In vivo microvascular clearance of albumin in renal and extrarenal tissues in puromycin aminonucleoside (PAN) induced nephrotic syndrome.

BACKGROUND: The nephrotic syndrome is characterized by generalized oedema considered to be due to the fall in serum albumin and to sodium retention. The aim of the present study was to investigate whether a generalized disturbance in vascular integrity contributes to the oedema formation. METHODS: We used the PAN-(puromycin aminonucleoside) nephritis model in order to induce the nephrotic syndrome in female Wistar rats. Eight rats were given PAN, 15 mg/100 g body weight, intraperitoneally 10 days prior to the study, whereas 21 rats served as controls. Albumin clearance to tissues was measured using a dual isotope technique. Repeated blood samples as well as samples from various muscles, kidney, liver, lung, heart, abdominal wall and from ascites fluid were taken to determine radioactivity and tissue dry-to-wet weights. Clearance of albumin (Clalb) from plasma to interstitium was calculated from the (linear) increment in 'plasma equivalent tissue albumin space' as a function of time, corrected for intravascular volume and oedema. The plasma and urine concentrations of albumin were determined in a parallel study by single radial diffusion using monospecific rabbit anti-rat antiserum in seven PAN animals and 13 controls. RESULTS: A marked fall in dry-to-wet weight ratios together with pronounced proteinuria, oedema and ascites were found in the PAN animals. Haematocrit decreased from 45% (32-51) to 30% (28-38) and serum albumin from 22.0 g/l (16.3-25.2) to 4.94 g/l (3.20-6.72) in control and PAN animals, respectively. However, Clalb apparently remained unchanged in the PAN animals in comparison to controls in most tissues examined. Thus, in these in vivo experiments there was no direct evidence of an increased extravasation of albumin in extrarenal tissues. CONCLUSIONS: There was no strong support for the contention that a generalized disturbance of capillary integrity outside the renal vasculature would contribute to the oedema formation in the PAN nephrotic syndrome.

Pharmacokinetics of cefepime dihydrochloride arginine in subjects with renal impairment.

In this study, the safety, tolerance, and pharmacokinetics of a single 1-g intravenous dose of cefepime (BMY-28142) were investigated. Twenty-three volunteers with various degrees of renal function were assigned to four trial groups according to glomerular filtration rates (GFR). Group IV consisted of five patients with end-stage renal disease undergoing treatment with hemodialysis. Cefepime concentrations in samples from plasma, urine, and infusion solutions were assayed with high-pressure liquid chromatography. The volume of distribution corresponded to the assumed extracellular fluid volume and did not differ significantly between the four groups. The area under the concentration-time curve increased as renal function decreased; in group II (GFR, 31 to 80 ml/[min x 1.73 m2]; n = 6), it was already three times higher than in group I (GFR, > or = 80 ml/[min x 1.73 m2]; n = 5). Mean residence time was 2.4, 6.8, 11.4, and 31.6 h for the four groups, respectively. Total clearance decreased (97.2, 34.6, 19.8, and 6.3 ml/[min x 1.73 m2]) with decreasing renal function, and a linear relationship between total plasma clearance and GFR was found with the regression equation y = 0.92x-2.0 (r = 0.991). Renal clearance was linearly correlated to GFR with the regression equation y = 0.87x-6.1 (r = 0.989), indicating that renal elimination is mainly by glomerular filtration. During hemodialysis, the extraction ratios were between 0.40 and 0.65. Dialysis clearance varied between 69.9 and 94.6 ml/(min x 1.73 m2).

Pharmacokinetics of meropenem in subjects with various degrees of renal impairment.

