Lack of effect of captopril on the sodium retention of the nephrotic syndrome

The mechanism of sodium retention in the nephrotic syndrome remains controversial, though the classic pathophysiological explanation is stimulation of the renin-angiotensin-aldosterone system. Recent evidence has shown that many patients with the nephrotic syndrome have a normal or low plasma renin activity suggesting that there might be an intrarenal cause for their sodium retention. We gave captopril, an oral angiotensin-converting enzyme inhibitor, during 10 separate episodes of sodium retention in nephrotic syndrome. There was evidence of stimulation of the renin system in 7 of these episodes. Despite a marked fall in plasma aldosterone, all patients continued to retain sodium and water and gain weight. This demonstrates that the sodium retention of nephrotic syndrome is not due to stimulation of the renin-angiotensin-aldosterone system, but must be due to some other mechanism, which is probably intrarenal.     

Steroid-induced hypertension in patients with nephrotic syndrome

In 35 initially normotensive patients with chronic glomerulonephritis and lupus nephritis (including 27 patients with nephrotic syndrome; NS), blood pressure (BP), urinary sodium excretion, plasma renin activity (PRA), plasma aldosterone level (PA), urinary aldosterone excretion (Au and blood volume were measured before and during prednisolone treatment. In 7 patients (all with NS) steroid-induced hypertension has developed. The patients prone to develop hypertension were hypervolemic nephrotics with initial depression of PRA, PA, Au, and severe sodium retention. In these patients prednisolone did not produce diuresis of natriuresis nor did it decrease proteinuria. In normo- and hypovolemic patients prednisolone produced significant diuresis and natriuresis and failed to induce hypertension. Thus, two types of response to prednisolone could be observed in patients with NS.     

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.     

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.     

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)     

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 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.     

Early and late adjustment to potassium loading in humans

We studied the adaptation to early (72 hr) and late (20 days) K loading (400 mmol/day, 4 equal meals every 6 hour) in six healthy humans. Throughout the study, each single K meal was followed by an acute transient rise in plasma K, aldosterone and kaliuresis. "K balance" (urinary K excretion approximately 80% of intake) was achieved in the second 24 hour period of K loading. This was associated with elevated plasma K and aldosterone, slightly negative sodium (Na) balance and stimulated plasma renin activity. At 20 days of K loading Na loss had been compensated. Plasma renin activity and aldosterone had returned to baseline, although the latter kept increasing after each single K meal. Compared to the first K meal, the K meals at 72 hours and 20 days of K loading were followed by more kaliuresis, while the natriuretic effect had disappeared. Abrupt discontinuation of K loading was followed by negative K balance, lasting only 24 hour, and by Na retention, lasting 72 hours. In conclusion, switching to a high K diet in humans is immediately followed by increased renal K excretion, and by Na loss. K excretion increases over a few days, while Na loss is halted. This can be explained by the rise in plasma aldosterone, secondary to elevated plasma K and renin activity. After weeks, renal adaptation forms an additional factor promoting K excretion and preventing natriuresis. The latter appears specifically from the Na retention which occurs after discontinuation of K loading in the absence of persistent aldosterone stimulation.     

Atrial natriuretic peptide and other vasoactive hormones in nephrotic syndrome

Plasma levels of atrial natriuretic peptide (ANP), arginine vasopressin (AVP), renin activity (PRA), aldosterone (PA), catecholamines and urinary prostaglandins (PG), as well as renal function were measured in children in the edematous state of the nephrotic syndrome before and after infusion of human serum albumin. Before albumin infusion, plasma levels of AVP, PRA, PA and noradrenaline (NA) and urinary excretion of PGE2, PGE-Met, PGF2 alpha were elevated. The mean value of plasma ANP was in the normal range. Albumin infusion produced a 36% increase in the calculated plasma volume. It was associated with a fivefold rise in the plasma level of ANP (31.6 +/- 22.6 vs. 151.4 +/- 52 fmol/ml mean, SD), and a significant fall in the levels of PRA, AVP, PA, and NA. Similarly, urinary concentration of PGE2, PGE-Met and PGF2 alpha fell. Urine flow, GFR, UNaV, FENa, and COsm increased significantly, while CH2O remained unchanged. The diuresis, natriuresis and GFR correlated with the level of plasma ANP, while urinary sodium excretion did not correlate with PA or NA levels. These findings suggest that ANP plays an important role in albumin induced natriuresis in children with nephrotic syndrome.     

