Atrial natriuretic peptide, sodium retention, and proteinuria in nephrotic syndrome

BACKGROUND.: Oedema formation in the nephrotic syndrome is primarily dueto tubular sodium retention. The pathogenetic role of alphaatrial natriuretic peptide (ANP), a hormonal promoter of natriuresisis unknown. METHODS.: In 31 patients (aged 35±11 years) with nephrotic syndromeand histopathological evidence of primary glomerulonephritis,we investigated plasma ANP concentration and its influence onrenal haemodynamics, natriuresis, and proteinuria (total protein,albumin, IgG excretion). Patients with a compensated treatedform of nephrotic syndrome due to primary glomerulonephritiswere included in the study. Serum creatinine levels were 1.4mg/dl. Diuretic medication was discontinued at least 24 h beforethe investigation was started. Patients were randomly assignedto ANP infusion (0.005 µg/kg*min; group II, n=15) or receivedplacebo (group III, n=16). Ten healthy subjects (group I) servedas normal controls. RESULTS.: In normal subjects (group I), ANP caused an increase in natriuresisfrom 14.5±4.2mmol/h to 26.4±11.1 mmol/h (P<0.01).In patients with nephrotic syndrome (group II), baseline sodiumexcretion of 10.5±6.0 mmol/h was increased to 19.6±14.8mmol/h with ANP infusion (P<0.01). No changes were seen inthe placebo group III. The absolute increase in ANP inducednatriuresis was not significantly different between group Iand II. However, plasma ANP levels were significantly higherin patients with nephrotic syndrome (166±87 pg/ml vs.74±21 pg/ml, P<0.05) and also reached higher levelsafter ANP infusion (P<0.01). Therefore, natriuresis was significantlyreduced when circulating ANP levels were taken into account(P<0.05). ANP administration resulted in an increase of totalprotein excretion in patients with the nephrotic syndrome (groupII, from 219±277 mg/h to 264±268 mg/h). Albuminelimination rose from 128±151 mg/h to 167±170mg/h (P<0.05) and IgG excretion from 4.91±6.67mg/hto 9.27±10.78mg/h (P<0.05). Healthy subjects alsoshowed a small but significant increase in albuminuria (48±38%,P<0.05). Low-dose ANP infusion did not, however, induce anysignificant alteration in GFR, ERPF and blood pressure. CONCLUSION.: ANP plasma concentrations in the steady state are elevated inpatients with the nephrotic syndrome. The natriuretic effectof ANP is reduced when referring to circulating ANP plasma levels.Elevated ANP levels enhance urinary protein excretion in thenephrotic syndrome. This is not due to modulation of GFR orFF, but is most probably attributable to increased glomerularpermeability.     

Atrial natriuretic peptide and the renal response to hypervolemia in nephrotic humans

To elucidate the abnormality of body fluid homeostasis that attends the nephrotic syndrome, we compared the atrial hormonal and renal excretory and vasomotor responses to water immersion of nephrotic patients (N = 10) with those of healthy controls (N = 9). Nephrotics exhibited depressed baseline levels of atrial natriuretic peptide (ANP, P less than 0.05) and lower rates of urine flow and sodium excretion (P less than 0.01). Although immersion-induced hypervolemia increased plasma ANP to equivalent levels (75 +/- 19 vs. 60 +/- 6 pg/ml), the disparity in corresponding urinary flow (5 +/- 1 vs. 13 +/- 2 ml/min, P less than 0.01) and sodium excretion (171 +/- 42 vs. 540 +/- 65 muEq/min, P less than 0.01) grew larger. In contrast, immersion caused an equivalent reduction of renal vascular resistance by 16 and 17%, respectively (P less than 0.01). Despite higher renal plasma flow and lower oncotic pressure of plasma, the glomerular filtration rate remained constant during immersion in both groups. Similar constancy of fractional clearances of dextrans of graded size suggests that immersion may have lowered the glomerular transcapillary hydraulic pressure difference (delta P). We conclude that renal vasomotor responsiveness to hypervolemia is preserved in nephrotics, but that the mediatory role of ANP in this response is uncertain. By contrast, diminished responsiveness of the distal nephron to the natriuretic action of endogenous ANP could contribute to edema formation in the nephrotic syndrome.     

