Coupling between renal tubular secretion and effect of bumetanide

The relationship between renal tubular secretion of bumetanide and its saluretic effect was studied in six healthy subjects before and after probenecid (1 gm IV). Bumetanide was determined in serum and urine by HPLC. Continuous intravenous infusion of bumetanide (200 micrograms/hr) gave an average diuresis at steady state of 15 +/- 3 ml/min. Corresponding plasma concentration, urinary excretion rate, and renal clearance of bumetanide averaged 14.3 +/- 2.3 ng/ml, 64 +/- 31 micrograms/30 min, and 145 +/- 59 ml/min. After probenecid there was a marked change in bumetanide kinetics. Average plasma concentration rose to 41.7 +/- 8.1 ng/ml, whereas renal clearance and urinary excretion rate fell to 15.1% and 29.5% of control. There was also a concomitant decrease in diuresis and saluresis to 47% and about 40% of control. Probenecid also reduced the renal clearance of para-aminohippurate and inulin to 67% and 75% of control. Since the fractional water and sodium chloride excretion was also reduced about 33% and 42%, it is concluded that a large part of the diuretic effect of bumetanide depends on its active tubular secretion. As with furosemide and piretanide, bumetanide diuresis is elicited from the luminal side of the human nephron.     

Immunoreactive N-terminal pro-atrial natriuretic peptide in human plasma: plasma levels and comparisons with alpha-human atrial natriuretic peptide in normal subjects, patients with essential hypertension, cardiac transplant and chronic renal failure

1. Plasma levels of immunoreactive N-terminal pro-atrial natriuretic peptide (N-terminal ANP) have been measured in 25 normal subjects, 29 patients with essential hypertension, six cardiac transplant recipients, seven patients with dialysis-independent chronic renal failure and 11 patients with haemodialysis-dependent chronic renal failure. Plasma was extracted on Sep-Pak cartridges and N-terminal ANP immunoreactivity was measured using an antibody directed against pro-ANP (1-30). 2. Plasma levels of N-terminal ANP (means +/- SEM) were 235.3 +/- 19.2 pg/ml in normal subjects and were significantly raised in patients with essential hypertension (363.6 +/- 36.3 pg/ml), in cardiac transplant recipients (1240.0 +/- 196.2 pg/ml), in patients with chronic renal failure not requiring dialysis (1636.6 +/- 488.4 pg/ml) and patients with chronic renal failure on maintenance haemodialysis (10336.1 +/- 2043.7 pg/ml). 3. There were positive and significant correlations between the plasma levels of N-terminal ANP and alpha-human ANP (alpha-hANP) with individual correlation coefficients of 0.68 within the normal subjects, 0.47 in patients with essential hypertension, 0.78 in patients with dialysis-independent chronic renal failure and 0.68 in patients with haemodialysis-dependent chronic renal failure (P less than 0.05 in every case).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of cefonicid in uraemic patients

Eight subjects with normal renal function and 20 uraemic patients with various degrees of renal insufficiency were given a single iv dose of 1.0 g cefonicid, as a bolus injection. Five groups of subjects were studied: group I, GFR greater than 80 ml/min, group II 30 less than GFR less than 80 ml/min, group III 10 less than GFR less than 30 ml/min, group IV GFR less than or equal to 10 ml/min and group V, haemodialysis patients. Cefonicid concentrations in plasma and urine were measured by microbiological assay (MA) and HPLC method. Results were similar with the two techniques. The mean peak plasma levels were 200-300 mg/l and the apparent volume of distribution was 0.18-0.20 1/kg for all patients. The elimination half-life (T 1(2) beta) increased as renal function decreased: 5.31 +/- 1.30 h in healthy subjects and 58.92 +/- 12.38 h in patients with end-stage renal disease. Urinary elimination of cefonicid was inversely related to the degree of renal impairment: 83% of the dose in 24 h in normal subjects and 13.6% of the dose in patients with severe renal failure. Total body clearance decreased from 23.9 +/- 3.4 ml/min/1.73 m2 (group I) to 1.9 +/- 0.2 ml/min/1.73 m2 (group V). Renal clearance fell from 19.0 +/- 4.9 ml/min/1.73 m2 (group I) to 1.0 +/- 0.4 ml/min/1.73 m2 (group IV). The fractional clearance and the non renal clearance were similar in normal subjects and in uraemic patients. Cefonicid is not haemodializable because of its high protein binding. Dosage of cefonicid should be adjusted according to the degree of renal impairment. Supplemental doses are not necessary after haemodialysis.     

