William N. Kelley, Thomas D. Patella
The term “gout” refers to a group of diseases that, when fully developed, are manifested by: 1) an increase in the level of urate in the serum; 2) repeated attacks characteristic acute arthritis, in which crystals of monosubstituted sodium urate monohydrate can be detected in leukocytes from the synovial fluid; 3) large deposits of sodium urate monohydrate (tophi), mainly in and around the joints of the limbs, sometimes leading to severe lameness and joint deformities; 4) damage to the kidneys, including interstitial tissues and blood vessels; 5) the formation of kidney stones from uric acid. All these symptoms can occur individually or in various combinations.
Prevalence and epidemiology. An absolute increase in the level of urate in serum is said to exist when it exceeds the solubility limit of monosubstituted sodium urate in this medium. At a temperature of 37°C saturated solution urate in plasma is formed at a concentration of approximately 70 mg/l. A higher level means supersaturation in a physico-chemical sense. Serum urate concentration is relatively elevated when it exceeds the upper limit of an arbitrarily defined normal range, usually calculated as the mean serum urate level plus two standard deviations in a population of healthy individuals grouped by age and sex. According to most studies, the upper limit for men is 70, and for women - 60 mg/l. From an epidemiological point of view, urate concentration c. serum levels of more than 70 mg/l increases the risk of gouty arthritis or nephrolithiasis.
Urate levels are affected by gender and age. Before puberty, serum urate concentration is approximately 36 mg/L in both boys and girls; after puberty, it increases more in boys than in girls. In men, it reaches a plateau after the age of 20 and then remains stable. In women aged 20-50 years, the urate concentration remains at a constant level, but with the onset of menopause it increases and reaches a level typical for men. It is believed that these age- and gender-related variations are associated with differences in the renal clearance of urate, which is obviously influenced by the content of estrogens and androgens. Other physiological parameters such as height, body weight, blood urea nitrogen and creatinine levels, and blood pressure are also correlated with serum urate concentration. Elevated serum urate levels are also associated with other factors, such as high ambient temperature, alcohol consumption, high social status or education.
Hyperuricemia, by one definition or another, is found in 2-18% of the population. In one of the examined groups of hospitalized patients, serum urate concentrations of more than 70 mg/l occurred in 13% of adult men.
The incidence and prevalence of gout is less than hyperuricemia. In the majority Western countries The incidence of gout is 0.20-0.35 per 1000 people: this means that it affects 0.13-0.37% of the total population. The prevalence of the disease depends on both the degree of increase in serum urate levels and the duration of this condition. In this regard, gout is mainly a disease of older men. Women account for only up to 5% of cases. In the prepubertal period, children of both sexes rarely become ill. The usual form of the disease only rarely appears before the age of 20 years, and the peak incidence occurs in the fifth 10th year of life.
Inheritance. In the USA, a family history is revealed in 6-18% of cases of gout, and with a systematic survey this figure is already 75%. The exact mode of inheritance is difficult to determine due to the influence of environmental factors on serum urate concentrations. In addition, the identification of several specific causes of gout suggests that it represents a common clinical manifestation of a heterogeneous group of diseases. Accordingly, it is difficult to analyze the pattern of inheritance of hyperuricemia and gout not only in the population, but also within the same family. Two specific causes of gout - deficiency of hypoxanthine guanine phosphoribosyltransferase and hyperactivity of 5-phosphoribosyl-1-pyrophosphate synthetase - are X-linked. In other families, inheritance follows an autosomal dominant pattern. Even more often, genetic studies indicate multifactorial inheritance of the disease.
Clinical manifestations. The complete natural evolution of gout goes through four stages: asymptomatic hyperuricemia, acute gouty arthritis, intercritical period and chronic gouty deposits in the joints. Nephrolithiasis can develop at any stage except the first.
Asymptomatic hyperuricemia. This is the stage of the disease in which serum urate levels are elevated but symptoms of arthritis, gouty joint deposits, or uric acid stones are not yet present. In men susceptible to classic gout, hyperuricemia begins during puberty, whereas in women at risk it usually does not appear until menopause. In contrast, with some enzyme defects (see below), hyperuricemia is detected already from the moment of birth. Although asymptomatic hyperuricemia may persist throughout the patient's life without apparent complications, the tendency for it to progress to acute gouty arthritis increases as a function of its level and duration. The risk of nephrolithiasis also increases as serum urate increases and correlates with uric acid excretion. Although hyperuricemia is present in virtually all gout patients, only approximately 5% of individuals with hyperuricemia ever develop the disease.
The stage of asymptomatic hyperuricemia ends with the first attack of gouty arthritis or nephrolithiasis. In most cases, arthritis precedes nephrolithiasis, which develops after 20-30 years of persistent hyperuricemia. However, in 10-40% of patients, renal colic occurs before the first attack of arthritis.
Acute gouty arthritis. The primary manifestation of acute gout is extremely painful arthritis, initially usually in one of the joints with scanty general symptoms, but later several joints are involved in the process against a background feverish state. The percentage of patients in whom gout immediately manifests itself as polyarthritis is not precisely established. According to some authors, it reaches 40%, but most believe that it does not exceed 3-14%. The duration of attacks varies, but is still limited, they are interspersed with asymptomatic periods. In at least half of the cases, the first attack begins in the joint of the metatarsal bone of the first toe. Eventually, 90% of patients experience attacks of acute pain in the joints of the first toe (gout).
Acute gouty arthritis is a disease primarily of the legs. The more distal the location of the lesion, the more typical the attacks. After the first toe, the process involves the joints of the metatarsal bones, ankles, heels, knees, wrist bones, fingers and elbows. Acute pain attacks in the shoulder and hip joints, joints of the spine, sacroiliac, sternoclavicular and lower jaw rarely appear, except in persons with a long-term, severe disease. Sometimes gouty bursitis develops, and most often the bursae of the knee and elbow joints are involved in the process. Before the first sharp attack of gout, patients may feel constant pain with exacerbations, but more often the first attack is unexpected and has an “explosive” character. It usually begins at night, and the pain in the inflamed joint is extremely severe. An attack can be triggered by a number of specific reasons, such as trauma, consumption of alcohol and certain medications, errors in diet, or surgery. Within a few hours, the intensity of the pain reaches its peak, accompanied by signs of progressive inflammation. In typical cases, the inflammatory reaction is so pronounced that it suggests purulent arthritis. Systemic manifestations may include fever, leukocytosis, and accelerated erythrocyte sedimentation. It is difficult to add anything to the classic description of the disease given by Syndenham:
“The patient goes to bed and falls asleep in good health. At about two o'clock in the morning he wakes up from acute pain in the first toe, less often - in the heel bone, ankle joint or metatarsal bones. The pain is the same as with a dislocation, and there is also the feeling of a cold shower. Then chills and trembling begin, and body temperature rises slightly. The pain, which was moderate at first, becomes increasingly severe. As it worsens, the chills and trembling intensify. After some time, they reach their maximum, spreading to the bones and ligaments of the tarsus and metatarsus. There is a feeling of stretching and tearing of the ligaments: gnawing pain, a feeling of pressure and bursting. Diseased joints become so sensitive that they cannot tolerate the touch of a sheet or shock from the steps of others. The night passes in agony and insomnia, attempts to place the sore leg more comfortably and constant searches for a body position that does not cause pain; throwing is as long as the pain in the affected joint, and intensifies as the pain worsens, so all attempts to change the position of the body and the sore leg are futile.”
The first attack of gout indicates that the concentration of urate in the serum has long been increased to such an extent that large quantities have accumulated in the tissues.
Intercritical period. Gout attacks may last for one or two days or several weeks, but usually resolve spontaneously. There are no consequences, and recovery seems complete. An asymptomatic phase begins, called the intercritical period. During this period, the patient does not make any complaints, which has diagnostic significance. If in approximately 7% of patients the second attack does not occur at all, then in approximately 60% the disease recurs within 1 year. However, the intercritical period can last up to 10 years and end with repeated attacks, each of which becomes increasingly longer, and remissions become less and less complete. With subsequent attacks, several joints are usually involved in the process; the attacks themselves become increasingly severe and prolonged and are accompanied by a feverish state. At this stage, gout can be difficult to differentiate from other types of polyarthritis, such as rheumatoid arthritis. Less commonly, chronic polyarthritis without remission develops immediately after the first attack.
Accumulations of urate and chronic gouty arthritis. In untreated patients, the rate of urate production exceeds the rate of its elimination. As a result, its quantity increases, and eventually accumulations of monosodium urate crystals appear in cartilage, synovial membranes, tendons and soft tissues. The rate of formation of these accumulations depends on the degree and duration of hyperuricemia and the severity of kidney damage. The classic, but probably not the most common site of accumulation is the helix or antihelix auricle(Fig. 309-1). Gouty deposits are also often localized along the ulnar surface of the forearm in the form of protrusions of the elbow bursa (Fig. 309-2), along the Achilles tendon and in other areas under pressure. It is interesting that in patients with the most pronounced gouty deposits, the helix and antihelix of the auricle are smoothed.