Effect on aging on plasma renin and aldosterone in normal man.

The influence of aging on the renin-angiotensin-aldosterone system was evaluated by comparing young (20 to 30 yr) with elderly (62 to 70 yr) healthy subjects. Despite comparable body sodium-fluid balance in the two age groups, serum renin concentration, plasma renin activity and aldosterone concentrations were lower in the elderly. The age-related decreases in circulating renin and aldosterone concentrations were slight while subjects were supine and receiving normal sodium intake; when upright and during sodium depletion, they were more pronounced. Inverse renin-blood pressure interrelations were noted during two of four study conditions involving normal sodium intake or mild sodium depletion (r = --0.44 and --0.47, respectively), but not during progressive sodium depletion. Plasma renin levels were decreased in the elderly regardless of the presence or absence of an inverse relationship with blood pressure. Aldosterone and cortisol responses to corticotropin infusion were unaltered in the elderly. It is concluded that aging may cause a decrease in circulating renin, with parallel lowering of plasma aldosterone concentrations.     

Renal dopaminergic system in nephrotic syndrome and after remission

Background. Although intrarenal dopamine is known to behave as an endogenous natriuretic hormone the role of the renal dopaminergic system in the sodium handling of nephrotic oedema remains unknown. Study design. We monitored the daily urinary excretion of free dopamine, L-DOPA - its precursor, and its metabolites, DOPAC and HVA, during sodium retention accompanying the nephrotic state and natriuresis leading to oedema mobilization in eight patients (mean age 8.0±2.4 years) with drug-induced remission of minimal-change nephrotic syndrome (MCNS). Results. During natriuresis the urinary levels of dopamine did not increase in any of the eight patients studied. Moreover, after remission of the nephrotic syndrome the urinary levels of dopamine were significantly lower than during the nephrotic state (1565.3±361.7 vs 2416.1±558.4, P=0.02). In contrast, the urinary excretion of L-DOPA increased markedly during natriuresis resulting from remission of proteinuria (from 87.0±40.5 up to 296.9±86.3 nmol/24 h; P<0.01). Conclusion. We conclude that the natriuretic response resulting from drug-induced remission of proteinuria in MCNS is accompanied by a decrease in the renal uptake/decarboxylation of L-DOPA to dopamine.     

Plasma atrial natriuretic peptide and natriuretic response to water immersion in patients with nephrotic syndrome.

Eight nonnatriuretic (daily Na excretion less than 50 mEq), 4 natriuretic (daily Na excretion greater than 50 mEq), and 4 steroid-responsive nephrotic patients, and 12 normal controls were studied with a 4-hour water immersion with measurements of electrolytes, plasma atrial natriuretic peptide (ANP), plasma renin activity (PRA), and plasma aldosterone (PA) [corrected]. Four nonnatriuretic patients further received 25 g albumin infusion, with a subsequent 2-hour water immersion study. The results are as follows: (1) In the nonnatriuretic patients, the extremely low basal Na excretion rate, high PRA, and PA levels indicated a state of active Na retention. In spite of the water-immersion induced suppression of PRA and PA and a comparable magnitude of plasma ANP increment, the natriuretic response to water immersion was blunted in the nonnatriuretic patients. (2) In the natriuretic patients, water immersion resulted in a similar magnitude of natriuresis but a higher degree of plasma ANP increment in comparison to the normal controls. (3) Natriuretic and plasma ANP responses to water immersion were not different between the steroid-responsive patients and normal controls. (4) The increase in plasma ANP and the suppression of PRA and PA after 25 g albumin infusion did not result in natriuresis until the further suppression of PRA and PA and the further stimulation of plasma ANP by subsequent water immersion. The above results indicate that the natriuretic and plasma ANP responses to water immersion are related to the basal Na status in nephrotic patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

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.     

