Effect of pefloxacin on experimental adriamycin-induced nephrotic syndrome.
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Biomedical subjects
Publications and source records attributed to R Poledne.
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BACKGROUNDS: Hyperlipidemia is not only a prominent complication of nephrotic syndrome, but it may also contribute to the further non-immunologic damage of glomeruli. Analogy between atherosclerosis and glomerular sclerosis was suggested. Treatment of hyperlipidemia may decrease proteinuria in nephrotic animals and subjects and possibly prevent the progression of glomerulosclerosis and renal failure. We decided to study the influence of therapy with the inhibitor of cholesterol synthesis, lovastatin, on the development of the experimental nephrotic syndrome induced by the administration of adriamycine in rats. METHODS AND RESULTS: Nephrotic syndrome was induced in rats by the intravenous administration of adriamycine. One group of animals was treated from the time of adriamycine adminstration with lovastatin. Lovastatin was also given to one group of control animals. Proteinuria increased significantly during 4 weeks in untreated adriamycine rats (from 0.93 + 0.57 to 12.76 + 11.95 g/mmol of urinary creatinine, p < 0.01), but it did not change significantly in adriamycine rats treated with lovastatin (from 0.98 + 0.69 to 1.90 + 4.25 g/mmol of creatinine, p = n.s.) and it was significantly lower than in untreated animals (p < 0.01). Plasma albumin decreased 12 weeks after adriamycine administration in untreated rats (from 21.16 + 1.45 to 10.58 + 3.83 g/l, p < 0.001) significantly more (p < 0.05) than in rats treated with lovastatin (from 20.01 + 2.18 to 15.34 + 2.66 g/l, p < 0.01). Lovastatin also ameliorated the increase of plasma cholesterol and eliminated the increase of plasma triglycerides in adriamycine rats. Metabolic changes were in all groups characterized by the increase of free fatty acids, possibly due to exaggerated lipolysis, but without significant change of glycaemia and plasma urea. Proteinuria was decreasing at the end of the observed period. Histologically there were only minimal changes in glomeruli, without significant glomerulosclerosis. CONCLUSIONS: Administration of lovastatin prevented the development of nephrotic syndrome in experimental adriamycine nephropathy in rats. This finding suggests the possible role of hyperlipidemia in the pathogenesis of glomerular damage and suggests the posibility to prevent glomerulosclerosis and renalisufficiency in some form on nephrotic syndrome by the effective hypolipidemic therapy.
BACKGROUND: Alcoholic liver disease may be in humans frequently complicated by mesangial proliferation and sclerosis. The influence of chronic ethanol administration on experimental nephrotic syndrome has not been, however, studied yet. METHODS AND RESULTS: Experimental nephrotic syndrome was induced in rats by the i.v. administration of adriamycin in ethanol fed rats and in rats given common laboratory chow. Chronic administration of ethanol was in nephrotic rats accompanied by the exaggerated lipolysis (free fatty acids were in control nephrotic rats lower than in nephrotic ethylic rats 6 weeks after adriamycin administration: 914.8 + 96.8 mumol/l vs. 1186.3 + 178.7 mumol/l, p < 0.01) and increased proteocatabolism; the development of nephrotic syndrome was ameliorated, or at least delayed, however, in ethylic rats (control nephrotic rats had higher proteinuria than nephrotic ethylic rats 3 weeks after adriamycin administration: 5.79 + 3.15 vs. 0.55 + 0.34 g protein/mmol creatinine, p < 0.01). In autopsy, diffuse global glomerulosclerosis was found in control nephrotic rats with only mild focal and segmental changes in nephrotic ethylic rats. CONCLUSIONS: Chronic ethanol administration ameliorated and/or delays the development of nephrotic syndrome in adriamycin nephropathy in rats. Mechanism of this effect of chronic ethanol feeding remains to be elucidated. Metabolic, immunosuppressive and renal haemodynamic effects of ethanol should be taken into consideration.
The genetic background of polygenic hypercholesterolemia was studied in hypercholesterolemic children consuming a diet identical to control individuals with low cholesterol concentrations. Significantly higher frequencies of "disadvantage" alleles, usually combined with a higher LDL cholesterol, were found in hypercholesterolemic individuals when polymorphisms in apolipoprotein E, apolipoprotein B--XbaI and LDL receptor--PvuII were studied.