Low-dose dopamine infusion, renal haemodynamics and urinary albumin excretion rate in insulin-dependent diabetics and in normal man

The effect of experimental renal vasodilatation by means of low-dose (2.0 micrograms/kg/min) intravenous dopamine infusion was investigated in 28 insulin-dependent diabetes mellitus (IDDM) patients with normal basal urinary albumin excretion rate (UAE) (less than 15 micrograms/min), 9 IDDM patients with UAE between 15-200 micrograms/min (microalbuminuria), and 7 normal subjects. Glomerular filtration rate (GFR) (thalamate clearance) showed a small increase with dopamine infusion, in the normoalbuminuric IDDM patients from 140 +/- 20 to 146 +/- 20 ml/min (2p less than 0.01), in the microalbuminuric IDDM patients from 146 to 151 ml/min (NS), and in normal subjects from 115 +/- 16 to 122 +/- 15 (2p less than 0.05). A marked increase in renal plasma flow (RPF) (hippuran clearance) was seen in all three groups--533 +/- 82 to 724 +/- 120 ml/min (2p less than 0.01), 574 +/- 69 to 777 +/- 140 ml/min (2p less than 0.01) and 523 +/- 87 to 749 +/- 145 ml/min (2p less than 0.05), respectively. Urinary albumin excretion rate (radioimmunoassay) increased from 5.3 x/divide 1.5 (tolerance factor) to 6.5 x/divide 1.8 micrograms/min (2p less than 0.05) in the normoalbuminuric IDDM patients and from 6.1 x/divide 2.1 to 7.8 x/divide 2.3 micrograms/min (2p less than 0.05) in the normal subjects, while no significant change was seen in the microalbuminuric group of diabetics. Kidney volume (ultrasonic scanning) was significantly enhanced in IDDM patients (294 +/- 73 ml vs. 196 +/- 49 ml). There was no significant correlation between kidney volume and the renal haemodynamic response to dopamine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma concentrations of atrial natriuretic peptide in various diseases

Using a radioimmunoassay for atrial natriuretic peptide (ANP) we studied plasma concentrations of immunoreactive ANP in order to investigate the pathophysiological role of ANP in patients with various diseases. Plasma ANP levels were elevated in patients with congestive heart failure (394 +/- 260 pg/ml, n = 8) and chronic renal failure (219 +/- 86 pg/ml, n = 11). In patients undergoing hemodialysis plasma ANP levels were markedly high and decreased after hemodialysis from 433 +/- 166 pg/ml to 204 +/- 92 pg/ml (n = 11). ANP was removed from blood to dialysate (21 +/- 13 pg/ml of dialysate, n = 6, dialysate flow: 500 ml/min). Plasma ANP level was conversely correlated with creatinine clearance (r = -0.812, p less than 0.001) in patients with renal diseases (n = 29). In patients with atrial fibrillation, pace maker implantation, lung disease, chronic glomerulonephritis, nephrotic syndrome, essential hypertension, liver disease and cerebrovascular disease, plasma ANP levels were not significantly different from those in normal subjects (70 +/- 32 pg/ml, n = 28). These results suggest that ANP may be a circulating hormone playing pathophysiological roles in congestive heart failure and chronic renal failure.     

