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UDC 616.617-003.7-08
MODERN IDEAS ABOUT THE METHODS OF TREATMENT OF UROLITHIASIS
Altai State Medical University, Barnaul V.M. Bryukhanov, G.V. Zharikova
The literature review describes the main methods of treatment of kidney stone disease. They include lithotripsy, pharmacotherapy, treatment with natural products (phytotherapy, mineral water). Based on numerous studies of recent years, it can be assumed that the organic matrix of the kidney stone is a promising target for litholysis. Key words: kidney stone disease, lithotripsy, pharmacotherapy, phytotherapy, litholysis.
Despite the high level of modern medicine problems in the treatment of urolithiasis is still not small. Etiology and pathogenesis of urolithiasis are very complex and multifactorial [1], therefore it is rather difficult to unequivocally determine the reasons for the insufficient effectiveness of anti-lithogenic therapy. But one of them, in our opinion, lies in the very nature of the kidney stone as the main pathological object by urolithiasis, and therefore the underlying object for therapeutic effects.
Kidney stone as an object of therapeutic effects by urolithiasis
A great difficulty in the early diagnosis and treatment of urolithiasis is the fact that the disease in most cases is asymptomatic until the calculus becomes large enough, disrupting urodynam-ics. In this situation, there is a need for litholysis - destruction of the concrement to small fragments capable of leaving the body with urine.
The methodology of litholysis and its effectiveness are largely determined by the biomineral properties of the calculus. It is well known that the main type of urinary stones are oxalate urolites [2,3,4,5,6,7,8]. They have the most solid structure, in connection with which their litholysis is the most complex.
Today there is no doubt that oxalate urolith is a complex organo-mineral aggregate consisting of biominerals of calcium oxalate and an organic matrix [9]. The study of the mechanical and strength properties of oxalate stone showed that the oxalate urolith section has a distinct radial structure, manifested in peculiar "rays" emanating from the center of the stone (Fig. 1).
In this case, the character of the dependence of the microhardness on the radial symmetry of the oxalate stone is such that this indicator has the greatest value in the border region, i.e. the greatest amount of the mineral component is concentrated in the surface layers of the stone [9]. Similar data were obtained in a number of other studies [10,11,12,13].
H—1—i—1—i—1—i—1—i—1—i—1—r^
0 2 + 6 a ID 12
r,ltut1
Fig. 1. Radial structure of renal urolith [according to A.I.
Neimark, V.V. Polyakov, N.A. Titarenko, 2000]
On the one hand, this agrees well with the generally accepted theories of lithogenesis, according to which stones are evolved from the organic core by precipitation of inorganic material on it [14]. In an applied aspect, this fact contributes to the understanding of the stability of the oxalate stone to litholytic influences. It is clear that it is quite difficult to destroy a stone whose hardness is maximal already on the surface. It is appropriate to add here that the hardness of calcium oxalate biomineral (whewellite and weddelite) on the Mohs scale is in the range of 3-4, i.e. they are characterized as minerals of medium hardness. For comparison, among biominerals, found in the human body, only hydroxyapatite and its derivatives have great
hardness (the value of hardness of hydroxyapatite on the Mohs scale is 5).
Thus, the mineral component of oxalate urolyth should not be recognized as the most beneficial target for litholytic effects, especially in the context of pharmacological treatment. Therefore, in recent years, more attention is paid to the study of the organic matrix of the stone. Naturally, this in many respects aims to advance in understanding the patho-genesis of nephrolithiasis. But at the same time, this knowledge can define a new vector of searching for effective methods of pharmacological litholysis.
The proteomic analysis of the organic matrix of oxalate stones, carried out in a number of recent studies, allows us to say with some certainty that the mass fraction of "organic" in the overall structure of the stone mainly varies in the range 2-5%,
sometimes reaching a level of about 10% [15 ,16]. At the same time, the number of matrix proteins is quite high, it can be counted in several tens or even hundreds.
