Sodium retention in nephrotic syndrome is due to an intrarenal defect: evidence from steroid-induced remission

There is increasing evidence that the sodium retention of nephrotic syndrome is directly due to an intrarenal mechanism and not to a low blood volume stimulating the renin-angiotensin-aldosterone system. However the mechanism of the natriuresis that occurs during remission is not known. Patients with nephrotic syndrome were therefore studied during steroid-induced remission. At the onset of natriuresis, blood volume and plasma albumin were low and did not change. Plasma renin activity and plasma aldosterone were initially high and both fell during the natriuresis. At the end of the natriuresis when patients had lost their oedema, plasma renin activity and plasma aldosterone rose to high levels, plasma albumin and blood volume remained low, and yet the patients were no longer retaining sodium and were in sodium balance. These observations suggest that the natriuresis of remission is due to the correction of an intrarenal mechanism causing the sodium retention. This study raises two major unanswered questions. Firstly, when the presumed intrarenal mechanism is corrected, what tells the kidney to excrete large amounts of sodium when the blood volume remains low? Secondly, why do the patients come back into sodium balance when the blood volume is low, and plasma renin activity and plasma aldosterone are elevated?     

Urinary kallikrein excretion in glomerulonephritis and nephrotic syndrome

To assess the possible role of the renal kallikrein-kinin system in the pathogenesis of glomerulonephritis (GN), 24 h urinary kallikrein excretion (Uka) was measured in normal controls and in 32 patients with GN, 16 of whom had nephrotic syndrome. Compared with controls, Uka was decreased in GN without nephrotic syndrome (4.6 +/- 2.8 nkat day-1, controls 11.5 +/- 3.5 nkat day-1) but was markedly increased in patients with nephrotic syndrome (26.7 +/- 9.9 nkat day-1). The increased kallikrein excretion in nephrotic syndrome was not explained by leakage from plasma, protein binding of active kallikrein, passive 'washout' due to changes in sodium and water excretion, or by increased activity of the renin-angiotensin-aldosterone system, but may relate to changes in extracellular volume, plasma oncotic pressure and volume, or other intrarenal haemodynamic or hormonal factors. Increased activity of the renal kallikrein-kinin system is not a uniform finding in glomerulonephritis, but may be an important aspect of nephrotic syndrome.     

Molecular mechanism of edema formation in nephrotic syndrome: therapeutic implications

Sodium retention and edema are common features of nephrotic syndrome that are classically attributed to hypovolemia and activation of the renin-angiotensin-aldosterone system. However, numbers of clinical and experimental findings argue against this underfill theory. In this review we analyze data from the literature in both nephrotic patients and experimental models of nephrotic syndrome that converge to demonstrate that sodium retention is not related to the renin-angiotensin-aldosterone status and that fluid leakage from capillary to the interstitium does not result from an imbalance of Starling forces, but from changes of the intrinsic properties of the capillary endothelial filtration barrier. We also discuss how most recent findings on the cellular and molecular mechanisms of sodium retention has allowed the development of an efficient treatment of edema in nephrotic patients.     

Over- or underfill: not all nephrotic states are created equal

Blessed were the days when it all made sense and the apparent mechanism for edema formation in nephrotic syndrome was straightforward: the kidneys lost protein in the urine, which lowered the plasma oncotic pressure. Thus, fluid leaked into the interstitium, depleting the intravascular volume with subsequent activation of renin/aldosterone and consequent avid renal sodium retention. As simple as that! Unfortunately, a number of clinical and laboratory observations have raised serious concerns about the accuracy of this “underfill” hypothesis. Instead, an “overfill” hypothesis was generated. Under this assumption, the nephrotic syndrome not only leads to urinary protein wasting, but also to primary sodium retention with consequent intravascular overfilling, with the excess fluid spilling into the flood plains of the interstitium, leading to edema. Recently, an attractive mechanism was proposed to explain this primary sodium retention: proteinuria includes plasma proteinases, such as plasmin, which activate the epithelial sodium channel in the collecting duct, ENaC. In this edition, further evidence for this hypothesis is being presented by confirming increased plasmin content in the urine of children with nephrotic syndrome and demonstrating ENaC activation. If correct, this hypothesis would provide a simple treatment for the edema: pharmacological blockade of ENaC, for instance, with amiloride. Yet, how come clinicians have not empirically discovered the presumed power of ENaC blockers in nephrotic syndrome? And why is it that some patients clearly show evidence of intravascular underfilling? The controversy of over- versus underfilling demonstrates how much we still have to learn about the pathophysiology of nephrotic syndrome.     