Gouty deposits are difficult to distinguish from rheumatoid and other types of subcutaneous nodules. They may ulcerate and secerate a whitish viscous liquid rich in monosodium urate crystals. Unlike other subcutaneous nodules, gouty deposits rarely disappear spontaneously, although they may slowly decrease in size with treatment. Detection of monosodium urate crystals in the aspirate (using a polarizing microscope) allows the nodule to be classified as gouty. Gout deposits rarely become infected. In patients with noticeable gouty nodules, acute attacks of arthritis appear to occur less frequently and are less severe than in patients without these deposits. Chronic gouty nodules rarely form before the onset of arthritis attacks.
Rice. 309-1. Gouty plaque in the helix of the auricle next to the ear tubercle.
Rice. 309-2. Protrusion of the elbow joint bursa in a patient with gout. You can also see accumulations of urate in the skin and a slight inflammatory reaction.
Successful treatment reverses the natural evolution of the disease. With the advent of effective antihyperuricemic drugs, only a small number of patients develop noticeable gouty deposits with permanent joint damage or other chronic symptoms.
Nephropathy. Some degree of renal dysfunction is observed in almost 90% of patients with gouty arthritis. Before the introduction of chronic hemodialysis, 17-25% of patients with gout died from renal failure. Its initial manifestation may be albumin or isosthenuria. In a patient with severe renal failure, it is sometimes difficult to determine whether it is due to hyperuricemia or whether the hyperuricemia is the result of kidney damage.
Several types of renal parenchymal damage are known. Firstly, this is urate nephropathy, which is considered to be the result of the deposition of monosodium urate crystals in the interstitial tissue of the kidneys, and secondly, obstructive uropathy, caused by the formation of uric acid crystals in the collecting ducts, renal pelvis or ureters, as a result of which the outflow of urine is blocked.
The pathogenesis of urate nephropathy is a subject of intense controversy. Despite the fact that monosodium urate crystals are found in the interstitial tissue of the kidneys of some patients with gout, they are absent in the kidneys of most patients. Conversely, urate deposition in the renal interstitium occurs in the absence of gout, although clinical significance these deposits are unclear. Factors that may contribute to the formation of urate deposits in the kidneys are unknown. In addition, in patients with gout there was a close correlation between the development renal pathology and hypertension. It is often unclear whether hypertension causes renal pathology or whether gouty changes in the kidneys cause hypertension.
Acute obstructive uropathy is a severe form of acute renal failure caused by the deposition of uric acid crystals in the collecting ducts and ureters. However, renal failure is more closely correlated with uric acid excretion than with hyperuricemia. Most often, this condition occurs in individuals: 1) with pronounced overproduction of uric acid, especially against the background of leukemia or lymphoma, undergoing intensive chemotherapy; 2) with gout and a sharp increase in uric acid excretion; 3) (possibly) after heavy physical activity, with rhabdomyolysis or seizures. Aciduria promotes the formation of poorly soluble non-ionized uric acid and therefore may increase crystal precipitation in either of these conditions. At autopsy, uric acid precipitates are found in the lumen of the dilated proximal tubules. Treatment aimed at reducing the formation of uric acid, accelerating urination and increasing the proportion of the more soluble ionized form of uric acid (monosodium urate) leads to a reversal of the process.
Nephrolithiasis. In the United States, gout affects 10-25% of the population, while the number of people with uric acid stones is approximately 0.01%. The main factor contributing to the formation of uric acid stones is increased excretion of uric acid. Hyperuricaciduria may result from primary gout, an inborn error of metabolism leading to increased uric acid production, myeloproliferative disease, and other neoplastic processes. If uric acid excretion in urine exceeds 1100 mg/day, the incidence of stone formation reaches 50%. The formation of uric acid stones also correlates with increased serum urate concentration: at a level of 130 mg/l and above, the stone formation rate reaches approximately 50%. Other factors contributing to the formation of uric acid stones include: 1) excessive acidification of urine; 2) urine concentration; 3) (probably) a violation of the composition of urine, affecting the solubility of uric acid itself.
In patients with gout, calcium-containing stones are more often found; their frequency in gout reaches 1-3%, while in the general population it is only 0.1%. Although the mechanism of this association remains unclear, hyperuricemia and hyperuricaciduria are detected with a high frequency in patients with calcium stones. Uric acid crystals could serve as a nucleus for the formation of calcium stones.
Associated conditions. Patients with gout typically suffer from obesity, hypertriglyceridemia, and hypertension. Hypertriglyceridemia in primary gout is closely related to obesity or alcohol consumption, and not directly to hyperuricemia. The incidence of hypertension in individuals without gout correlates with age, sex, and obesity. When these factors are taken into account, it turns out that there is no direct relationship between hyperuricemia and hypertension. The increased incidence of diabetes is also likely to be related to factors such as age and obesity rather than directly to hyperuricemia. Finally, the increased incidence of atherosclerosis has been attributed to concurrent obesity, hypertension, diabetes, and hypertriglyceridemia.
Independent analysis of the role of these variables points to obesity as having the greatest importance. Hyperuricemia in obese individuals appears to be associated with both increased production and decreased excretion of uric acid. Chronic consumption of alcohol also leads to its overproduction and insufficient excretion.
Rheumatoid arthritis, systemic lupus erythematosus, and amyloidosis rarely coexist with gout. The reasons for this negative association are unknown.
Acute gout should be suspected in any person with sudden onset of monoarthritis, especially in the distal joints lower limbs. In all these cases, aspiration of synovial fluid is indicated. The definitive diagnosis of gout is made based on the detection of monosodium urate crystals in leukocytes from the synovial fluid of the affected joint using polarizing light microscopy (Fig. 309-3). The crystals have a typical needle shape and negative birefringence. They can be detected in the synovial fluid of more than 95% of patients with acute gouty arthritis. The inability to detect urate crystals in the synovial fluid with a careful search and compliance with the necessary conditions allows us to exclude the diagnosis. Intracellular crystals have diagnostic value, but do not exclude the possibility of the simultaneous existence of another type of arthropathy.
Gout may be accompanied by infection or pseudogout (deposition of calcium pyrophosphate dihydrate). To rule out infection, one should Gram stain the synovial fluid and try to culture the flora. Calcium pyrophosphate dihydrate crystals exhibit weakly positive birefringence and are more rectangular than monosodium urate crystals. With polarizing light microscopy, the crystals of these salts are easily distinguished. Puncture of the joint with suction of synovial fluid does not need to be repeated during subsequent attacks, unless a different diagnosis is suspected.
Aspiration of synovial fluid retains its diagnostic value even during asymptomatic intercritical periods. In more than 2/3 of aspirates from the first metatarsal joints of the digital phalanges in patients with asymptomatic gout, extracellular urate crystals can be detected. They are detected in less than 5% of people with hyperuricemia without gout.
Synovial fluid analysis is important in other ways as well. The total number of leukocytes in it can be 1-70 109/l or more. Polymorphonuclear leukocytes predominate. As in other inflammatory fluids, clots of mucin are found in it. The concentrations of glucose and uric acid correspond to those in the serum.
In patients in whom synovial fluid cannot be obtained or intracellular crystals cannot be detected, the diagnosis of gout can presumably be reasonably made if: 1) hyperuricemia is detected; 2) classic clinical syndrome and 3) severe reaction to colchicine. In the absence of crystals or this highly informative triad, the diagnosis of gout becomes hypothetical. A sharp improvement in the condition in response to treatment with colchicine is a strong argument in favor of the diagnosis of gouty arthritis, but still not a pathognomonic sign.
Rice. 309-3. Crystals of monosodium urate monohydrate in joint aspirate.
Acute gouty arthritis should be differentiated from mono- and polyarthritis of other etiologies. Gout is a common initial manifestation, and many diseases are characterized by tenderness and swelling of the first toe. These include soft tissue infection, purulent arthritis, inflammation joint capsule on the outer side of the first finger, local injury, rheumatoid arthritis, degenerative arthritis with acute inflammation, acute sarcoidosis, psoriatic arthritis, pseudogout, acute calcific tendonitis, palindromic rheumatism, Reiter's disease and sporotrichosis. Sometimes gout can be confused with cellulitis, gonorrhea, fibrosis of the plantar and calcaneal surfaces, hematoma and subacute bacterial endocarditis with embolization or suppuration. Gout, when other joints are involved, such as the knee, must be differentiated from acute rheumatic fever, serum sickness, hemarthrosis, and involvement of peripheral joints in ankylosing spondylitis or inflammation of the intestine.
Chronic gouty arthritis should be distinguished from rheumatoid arthritis, inflammatory osteoarthritis, psoriatic arthritis, enteropathic arthritis and peripheral arthritis accompanied by spondyloarthropathy. Chronic gout is supported by a history of spontaneous relief of monoarthritis, gouty deposits, typical changes on a radiograph, and hyperuricemia. Chronic gout may resemble other inflammatory arthropathies. Existing effective treatments justify the effort to confirm or rule out the diagnosis.
