Plasma concentrations of immunoreactive-atrial natriuretic polypeptide in patients on hemodialysis

Plasma concentrations of immunoreactive (IR)-atrial natriuretic polypeptide (ANP) were measured before and after hemodialysis (HD) as well as isolated ultrafiltration (UF) in 9 patients with end-stage renal disease. There were significant falls in plasma concentrations of IR-ANP during both UF (from 78.6 +/- 109.7 to 45.4 +/- 56.8 pg/ml; mean +/- SD; p less than 0.025) and HDs (from 84.7 +/- 48.6 to 35.0 +/- 28.4 (p less than 0.01) on first HD; from 73.7 +/- 74.2 to 31.8 +/- 21.8 pg/ml (p less than 0.01) on later HD). There were distinct positive correlations between blood pressures and plasma concentrations of IR-ANP. These results support the view that ANP is secreted mainly by the expansion of blood volume. The fall in plasma concentrations of IR-ANP after HD seems to be caused by the decrease of blood volume, but not by removal due to dialysis of the peptide. However, the physiological role of ANP in patients with end-stage renal disease remains unknown.     

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.     

Plasma concentration of human atrial natriuretic polypeptide in patients with impaired renal function

Using direct radioimmunoassay, the plasma concentration of human atrial natriuretic polypeptide (hANP) was measured in patients with impaired renal function. Patients on maintenance hemodialysis (HD) and those still on medical management (non-HD) were examined. In 13 non-HD patients with serum creatinine values from 2.0 to 8.3 mg/dl, mean plasma hANP (+/- SE) was 404 +/- 23 pg/ml, while it was 236 +/- 11 pg/ml in the normal control group (n = 15) and the difference was significant (p less than 0.001). In all patients as a whole, there was a positive correlation between plasma hANP and mean blood pressure (r = 0.56, p less than 0.05) but no correlation was present between plasma hANP and renal function. Fifty-six HD patients were divided into 2 groups depending on blood pressure level. Plasma levels of hANP in the hypertensive (BP greater than or equal to 150/90 mmHg, n = 21) and in the normotensive (BP less than 150/90 mmHg, n = 35) HD group were 588 +/- 58 pg/ml and 364 +/- 29 pg/ml, respectively, with plasma hANP in both HD groups significantly higher than in the controls (p less than 0.001). There was also a significant difference of plasma hANP between hypertensive and normotensive HD patients (p less than 0.01). However, when the normotensive HD group without cardiomegaly (cardiothoracic ratio less than 50%, n = 17) was compared with the control, the value of plasma hANP was not statistically different from that of the control group. These results suggest that plasma hANP in patients with impaired renal function is influenced by blood pressure and/or cardiac condition.     

Plasma level of atrial natriuretic peptide as an indicator of increased cardiac load in uremic patients

Plasma levels of atrial natriuretic peptide (ANP) were measured by radioimmunoassay in 43 non-dialyzed uremic patients at rest and during maximal exercise to assess the possible relationship between plasma ANP levels and cardiac function, as judged by M-mode echocardiography and exercise tolerance. Patients with poor exercise capacity (exercise time less than 6 min) on dynamic exercise test had decreased left ventricular ejection fraction, increased left atrial diameter, and increased left ventricular mass index (LVMI), compared with patients with better exercise capacity (exercise time greater than 6 min). Plasma ANP was significantly higher in patients with poor exercise capacity and impaired cardiac function (202 pg/ml [95% confidence interval 119 to 284] at rest and 227 pg/ml [149 to 304] during exercise), compared with patients with better exercise capacity (75 pg/ml [50 to 102], p less than 0.005, and 123 pg/ml [80 to 167], p less than 0.05, respectively). Plasma ANP increased significantly (p less than 0.005) during exercise only in patients with better cardiac function. The best correlation among the variables studied was found between LVMI and plasma ANP concentration at rest (r = 0.56, p less than 0.001) and during exercise (r = 0.51, p less than 0.005), whereas neither blood pressure nor renal function showed any significant correlation with ANP levels. We conclude that plasma ANP levels are elevated in uremic patients with impaired cardiac function, correlating with increased LVMI. Plasma ANP determinations are useful in identifying increased cardiac load and consequent cardiac hypertrophy and dysfunction with known associations with increased cardiovascular mortality in patients with chronic renal failure.     

