The most common disorders of purine metabolism are hyperuricemia and hyperuricosuria. Hyperuricosuria, as a rule, is secondary to hyperuricemia and is a consequence of the removal by the kidneys of an excess amount of urates in the blood plasma.
Their prevalence, according to different authors, ranges from 5 to 24%. With a greater frequency, they are detected in men and in the postmenopausal period - in women.
Hyperuricemia is divided into primary (there is no previous predisposing pathology) and secondary (develops as a complication of an existing pathological condition), as well as hyperproduction (metabolic), in which purine synthesis is enhanced, hypoexcretion (renal), in which renal elimination of urates is reduced, and mixed.
The development of primary hyperproductive hyperuricemia (HY) can be caused by various enzyme defects: lack of glutaminase, deficiency of a specific enzyme - hypoxanthine-guanine-phosphoribosyl-transferrase, hypoproduction of uricase, increased activity of phosphoribosyl-pyrophosphate synthetase, xanthine oxidase hyperactivity. High uric acid levels are also seen in some hereditary diseases- Lesch-Nihan syndrome, type I glycogenosis (Girke's disease). Factors also play a great role in the development of the manifestations of the disease the environment, and above all physical activity and the nature of the diet.
Secondary hyperproductive HU develops in all diseases accompanied by increased metabolism or degradation of nucleoproteins. It is also typical for conditions associated with tissue hypoxia and a decrease in the level of ATP in tissues, heavy smoking, chronic respiratory failure, alcoholism (Table 8.9).
Primary hypoexcretionary HU is due to specific renal hereditary defects in urate transport. It is observed in familial cases of urate nephropathy or juvenile gout. The disease usually debuts at a young age with symptoms of articular gout, against which a sharply reduced MK clearance and low fractional excretion are found.
Secondary hypoexcretional TU is observed when various diseases and kidney conditions, accompanied by a decrease in the functioning of the renal mass, a decrease in glomerular filtration and / or impaired tubular transport of Urates (Table 8.9). This occurs with chronic renal failure, dehydration with diabetes insipidus and inadequate intake of diuretics, fasting, diabetic ketoacidosis, acute alcohol intoxication, as well as with prolonged use of salicylates even in low doses of ethambutol and nicotinic acid.
The main causes of secondary hyperuricemia
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Mixed hyperuricemia usually develops in an advanced process, when uric acid accumulates both due to increased synthesis and as a result of decreased excretion by damaged kidneys.
Before considering the features of the pathogenesis of purine metabolism disorders, let us highlight the main points of the physiology and pathology of MC metabolism (modern views on this problem were most fully presented in the work of L.A. Nikitina):
Uric acid is the end product of the catabolism of purine nucleotides that make up nucleic acids(DNA, RNA), high-energy compounds (ATP, ADP, HDF, GMF) and some vitamins;
In the human body, it is formed in all tissues, mainly in the liver;
Uric acid is a weak keto acid. In the extracellular fluid, it is predominantly in a dissociated state with a predominance of monosodium urate;
The solubility of uric acid compounds increases with an increase in the pH of the medium and decreases with a decrease in it, as well as if the concentration of urates exceeds 0.66 mmol / L. This plays a decisive role in the formation of urate crystals in tissues in violation of purine metabolism;
On average, about 750 mg (approximately 10 mg / kg MT) are formed and released per day. At the same time, 75-80% of it is excreted by the kidneys, the rest is excreted mainly through the intestine, where it is broken down under the action of bacterial uricolysis to CO2 and 1CHNZ. With dysbacteriosis, the excretion of MC through the intestine is sharply reduced;
The modern scheme of excretion of MC in urine includes 4 stages: 1) 100% filtration of blood plasma urates through the glomerular membrane; 2) presecretory reabsorption of 98-99% of urates in the initial segment of the proximal tubule; 3) massive secretion (40-50% of the concentration in blood plasma) of urates in the middle and partially in the initial segment of the proximal tubule; 4) postsecretory reabsorption of 78-92% of the received urates in the final segment of the proximal tubule;
MK competes with organic acids for secretion from the blood into the lumen of the tubule;
The level of uricemia in men is on average 0.06 mmol / L higher than in women and increases with age. After 50 years, the sex differences in the MC content are smoothed out;
In a healthy person, the metabolic fund of uric acid in the body is about 1-1.2 g. In violation of purine metabolism, it can increase to 15-35 g.
With excessive production of uric acid, the kidneys accordingly increase the excretion of urate in the urine (compensatory hyperuricosuria), maintaining normouricemia until, due to specific urate damage, the kidneys begin to lose this ability, which ultimately leads to hyperuricemia. Kidney damage progressively progresses to chronic renal failure.
Clinically, hyperuricemia can manifest with gout with tophi and gouty arthritis, hyperuricosuria - with gouty nephropathy and urolithiasis. These diseases are often a staged manifestation of the same pathological process.
The classification of gout is based on different types of hyperuricemia. By etiology, it is divided into primary and
secondary, and by pathogenesis - on metabolic (hyperproduction) and renal (hypoexcretion). Clinical and laboratory features of various types of gout are presented in table. 8.10.
The complete evolution of gout goes through four stages: asymptomatic hyperuricemia, acute gouty arthritis, intercritical period and chronic gouty urate deposits in the joints. Nephrolithiasis can develop at any stage of gout development, except for the first. Among the articular variants of gout along the course of the disease, there are: acute gouty arthritis, intermittent arthritis and chronic arthritis with the formation of paraarticular tophi.
Asymptomatic hyperuricemia is a premorbid condition. Moreover, such hyperuricemia can be observed in patients throughout life and not manifest any clinical symptoms. On the other hand, this kind of thesaurysmosis is a serious predisposing factor for the development of both the articular form of gout and uric acid urolithiasis.
Typical current gout is characterized by the periodic development of extremely acute arthritis with typical symptoms of "painful joint attacks". In more than 30-40% of patients, arthritis first affects the metatarsophalangeal joint of the first toe. With the progression of the disease, all new joints are gradually involved in the process. V chronic stage functional lesions of the joints outside of the articular attack persist and are associated with both deformation of the articular surfaces and the deposition of uric acid crystals in the para-articular tissues with the formation of tophuses. The formation of tophi on the auricles and in the inter-tendinous spaces is quite typical. In addition, uric acid crystals are often deposited in the kidneys and skin.
Diagnostic relevance various symptoms gout can be formalized (Table 8.11).
Clinical laboratory mountain features of the types of gout
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| Table 8.] Diagnostic criteria for gout according to K.P. Kryakunov
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Uric acid, formed in excess due to impaired purine metabolism, is effectively removed from the body by healthy kidneys. With significant hyperuricemia, urate crystals, penetrating into the tissues of the joints, tubules and interstitial tissue of the kidney, cause damage there, in response to which a cellular inflammatory reaction develops. Polymonuclear phagocytes striving to the damaged tissue perform their function by phagocytizing MC crystals and tissue “fragments”. As a result of the interaction of phagocytes, primarily macrophages, T- and B-lymphocytes, antibodies are produced, which, when combined with tissue antigens, form immune complexes that trigger a whole cascade of immune-inflammatory reactions.
Thus, the imbalance in the metabolism of purines in patients with gout is accompanied by changes in the immune system, in particular, as a result of the inferiority of the cellular genome with abnormalities at the DNA level in T-lymphocytes, the identification of high titers of antibodies to the DNA of the kidney tissue. Taking into account that a full-fledged pathway of purine metabolism is necessary to maintain normal reactions of humoral and cellular immunity, a number of authors come to the conclusion that disorders in the immune response in patients with gout can be of both primary and secondary nature. Primary damage to the immune system develops as a result of impaired purine metabolism in immunocompetent cells, and secondary disorders immune status- due to prolonged exposure to hyperuricemia and / or chronic autoimmune inflammation.
Hyperuricemia leads to an increase in the content of uric acid in the synovial fluid, its loss in the form of needle crystals, followed by penetration into the cartilage and synovial membrane. Through defects in the cartilage, uric acid penetrates to the subchondral bone, where tofus are also formed, and destruction of the bone substance occurs (X-ray symptom of a “punch”). At the same time, synovitis with hyperemia, proliferation of synoviocytes and lymphoid infiltration occurs in the synovial membrane. It should be noted that the development of acute gouty arthritis does not occur at the very moment of a sharp increase in the content of uric acid in the blood, but more often at the time of its decrease after the previous increase.
The defeat of various internal organs of varying severity in the chronic course of gout was found in more than 2/3 of the examined patients. The kidneys are most commonly affected. The frequency of kidney damage in gout is high and, according to different authors, is from 30 to 65%. Clinically, this can be manifested by uric acid nephropathy and urate nephrolithiasis.
Distinguish between acute and chronic uric acid nephropathy
Acute uric acid nephrottia is characterized by the precipitation of uric acid crystals, mainly in the collecting ducts. It is usually fleeting, has a tendency to recurrence, is induced by intercurrent diseases, significant physical activity, thermal treatments, eating food rich in purines, especially in combination with alcohol. Its most typical manifestation is the episodic appearance of brown urine, sometimes accompanied by an increase in blood pressure. The extreme severity of acute uric acid nephropathy is acute renal failure, which often requires hemodialysis. This type of kidney damage is more typical for secondary disorders of uric acid metabolism, but there is a possibility of its development in primary gout with extreme hyperuricosuria.
Chronic gouty nephropathy can manifest as chronic hyperuricosuric persistent obstructive tubular nephropathy, chronic interstitial nephritis, and chronic glomerulonephritis. In the course of chronic gouty nephropathy, 3 stages can be distinguished (see Table 8.10). Stage I - hyperuricosuric - is characterized by hyperuricosuria with often normal or slightly elevated levels of uric acid in the blood plasma. Kidney damage is manifested by microalbuminuria and increased activity of N-acetyl-O-glucosaminidase (NAG). // stage - hyperuricemic - characterized by hyperuricemia with normal, slightly increased or decreased daily excretion of uric acid. Kidney damage is manifested by nocturia, a decrease in the relative density of urine, impaired osmoregulatory function, and an increase in proteinuria. This stage is a reflection of the state when the kidneys, due to their damage, are not able to compensate for the increased urate load. Stage III- azotemic - manifested by significant hyperuricemia, low daily excretion of MC, increased plasma creatinine concentration, decreased glomerular filtration, development of chronic renal failure.
Tubulointerstitial lesions prevail in most cases in the early stages of the disease, glomerular - in the terminal phase of the disease, where pronounced glomerulo- and angiosclerosis is observed.
Chronic renal failure differs in slow progression, especially with baseline blood creatinine, not exceeding 440 μmol / l (CRF-PA), with adequate control of hyperuricemia. Terminal uremia occurs in 4% of patients. It develops later than in patients with end-stage CRF caused by another pathology. Typical gouty arthritis persists with hemodialysis treatment. Exacerbations often coincide with intensification of hemodialysis and significant dehydration.