Pathophysiology of hyperuricemia. Classification. Hyperuricemia is a biochemical sign and serves as 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. About 2/3 of uric acid is excreted in the urine (300-600 mg/day), and about 1/3 is excreted 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 (Table 309-1). 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 the metabolic and renal types of hyperuricemia. With careful examination, both mechanisms for the development of hyperuricemia can be detected in a large number of patients with gout. In these cases, the condition is classified according to its predominant component: renal or metabolic. This classification applies primarily to those cases where gout or hyperuricemia are the main manifestations of the disease, that is, when gout is not secondary to another acquired disease and does not represent a subordinate symptom of a congenital defect that initially causes some other serious disease, not gout. Sometimes primary gout has a specific genetic basis. Secondary hyperuricemia or secondary gout are cases when they develop as symptoms of another disease or as a result of taking certain pharmacological agents.
Table 309-1. Classification of hyperuricemia and gout
Overproduction of uric acid. Overproduction of uric acid, by definition, means excretion of more than 600 mg/day after following a purine-restricted diet for 5 days. Such cases appear to account for less than 10% of all cases of the disease. The patient has accelerated de novo synthesis of purines or increased circulation of these compounds. In order to imagine the basic mechanisms of the corresponding disorders, one should analyze the pattern of purine metabolism (Fig. 309-4).
Purine nucleotides - adenylic, inosinic and guanic acids (AMP, IMP and GMP, respectively) - 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 from non-purine precursors and passing through a series of steps until the formation of IMP, which serves as a common intermediate purine nucleotide. Inosinic acid can be converted to either AMP or HMP. Once purine nucleotides are formed, they are used to synthesize nucleic acids, adenosine triphosphate (ATP), cyclic AMP, cyclic GMP, and some cofactors.
Rice. 309-4. Scheme of purine metabolism.
1 - amidophosphoribosyltransferase, 2 - hypoxanthine guanine phosphoribosyltransferase, 3 - PRPP synthetase, 4 - adenine phosphoribosyltransferase, 5 - adenosine deaminase, 6 - purine nucleoside phosphorylase, 7 - 5"-nucleotidase, 8 - xanthine oxidase.
Various purine compounds are broken down into purine nucleotide monophosphates. Guanic acid is converted through guanosine, guanine and xanthine to uric acid, IMP breaks down through inosine, hypoxanthine and xanthine to the same uric acid, and AMP can be deaminated to IMP and further catabolized through inosine to uric acid or converted to inosine in an alternative way with the intermediate formation of adenosine .
Despite the fact that the regulation of purine metabolism is quite complex, the main determinant of the rate of uric acid synthesis in humans appears to be the intracellular concentration of 5-phosphoribosyl-1-pyrophosphate (PRPP). As a rule, when the level of PRPP in the cell increases, the synthesis of uric acid increases, and when its level decreases, it decreases. Despite some exceptions, in most cases this is the case.
Excess uric acid production in a small number of adult patients is a primary or secondary manifestation of an inborn error of metabolism. Hyperuricemia and gout may be the primary manifestation of partial deficiency of hypoxanthine guanine phosphoribosyltransferase (reaction 2 in Fig. 309-4) or increased activity of PRPP synthetase (reaction 3 in Fig. 309-4). In Lesch-Nyhan syndrome, almost complete deficiency of hypoxanthine guanine phosphoribosyltransferase causes secondary hyperuricemia. These serious congenital anomalies are discussed in more detail below.
For the mentioned inborn errors of metabolism (hypoxanthine guanine phosphoribosyltransferase deficiency and excess activity of PRPP synthetase), less than 15% of all cases of primary hyperuricemia due to increased 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 due to many causes. In some patients, increased excretion of uric acid is due, as in primary gout, to accelerated de novo purine biosynthesis. In patients with glucose-6-phosphatase deficiency (type I glycogen storage disease), uric acid production is constantly increased, as well as de novo biosynthesis of purines is accelerated (see Chapter 313). Overproduction of uric acid with this enzyme abnormality is due to a number of mechanisms. Accelerated de novo purine synthesis may in part result from accelerated PRPP synthesis. In addition, the accelerated breakdown of purine nucleotides contributes to increased 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 continuous correction of the hypoglycemia typical of this disease.
In most patients with secondary hyperuricemia due to excess production of uric acid, the main disorder is obviously an acceleration of the turnover of nucleic acids. Increased activity of the bone marrow or a shortening of the life cycle of cells of other tissues, accompanied by an acceleration of the turnover of nucleic acids, is characteristic of many diseases, including myeloproliferative and lymphoproliferative diseases, multiple myeloma, secondary polycythemia, pernicious anemia, some hemoglobinopathies, thalassemia, others hemolytic anemia, infectious mononucleosis and a number of carcinomas. Accelerated turnover of nucleic acids, in turn, leads to hyperuricemia, hyperuricaciduria and a compensatory increase in the rate of de novo purine biosynthesis.
Reduced excretion. In a large number of patients with gout, this rate of uric acid excretion is achieved only when the plasma urate level is 10-20 mg/l above normal (Fig. 309-5). This pathology is most pronounced in patients with normal uric acid production and is absent in most cases of its overproduction.
Urate excretion depends on glomerular filtration, tubular reabsorption and secretion. Uric acid is apparently completely filtered in the glomerulus and reabsorbed in the proximal tubule (i.e., undergoes presecretory reabsorption). In the underlying segments of the proximal tubules it is secreted, and in the second site of reabsorption - in the distal part of the proximal tubule - it is once again subject to partial reabsorption (postsecretory reabsorption). Although some of it may be reabsorbed in both the ascending limb of the loop of Henle and the collecting duct, these two sites are considered less important from a quantitative point of view. Attempts to more accurately elucidate the localization and nature of these latter areas and to quantify their role in the transport of uric acid in a healthy or sick person, as a rule, were unsuccessful.
Theoretically, impaired renal excretion of uric acid in most patients with gout could be caused by: 1) a decrease in filtration rate; 2) increased reabsorption or 3) decreased secretion rate. There is no definitive evidence for 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 a result of decreased renal excretion of uric acid. A decrease in glomerular filtration rate leads to a decrease in the filtration load of uric acid and, thereby, to hyperuricemia; This is why hyperuricemia develops in patients with kidney pathology. In some kidney diseases (polycystic disease and lead nephropathy), other factors, such as decreased secretion of uric acid, have been postulated to play a role. Gout rarely complicates hyperuricemia secondary to renal disease.
One of the most important causes of secondary hyperuricemia is treatment with diuretics. The decrease in circulating plasma volume they cause leads to increased tubular reabsorption of uric acid, as well as to a decrease in its filtration. In hyperuricemia associated with diuretic use, a decrease in uric acid secretion may also be important. A number of other drugs also cause hyperuricemia through unidentified renal mechanisms; These drugs include acetylsalicylic acid (aspirin) in low doses, pyrazinamide, nicotinic acid, ethambutol and ethanol.
Rice. 309-5. The rate of uric acid excretion at different levels plasma urate in individuals without gout (black symbols) and in patients with gout (open symbols).
Large symbols indicate average values, small symbols indicate individual data for several average values (the degree of dispersion within groups). Studies were conducted under basal conditions, after RNA ingestion, and after lithium urate administration (by: Wyngaarden. Reproduced with permission from Academic Press).
It is believed that impaired renal excretion of uric acid is an important mechanism for hyperuricemia, which accompanies a number of pathological conditions. In hyperuricemia associated with adrenal insufficiency and nephrogenic diabetes insipidus, a decrease in circulating plasma volume may play a role. In a number of situations, hyperuricemia is considered to be the result of competitive inhibition of uric acid secretion by excess organic acids, which are secreted, apparently, using the same renal tubular mechanisms as uric acid. Examples include fasting (ketosis and free fatty acids), alcoholic ketosis, diabetic ketoacidosis, maple syrup disease and lactic acidosis of any origin. In conditions such as hyperpara- and hypoparathyroidism, pseudohypoparathyroidism and hypothyroidism, hyperuricemia may also have a renal basis, but the mechanism of occurrence of this symptom is unclear.
Pathogenesis of acute gouty arthritis. The reasons that cause the initial crystallization of monosodium urate in the joint after a period of asymptomatic hyperuricemia for approximately 30 years are not fully understood. Persistent hyperuricemia eventually leads to the formation of microdeposits in the squamous cells of the synovium and, probably, to the accumulation of monosodium urate in cartilage on proteoglycans with a high affinity for it. For one reason or another, apparently including trauma with the destruction of microdeposits and acceleration of the turnover of cartilage proteoglycans, urate crystals are occasionally released into the synovial fluid. Other factors, such as low joint temperature or inadequate reabsorption of water and urate from synovial fluid, can also accelerate its deposition.
When a sufficient number of crystals are formed in the joint cavity, an acute attack is provoked by a number of factors, including: 1) phagocytosis of crystals by leukocytes with the rapid release of chemotaxis protein from these cells; 2) activation of the kallikrein system; 3) activation of complement with the subsequent formation of its chemotactic components: 4) the final stage of rupture of leukocyte lysosomes by urate crystals, which is accompanied by a violation of the integrity of these cells and the release of lysosomal products into the synovial fluid. While some progress has been made in understanding the pathogenesis of acute gouty arthritis, questions regarding the factors determining the spontaneous cessation of an acute attack and the effect of colchicine still await answers.
