Plasma separation in patients with bronchial asthma, atopic dermatitis and hyperimmunoglobulinaemia E.

The effect of intensive plasma separation performed eight times within 5 weeks in four patients with atopic dermatitis, bronchial asthma and hyperimmunoglobulinaemia E was followed as regards clinical symptoms and changes in the concentrations of serum (S) IgE, S IgG, S IgA, S IgM, plasma complement C3 split products, S transferrin, blood eosinophils, chemotaxis of neutrophil cells and histamine metabolites in urine in samples obtained consecutively during the period of observation. The occurrence of circulating immune complexes (IC) was analysed by a polyclonal rheumatoid factor (pRF) agglutination inhibition assay and an IgE IC specific technique. IgE IC were demonstrated in three of the patients prior to plasma separation, complexed IgE was 2-3% of the total concentration of S IgE. In one patient complexes were detected by the pRF agglutination inhibition assay, also. In the three patients with IgE IC, the complexes disappeared during treatment, but recurred in two of the patients shortly after the last plasma separation. Shortly after eight separations the S IgE was reduced in all patients to a mean level of 46% of the pre-exchange concentrations. During the following 3 weeks the relative increase of S IgE in three of the patients was similar to the values obtained for S IgG. Serum IgG was subnormal in all patients during the period of treatment. Increasing numbers of eosinophils were observed in three of the patients after the fifth separation procedure. The histamine metabolite 1,4-methylimidazoleacetic (1,4- MIAA ) in urine was increased in all patients, but no significant changes were observed during the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminoglycoside toxicity - a review of clinical studies published between 1975 and 1982.

The present survey of aminoglycoside nephro- and ototoxicity covers approximately 10,000 patients reported on in clinical trials published between 1975 and 1982. Included in the survey were clinical trials with at least 15 patients evaluable for nephro and/or ototoxicity provided relevant data were given on methodology, patient material and aminoglycoside dosage. Each publication was evaluated by both investigators and relevant data entered into a chart. One hundred and forty-four published trials were surveyed; 139, 63 and 34 for renal, cochlear and vestibular side effects, respectively. Frequencies were calculated as number of patients with side effect of total number of evaluated patients. In the average overall figures toxicity labelled by respective authors as 'definitely', 'probably' and 'possibly' related to study drug is included. When available, frequencies of toxicity 'definitely' and 'probably' related to study drug were analysed separately. The average daily dosages of gentamicin, tobramycin, netilmicin and amikacin were 3.9, 3.8, 5.2 and 15.4 mg/kg, respectively. The average frequencies of nephrotoxicity for gentamicin and tobramycin were 14.0 and 12.9%, respectively, and of netilmicin and amikacin 8.7 and 9.4%, respectively. The average frequency of cochlear toxicity was 13.9% for amikacin, 8.3 and 6.1% for gentamicin and tobramycin, respectively, and 2.4% for netilmicin. The material available for evaluation of vestibular toxicity was considerably smaller. The average frequencies for gentamicin, tobramycin and amikacin were similar (3.2 to 3.7%) while netilmicin again exhibited a somewhat lower figure (1.4%). The overall figures and the clinical ranking that they imply were basically substantiated when prospective comparative trials were analysed separately. However, some inconsistencies go unexplained: for example the frequency of gentamicin nephrotoxicity was markedly higher in trials where it was compared to tobramycin (20 trials) than when it was compared to netilmicin (16 trials).

The effect of chlorpromazine pretreatment on the vascular function of kidneys damaged by warm ischaemia and cold storage in Collins' solution.

Vascular resistance was determined in 40 rabbit kidneys after graded warm ischaemia up to 60 minutes and preservation in Collins' solution for 24 and 48 hours. Half of the animals were treated with chlorpromazine 3.5 mg/kg before induction of the ischaemia. Vascular function was determined during short-term perfusion with TIS-U-SOL at 4 degrees C. The experiments showed that warm ischaemia of 30 and 60 minutes duration gave an increase in vascular resistance. The increase was, however, smaller in kidneys pretreated with chlorpromazine. Preservation in Collins' solution for 24 and 48 hours did not change this correlation. Determination of the weights and thereby formation of oedema showed that all kidneys preserved had a small increase in weight. No difference was found between pretreated kidneys and untreated kidneys. It is concluded that pretreatment with chlorpromazine is capable of diminishing vascular contraction during the warm ischaemic period and that preservation in Collins' solution for up to 48 hours does not alter this beneficial effect.