Metabolic clearance rate of arginine vasopressin in severe chronic renal failure.

1. The metabolic clearance rate of arginine vasopressin was determined using a constant infusion technique in normal subjects and patients with chronic renal failure immediately before commencing dialysis. Endogenous arginine vasopressin was suppressed in all subjects before the infusion with a water load. 2. Plasma arginine vasopressin concentrations were determined using a sensitive and specific radioimmunoassay after Florisil extraction. The detection limit of the assay was 0.3 pmol/l, and intra- and inter-assay coefficients of variation at 2 pmol/l were 9.7% and 15.3%, respectively. 3. In normal subjects, the metabolic clearance rate was determined at two infusion rates producing steady-state concentrations of arginine vasopressin of 1.3 and 4.4 pmol/l. In the patients with renal failure, a single infusion rate was used, producing a steady-state concentration of 1.5 pmol/l. 4. At comparable plasma arginine vasopressin concentrations, metabolic clearance rate was significantly reduced in patients with renal failure (normal 1168 +/- 235 ml/min versus renal failure 584 +/- 169 ml/min; means +/- SD; P < 0.001). 5. Free water clearance was significantly reduced in normal subjects during the arginine vasopressin infusion from 8.19 +/- 2.61 to -1.41 +/- 0.51 ml/min (P < 0.001), but was unchanged in the patients with renal failure after attaining comparable plasma arginine vasopressin concentrations. 6. In normal subjects there was a small but significant fall in metabolic clearance rate at the higher steady-state arginine vasopressin concentration (1168 +/- 235 ml/min at 1.3 pmol/l versus 1059 +/- 269 ml/min at 4.4 pmol/l; P = 0.016).(ABSTRACT TRUNCATED AT 250 WORDS)     

Blood levels and renal effects of atrial natriuretic peptide in normal man.

Since mammalian atria were recently found to contain vasoactive and natriuretic peptides, we investigated the following in normal humans: plasma human atrial natriuretic peptide concentrations, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), urinary water and electrolyte excretion, blood pressure (BP), and catecholamine, antidiuretic hormone (ADH), angiotensin II, and aldosterone levels before, during, and after intravenous administration of the newly synthetized alpha-human atrial natriuretic peptide (alpha hANP). In 10 subjects alpha hANP given as an initial bolus of 50 micrograms followed by a 45-min maintenance infusion at 6.25 micrograms/min increased plasma alpha hANP from 58 +/- 12 to 625 +/- 87 (mean +/- SEM) pg/ml; caused an acute fall in diastolic BP (-12%, P less than 0.001) and a hemoconcentration (hematocrit +7%, P less than 0.01) not fully explained by a negative body fluid balance; increased GFR (+15%, P less than 0.05) despite unchanged or decreased ERPF (filtration fraction +37%, P less than 0.001); augmented (P less than 0.05- less than 0.001) urinary chloride (+317%), sodium (+224%), calcium (+158%), magnesium (+110%), phosphate excretion (+88%), and free water clearance (from -0.76 to +2.23 ml/min, P less than 0.001) with only little change in potassium excretion; and increased plasma norepinephrine (P less than 0.001) while plasma and urinary epinephrine and dopamine, and plasma ADH, angiotensin II, and aldosterone levels were unchanged. The magnitude and pattern of electrolyte and water excretion during alpha hANP infusion could not be accounted for by increased GFR alone. Therefore, in normal man, endogenous alpha hANP seems to circulate in blood. alpha hANP can cause a BP reduction and hemoconcentration which occur, at least in part, independently of diuresis and are accompanied by sympathetic activation. An increase in GFR that occurs in the presence of unchanged or even decreased total renal blood flow is an important but not sole mechanism of natriuresis and diuresis induced by alpha hANP in man.     