肾病综合征钠潴留状态下血管紧张素和醛固酮的变化

本文对２８例肾病综合征在钠潴留状态下，即尿钠排出小于钠的摄入三天以上，体重每日至少增加０．５ｋｇ，用放射免疫法测定其血管紧张素Ⅱ（ＡＴＩ）和醛固酮（Ａｌｄ）。结果显示钠潴留和ＡＴⅡ、Ａｌｄ缺乏相关性。ＡＴⅡ和血白蛋白呈负相关。而ＡＴⅡ、Ａｌｄ和红细胞压积、肾小球滤过率无关。     

Hypertension in adult onset diabetes mellitus: abnormal renal hemodynamics and endogenous vasoregulatory factors

We evaluated 10 adult onset diabetics who developed hypertension well after the onset of glucose intolerance. Systemic and renal hemodynamics, intravascular volume, the renin-angiotensin-aldosterone axis, and the renal kallikrein-kinin system were examined at extremes of sodium intake, and compared to results from matched normotensive and essential hypertensive subjects. On unrestricted sodium diet, the diabetics, compared to normotensives, had significantly decreased blood volume (p less than 0.01), and preservation of renal plasma and blood flow, but significantly elevated renal vascular resistance (p less than 0.05), decreased creatinine clearance (p less than 0.01), and decreased filtration fraction (p less than 0.01). On restricted sodium intake, diabetics, compared to normotensives, had reduced urinary kallikrein activity (p less than 0.01) and reduced ambulatory plasma renin activity (p less than 0.01). Essential hypertensives were similar to diabetics in that both had reduced intravascular volume, elevated renal vascular resistance, and reduced levels of stimulated urinary kallikrein and ambulatory renin activities, but plasma aldosterone concentrations were reduced in diabetics compared to both normotensives and essential hypertensives under all dietary conditions. The ratio urinary kallikrein activity/supine plasma renin activity in diabetics correlated with renal blood flow (p less than 0.05), and inversely with renal vascular resistance (p less than 0.05). We conclude that these hypertensive diabetics have multiple abnormalities in intrarenal hemodynamics that may be related, in part, to abnormal activities of the renal enzymes renin and kallikrein. The kallikrein defect may be an etiologic factor in their hypertension.     

Role of uroguanylin, a Peptide with natriuretic activity, in rats with experimental nephrotic syndrome

Uroguanylin induces natriuresis and diuresis in vivo as well as in vitro and is found mainly in the intestine and the kidney. However, the roles of uroguanylin in nephrotic syndrome, which is associated with sodium and water retention, have not been determined. Therefore, changes in the urine and plasma concentration of immunoreactive uroguanylin (ir-uroguanylin) and its mRNA expression in the kidney and intestine were examined using rats with puromycin aminonucleoside (PAN)-induced nephrosis. Male Sprague-Dawley rats were separated into control and nephrotic groups, and then the urinary excretion of sodium, protein, and ir-uroguanylin was examined over time. The plasma levels and renal and intestinal mRNA expression of uroguanylin at the periods of sodium retention and remarkable natriuresis also were evaluated. The sequential changes of urinary ir-uroguanylin excretion in the nephrotic group were similar to those of urinary sodium excretion. When the urinary excretion of ir-uroguanylin and sodium peaked, the plasma level of ir-uroguanylin also increased compared with that of the control group. Uroguanylin mRNA expression in the kidney increased during the period of sodium retention and then decreased during the period of remarkable natriuresis. Uroguanylin mRNA expression in the small intestines of control and nephrotic rats were identical. However, in a unilateral PAN-induced proteinuria, uroguanylin expression significantly increased in the PAN-perfused kidney compared with that in the opposite kidney. Considering the natriuretic effect of uroguanylin, these results suggested that uroguanylin plays an important role as a natriuretic factor in nephrotic syndrome via both the circulation and the kidney itself.     