The effect of netilmicin and other aminoglycosides on renal function. A survey of the literature on the nephrotoxicity of netilmicin.

The antibiotics of the aminoglycoside group are all potentially nephrotoxic. Aminoglycosides are exclusively excreted via the kidneys by glomerular filtration. On passing the proximal tubular cells of the nephron, an active reabsorption and intracellular concentration, 10-20 times the serum concentration, take place. Aminoglycosides are trapped in the lysozymes and inhibit cell metabolism. Functional changes are at first discrete, comprising polyuria, slight proteinuria, enzymuria and glycosuria. With more progressive changes the glomerular filtration rate decreases, followed by increased blood urea and serum-creatinine. The urine contains protein, casts and shedded tubular cells. Ultimately, but rarely, oligo-anuric renal failure may be encountered. Compared with gentamicin, the newer aminoglycosides, amikacin, tobramycin and netilmicin show in animal experiments a decreasing nephrotoxicity in the mentioned order. Extensive studies have demonstrated that netilmicin may be the drug with the least nephrotoxic potential. Clinical studies confirm that netilmicin is less nephrotoxic than gentamicin and compares favourably with tobramycin and amikacin. A survey of the literature is given.

The 125I-Hippuran renogram in rabbit kidneys after graded warm ischaemia.

125I-Hippuran renography was performed after temporary renal arterial clamping in contralateral nephrectomized rabbits. Mean renograms for the experimenttal groups were calculated for 0, 1, 1 1/2, 2, 2 1/2 and 3 h of warm ischaemia. The appearance phase, the 1 min uptake phase and excretion ratio were evaluated. The kidney function was monitored by serum-creatinine. Warm ischaemia of 1, 1 1/2 and 2 h resulted in a late maximum peak and delayed excretion, and for the last group in an accumulation curve. The uptake capacity was normal for these groups. Protracted ischaemia of 2 1/2 and 3 h affected also the appearance and uptake phase resulting in a slower and decreased Hippuran uptake of 50% and 34% respectively. Duration of warm ischaemia and changes in the renogram were well correlated. A normal uptake phase predicts restitution of the kidney function and 100% survival.

Renographic evaluation of kidney preservation with chlorpromazine.

The effect of chlorpromazine pretreatment of kidneys then damaged by warm ischemia was investigated. The ischemia was inflicted on rabbit kidneys by renal arterial occlusion of 1 1/2 and 3 hours' duration after contralateral nephrectomy. Pretreatment with chlorpromazine, 3.5 mg/kg, was given intravenously before arterial clamping. I-125 Hippuran renography was performed before clamping, immediately after clamp release, and at 2, 4, 6, and 14 days later. Serum creatinine and survival rate were followed. Comparison with untreated control groups was made. The effect on tubular function was investigated by measuring I-125 Hippuran uptake in pretreated slices of renal cortex (compared with untreated contralateral kidney) 48 hr after circulation was restored to the ischemic kidney. Chlorpromazine pretreatment improved recovery from ischemic damage: the renograms showed improved Hippuran uptake after clamp removal, and return to normal was faster. Survival rate after 3 hr of ischemia increased from 1/10 to 6/10 in the pretreated group, and serum creatinine recovered earlier. Hippuran uptake in slices of cortex showed no significant improvement because of pretreatment. It is concluded that the beneficial effect of chlorpromazine pretreatment must be because of decreased vascular resistance, leading to long-lasting increased postischemic renal blood flow.

Sequential [125I]-o-iodohippurate renograms from rabbit kidneys after temporary renal ischemia.