Five healthy volunteers and 18 patients with various degrees of renal impairment received 500 mg of meropenem intravenously as a 30-min infusion. Five dialysis patients were dosed 2 h prior to hemodialysis, and four of them were also dosed between hemodialysis treatments. Plasma and urine samples were collected for up to 48 h and 12 h, respectively. Concentrations of meropenem and its open ring metabolite ICI 213,689 were determined by high-performance liquid chromatography and radioimmunoassay, respectively. The subjects were divided into four groups with glomerular filtration rates (GFR) of greater than 80, 30 to 80, 5 to 29, or less than 5 ml/min. There were linear correlations between the GFR and the rates for total plasma clearance as well as renal clearance of meropenem (group mean values for total clearance of 186, 74, 53, and 19 ml/min/1.73 m2, respectively). In subjects with normal renal function, nonrenal clearance accounted for approximately 20% of total elimination, increasing to about 50% in patients with GFR between 5 and 29 ml/min/1.73 m2. The terminal half-life of meropenem increased from 0.9 h in the healthy volunteers to 6.8 h in patients with end-stage renal disease. The half-life of ICI 213,689 was 2.31 h in the healthy volunteers and increased to 23.6 h in patients with GFR of 5 to 29 ml/min. In patients with end-stage renal disease, half-lives could not be measured, as concentrations were hardly declining during the 48-h observation period. The area under the concentration-time curve for meropenem increased more than 10-fold. Both meropenem and its open ring metabolite were readily dialyzable, with dialysis clearances of 79 and 81 ml/min/1.73 m2, respectively.

99mTc plasmin in 394 consecutive patients with suspected deep venous thrombosis.

Three hundred and ninety four consecutive out-patients with suspected deep venous thrombosis (DVT) were investigated with the 99mTc-plasmin test and physical examination and 307 of them with phlebography. Fresh thrombi were present in 124 patients and the plasmin test was pathological in 118 of these (sensitivity 95%). The thrombi that were missed were all located below the knee and measured less than 10 cm on the phlebographic films. The predictive values of negative and positive tests were 91% and 49%, respectively. The predictive value of a positive test was higher with an increasing number of measuring points with a pathological uptake. To get the final result, a single series of measurements 5 min after injection was sufficient. If clinical signs of inflammation were present. the plasmin test was usually pathological. Median time for the plasmin test to become normal during anticoagulant therapy was 14 days for calf DVT and 6 months for proximal DVT. The plasmin test was found to be useful as a screening test in patients without extensive signs of inflammation in the legs. It has a high sensitivity even in patients with long-standing symptoms.

Need for long-term anticoagulant treatment in symptomatic calf-vein thrombosis.

The need for oral anticoagulation in patients with calf-vein thrombosis was examined in a randomised study of 51 patients, of whom 23 received warfarin for 3 months and 28 did not. Both groups received an initial course of heparin and all wore compression stockings. Progress was monitored by the use of serial isotope tests and physical examination. Phlebography was repeated if recurrence was suspected. During the first 3 months, 8 patients in the non-warfarin group (29%) had recurrences compared with none in the warfarin group (p less than 0.01). 5 patients had recurrence with proximal extension and 1 patient had a pulmonary embolus. After 1 year, 22 out of 23 patients in the warfarin group had not had a recurrence, compared with 19 out of 28 (p less than 0.02). The findings indicate that oral anticoagulants should be given to all patients with thrombi that produce symptoms. Treatment for 3 months seems to be sufficient.

Double blind comparison between iohexol and metrizoate in phlebography of the lower limb.

A new, non-ionic low osmolar contrast medium, iohexol 240 mg I/ml, has been tested in a randomized double blind parallel investigation versus meglumine-Ca metrizoate 200 mg I/ml. The study was performed to evaluate the suitability of the contrast medium in phlebography. No post-phlebographic complications were seen in the 24 patients examined with iohexol 240 mg I/ml or in 8 patients examined with iohexol 300 mg I/ml. In the 19 patients examined with metrizoate 200 mg I/ml, 7 had a post-phlebographic thrombotic complication (37%). The radiographic image quality was not significantly different between the two contrast media, neither were the immediate side effects during contrast injections. It has thus been shown that iohexol is a suitable contrast medium in phlebography of the lower limb and that it is preferable to conventional contrast media.