Acute renal effects of sulindac and indomethacin in chronic renal failure

The effects of 2 days of oral dosing with sulindac (200 mg twice a day) or indomethacin (75 mg twice a day) on glomerular filtration rate, urinary excretion of prostaglandin E2, sodium homeostasis, and other renal function parameters were investigated in eight patients with chronic stable impaired renal function. Indomethacin reduced creatinine clearance (from 41.0 +/- 7.9 to 30.3 +/- 6.3 ml/min) and increased serum levels of creatinine and beta 2-microglobulin. Sulindac had no effect on any of these parameters. Both drugs induced depression of urinary prostaglandin E2 excretion; this depression was greater after indomethacin. Urinary sodium excretion fell from 144.4 +/- 18.7 to 85.5 +/- 9.7 mmol/24 hr after indomethacin and from 131.7 +/- 11.6 to 103.4 +/- 13.3 mmol/24 hr after sulindac. Body weight increased 1.2 kg after indomethacin but was not changed by sulindac. Plasma renin activity was reduced from 2.3 +/- 0.8 to 1.7 +/- 0.6 nmol/L/hr by sulindac and from 2.8 +/- 0.8 to 1.5 +/- 0.5 nmol/L/hr by indomethacin. Urinary N-acetyl-beta-glucosaminidase and kallikrein excretion was not changed by either drug. Our data suggest that sulindac affects renal prostaglandin E2 synthesis and sodium excretion in patients with severe renal failure to a lesser extent than does indomethacin. Sulindac still seems to be the drug of choice in this group of patients, but glomerular filtration rate, body weight, and electrolyte balance should be carefully monitored.     

Elimination of amphotericin B in impaired renal function

The influence of impaired renal function on the steady-state plasma clearance of amphotericin B was determined in seven patients with creatinine clearances ranging from zero to normal. Contrary to previous reports, steady-state plasma concentrations of total drug were lower in uremic patients than in patients with normal renal function. Total plasma clearance of amphotericin B ranged from 16.7 to 39.9 ml/min, correlated directly with the plasma creatinine concentration, and correlated inversely with the creatinine clearance. Urinary excretion of unchanged drug accounted for less than 10% of the dose. In 10 healthy subjects, mean percent of amphotericin B unbound in plasma was 3.55 +/- 0.32 (SD). Binding was determined in a further group of 10 uremic patients. Mean unbound percent (4.15 +/- 0.73, SD) was higher than in the healthy subjects, and the binding ratio (molar concentration of bound to unbound drug) correlated weakly with the creatinine clearance. This suggests that plasma clearance of unbound amphotericin B and, therefore, steady-state plasma concentrations of unbound drug are not affected by renal impairment, and that dosage requirements will be overestimated if based on measurements of total drug plasma concentration.     

Pharmacokinetics and protein binding of cefpiramide in patients with alcoholic cirrhosis

The pharmacokinetics of cefpiramide, a new cephalosporin, were investigated after a single 1 gm intravenous injection in 11 patients with alcoholic cirrhosis and compared with those of 11 healthy subjects. In patients with cirrhosis the plasma elimination half-life was three times longer than that in normal subjects. The total plasma clearance was decreased significantly (p less than 0.001): 12.3 +/- 6.5 ml/min in patients and 25.6 +/- 4.6 ml/min in healthy volunteers, respectively. The urinary excretion of unchanged drug (percent of intravenous dose) for patients (69.8% +/- 29.9%) was statistically higher (p less than 0.01) than that for subjects (16.2% +/- 3.9%). The renal elimination became increasingly important with hepatic impairment. Protein binding of cefpiramide was reduced significantly in the group with cirrhosis. The average unbound fraction was 10.4% +/- 9.5% in patients with cirrhosis and 1.9% +/- 0.3% in normal subjects (p less than 0.01). Because the rate of elimination from plasma in patients is slower, the dosage regimen of cefpiramide would probably be modified in cirrhosis.     