Serial renography with [125I]-o-iodohippurate was performed in 42 rabbits after temporary clamping of the renal artery for 1--3 hr and contralateral nephrectomy. Renograms were done before and after warm ischemia and followed 2, 4, 6, and 14 days after restoration of circulation. Correlation was found between duration of ischemia and severity of postischemic renographic changes. Most sensitive was the third phase, which showed distortion after 1 hr of ischemia; the second phase decreased after 2 1/2 hours of ischemia. The profound changes seen on the second day were shown to be due to further damage of the tubular cell system after restored flow. In vitro [125I]-o-iodohippurate uptake in cortex slices showed a significant decrease after warm ischemia damage and 48 hours restored flow. The second phase recovered more rapidly than the excretory function.

The pH-dependent influence of aminoglycoside antibiotics on iodohippurate accumulation in rabbit renal cortical slices.

The effects of aminoglycoside antibiotics on 125I-hippurate (OIH) accumulation in rabbit renal cortical slices were assessed in vitro using incubation media with pH-values ranging from 6.4 to 8.4 and containing streptomycin, kanamycin, amikacin, gentamicin and tobramycin in concentrations ranging from 100 to 2,000 microgram base/ml. The aminoglycoside-induced inhibition of OIH accumulation was clearly pH-dependent and most pronounced at alkaline pH-values. At pH 6.4 and 7.4 the aminoglycosides had either no or only moderate effects on OIH accumulation, while all drugs produced a distinct depression in accumulation at pH 7.9 and 8.4. The microbiologically inert N-acetyl gentamicin had no influence on accumulation. The influence of aminoglycosides on OIH accumulation is probably related to the pKa-values of these drugs and implies the presence of free amino groups.

Effects of polymyxin antibiotics on iodohippurate accumulation in rabbit renal cortical slices.

The in vitro effects of polymyxin antibiotics on 0-125I-hippurate (OIH) accumulation in rabbit renal cortical slices were studied using incubation media with pH ranging from 6.9 to 7.9 and containing polymyxin B sulfate, colistin sulfate, sodium colistimethate and antibacterially inactive N-succinyl colistin in concentrations ranging from 1 to 2,000 microgram base/ml. Polymyxin B, colistin and colistimethate depressed OIH accumulation significantly in concentrations greater than or equal to 300 microgram/ml. The effects on accumulation were clearly pH-dependent and most pronounced at alkaline pH. N-Succinyl colistin had only a marginal influence on accumulation, even in high concentrations. Colistimethate produced a significantly smaller decrease in accumulation at all pH values than both polymyxin B and colistin. The results suggest that the presence of free amino groups is necessary to obtain a decrease in accumulation and correlate with the known in vivo nephrotoxicity of these antibiotics.

Vascular function in kidneys preserved by simple cold storage in Sacks' or Collins' solutions.

Vascular resistance was determined in 40 kidneys after preservation in Collins' or Sacks' solution for 24 and 48 hours. Kidneys without warm ischaemia and kidneys with up to 60 min of warm ischaemia prior to preservation were investigated, vascular resistance was determined during short time perfusion with Tis-U-Sol at 4 degrees. The experiments showed that cold preservation of kidneys with no warm ischaemia or 15 min of warm ischaemia gave a small increase in vascular resistance, independent of the solution used. 30 and 60 min of warm ischaemia gave a considerable increase in vascular resistance, but less increase was found in kidneys preserved in Sacks' solution. Determination of the weights and thereby formation of oedema showed slight dehydration in kidneys preserved in Sacks' solution. Kidneys preserved in Collins' solution showed small increase in weight. No correlation was, however, found between the vascular resistance and degree of oedema.

Aminoglycoside nephrotoxicity. I. Effects of aminoglycoside antibiotics on iodohippurate accumulation in rabbit renal cortical slices.