Role of the renin-angiotensin-aldosterone system in the regulation of plasma potassium in chronic renal disease.

The relationship between plasma potassium concentration and the renin-angiotensin-aldosterone system was evaluated in ten patients with chronic renal failure (creatinine clearance 10-56 ml/min). Under basal conditions and following various stimulation maneuvers, normokalemic patients demonstrated normal plasma renin and aldosterone levels. Five of six patients with hyperkalemia had diminished function of the renin-angiotensin-aldosterone system; their ability to conserve sodium during salt depletion was less than that of normokalemic patients. The data suggest that the maintenance of plasma potassium levels in these patients is dependent of the presence of a normally functioning renin-angiotensin-aldosterone system; aldosterone activity may be an important determinant of sodium conservation in patients with renal failure.     

Distal nephron sodium-potassium exchange in children with nephrotic syndrome

While recent literature data suggest that a primary impairment in sodium excretion is the basic abnormality in the pathogenesis of edema formation in the nephrotic syndrome, there is ample evidence that functional hypovolemia contributes to stimulation of renal sodium and fluid retention. Vasoactive hormones such as renin and aldosterone are involved in this process. Discrimination between both mechanisms would be possible by assessment of aldosterone bioactivity and will have therapeutical consequences by indicating the need for administration of i.v. albumin or diuretics. In this paper, several indices of aldosterone bioactivity were assessed in 85 patients with minimal lesion nephrotic syndrome (118 measurements were performed in patients while in remission and 210 following relapses), and in 41 nephrotic patients with different types of nephropathy and were related to plasma renin and aldosterone levels. A better correlation was found between log aldosterone and U(K+)/U(Na+) + U(K+) ratio than with other parameters measuring renal potassium handling such as transtubular potassium gradient, fractional excretion of potassium and urine K+/urine Na+ or urine K+ creatinine ratios. In patients with renal sodium retention (FE(Na)% less than 0.5), an U(K+)/U(Na+) + U(K+) ratio higher than 0.60 identifies patients with increased aldosterone levels and indicates functional hypovolemia. This index may therefore be used to assess which patients will benefit from i.v. albumin administration.     

Effect of the angiotensin converting enzyme inhibitor, captopril (SQ14,225), on orthostatic sodium and water retention in patients with idiopathic edema

Captopril (SQ14,225), an orally administered angiotensin converting enzyme inhibitor, was given to 8 patients with idiopathic edema, in order to study the role of the renin-angiotensin-aldosterone system in orthostatic sodium and water retention. Compared to 5 normal subjects, patients with idiopathic edema showed significantly greater reduction in water and sodium excretion, and greater increment in plasma aldosterone and plasma renin activity, in the upright posture. Captopril significantly restored water and sodium excretion, attenuated the increment in plasma aldosterone, and enhanced the rise in plasma renin activity in patients with idiopathic edema. The effects of captopril on these variables were not remarkable in normal subjects. These results suggest that an enhanced response of the renin-angiotensin-aldosterone system to standing plays an important role in the pathophysiology of idiopathic edema.     

Intra- and extrarenal factors of oedema formation in the nephrotic syndrome

The role of intra- and extrarenal factors in oedema formation in children with nephrotic syndrome is reviewed. Oedema reflects an abnormal accumulation of fluid within the interstitial tissue. At the capillary level oedema develops when increased lymph flow is no longer effective for the removal of interstitial fluid and the maintenance of intravascular volume. Alterations of intrarenal haemodynamics and tubular sodium reabsorption contribute to sodium retention. Recent studies suggest that during oedema formation reduced effective circulatory volume triggers changes in various hormonal systems, such as renin-angiotensin-aldosterone, noradrenaline, dopamine, vasopressin, prostaglandins and natriuretic factors, which contribute to sodium and water retention. It appears that the release of atrial natriuretic peptide following central volume expansion is responsible for the increased urine flow and natriuresis after intravenous administration of albumin.     

Role of renin angiotensin aldosterone on minimal change nephrotic syndrome

Plasma volume (PV), plasma renin activity (PRA) and plasma aldosterone (PA) were examined serially at the edema forming stage, the stage of diuresis, and the stage of remission in 11 patients. These patients were steroid responsive, minimal change nephrotic syndrome with normal kidney function. PV was expressed as a percentage of the normal reference value, which was obtained from PV and body height in 44 normal volunteers. PV decreased significantly at the edema-forming stage and increased at the stage of the diuresis. A significant inverse correlation was obtained between PV and PRA. PRA correlated significantly with PA. The amount of 24 hour urinary sodium excretion severely reduced at the edema-forming stage and increased at the stage of diuresis: thus showing a significant inverse correlation with PA. In conclusion, renin-angiotensin-aldosterone system plays a role as a compensatory mechanism to the intravascular volume status in minimal change nephrotic syndrome, but, its' contribution to the genesis of edema is unsusceptible.     