HEMODYNAMIC, RENAL, AND ENDOCRINE EFFECTS OF 4- H INFUSIONS OF HUMAN ATRIAL NATRIURETIC PEPTIDE IN NORMAL VOLUNTEERS

A synthetic human atrial natriuretic peptide of 26 aminoacids [human (3-28)ANP or hANP] was infused into normal male volunteers. Six subjects were infused for 4 h at 1-wk intervals with either hANP at the rate of 0.5 or 1.0 microgram/min or its vehicle in a single-blind randomized order. Human (3-28)ANP at the dose of 0.5 microgram/min raised immunoreactive plasma ANP levels from 104 +/- 17 to 221 +/- 24 pg/ml (mean +/- SEM), but it induced no significant change in blood pressure, heart rate, effective renal plasma flow, glomerular filtration rate, or renal electrolyte excretion. At the rate of 1.0 microgram/min, human (3-28)ANP increased immunoreactive plasma ANP levels from 89 +/- 12 to 454 +/- 30 pg/ml. It reduced effective renal plasma flow from 523 +/- 40 to 453 +/- 38 ml/min (P less than 0.05 vs. vehicle), but left glomerular filtration rate unchanged. Natriuresis rose from 207 +/- 52 to 501 +/- 69 mumol/min (P less than 0.05 vs. vehicle) and urinary magnesium excretion from 3.6 +/- 0.5 to 5.6 +/- 0.5 mumol/min (P less than 0.01 vs. vehicle). The excretion rate of the other electrolytes, blood pressure, and heart rate were not significantly modified. At both doses, human (3-28)ANP tended to suppress the activity of the renin-angiotensin-aldosterone system. In 3 additional volunteers, the skin blood flow response to human (3-28)ANP, infused for 4 h at the rate of 1.0 microgram/min, was studied by means of a laser-doppler flowmeter. The skin blood flow rose during the first 2 h of peptide administration, then fell progressively to values below baseline. After the infusion was discontinued, it remained depressed for more than 2 h. Thus, in normal volunteers, human (3-28)ANP at the dose of 1.0 microgram/min produced results similar to those obtained previously with rat (3-28)ANP. It enhanced natriuresis without changing the glomerular filtration rate while effective renal plasma flow fell. It also induced a transient vasodilation of the skin vascular bed.     

Kinetics, dynamics, and bioavailability of bumetanide in healthy subjects and patients with chronic renal failure

Six patients with chronic renal failure (CRF group) and four healthy subjects (HS group) were given 5 mg oral and intravenous doses of bumetanide in a random, crossover design. The CRF group had significantly lower plasma and renal clearances, resulting in a five-to sixfold reduction in the fractional urinary excretion of the drug. The percent free drug in plasma for the CRF group was more than double that for the HS group, and significant correlations were observed for volume of distribution at steady state vs. percent free (r = 0.661; P less than 0.05), nonrenal clearance vs. percent free (r = 0.796; P less than 0.01), and renal clearance vs. creatinine clearance (r = 0.995; P less than 0.001). Although bioavailability was relatively consistent among the HS (0.664 +/- 0.112) and CRF (0.689 +/- 0.149) groups, the absorption-time profiles were more irregular for both groups. Cumulative sodium excretion and overall efficiency of response to bumetanide did not differ significantly between the two routes of administration in either group.     

Ofloxacin pharmacokinetics in renal failure.