Treatment. Treatment for gout includes: 1) if possible, quick and careful relief of an acute attack; 2) prevention of relapse of acute gouty arthritis; 3) prevention or regression of complications of the disease caused by the deposition of monosubstituted sodium urate crystals in the 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. For acute gouty arthritis, anti-inflammatory treatment is carried out. The most commonly used 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 treatment is continued until: 1) the patient’s condition improves; 2) there will be no adverse reactions from the gastrointestinal tract or 3) the total dose of the drug will not reach 6 mg due to the lack of effect. Colchicine is most effective if treatment is started soon after symptoms appear. In the first 12 hours of treatment, the condition improves significantly in more than 75% of patients. However, in 80% of patients, the drug causes adverse reactions from the gastrointestinal tract, which may appear before clinical improvement or simultaneously with it. When administered orally, the maximum plasma level of colchicine is reached after approximately 2 hours. Therefore, it can be assumed that its administration at 1.0 mg every 2 hours is less likely to cause the accumulation of a toxic dose before the therapeutic effect occurs. 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 administration, 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, repeat the administration of 1 mg twice with an interval of 6 hours. When administering colchicine intravenously, special precautions should be taken. It has an irritating effect and, if it enters the tissue surrounding the vessel, can cause sharp pain and necrosis. It is important to remember that the intravenous route of administration requires care 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. Both oral and parenteral administration of colchicine can suppress 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 pathology of the liver, bone marrow or kidneys, 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 prescribed to patients with neutropenia.
Other anti-inflammatory drugs are also effective for acute gouty arthritis, including indomethacin, phenylbutazone, naproxen, and fenoprofen.
Indomethacin can be prescribed for oral administration at a dose of 75 mg, after which the patient should receive 50 mg every 6 hours; 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 disturbances, sodium retention, and central nervous system symptoms. Although these doses may cause side effects in up to 60% of patients, indomethacin is generally better tolerated than colchicine and is probably the drug of choice for acute gouty arthritis. To increase the effectiveness of treatment and reduce the manifestations of pathology, the patient should be warned that taking anti-inflammatory drugs should be started at the first sensation of pain. Drugs that stimulate uric acid excretion and allopurinol are ineffective in acute gout attacks.
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, whether oral or intravenous, moderate doses should be given over several days as glucocorticoid concentrations decrease rapidly and their effect ceases. Intra-articular administration of a long-acting steroid drug (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 appropriate 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 administration of colchicine or indomethacin; 2) controlled reduction of body weight in obese patients; 3) eliminating known triggers, such as large amounts of alcohol or foods rich in purines; 4) use of antihyperuricemic drugs.
Daily use of small doses of colchicine effectively prevents the development of subsequent acute attacks. Colchicine in a daily dose of 1-2 mg is effective in almost 1/4 of patients with gout and is ineffective in approximately 5% of patients. In addition, this treatment program is safe and has virtually no side effects. However, if the serum urate concentration is not maintained within normal limits, the patient will only be spared from acute arthritis, and not from other manifestations of gout. Maintenance treatment with colchicine is especially indicated during the first 2 years after starting antihyperuricemic drugs.
Prevention or stimulation of the reverse development of gouty deposits of monosubstituted sodium urate in tissues. Antihyperuricemic drugs are quite effective in reducing serum urate concentrations, so they should be used in patients with: 1) one or more attacks of acute gouty arthritis; 2) one gouty deposit or more; 3) uric acid nephrolithiasis. The purpose of their use is to maintain serum urate levels below 70 mg/l; i.e., at 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 decreasing the production of uric acid. Antihyperuricemic agents generally do not have anti-inflammatory effects. Uricosuric drugs reduce serum urate levels by increasing its renal excretion. Although a large number of substances have this property, the most effective ones used in the United States are probenecid and sulfinpyrazone. Probenecid is usually prescribed at an initial dose of 250 mg twice daily. Over several weeks, it is increased to ensure a significant reduction 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. Major side effects include hypersensitivity, skin rash and gastrointestinal symptoms. Despite rare cases of toxicity, these adverse reactions force almost 1/3 of patients to stop treatment.
Sulfinpyrazone is a metabolite of phenylbutazone that lacks anti-inflammatory effects. Treatment with it begins at a dose of 50 mg twice a day, gradually increasing the dose to a maintenance level of 300-400 mg/day 3-4 times. Maximum efficiency 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, treatment failure may be due to a violation of the drug regimen, concomitant use of salicylates, or impaired renal function. Acetylsalicylic acid(aspirin) at any dose blocks the uricosuric effect of probenecid and sulfinpyrazone. They become less effective when creatinine clearance is below 80 ml/min and cease action at creatinine clearance of 30 ml/min.
With a negative urate balance caused by treatment with uricosuric drugs, the serum urate concentration decreases and urinary excretion of uric acid exceeds the baseline 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 its original values. A transient increase in its excretion, usually lasting only a few days, can cause the formation of kidney stones in 1/10 of the patients. In order to avoid this complication, uricosuric drugs should be started with small doses, gradually increasing them. Maintaining increased urinary output with adequate hydration and alkalinization of the urine by oral administration of sodium bicarbonate alone or with acetazolamide reduces the likelihood of stone formation. The ideal candidate for treatment with uricosurics is a patient under 60 years of age, on a regular diet, with normal renal function and uric acid excretion of less than 700 mg/day, and with no history of renal stones.
Hyperuricemia can also be corrected with allopurinol, which reduces the synthesis of uric acid. It inhibits xanthine oxidase (see reaction 8 in Fig. 309-4), which catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid. Although allopurinol has a half-life of only 2-3 hours in the body, it is converted primarily to oxypurinol, which is an equally effective xanthine oxidase inhibitor 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 allopurinol's main metabolite, it can be administered once daily. Because oxypurinol is excreted primarily in the urine, its half-life is prolonged in renal failure. In this regard, in case of 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. Overall frequency side effects reaches 20%; they often develop in renal failure. Only in 5% of patients their severity forces them to stop treatment with allopurinol. When prescribing it, drug-drug interactions should be taken into account, as it increases the half-life of mercaptopurine and azathioprine and increases the toxicity of cyclophosphamide.
Allopurinol is preferred to uricosuric drugs for: 1) increased (more than 700 mg/day, subject to general diet) excretion of uric acid in urine; 2) impaired renal function with creatinine clearance less than 80 ml/min; 3) gouty deposits in the joints, regardless of kidney function; 4) uric acid nephrolithiasis; 6) gout that is not affected by uricosuric drugs due to their ineffectiveness or intolerance. In rare cases of ineffectiveness of each drug used separately, allopurinol can be used simultaneously with any uricosuric agent. This does not require a change in drug dose and is usually accompanied by a decrease in serum urate levels.
No matter how rapid and pronounced the decrease in serum urate levels is, acute gouty arthritis may develop during treatment. In other words, starting treatment with any antihyperuricemic drug may precipitate 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. Therefore, before starting antihyperuricemic drugs, it is advisable to start prophylactic colchicine and continue it until the serum urate level is within the normal range for at least a year or until all gouty deposits have dissolved. Patients should be aware of the possibility of exacerbations in early period treatment. Most patients with large deposits in the joints and/or renal failure should sharply limit their dietary intake of purines.
Prevention of acute uric acid nephropathy and treatment of patients. In case of acute uric acid nephropathy, intensive treatment must be started immediately. Initially, urine output should be increased with large fluid loads and diuretics, such as furosemide. The urine is alkalinized so that uric acid is converted into the more soluble monosodium urate. Alkalinization is achieved using sodium bicarbonate - alone or in combination with acetazolamide. Allopurinol should also be administered to reduce the formation of uric acid. Its initial dose in these cases is 8 mg/kg per day once. After 3-4 days, if renal failure persists, the dose is reduced to 100-200 mg/day. For uric acid kidney stones, treatment is the same as for uric acid nephropathy. In most cases, it is sufficient to combine allopurinol with large amounts of fluid intake only.
Management of patients with hyperuricemia. Examination of patients with hyperuricemia is aimed at: 1) identifying its cause, which may indicate another serious disease; 2) assessment of damage to tissues and organs and its degree; 3) identification of associated disorders. In practice, all these problems are solved simultaneously, since the decision regarding the meaning of hyperuricemia and treatment depends on the answer to all these questions.
The most important results for hyperuricemia are urine test results for uric acid. If there is a history of urolithiasis, a survey of the abdominal cavity and intravenous pyelography are indicated. If kidney stones are detected, they may be useful analysis for uric acid and other components. In case of joint pathology, it is advisable to examine the synovial fluid and take x-rays of the joints. If there is a history of lead exposure, urinary excretion following a calcium-EDTA infusion may be necessary to diagnose gout associated with lead poisoning. If increased uric acid production is suspected, 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 does not have a clear answer. As a rule, treatment is not required unless: 1) the patient has no 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. Hypoxanthine guanine phosphoribosyltransferase deficiency. Hypoxanthine guanine phosphoribosyltransferase catalyzes the conversion of hypoxanthine to inosinic acid and guanine to guanosine (see reaction 2 in Fig. 309-4). PRPP serves as a phosphoribosyl donor. Hypoxanthine guanyl phosphoribosyltransferase deficiency leads to a decrease in the consumption of PRPP, which accumulates in higher than normal concentrations. Excess PRPP accelerates de novo purine biosynthesis and consequently increases uric acid production.