One of the most modern and informative studies in this context is the work of Japanese scientists in 2015 [17]. They analyzed 13 samples of oxalate stones from different patients. It turned out that according to the mineral composition of 4 stones only whewellite (calcium oxalate monohydrate), 3 - only whewellite (calcium oxalate dihydrate), 5 - mixture of whewellite and weddelite and 1 - mixture of weddelite and hydroxyapatite. As a result of proteomic analysis, 65 proteins were identified (Table 1). The identification criterion was the presence in the protein structure of at least 3 peptides consisting of not less than 5 amino acids.
Proteins identified in the organic matrix of oxalate stones Table1
№ Category of protein attribution Protein name
1 Cellular (biogenesis, structure, - Annexin I
membrane) - Annexin II
- Proteoglycan 2
- Collagen-2-alpha
- Collagen-3-alpha
- Dendrin
- Gene DIO-3
- Filamin-C
- Histone H3
- Histone H4
- Histone 1 H2B1 cluster
- Hist2H4
- Nesprin-1
- Nucleolin
- Obscurine
- Peroxinl
- Proteas-associated protein EMC 29
- Proteoglycan 4
- Rho-associated protein kinase 1
- Tamm-Horsfall protein
- Utrophin
- Zn-finger protein
2 Coagulation - Gas6 - Protein Z (vitamin K-dependent plasma glycoprotein) - Protein S - Prothrombin
3 Proteins of cell adhesion - Dermeidine - Myosin (not muscular)
4 Proteins of cell damage - heat shock protein 90 alpha - heat shock protein 90 beta
5 Proteins of other processes - Calcreticilin
- Protein-5, binding fatty acids - Gamma-glutamyl hydrolase - Osteopontin - Ubiquitine and/or ribosomal protein S27a
6 Proteins of immune recognition and protection - Calgranulin A - Calgranulin B - Calgranulin C, S 100 calcium-binding protein 12 - Catepsin G - Protein binding component of complement 4 - Component of complement C3 (chain A) - Component of complement C3 (chain B) - Component of complement C3 (chain C) - Component of complement C3 (chain D) - Cystatin A - a-defensin - Elastase 2 - Eosinophil peroxidase - Region V of the heavy chain Ig - Lactoferrin - Lipokalin 1 - Lysozyme - MAp-19 - Myeloperoxidase
7 Plasma proteins - Apolipoprotein A-I
- Apolipoprotein A-IV
- Apolipoprotein B-100
- Apolipoprotein C-I (sequence 1-38)
- Plasma albumin
- Fetuin-A, a-2-HS-glycoprotein
- Vitronectin
- Fibrinogen fragment D, chain C
- Fibrinogen fragment D, chain A
- Component of plasma amyloid P
8 Transport proteins - Hemoglobin
It is interesting that none of the identified proteins were detected in all 13 stones at once. This may mean that some of them do not participate in the pathogenesis of nephrolithiasis and, apparently, got into the organic matrix accidentally. However, some regularities were revealed quite clearly. So, for example, osteopontin, prothrombin and protein Z were found together in all whewellite-containing stones, which agrees well with known data on the role of these substances in the process of stone formation. In this case, the component of the plasma amyloid P was detected in all the whewellite-containing stones. Apparently, there is a certain specificity of the participation of these substances in the crystallization of both types of oxalate minerals. Finally, the presence in the matrix of substances such as calgranu-lins A and B and histone H4 indicates a certain role of leukocytes and monocytes in the development of nephrolithiasis.
Two years earlier, a group of Indian scientists published data according to which 5 new protein molecules were found in the organic matrix of ox-alate stones [19]. These were ethanolamine-phos-phate cytidylyltransferase, a protein similar to GT-Phase-activated Ras, UDP-glucose: glycoprotein glycosyltransferase 2, RIMS-binding protein 3A, macrophage-coating protein. At that, the first two
showed the properties of the promoter of crystallization, the other two showed inhibitor properties, and the latter could play a dualistic role depending on the conditions.