Mitral valve disease and atrial natriuretic polypeptide

We compared plasma ANP concentration and atrial content of ANP as well as plasma concentrations of other fluid regulating hormones and renal function between the MVR group (n = 12) and the non MVR group (n = 14) during open heart surgery. Preoperatively there was no significant difference in plasma ADH and ACTH between two groups, however plasma ANP was significantly higher in the MVR group (96.9 +/- 16.2 pg/ml) than in the non MVR group (22.8 +/- 8.6 pg/ml) (p less than 0.01). During extracorporeal circulation ANP was at a low level because of aortic clamping. Tissue concentration of ANP in right appendages was higher (p less than 0.02) in the MVR group (61.8 +/- 11.8 nmol/g wet weight) (n = 6) than that in the non MVR group (14.9 +/- 3.1 nmol/g wel weight) (n = 15). Also, concentration in left appendages of the MVR group (50.0 +/- 10.4 nmol/g wet weight) (n = 4) was higher than that in right appendages of the non MVR group (p less than 0.05). From these results it may be concluded that increased secretion of ANP is elicited by left atrial load and probably playing an important role on circulating blood volume regulation.     

Clinical significance of natriuretic peptides and cyclic GMP in hemodialysis patients with coronary artery disease

BACKGROUND: Plasma concentrations of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and cyclic guanosine monophosphate (cGMP) are suitable markers of 'dry body weight' (DW) in hemodialysis (HD) patients. However, it is still unknown whether these markers can be applied to patients with renal failure and coronary artery disease (CAD). We examined the reliability of these peptides as volume markers in HD patients with CAD. We also assessed the relationship between natriuretic peptides and indices of left ventricular (LV) function. METHODS: Plasma concentrations of ANP, BNP and cGMP were determined before and after HD in patients with CAD (group 1, n = 19, mean age 63 +/- 12 years) and were compared with those of patients without cardiac disease (group 2, n = 20, age 61 +/- 15 years). Using data obtained by cardiac catheterization, we examined the relationship between natriuretic peptides and indices of LV function in HD patients with CAD. RESULTS: Baseline ANP (244 +/- 205 pg/ml), BNP (713 +/- 928 pg/ml) and cGMP (29.6 +/- 21.6 pmol/ml) were significantly higher in group 1 than in 11 healthy volunteers (18.6 +/- 9.9 pg/ml, 7.7 +/- 7.6 pg/ml, cGMP 8.9 +/- 4.9 pmol/ml, respectively). HD significantly reduced plasma ANP (87 +/- 75 pg/ml) and BNP (477 +/- 702 pg/ml) although they were still above normal control. HD reduced plasma cGMP (7.2 +/- 4.5 pmol/ml) to normal values, suggesting the elimination of cGMP across the dialyzers. Baseline levels of ANP, BNP and cGMP in group 2 were less than those of group 1 but higher than the control. HD reduced natriuretic peptides in group 2 to levels lower than those in post-HD group 1. After HD, there was no significant correlation between reductions in body weight and changes in ANP or BNP. Baseline ANP and BNP levels closely correlated with pulmonary artery pressure, pulmonary artery wedge pressure, left ventricular end-diastolic pressure and left ventricular ejection fraction. A significant correlation was observed between BNP levels and the severity of CAD. CONCLUSION: ANP, BNP and cGMP seem to be a useful markers for fluid overload but not for DW in HD patients with CAD. Plasma ANP and BNP might be useful markers for left ventricular function.     

Plasma atrial natriuretic factor (alpha ANF) during hemodialysis (HD) and hemofiltration (HF).

