particularly the afferent and efferent arterioles, as well as the tubules are innervated by the sympathetic nervous system.41.DiBona G.F. Role of the renal nerves in renal sodium retention and edema formation.Trans Am Clin Climatol Assoc. 1990; 101 (discussion 44–5): 38-44PubMed Google Scholar Activation of the renal sympathetic nerves causes an increase in afferent and efferent vascular resistance (independent of angiotensin II42.Pelayo J.C. Renal adrenergic effector mechanisms: glomerular sites for prostaglandin interaction.Am J Physiol. 1988; 254: F184-F190PubMed Google Scholar) and increased renin release with subsequent increases in angiotensin II, all of which serve to increase sodium reabsorption.41.DiBona G.F. Role of the renal nerves in renal sodium retention and edema formation.Trans Am Clin Climatol Assoc. 1990; 101 (discussion 44–5): 38-44PubMed Google Scholar In a study of nephrotic rats in the edema-forming stages, DiBona41.DiBona G.F. Role of the renal nerves in renal sodium retention and edema formation.Trans Am Clin Climatol Assoc. 1990; 101 (discussion 44–5): 38-44PubMed Google Scholar showed that compared with control rats, nephrotic rats have higher basal renal sympathetic nerve activity, decreased excretion of intravenous isotonic saline, and less suppression of renal sympathetic nerve activity following isotonic saline infusion. Following renal sympatheti