The effects of aminoglycoside antibiotics on the accumulation of O-125I-hippurate (OIH) in rabbit renal cortical slices were assessed in an attempt to establish an in vitro model for aminoglycoside nephrotoxicity. Accumulation of OIH was measured after incubation of cortex slices in media containing aminoglycosides in different concentrations. All aminoglycosides depressed OIH accumulation in the following minimum concentrations: Dihydrostreptomycin and kanamycin, 2,000 microgram/ml (P less than 0.01); streptomycin and neomycin, 1,000 microgram/ml (P less than 0.05 and P less than 0.01); amikacin and tobramycin, 300 microgram/ml (P less than 0.05); gentamicin, 100 microgram/ml (P less than 0.05). A concentration of 2,000 microgram/ml caused the following reduction in OIH accumulation: Dihydrostreptomycin, 19.3%; streptomycin, 28.9%; kanamycin, 23.8%; neomycin, 62.5%; gentamicin, 68.0%; amikacin and tobramycin, 100%. Changes in pH of the incubation media after addition of aminoglycosides were only partially responsible for the observed depression of OIH accumulation and there was no evidence of substrate competition between aminoglycosides and OIH. The in vitro model described here appears to be inadequate as a sole predictor of aminoglycoside nephrotoxicity, but may provide a supplementary tool in the investigation of aminoglycoside proximal tubular cell toxicity.

The influence of warm ischaemia on renal function and pathology.

Temporary occlusion of the left renal artery for 0-180 min after contralateral nephrectomy was undertaken in 51 rabbits. The correlation between the injury of warm ischaemia and kidney function, survival and histology was evaluated. After 0, 60, 90 and 120 min occlusion, all animals survived and normal renal function was restored. After occlusion for 150 min only 4 of 10 animals survived, and normal renal function was not re-established. 180 min occlusion was detrimental to the animals. Only one out of ten survived with severely damaged kidney function. Histological findings were consistent with the experimental observations of renal function.

The effect of chlorpromazine and heparin pretreatment on kidney viability and function after warm ischaemic damage.

The influence of chlorpromazine and heparin pretreament on kidney function and histology has been investigated in rabbit kidneys damaged by warm ischaemia. Three experimental groups were investigated. One in which animals were pretreated with heparin, one group pretreated with heparin and chlorpromazine, and one group without pretreatment. The left renal artery was temporarily clamped for 3 hours and the kidneys recirculated. After 2-3 weeks a delayed contralateral nephrectomy was made, and after another 2-3 weeks all kidneys were studied histologically. Kidney function was measured by determination of serum-creatinine. The experiments showed, that all animals survived with impaired renal function. Pretreatment with chlorpromazine and heparin did not affect the final results. Secerity of the ischaemic damage, histologically evaluated was the same in all groups.

The effect of chlorpromazine pretreatment on renal function and pathology in kidneys damaged by warm ischaemia.

The influence of chlorpromazine pretreatment on kidney function and survival after temporary occlusion of the renal artery was investigated. Three hours of clamping of the renal artery and contralateral nephrectomy was performed in a group of ten rabbits pretreated with 3.5 mg/kg chlorpromazine and compared with a previously published control group of untreated animals. Chlorpromazine pretreatment improved survival. The kidney function, estimated by serum-creatinine, showed an earlier onset of function and the surviving animals regained nearly normal function. Histological examination revealed mild to moderate ischaemic changes, whereas the control group showed more profound damages.

The effect of chlorpromazine pretreatment on the vascular resistance in kidneys following warm ischaemia.

In studies of 45 rabbits pretreated by chlorpromazine, clamping of the renal artery was performed. Chlorpromazine 3.5 mg/kg was given intravenously 15 min before arterial clamping. The duration of the clamping period ranged from 0 to 180 min. After removal of the kidneys the influence of the pretreatment on the vascular resistance was examined in perfusion studies. Resistance patterns were measured during hypothermic perfusion. The results were compared with an identical group without pretreatment. The vascular resistance rose with the duration of clamping but was lower than in the control group. The maximal resistance attained after 60 min of clamping was approximately 50% lower. In another series of chlorpromazine pretreated animals clamping of the renal artery for 180 min was followed by reestablishment of the circulation for 24 and 48 hours. Perfusion studies were performed on kidneys after removal. The results were compared with a group without pretreatment. The vascular resistance was found to return to normal values more rapidly when the animals had been pretreated with chlorpromazine.

The integrity of tubular cell function after preservation in Collins' or Sacks' solution.