Urolithiasis is found in 10-22% of patients with primary gout. In some patients, nephrolithiasis develops before the first attack of gouty arthritis. Factors predisposing to the development of nephrolithiasis in gout include persistent acidification of urine, increased urinary excretion of uric acid, and decreased urine output.
In a significant part of patients, chronic kidney damage with gout and hyperuricemia is characterized by a latent course and gradual development renal failure. It is based on chronic inflammatory process with damage to the glomerular apparatus, as well as the interstitium of the kidneys.
Among the mechanisms of the damaging effect of uric acid on the kidneys, the following are currently being discussed: a direct nephrotoxic effect, the interaction of sodium urate crystals with polymorphonuclear leukocytes, leading to the development of an inflammatory reaction.
Glomerulonephritis can be one of the clinically important variants of kidney damage in gout. It is characterized by a predominance of hematuria and a steady progression towards chronic renal failure. An essential feature of gouty glomerulonephritis is episodes of reversible deterioration of renal function caused by transient uric acid blockade of a part of the renal tubules, developing under conditions of dehydration and decreased urine output. A typical manifestation of glomerulonephritis in gout is a decrease in the ability of the kidneys to osmotic concentration of urine, which is detected in about 1/3 of patients with still preserved nitrogen excretory function of the kidneys. Often, simultaneously with the development of glomerulonephritis, vascular damage occurs at the level of the microvasculature (including the kidneys). The reason is the activation by uric acid crystals of complement, leukocytes and platelets, followed by damage to the vascular endothelium.
Of particular interest are renal lesions in the so-called "asymptomatic" hyperuricemia. In this case, latent kidney damage develops, which is based on severe morphological changes in the renal tissue in young people with moderate hyperuricemia and normal blood pressure. Morphological changes are reduced to glomerulosclerosis, thickening of the tubular basement membrane, tubular atrophy, interstitial and vascular sclerosis. In the pathogenesis of these lesions, the leading role is played by tubular obstruction.
Among patients with chronic glomerulonephritis, there is a group of people with persistent hyperuricemia and / or hyperuricosuria. A feature of the clinical manifestations of such glomerulonephritis in patients is the predominant prevalence of this condition among men, pronounced gross hematuria, a decrease in the concentration function of the kidneys up to isostenuria, which often develops long before azotemia, as well as the possibility of gouty arthritis several years after the detection of persistent urinary syndrome. Distinctive feature cellular immunity in such patients there is a high (up to 80%) frequency of sensitization to antigens of the epithelium of the brush border of the renal tubules with simultaneous detection of antibodies in the blood in a high titer to these antigens. The inclusion of immune mechanisms leads to damage to the glomerular apparatus of the kidney, which a number of researchers explain by the cross-reacting properties of the glomerular and tubular antigen against the background of an autoimmune process.
From this point of view, hyperuricemia and hyperuricosuria can be considered as a possible etiopathogenetic factor in the development and progression of chronic glomerulonephritis.
In addition to hyperuricemia and disorders in the immune system, lipids play an important role in the genesis of gouty nephropathy. Hyperlipidemia is considered as one of the factors in the progression of gouty nephritis and the manifestation of nephrotic syndrome. The frequency and degree of beta-lipoproteinemia and triglyceridemia, increasing with the progression of renal failure, confirm this. Li-poproteins are deposited in the glomeruli and blood vessels of the kidneys. All this leads to sclerosis of the glomeruli and wrinkling of the kidneys with the development of arterial hypertension and an increase in renal failure. It is believed that the development of hyperlipoproteinemia contributes to
the progression of systemic atherosclerotic lesions.
Although the relationship between gout and atherosclerosis has been known for a long time, the role of gout as an independent risk factor for atherosclerosis is still debated. According to some reports, the prevalence of atherosclerosis in patients with gout is 10 times higher than in the general population. In addition to lipid metabolism disorders, gout is characterized by typical changes in the regulatory system aggregate state blood, which are typical for patients with atherosclerosis.
Yu.A. Pytel and sotr. found that a possible link between hyperuricemia and hyperglycemia. With hyperuricemia, the body can accumulate alloxan, a product of oxidation and decay of MC. It has been proven that this metabolite can cause necrosis of basophilic insulocytes of pancreatic islets without a clear lesion of the endocrine part of the gland.
Thus, the pathogenesis of gout is characterized by the closure of a number of "vicious" circles:
The development of primary hyperuricemia leads to toxic kidney damage as the main factor in the progression of gout, up to the development of chronic renal failure, and the excretion of uric acid decreases below normal values already at the earliest stages of hyperuricemic nephropathy;
Uric acid and its derivatives, accumulating in tissues, initiate the development of an immunopathological inflammatory reaction with disturbances in the activity of the monocytic-macrophage system and segmental-nuclear leukocytes. Disturbances in the cellular and humoral links of immunity, burdening each other, lead to the development of an autoimmune process;
In a significant part of patients with gout, along with impaired uric acid metabolism, disorders of carbohydrate and lipid metabolism are noted with a rapidly progressing and torpid course of atherosclerotic vascular lesions and type II diabetes mellitus. These violations have a mutually aggravating effect.
The main cause of death in patients with gout is uremia, as well as heart failure, heart attacks and strokes associated with nephrogenic arterial hypertension and atherosclerosis.
Therapeutic approaches. Treatment for gout is based on a combination of three main components: diet, basic therapy and symptomatic therapy, which are aimed primarily at relieving articular syndrome and reducing hyperuricemia.
Diet. Anti-gout diet (diet No. 6 according to AA. Pokrovsky) provides for a sharp restriction on the consumption of foods rich in purines (brains, liver, kidneys, tongue, caviar, herring, canned fish, legumes, mushrooms, cauliflower, spinach, peanuts, coffee, tea, cocoa, chocolate, yeast), and in some cases - and oxalic acid, reducing the amount of proteins and lipids consumed, fasting (dairy, vegetable or fruit) days 2 times a week. The appointment of alkaline mineral waters is advisable.
Basic therapy. When determining the program of drug therapy for gout with drugs that normalize the metabolism and excretion of purines, several conditions must be met:
Consideration of the type of disorder of purine metabolism; with rare exceptions, to begin drug treatment should only be in the interictal period;
Maintaining a high daily urine output (more than 2 liters) and using drugs that alkalinize urine;
Treatment should be persistent (breaks for more than 2-3 days are not allowed) and long-term (for years), subject to a strict nutritional and active motor regimen.
There are several specialty drugs that can be basically divided into two large groups. The first group of drugs for basic therapy consists of drugs that block the synthesis of uric acid - uricodepressors, the second group consists of drugs that enhance the excretion of uric acid - uricosuretics.
An inhibitor of uric acid synthesis - allopurinol (milurite Eg18, allocyme ga \ ya1, ziloric Shcitsoc.purinol Lic1 \\ lg Mehrce, urozin Boebenger Maenchin, sanfipurol ganoy - \ Vm1: - hor) - has a specific the ability to inhibit the enzyme xanthine oxidase, which ensures the conversion of hypoxanthine to xanthine and then xanthine to uric acid. It is effective in treating all types of hyperuricemia, however, to the greatest extent:
In patients with gout with obvious hyperproduction of uric acid, nephrolithiasis, renal failure, tophi and with previously noted ineffectiveness of uricosuretics;
In patients with urolithiasis of any genesis with a daily excretion of uric acid above 600 mg / day, as well as in patients with uric acid nephropathy or with a high risk of its development.
The initial dose of allopurinol for mild forms of primary gout - 200-300 mg per day - with severe forms can reach 400-600 mg in 2-3 doses. A decrease in the level of uric acid in the blood to normal (0.32 mmol / l) is usually achieved in 2-3 weeks, this determines the transition to maintenance doses of the drug (100-200 mg / day). For patients with hyperuricemia of various origins with impaired renal partial functions, the dose of allopurinol should be reduced by 25-30%. In such cases, the combination of allopurinol with uricoeliminators is justified - in the form of allomarone, the tablet of which contains 100 mg of allopurinol and 20 mg of benzobromarone.
The use of uricodepressors and, first of all, allopurinol is quite effective. However, its side effects and toxic effects are manifested in 5-20% of patients. It should be borne in mind that in about 1/4 of patients with gout, liver function is impaired to one degree or another, which requires special care when prescribing allopurinol. Difficulties in achieving relief of purine metabolism disorders dictated the need to search for new methods of their correction. In this regard, the experience of using purine antagonists is interesting. However, as noted by O.V. Sinyachenko (1990), this method of treatment has clear indications and contraindications and cannot be widely used in patients with gout.
Uricosuretics reduce the plasma uric acid content by increasing its renal excretion. This is achieved by partially suppressing uric acid reabsorption in the proximal tubule or through other mechanisms. The group of uricosuretic drugs includes probenecid, etebenecid (etamide), acetylsalicylic acid in high doses, sulfinpyrazone, ketazone, benzbromarone, etc. Indications for their isolated use may be:
Absence of severe gouty nephropathy;
Mixed type of gout with daily excretion of urate less than 3.5 mmol (intolerance to allopurinol.
The drug of the first choice is considered probenecid Vetar Pbana (Benemid). The initial dose is 0.5 g 2 times a day, which then rises to an effective dose, usually 1.5-2 g per day, and remains at this level until uricemia normalizes. Maintenance dose - 0.5 g 1-2 times a day. In large doses, it increases the excretion of uric acid, blocking tubular readsorption, in small doses, it only blocks tubular secretion. The action of the drug is blocked by salicylates. For its part, probenecid disrupts the renal excretion of penicillins and indomethacin, heparin metabolism, which should be taken into account when using this uricoeliminator against the background of the use of anticoagulants. Less effective is etebenecid (etamide), which also inhibits the readsorption of uric acid in the renal tubules. The usual dose of etamide for adults: 0.35 g 4 times a day, course - 10-12 days; after a one-week break, the course can be repeated. In acute attacks of gout, etamide is practically ineffective, has no analgesic effect, and the use of NSAIDs is difficult.
Sulfinpyrazone (anturan Clya) is a pyrosolidone (butadione) derivative. It also does not have a significant analgesic and anti-inflammatory effect, but it is an active antiplatelet agent, which makes it possible to use it in the recovery period after myocardial infarction. The daily dose of Anturan is 400-600 mg in 2-3 doses after meals. It is well absorbed, the duration of action of one dose is 8-12 hours. When the effect is achieved, they switch to a maintenance dose of the drug - 100 mg 2-3 times a day. Another derivative of pyrosolidone, ketazone (kebuzon lecNa), on the contrary, has a pronounced anti-inflammatory effect. This allows you to use it during an acute attack of gout in an injectable form (20% solution of 5 ml), 1-2 g per day for 2 days, then 3-4 tablets (0.25 mg each) until the signs of arthritis disappear, with switching to 1 tablet as a maintenance dose. With a small volume of excreted urine and renal calculi of any type, these uricosuric agents are contraindicated.