The pharmacokinetics of ofloxacin were investigated in 12 normal subjects and 21 uremic patients after the administration of a single oral 200-mg dose. An open three-compartment body model was used to calculate ofloxacin pharmacokinetic parameters. In healthy subjects, the peak plasma level averaged 2.24 +/- 0.90 micrograms/ml and was obtained at 0.83 +/- 0.31 h. The absorption rate constant was 4.22 +/- 1.64 h-1. The terminal half-life was 7.86 +/- 1.81 h. The apparent volume of distribution was 2.53 +/- 0.78 liters/kg. Total body and renal clearances were 241.4 +/- 53.8 and 196.5 +/- 42.9 ml/min per 1.73 m2, respectively. A total of 68.4 +/- 11.9% of the dose was recovered unchanged in 24-h urine. In uremic patients, the terminal half-life increased in relation to the degree of renal failure: from 8 h in normal subjects to 37 h in severely uremic patients. Renal insufficiency did not significantly modify the peak plasma level, the apparent volume of distribution, the fractional clearance, or the nonrenal clearance of ofloxacin. However, the time to peak level was delayed in patients with creatinine clearance of less than 30 ml/min. Linear relationships were found between ofloxacin pharmacokinetic parameters and glomerular filtration rate data. Ofloxacin is only very slightly removed by hemodialysis. Dosage adjustments of ofloxacin in uremic patients are proposed.     

Measurement of urinary annexin V by ELISA and its significance as a new urinary-marker of kidney disease

To confirm the significance of excretion of annexin V into the urine and the change of urinary annexin V concentration in kidney disease, a sandwich enzyme-linked immunosorbent assay (ELISA) was developed using two monoclonal antibodies. Urinary annexin V concentration was measured in healthy individuals and patients with kidney and other diseases. Urinary annexin V did not change over a range of pH between 5.0 and 8.0, and was stable during the course of the study for 24 h at room temperature and for 8 days at 4 degrees C. The mean urinary annexin V concentration in 105 normal healthy individuals was 1.5+/-1.5 ng/ml, while that in patients with nephrotic syndrome and systemic lupus erythematosis (SLE) nephritis was 9.3+/-9.1 and 6.6+/-6.7 ng/ml, respectively, and that in IgA nephropathy and chronic renal failure was 2.6+/-2.1 and 1.3+/-0.7 ng/ml, respectively. Annexin level correlated with urinary protein concentration (r=0. 717), but not the serum creatinine concentration, blood urea nitrogen (BUN) and 24-h creatinine clearance. Mean urinary annexin V concentration in patients with ischemic heart disease, hypertension, and diabetes mellitus was 1.4+/-1.0, 1.4+/-1.1, and 1.7+/-1.3 ng/ml, respectively. In one case of relapsing nephrotic syndrome, the urinary annexin V concentration was markedly increased in the early phase after admission and then decreased. This patient later required hemodialysis. These results suggest that a high urinary annexin V concentration may be an indicator of acute renal injury related to the urinary protein level.     

Pharmacokinetics of ofloxacin in severe chronic renal failure

The pharmacokinetics of ofloxacin were studied in patients with severe renal impairment. In five healthy subjects and nine patients with chronic renal failure (CRF) (creatinine clearance [CCR] less than 20 ml/min) receiving 100 mg of ofloxacin orally in the fasted state, the serum concentration was measured over the subsequent 48 hours. Intracorporeal dynamics were examined, employing a one-compartment open model. Ofloxacin levels were measured using the paper disk method. The half-life of ofloxacin was markedly prolonged, to 23.1 +/- 7.0 hr in the CRF group versus 2.9 +/- 0.5 hr for healthy subjects. In the CRF group, the maximum concentration and area under the curve were greater than in healthy subjects. There were no significant differences in volume of distribution between the two groups. The renal clearance of ofloxacin decreased from 261.0 +/- 46.6 ml/min in healthy subjects to 8.0 +/- 4.7 ml/min in the CRF group and correlated significantly with CCR in the CRF group (r = .88, P less than 0.01). There were no significant differences in nonrenal clearance between the two groups. The 24-hour renal excretion of ofloxacin averaged 91.9 +/- 5.4% and 14.1 +/- 5.5% of the dose in the healthy and CRF groups, respectively. In three hemodialysis patients on the regular hollow-fiber dialyser, the dialysance of ofloxacin was about 50% that of creatinine. Based on these findings, a reduction in the dose of ofloxacin is necessary in patients with CRF. In the hemodialyzed patients, its high dialyzability should be considered when deciding dose regimens.     