Role of aldosterone in the sodium retention of patients with nephrotic syndrome

The role of aldosterone in the abnormal sodium retention in patients with nephrotic syndrome has been debated. In fact, studies using a converting enzyme inhibitor to lower plasma aldosterone have rejected such a role. We therefore studied 5 nephrotic patients and 6 control subjects by using the more specific aldosterone antagonist, spironolactone. After withdrawal of diuretics 5 days prior to the study, the nephrotic patients and control subjects were placed on a high-sodium diet (285 +/- 6 mEq/day) for 8 days. After 4 days, spironolactone 200 mg p.o., b.i.d., was given for the remaining 4 days. Plasma renin activity and plasma aldosterone levels were similar in both nephrotic patients and control subjects before the study, after sodium loading and after spironolactone had been given. After 4 days of high sodium intake control subjects were in sodium balance, but the nephrotic patients were in a positive sodium balance (approx. 80 mEq/day; p less than 0.01). On days 3 and 4 of spironolactone, the nephrotic patients exhibited an increase in urinary sodium excretion (205 +/- 20 vs. 312 +/- 13 mEq/day; p less than 0.005) but not the control subjects (279 +/- 16 vs. 286 +/- 13 mEq/day; NS). It is therefore concluded that aldosterone is a significant contributor to the sodium retention in patients with nephrotic syndrome.     

Interstitial inflammation,sodium retention,and the pathogenesis of nephrotic edema: a unifying hypothesis

BACKGROUND: The pathophysiology of edema in the nephrotic syndrome is controversial. Some investigators believe that sodium retention may result from a primary renal defect that causes an "overfilled" blood volume. In contrast, other authors believe that fluid escapes the vascular compartment due a low oncotic pressure, and sodium retention is a compensatory physiological response to an "underfilled" blood volume. The patients that best fit the "underfilled" hypothesis are children with minimal-change nephrotic syndrome (MCNS). METHODS: We analyzed critically the available evidence for and against each proposed pathogenic mechanism in the light of recent evidence indicating that the inflammatory infiltrate may play a role in primary renal sodium retention. RESULTS: Inflammatory infiltrate in the kidney is a constant characteristic in nephrotic syndrome associated with primary sodium retention and it is absent in most cases of MCNS in children CONCLUSIONS: We propose that primary sodium retention in the nephrotic syndrome depends on the existence and the intensity of renal inflammatory infiltrate, conspicuously absent in most cases of MCNS in children and present in other conditions associated with massive proteinuria. The tubulointerstitial inflammatory infiltrate is associated with increased vasoconstrictive mediators that result in increased tubular sodium reabsorption and with glomerular hemodynamic changes that reduce filtered sodium load.     

Absence of sodium and water retention in rats with severe proteinuria

Studies with two models of immunologically mediated glomerular disease in the rat, chronic serum sickness and Heymann nephritis, show that fluid retention can be dissociated from other signs of the nephrotic syndrome (excessive proteinuria, hypoalbuminemia, hypercholesterolemia). Clinical evidence of fluid retention (increased body weight, decreased hematocrit, ascites) was only detected in severe chronic serum sickness and coincided with an abrupt drop in urinary sodium concentration and sodium excretion. Severe proteinuria was not associated with sodium and water retention in moderate chronic serum sickness and in Heymann nephritis. These observations support the hypothesis that, in conditions of severe proteinuria, an intrarenal defect in sodium excretion rather than a systemic factor, leads to fluid retention.     

Reduced 11beta-hydroxysteroid dehydrogenase activity in experimental nephrotic syndrome.