The population of Czechoslovakia is at high risk of premature atherosclerosis. Normal DNA polymorphism at the low density lipoprotein receptor (LDLR) locus detectable with the restriction enzyme PvuII was analyzed in Czech children with a high or a low concentration of total serum cholesterol. The PvuII restriction site was found significantly more often in the low cholesterol group than in the high cholesterol group. Thus, normal genetic variation at the LDLR locus contributes to the population variation in cholesterol in children in the population studied.
The substantial role of monocytes in atherogenesis has been demonstrated recently. The feedback regulation of endogenous cholesterol synthesis in monocytes of young myocardial infarction survivors was determined and compared to that of age- and sex-matched controls. The cholesterol synthesis in monocytes of one half of patients was three times higher compared to that of controls whereas the other half showed a rate within the range of controls.
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The regulation of the human apolipoprotein (apo) B gene that plays a crucial role in lipid metabolism is apparently very complex, with multiple cis- and trans-acting regulatory factors. One of these factors is an enhancer region in the second intron. In this region a point mutation at position + 722 has been found that is detectable by the restriction enzyme StyI. The report of Levy-Wilson et al. (1991) could suggest that the mutant allele (abolished StyI site) is associated with hypocholesterolemia. To investigate further the possible effect of this mutation on plasma cholesterol levels, we have compared the frequency of the mutant allele between 206 hypercholesterolemic Norwegian or Czech subjects on one hand, and 165 hypocholesterolemic Norwegian or Czech subjects on the other hand. No significant difference in frequency was found between the hypercholesterolemic and the hypocholesterolemic groups. This finding indicates either that the mutation at position + 722 does not affect the enhancer activity or that this in vitro enhancer activity is of little or no clinical significance. One of the Norwegian hypercholesterolemic subjects who was of Czech descent possessed the apoB 3500 mutation that leads to defective binding of low density lipoprotein (LDL) to the LDL receptors. Haplotype analysis of the apoB gene in her family showed that the mutation-bearing allele was identical to that reported in other countries, indicating a common gene source.
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The Prague Hereditary Hypercholesterolaemic (PHHC) rat is a strain of the Wistar rat very sensitive to dietary cholesterol. The dynamics of changes in serum and liver lipids and lecithin: cholesterol acyltransferase (LCAT) were studied immediately after the switch to a high cholesterol diet. Immediate cumulation of free and esterified cholesterol in the liver after the increase in alimentary cholesterol intake is supposed to be the regulating step leading to a subsequent increase in serum cholesterol concentration. Activity of LCAT was negatively correlated to the concentration of free cholesterol in the liver, very early after the cholesterol diet was introduced, a possibility of a down regulation of enzyme synthesis similarly to the regulation of synthesis of cholesterol in hepatocytes was observed.
In a group of 2000 Prague children aged 11-12 years the distribution of serum cholesterol levels was assessed. For further investigations 100 children with cholesterol levels above the 95th percentile (HYPER) were selected and 100 children with values between the 5th and 10th percentile (HYPO). Children and parents were subjected to detailed clinical and laboratory examination, in children the three-day dietary intake was assessed. Boys of the HYPER group had significantly higher LDL, HDL and VLDL cholesterol levels as well as levels of apolipoprotein B and less favourable values of the atherogenic index (AI). Girls of the HYPER group had significantly higher mean values of LDL-cholesterol and apolipoprotein B and also less favourable values of the AI. In the group HYPER children no abnormalities were detected in the carbohydrate metabolism nor a higher incidence of obesity although they differed significantly from children in the HYPO group as regards parameters of the lipid spectrum. The energy value of the consumed diet of children in the HYPER and HYPO group does not differ significantly. Although in boys of the HYPER group there was a higher ratio of total fat and animal fat (p less than 0.05), neither the percentage ratio of fatty acids nor the P:S ratio differed significantly in children of the HYPER and HYPO group. Parents of children of the HYPER group had significantly higher mean cholesterol, apolipoprotein B, LDL cholesterol values and less favourable values of the atherogenic index than parents of children of the HYPO group. The incidence of hypercholesterolaemia in the families of these children was also significantly higher.