Urinary excretion of albumin and beta-2-microglobulin in hypertensive and normotensive renal transplant recipients during urinary diluting and concentrating tests

Urinary excretion of albumin and beta-2-microglobulin was measured in nine hypertensive and nine normotensive renal transplant recipients and 10 healthy control subjects before and after an oral water load of 20 ml (kg body weight)-1 (study 1) and in eight hypertensive and 11 normotensive renal transplant recipients and 11 healthy control subjects during 24-h water deprivation (study 2). In both studies 1 and 2 urinary albumin excretion was significantly higher (p less than 0.01) in the hypertensive renal transplant recipients that in the normotensive patients and the control subjects (levels before loading; hypertensives: 23.9 micrograms/min (median), range 7.5-58.7; normotensives: 3.4 micrograms/min, range 1.0-49.3; controls: 2.9 micrograms/min, range 1.3-10.3). Urinary albumin excretion was significantly positive correlated to both systolic, diastolic and mean blood pressure (for mean blood pressure: rho = 0.625, n = 18, p less than 0.01) in transplanted patients. Albumin excretion tended to increase after water loading and to decrease during water deprivation in all groups. Beta-2-microglobulin excretion was approximately the same in all groups in both studies 1 and 2 and was not correlated to blood pressure. During a follow-up period of at least 18 months, none of the renal transplant recipients developed signs of chronic graft failure. Increased urinary albumin excretion in hypertensive renal transplant recipients thus appears to be caused by increased glomerular permeability that may be due to glomerular damage induced by arterial hypertension corresponding to the findings in essential hypertension.     

Increased plasma histamine levels in uraemic pruritus

1. We determined plasma levels of histamine in uraemic patients and examined their correlation with the presence of pruritus. 2. In 27 patients with chronic renal failure, plasma histamine levels were analysed by radioimmunoassay and were compared with those of 40 healthy adult subjects. The control population showed plasma histamine concentrations of 185 +/- 33 pg/ml, which were significantly lower than those of the patients with renal insufficiency. The highest levels (552 +/- 116 pg of histamine/ml) were found in 16 patients with chronic renal failure (mean serum creatinine 5.1 +/- 1.0 mg/dl) and severe itching. 3. Twelve patients with pronounced pruritus who were on maintenance haemodialysis (serum creatinine 9.2 +/- 1.2 mg/dl) had a mean plasma histamine concentration of 515 +/- 81 pg/ml. Fifteen patients on regular haemodialysis (serum creatinine 9.0 +/- 1.5 mg/dl) and who experienced itching had plasma histamine levels (322 +/- 40 pg/ml) which were significantly lower (P less than 0.01) than those of the patients with pruritus but which were elevated compared with those of the control population (P less than 0.01). 4. No correlation could be found between increased plasma histamine levels and the type of dialysis membrane used or the method of sterilization of the membrane. 5. Haemodialysis alone did not reduce plasma histamine concentrations, although high concentrations could be detected in the ultrafiltrate. In six patients a rapid decrease in plasma histamine concentration from 565 +/- 134 pg/ml to within the normal range could be detected after 60 min of combined haemodialysis and haemoperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma bone Gla protein concentrations in healthy adults. Dependence on sex, age, and glomerular filtration