Other data are known that reveal the structural features of the organic matrix of oxalate stones. Thus, in one of the studies, 33 unique matrix proteins were detected, 90% of which were never detected in the matrix, and 70% of them, according to their known properties, are inflammation or cell defense proteins [15]. Close in nature results were obtained by analyzing the structure of 25 stones. It turned out that the organic matrix contains hundreds of proteins, among which the proteins associated with the inflammatory response prevail [16].
Whatever it was, the accumulating array of experimental data allows us to modernize and expand our view on the role of the organic matrix of stones in the nephrolithiasis problem. Given the diversity of its protein composition, the potential role of these proteins in the development and prevention of nephrolithiasis [17], it can not be ruled out that the organic matrix can be a target for litholysis (or prevention of lithogenesis), including pharmacological character. In the modern literature even the corresponding term is proposed: the proteomic approach. It is logical to assume that the destruction of the matrix (or a change in its
structure and function) will lead to loss of integrity of the overall structure of the microlite, and therefore, will determine the litholytic effect. Indirect confirmation of the legality of such a hypothesis may be the results of studies according to which there is a dissolution or degradation of the crystals of venellite in the culture of renal tubular cells under the influence of endolysos [18]. Since the target for the action of lysosomal enzymes can only be an organic substrate, it can be assumed that the results were due to the fermentation of certain organic structures involved in the formation of biominerals and their interaction with cells.
Lithotripsy
It is no exaggeration to note that for more than 30 years, the main weapon of the urologist in the treatment of urolithiasis is lithotripsy in various variants [20,21,22,23,24,25]. The introduction of this method into practice was held in 1982 by the German professor K. Shossi, who demonstrated a 90% effectiveness of lithotripsy in 498 patients [26]. In Russia, the first lithotripsy was performed in 1987 in the Urology Institute [26]. Since then the method has been continuously improved. Thanks to him, the number of surgical interventions for kidney stones has been reduced many times, and mortality from KSD and postoperative complications has decreased almost threefold in the first 15 years [27]. And yet, the original euphoria long ago passed. The expected solution to all problems has not taken place. The reason for this is the abundance of shortcomings in the method and unsolved issues. Quoting Professor V.V. Du-tov, "... What is the fate of the residual fragments of the stone after lithotripsy? Are these residual fragments significant to the patient and the physician? What is the risk of developing arterial hypertension and other complications of lithotripsy? What should be the approach to the treatment of single, multiple and coral stones, as well as ure-teral stones? What are the features of therapeutic tactics in the combination of urolithiasis with in-fravesicular obstruction? What are the characteristics of lithotripsy in children, as well as in patients with single and abnormal kidneys? What are the limits of the use of lithotripsy? What is the role of modern endoscopic technologies in combination with ESWL in the treatment of kidney stones and ureters? What are the economic aspects of modern methods of treating urolithiasis? And, finally, what is the place of open surgical interventions in the treatment of KSD patients at the present stage ...? [27]. Apparently, there are a lot of questions. However, to implore the merits of this method would be incorrect.
What is the nature of the litholytic effect of lithotripsy? The general essence of the method is reduced to the creation near the microlite of conditions under which the energy of the external ac-
tion exceeds the hard characteristics of the stone, and it collapses. Today there is no unambiguous understanding of the mechanism of lithotripsy. However, the study of the issue is very active. So, in 2005 a group of European researchers, analyzing a large array of data, identified 4 possible mechanisms of stone destruction against lithotripsy [28].
- Hopkinson-effect - chipping of the stone material by stretching tension in the reflected wave;
- Cavitation - leads to the formation of a shock wave due, for example, the passage of ultrasound through an aqueous medium that fragments the stone;
- Quasistatic compression - fragmentation of the stone, due to the exceeding of the compres-sive strength threshold under the influence of external influence;
- Mechanism of dynamic fatigue - accumulating destruction of the stone configuration, caused by repeated shock waves for a certain period of time.
Nevertheless, the authors agree that none of these mechanisms fully explains the phenomenon of the formation of a shock wave that destroys a stone. However, each of them contributes to the understanding of the physics of the process.