Lesch-Nyhan syndrome is an X-linked disorder. Characteristic biochemical disorder with it lies in a pronounced deficiency of hypoxanthine guanine phosphoribosyltransferase (see reaction 2 in Fig. 309-4). Patients experience hyperuricemia and excessive overproduction of uric acid. In addition, they develop peculiar neurological disorders, characterized by self-mutilation, choreoathetosis, spastic muscle condition, as well as delayed growth and mental development. The incidence of this disease is estimated at 1:100,000 newborns.
Approximately 0.5-1.0% of adult patients with gout with excess production of uric acid have a partial deficiency of hypoxanthine guanine phosphoribosyltransferase. Usually, their gouty arthritis manifests itself at a young age (15-30 years), the frequency of uric acid nephrolithiasis is high (75%), sometimes some neurological symptoms are added, including dysarthria, hyperreflexia, impaired coordination and/or mental retardation. The disease is inherited as an X-linked trait, so it is transmitted to men from female carriers.
The enzyme whose deficiency causes this disease (hypoxanthine guanine phosphoribosyltransferase) is of significant interest to geneticists. With the possible exception of the globin gene family, the hypoxanthine guanine phosphoribosyltransferase locus is the most studied single gene in humans.
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 hypoxanthine guanine phosphoribosyltransferase (Table 309-2). In each of them, the replacement of one amino acid leads to either a loss of the catalytic properties of the protein or a decrease in the constant concentration of the enzyme due to a decrease in synthesis or acceleration of the breakdown of the mutant protein.
The DNA sequence complementary to the messenger RNA (mRNA) that encodes gyloxanthine guanine phosphoribosyltransferase has been cloned and deciphered. As a molecular probe, this sequence was used to identify carrier status in women at risk in whom carrier status could not be detected by conventional means. The human gene was transferred into a mouse using a bone marrow transplant infected with a vectored retrovirus. The expression of human hypoxanthine guanine phosphoribosyltransferase in the mouse treated in this way has been determined with certainty. Recently, a transgenic line of mice has also been obtained in which the human enzyme is expressed in the same tissues as in humans.
The accompanying biochemical abnormalities that cause the pronounced neurological manifestations of Lesch-Nyhan syndrome have not been sufficiently deciphered. Post-mortem examination of the patients' brains revealed signs of a specific defect in the central dopaminergic pathways, especially in the basal ganglia and nucleus accumbens. Relevant in vivo data were obtained using positron emission tomography (PET) in patients with hypoxanthine guanine phosphoribosyltransferase deficiency. In the majority of patients examined by this method, a disorder of 2-fluoro-deoxyglucose metabolism in the caudate nucleus was detected. The relationship between the pathology of the dopaminergic nervous system and the disorder of purine metabolism remains unclear.
Hyperuricemia caused by partial or complete deficiency of hypoxanthine guanine phosphoribosyltransferase can be successfully treated with the xanthine oxidase inhibitor allopurinol. In this case, 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 associated with Lesch-Nyhan syndrome.
Variants of PRPP synthetase. Several families have been identified whose members had increased activity of the enzyme PRPP synthetase (see reaction 3 in Fig. 309-4). All three known types mutant enzymes have increased activity, which leads to an increase in the intracellular concentration of PRPP, acceleration of purine biosynthesis and increased excretion of uric acid. This disease is also inherited as an X-linked trait. 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 often form. In several children, increased activity of PRPP synthetase was combined with nerve deafness.
Other disorders of purine metabolism. Adenine phosphoribosyltransferase deficiency. Adenine phosphoribosyltransferase catalyzes the conversion of adenine to AMP (see reaction 4 in Fig. 309-4). The first person to be found to be deficient in this enzyme was heterozygous for this defect, clinical symptoms he was missing. It was then found that heterozygosity for this trait is quite widespread, probably with a frequency of 1:100. Currently, 11 homozygotes for deficiency of this enzyme have been identified, whose kidney stones consisted of 2,8-dioxyadenine. Because of its chemical similarity, 2,8-dihydroxyadenine is easily confused with uric acid, so these patients were initially misdiagnosed with uric acid nephrolithiasis.
Table 309-2. Structural and functional disorders in mutant forms of human hypoxanthine guanine phosphoribosyltransferase
Note. PRPP means 5-phosphoribosyl-1-pyrophosphate, Arg means arginine, Gly means glycine, Ser means serine. Leu - leucine, Asn - asparagine. Asp- aspartic acid, ? - replaced (according to Wilson et al.).
For adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency, see Chap. 256.
Xanthine oxidase deficiency. Xanthine oxidase catalyzes the oxidation of hypoxanthine to xanthine, xanthine to uric acid, and adenine to 2,8-dioxyadenine (see reaction 8 in Fig. 309-4). Xanthinuria, the first congenital disorder of purine metabolism deciphered at the enzymatic level, is caused by a deficiency of xanthine oxidase. As a result, in patients with xanthinuria, hypouricemia and hypouricaciduria are detected, as well as increased urinary excretion of oxypurines-hypoxanthine and xanthine. Half of the patients do not complain, and in 1/3 xanthine stones form in the urinary tract. Several patients developed myopathy, and three developed polyarthritis, which could be a manifestation of crystal-induced synovitis. In the development of each of the symptoms great value cause xanthine to precipitate.
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 main defect was postulated to be a deficiency of the molybdate cofactor necessary for the functioning of both enzymes, treatment with ammonium molybdate was ineffective. A patient who was completely on parenteral nutrition developed a disease simulating combined deficiency of xanthine oxidase and sulfate oxidase. After treatment with ammonium molybdate, enzyme function was 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 (IPA). This reaction is an integral part of the purine nucleotide cycle and appears to be important for maintaining the processes of energy production and utilization in skeletal muscle.
Deficiency of this enzyme is detected only in skeletal muscle. Most patients experience myalgia, muscle spasms and a feeling of fatigue during physical activity. 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. Clinical symptoms with it are the same as with metabolic myopathy. Creatinine kinase levels are elevated in less than half of the cases. Electromyographic studies and conventional histology of muscle biopsies can reveal nonspecific changes. Presumably, adenylate deaminase deficiency can be diagnosed based on the results of a performance test of the ischemic forearm. In patients with deficiency of this enzyme, ammonia production is reduced because the deamination of AMP is blocked. The diagnosis should be confirmed by direct definition AMP deaminase activity in skeletal muscle biopsy, since. reduced 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.
William N. Kelley, Thomas D. Patella
The term “gout” refers to a group of diseases that, when fully developed, are manifested by: 1) an increase in the level of urate in the serum; 2) repeated attacks of characteristic acute arthritis, in which monohydrate monohydrate sodium urate can be detected in leukocytes from the synovial fluid; 3) large deposits monosodium urate monohydrate (tophi), mainly in and around the joints of the extremities, sometimes leading to severe lameness and joint deformities; 4) damage to the kidneys, including interstitial tissues and blood vessels; 5} formation of kidney stones from uric acid. All these symptoms can occur individually or in various combinations.
Prevalence and epidemiology. An absolute increase in the level of urate in serum is said to exist when it exceeds the solubility limit of monosubstituted sodium urate in this medium. At a temperature of 37°C, a saturated solution of urate in plasma is formed at a concentration of approximately 70 mg/l. A higher level means supersaturation in a physico-chemical sense. Serum urate concentration is relatively elevated when it exceeds the upper limit of an arbitrarily defined normal range, usually calculated as the mean serum urate level plus two standard deviations in a population of healthy individuals grouped by age and sex. According to most studies, the upper limit for men is 70, and for women - 60 mg/l. From an epidemiological point of view, urate concentration c. serum levels greater than 70 mg/l increases the risk of gouty arthritis or nephrolithiasis.
Urate levels are affected by gender and age. Before puberty, serum urate concentration is approximately 36 mg/L in both boys and girls; after puberty, it increases more in boys than in girls. In men, it reaches a plateau after the age of 20 and then remains stable. In women aged 20-50 years, the urate concentration remains at a constant level, but with the onset of menopause it increases and reaches a level typical for men. It is believed that these age- and gender-related variations are associated with differences in the renal clearance of urate, which is obviously influenced by the content of estrogens and androgens. Other physiological parameters such as height, body weight, blood urea nitrogen and creatinine levels, and blood pressure are also correlated with serum urate concentration. Elevated serum urate levels are also associated with other factors, such as high ambient temperature, alcohol consumption, high social status or education.
Hyperuricemia, by one definition or another, is found in 2-18% of the population. In one of the examined groups of hospitalized patients, serum urate concentrations of more than 70 mg/l occurred in 13% of adult men.
The incidence and prevalence of gout is less than hyperuricemia. In most Western countries, the incidence of gout is 0.20-0.35 per 1000 people: this means that it affects 0.13-0.37% of the total population. The prevalence of the disease depends on both the degree of increase in serum urate levels and the duration of this condition. In this regard, gout is mainly a disease of older men. Women account for only up to 5% of cases. In the prepubertal period, children of both sexes rarely become ill. The usual form of the disease only rarely appears before the age of 20 years, and the peak incidence occurs in the fifth 10th year of life.