Plasma concentrations of immunoreactive alpha ANF were measured before, during, and after 3 hours of hemodialysis (HD) and hemofiltration (HF). In seven healthy subjects plasma alpha ANF concentrations were measured to serve as controls. Highly elevated pre-treatment alpha ANF levels were obtained in the HD group (286 +/- 52 pg/ml, mean +/- SE), and in the HF group (275 +/- 48 pg/ml) as compared with the controls (40 +/- 3 pg/ml). The effect of both HD and HF on the alpha ANF concentration was not significant after the first hour of treatment. However, a significant decrease was obtained after the second (HD = 244 +/- 49, HF = 140 +/- 17) and third hours (HD = 244 +/- 48, HF = 135 +/- 15) (p less than 0.05) in both treatments. A steeper decline in the alpha ANF concentration was notable during HF compared with HD. There was a significant difference (p less than 0.05) when both modalities were compared at the end of treatment. A correlation (r2 = 0.98, p less than 0.001) was noted between changes in the alpha ANF levels and the ultrafiltration (UF) volumes only during HF. Plasma alpha ANF concentrations at the filter outlet were lower than at the inlet in both groups. It is concluded that the plasma alpha ANF concentrations are highly elevated in chronic renal failure patients. Despite the decrease in these concentrations during HD and HF it did not reach the normal plasma level. Monitoring of plasma alpha ANF may be a useful indicator for the extracellular volume status during HD and HF treatments.     

Renal and hemodynamic effects of synthetic atrial natriuretic peptide in dogs with chronic renal failure

The present experiments were performed to clarify the renal and hemodynamic effects of atrial natriuretic peptide (ANP) in dogs with chronic renal failure (CRF; produced by 5/6 nephrectomy 3-4 weeks before study). Synthetic alpha-hANP was administered intravenously (0.1 micrograms/kg body weight for 30 min) with a priming bolus injection (1.0 micrograms/kg body weight) to anesthetized controls (n = 8) and CRF-dogs (n = 10). The effects of ANP on renal function, cardiac function, lithium clearance, and plasma ANP levels during clearance studies were determined. Effects of ANP on the hemodynamics were observed to the same degree in both groups. An increase in inulin clearance (CIn) was noted only in the CRF-dogs (7.5 +/- 2.1 to 9.6 +/- 2.9 ml/min; p less than 0.01). The infusion of ANP increased the urine volume, absolute sodium excretion, and osmolar clearance in the control and CRF groups. The fractional excretion of lithium (FELi), a marker of the proximal reabsorption of sodium, was higher at baseline in the CRF group (control group, 24.4 +/- 6.7 vs. CRF group, 41.5 +/- 13.2%; p less than 0.001). Following ANP infusion, FELi increased in both groups. The plasma ANP levels were monitored during the clearance study, and those of the CRF group were higher throughout the experiments. Thus, extrinsic ANP induced diuresis and natriuresis in CRF-dogs, produced by nephron mass reduction. Discrepancies in the pattern of response and plasma ANP levels were observed between the controls and CRF-dogs, suggesting that the action and metabolic clearance rate of ANP were altered in the CRF state.     

Interleukin-18, interleukin-18 binding protein and impaired production of interferon-gamma in chronic renal failure

Uremia is associated with suppressed cellular immune responses, manifested, in part, by impaired interferon-gamma (IFNgamma) production. We investigated the influence of kidney function on plasma levels of interleukin-18 binding protein (IL-18BP), the naturally occurring inhibitor of IL-18. METHODS: Plasma levels of IL-18, IL-18BP and IFNgamma were measured by specific immunoassays in patients with normal kidney function (NKF, n = 29), in patients with chronic renal insufficiency (CRI, n = 29), and in patients on hemodialysis (HD, n = 40). In addition, Staphylococcus epidermidis-induced production of IFNgamma and IL-18 in whole blood cultures was determined in 12 patients on HD and compared to production in 9 controls with NKF. RESULTS: Plasma IL-18 (mean +/- SEM) in NKF was 17.9 +/- 3.6 pg/ml, in CR142.6 +/- 7.0 pg/ml (p < 0.01), and in HD 93.5 +/- 13.6 pg/ml (p < 0.001). The level of IL-18BP in NKF was 3.4 +/- 0.4 ng/ml, in CRI 7.5 +/- 0.7 ng/ml (p < 0.001), and in HD 13.1 +/- 0.8 ng/ml (p < 0.001). Plasma IL-18BP was inversely correlated with creatinine clearance (correlation coefficient: -0.7479). The level of free IL-18 was calculated in NKF to be 13.8 +/- 3.3 pg/ml, in CRI 23.6 +/- 3.9 pg/ml (not significant), and in HD 39.6 +/- 5.9 pg/ml (p < 0.001). Stimulated whole blood production of IFNgamma in NKF was 185 +/- 74 pg/10(6) mononuclear cells (PBMC), but suppressed in HD to 27.3 +/- 16 pg/10(6) PBMC (p < 0.05). CONCLUSION: In uremia, retention of IL-18BP does not suffice to neutralize most of the concomitantly raised levels of total IL-18 resulting in elevated levels of free IL-18. Nevertheless, IFNgamma production in whole blood is reduced in patients on HD. Therefore, suppression of IFNgamma production in uremia may be due to inhibitors of IFNgamma production other than IL-18BP.     