A promising uricosuric agent is benzbromarone (desuric baar, as well as normulate, hipuric), which not only intensely suppresses the reabsorption of urates, but to some extent also blocks the synthesis of purines. In addition, under the influence of benzbromarone, the excretion of purines through the intestine is enhanced. The indication for its appointment is both primary gout and latent and secondary hyperuricemia. Benzbromarone preparations are prescribed gradually, starting at 50 mg per day; if during laboratory monitoring a clear decrease in uricemia is not achieved, they switch to an average dose of 100 mg (1 tablet of desuric or normulate). In acute attacks of gout, a short course of high doses is sometimes carried out at once - 150-200 mg per day for 3 days, followed by a transition to a maintenance dose of the drug. With increased pain in the affected joints against the background of benzbromarone, NSAIDs are indicated. Gastrointestinal upset (diarrhea) - enough rare complication but it can be reduced by using a micronized form (hipuric), the equipotential tablet of which contains 80 mg of benzbromarone.
Uricosuretics are effective in 70-80% of patients. In about 9%, they provoke the formation of calculi in the kidneys. The effectiveness of uricosuretics decreases with distinct violations renal function... When decreasing glomerular filtration for creatinine clearance below 30 ml / min, they become completely ineffective.
It is possible to increase the excretion of uric acid with the help of enterosorbents. As XV believed. KOIT (1976), with the help of coal, adopted reg 05, it is possible to remove from the body not only creatinine, but also uric acid. According to S. Sporciano et al. , the appointment of coke oven coal at a dose of 20-50 g per day significantly reduced the concentration of uric acid in the blood. Similar data were obtained by M. Max \\ e11 et al. (1972). As B.G. Lukichev et al. , in the course of enterosorption with the use of the SKN carbon sorbent, a statistically significant decrease in the concentration of blood triglycerides in renal patients was determined already on the 10th day, and by the 30th day, while maintaining the trend towards a decrease in triglycerides, a decrease in total blood serum cholesterol was observed. The same authors propose, as a test to determine the indications for ES in nephropathy, a trial prescription of such drugs for a period of 10 days. If, after the specified period, a decrease or stabilization of blood creatinine, lipids and other substances characterizing the pathology is recorded, then the treatment should be continued. It should be noted that in order to achieve a clear positive clinical and laboratory effect, ES should be carried out persistently and for a long time - at least a month.
Symptomatic therapy for gout includes relief of articular gouty attacks, prevention and treatment of urolithiasis, and correction of concomitant metabolic disorders.
The most powerful remedy for stopping acute gouty arthritis is colchicine, the mechanism of action of which is to suppress the migration of neutrophils and their phagocytosis of uric acid crystals. However, in some cases, when treating gout with colchicine, complications associated with its toxicity develop. In this case, you have to quickly reduce and / or stop taking the drug. It has been found that colchicine is not effective in 25-40% of patients. Symptomatic remedies for stopping gouty attacks include non-steroidal anti-inflammatory drugs of the pyrazolone (butadion, reopirin, ketazone, phenylbutazone, etc.) and indole (indomethacin) series. However, they also have certain side effects and limited effectiveness. Sometimes an acute articular attack can be stopped only with local, intra-articular, or even systemic use of GCS.
A whole group of granular oral preparations is used to dissolve calculi containing uric acid or to prevent their formation (Uralit-11, Blemaren, Soluran, Solimok). The basis of these drugs are citric acid salts, which provide a weakening of the acidic reaction of urine and thereby prevent the loss of urate in the form of crystals. Some of these drugs can be used to alkalize the urine in the use of cytostatics and in the treatment of porphyria cutaneous tarda. In cases with a rack sour reaction urine (pH less than 5.5) and the presence of calculi consisting of a mixture of oxalates and urates, it is preferable to use Magurlit and Oxalit C. To achieve the maximum effect, it is desirable that the urine reaction is within the pH 6.0-6.4. Exceeding this level contributes to the formation of phosphate or practically insoluble urate-oxalate calculi.
Side effects of drug therapy. Increasingly, there is information about the presence of contraindications to long-term use of uricodepressor and uricosuric drugs, as well as
NSAIDs in patients with gouty nephritis. Thus, long-term use of allopurinol can cause hepatotoxic and nephrotoxic effects, which makes it necessary to reduce the dose of the drug or completely cancel it, to search for other drugs that can affect purine metabolism. It has been established that the use of etamide and its analogues from the group of uricosuric drugs is contraindicated in urolithiasis, as well as in the progression of chronic renal failure. Long-term use of drugs of this group for gouty nephropathy is also undesirable due to a real increase in the risk of calculus formation in the kidneys.
NSAIDs used to treat arthritis and arthralgias in patients with gout often contribute not only to an increase in the concentration of uric acid in the blood, but also to the progression of tubulointerstitial nephritis, one of the most common variants of gouty nephropathy. The progression of urinary syndrome, arterial hypertension, urolithiasis is noted both with irregular intake of uricosuric, uricodepressor drugs, uroantiseptics, citrate mixtures, antihypertensive and diuretic drugs, and with the regular use of these drugs in the complex therapy of gout with gouty nephropathy.
Consequently, long-term treatment of patients with conventional anti-gout drugs against the background of clear positive dynamics in the joints and a decrease in subcutaneous tophi does not prevent the deterioration of renal function. Moreover, in the presence of signs of formed nephropathy, additional medical damage to the interstitium and tubules can significantly accelerate the development of chronic renal failure. The need to search for new methods of treatment is especially acute in patients with poor tolerance to traditional drugs or with the development of resistance to them.
Extracorporeal hemorrhage. The first attempt to use extracorporeal hemocorrection in the treatment of patients with gout in the form of hemosorption was undertaken in the late 80s by A.A. Matulis et al. ... However, this method was not without its drawbacks, it was often poorly tolerated by such patients and often had complications. We have been studying the effectiveness of apheresis technology in the complex treatment of gout for a long time.
Based on the results of research and clinical experience, we consider the indicated supplement traditional therapy gout by course application of extracorporeal hemocorrection in the following cases:
With the development of resistance to drugs that stop the articular gout attack, or to drugs for the basic therapy of gout;
In case of intolerance or poor tolerance of the basic therapy drugs for gout, or drugs that stop the articular attack;
With a steadily progressive course of gout;
In the presence of progression of gouty nephropathy;
With severe immunological disorders. Initially, the operation of choice was non-selective plasmapheresis. At the end of the course of treatment, all patients who received PF noted positive clinical dynamics in the form of improved well-being, absence of arthralgia, and increased joint mobility. Nonselective IF significantly reduced the CEC content in the blood plasma of patients with gouty nephropathy. There was a tendency to normalization of the concentration of sialic acids, fibrinogen, to a decrease below normal in the content of platelets in general analysis blood and relative density of urine. However, one third of the patients had poor tolerance to the operation. The disadvantage was the frequent development of the phenomenon of "rebound", manifested clinically by a sharp increase in the articular syndrome with a simultaneous increase in the blood concentration of uric acid and various inflammatory mediators involved in the pathogenesis and determining the clinical picture of gout. This forced to stop treatment and return to conventional drug therapy.
More efficient and rational is the conditionally selective operation with cryosorbed autoplasma (KSAP). The autoplasma modification is based on the plasma cryoprocessing technique presented above. It was found that in the treated autoplasm, the level of uric acid decreased by an average of 90%, MSM - by 78%, CEC - by 78%, fibrinogen - by 64%, creatinine - by 61%, triglycerides - by 56%, beta-lipop- roteins - by 48%, urea - by 38%, cholesterol - by 37%, IgC - by 36%, IgA - by 28%, with a slight elimination of total protein (by 14%) and albumin (by 15% ).
With the course application, such a method of hemocorrection has a more pronounced detoxification, immunocorrective, rheocorrective and delipidizing effect and greater selectivity to pathogenic factors than nonselective PF. In addition to the removal of uric acid during extracorporeal surgery, its excretion by the kidneys significantly increases.
In all 173 patients, clinical and laboratory remission was obtained, which manifested itself in the relief of arthralgias, the disappearance of arthritis symptoms, an increase in the functional ability of the joints, an improvement in well-being, and the normalization of laboratory and functional parameters. The tolerability of operations in the course was good, the frequency of the "uricemic ricochet" phenomenon was significantly reduced, the effect was more pronounced, remission was longer. In addition, angina attacks were reduced in the presence of concomitant ischemic heart disease, arterial hypertension decreased, sensitivity to basic therapy increased, and the frequency of its side effects significantly decreased.
Particularly noteworthy is the stability of renal function indicators (secretory-excretory activity of the tubular apparatus on isotope renography, increased ranges of relative urine density in the Zimnitsky test, glomerular filtration and tubular reabsorption) in 26 patients with diagnosed gouty nephropathy both immediately after the course of operations and six months later. after her. This was most noticeably manifested when comparing the group of patients who received complex treatment using a course of plasma exchange KSAP, and conventional pharmacological therapy.
The combination of plasma sorption with plasma exchange KSAP allows to optimize the treatment, to make it more rational. The course of hemocorrection in this case consists of 2 plasmapheresis operations with plasmasorption and 2-3 KSAP software operations. The volume of exfusion during plasmapheresis is 35-40% VCP, the volume of plasma sorption is 1 VCP. Volume replacement and processing of the resulting plasma are performed in the same way as with the KSAP software. The plasma exfused during the first two operations is reinfused to the patient during the third operation. When using such a treatment regimen, the efficiency of uric acid removal is significantly (1.6 times) increased. A positive effect and long-term remission is achieved in 72% of patients with hyperuricemia more than 500 μmol / L, the most resistant to the therapy. If therapy is ineffective, it is necessary to consider the advisability of prescribing uricodepressors in parallel with efferent therapy. ... The criterion for the sufficiency of the course application of operations is the normalization of the level of uric acid.
Gout and other disorders of purine metabolism
William N. Kelly, Thomas D. Palilla ( William N. Kelley, Thomas D. Patella)
Pathophysiology of hyperuricemia.Classification. Hyperuricemia refers to biochemical signs and is a necessary condition for the development of gout. The concentration of uric acid in body fluids is determined by the ratio of the rates of its production and elimination. It is formed by the oxidation of purine bases, which can be of both exogenous and endogenous origin. Approximately 2/3 of uric acid is excreted in the urine (300-600 mg / day), and about 1/3 through the gastrointestinal tract, where it is ultimately destroyed by bacteria. Hyperuricemia may be due to an increased rate of uric acid production, decreased renal excretion, or both.