Inheritance. In the USA, a family history is revealed in 6-18% of cases of gout, and with a systematic survey this figure is already 75%. The exact mode of inheritance is difficult to determine due to the influence of environmental factors on serum urate concentrations. In addition, the identification of several specific causes of gout suggests that it represents a common clinical manifestation of a heterogeneous group of diseases. Accordingly, it is difficult to analyze the pattern of inheritance of hyperuricemia and gout not only in the population, but also within the same family. Two specific causes of gout - deficiency of hypoxanthine guanine phosphoribosyltransferase and hyperactivity of 5-phosphoribosyl-1-pyrophosphate synthetase - are X-linked. In other families, inheritance follows an autosomal dominant pattern. Even more often, genetic studies indicate multifactorial inheritance of the disease.
Clinical manifestations. The complete natural evolution of gout goes through four stages: asymptomatic hyperuricemia, acute gouty arthritis, intercritical period and chronic gouty joint deposits. Nephrolithiasis can develop at any stage except the first.
Asymptomatic hyperuricemia. This is the stage of the disease in which serum urate levels are elevated but symptoms of arthritis, gouty joint deposits, or uric acid stones are not yet present. In men susceptible to classic gout, hyperuricemia begins during puberty, while in women from the ka group it usually does not appear until menopause. In contrast, with some enzyme defects (hereinafter), hyperuricemia is detected already from the moment of birth. Although asymptomatic hyperuricemia may persist throughout the patient's life without apparent complications, the tendency for it to progress to acute gouty arthritis increases as a function of its level and duration. nephrolithiasis also increases as serum urate increases and correlates with uric acid excretion. Although hyperuricemia is present in virtually all gout patients, only approximately 5% of individuals with hyperuricemia ever develop the disease.
The stage of asymptomatic hyperuricemia ends with the first stage of gouty arthritis or nephrolithiasis. In most cases, arthritis precedes nephrolithiasis, which develops after 20-30 years of persistent hyperuricemia. However, in 10-40% of patients, renal colic occurs before the first stage of arthritis.
Acute gouty arthritis. The primary manifestation of acute gout is extremely painful arthritis at first, usually in one of the joints with scanty general symptoms, but later several joints are involved in the process against a background of a feverish state. The percentage of patients in whom gout immediately manifests itself as polyarthritis is not precisely established. According to some authors, it reaches 40%, but most believe that it does not exceed 3-14%. The duration of ptups varies, but is still limited, they are interspersed with asymptomatic periods. In at least half of the cases, the first ptup begins in the joint of the metatarsal bone of the first toe. Ultimately, 90% of patients experience acute pain in the joints of the first toe (gout).
Acute gouty arthritis is a disease primarily of the legs. The more distal the location of the lesion, the more typical ptupy. After the first toe, the process involves the joints of the metatarsal bones, ankles, heels, knees, wrist bones, fingers and elbows. Acute pain attacks in the shoulder and hip joints, joints of the spine, sacroiliac, sternoclavicular and lower jaw rarely appear, except in persons with a long-term, severe disease. Sometimes gouty bursitis develops, and most often the bursae of the knee and elbow joints are involved in the process. Before the first sharp attack of gout, patients may feel constant pain with exacerbations, but more often the first attack is unexpected and has an “explosive” character. It usually begins at night, and the pain in the inflamed joint is extremely severe. Ptup can be triggered by a number of specific reasons, such as injury, consumption of alcohol and certain medications, dietary errors, or surgery. Within a few hours, the intensity of the pain reaches its peak, accompanied by signs of progressive inflammation. In typical cases, the inflammatory reaction is so pronounced that it suggests purulent arthritis. Systemic manifestations may include fever, leukocytosis, and accelerated erythrocyte sedimentation. It is difficult to add anything to the classic description of the disease given by Syndenham:
“The patient goes to bed and falls asleep in good health. At about two o'clock in the morning he wakes up from acute pain in the first toe, less often in the heel bone, ankle joint or metatarsal bones. The pain is the same as with a dislocation, and even the feeling of a cold shower is combined. Then chills and trembling begin, and body temperature rises slightly. The pain, which was moderate at first, becomes increasingly severe. As it worsens, the chills and trembling intensify. After some time, they reach their maximum, spreading to the bones and ligaments of the tarsus and metatarsus. There is a feeling of stretching and tearing of the ligaments: gnawing pain, a feeling of pressure and bursting. Diseased joints become so sensitive that they cannot tolerate the touch of a sheet or shock from the steps of others. The night passes in agony and insomnia, attempts to place the sore leg more comfortably and constant searches for a body position that does not cause pain; throwing is as long as the pain in the affected joint, and intensifies as the pain worsens, so all attempts to change the position of the body and the sore leg are futile.”
The first stage of gout indicates that the concentration of urate in the serum has long been increased to such an extent that large quantities have accumulated in the tissues.
Intercritical period. Gout attacks may last for one or two days or several weeks, but usually resolve spontaneously. There are no consequences, and recovery seems complete. An asymptomatic phase begins, called the intercritical period. During this period, the patient does not make any complaints, which has diagnostic significance. If in approximately 7% of patients the second stage does not occur at all, then in approximately 60% the disease recurs within 1 year. However, the intercritical period can last up to 10 years and end with repeated ptups, each of which becomes increasingly longer, and remissions become less and less complete. With subsequent ptups, several joints are usually involved in the process; the ptups themselves become increasingly severe and prolonged and are accompanied by a feverish state. At this stage, gout can be difficult to differentiate from other types of polyarthritis, such as rheumatoid arthritis. Less commonly, chronic polyarthritis without remission develops immediately after the first episode.
Accumulations of urate and chronic gouty arthritis. In untreated patients, the rate of urate production exceeds the rate of its elimination. As a result, its quantity increases, and eventually accumulations of monosodium urate crystals appear in cartilage, synovial membranes, tendons and soft tissues. The rate of formation of these accumulations depends on the degree and duration of hyperuricemia and the severity of kidney damage. The classic, but certainly not the most common site of accumulation is the helix or antihelix of the auricle (309-1). Gouty deposits are also often localized along the ulnar surface of the forearm in the form of protrusions of the elbow bursa (309-2), along the Achilles tendon and in other areas under pressure. It is interesting that in patients with the most pronounced gouty deposits, the helix and antihelix of the auricle are smoothed.
Gouty deposits are difficult to distinguish from rheumatoid and other types of subcutaneous nodules. They may ulcerate and secerate a whitish viscous fluid rich in monosodium urate crystals. Unlike other subcutaneous nodules, gouty deposits rarely disappear spontaneously, although they may slowly decrease in size with treatment. Detection of monosubstituted sodium urate in the aspirate of kthalls (using a polarizing microscope) allows us to classify the nodule as gouty. Gout deposits rarely become infected. In patients with noticeable gouty nodules, acute arthritis appears to occur less frequently and is less severe than in patients without these deposits. Chronic gouty nodules rarely form before the onset of arthritis.
309-1.Gouty plaque in the helix of the auricle next to the ear tubercle.
309-2. Protrusion of the elbow joint bursa in a patient with gout. You can also see accumulations of urate in the skin and a slight inflammatory reaction.
Successful treatment reverses the natural evolution of the disease. With the advent of effective antihyperuricemic agents, only a small number of patients develop noticeable gouty deposits with permanent joint damage or other chronic symptoms.
Nephropathy. Some degree of renal dysfunction is observed in almost 90% of patients with gouty arthritis. Before the introduction of chronic hemodialysis, 17-25% of patients with gout died from renal failure. Its initial manifestation may be albumin or isosthenuria. In a patient with severe renal failure, it is sometimes difficult to determine whether it is due to hyperuricemia or whether the hyperuricemia is the result of kidney damage.
Several types of renal parenchymal damage are known. Firstly, this is urate nephropathy, which is considered the result of the deposition of monosodium urate kthalls in the interstitial tissue of the kidneys, and secondly, obstructive uropathy, caused by the formation of uric acid kthalls in the collecting ducts, renal pelvis or ureters, as a result of which the outflow of urine is blocked.
The pathogenesis of urate nephropathy is a subject of intense controversy. Despite the fact that monosodium urate crystals are found in the interstitial tissue of the kidneys of some patients with gout, they are absent in the kidneys of most patients. Conversely, urate deposition in the renal interstitium occurs in the absence of gout, although the clinical significance of these deposits is unclear. Factors that may contribute to the formation of urate deposits in the kidneys are unknown. In addition, in patients with gout, there was a close correlation between the development of renal pathology and hypertension. It is often unclear whether hypertension causes renal pathology or whether gouty changes in the kidneys cause hypertension.