Of interest is a new technology for electro-pulsed destruction of biological stones. Its essence lies in the fact that a nanosecond high-voltage pulse is applied to the urinary stone, as a result of which the dielectric breaks down, which is the stone, and the electric current flows through the plasma channels formed in the volume of the dielectric. As a result, tensile thermomechanical stresses arise in the stone, which lead to its cracking and, ultimately, destruction [29].
Nevertheless, each of these mechanisms is more or less able to cause damage to healthy tissues and organs. This, along with a group of concomitant factors (localization and size of the stone, the constitution of the body, the state of urody-namics, etc.), explains the rather traumatic nature of the method and a number of significant side effects [27,26]. These include hypertension, obstructive pyelonephritis, "stone path", impaired kidney function, hematoma formation, etc. [27,26]. Therefore, increasing the effectiveness of lithotripsy with a decrease in its trauma is today one of the main tasks of urologists. But at the same time, this circumstance preserves the high urgency of developing effective methods of drug therapy for the KSD.
Drugs in the treatment of urolithiasis
The problem of effective pharmacological correction of nephrolithiasis has always existed and evolved with the accumulation of knowledge about the etiology and pathogenesis of the KSD and the experience of its treatment. Today certain progress has been achieved, some therapeutic schemes have been worked out, directions for find-
ing new approaches to the treatment of the KSD have been formed, but it should be recognized that the pharmacological support for the treatment of patients with KSD clearly lags behind the modern needs of medicine.
At the moment, only a few groups of drugs have become widespread in the treatment of the KSD. Thus, for example, the appointment of thiazide diuretics with calcium forms of nephrolithiasis remains relevant [30,31,32,33,34,35]. It is generally believed that thiazides, reabsorbing calcium ions in the kidneys, reduce their concentration in the urine and thereby weaken the synthesis of insoluble calcium biominerals [32,34]. However, the side effects of thiazides are well known, which speaks for itself in the context of criticism of this approach.
Moreover, a-blockers (especially tamsulosin) are actively used in anti-lithogenic therapy. In a large study, involving 5,864 patients with KSD, it was found that the appointment of a-blockers is accompanied by a number of beneficial effects. In particular, the period of excretion of kidney stones was shortened 2.9 times and the number of episodes requiring the appointment of analgesics for symptomatic indications was significantly reduced [36]. Similar data are recorded in other studies devoted to this group of drugs [37]. It is generally believed that their beneficial effect in KSD is based on a decrease in the ureter's tone and frequency of peristalsis, as well as dilatation of the ureteral lumen [37,36].
For a similar purpose, calcium channel blockers of the nifedipine group can be used [26]. A number of studies have shown a significant improvement in the removal of stones and their fragments in the administration of nifedipine [26,38]. There have also been attempts to compare the efficacy of tamsulosin and nifedipine. According to their results, a certain predominance of the effect remained behind the a-adrenoblocker [38,39].
Unforgettable is the use of citric acid salts in the KSD, especially potassium and magnesium citrate [30,31,32]. Citrate is a natural inhibitor of crystallization [2]. It chelates calcium ions in the urine, reducing their reactivity. And besides, with the use of these drugs, the urine pH shifts to the alkaline side, which, according to conservative ideas, is a factor preventing the crystallization of oxalate biomineral [2,40,41]. True, in this direction new research results begin to appear that call into question the peremptory nature of this view of the problem. Thus, it has been established that when the pH of the medium is raised to 8, the crystallization of calcium oxalate monohydrate is indeed significantly reduced. However, under these conditions, the intensity of calcium crystallization of oxalate dihydrate increases [42]. And nevertheless, the need to prescribe citrate with nephrolithi-asis today is not in doubt.