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)     

Atrial natriuretic peptide in renal development

Although discovered little more than a decade ago, atrial natriuretic peptide (ANP) has been shown to play a significant role in the maintenance of sodium homeostasis. Immediately after birth, plasma ANP concentration is very high concurrent with right atrial dilatation and a high urinary excretion of cyclic GMP (cGMP), the second messenger for ANP. Following postnatal diuresis and natriuresis, atrial volume, plasma ANP concentration, and urinary cGMP excretion decrease to baseline levels. In the ensuling suckling period, the diuretic and natriuretic response to acute saline volume expansion are attenuated, an effect which is offset by the lower hematocrit at this age. Increase in hematocrit by isovolemic exchange transfusion results in a greater rise of plasma ANP concentration following volume expansion, but a reduced excretion of cGMP. Intravenous infusion of ANP results in greater plasma ANP concentration, and greater urinary excretion of cGMP and sodium, in adult than in young rats. This increased metabolic clearance of ANP during early development is due at least in part to increased activity of clearance receptors. In addition, neutral endopeptidase contributes to removal of circulating ANP in maturing as well as adult rats. Infusion of ANP in neonatal or adult rats results in accumulation of cGMP in glomerular podocytes, with a higher threshold for activation in immature animals. Despite the similar response of intracellular generation of cGMP following exposure to ANP in neonatal and adult rats, egression of ANP out of glomeruli is low in neonates, an effect that is due to immaturity of an organic acid transporter. It is possible that these maturational differences in the processing of cGMP account for the developmental changes in renal response to ANP or to acute volume expansion.     

Plasma concentration and renal effect of human atrial natriuretic peptide in nephrotic syndrome

To elucidate the pathophysiological role of atrial natriuretic peptide (ANP) in nephrotic syndrome, the plasma level of ANP and renal response to exogenous human alpha-ANP (alpha-hANP) were measured in untreated adult patients with idiopathic nephrotic syndrome (NS) and compared with those of normal volunteers (NL). The plasma concentration of immunoreactive ANP (ir-ANP) in NS (112 +/- 9.8 pg/ml, n = 9, mean +/- SE) was not significantly different from that in NL (98 +/- 8.0 pg/ml, n = 13). However, a significant positive correlation was observed between the plasma ir-ANP level and blood volume in NS (r = 0.714, p less than 0.05). In an infusion study with synthetic alpha-hANP (25 to 100 ng/kg/min), the urine flow rate increased from 0.67 +/- 0.08 to 7.11 +/- 1.08 ml/min in NL (n = 5, p less than 0.01) and from 0.64 +/- 0.16 to 2.88 +/- 0.70 ml/min in NS (n = 9, p less than 0.05) and the urinary sodium excretion increased from 115 +/- 16 to 466 +/- 62 microEq/min in NL (p less than 0.01) and from 51 +/- 8 to 207 +/- 58 microEq/min in NS (p less than 0.01). The absolute and percent changes in urine flow rate and the absolute change in sodium excretion were lower in NS (p less than 0.05) than in NL. The percent change in sodium excretion in NS did not differ from that in NL. In 2 patients with high plasma ir-ANP concentrations, however, infusion of ANP induced poor sodium excretion (59 and 95 microEq/min at 100 ng/kg/min ANP infusion, respectively). Hemodynamic and renal parameters such as blood pressure, pulse rate and creatinine clearance were similarly affected in both NL and NS. We also found that the urinary excretion of protein was significantly increased in NS (p less than 0.05) during infusion of alpha-hANP. Our data suggest that the plasma level of ir-ANP is regulated by blood volume status, and that the renal responsiveness to ANP, at least in part, contributes to water and sodium retention in NS.     