Hyperuricemia and gout can be divided into metabolic and renal. With metabolic hyperuricemia, the production of uric acid is increased, and with hyperuricemia of renal origin, its excretion by the kidneys is reduced. It is not always possible to clearly distinguish between metabolic and renal types of hyperuricemia. With a careful examination, in a large number of patients with gout, both mechanisms of the development of hyperuricemia can be detected. In these cases, the condition is classified according to the predominant component: renal or metabolic. This classification refers primarily to those cases when gout or hyperuricemia are the main manifestations of the disease, that is, when gout is not secondary to another acquired disease and is not a subordinate symptom of a congenital defect that initially causes some other serious disease, not gout. Sometimes primary gout has a genetic basis. Secondary hyperuricemia or secondary gout refers to cases when they develop as symptoms of another disease or as a result of taking certain pharmacological agents.
Overproduction of uric acid. Overproduction of uric acid, by definition, means its excretion in an amount of more than 600 mg / day after following a purine-restricted diet for 5 days. Such cases seem to account for less than 10% of all cases of the disease. The patient has an accelerated synthesis of purines de novo or the circulation of these connections is increased. In order to understand the main mechanisms of the corresponding disorders, it is necessary to analyze the scheme of purine metabolism.
Purine nucleotides - adenylic, inosinic and guanic acids (respectively AMP, IMP and GMP) - are the end products of purine biosynthesis. They can be synthesized in one of two ways: either directly from purine bases, i.e. GMP from guanine, IMP from hypoxanthine and AMP from adenine, or de novo starting with non-purine precursors and going through a series of steps to the formation of IMP, which serves as a common intermediate purine nucleotide. Inosinic acid can be converted to either AMP or HMP. After the formation of purine nucleotides, they are used for the synthesis of nucleic acids, adenosine triphosphate (ATP), cyclic AMP, cyclic HMP, and some cofactors.
Various purine compounds are degraded to monophosphates of purine nucleotides. Guanic acid is converted through guanosine, guanine ixanthine into uric acid, IMP is degraded through inosine, hypoxanthine and xanthine to the same uric acid, and AMP can be deaminated into IMP and then catabolized through inosine into uric acid or converted to inosine by an alternative pathway with adenosine ...
Despite the fact that the regulation of purine metabolism is rather complicated, the main determinant of the rate of uric acid synthesis in humans is apparently the intracellular concentration of 5-phosphoribosyl-1-pyrophosphate (FPPP). As a rule, with an increase in the level of PRPF in the cell, the synthesis of uric acid increases, with a decrease in its level, it decreases. Despite some exceptions, this is the case in most cases.
Excessive production of uric acid in a small number of adult patients is the primary or secondary manifestation of congenital metabolic disorders. Hyperuricemia and gout may be the primary manifestation of partial deficiency of hypoxanthine guanine phosphoribosyl transferase or increased activity of PRPP synthetase. In Lesch-Nyhan syndrome, an almost complete deficiency of hypoxanthine guanine phosphoribosyltransferase causes secondary hyperuricemia. These serious congenital anomalies are discussed in more detail below.
For the aforementioned congenital metabolic disorders (hypoxanthingguanine phosphoribosyltransferase deficiency and excessive PRPP synthetase activity), less than 15% of all cases of primary hyperuricemia caused by an increase in uric acid production are determined. The reason for the increase in its production in most patients remains unclear.
Secondary hyperuricemia associated with increased production of uric acid can be associated with many causes. In some patients, the increased excretion of uric acid is due, as in primary gout, to the acceleration of purine biosynthesis. de novo ... In patients with glucose-6-phosphatase deficiency (type I glycogen storage disease), uric acid production is constantly increased, as well as purine biosynthesis is accelerated de novo ... Overproduction of uric acid in this enzymatic abnormality is due to a number of mechanisms. Acceleration of Purine Synthesis de novo may partly be the result of the accelerated synthesis of the FRPF. In addition, the accelerated breakdown of purine nucleotides contributes to an increase in the excretion of uric acid. Both of these mechanisms are triggered by a deficiency of glucose as an energy source, and uric acid production can be reduced by permanently correcting the hypoglycemia typical of this disease.
In the majority of patients with secondary hyperuricemia due to excessive production of uric acid, the main violation is, obviously, in the acceleration of the turnover of nucleic acids. Increased bone marrow activity or shortening life cycle cells of other tissues, accompanied by an acceleration of the circulation of nucleic acids, are characteristic of many diseases, including myeloproliferative and lymphoproliferative diseases, multiple myeloma, secondary polycythemia, pernicious anemia, some hemoglobinopathies, thalassemia, other hemolytic anemias, infectious mononucleosis and a number of carcinomas. The accelerated circulation of nucleic acids, in turn, leads to hyperuricemia, hyperuricaciduria and a compensatory increase in the rate of purine biosynthesis de novo.
Reduced excretion. In a large number of patients with gout, this rate of excretion of uric acid is achieved only when the level of urate in plasma is 10-20 mg / l above normal. This pathology is most pronounced in patients with normal production of uric acid and is absent in most cases of its hyperproduction.
Urate excretion depends on glomerular filtration, tubular reabsorption, and secretion. Uric acid is apparently completely filtered in the glomeruli and reabsorbed in the proximal tubules (i.e., undergoes presecretory reabsorption). In the lower segments of the proximal tubule, it is secreted, and in the second reabsorption site - in the distal proximal tubule - it is once again subjected to partial reabsorption (postsecretory reabsorption). Despite the fact that some part of it can be reabsorbed both in the ascending knee of the loop of Henle and in the collecting duct, these two areas are considered less important from a quantitative point of view. Attempts to more accurately clarify the localization and nature of these latter areas and to quantify their role in the transport of uric acid in a healthy person or a patient, as a rule, have been unsuccessful.
Theoretically, impaired renal excretion of uric acid in most patients with gout could be due to: 1) a decrease in the filtration rate; 2) increased reabsorption, or 3) a decrease in the rate of secretion. There is no indisputable data on the role of any of these mechanisms as a major defect; it is likely that all three factors are present in patients with gout.
Many cases of secondary hyperuricemia and gout can be considered the result of a decrease in renal excretion of uric acid. A decrease in the glomerular filtration rate leads to a decrease in the filtration load of uric acid and, thereby, to hyperuricemia; in patients with kidney pathology, this is why hyperuricemia develops. In some kidney diseases (polycystic and lead nephropathy), other factors such as decreased uric acid secretion have been postulated. Gout rarely complicates secondary hyperuricemia due to kidney disease.
Diuretic treatment is one of the most important causes of secondary hyperuricemia. The decrease in the volume of circulating plasma caused by them leads to an increase in the tubular reabsorption of uric acid, as well as to a decrease in its filtration. With hyperuricemia, the associated pathogenesis of acute gouty arthritis, some progress has been made, then questions regarding the factors that determine the spontaneous termination of an acute attack and the effect of colchicine still await an answer.
Treatment. Treatment for gout includes: 1) as soon as possible and careful relief of an acute attack; 2) prevention of recurrence of acute gouty arthritis; 3) prevention or regression of complications of the disease caused by the deposition of crystals of monosodium urate in joints, kidneys and other tissues; 4) prevention or regression accompanying symptoms such as obesity, hypertriglyceridemia, or hypertension; 5) prevention of the formation of uric acid kidney stones.
Treatment for an acute attack of gout. In acute gouty arthritis, anti-inflammatory treatment is given. The most commonly used drug is colchicine. It is prescribed for oral administration, usually at a dose of 0.5 mg every hour or 1 mg every 2 hours, and the treatment is continued until: 1) the patient's condition is relieved; 2) will not appear adverse reactions from the side gastrointestinal tract or 3) the total dose of the drug will not reach 6 mg with no effect. Colchicine is most effective when treatment is started soon after symptoms appear. In the first 12 hours of treatment, the condition significantly improves in more than 75% of patients. However, in 80% of patients, the drug causes side reactions from the gastrointestinal tract, which may appear before clinical improvement of the condition or simultaneously with it. When taken orally, the maximum plasma level of colchicine is reached after about 2 hours. Therefore, it can be assumed that taking 1.0 mg every 2 hours is less likely to cause a toxic dose accumulation before the onset of a therapeutic effect. Since, however, the therapeutic effect is related to the level of colchicine in leukocytes, and not in plasma, the effectiveness of the treatment regimen requires further evaluation.
With intravenous administration of colchicine, side effects from the gastrointestinal tract do not occur, and the patient's condition improves faster. After a single injection, the level of the drug in leukocytes increases, remaining constant for 24 hours, and can be determined even after 10 days. As an initial dose, 2 mg should be administered intravenously, and then, if necessary, the administration of 1 mg should be repeated twice with an interval of 6 hours. Special precautions should be taken with intravenous administration of colchicine. It renders irritating effect and if it enters the tissue surrounding the vessel, it can cause severe pain and necrosis. It is important to remember that the intravenous route of administration requires accuracy and that the drug should be diluted in 5-10 volumes of normal saline solution, and the infusion should be continued for at least 5 minutes. Colchicine, when administered orally or parenterally, can inhibit bone marrow function and cause alopecia, liver cell failure, mental depression, seizures, ascending paralysis, respiratory depression, and death. Toxic effects are more likely in patients with liver, bone marrow or kidney disease, as well as in those receiving maintenance doses of colchicine. In all cases, the dose of the drug must be reduced. It should not be given to patients with neutropenia.
Other anti-inflammatory drugs, including indomethacin, phenylbutazone, naproxen, and phenoprofen, are effective in acute gouty arthritis.
Indomethacin can be administered orally at a dose of 75 mg, after which every 6 hours the patient should receive 50 mg; treatment with these doses continues the next day after the symptoms disappear, then the dose is reduced to 50 mg every 8 hours (three times) and to 25 mg every 8 hours (also three times). Side effects of indomethacin include gastrointestinal upset, sodium retention, and central nervous system symptoms. Although these doses can cause side effects in up to 60% of patients, indomethacin is generally easier to tolerate than colchicine and is probably the treatment of choice in acute gouty arthritis. To increase the effectiveness of treatment and reduce the manifestations of the patient's pathology, it should be warned that taking anti-inflammatory drugs should be started at the first sensations of pain. Drugs that stimulate the excretion of uric acid and allopurinol are ineffective in an acute attack of gout.
In acute gout, especially when colchicine and nonsteroidal anti-inflammatory drugs are contraindicated or ineffective, systemic or local (i.e., intra-articular) administration of glucocorticoids is beneficial. For systemic administration, be it oral or intravenous, moderate doses should be prescribed over several days, since the concentration of glucocorticoids rapidly decreases and their effect ceases. Intra-articular administration of a long-acting steroid (for example, triamsinolone hexacetonide at a dose of 15-30 mg) can stop an attack of monoarthritis or bursitis within 24-36 hours. This treatment is especially advisable if it is impossible to use a standard drug regimen.