In recent years, the development of the approach has targeted pathogenetic treatment of the KSD. This was the logical consequence of a real breakthrough in the study of the pathogenesis of neph-rolithiasis that occurred at the beginning of the 21st century. As a result, it became possible to identify potential targets for targeted pharmacological effects. One of the studies in this direction was conducted at the Department of Pharmacology of the Altai State Medical University. The effectiveness of targeted correction of nephrolithiasis by pharmacological stimulation of the formation of a fragment of prothrombin 1 in the renal tubules was studied due to an increase in protrombin production in the liver, an increase in the sensitivity of renal tissues to insulin, inhibition of the initial phase of crystallization due to blockade of calcium channels on the nephrocyte membrane, etc. [43]. Similar studies are conducted in the United States, Japan and other countries [44].
A separate area of KSD drug therapy should be recognized as the use of natural products. The state of affairs in this matter is very ambiguous. On the one hand, today's pharmaceutical market is full of all kinds of drugs, phyto-spe-cies, dietary supplements, etc., which supposedly relieve kidney stones. Many of them are purely commercial products and do not deserve scientific attention. But there are a number of those whose application is justifiably and scientifically confirmed. Moreover, the above-mentioned targeted approach to the search for new methods of treatment of KSD allows us to consider natural products as polytarget means, i.e. able to correct several parts of the pathogenesis of nephrolithiasis. Finally, it can not be ruled out that some natural products, especially of peptide or amino acid nature, can directly or indirectly affect the organic matrix of the stone, destroying it or hampering its formation. All this induces a more detailed analysis of the antilithogenic properties of modern agents of natural origin, which will be the subject of the next section of this chapter.
Means of natural origin in the treatment of urolithiasis
Plant-based drugs
In addition to drug treatment of urolithiasis, phytotherapy is of great importance, which today is considered by specialists not only as an auxiliary tool, but also as a basic approach to the treatment of KSD [43,45]. The reason for this, in our opinion, is the potentially polytargetal character of the antilithogenic effect of phytopreparations. Due to the variety of its phytochemical composition, many plants can have a versatile effect that promotes litholysis and/or lithokinesis (excretion of uroliths from the kidneys without their destruction) [46,47,43,45]. In addition, the absence of side effects, mild effects, a simple regimen of recep-
tion are also the undimmed benefits of phytotherapy. But on the other hand, the diversity of BAS in the composition of plants, their poor knowledge, apparently, is the obstacle that restrains the scientifically-based development of the pharmacology of phytopreparations in the KSD. And yet, in recent decades, research on the antilithogenic properties of phytopreparations has been fairly active. A large number of studies are devoted to the means of plant origin: various infusions, decoctions, preparations based on medicinal plant raw materials [46,47,43,45,48].
According to modern ideas, the antilithogenic effect of most phytopreparations is based on the tetrad of effects: diuretic, antispasmodic, antioxidant and anti-inflammatory. In addition, antibacterial properties of preparations, their metabolic effects, sorption capacity and a number of other specific properties may additionally benefit.
The above-mentioned effects are covered by a number of pharmacopoeial plants, such as horsetail, common bearberry, kidney tea, cowberry, black elder, birdwort, etc. They are fairly well studied and described many times. A number of studies devoted to the specific activity of some of them with nephrolithiasis are known. For example, the use of the extract of renal tea (Orthosiphon stamineus) under conditions of experimental oxalate nephrolithiasis was accompanied by a significant weakening of nucleation and aggregation of calcium oxalate crystals, which, in the opinion of the authors, was associated with an effect on the expression of osteopontin [49]. Another type of kidney tea (Orthosiphon grandiflorum) also significantly reduced the crystallization of calcium ox-alate in esperiment, which was accompanied by an increase in the level of catalase and superoxide dis-mutase in the kidney tissue [50]. At the same time, it is interesting that other authors did not find any significant antilithogenic activity of kidney tea (Orthosiphon grandiflorum) in the simulation of experimental oxalate nephrolithiasis [51].