Atrial natriuretic factor in the acute nephritic and nephrotic syndromes

Because the role of systemic hormones in the pathophysiology of edema in acute renal disease remains incompletely understood, we compared the levels of atrial natriuretic factor (ANF) and plasma renin activity (PRA) in patients with acute glomerulonephritis (AGN), nephrotic syndrome (NS), and normal individuals during salt deprivation and salt loading. Sixteen patients with AGN (10 males) and nine patients with NS and hypoalbuminemia (7 males) were studied on admission, and after recovery (12 AGN patients) or remission (4 NS patients). Eighteen normal controls were each studied after five days on a low (20 mEq Na/day), regular (120 mEq Na/day) and high (300 mEq Na/day) dietary salt intake. Patients with AGN and NS had comparable edema (AGN 2.8 +/- 0.53 kg; NS 3.36 +/- 0.47 kg; SE) and urinary Na excretion (mean +/- SEM: AGN 0.97 +/- 0.11 mEq/hr; NS 1.06 +/- 0.16 mEq/hr), but AGN patients had five times higher ANF (AGN 27.2 +/- 4.06 fmol/ml; NS 5.51 +/- 1.02 fmol/ml; P less than 0.001) and six times lower PRA ng/liter.sec levels (AGN 0.187 +/- 0.047; NS 1.144 +/- 0.222; P less than 0.001) than NS patients. The degree of edema was correlated with ANF levels in AGN patients (P less than 0.001) but not in NS patients. There was a strong exponential negative correlation (r = -0.773, P less than 0.0001) between ANF and PRA, in which AGN patients and Na-restricted controls were located in the opposite ends of the volume sensing-response, and NS patients in the middle, alongside controls with regular Na intake.(ABSTRACT TRUNCATED AT 250 WORDS)     

Atrial natriuretic peptide levels in the sleep apnoea/hypopnoea syndrome.

BACKGROUND--Patients with the sleep apnoea/hypopnoea syndrome have increased salt and water excretion at night which has been reported to be associated with an increase in plasma levels of atrial natriuretic peptide (ANP). A study was performed to determine whether any rise in plasma ANP levels was related to nocturnal hypoxaemia. METHODS--Nine patients with sleep apnoea/hypopnoea syndrome were studied on two nights, one breathing air and the other 28% oxygen, the order being randomised. Venous levels of ANP, aldosterone, and renin activity were measured. RESULTS--No decrease in plasma ANP levels on oxygen was seen, and, indeed, there was no evidence of an overnight increase in ANP levels. CONCLUSION--Oxygen therapy does not diminish nocturnal plasma ANP levels in patients with sleep apnoea/hypopnoea syndrome.     

Atrial natriuretic peptide, brain natriuretic peptide and c-type natriuretic peptide: effects on testicular microcirculation and immunohistochemical localization

The effect of local injection of atrial (ANP), brain (BNP) and C-type (CNP) natriuretic peptides and an ANP antagonist (HS-142–1) on testicular microcirculation and vasomotion was studied using laser Doppler flowmetry. The natriuretic peptides were also localized immunohistochemically within the testis.
ANP, BNP-32, CNP-22 and CNP-53 all caused a dose-related increase in testicular blood flow. The effect of ANP was blocked by concomitant injection of the ANP antagonist. Immunoreactive (ir) CNP and ir BNP were found in Leydig cells whereas ir ANP was observed in the seminiferous tubules. It is suggested that the natriuretic peptides could play a role in local regulation of the testicular microcirculation.     