Collins' solution is an excellent medium for kidney preservation by simple cold storage before transplantation. Efforts by Sacks et al. to improve this technique by modifying the composition seemed promising. A comparison between ability of these two media to preserve the tubular cell was attempted. The viability of the tubular cells was evaluated by measuring the 125 I Hippuran uptake in cortex slices taken from kidneys preserved for 24 and 48 hr in the respective solutions. Kidneys exposed to as well as kidneys not exposed to warm ischaemia were used. Collins' solution was found to be superior in protecting the cell function. Nonetheless intracellular oedema during preservation was greater after preservation in this solution as compared with cells preserved in Sacks' solution.

The effect of chlorpromazine pretreatment on tubular function in kidney preservation.

The effect of Chlorpromazine pretreatment on tubular function was investigated. Hippuran uptake in cortex slices from rabbit kidneys was measured after one hour of incubation in a medium containing Hippuran. Before measurement the kidneys were exposed to varying periods of warm ischaemia or/and cooled and preserved for 24 hours in Collins solution. Chlorpromazine treated and untreated groups of animals were compared, the results obtained were identical in both groups. In contra distinction to these findings, addition of Chlorpromazine to the incubation fluid inhibited uptake of Hippuran in the kidney slices. The effects of pretreatment with Chlorpromazine on the kidney function after ischaemic damage were demonstrated. Serum-creatinine and survival were compared in a treated and an untreated group after 3 hours of temporary clamping of the renal artery. Pretreatment resulted in earlier onset of function and better survival. It is concluded that the antimetabolic effect of Chlorpromazine is opposed to its vasodilatory properties is of little practical importance for the viability of the kidney damaged by ischaemia.

The collateral blood flow and hippuran clearance of the rabbit kidney after occlusion of the renal artery.

The collateral blood flow to the rabbit kidney was determined by two methods: (1) measurement of the venous flow after clamping of the renal artery and (2) Hippuran clearance of the clamped kidney. The collateral blood flow was found to be 0.012 ml/min/g kidney equivalent to 0.2% of the entire blood flow to the rabbit kidney. Compared with collateral blood flow in other mammals (as humans and dogs) with a collateral flow of 6.2% of the normal flow, the collateral blood flow in the rabbit is very modest. The cranial ureteric artery contributes more than 90% of the entire blood flow, while capsular perforants, important in other mammals, play no role in the supply of the rabbit kidney. Only 50% of the collateral blood flow passes the tubular system. Flow to the medulla calculated from Hippuran clearance was 35% greater than flow to the cortical part of the kidney. The subcapsular cortical tubuli were able to absorb Hippuran from the peritoneal fluid and surrounding tissues after the kidney was dissected free from its surroundings and all vessels severed. Absorption corresponded to an arbitrary serum flow of 0.0002 ml/min/g.

The uptake of hippuran in kidney slices employed as a viability test.

125J Hippuran uptake in slices from rabbit kidneys was measured in kidneys damaged by warm ischaemia alone as well as by warm ischaemia combined with 24 hours of cold ischaemia. The Hippuran uptake was calculated as the ratio between radioactivity in the slices and the activity in the incubation medium as a slice/medium ratio (S/M). S/M was unchanged after 15 minutes, 30 minutes and 1 hour of warm ischaemia, while in kidneys exposed to 2 hours of warm ischaemia a 15% decrease in S/M ratio compared with control values was noted. A 53% decrease was observed after 3 hours of warm ischaemia and 73% and 91% after 4 and 5 hours respectively. Twenty-four hours of cold ischaemia alone did not alter the Hippuran uptake, but prolonging this with 15 minutes of warm ischaemia precipitated a significant fall (25%) in S/M. This value remained constant during the first hour of warm ischaemia, but a fall of 64% was observed after 2 hours of warm and 24 hours of cold ischaemia. These findings were in agreement with experiments on kidneys damaged by arterial occlusion and recirculated. Two hours of warm ischaemia was the maximal damage the kidneys could endure and still regain normal function. After simple preservation methods with Collins solution for 24 hours, 1 additional hour of warm ischaemia was the maximal ischaemic damage the kidney was able to withstand. Hippuran uptake in kidney slices appears to be well correlated to the kidneys' ability to regain normal function after ischaemic damage.