Water immersion-induced alterations of plasma atrial natriuretic peptide level and its relationship to the renin-angiotensin-aldosterone system and vasopressin secretion in acute and chronic renal failure

Water immersion (WI)-induced alterations of circulating plasma volume (PV), plasma renin activity (PRA), plasma levels of aldosterone (Ald), vasopressin (AVP) and atrial natriuretic peptide (ANP) were examined in 12 patients with noninflammatory acute renal failure (ARF) at the anuric/oliguric phase, in 20 hemodialyzed patients with chronic renal failure and in 15 healthy subjects. Patients with acute and chronic renal failure showed significantly elevated basal ANP concentrations (138.67 +/- 12.88 and 295.8 +/- 21.87 pg/ml, respectively) as compared with normals (74.54 +/- 4.1 pg/ml) and significantly elevated PRA (20.85 +/- 3.24 and 6.60 +/- 0.94 ng/ml/h, respectively versus 2.33 +/- 0.31 ng/ml/h), plasma levels of Ald (16.11 +/- 1.26 and 18.11 +/- 1.58 ng/dl, respectively versus 12.71 +/- 1.03 ng/dl) and AVP (6.95 +/- 0.62 and 6.08 +/- 0.54 pg/ml, respectively versus 2.68 +/- 0.48 pg/ml). After 2 hrs of WI a significant decline of PRA, Ald and AVP but an increase of ANP was noted in all examined groups. The absolute WI-induced increase in plasma ANP was significantly less marked in uremic patients than in normals. The endocrine profile of patients with ARF differed only quantitatively from that of patients with CRF both under basal and WI conditions. WI was followed by a significant increase of PV which was significantly more marked in patients with ARF (+ 16.42 +/- 1.73%) than in CRF (10.57 +/- 0.37%) and in normals (+11.3 +/- 1.6%). Only in healthy subjects a significant correlation was found between WI-induced changes of PV and ANP, PRA and Ald, and between PRA and AVP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Molecular forms of plasma atrial natriuretic peptide (ANP) after three kinds of ANP releasing stimulation

This study analyzed by high performance gel permeation chromatography (HPGC) molecular forms of atrial natriuretic peptide (ANP) in plasma from anesthetized dogs stimulated by balloon inflation at the main pulmonary artery (Group A, n = 4), right atrial pacing (Group B, n = 4) and low-molecular dextran injection to right atrium (Group C, n = 4). Mean pulmonary arterial (PA) pressure, mean right atrial (RA) pressure, mean arterial pressure, heart rate and ECG were monitored by polygraph system Mean PA pressure in Group A, heart rate in Group B and mean RA pressure in Group C increased significantly by the stimulation (p less than 0.01, p less than 0.001 and p less than 0.05 respectively). Other parameters were not changed significantly in the three groups. There were significant increases in ANP concentration after the three stimulations (Group A: 52.4 +/- 5.4 (SD) pg/ml----86.4 +/- 12.2 (SD) pg/ml, Group B: 43.8 +/- 6.7 (SD) pg/ml----72.0 +/- 14.1 (SD) pg/ml, Group C: 42.7 +/- 8.8 (SD) pg/ml----69.3 +/- 10.0 (SD) pg/ml; each p less than 0.01). Gel filtration profiles showed that the increased form of plasma ANP in the three groups was alpha-ANP. These results suggest that alpha-ANP may be a main molecular form in plasma from dogs stimulated by the stretch of pulmonary arterial wall and right atrial wall, and atrial pacing.     