Atrial natriuretic peptide in children with idiopathic hypercalciuria

We measured plasma atrial natriuretic peptide (ANP) levels in 30 children with idiopathic hypercalciuria (IH) and 19 normal controls (NC). A calcium (Ca) loading test was performed in all patients to determine the type of IH. Subsequently plasma ANP, cAMP and renin activity (PRA), serum total and ionized Ca, intact parathyroid hormone, aldosterone, and 1,25-dihydroxyvitamin D as well as urine Ca, cAMP, and electrolytes were determined in all subjects. The mean (SD) plasma ANP levels were significantly lower in patients with renal hypercalciuria (RH) [21.4 (4.8) pg/ml] than in those with absorptive hypercalciuria (AH) [26.8 (7.6) pg/ml, P<0.05] and NC [27.6 (6.6) pg/ml, P<0.01]. PRA was significantly lower in AH [2.9 (1.3) ng/ml per hour] than in RH patients [7.8 (6.8) ng/ml per hour, P<0.01] and in NC [6.8 (4.6) ng/ml per hour, P<0.005]. Serum aldosterone values were significantly lower in AH [14.5 (11.4) ng/dl] than in RH patients [25.4 (14.1) ng/dl, P<0.05] and in NC [32.6 (20.5), P<0.001]. The lower plasma ANP levels in RH than in AH patients and in NC may be due to Ca depletion. The lower PRA and serum aldosterone levels in AH than in RH patients and in NC may be attributed to Ca excess. Received: 18 November 1998 / Revised: 4 October 1999 / Accepted: 5 October 1999     

Effect of synthetic human atrial natriuretic peptide (102-126) in nephrotic syndrome

Synthetic human ANP (102-126) or vehicle was intravenously administered to eight patients with non-edematous nephrotic syndrome to study its effect on protein and sodium excretion. ANP was given in ascending doses, each dose for one hour, two to three days apart. Four patients received 0.03, 0.10 and 0.45 microgram/kg/min of ANP, and four received 0.015, 0.06 and 0.20 microgram/kg/min. Natriuresis increased at all doses; by 179 +/- 13.6% (mean +/- SEM; P less than 0.05) at 0.015 microgram/kg/min and by 660 +/- 71.5% (P less than 0.01) at 0.20 microgram/kg/min. Urinary albumin excretion increased by 138 +/- 30.1% (P less than 0.05) at 0.015 microgram/kg/min of ANP and by 534 +/- 132% (P less than 0.01) at 0.20 microgram/kg/min. Immunoglobulin G excretion increased proportionally to albumin excretion. Hematocrit and serum albumin concentration increased after ANP. In each patient the percent reduction of plasma volume calculated from the effect on serum albumin was smaller than the hemoconcentration calculated from the effect on hematocrit, suggesting a loss of albumin from the intravascular compartment. This could not be accounted for by the increased glomerular filtration of albumin. Blood pressure and effective renal plasma flow decreased and filtration fraction increased after ANP. Plasma renin was suppressed at lower doses of ANP but was stimulated, together with plasma noradrenaline, at higher doses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Atrial natriuretic peptide and sodium homeostasis in chronic renal failure

In order to evaluate the possible role of vasoactive hormones in the mechanism of exaggerated sodium loss due to reduced renal mass we measured plasma concentration of atrial natriuretic peptide (ANP), aldosterone, plasma renin activity (PRA), plasma noradrenaline, and dopamine, in 12 children with advanced chronic renal failure (mean C_In17.8-2.6,x± SEM, C_PAH93.5±17 ml/min per 1.73 m², FE_Na7.0±0.95%). No patient had clinical signs of volume overload. Plasma concentrations of ANP were not significantly different from those of healthy agematched controls (29.2±7.2 vs 23.2±3.1 fmol/ml) and did not correlate with urinary sodium excretion. Plasma concentrations of aldosterone, PRA and noradrenaline, were also within the physiological range, while plasma dopamine levels were elevated (260±36 vs 98±11 pg/ml, <0.001). Our data do not support the notion that ANP or the renin-aldosterone axis play a major role in the adaptation of remaining nephrons to maintain long-term sodium balance in normotensive children with chronic renal failure.     

