Method for modeling chronic toxic nephropathy

IPC classes for russian patent Method for modeling chronic toxic nephropathy (RU 2253153):

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Method for modeling chronic toxic nephropathy / 2253153
At studying the mechanisms of heavy metals toxic action, in particular, cadmium upon renal function, it is suggested to introduce cadmium sulfate solution into stomach once daily for 2 mo at the dosage of 0.5 mg/kg, on conversion to metal, where cadmium corresponds to 0.5 mg per 1 ml solution. The present innovation enables to study the pathology in dynamics of development and elaborate and searching preparations for treating and preventing chronic toxic nephropathy.

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FIELD: medicine, experimental biology, ecology, toxicology.

SUBSTANCE: at studying the mechanisms of heavy metals toxic action, in particular, cadmium upon renal function, it is suggested to introduce cadmium sulfate solution into stomach once daily for 2 mo at the dosage of 0.5 mg/kg, on conversion to metal, where cadmium corresponds to 0.5 mg per 1 ml solution. The present innovation enables to study the pathology in dynamics of development and elaborate and searching preparations for treating and preventing chronic toxic nephropathy.

EFFECT: higher efficiency.

1 ex, 3 tbl

The invention relates to medicine, experimental biology, ecology, toxicology, and can be used for investigation of the mechanisms of toxic action of heavy metals, particularly cadmium on renal function.

In the last decade has dramatically increased the interest to cadmium, as a chemical element, polluting the environment and affecting the health of the population, due to the increasing scale of production and application of this element in the industry. The literature provides a wealth of information about the consequences of excessive inflow of cadmium in the body. The most widely known case of the development of the most severe forms of chronic cadmium poisoning is a disease “Itay-Itay”, first identified in 1946 in Toyama Prefecture (Japan), where the soil, water and food contains large amounts of cadmium (Nfessio,1969). The disease is characterized by impaired calcium metabolism, pronounced disorder and Fanconi syndrome. Shown (Masogoat, Nagakawa, 1984; Masogoat, Ohanesian, 1986)that the main bodies with a maximum accumulation and manifestation of the damaging effects of cadmium are the liver and kidneys, and the degree and nature of its damaging effects depends upon the route of exposure and the magnitude of the metal concentration in the cell. The process of purification is organisme from cadmium is characterized by a very low speed with an effective process of elimination half-life equal to 140±20 days. These facts outlined the feasibility of using cadmium compounds to create a model of chronic toxic nephropathy.

Closest to the claimed method is (however I.G. Experimental and clinical analysis of the mechanisms of action of mineral water “TIB-2 on renal function//abstract of thesis. on saisc. wcstcrn - 2003. - C.11) modeling toxic kidney damage produced by single subcutaneous injection of nephrotoxic mixture consisting of 0.5 mg uranylacetate dissolved in 0.5 ml of glycerol per 100 g of body weight.

The disadvantages of this model is that not investigated long-term effects of toxic substances on the body, and as a nephrotoxic substance is a special mixture that is not present in the surrounding environment and is not a pollutant.

The claimed invention is directed to solving the challenge in developing a model of chronic toxic nephropathy substance that is a common environmental pollutant.

The solution of this problem allows us to expand the understanding of the effect of accumulation of cadmium in the organism, its damaging impact on the structure of the kidney tissue and its function during prolonged exposure to heavy metal; to create a way of modeling granitescientiec nephropathy, increase reproducibility, easy to experiment on animals and cost-effective.

To achieve this, the technical result of the claimed invention, a method of modeling a chronic toxic nephropathy includes the following significant features: as toxic substances animal intragastric is introduced a solution of cadmium sulfate in a dose of 0.5 mg/kg in two months.

This method differs from the prototype using toxic substances - cadmium sulfate, is widespread in the environment, as well as a long introduction to create a model of chronic toxic nephropathy.

Among the distinctive features of the claimed invention and the technical result is the following causal relationship: long-term administration of a solution of sulphate of cadmium in a dose of 0.5 mg/kg leads to chronic toxic nephropathy, which is more convenient and close to the natural conditions model.

According to the authors the information set of essential features that characterize the essence of the claimed invention, is not known, which allows to make a conclusion about conformity of the invention, the criterion of “novelty”.

According to the authors, the essence of the claimed invention should not be for experts explicitly from izvestno the level of medicine, since it is not detected above the possibility of obtaining way of modeling toxic nephropathy, which allows to conclude that the criterion of “inventive step”.

The set of essential features that characterize the invention, in principle, can be repeatedly used in medicine with the result of being more accurate and easily reproducible method for the development of chronic toxic nephropathy, which allows to make a conclusion about conformity of the invention, the criterion of “industrial applicability”.

The method is as follows.

To obtain a toxic substance cadmium sulfate dissolved in sterile distilled water so that per unit of solution equal to 1 ml, is 0.5 mg cadmium (in terms of metal). For every 100 g weight rats injected 0.1 ml toxic solution that is not excessive water stress on the organism of experimental animals. A solution of sulphate of cadmium is introduced through a tube into the stomach every day 1 time per day for two months.