Production and metabolic clearance of calcitriol in acute renal failure

Metabolic clearance rate (MCR) and production rate (PR) of calcitriol were studied three and seven days after ischemic acute tubular necrosis (ATN). Creatinine clearance was decreased three days after clamping the renal arteries (0.42 +/- 0.03 ml/min/100 g, N = 6 in ATN vs. 0.68 +/- 0.09, N = 7 in sham controls; P less than 0.001). Plasma concentrations (24.1 +/- 1.9 pg/ml) and PR of calcitriol (9.8 +/- 0.91 ng/kg/day) were significantly lower in ATN rats three days after ischemic insult when compared to sham control rats, respectively (76.6 +/- 7.3 pg/ml, and 29.6 +/- 3.3 ng/kg/day; both P less than 0.01). The MCRs of calcitriol were not different between ATN (0.28 +/- 0.02 ml/min/kg) and sham control rats (0.27 +/- 0.01). By the seventh day after ischemic injury, when creatinine clearance of ATN rats returned to normal, both the PR and plasma concentrations of calcitriol also returned to normal values in these animals. In order to assess the effect of uremia on calcitriol metabolism, MCR and PR of calcitriol were measured in rats with reinfusion of their urines for 24 hours. The PR of calcitriol was significantly decreased (9.42 +/- 1.21; vs. controls, 20.5 +/- 2.9 ng/kg/day, P less than 0.001) in uremic animals. Since decreased PR of calcitriol was also accompanied by decreased MCR of calcitriol, plasma concentrations of calcitriol of the uremic rats with intact kidneys remained within normal values. We conclude that the PR of calcitriol is decreased early in ATN rats. Although the MCR was not decreased in mild ATN rats, it may decrease in severe acute renal failure.     

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.     

Calcitriol metabolism in patients with chronic renal failure

We studied calcitriol metabolism in white patients with chronic renal failure and in age- and sex-matched normal subjects. The plasma levels of calcitriol (21.9 +/- 1.6 pg/mL, n = 7, v control, 37.4 +/- 2.9 pg/mL, P less than 0.001), metabolic clearance rate (MCR) of calcitriol (0.45 +/- .01 mL/min/kg v control, 0.58 +/- .02 mL/min/kg, P less than 0.001), and production rate (PR) of calcitriol (14.2 +/- 1.0 ng/kg/d v control, 31.8 +/- 3.2 ng/kg/d, P less than 0.001) were significantly lower in patients with moderate renal failure (average creatinine clearance, 0.59 +/- 0.01 mL/s [35.1 +/- 6.1 mL/min]) when compared with the respective values of normal control subjects. The MCR of calcitriol was determined again in patients with renal failure after they received calcitriol, 1 microgram/d, for 1 week. The MCR remained unchanged (0.46 +/- .04 mL/min/kg, n = 7) and plasma levels of calcitriol were increased to 34.6 +/- 2.77 pg/mL. The mechanism by which the MCR of calcitriol decreases in renal failure is partly due to the presence of inhibitory factors of degradation enzymes in uremic plasma. When the ultrafiltrates of uremic plasma obtained from hemodialysis patients were infused to normal Sprague-Dawley rats, the MCRs of calcitriol (0.20 +/- .01 mL/min/kg, n = 6) were markedly suppressed in comparison to those of rats infused with the ultrafiltrates of normal plasma (0.37 +/- .01 mL/min/kg, n = 6, P less than 0.001). The uremic plasma also contained factors that inhibit the synthesis of calcitriol. We conclude that metabolic degradation of calcitriol is decreased in patients with renal failure, and uremic plasma contains inhibitory factors that suppress the synthesis and degradation of calcitriol.     

Endothelin in chronic renal failure.

The aims of the present study were to determine plasma endothelin (ET) in chronically uraemic patients, the renal clearance of endogenous ET in normal dog and man, and the effect of acute volaemic expansion on ET. The mean plasma ET concentration in haemodialysis patients was 57.5 +/- 5 pg/ml before haemodialysis and remained unchanged at 52.5 +/- 5 pg/ml after haemodialysis. They were thus significantly elevated both before and after haemodialysis (P less than 0.01) compared with plasma ET in normal subjects of 20.8 +/- 0.8 pg/ml. There was no evidence of ET clearance across the cuprophane membrane of the dialyser. Resting plasma ET values in the 15 non-dialysed uraemic patients ranged between 20 and 52.5 pg/ml (mean 38.2 +/- 2.3 pg/ml), significantly greater than those observed in controls (P less than 0.01). In CAPD patients, plasma ET was also significantly (P less than 0.01), elevated (63 +/- 10 pg/ml) when compared to controls, and similar to those observed in patients before haemodialysis. In dogs, mean ET did not diminish between the aorta and the renal vein (28.1 +/- 1 versus 28.4 +/- 2 pg/ml). In man mean ET did not significantly decline between the renal artery and the renal vein (17 +/- 3 to 13 +/- 0.8 pg/ml). In the seven healthy subjects who received 2000 ml of isotonic saline intravenously ET remained unchanged (24 +/- 2; 23 +/- 1 and 23 +/- 2 pg/ml before and 1 and 2 h after starting hydration respectively). We have thus shown that plasma ET is elevated in patients with chronic renal failure especially those on dialysis and CAPD.(ABSTRACT TRUNCATED AT 250 WORDS)     