Atrial natriuretic peptide in dehydrated Long-Evans rats and Brattleboro rats

Atrial natriuretic peptide (ANP) was measured by radioimmunoassay in atrial and plasma extracts from normal Long-Evans (LE) rats and Brattleboro-strain diabetes insipidus (DI) rats. LE rats, dehydrated for 72 hours, had an increased plasma osmolality and plasma vasopressin. They also demonstrated a higher atrial immunoreactive ANP (IR-ANP) content than hydrated animals (72 hr dehydration: 178.2 +/- 30.4 micrograms/g wet weight atria, mean +/- SE, control: 60.4 +/- 8.2; P less than 0.001). Plasma IR-ANP in dehydrated LE rats tended to be lower than hydrated LE but this was not statistically significant [72 hr dehydration: 61.9 +/- 5.9 pg/ml, control: 82.4 +/- 8.2]. IR-ANP concentration in atrial extracts from DI rats, without detectable plasma vasopressin levels but with increased plasma osmolality, was not different from that in hydrated LE rats (DI: 100.6 +/- 13.2 micrograms/g). There was also no significant difference between plasma IR-ANP in DI and hydrated LE rats (DI: 100.2 +/- 11.9 pg/ml). The atrial IR-ANP concentration in DI rats was decreased by infusion with either arginine-vasopressin (AVP) or 1-deamino-8-arginine vasopressin (DDAVP), and plasma IR-ANP was increased significantly by both infusions (AVP: 171.3 +/- 18.1 pg/ml, DDAVP: 179.5 +/- 24.6). Thus, changes in atrial and plasma IR-ANP concentration appeared to be associated with changes in water balance but not with plasma AVP levels, indicating that the changes in volume may be a more important factor controlling ANP release in vivo than vasopressin itself.     

Atrial natriuretic peptide induces postprandial lipid oxidation in humans

OBJECTIVE—Atrial natriuretic peptide (ANP) regulates arterial blood pressure. In addition, ANP has recently been shown to promote human adipose tissue lipolysis through cGMP-mediated hormone-sensitive lipase activation. We hypothesized that ANP increases postprandial free fatty acid (FFA) availability and energy expenditure while decreasing arterial blood pressure.RESEARCH DESIGN AND METHODS—We infused human ANP (25 ng · kg⁻¹ · min⁻¹) in 12 men (age 32 ± 0.8 years, BMI 23.3 ± 0.4 kg/m²) before, during, and 2 h after ingestion of a standardized high-fat test meal in a randomized, double-blind, cross-over fashion. Cardiovascular changes were monitored by continuous electrocardiogram and beat-by-beat blood pressure recordings. Metabolism was monitored through venous blood sampling, intramuscular and subcutaneous abdominal adipose tissue microdialysis, and indirect calorimetry.RESULTS—ANP infusion decreased mean arterial blood pressure by 4 mmHg during the postprandial phase (P < 0.01 vs. placebo). At the same time, ANP induced lipolysis systemically (P < 0.05 vs. placebo) and locally in subcutaneous abdominal adipose tissue (P < 0.0001 vs. placebo), leading to a 50% increase in venous glycerol (P < 0.01) and FFA (P < 0.05) concentrations compared with placebo. The increase in FFA availability with ANP was paralleled by a 15% increase in lipid oxidation rates (P < 0.05 vs. placebo), driving a substantial increase in postprandial energy expenditure (P < 0.05 vs. placebo).CONCLUSIONS—Our data identify the ANP system as a novel pathway regulating postprandial lipid oxidation, energy expenditure, and concomitantly arterial blood pressure. The findings could have therapeutic implications.A modest mismatch between energy intake and expenditure elicits major changes in body weight over years. Total daily energy expenditure comprises resting metabolic rate, physical activity, and postprandial thermogenesis. Measures that increase postprandial thermogenesis could prevent or treat obesity. Pharmacological strategies to augment energy expenditure have been unsuccessful because of side effects (1). Manipulation of adrenergic transmission is associated with increased thermogenesis, blood pressure elevations, and other cardiac side effects (2). Atrial natriuretic peptide (ANP) has recently been shown to promote adipose tissue lipolysis through cGMP-mediated, hormone-sensitive lipase activation (3). ANP-mediated lipolysis has only been observed in primates such as macaques and humans but not in other species (4). ANP increases circulating free fatty acid (FFA) levels in human subjects (5–8). Previous studies with adrenergic agonists suggested that increased circulating FFA concentrations can drive an increase in energy expenditure (9). In our earlier studies, ANP-mediated lipolysis did not alter energy expenditure in the fasted state, whereas lipid oxidation rate increased slightly (6,8). We now tested the hypothesis that ANP augments postprandial FFA availability, lipid oxidation, and energy expenditure while concomitantly decreasing blood pressure in healthy young men.     