Prevention. After stopping an acute attack, a number of measures are used to reduce the likelihood of relapse. These include: 1) daily prophylactic intake of colchicine or indomethacin; 2) controlled weight loss in obese patients; 3) elimination of known provoking factors, such as large amounts of alcohol or foods rich in purines; 4) the use of antihyperuricemic drugs.
Small doses of colchicine taken daily are effective in preventing subsequent acute attacks. Colchicine in a daily dose of 1-2 mg is effective in almost 1/4 of patients with gout and ineffective in about 5% of patients. In addition, this treatment program is safe and has few side effects. However, if the concentration of urate in serum is not maintained within the normal range, then the patient will be spared only from acute arthritis, and not from other manifestations of gout. Colchicine maintenance treatment is especially indicated during the first 2 years after starting antihyperuricemic agents.
Prevention or stimulation of the reverse development of gouty deposits of monosodium urate in tissues. Antihyperuricemic agents are quite effective in reducing the concentration of urate in serum, so they should be used in patients with: 1) one attack of acute gouty arthritis or more; 2) one or more gouty deposits; 3) uric acid nephrolithiasis. Their purpose is to maintain serum urate levels below 70 mg / L; that is, in the minimum concentration at which urate saturates the extracellular fluid. This level can be achieved with drugs that increase renal excretion of uric acid, or by reducing the production of this acid. Antihyperuricemic agents usually do not have anti-inflammatory effects. Uricosuric drugs reduce serum urate levels by increasing renal excretion. Despite the fact that this property is possessed by a large number of substances, the most effective substances used in the USA are probenecid and sulfinpyrazone. Probenecid is usually prescribed at an initial dose of 250 mg twice daily. Over several weeks, it is increased to provide a significant decrease in serum urate concentration. In half of the patients, this can be achieved with a total dose of 1 g / day; the maximum dose should not exceed 3.0 g / day. Since the half-life of probenecid is 6-12 hours, it should be taken in equal doses 2-4 times a day. The main side effects include hypersensitivity, skin rash, and gastrointestinal symptoms. Despite rare cases toxic action, these adverse reactions force almost 1/3 of patients to discontinue treatment.
Sulfinpyrazone is a phenylbutazone metabolite devoid of anti-inflammatory action. They begin treatment with a dose of 50 mg twice a day, gradually increasing the dose to a maintenance level of 300-400 mg / day for 3-4 times. The most effective daily dose is 800 mg. Side effects are similar to those of probenecid, although the incidence of bone marrow toxicity may be higher. Approximately 25% of patients stop taking the drug for one reason or another.
Probenecid and sulfinpyrazone are effective in most cases of hyperuricemia and gout. In addition to drug intolerance, the ineffectiveness of treatment may be associated with a violation of the regimen of their intake, concomitant use of salicylates or impaired renal function. Acetylsalicylic acid (aspirin) in any dose blocks the uricosuric effect of probenecid and sulfinpyrazone. They become less effective at creatinine clearance below 80 ml / min and cease to act at a clearance of 30 ml / min.
With a negative urate balance due to treatment with uricosuric drugs, the concentration of urate in the serum decreases, and the excretion of uric acid in the urine exceeds the initial level. Continuation of treatment causes the mobilization and release of excess urate, its amount in the serum decreases, and the excretion of uric acid in the urine almost reaches the initial values. A transient increase in its excretion, usually lasting for only a few days, can cause the formation of kidney stones in 1/10 of patients. In order to avoid this complication, taking uricosuric drugs should be started with small doses, gradually increasing them. Maintaining increased urination with adequate hydration and alkalinization of urine by oral administration of sodium bicarbonate alone or together with acetazolamide reduces the likelihood of calculus. An ideal candidate for treatment with uricosuric agents is a patient under 60 years of age who is on a normal diet, with normal renal function and uric acid excretion of less than 700 mg / day, with no history of kidney stones.
Hyperuricemia can also be corrected with allopurinol, which decreases uric acid synthesis. It inhibits xanthine oxidase, which catalyzesoxidation of hypoxanthine to xanthine and xanthine to uric acid. Despite the fact that the half-life of allopurinol in the body is only 2-3 hours, it is converted mainly into hydroxypurinol, which is an equally effective inhibitor of xanthine oxidase, but with a half-life of 18-30 hours. In most patients, a dose of 300 mg / day is effective. Because of the long half-life of the main metabolite, allopurinol, it can be administered once a day. Because oxypurinol is excreted primarily in the urine, its half-life is lengthened in renal failure. In this regard, with severe renal impairment, the dose of allopurinol should be halved.
Serious side effects of allopurinol include gastrointestinal dysfunction, skin rashes, fever, toxic epidermal necrolysis, alopecia, bone marrow suppression, hepatitis, jaundice, and vasculitis. The overall incidence of side effects reaches 20%; they are more likely to develop with renal failure. Only in 5% of patients, their severity forces to stop treatment with allopurinol. Drug interactions should be taken into account when prescribing it, as it increases the half-lives of mercaptopurine and azathioprine and increases the toxicity of cyclophosphamide.
Allopurinol is preferred over uricosuric drugs for: 1) increased (more than 700 mg / day, subject to a general diet) urinary excretion of uric acid; 2) impaired renal function with creatinine clearance less than 80 ml / min; 3) gouty deposits in the joints, regardless of renal function; 4) urate nephrolithiasis; 6) gout, which does not respond to uricosuric drugs due to their ineffectiveness or intolerance. In rare cases of ineffectiveness of each drug used alone, allopurinol can be used concurrently with any uricosuric agent. This does not require a dose change and is usually accompanied by a decrease in serum urate.
No matter how rapid and pronounced the decrease in serum urate levels may be, acute gouty arthritis may develop during treatment. In other words, starting treatment with any anti-hyperuricemic drug can trigger an acute attack. In addition, with large gouty deposits, even against the background of a decrease in the severity of hyperuricemia for a year or more, relapses of attacks may occur. In this regard, before starting anti-hyperuricemic agents, it is advisable to start prophylactic colchicine intake and continue it until the serum urate level is within the normal range for at least a year or until all gouty deposits are dissolved. Patients should be aware of the possibility of exacerbations in the early period of treatment. Most patients with large deposits in the joints and / or renal failure should sharply limit the intake of purines with food.
Prevention of acute uric acid nephropathy and treatment of patients. In acute uric acid nephropathy, it is necessary to start immediately intensive treatment... First, urine flow should be increased with heavy water loads and diuretics such as furosemide. The urine is alkalized to convert uric acid to the more soluble monosodium urate. Alkalinization is achieved with sodium bicarbonate, alone or in combination with acetazolamide. Allopurinol should also be given to reduce the production of uric acid. Its initial dose in these cases is 8 mg / kg per day as a single dose. After 3-4 days, if renal failure persists, the dose is reduced to 100-200 mg / day. With uric acid kidney stones, treatment is the same as for uric acid nephropathy. In most cases, it is sufficient to combine allopurinol only with a large fluid intake.
Management of patients with hyperuricemia.Examination of patients with hyperuricemia is aimed at: 1) finding out its cause, which may indicate another serious disease; 2) assessment of tissue and organ damage and its degree; 3) identification of accompanying violations. In practice, all these problems are solved simultaneously, since the decision regarding the significance of hyperuricemia and treatment depends on the answer to all these questions.
The most important in hyperuricemia is the urinalysis for uric acid. If a history of urolithiasis is indicated, an overview of the abdominal cavity and intravenous pyelography are shown. When kidney stones are found, testing for uric acid and other components may be helpful. In case of joint pathology, it is advisable to investigate synovial fluid and take X-rays of the joints. If there is a history of lead exposure, urinary excretion after calcium-EDTA infusion may be required to diagnose lead-related gout. If increased production of uric acid is expected, determination of the activity of hypoxanthine guanine phosphoribosyltransferase and PRPP synthetase in erythrocytes may be indicated.
Management of patients with asymptomatic hyperuricemia. The question of the need to treat patients with asymptomatic hyperuricemia has no clear answer. As a rule, treatment is not required, unless: 1) the patient does not make complaints; 2) there is no family history of gout, nephrolithiasis, or renal failure; or 3) uric acid excretion is not too high (more than 1100 mg / day).
Other disorders of purine metabolism, accompanied by hyperuricemia and gout. Deficiency of hypoxanthingguanine phosphoribosyltransferase. Hypoxanthine guanine phosphoribosyltransferase catalyzes the conversion of hypoxanthine to inosinic acid and guanine to guanosine. The phosphoribosyl donor is FRPP. Insufficiency of hypoxanthinleads to a decrease in the consumption of FPPF, which accumulates in higher than normal concentrations. Excess PRPF accelerates purine biosynthesis de novo and therefore increases the production of uric acid.
Lesch-Nyhan syndrome is an X-linked disease. A characteristic biochemical disorder with it is a pronounced deficiency of hypoxanthine guanine phosphoribosyl transferase. Patients have hyperuricemia and excessive hyperproduction of uric acid. In addition, they develop peculiar neurological disorders, characterized by self-mutilation, choreoathetosis, muscle spasticity, as well as growth and mental retardation. The incidence of this disease is estimated as 1: 100,000 newborns.
In approximately 0.5-1.0% of adult patients with gout with excessive production of uric acid, partial deficiency of hypoxanthine guanine phosphoribosyltransferase is revealed. Usually, they have gouty arthritis at a young age (15-30 years), a high frequency of uric acid nephrolithiasis (75%), sometimes some neurological symptoms join, including dysarthria, hyperreflexia, impaired coordination and / or mental retardation. The disease is inherited as a trait linked to the X chromosome, so it is transmitted to men from female carriers.
The enzyme, the deficiency of which causes this disease (hypoxanthine guanine phosphoribosyltransferase), is of significant interest to geneticists. With the possible exception of the globin gene family, the hypoxanthingguanine phosphoribosyltransferase locus is the most studied single human gene.
Human hypoxanthine guanine phosphoribosyltransferase was purified to a homogeneous state and its amino acid sequence was determined. Normally, its relative molecular weight is 2470, and the subunit consists of 217 amino acid residues. The enzyme is a tetramer consisting of four identical subunits. There are also four variant forms of hypoxanthingguanine phosphoribosyltransferase. In each of them, the replacement of one amino acid leads either to a loss of the catalytic properties of the protein, or to a decrease in the constant concentration of the enzyme due to a decrease in the synthesis or acceleration of the decay of the mutant protein.
The DNA sequence complementary to messenger RNA (mRNA), which encodes hyloxanthine guanine phosphoribosyltransferase, has been cloned and decoded. As a molecular probe, this sequence was used to identify the state of carriage in women at risk, in whom carriage could not be detected by conventional methods. The human gene was transferred to the mouse through bone marrow transplantation infected with a vector retrovirus. The expression of human hypoxanthingguanine phosphoribosyltransferase in a mouse treated in this way was definitely established. Recently, a transgenic mouse strain has also been obtained in which the human enzyme is expressed in the same tissues as in humans.