BACKGROUND: The disease state of the nephrotic syndrome is characterized by abnormal renal sodium retention that cannot be completely explained by a secondary hyperaldosteronism for the following reasons. Firstly, in rats an enhanced sodium retention is observed before proteinuria with intravascular volume depletion occurs. Secondly, in patients with the nephrotic syndrome, volume expansion with hypertension has been reported despite suppression of the renin-aldosterone system. Therefore, another mechanism for sodium retention must be postulated for this disease state. We hypothesize that this mechanism is a reduced 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2) activity, a phenomenon known to cause enhanced access of cortisol or corticosterone to the mineralocorticoid receptor. METHODS: We assessed the 11beta-HSD activity by measuring the urinary ratio of tetrahydrocorticosterone (THB) plus 5alpha-tetrahydrocorticosterone (5alpha-THB) to 11-dehydro-tetrahydrocorticosterone (THA) by gas chromatography-mass spectrometry in rats with puromycin aminonucleoside (PAN)-induced proteinuria and with adriamycin nephrosis. Furthermore, the plasma ratios of corticosterone to 11-dehydrocorticosterone were measured. RESULTS: The urinary ratio of (THB+5alpha-THB)/THA increased in all animals following injection of PAN or adriamycin, indicating a reduced activity of 11beta-HSD. The reduced activity of 11beta-HSD was confirmed by an increased plasma ratio of corticosterone to 11-dehydrocorticosterone. The changes in the glucocorticoid metabolite ratios were already present before significant proteinuria appeared. CONCLUSION: PAN- or adriamycin-treated rats develop proteinuria with a reduced activity of 11beta-HSD, a mechanism contributing to the abnormal sodium retention in nephrotic syndrome.     

Urine kallikrein excretion in relation to renal sodium handling in minimal change nephrotic syndrome.

Twenty-four-hour urine kallikrein excretion (Uka), urine protein excretion, renal sodium handling, and the activity of the renin-angiotensin-aldosterone system were serially studied in 11 children at three different stages of the minimal change nephrotic syndrome (MCNS)-edema forming state, proteinuric steady state in which a relapse of the disease was just starting but no edema as yet and remission. The value for Uka was significantly increased in the edema forming state in contrast to the normal values of proteinuric steady state and remission. Serum sodium concentration was only decreased in the edema forming state and the degree of hypoalbuminemia and proteinuria did not differ between the edema forming and proteinuric steady states. Urine volume, absolute and fractional sodium excretion were significantly decreased in the edema forming and proteinuric steady states as compared with those in remission, suggesting that sodium retention was present in both states of the disease although the change in these parameters was more profound in the edema forming state than in the proteinuric steady state. Creatinine clearance did not differ among each stage of the disease. Plasma renin activity and plasma aldosterone concentration were significantly increased in the edema forming state as compared with those in the proteinuric steady state and remission. Plasma renin activity and plasma aldosterone concentration were significantly correlated directly with Uka and plasma aldosterone concentration was correlated inversely with urine sodium excretion. No relation was noted between Uka and other variables.(ABSTRACT TRUNCATED AT 250 WORDS)     

Functional relationships in the nephrotic syndrome

An analysis of 70 observations in patients with the nephrotic syndrome (NS) on a low sodium diet is presented. The following parameters were determined: plasma volume, plasma renin activity, plasma aldosterone concentration, serum albumin, urinary sodium and protein excretion, and creatinine clearance. In 41 instances glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined on the basis of 51Cr-EDTA and 125I-hippuran clearances, and the filtration fraction (FF) was calculated. The results in patients with minimal lesions (ML) and those with histological glomerular lesions (HL) were compared to determine whether these groups can be separated on the basis of signs of hypovolemia and primary renal sodium retention. Although a higher proportion of the ML patients showed extreme sodium retention and elevated plasma renin and aldosterone levels, these values tended to overlap and no differences were found for blood volume, blood pressure, and overall renal function between the groups. FF was markedly and equally depressed in both groups: 13.5 +/- 1.6% in the ML and 14.2 +/- 1.1% SEM in the HL group (NS). Analysis of the within-group relationships between the parameters under study revealed relatively few correlations, which supports the hypothesis that primary impairment of renal water and salt excretion is an important if not overruling factor in patients with the NS.     

Renin-angiotensin-aldosterone system in nephrotic syndrome

Previous studies on the renin-angiotensin-aldosterone system and fluid volumes in patients with nephrotic syndrome have not considered the nature of the underlying renal lesion. We compared plasma renin concentration (PRC), plasma aldosterone (PA), and plasma volume in three groups of patients: five nephrotic patients with minimal change disease on renal biopsy, seven nephrotic patients with other renal histopathology, and a control group of eight patients investigated for glomerulonephritis with no past or present nephrosis. PRC and PA were significantly greater in nephrotic patients with minimal change disease than other renal histopathology (Supine PRC 42 +/- 7 microIU/mL compared with 14 +/- 4, P less than 0.01; ambulant PRC 56 +/- 7 microIU/mL compared with 29 +/- 10, P less than 0.05; supine PA 158 +/- 55 pg/mL compared with 53 +/- 13, P less than 0.05; and ambulant PA 167 +/- 57 pg/mL compared with 29 +/- 10, P less than 0.05. Plasma volume was similar in all three groups, contrary to predictions from the Starling capillary fluid exchange hypothesis. Nephrosis may be characterized by different pathophysiologic groups according to the underlying renal histopathology. High plasma renin and aldosterone levels may be markers for minimal change disease.     