The distribution of cholesterol values was established in a group of 2,000 Prague children aged 11-12 years. Of these, 100 children with cholesterol values exceeding the 95th percentile (HYPER), and 100 children with values between the 5th and the 10th percentiles (HYPO) were selected for follow-up. In addition to a thorough clinical and laboratory examination in children and parents, three-day food consumption was registered in children. Even though differing significantly from those assigned to the HYPO group in lipid spectrum parameters, HYPER group children did not show any abnormalities in carbohydrate metabolism or increased incidence of obesity. There is no significant difference in the energy values of food consumed by HYPER and HYPO children. Although a significantly higher proportion (in per cent) of total lipids and animal fat consumption was found in HYPER boys (p less than 0.05), the proportions (in per cent) of fatty acids, and the unsaturated/saturated fatty acid ratio in HYPER and HYPO children did no differ significantly. Parents of HYPER children showed significantly higher mean values of cholesterol, apolipoprotein B, LDL cholesterol and more unfavourable atherogenic index values. Hypercholesterolaemia aggregation in both parents was likewise significantly higher in children assigned to the HYPER group.
Changes in the lipoprotein metabolism of 15 patients with nephrotic syndrome concomitant with various types of the underlying renal disease after methylprednisolone therapy were investigated. Following methylprednisolone therapy, nephrotic syndrome remission was achieved only in three patients with minimal change disease. In these patients, total cholesterol (TC) and free cholesterol (FC) decreased and an increase in HDL-C and the HDL-C/TC ratio was found. In the remaining 12 patients, while marked proteinuria persisted after therapy, a significant increase in HDL-C (from 1.38 to 1.83 mmol/l) was noted with no significant changes in TC, FC and TG. Our results suggest that methylprednisolone may affect lipoprotein metabolism without necessarily exerting a favourable effect on the course of kidney disease.
An optimum blood level of cyclosporine-A (Cs-A) after allotransplantation in rats is very important for the survival of the transplanted organ. An auxiliary allotransplantation of the heart into the abdominal cavity were carried out in 10 rats. A Cs-A blood level of 200 to 300 ng ml was obtained by administration in the animal food in a dosage of 7 mg kg body weight day. A rejection of the graft was prevented in this way without any symptom of toxicity during 90 days. The results of the experiments were well reproducible. The obtained Cs-A blood level is relatively stationary, frequent laboratory tests are not necessary.
Technetium 99m Tc labelled lipoproteins are novel diagnostic agents suitable for the study of the lipoprotein metabolism and prospectively for picturing the specific receptors. The paper reports the first results of the preparation and quality evaluation of very low density lipoproteins (VLDL) labelled with technetium 99m Tc. This radionuclide is, due to its advantageous properties, preferentially employed in nuclear medicine. The present paper resulted in a successful attempt to bind technetium 99m Tc to a lipoprotein carrier with selective transport and targeted organ-specific biodistribution.
Embolization of the renal arterial bed with embolization agent Vilan 500 was performed in 13 dogs. Embolized kidneys shrink after the procedure and the functional parenchyma is extinguished. Peripheral PRA values were followed to find out whether renin production by the embolized kidney is extinguished (the non-embolized kidney was surgically removed). In nine of the thirteen dogs peripheral PRA decreased below 0.5 ng/ml/h; this renin activity can be considered extrarenal. Embolization of the kidneys with Vilan 500 can thus substitute surgical nephrectomy in patients with secondary renal hypertension.
The in vivo inflow rate of low density lipoprotein (LDL) cholesterol to the thoracic aorta, renal and coronary arteries was studied in minipigs with endogenously labelled 3H-cholesterol LDL. The LDL cholesterol inflow rate to these arteries was three to five times higher in animals with hypercholesterolemia and experimental atherosclerosis compared to the controls. Moreover, the inflow rate of LDL cholesterol to the control intact arteries was so high that the cumulation of arterial cholesterol cannot be regarded simply as one-way transport and the amount of cholesterol present in the arterial wall is the result of the equilibrium between LDL cholesterol inflow and transport out from the wall.
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