Low-dose nitric oxide inhibition produces a negative sodium balance in conscious dogs

Nitric oxide modulates renal hemodynamics and salt and water handling. Studies on the latter have provided conflicting results, however. Electrolyte and water balances were therefore studied in 28 beagles for 4 d, to determine the various effects of nitric oxide synthase (NOS) inhibition on renal function. The dogs were chronically equipped with aortic occluders to reduce renal perfusion pressure (RPP), bladder catheters, and catheters for measurements of RPP and mean arterial BP. A swivel system allowed free movement within the kennels. In a first set of experiments, a nonpressor dose of L-Nomega-nitroarginine (LN) (3 microg/min per kg body wt) was administered, to prevent increases in mean arterial BP and thus pressure effects on renin release and natriuresis. Remarkably, the nonpressor dose of LN caused a negative sodium balance. The natriuretic effect may involve reduced plasma renin activity, reduced aldosterone concentrations, and increased atrial natriuretic peptide concentrations. Changes in aldosterone levels, however, were the only parameters to parallel the time course of sodium excretion. In a second set of experiments, a sodium-retaining challenge was elicited by reduction of RPP. Dogs without NOS inhibition escaped sodium retention during RPP reduction after 2 d ("pressure escape"). LN neither ameliorated nor aggravated the sodium-retaining effect of reduced RPP, nor did it compromise the accomplishment of pressure escape. In conclusion, inhibition of NOS with a low dose of LN results in a reduction of total-body sodium. This effect mainly relies on reduced aldosterone concentrations. Furthermore, LN does not change the regulatory response to long-term RPP reduction.     

Renin inhibition improves pressure natriuresis in essential hypertension

Pressure natriuresis (PN), i.e., a rise in renal sodium excretion in response to a higher BP, is involved in long-term BP regulation. PN is blunted in essential hypertension, but the mechanism is unknown. This study assessed the role of the renin-angiotensin-aldosterone system (RAAS) in PN in eight essential hypertensive men from the individual correlations between spontaneous fluctuations in BP and time corresponding changes in sodium excretion (collected at 2- and 4-h intervals for 48 h), during strict sodium balance, without treatment, and during renin inhibition (remikiren, 600 mg oral compound). Without treatment, daily values for mean arterial pressure were 109.5 +/- 1.9 and 107 +/- 1.9 mmHg, for urinary sodium excretion were 37.2 +/- 2.8 and 42.0 +/- 2.8 mmol/24 h, and for plasma renin activity were 2.34 +/- 0.48 and 2.23 +/- 0.44 nmol/L per h, respectively, for two consecutive days. During remikiren treatment, mean arterial pressure was 101.9 +/- 1.7 and 100.8 +/- 1. 7 mmHg (P: < 0.05, versus baseline). Urinary sodium excretion was 39. 3 +/- 3.7 and 45.2 +/- 5.3 mmol/24 h (not significant versus baseline), and plasma renin activity was 0.79 +/- 0.11 and 0.82 +/- 0.13 nmol/L per h (P: < 0.05 versus baseline). During remikiren treatment, BP correlated positively with sodium excretion in all patients but in only three of eight patients without treatment. The slope of the regression equation was steeper during remikiren treatment in seven of eight patients. Thus, the relationship between BP and natriuresis was more readily apparent during RAAS blockade, suggesting that RAAS activity blunts PN in hypertensive patients. Improved PN may contribute to the hypotensive effect of RAAS blockade and to maintenance of sodium balance at a lower BP level without volume expansion.     

Renal and endocrine effects of fenoldopam and metoclopramide in normal man

The effects of fenoldopam (FD), a selective dopamine-1 (DA1) agonist in doses from 0.05 to 0.50 micrograms/kg/min and of the aselective dopamine antagonist metoclopramide (MCP) on blood pressure (BP), sodium excretion and renal hemodynamics were investigated in 10 healthy volunteers. During FD infusion the diastolic BP fell 9 mm Hg with a rise in heart rate. During combined infusion of FD and MCP no changes in BP occurred. Effective renal plasma flow rose for all doses of FD with a maximal increase of 36% and was not influenced by MCP infusion. Glomerular filtration rate remained unchanged. FD induced an increase in sodium and calcium excretion compared to placebo study, which was abolished by MCP. A marked rise of plasma renin activity during FD infusion was noted, blunted by MCP. MCP induced a marked increase of aldosterone, sustained, but blunted, during subsequent FD infusion, suggesting a DA1-mediated influence on aldosterone secretion. During infusion of FD alone, an increased urinary dopamine excretion was observed. We conclude that FD induces: (1) systemic and renal vasodilation and (2) natriuresis by direct stimulation of DA1 receptors in the proximal tubule, which is (partially) counteracted by a rise of plasma renin activity and subsequently of aldosterone.