Study on the assay of uremic protein-binding inhibitors: furan compound and hippuric acid]

Plasma levels of 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (FA) and hippuric acid (HA) were studied in healthy subjects, uremic patients undergoing continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD). Analysis of FA and HA in the plasma were performed by gas chromatography with capillary column. The mean value of FA in HD patients (16.7 +/- 6.1 micrograms/ml) was significantly higher than these in healthy subjects (3.6 +/- 1.0 micrograms/ml) and in patients on CAPD (4.1 +/- 3.7 micrograms/ml) (p less than 0.01). HA levels in CAPD and HD groups were higher than those in healthy controls (2.4 +/- 0.8 micrograms/ml). In addition, the values in HD patients (46.7 +/- 53.5 micrograms/ml) were more increased than those in CAPD (18.5 +/- 16.5 micrograms/ml) (p less than 0.05). Approximately 95% of total FA and 25% of HA were bound to the plasma protein. However, the plasma level of HA was significantly reduced by HD therapy, whereas that of FA was not altered. In the previous study, it was described that no effect of HD on the percent of the binding of acid drugs to the plasma protein in the uremic plasma was observed. Therefore it is supposed that FA is more involved in the binding of drugs to the plasma protein in comparison with HA. The peritoneal losses of FA and HA in CAPD were 2.3 +/- 1.3 mg/day and 276 +/- 40 mg/day, respectively. As the duration of HD became longer, plasma concentrations of FA in HD patients were more increased. In general, they were maintained to be comparatively low in patients on CAPD.(ABSTRACT TRUNCATED AT 250 WORDS)     

Low dialysance of asymmetric dimethylarginine (ADMA)--in vivo and in vitro evidence of significant protein binding

BACKGROUND: Increased blood levels of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) predict cardiovascular mortality in patients with end-stage renal disease. Despite its low molecular weight, available information on the impact of hemodialysis (HD) on ADMA plasma levels is controversial. METHODS: We assessed plasma concentrations, dialyzer clearance and total amount of ADMA removed in 30 patients with end-stage renal disease during regular HD. In addition, plasma ADMA levels were assessed in 10 patients with acute renal failure treated with extended HD. RESULTS: Regular HD decreased plasma creatinine (from 774 +/- 42 to 312 +/- 17 micromol/l) and urea (from 24.5 +/- 1.5 to 8.4 +/- 0.5 mmol/l) concentrations significantly (both p < 0.001), whereas plasma ADMA remained unchanged (4.35 +/- 0.19 vs. 4.76 +/- 0.24 micromol/l). ADMA clearance was 92 +/- 6 ml/min, and the total amount removed in the spent dialysate was 37 +/- 4 micromol. The clearances of creatinine (161 +/- 3 ml/min) and of urea (173 +/- 3 ml/min) were significantly higher. Furthermore, even during extended HD, plasma ADMA concentrations did not decrease significantly (1.73 +/- 0.22 vs. 1.63 +/- 0.18 micromol/l). CONCLUSION: In conclusion, dialysance of ADMA is markedly lower than expected from its molecular weight because of significant protein binding of the substance. Since markedly increased ADMA blood concentrations have been linked to cardiovascular complications due to atherosclerosis in patients with ESRD, new strategies should be evaluated to remove this putative uremic toxin.     