And yet, the main body of research on the effectiveness of phytopreparations in urolithiasis is covered by plants that are not considered pharma-copeial in Russia. Only for the period from 2011 to 2017 in the scientific literature there had been described the beneficial effect on the course of oxalate nephrolithiasis of extractive preparations of such plants as [52, 53, 54, 55, 56-59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75-80, 81, 82-86, 87, 88, 89, 90, 91, 92-95, 96, 97-101, 102, 103, 104, 105, 106, 107]:
- gourd (Lagenaria siceraria);
- common origanum (Origanum vulgare);
- barberry common (Berberis vulgaris);
- Terminalia arjuna (Terminalia arjuna);
- Cherry (Cerasus Avium);
- Desmodium styrafolium (Desmodium styraci-folium);;
- plantain banana (Musa paradisiaca);
- Bergania ligulata (Bergenia ligulata);
- Bermuda grass (Cynodon dactylon);
- Mastic tree (Pistacia lentiscus);
- Malva neglecta (Malva Neglecta);
- rupture wort (Herniaria glabra);
- quick grass (Agropyron repens);
- saffron crocus (Crocus sativus);
- old-man's-pepper (Achillea millefolium);
- horse vetch (Dolichos biflorus);
- climbing fern (Lygodium japonicum);
- Hairy Bergenia (Bergenia ciliate);
- Pedalium murex (Pedalium murex);
- Copaifera langsdorffii (Copaifera langsdorffii);
- coconut palm (Cocos nucifera);
- Venus's-hair (Adiantum capillus);
- Indian nightshade (Solanum xanthocarpum);
- Hygrophila auriculata (Hygrophila spinose);
- common Saint-John's wort (Hypericum perfo-ratum);
- chaff-flower (Achyranthes aspera);
- curly parsley (Petroselinum sativum);
- punica granatum (Punica granatum);
- nutmeg flower (Nigella sativa);
- Pyrrosiae petiolosa (Pyrrosiae petiolosa);
- dog-rose (Rosa canina);
- Hibiscus sabdariffa (Hibiscus sabdariffa);
- Phyllanthus amarus (Phyllanthus amarus);
- toothpick ammi (Ammi visnaga);
- silver whitlowwort (Paronychia argentea);
- water plantain (Alisma orientalis);
- hairy burstwort (Herniaria hirsute);
- Phyllanthus niruri (Phyllantus niruri);
- putchok (Costus arabicus);
- White Peony (Paeoniae Alba);
- Phlogacanthus thyrsiformis (Phlogacanthus thyrsiformis);
- wild spin (Chenopodium album);
- catmint (Glechoma longituba);
- helichrysum (Helichrysum graveolens);
- common snowball (Viburnum opulus);
- Holarrhena antidysenterica (Holarrhena anti-dysenterica);
- safflower (Carthamus tinctorius)
As is known, the principle of combining several herbal preparations is common in phytotherapy. The same is true for phytopreparations for the treatment of KSD. So, in our country in clinical conditions, the use of "Kanefron" and "Prolit-septo" by KSD was successfully tested [46,47,108]. These agents contain a combination of plant components, possessing a diuretic, anti-inflammatory, antispas-modic, antimicrobial, vasodilator and nephropro-tective action. Also, patients with nephrolithiasis are assigned urolesan, phytolysin and other combined phytopreparations [43]. A search is also being conducted for new combined phytoprepara-tions for the treatment of KSD. In 2015, a study was conducted in Spain on the anti-lithogenic activity of Herbensurina herbal medicine containing ex-
tracts of pharmacopeia plants of black elder (Sam-bucus nigra), Equisetum arvense, as well as Agro-pyron repens and herniary breastwort (Herniaria glabra). The use by nephrolithiasis induced by eth-ylene glycol in rats promoted a decrease in crystal-luria relative to the control group [109].
Attempts are being made to study the antilitho-genic properties of specific groups of biologically active substances that are part of medicinal plants. For example, it has been shown that when epigalocatechin-3-gallate, the main antioxidant of green tea leaves, is used, the binding of calcium crystals of oxalate monohydrate to the cells of renal tubules is reduced by inhibiting the release of alpha-enolase from the cytoplasm onto the outer side of the cell membrane [75]. Glycoside derivatives of hydroxyanthraquinone in the experiment demonstrated the ability to prevent the formation of crystals of calcium oxalate [110]. The ability of crocin, the main biologically active substance of Saffron, is also shown to inhibit calcium oxa-late lithogenesis, which was associated with its antioxidant properties [111]. Saponins of Solanum xanthocarpum under conditions of experimental oxalate nephrolithiasis reduced the amount of renal microlites. It was found that these substances increase the level of glycosaminoglycan in the kidneys - one of the known inhibitors of intrarenal crystallization [112,113]. In addition, the anti-uro-lithic properties of berberine, kellin, visnagine and others were established in the experiments [114,111,115,116,117,118].