The accompanying biochemical anomalies that cause pronounced neurological manifestations of Lesch-Nyhan syndrome have not been sufficiently deciphered. Postmortem examination of the brain of patients showed signs of a specific defect in the central dopaminergic pathways, especially in the basal ganglia and nucleus accumbens ... Relevant data in vivo obtained by positron emission tomography (PET) performed in patients with hypoxanthine guanine phosphoribosyl transferase deficiency. In the majority of patients examined by this method, a violation of the metabolism of 2'-fluoro-deoxyglucose in the caudate nucleus was revealed.The connection between the pathology of the dopaminergic nervous system and the violation of purine metabolism remains unclear.
Hyperuricemia due to partial or complete deficiency of hypoxanthine guanine phosphoribosyltransferase is successfully treated with allopurinol, a xanthine oxidase inhibitor. At the same time, a small number of patients develop xanthine stones, but most of them with kidney stones and gout are cured. There are no specific treatments for neurological disorders in Lesch-Nyhan syndrome.
Variants of FRPP synthetase. Several families were identified whose members had an increased activity of the enzyme PRPP synthetase. All three known types of mutant enzyme have increased activity, which leads to an increase in the intracellular concentration of PRPF, an acceleration of purine biosynthesis, and an increase in the excretion of uric acid. This disease is also inherited as a trait linked to the X chromosome. As with partial deficiency of hypoxanthine guanine phosphoribosyltransferase, with this pathology, gout usually develops in the second or third 10 years of life and uric acid stones are often formed. In several children, the increased activity of PRPF synthetase was combined with nervous deafness.
Other disorders of purine metabolism.Lack of adenine phosphoribosyltransferase. Adenine phosphoribosyltransferase catalyzes the conversion of adenine to AMP. The first person who was found to be deficient in this enzyme was heterozygous for this defect and had no clinical symptoms. Then it was found that heterozygosity for this trait is widespread, probably with a frequency of 1: 100. Currently, 11 homozygotes have been identified for this enzyme deficiency, in which kidney stones consisted of 2,8-dioxyadenine. Due to its chemical similarity, 2,8-dioxyadenine is easily confused with uric acid, so these patients were initially mistakenly diagnosed with uric acid nephrolithiasis.
Xanthine oxidase deficiency ... Xanthine oxidase catalyzes the oxidation of hypoxanthine to xanthine, xanthine to uric acid and adenine to 2,8-dioxyadenine. Xanthinuria, the first congenital disorder of purine metabolism, deciphered at the enzymatic level, is due to xanthine oxidase deficiency. As a result, patients with xanthinuria show hypouricemia and hypouricaciduria, as well as increased urinary excretion of oxypurines-hypoxanthine and xanthine. Half of the patients have no complaints, and in 1/3 xanthine stones form in the urinary tract. Several patients developed myopathy, three developed polyarthritis, which could be a manifestation of crystal-induced synovitis. In the development of each of the symptoms, the deposition of xanthine into the sediment is of great importance.
In four patients, congenital xanthine oxidase deficiency was combined with congenital sulfate oxidase deficiency. The clinical picture in newborns was dominated by severe neurological pathology, which is characteristic of isolated sulfate oxidase deficiency. Despite the fact that the deficiency of the molybdate cofactor necessary for the functioning of both enzymes was postulated as the main defect, treatment with ammonium molybdate was ineffective. A patient who was completely on parenteral nutrition, developed a disease simulating a combined deficiency of xanthine oxidase and sulfate oxidase. After the treatment with ammonium molybdate, the function of enzymes completely normalized, which led to clinical recovery.
Myoadenylate deaminase deficiency ... Myoadenylate deaminase, an isoenzyme of adenylate deaminase, is found only in skeletal muscle. The enzyme catalyzes the conversion of adenylate (AMP) to inosinic acid (IMP). This reaction is an integral part of the purinonucleotide cycle and, apparently, is important for maintaining the processes of production and utilization of energy in skeletal muscle.
Deficiency of this enzyme is found only in skeletal muscle. Most patients develop myalgias, muscle cramps, and fatigue during exercise. Approximately 1/3 of patients complain of muscle weakness even in the absence of exercise. Some patients have no complaints.
The disease usually manifests itself in childhood and adolescence. Its clinical symptoms are the same as in metabolic myopathy. The level of creatinine kinase is elevated in less than half of the cases. Electromyographic studies and routine histology of muscle biopsies reveal nonspecific changes. Presumably, adenylate deaminase deficiency can be diagnosed based on the results of an ischemic forearm performance test. In patients with a deficiency of this enzyme, the production of ammonia is reduced, since the deamination of AMP is blocked. The diagnosis should be confirmed by direct determination of AMP-deaminase activity in skeletal muscle biopsy specimens, since decreased ammonia production during work is also characteristic of other myopathies. The disease progresses slowly and in most cases leads to some decrease in performance. There is no effective specific therapy.
Adenyl succinase deficiency ... Patients with adenyl succinase deficiency lag behind in mental development and often suffer from autism. In addition, they suffer from convulsive seizures, their psychomotor development is delayed, and a number of movement disorders are noted. Urinary excretion of succinylaminoimidazole carboxamidriboside and succinyladenosine is enhanced. The diagnosis is made by detecting partial or complete absence of enzyme activity in the liver, kidneys, or skeletal muscles. In lymphocytes and fibroblasts, its partial deficiency is determined. The prognosis is unknown and no specific treatment has been developed.
T.P. Harrison. Principles of internal medicine.Translation by Ph.D. A. V. Suchkova, Ph.D. N. N. Zavadenko, Ph.D. D. G. Katkovsky
Exchange of deoxyuridyl nucleotides
Deoxyuridyl nucleotides are intermediate products of the synthesis of thymidyl nucleotides. dUTP is easily recognized by DNA polymerases and can be used for DNA synthesis instead of dTTP. When uracil replicates in the DNA structure, it forms a complementary pair with adenine, so that the information recorded on the DNA is not lost. However, dUMP can arise in the DNA structure by spontaneous deamination of dCMP. In this case, a mutation occurs during replication, since the complementary base of cytosine is guanine, and not adenine.
A simple mechanism works to prevent the incorporation of uridine nucleotides into DNA in cells. The enzyme dUTPase converts dUTP (a substrate for DNA polymerase) into dUMP (not a substrate for DNA polymerase), which is used for the synthesis of thymidyl nucleotides, since dUMP is converted first to dTMP, and then dTTP.
The final product of the breakdown of purine nucleotides, uric acid, is characterized by low solubility in water; its sodium salt is characterized by a higher solubility. The form in which uric acid is found in biological fluids (blood, urine, cerebrospinal fluid) depends on the pH of this fluid. The pK value for the proton N9 is 5.75, and for the proton N-l-10.3. This means that under physiological conditions, that is, at normal pH of physiological fluids, it is possible to detect both uric acid itself and its monosodium salt (sodium urate). In liquids with a pH below 5.75, uric acid is the main molecular form. At pH 5.75, the acid and its salt are present in equimolar amounts. At pH above 5.75, the dominant form is the sodium salt of uric acid.
Purine metabolic disorders include hyperuricemia, hypouricemia, and immunodeficiency diseases.
A very high concentration of uric acid in the blood leads to a fairly common group of diseases called gout. The incidence of gout varies by country and is around 3/1000. Gout is a group of pathological conditions associated with markedly increased levels of urate in the blood (normally 3-7 mg / 100 ml). Hyperuricemia does not always present with any symptoms, but, in some people, it contributes to the deposition of sodium urate crystals in joints and tissues. In addition to the severe pain accompanying an exacerbation, repeated attacks lead to tissue destruction and severe arthritis-like disorders. The term gout should be limited to hyperuricemia with the presence of such gouty deposits.
Below is a table indicating possible reasons metabolic disorders of purine nucleotides
Protein food contains purines in a capacious concentration. These organic substances are " building material»Human genes, representatives of flora and fauna. In case of an imbalance of purines, it is necessary to correct daily menu so that food ingredients replenish their supply, support overall health, especially for people at risk. To avoid serious pathologies of the body, it is important to respond in a timely manner to the first signs of the disease, not to start pathological process.
What are Purines and Uric Acid
Purines are chemical compounds that are the basis of nucleic acids and are directly involved in the formation and structure of DNA and RNA molecules. According to their pharmacological properties, purines help to assimilate vitamins and micro- / macroelements, stabilize and support metabolism. Such medical concepts, as "purines and gout" are closely related, it remains only to focus on the so-called "intermediate link of this chain" - uric acid (Acidum uricum).
When cells die, the process of destruction of purines to uric acid predominates. it natural state the body, where the latter component acts as a natural antioxidant that reliably protects blood vessels from destruction. If the level of uric acid rises rapidly, we are talking about a progressive pathology associated with chronic kidney dysfunction. As a result, the concentration of Acidum uricum in excess of the norm increases in the tendons, joints, internal organs and the disease is called gouty arthritis or gout.
Purine exchange
This is a set of processes of synthesis and decay of purine nucleotides, where the latter are dominated by the remains of the nitrogenous purine base and phosphate acid, ribose carbohydrates (deoxyribose). Such a harmonious composition is necessary to maintain lipid metabolism, in violation of which the body weight increases, a jump in blood pressure prevails, and pronounced symptoms of cardiovascular diseases, prone to chronic course, progress.
Purine compounds are represented by such derivatives of the heterocyclic nitrogenous base of purine as adenine, guanine and hypoxanthine, which underlie the permissible level of renewal of nucleic acids and proteins in the body, the constancy of energy metabolism. Inhibition of the synthesis of purine nucleotides slows down the growth of tissues, and the concentration of uric acid may pathologically increase. To achieve balance, it is important to determine where and which purine bases in food will be contained, and how their consumption affects health.
Purine consumption rates
The recommended daily intake of this ingredient in the body should vary between 700-1,000 mg. The main source of purines should be plant foods in the daily diet. If you eat more meat products, the risk of gout is especially high for patients at risk. When the concentration of uric acid exceeds the permissible norm, it is necessary to reduce the volume of food ingredients with a capacious content of purines, to reduce the daily norm of nucleotides to 100-150 mg. Otherwise, relapse cannot be avoided.
Purines in food - table
If you do not control this indicator, chronic diseases that are prone to recurrence develop in the body of a sick person. Purines in food are important components, therefore, with an imbalance of those, it is required to introduce certain changes in the usual daily menu, adhere to therapeutic diet dietary table number 6. Below is a table according to which you can find out the concentration organic compounds per 100 g of product:
| Food product name | |
| egg | |
| Black tea | |
| chocolate white | |
| calf beef liver | |
| meat from young animals | |
| fatty fish | |
| green vegetables | |
| fruits (cherries, cherries, grapes, strawberries, blueberries) | |
| asparagus beans | |
| peas and all legumes |
Diet in violation of purine metabolism
The patient begins to be interested in the content of purines in food products when there is an imbalance of nucleic acids in his own body. In such a clinical picture, the doctor recommends adhering to a therapeutic diet in order to exclude another recurrence of gout. Such a recommendation is also appropriate for other diseases, among which are urolithiasis, acute or chronic nephritis, uric acid diathesis, renal failure, cystinuria, hyperuricemia, oxaluria. Here are some valuable tips from the experts:
- It is important to avoid a long or short-term hunger strike, since in this case the concentration of uric acid in the body grows abnormally and can provoke a relapse of the underlying disease.