Acute obstructive uropathy is a severe form of acute renal failure caused by the deposition of uric acid in the collecting ducts and ureters. However, renal failure is more closely correlated with uric acid excretion than with hyperuricemia. Most often, this condition occurs in individuals: 1) with pronounced overproduction of uric acid, especially against the background of leukemia or lymphoma, undergoing intensive chemotherapy; 2) with gout and a sharp increase in uric acid excretion; 3) (possibly) after heavy physical activity, with rhabdomyolysis or seizures. Aciduria promotes the formation of poorly soluble non-ionized uric acid and may therefore enhance talc precipitation in either of these conditions. At autopsy, uric acid precipitates are found in the lumen of the dilated proximal tubules. Treatment aimed at reducing the formation of uric acid, accelerating urination and increasing the proportion of the more soluble ionized form of uric acid (monosodium urate) leads to a reversal of the process.
Nephrolithiasis. In the United States, gout affects 10-25% of the population, while the number of people with uric acid stones is approximately 0.01%. The main factor contributing to the formation of uric acid stones is increased excretion of uric acid. Hyperuricaciduria may result from primary gout, an inborn error of metabolism leading to increased uric acid production, myeloproliferative disease, and other neoplastic processes. If uric acid excretion in urine exceeds 1100 mg/day, the incidence of stone formation reaches 50%. The formation of uric acid stones also correlates with increased serum urate concentration: at a level of 130 mg/l and above, the stone formation rate reaches approximately 50%. Other factors that contribute to the formation of uric acid stones include: 1) excessive acidification of urine; 2) concentrated urine; 3) (probably) a violation of the composition of urine, affecting the solubility of uric acid itself.
In patients with gout, calcium-containing stones are more often found; their frequency in gout reaches 1-3%, while in the general population it is only 0.1%. Although the mechanism of this association remains unclear, hyperuricemia and hyperuricaciduria are detected with a high frequency in patients with calcium stones. Uric acid crystals could serve as a nucleus for the formation of calcium stones.
Associated conditions. Patients with gout typically suffer from obesity, hypertriglyceridemia, and hypertension. Hypertriglyceridemia in primary gout is closely related to obesity or alcohol consumption, and not directly to hyperuricemia. The incidence of hypertension in individuals without gout correlates with age, sex, and obesity. When these factors are taken into account, it turns out that there is no direct relationship between hyperuricemia and hypertension. The increased incidence of diabetes is also likely to be related to factors such as age and obesity rather than directly to hyperuricemia. Finally, the increased incidence of atherosclerosis has been attributed to concurrent obesity, hypertension, diabetes, and hypertriglyceridemia.
Independent analysis of the role of these variables points to obesity as having the greatest importance. Hyperuricemia in obese individuals appears to be associated with both increased production and decreased excretion of uric acid. Chronic consumption of alcohol also leads to its overproduction and insufficient excretion.
Rheumatoid arthritis, systemic lupus erythematosus, and amyloidosis rarely coexist with gout. The reasons for this negative association are unknown.
Acute gout should be suspected in any person with sudden onset of monoarthritis, especially in the distal joints of the lower extremities. In all these cases, aspiration of synovial fluid is indicated. The definitive diagnosis of gout is based on the detection of monosodium urate crystals in leukocytes from the synovial fluid of the affected joint using polarizing light microscopy (309-3). Crystals have a typical needle-like shape and negative birefringence. They can be detected in the synovial fluid of more than 95% of patients with acute gouty arthritis. The inability to detect urate crystals in synovial fluid with a thorough search and compliance with the necessary conditions allows us to exclude the diagnosis. Intracellular talli have diagnostic value, but do not exclude the possibility of the simultaneous existence of another type of arthropathy.
Gout may be accompanied by infection or pseudogout (deposition of calcium pyrophosphate dihydrate). To rule out infection, one should Gram stain the synovial fluid and try to culture the flora. Calcium pyrophosphate dihydrate crystals exhibit weakly positive birefringence and are more rectangular than monosodium urate crystals. With polarization light microscopy, the crystals of these salts are easily distinguished. Puncture of the joint with suction of synovial fluid does not need to be repeated at subsequent procedures, unless a different diagnosis is suspected.
Aspiration of synovial fluid retains its diagnostic value even during asymptomatic intercritical periods. In more than 2/3 of aspirates from the first metatarsal joints of the digital phalanges in patients with asymptomatic gout, extracellular urate crystals can be detected. They are detected in less than 5% of people with hyperuricemia without gout.
Synovial fluid analysis is important in other ways as well. The total number of leukocytes in it can be 1-70 10 9 / l or more. Polymorphonuclear leukocytes predominate. As in other inflammatory fluids, clots of mucin are found in it. The concentrations of glucose and uric acid correspond to those in the serum.
In patients in whom synovial fluid cannot be obtained or intracellular talli cannot be detected, the diagnosis of gout can presumably be reasonably made if: 1) hyperuricemia; 2) the classic clinical syndrome and 3) a pronounced reaction to colchicine are identified. In the absence of kthalls or this highly informative triad, the diagnosis of gout becomes hypothetical. A sharp improvement in the condition in response to treatment with colchicine is a strong argument in favor of the diagnosis of gouty arthritis, but still not a pathognomonic sign.
309-3. Crystals of sodium urate monohydrate in joint aspirate.
Acute gouty arthritis should be differentiated from mono- and polyarthritis of other etiologies. Gout is a common initial manifestation, and many diseases are characterized by tenderness and swelling of the first toe. These include soft tissue infection, purulent arthritis, inflammation of the joint capsule on the outer side of the first finger, local trauma, rheumatoid arthritis, degenerative arthritis with acute inflammation, acute sarcoidosis, psoriatic arthritis, pseudogout, acute calcific tendinitis, palindromic rheumatism, Reiter's disease and sporotrichosis . Sometimes gout can be confused with cellulitis, gonorrhea, fibrosis of the plantar and calcaneal surfaces, hematoma and subacute bacterial endocarditis with embolization or suppuration. Gout, when other joints are involved, such as the knee, must be differentiated from acute rheumatic fever, serum sickness, hemarthrosis, and involvement of peripheral joints in ankylosing spondylitis or inflammation of the intestine.
Chronic gouty arthritis should be distinguished from rheumatoid arthritis, inflammatory osteoarthritis, psoriatic arthritis, enteropathic arthritis and peripheral arthritis accompanied by spondyloarthropathy. Chronic gout is supported by a history of spontaneous relief of monoarthritis, gouty deposits, typical changes on a radiograph, and hyperuricemia. Chronic gout may resemble other inflammatory arthropathies. Existing effective treatments justify the effort to confirm or rule out the diagnosis.
Pathophysiology of hyperuricemia. Classification. Hyperuricemia is a biochemical sign and serves as 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 is excreted 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 (Table 309-1). 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 the metabolic and renal types of hyperuricemia. With careful examination, both mechanisms for the development of hyperuricemia can be detected in a large number of patients with gout. In these cases, the condition is classified according to its predominant component: renal or metabolic. This classification applies primarily to those cases where gout or hyperuricemia are the main manifestations of the disease, that is, when gout is not secondary to another acquired disease and does not represent a subordinate symptom of a congenital defect that initially causes some other serious disease, not gout. Sometimes primary gout has a specific genetic basis. Secondary hyperuricemia or secondary gout are cases when they develop as symptoms of another disease or as a result of taking certain pharmacological agents.
Table 309-1. Classification of hyperuricemia and gout
| Metabolic defect | Inheritance |
|
| Metabolic (10%) |
||
| Primary |
||
| Molecular defect unknown | Not installed | Polygenic |
| Caused by defects in specific enzymes | ||
| Variants of PRPP synthetases with increased activity | Hyperproduction of PRPP and uric acid | X-linked |
| Partial hypoxanthine guanine phosphoribosyl transferase deficiency | Overproduction of uric acid, increased biosynthesis of purines de novo due to excess PRPP | |
| Secondary |
||
| Due to increased denovo purine biosynthesis | ||
| Insufficiency or absence of glucose-b-phosphatase | Overproduction and insufficient excretion of uric acid; Glycogen storage disease type I (von Gierke) | Autosomal recessive |
| Almost complete deficiency of hypoxanthine guanine phosphoribosyltransferase | Hyperproduction of uric acid; Lesch-Nyhan syndrome | X-linked |
| Due to accelerated turnover of nucleic acids | Overproduction of uric acid | |
| Renal (90%) |
||
| Primary | ||
| Secondary | ||
Overproduction of uric acid. Overproduction of uric acid, by definition, means excretion of more than 600 mg/day after following a purine-restricted diet for 5 days. Such cases appear to account for less than 10% of all cases of the disease. The patient has accelerated de novo synthesis of purines or increased circulation of these compounds. In order to imagine the basic mechanisms of the corresponding disorders, one should analyze the pattern of purine metabolism (309-4).
Purine nucleotides - adenylic, inosinic and guanic acids (AMP, IMP and GMP, respectively) - 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 from non-purine precursors and passing through a series of steps until the formation of IMP, which serves as a common intermediate purine nucleotide. Inosinic acid can be converted to either AMP or HMP. Once purine nucleotides are formed, they are used to synthesize nucleic acids, adenosine triphosphate (ATP), cyclic AMP, cyclic GMP, and some cofactors.
309-4. Scheme of purine metabolism.
1 - amidophosphoribosyltransferase, 2 - hypoxanthine guanine phosphoribosyltransferase, 3 - PRPP synthetase, 4 - adenine phosphoribosyltransferase, 5 - adenosine deaminase, 6 - purine nucleoside phosphorylase, 7 - 5-nucleotidase, 8 - xanthine oxidase.