Summarizing the above, we note that phyto-therapy occupies a significant niche in the practice of treating urolithiasis. However, its principles are rather conservative. The number of plants with declared antilithogenic properties is constantly increasing, but there is no qualitative breakthrough. Perhaps the new perspective will open up the already mentioned proteomic approach. And the first steps have already been taken. Thus, it was found that 4 proteins isolated from the plant Terminalia arjuna (Kukubha) exert a pronounced preventive effect on the adhesion of calcium oxa-late crystals to the cell surface [119]. Study of their structure showed that they contain sequences close to such proteins as Nuclear pore anchor, DEAD Box ATP-dependent Helicase 45 RNA, homologue 1 Lon protease and Heat-shock protein 90-3 [119]. Interestingly, some of these proteins, in particular Heat-shock protein, have been identified in the structure of the organic matrix of the stone, as we mentioned above.
Mineral water
The use of mineral waters by urolithiasis is known for a long time. Their assortment is quite large, and the medical effects are well studied [120-126]. First, the very fluid intake increases the volume of urine, and therefore, reduces its su-
persaturation with lithogenic ions and crystalline material. The dependence of the urine supersaturation of urine on the volume of fluid consumed is sufficiently well studied [2]. Secondly, the antilitho-genic effect of mineral waters is largely determined by their mineral composition. The presence of such ions as Mg2+, Zn2+, Cl- etc. due to competitive interi-onic interaction can weaken the formation of sparingly soluble calcium salts [2]. And thirdly, some mineral waters have an alkaline character, which makes it possible to alkalize urine, reducing the aggregation of calcium oxalate monohydrate [2].
In general, the opinion of specialists is that mineral waters are relevant only in the context of rehabilitation of patients who underwent lithotripsy or operative intervention for kidney stones, and also for the prevention of recurrences of the KSD.
Antitilogenic agents of different natural origin
Drugs of natural origin, not related to phy-topreparations, today remain, perhaps, the least studied group. At the same time, their potential can be very large. Including in the context of the pro-teomic approach.
Among the officially registered drugs from the group described today, the anti-lithogenic properties of the Histochrome agent, whose active ingredient is the natural pigment echinochrome A, obtained from the shell of sea urchins, have been experimentally studied. Based on the obtained data, its effect can be explained by antioxidant and chelating properties [43].
Research studies have shown that the Sarghassum Wightii algae extract, rich in polyphenol flo-rantain, can prevent the nucleation, aggregation and growth of calcium oxalate crystals on the model of oxalate nephrolithiasis [127]. In addition, the porcine extract of Poria in the experiment demonstrated pronounced antioxidant and renoprotective properties against oxidative stress caused by calcium oxalate monohydrate [128].
Summarizing all of the above, we note that the modern look at the search for targets for therapy KSD allows us to consider the proteomic approach as one of the most promising. At the same time, despite the existing achievements in the phar-macotherapy of the KSD, there are practically no pharmacological agents that can implement this approach.
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Contacts
Corresponding author: Zharikova Ganna Viktor-ovna, lecturer of the Department of General and Biological Chemistry, Clinical laboratory diagnosis of ASMU, Barnaul. 656038, Barnaul, Lenina Prospekt, 40. Tel.: (3852) 566938 E-mail: ganna1704@mail.ru
Bryukhanov Valery Mikhailovich, Doctor of Medical Sciences, Professor of the Department of Pharmacology of ASMU, Barnaul. 656038, Barnaul, Lenina Prospekt, 40. Tel.: (3852) 566812 E-mail: bvm@agmu.ru