Atrial natriuretic peptide and N-terminal atrial natriuretic peptide in plasma reflect right ventricular volumes following coronary artery surgery

Background: Atrial natriuretic peptide (ANP) and the more stable N-terminal fragment (N-ANP) of prohormone are peptides, released in equimolar amounts from cardiac myocytes in response to atrial stretch or ventricular overload and myocardial ischaemia. Protection of the right ventricular (RV) myocardium during ischaemia in cardiac surgery is difficult, especially in patients with severe right coronary artery (RCA) disease. This prospective study was designed to ascertain a possible relationship between changes in plasma ANP/N-ANP concentration and RV function in RCA-diseased patients.
Methods: Plasma ANP and N-ANP concentrations and RV function, measured by fast-response thermodilution, were determined serially in 15 patients with total RCA stenosis and in another 15 with no significant RCA disease (controls) before, during and after coronary artery surgery.
Results: The RV ejection fraction was lower and the RV end-systolic volume index higher in the RCA-diseased patients than in the controls ( P < 0.05) on the second postoperative day, and both ANP and N-ANP were higher in the RCA patients ( P < 0.05) from 6 h after cardiopulmonary bypass till the second postoperative day. At the same time the changes in N-ANP concentrations from the levels before induction of anaesthesia correlated with RV ejection fraction and RV volume indexes, but not with heart rate or parameters indirectly reflecting left-sided loading. Right atrial pressure did not differ between the groups nor did it increase significantly during the study.
Conclusions: The relationships found between N-ANP and RV volume indexes and RV ejection fraction suggest ventricular expression of ANP: ANP release may be stimulated by RV distension, the more so the poorer the RV function.     

Atrial natriuretic peptide and arginine vasopressin in pregnancy and pregnancy-induced hypertension

Atrial natriuretic peptide (ANP) and arginine vasopressin concentrations were measured in 9 patients with pregnancy-induced hypertension. The results were compared to those found in 7 normal pregnant women matched for age, duration of pregnancy, and parity. Plasma ANP levels were significantly higher in the pregnancy-induced hypertension patients than in the control group. Plasma arginine vasopressin concentrations, however, were not significantly different in the two populations. The mechanism of the observed rise in ANP concentrations in the patients with pregnancy-induced hypertension is not known. However, it may be related to a rise in intra-atrial pressures secondary to hypertension, an increase in baroreceptor discharge as a result of hypertension, or, less likely, the ANP may be released from extracardiac sites.     

成人原发性肾病综合征血容量与肾素,醛固酮,心钠素的关系

探讨成人原发性肾病综合征(NS)血容量与肾素、醛固酮及心钠素的关系。方法 应用~(113)mInCl标记转铁蛋白稀释法测定血容量,放免法测定血浆激素水平。对水肿期NS28例、正常26例及其中NS缓解期随访18例进行检测。结果 (1)水肿期NS血容量与正常组无差别,血浆肾素活性(PRA)、血管紧张素Ⅱ(ATⅡ)、醛固酮(Ald)、心钠素(ANP)水平均较正常组高,白蛋白、各激素水平与血容量无显著相关;(2)缓解期与水肿期比较,总的血容量无差异,Ald、ANP显著降低,PRA、ATⅡ则无明显差异;(3)Ald与24小时尿排钠(UNaV)显著负相关。结论 Ald和ANP是NS钠排泄的主要调节因子。