The effects of atrial natriuretic peptide on urinary protein excretion in patients with renal parenchymal disease and those with diabetic mellitus

The effects of atrial natriuretic peptide (ANP) on urinary protein excretion were examined in patients with renal parenchymal diseases (RPD, n = 18) and those with diabetes mellitus (DM, n = 12). Before and 30 min after intravenous injection of ANP (50 micrograms), urine samples were collected. ANP injection increased urinary volume and urinary sodium excretion in both groups. In RPD, urinary protein excretion (UprV) increased by 87% (1.5 +/- 0.7 [SEM] to 2.8 +/- 1.1 mg/min, p less than 0.05). ANP also increased UprV in patients with diabetic nephropathy [N(+); 1.7 +/- 0.8 to 5.0 +/- 2.5 mg/min, p less than 0.05] and those without nephropathy [N(-); 0.10 +/- 0.02 to 0.22 +/- 0.07 mg/min, p less than 0.05]. Since ANP increased creatinin clearance in both groups (+9.4 +/- 2.5 ml/min in RPD and +24.1 +/- 3.5 ml/min in DM, p less than 0.01 for both), urinary protein to creatinine excretion ratios (UprV/UcrV) were determined, which should be a parameter of glomerular protein permeability. The UprV/UcrV ratio increased by 48% (p less than 0.01) and 24% (p less than 0.05) in RPD and in DM, respectively. ANP did not change urinary composition of albumin and globulin. In RPD, increases in UprV by ANP were positively related to the basal serum creatinin levels (r = 0.57, p less than 0.01). In DM group, ANP-induced increases in the UprV/UcrV ratio were higher in the N(+) subgroup than in the N(-) subgroup (+0.8 +/- 0.4 vs +0.09 +/- 0.04, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Elevated plasma atrial natriuretic peptide level in the early phase of microalbuminuria in patients with non-insulin-dependent diabetes mellitus

Plasma atrial natriuretic peptide (ANP) levels were examined in 66 patients with non-insulin-dependent diabetes mellitus (NIDDM), and in 9 age-matched normal controls and 18 hypertensive controls. The diabetic patients were classified into three groups according to random urine albumin/creatinine ratio (ACR, mg/g or mg/88.4 nM); group 1 (normo-albuminuria, ACR less than 20, n = 34), group 2 (borderline microcalbuminuria, 20 less than or equal to ACR less than 100, n = 17) and group 3 (manifest microalbuminuria and macroalbuminuria, 100 less than or equal to ACR less than 2000, n = 15). Plasma ANP levels (pg per ml) were significantly elevated in group 2 (46.0 +/- 19.0 SD) when compared with either normal controls (23.8 +/- 14.2), group 1 (28.9 +/- 15.6) or group 3 (26.0 +/- 12.9). This increase in plasma ANP levels was not related to hypertension. Furthermore, plasma ANP levels correlated positively with log(ACR) among the patients with ACR under 100 (groups 1 and 2 combined, r = 0.4701, p less than 0.01). These results suggest that an elevated plasma ANP level in the early phase of microalbuminuria possibly plays a pathophysiological role in the development of nephropathy in NIDDM patients.     

Assessment of dry body-weight in haemodialysis patients by the biochemical marker cGMP

We investigated whether cGMP might be a suitable marker of ideal weight in chronic haemodialysis patients. In 20 patients on chronic haemodialysis (10 males, 10 females, mean age 55.5 +/- 7.4 years; mean interdialytic weight gain 2.4 +/- 1.1 kg) we determined plasma ANP and cGMP values before and after several haemodialysis treatments. ANP and cGMP before haemodialysis were markedly elevated (ANP 255 +/- 190 pg/ml; cGMP 28.6 +/- 16.2 pmol/ml). A significant decrease was found after haemodialysis (ANP 169 +/- 88 pg/ml; cGMP 13.5 +/- 7.4 pmol/ml). These values were still well above normal. There was a significant positive correlation between excessive body-weight delta P (difference between actual weight and estimated ideal weight), indicating fluid overload and ANP before (r = 0.57; P less than 0.001) and after haemodialysis (r = 0.47; P less than 0.001) as well as cGMP before (r = 0.42; P less than 0.01) and after haemodialysis (r = 0.85; P less than 0.0001). With cGMP and delta P after haemodialysis, the correlation appeared to be close enough for clinical application. All patients with a cGMP value of 18 pmol/ml or more after haemodialysis had an excessive body-weight of at least 0.5 kg. We conclude from these data that the plasma cGMP value determined immediately after haemodialysis is a sensitive marker for hyperhydration in patients with end-stage renal disease.