Changes in the renin-angiotensin-aldosterone system in glomerulonephritis

The performance of the renin-angiotensin-aldosterone system and water-salt balance was studied in 69 patients with various patterns (both clinical and morphological) of glomerulonephritis. The author revealed that the levels of total and nonactive renin in the plasma of patients prone to membranous proliferative nephritis were higher than both in controls and in the patients with mesangial proliferative disease. Though there was no difference in the levels of active renin. Besides, it was stated that the renin-angiotensin system more strongly governed the pathogenesis of arterial hypertension in patients with membranous proliferative nephritis than in those who suffered from mesangial proliferative patterns of the disease. As the blood pressure levels turned to be dependent both on the levels of plasma and total renin the author established the existence of a mixed mechanism of hypertension occurrence in the patients with glomerulonephritis. Conversion of the nonactive part of renin into the active one promoted the rise of blood pressure. Therefore, in this case the increased levels of the renin nonactive fraction could be regarded as a risk factor for the occurrence of the hypertensive syndrome. The patients with glomerulonephritis enrolled in the study and 15 controls demonstrated a significant feedback correlation between the levels of total and nonactive renin as well as between the exchangeable sodium and its extracellular levels; the degree of correlation in hypertensive patients varied. It was demonstrated that hyperkalemia could be a reason for an increase in aldosterone levels observed in patients with renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal clearance of endogenous erythropoietin in patients with proteinuria

Recent data indicated the importance of urinary losses of erythropoietin (Epo) in the pathogenesis of anaemia in patients with nephrotic syndrome. In the present study we aimed to investigate plasma and urinary Epo levels and their renal handling in relation to β₂-microglobulin (β₂m), sodium metabolism and the renin-angiotensin-aldosterone system (RAAS), respectively, in patients with sub-nephrotic range proteinuria (SNP), microalbuminuric diabetics and hypertensives, and in healthy subjects studied on a standardized diet containing 120 mmol sodium and 70 g protein per day. We found that patients with SNP were characterized by lower plasma levels of Epo than healthy subjects but no differences were found in urinary excretion of Epo, endogenous Epo clearance and its fractional excretion (FE_Epo). There were no differences between groups in FEβ_2m and FE_Na and plasma aldoterone levels but plasma renin activity was higher in patients with SNP than in the controls. No relationships were found between Epo levels and activity of the RAAS and sodium metabolism, respectively. Our data suggest that lower levels of plasma Epo in patients with SNP and normal renal excretory function are not due to urinary losses of Epo but rather to the decreased production/degradation ratio.     

Pathogenesis of oedema in nephrotic syndrome: Role of epithelial sodium channel

SUMMARY:   Nephrotic syndrome is associated with avid sodium retention, leading to the development of oedema and ascites. Studies in experimental animals suggest that sodium retention in nephotic syndrome is due to increased sodium re-absorption in the collecting duct, which is also the action site of vasoregulatory hormones. However, the mechanisms underlying sodium retention in nephrotic syndrome are incompletely understood and the molecular basis remains undefined. This review summarizes recent insight into the role of epithelial sodium channels (ENaC) in animal models of nephrotic syndrome induced by puromycin aminonucleoside – or HgCl₂ treatment. The sodium retention associated with nephrotic syndrome is caused by increased sodium re-absorption in the aldosterone-sensitive distal nephron segments including the connecting tubule and collecting duct, in which an increased apical targeting of ENaC subunits also plays an important role in the development of sodium retention in nephrotic syndrome.     

Pathogenesis of oedema in nephrotic syndrome: role of epithelial sodium channel

Nephrotic syndrome is associated with avid sodium retention, leading to the development of oedema and ascites. Studies in experimental animals suggest that sodium retention in nephotic syndrome is due to increased sodium re-absorption in the collecting duct, which is also the action site of vasoregulatory hormones. However, the mechanisms underlying sodium retention in nephrotic syndrome are incompletely understood and the molecular basis remains undefined. This review summarizes recent insight into the role of epithelial sodium channels (ENaC) in animal models of nephrotic syndrome induced by puromycin aminonucleoside - or HgCl(2) treatment. The sodium retention associated with nephrotic syndrome is caused by increased sodium re-absorption in the aldosterone-sensitive distal nephron segments including the connecting tubule and collecting duct, in which an increased apical targeting of ENaC subunits also plays an important role in the development of sodium retention in nephrotic syndrome.