Plasma bone Gla protein (BGP) was determined by radio-immunoassay in 266 healthy adults, men (n = 132) and women (n = 134), aged 20-79 years. In the women aged 30-69 years, plasma BGP increased significantly with age (r = 0.44, p less than 0.001), and a particularly steep increase was seen from 1.1 +/- 0.5 (mean +/- 1 SD) in the fifth decade to 2.0 +/- 1.4 nmol/l in the seventh decade. In men, aged 30-69 years, no correlation was found between plasma BGP and age (r = -0.07, NS). Plasma bone Gla protein is removed from the circulation mainly by the kidneys and the increased plasma BGP in the women could be caused by decreased renal clearance. The interrelationship was analysed by means of partial correlation. When creatinine clearance was held constant in women, BGP still correlated positively with age (r = 0.40, p less than 0.001), but not with creatinine clearance (r = 0.003, NS) when age was fixed. Plasma BGP was significantly increased above normal in 35 patients with chronic renal failure (10.2 +/- 14.6 nmol/l). Non-linear regression analysis showed that plasma BGP was within the normal range when 24-h creatinine clearance was greater than 30 ml/min, and large increases in plasma BGP did not occur until the 24-h creatinine clearance was below 20 ml/min. We conclude that, in normal subjects and patients with mild to moderate renal failure, plasma elevations of BGP reflect increased bone turnover rather than decreased renal clearance.     

Bumetanide kinetics in renal failure

To study the effects of renal failure on bumetanide kinetics, we administered single intravenous doses of 1.0 mg/3.08 microCi 14C-bumetanide to six healthy subjects and 22 patients with variable degrees of renal failure. The kinetics of 14C-bumetanide and total 14C were adequately described by a two-compartment open model in the control subjects and in the patients. The volume of the central compartment and the distribution t1/2 were of the same order in both groups, whereas the mean (+/- SE) volume at steady state was larger (22.1 +/- 1.6 and 16.9 +/- 1.0 L) and the elimination t1/2 was longer (1.9 +/- 0.2 and 1.4 +/- 0.1 hours) in patients with renal failure than in healthy controls. Bumetanide renal clearance was lower (10 +/- 3 and 90 +/- 13 ml/min) in patients than in subjects and correlated with creatinine clearance (r = 0.784) and log serum creatinine level (r = -0.843), whereas nonrenal clearance was significantly higher in the patients (153 +/- 14 and 99 +/- 6 ml/min). Bumetanide total plasma clearance did not significantly change. The non-protein-bound, free fraction of bumetanide was higher in patients and correlated with plasma albumin levels (r = -0.777). The kinetics of total 14C showed similar but greater changes than those of 14C-bumetanide. Thus the most important changes in bumetanide kinetics in patients with renal failure are low renal clearance and a high free fraction, with a consequent increase in nonrenal clearance, volume of distribution, and elimination t1/2.     

Atrial natriuretic factor and changes in dietary sodium intake in patients with chronic renal failure

1. In order to examine the potential role of atrial natriuretic factor in modulating the increased sodium excretion per nephron in chronic renal failure, we studied 12 uraemic patients on the last day of two successive 7 day periods during which their sodium intake was 100 and 20 mmol of sodium/day, respectively. 2. There was a parallel decrease from 6.31 +/- 0.75 to 2.17 +/- 0.32% in the fractional excretion of filtered sodium and from 234.4 +/- 74.9 to 80.6 +/- 20.3 pg/ml (supine position) or 140.1 +/- 43.6 to 60.7 +/- 14.6 pg/ml (upright position) in plasma atrial natriuretic factor. Both parameters were significantly correlated during the two periods of different sodium intake (P less than 0.05). The ratio of plasma guanosine 3':5'-cyclic monophosphate to plasma creatinine changed proportionally to plasma atrial natriuretic factor. Plasma aldosterone and plasma renin activity increased during the sodium-depleted period but only plasma renin activity was significantly correlated with fractional excretion of filtered sodium. 3. The predominant role of atrial natriuretic factor compared with that of aldosterone in the renal response to varying sodium intake is suggested both by regression analysis and by the effect of 5 day's treatment with a converting enzyme inhibitor (enalapril) in six other uraemic patients on a normal (100 mmol/day) sodium intake. Such treatment, although resulting in a significant increase in plasma renin activity and a significant decrease in plasma aldosterone, at least in the supine position, did not modify the fractional excretion of sodium and plasma atrial natriuretic factor.(ABSTRACT TRUNCATED AT 250 WORDS)