- When choosing meat products, it is important not to forget that the concentration of purine in muscle tissues is directly proportional to the intensity of their functionality in the body. Fatty meats are better left in the past, and give preference to a rabbit, chicken, turkey.
- A purine diet for gout should limit the intake of drinks that speed up the elimination of fluids from the body, such as coffee, soda, strong tea for breakfast. And here fresh juices on the menu are only welcome, additionally enrich the body with vitamins.
- With an exacerbation of gout, it is important to temporarily exclude vegetable broths and soups, meat and fish dishes of high fat content from the therapeutic diet, and give preference to vegetarian soups.
- It is necessary to give up bad habits, lead a healthy lifestyle, control the daily diet and avoid one of the forms of obesity.
- It is necessary to use only the right fats, among which corn, olive, sunflower oil is welcome. In addition, the intake of vitamins P2, PP, C is encouraged.
Low-purine
The main goal is to reduce the rate of uric acid and its salts formed after the metabolism of purines and a change in the reaction of urine towards an alkaline environment. Doctors recommend sticking to a dietary table of 6, which includes limiting purines, reducing daily sodium chloride doses, and eliminating oxalic acid altogether. Proteins should be reduced to 70 - 80 g, fats - up to 80 - 90 g, carbohydrates - up to 400 g. Drinking regime - up to 2 liters or more. The energy value of the daily diet varies between 2 700-3 000 kcal.
Alkalinization of urine increases the solubility of urates, accelerates the excretion of Acidum uricum from the body, disrupts the process of their formation. Everyday food is negotiated with a specialist, and it is important not to violate such rules. Below are the foods allowed on a hypopurine diet for every day:
- vegetables: eggplant, zucchini, potatoes, tomatoes, cucumbers;
- fruits: apples, apricots, apples;
- dairy products: milk, kefir, yogurt;
- poultry: turkey, chicken;
- meat products: rabbit.
Purines such as caffeine, theophylline and theobromine, contained in cocoa, coffee, tea and chocolate, do not pose a significant danger, but their allowable doses in the daily menu should be minimal. But the categorically prohibited foods with a low-purine diet are presented below, completely excluded from the daily diet of patients:
- legumes, lentils, sorrel;
- sausage products;
- confectionery;
- Fish and seafood;
- alcoholic and carbonated drinks.
Antipurine
In this case, you need to eat up to 4 - 5 times a day, while it is important to limit the consumption of refractory fats. Foods rich in purines and oxalic acid are also banned. Salt, spices negatively affect the concentration of Acidum uricum, therefore, certain restrictions must be introduced. If you eat right, maintaining the permissible concentration of purines in the blood, you can prolong the period of remission, forget about unpleasant attacks.
Sitting on an anti-purine diet, it is advisable to control the daily doses of proteins within 70 - 80 g, fats - up to 80 - 90 g, carbohydrates - up to 400 g. green tea, natural juices and medicinal decoctions. The energy value of the daily ration varies in the range of 2,200 - 2,500 kcal. With regard to daily nutrition, the following food ingredients must be distinguished from the prohibited foods.
The invention relates to medicine, namely to the physical analysis of liquid biological materials, and can be used to diagnose violations of purine metabolism in children. Morphological studies of urine are carried out by studying the texture of its liquid crystal structure in dynamics in a bright field and in polarized light. A drop of urine is applied to the surface of the slide and covered with a cover glass. Keeping environmental conditions constant, the preparation is kept until the appearance of pronounced typical structures on the slide. A study of the drug is carried out by examining the entire surface. If single typical crystals of uric acid and small amounts of round yellow non-birefringent crystals, birefringent hexagonal or rosette-like small crystals, small skeletal dendrites are observed simultaneously on the slide, then the absence of a violation of purine metabolism is diagnosed. If the slide is simultaneously observed in a large number atypical crystals of uric acid of various shapes, birefringent needle-shaped crystals, atypical birefringent and non-birefringent crystals, as well as in large quantities in combination or separately, crystals of cholesterol and large skeletal dendrites, then diagnose the presence of impaired purine metabolism. The technical result consists in increasing the sensitivity and accuracy of diagnostics.
The invention relates to medicine, in particular to the physical analysis of liquid biological materials, and can be used as an additional test for rapid diagnosis of kidney disease in children in the early stages and rapid assessment of the effectiveness of therapy.
A known method for diagnosing pathology of renal function, including in children, according to which a general urine test is performed (Kamyshev BC \ Clinical laboratory tests from A to Z, their diagnostic profiles \, reference manual, Minsk: Belaruskaya Navuka, 1999, p. .229).
The disadvantage of the known method is that it allows to reveal only the fact of the presence of impaired renal function and does not allow to state the presence specific disease, in particular a violation of purine metabolism.
Thus, the known method for diagnosing the pathology of renal function during implementation does not ensure the achievement of the technical result, which consists in the possibility of diagnosing a violation of purine metabolism.
The closest to the proposed method is a method for diagnosing a violation of purine metabolism, including in children, according to which a morphological study of urine is carried out, namely, the level of uric acid in the urine is determined and in case of a deviation from the norm, a violation of purine metabolism is diagnosed. (Kamyshev B.C. \ Clinical laboratory tests from A to Z and their diagnostic profiles \, reference manual, Minsk: Belaruskaya Navuka, 1999, pp. 233-235).
The disadvantage of this method primarily lies in the fact that it determines only the amount of uric acid in the urine and does not allow to determine the form of uric acid, namely to reveal its presence atypical form, which is characterized by the presence in the urine of sodium urates - the monosodium salt of uric acid. The latter is a characteristic sign of impaired purine metabolism. This reduces the reliability of the diagnosis. The presence of certain limits of the norm for the quantitative content of uric acid in urine makes it possible to ascertain the presence of pathology only when they are exceeded, i.e. already at the stage of the disease. This reduces the sensitivity of the known method and does not allow the diagnosis of pathology at earlier stages, when the disease has not yet developed, and to prevent its chronicity. For the same reason, the known method makes it possible to evaluate the effectiveness of therapy only with a noticeable improvement in the patient's condition. The presence of a tolerance for deviation from the norm, which is the result of averaging the individual characteristics of the patient's organism, does not allow taking into account the individual characteristics of a particular patient when diagnosing, which also reduces the reliability of the diagnostic results. In addition, the known method is difficult to implement and requires highly qualified personnel to obtain reliable diagnosis... Dependence of diagnostic results on personal qualities the laboratory assistant reduces their reliability.
Thus, the known method for diagnosing a violation of purine metabolism, including in children, revealed as a result of a patent search, when implemented, does not allow achieving a technical result, which consists in increasing the reliability of the diagnosis, in increasing the sensitivity of the method, in simplifying the diagnostic method.
The proposed invention solves the problem of creating a method for diagnosing violations of purine metabolism in children, the implementation of which allows you to achieve the technical result, which consists in increasing the reliability of diagnosis, in increasing the sensitivity of the method, in simplifying the diagnostic method.
The essence of the invention lies in the fact that in a method for diagnosing a violation of purine metabolism in children, including a morphological study of urine, analysis of the results and a statement of the absence or presence of a violation of purine metabolism, morphological studies are carried out by studying the texture of the liquid crystal structure of urine in dynamics in a bright field and in a polarized light, for which a drop of urine is applied to the surface of the slide, then, maintaining the environmental conditions constant, the drug is kept until pronounced typical textures appear on the slide, after which the preparation is examined by examining the entire surface of the sample in a bright field, and then polarization is performed. optical examination of the preparation, the results of the examination are recorded, while, if at the same time single typical crystals of uric acid are observed on the slide in small amounts: round yellow non-birefringent crystals, birefringent hexagonal and whether rosette-like small crystals, small skeletal dendrites, then the absence of a violation of purine metabolism is diagnosed if uric acid crystals of various shapes, birefringent needle-shaped crystals, atypical birefringent and non-birefringent crystals in combination or in large quantities are simultaneously observed on the slide separately, cholesterol crystals and large skeletal dendrites, then diagnose the presence of a violation of purine metabolism.
The technical result is achieved as follows. Many liquid biological media of the human body are capable of crystallizing, and under certain conditions, they pass into an intermediate liquid-crystalline state. In the liquid-crystalline state, the medium, while maintaining fluidity, exhibits specific crystal patterns - textures in polarized light. It is known that biological fluids are multicomponent systems, most of which exhibit structural heterogeneity (heterogeneity) and are highly sensitive to the composition and form of existence of components. The composition of biofluids adequately reflects the physiological state of the human body, as well as the functional usefulness of its individual organs and systems. For example, regulatory mechanisms and pharmacological factors affect the quantitative content of protein and calcium salts in urine, the ratio of saturated and unsaturated lipids in the blood serum, the nature of the aggregation of the bile lipid complex, the amount of phospholipids, cholesterol derivatives and its esters exhibiting liquid crystalline properties. These changes at the fine molecular level are manifested, in particular, in the features of the aggregation of biological fluids at the level of microstructures. The morphology of the textures of the liquid crystal phase correlates with the state of the organism and changes in the presence of pathology, which makes it possible to observe this in dynamics in a bright field and in polarized light at ordinary optical magnifications (USSR AS No. 1209168, А 61 В 10/00, 07.02. 86; USSR inventor's certificate No. 1486932, G 01 N 33/92, 06/15/89; USSR inventors No. 1723527, G 01 N 33/92, 03/30/92; RF patent No. 2173462, G 01 N 33 / 48, 33/68, 10.09.2001; RF patent No. 2170432, G 01 N 33/48, 33/68, 10.07.2001).
In the proposed method for the diagnosis of violations of purine metabolism in children using a morphological study of the biological environment, namely urine. The biological fluid - urine - is a product of the kidneys and its composition adequately reflects them functional state... Due to the fact that urine is able to crystallize, passing through an intermediate liquid-crystalline state, it is possible to morphological study of urine by studying the texture of the liquid-crystal structure of urine in dynamics in a bright field and in polarized light by examining the entire surface of the sample.
In the proposed method for research, a preparation is prepared from urine, for which a drop of urine is applied to a glass slide. Due to the fact that the preparation remains open, the possibility of evaporation of a liquid medium from it and the formation of a crystalline pattern - texture - on the slide is provided. Preservation of constant environmental conditions during the exposure of the drug ensures the reliability of the research results. The formation of pronounced typical basic textures on the slide marks the end of the aggregation process. This makes it impractical to further increase the holding time of the preparation and determines the time of the beginning of the study of the texture.