Example. Rats male Wistar rats weighing 200-300 g were injected through a tube into the stomach of a solution of sulphate of cadmium in a dose of 0.5 mg/kg every day for two months. The study of the functional state of the kidneys was performed every two weeks that include the Alo definition of diuresis, glomerular filtration, tubular reabsorption of water, excretion of sodium, potassium and calcium. Change all indicators were determined relative to a reference - intact group.

The rat 0.5 mg/kg of cadmium sulfate through a tube into the stomach (table 1; 2) caused an increase in spontaneous diuresis after 2 months of the experiment (p<0,05) by reducing tubular reabsorption of water (p<0,05). In terms of research tended to also increase the excretion of sodium, which by the end of the second month was significantly increased (p<0,05). Excretion of calcium increased already after 2 weeks (p<0,001), but Ceres,5 months she declined, and by the end of the experiment increased excretion of calcium was close to significant (p<0,1).

After 1 and 2 months of the experiment, rats were killed with the use of thiopental to study the kidneys. Determination of cadmium in the kidneys, the urine and the excretion of urine revealed a significant increase in the metal content within 2 months of the experiment that display data table 3.

Table 1
The basic processes of urine formation in rats in conditions of spontaneous diuresis on the background intragastric administration of cadmium sulfate in a dose of 0.5 mg/kg (M±m)
Long is inost introduction; (CdS₄0.5 mg/kg)	The processes of urine formation
	Diuresis, ml/HR/100 g	Filtration, ml/HR/100 g	The reabsorption, %
BACKGROUND	0,0912±0,014	17,05±3,8	99,44±0,10
2 weeks	0,106±0,015	17,7±0,65	99.41±0,08
1 month	0,109±0,025	shed 15.37±1,045	99,29±0,07
1.5 months	0,0978±0,006	16,35±2,62	99,42±0.13
2 months	0,132±0,008*)	1B,09±1,32	99,17±0,06*)
*) - R relative to the background
Table 2
Excretion of electrolytes and proteinuria in rats in conditions of spontaneous diuresis on the background intragastric administration of cadmium sulfate in a dose of 0.5 mg/kg (M±m)
The duration of administration; (CdS₄0.5 mg/kg)	The former is Greece electrolytes, µmol/hour/100 g
	CA	Na	To
BACKGROUND	0,22±0,025	11,2±1,26	5,68±0,46
2 weeks	0,378±0,0327	10,0±1,18	5,54±0,8
1 month	0,303±0,046	12,22±1,59	5,48±0,37
1.5 months	0,236±0,015	15,24±2,66	4,72±0,84
2 months	0,27±0,01	16.28 per±2,19*)	5,43±1,15
*) - R relative to the background
Table 3
Accumulation of cadmium in the kidneys, the content in the urine and the excretion of urine when intragastric introduction of sulphate of cadmium in a dose of 0.5 mg/kg (M±m)
The duration of administration; (CdS₄0.5 mg/kg)	Kidney, ug/g	Urine, ex-I; µ g/HR/100 g	Urine, sod-s; mg/ml
BACKGROUND	0,156±0,03	0,00218±0,0006	0,024±to 0.032
After 2 months	31,29±1,38*)	0,0798±0,02*)	0,605±is 0.135*)
*) - R relative to the background

For histological examination of tissue samples of kidney were fixed in 10% neutral formalin, and then was subjected to fill in paraffin and subsequent preparation of slices of a thickness of 7-8 microns. Sections were stained with hematoxylin and eosin. The study sections were performed in transmitted light using a microscope Micmed-1 under magnification 80×200×400. Histological examination revealed focal dystrophic and necrobiotic changes of the epithelium of convoluted tubules, in the lumen of the tubules protein mass, desquamated epithelium. Loosening, maloideae swelling of the membrane structures of the capillary loops of vascular glomeruli and Bowman capsule - Shumlyanskiy, endothelin capillary loops of the kidney. Venous blood and plasma wetting of the walls of blood vessels predominantly cerebral layer. Focal penascola small cortical and medullary vessels. Reactive changes fibrous structures stroma of the kidney.

Funk is optional changes in renal tissue were confirmed by histological studies, revealed a picture of toxic nephropathy (toxic tubulointerstitial jade).

The proposed method for modeling chronic toxic nephropathy is effective, allows us to study this pathology in the dynamics of development and can contribute to the development and Fund-raising for the treatment and prevention of chronic toxic nephropathy.

A method for simulating chronic toxic nephropathy, including the introduction of toxic substances in experimental animals, characterized in that as the Toxics use a solution of sulphate of cadmium introduced into the stomach 1 time per day every day for two months at a dose of 0.5 mg/kg, calculated on the metal, where per unit of solution equal to 1 ml, is 0.5 mg cadmium.