After that, a study of the drug is carried out by examining the entire surface of the sample in a bright field, and then a polarization-optical study of the drug is carried out, the results of the examination are recorded. Since the examination of the surface of the preparation is performed twice: in a bright field and in polarized light, this makes it possible to reliably identify texture crystals. This is because, for example, uric acid crystals in an atypical form are similar to oxalate crystals, but unlike them, uric acid crystals are not visible in polarized light. Crystals of sodium urate have a widespread acicular shape, but unlike others in polarized light, they birefringently.
If on a glass slide, after studying the texture of the liquid crystal structure of urine in a bright field and in polarized light, single typical crystals of uric acid, rounded yellow non-birefringent crystals in a small amount, birefringent hexagonal or rosette-like small crystals are observed, small skeletal dendrites are diagnosed, then exchange. This is explained as follows. A sign of impaired purine metabolism is the presence of an atypical form of uric acid, namely when uric acid in the urine is in the form of sodium urate. It has been experimentally proven that round yellow non-birefringent crystals are crystals of ordinary urates; birefringent hexagonal or rosette-shaped small crystals - calcium oxalate crystals; small skeletal dendrites - crystals of protein-lipid-salt complexes. The presence in the texture of the above-mentioned small crystals of the test urine drop in combination with single typical crystals of uric acid with the simultaneous absence of crystals indicating the presence of sodium urates in the test drop of urine indicates the compliance with the norm of the qualitative and quantitative composition of the test urine. In this case, the presence of precisely small birefringent hexagonal or rosette crystals and small crystals of skeletal dendrites indicates the presence of calcium oxalates and crystals of protein-lipid-salt complexes in an insignificant amount in the urine drop under study. This is additional information, confirming the absence of impaired renal function, and increases the reliability of the diagnosis of the proposed method.
If a large number of atypical crystals of uric acid of various shapes, birefringent needle-shaped crystals, atypical birefringent and non-birefringent crystals, as well as cholesterol crystals and large skeletal dendrites, are simultaneously observed on the slide, then the presence of a violation of purine metabolism is diagnosed.
The presence of atypical crystals of uric acid of various shapes indicates a qualitative change in the composition of urine, which is not characteristic of the composition of urine in normal conditions. The presence of sodium urate crystals indicates that their concentration in uric acid is increased and exceeds the solubility of sodium urate in urine. The presence in the urine at the same time of atypical crystals of uric acid and crystals of sodium urate - birefringent needle-shaped crystals - allows you to reliably diagnose a violation of purine metabolism.
The presence in the texture of the investigated urine drop in combination or separately of cholesterol crystals and large skeletal dendrites provides additional confirmatory information for the diagnosis of impaired purine metabolism, which increases its reliability. This is explained by the fact that the presence of cholesterol crystals in the urine indicates the activation of lipid peroxidation and instability of the kidney cell membranes, and the presence of large skeletal dendrites in the urine indicates the presence of a large amount of protein-lipid-salt complexes in the urine. The presence of atypical birefringent and non-birefringent crystals confirms the atypical form of uric acid.
Thus, the texture of the liquid crystal structure of the studied liquid - urine - gives us a complete picture of its qualitative and quantitative composition, and examination of the texture of the investigated urine drop on a microscope slide by studying the texture of the liquid crystal structure of urine in dynamics in a bright field and in polarized light allows us to obtain complete information about the morphology of the urine drop under study, both in qualitative and quantitative content, which makes it possible to increase the reliability of the diagnosis of impaired purine metabolism. At the same time, a great qualification of a laboratory assistant is not required, since the research results are the result of a visual review of the drug and do not require additional processing of the research results. It also improves diagnostic results. The comparative simplicity of the method also increases its reliability, as it reduces the likelihood of error.
In addition, it is known that the quantitative ratio of uric acid and urate in urine depends on the acidity of urine. In a weakly acidic environment with urine pH below 5.75, sodium urates in urine are represented by uric acid. At urine pH 5.75, uric acid and its monosodium salt are equimolar. At urine pH above 5.75, i.e. when the pH of the medium changes to alkaline side sodium urates become the dominant form of uric acid. This confirms once again that the presence and amount of sodium urate crystals in the urine drop under study can be used to judge the acidity of urine, which is reliable information for diagnosing a violation of purine metabolism and increases the reliability of the diagnosis.
The proposed method, in contrast to the prototype, allows you to diagnose the disease at an early stage. This is due to the fact that in the prototype method there is a tolerance for the norm of the level of uric acid in the urine. As a result, this does not allow one to take into account that in initial stage disorders of purine metabolism, the acidity of urine is heterogeneous, and both uric acid in a typical form and crystals of sodium urate can be simultaneously present in the urine. The claimed method, in contrast to the prototype, allows you to get a complete true picture morphological composition urine on this moment time, which makes it possible to detect the presence of sodium urate crystals in the urine at an early stage of the disease in the absence of visible signs of the disease. As a result, the sensitivity of the method increases.
Since the method uses the nature of textures (crystalline pattern) as an assessment criterion, which corresponds to a well-defined composition of the biological fluid under study, the proposed method, when diagnosing, automatically takes into account the physiological corridor, which makes it possible to take into account the individual characteristics of the organism of a particular patient, which increases the information content and reliability of the method ...
In addition, the proposed method for diagnosing a violation of purine metabolism in children in comparison with the prototype provides an additional technical result, which consists in the possibility of using the method for rapid assessment of the effectiveness of therapy used in the treatment of violations of purine metabolism. The achievement of an additional technical result is ensured due to the adequacy of the change in the nature of the texture of the investigated urine drop when the qualitative or quantitative composition of urine changes or when they change in combination with the ability to obtain a complete true picture of the morphological composition of urine in the form of its texture at a given time, i.e. in combination with the increased sensitivity of the proposed method.
Thus, the claimed method of violation of purine metabolism in children during implementation ensures the achievement of a technical result, which consists in increasing the reliability of the diagnosis, in increasing the sensitivity of the method, in simplifying the diagnostic method, and also allows, in comparison with the prototype, to obtain an additional technical result, which consists in the possibility of using the declared a method for rapid assessment of the effectiveness of therapy used in the treatment of purine metabolism disorders.
A method for diagnosing a violation of purine metabolism in children is as follows. Morphological studies of urine are carried out by studying the texture of its liquid crystal structure in dynamics in a bright field and in polarized light. For this, a drop of urine is applied to the surface of the slide. Then, keeping the environmental conditions constant, the preparation is kept until the appearance of pronounced typical textures on the slide. After that, a study of the drug is carried out by examining the entire surface of the sample in a bright field, and then a polarization-optical study of the drug is carried out. The results of the inspection are recorded. Moreover, if single typical crystals of uric acid are simultaneously observed on the slide and in small amounts: round yellow non-birefringent crystals, birefringent hexagonal or rosette-like small crystals, small skeletal dendrites, then the absence of impaired purine metabolism is diagnosed. If a large number of atypical crystals of uric acid of various shapes, birefringent needle-shaped crystals, atypical birefringent and non-birefringent crystals, as well as large amounts of cholesterol crystals and large skeletal dendrites are observed in combination or separately, are simultaneously observed on the glass slide, then the presence of a violation of purine ...
In all examples of the method for preparing preparations from urine, pre-processed glass slides were taken. We paid attention to the quality of the processing of the glass slide in order to avoid artifacts during the research. The slide is washed with distilled water, then degreased by immersion in 96% medical alcohol and wiped dry in one direction with a dry sterile cloth.
The formation of textures occurs due to evaporation from the edges of the preparation and, first of all, manifests itself in the peripheral areas, therefore, the viewing began from the peripheral areas. Then the central regions were examined.
For an insignificant (or small) number of crystals was taken when the crystals occupy no more than 20% of the area of the field of view at 150x magnification and no more than 2 out of five ... seven fields of view.
The case when the crystal is in 1/4 of the field of view and occupies less than 0.1 from it was taken as the small size of the crystals.
Viewing in a bright field was carried out with diluted nicols at a magnification of × 150 ... × 250. The entire surface of the sample was examined by longitudinal transverse scanning with a step equal to the magnitude of the field of view.
Viewing in polarized light was carried out with crossed nicols at a magnification of × 150 ... × 250. The entire surface of the sample was examined by longitudinal transverse scanning with a step equal to the magnitude of the field of view.
All discovered features were recorded. Microscopes of the BIOLAM series (with polarized filters), POLAM, MBI can be used for research. Example
1. Patient A., 6 years old, examination. Preliminary, express diagnostics were carried out in accordance with the claimed method.
When examining an open urine drop in a bright field and in polarized light on a microscope slide, we simultaneously observed: single crystals of uric acid of a typical shape, non-birefringent, rounded yellow non-birefringent crystals predominantly along the edge of the drop, birefringent hexagonal or rosette-like small fine crystals with a small amount of non-birefringent the center of the drop in a small amount.
Diagnosis: absence of impaired purine metabolism.
2. Patient D., 7 years old, examination. Preliminary, express diagnostics were carried out in accordance with the claimed method.
When examining an open urine drop in a bright field and in polarized light on a microscope slide, atypical crystals of uric acid, birefringent needle crystals of sodium urate, atypical birefringent and non-birefringent crystals, as well as a large amount in combination of cholesterol droplets were observed in large quantities along the entire surface. and large skeletal dendrites.
Diagnosis: disorders of purine metabolism.
In both cases, the diagnosis was confirmed by conventional laboratory tests.
A method for diagnosing a violation of purine metabolism in children, including a morphological study of urine, analysis of the results and a statement of the absence or presence of a violation of purine metabolism, characterized in that morphological studies are carried out by studying the texture of the liquid crystal structure of urine in dynamics in a bright field and in polarized light, for which a drop of urine is applied to the surface of the slide, then, keeping the environmental conditions constant, the drug is kept until pronounced typical textures appear on the slide, after which the drug is examined by examining the entire surface of the sample in a bright field, and then a polarization-optical study of the drug is carried out, the results of the examination are recorded, while, if at the same time, single typical crystals of uric acid and, in small quantities, round yellow non-birefringent crystals, birefringent hexagonal or rosette-shaped m spicy crystals, small skeletal dendrites, then they diagnose the absence of a violation of purine metabolism, if a large amount of atypical crystals of uric acid of various shapes, birefringent crystals of acicular shape, atypical birefringent and non-birefringent crystals, or in large quantities in combination, are simultaneously observed on the slide separately, cholesterol crystals and large skeletal dendrites, then diagnose the presence of a violation of purine metabolism.
The invention relates to medicine, namely to the physical analysis of liquid biological materials, and can be used to diagnose violations of purine metabolism in children
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