Various purine compounds are broken down into purine nucleotide monophosphates. Guanic acid is converted through guanosine, guanine and xanthine to uric acid, IMP breaks down through inosine, hypoxanthine and xanthine to the same uric acid, and AMP can be deaminated to IMP and further catabolized through inosine to uric acid or converted to inosine in an alternative way with the intermediate formation of adenosine .
Despite the fact that the regulation of purine metabolism is quite complex, the main determinant of the rate of uric acid synthesis in humans appears to be the intracellular concentration of 5-phosphoribosyl-1-pyrophosphate (PRPP). As a rule, when the level of PRPP in the cell increases, the synthesis of uric acid increases, and when its level decreases, it decreases. Despite some exceptions, in most cases this is the case.
Excess uric acid production in a small number of adult patients is a primary or secondary manifestation of an inborn error of metabolism. Hyperuricemia and gout may be the primary manifestation of partial deficiency of hypoxanthine guanine phosphoribosyltransferase (reaction 2 of 309-4) or increased activity of PRPP synthetase (reaction 3 of 309-4). In Lesch-Nyhan syndrome, almost complete deficiency of hypoxanthine guanine phosphoribosyltransferase causes secondary hyperuricemia. These serious congenital anomalies are discussed in more detail below.
For the mentioned inborn errors of metabolism (hypoxanthine guanine phosphoribosyltransferase deficiency and excess activity of PRPP synthetase), less than 15% of all cases of primary hyperuricemia due to increased 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 due to many causes. In some patients, increased excretion of uric acid is due, as in primary gout, to accelerated denovo purine biosynthesis. In patients with glucose-6-phosphatase deficiency (type I glycogen storage disease), the production of uric acid is constantly increased, as well as de novo biosynthesis of purines is accelerated (Chapter 313). Overproduction of uric acid with this enzyme abnormality is due to a number of mechanisms. Accelerated de novo purine synthesis may in part result from accelerated PRPP synthesis. In addition, the accelerated breakdown of purine nucleotides contributes to increased 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 continuous correction of the hypoglycemia typical of this disease.
In most patients with secondary hyperuricemia due to excess production of uric acid, the main disorder is obviously an acceleration of the turnover of nucleic acids. Increased bone marrow activity or shortened life cycle of cells of other tissues, accompanied by accelerated turnover 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 carcinoma. Accelerated turnover of nucleic acids, in turn, leads to hyperuricemia, hyperuricaciduria and a compensatory increase in the rate of de novo purine biosynthesis.
Reduced excretion. In a large number of gout patients, this rate of uric acid excretion is achieved only when the plasma urate level is 10-20 mg/l above normal (309-5). This pathology is most pronounced in patients with normal uric acid production and is absent in most cases of its overproduction.
Urate excretion depends on glomerular filtration, tubular reabsorption and secretion. Uric acid is apparently completely filtered in the glomerulus and reabsorbed in the proximal tubule (i.e., undergoes presecretory reabsorption). In the underlying segments of the proximal tubules it is secreted, and in the second site of reabsorption - in the distal part of the proximal tubule - it is once again subject to partial reabsorption (postsecretory reabsorption). Although some of it may be reabsorbed in both the ascending limb of the loop of Henle and the collecting duct, these two sites are considered less important from a quantitative point of view. Attempts to more accurately elucidate the localization and nature of these latter areas and to quantify their role in the transport of uric acid in a healthy or sick person, as a rule, were unsuccessful.
Theoretically, impaired renal excretion of uric acid in most patients with gout could be caused by: 1) a decrease in filtration rate; 2) increased reabsorption or 3) a decrease in the rate of secretion. There is no definitive evidence for the role of any of these mechanisms as a primary defect; it is likely that all three factors are present in patients with gout.
Many cases of secondary hyperuricemia and gout can be considered a result of decreased renal excretion of uric acid. A decrease in glomerular filtration rate leads to a decrease in the filtration load of uric acid and, thereby, to hyperuricemia; This is why hyperuricemia develops in patients with kidney pathology. In some kidney diseases (polycystic disease and lead nephropathy), other factors, such as decreased secretion of uric acid, have been postulated to play a role. Gout rarely complicates hyperuricemia secondary to renal disease.
One of the most important causes of secondary hyperuricemia is treatment with diuretics. The decrease in circulating plasma volume they cause leads to increased tubular reabsorption of uric acid, as well as to a decrease in its filtration. In hyperuricemia associated with diuretic use, a decrease in uric acid secretion may also be important. A number of other drugs also cause hyperuricemia through unknown renal mechanisms; These drugs include acetylsalicylic acid (aspirin) in low doses, pyrazinamide, nicotinic acid, ethambutol and ethanol.
309-5. Rates of uric acid excretion at different plasma urate levels in individuals without gout (black symbols) and in individuals with gout (open symbols).
Large symbols indicate average values, small symbols indicate individual data for several average values (the degree of dispersion within groups). Studies were conducted under basal conditions, after RNA ingestion, and after lithium urate administration (by: Wyngaarden. Reproduced with permission from AcademicPress).
It is believed that impaired renal excretion of uric acid is an important mechanism for hyperuricemia, which accompanies a number of pathological conditions. In hyperuricemia associated with adrenal insufficiency and nephrogenic diabetes insipidus, a decrease in circulating plasma volume may play a role. In a number of situations, hyperuricemia is considered to be the result of competitive inhibition of uric acid secretion by excess organic acids, which are secreted, apparently, using the same mechanisms of the renal tubules as uric acid. Examples include fasting (ketosis and free fatty acids), alcoholic ketosis, diabetic ketoacidosis, maple syrup disease, and lactic acidosis of any cause. In conditions such as hyperpara- and hypoparathyroidism, pseudohypoparathyroidism and hypothyroidism, hyperuricemia may also have a renal basis, but the mechanism of occurrence of this symptom is unclear.
Pathogenesis of acute gouty arthritis. The reasons that cause the initial crystallization of monosodium urate in the joint after a period of asymptomatic hyperuricemia for approximately 30 years are not fully understood. Persistent hyperuricemia eventually leads to the formation of microdeposits in the squamous cells of the synovium and, probably, to the accumulation of monosodium urate in cartilage on proteoglycans with a high affinity for it. For one reason or another, apparently including trauma with the destruction of microdeposits and acceleration of the turnover of cartilage proteoglycans, urate crystals are occasionally released into the synovial fluid. Other factors, such as low joint temperature or inadequate reabsorption of water and urate from synovial fluid, can also accelerate its deposition.
When a sufficient number of kthalls are formed in the joint cavity, acute arthritis is provoked by a number of factors, including: 1) phagocytosis of kthalls by leukocytes with the rapid release of chemotaxis protein from these cells; 2) activation of the kallikrein system; 3) activation of complement with the subsequent formation of its chemotactic components: 4 ) the final stage of cleavage of lysosomes of leukocytes by urate ctalls, which is accompanied by a violation of the integrity of these cells and the release of lysosomal products into the synovial fluid. While some progress has been made in understanding the pathogenesis of acute gouty arthritis, questions regarding the factors determining the spontaneous cessation of acute gouty arthritis and the effect of colchicine still await answers.
Treatment. Treatment for gout involves: 1) whenever possible, rapid and careful relief of acute arthritis; 2) prevention of relapse of acute gouty arthritis; 3) prevention or regression of complications of the disease caused by the deposition of monosodium urate crystals in the joints, kidneys and other tissues; 4) prevention or regression of associated symptoms such as obesity, hypertriglyceridemia or hypertension; 5) prevention of the formation of uric acid kidney stones.
Treatment for acute gout. For acute gouty arthritis, anti-inflammatory treatment is carried out. The most commonly used 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 treatment is continued until: 1) relief of the patient’s condition occurs; 2) adverse reactions from the gastrointestinal tract appear or 3) the total dose of the drug does not reach 6 mg due to lack of effect. Colchicine is most effective if treatment is started soon after symptoms appear. In the first 12 hours of treatment, the condition improves significantly in more than 75% of patients. However, in 80% of patients, the drug causes adverse reactions from the gastrointestinal tract, which may appear before clinical improvement or simultaneously with it. When administered orally, the maximum plasma level of colchicine is reached after approximately 2 hours. Therefore, it can be assumed that its administration at 1.0 mg every 2 hours is less likely to cause the accumulation of a toxic dose before the therapeutic effect occurs. 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 administration, 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, repeat the administration of 1 mg twice with an interval of 6 hours. When administering colchicine intravenously, special precautions should be taken. It has an irritating effect and, if it enters the tissue surrounding the vessel, can cause severe pain and necrosis. It is important to remember that the intravenous route of administration requires care 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. Both oral and parenteral administration of colchicine can suppress 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 pathology of the liver, bone marrow or kidneys, 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 prescribed to patients with neutropenia.
Other anti-inflammatory drugs are also effective for acute gouty arthritis, including indomethacin, phenylbutazone, naproxen, and fenoprofen.
Indomethacin can be prescribed for oral administration at a dose of 75 mg, after which the patient should receive 50 mg every 6 hours; 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 disturbances, sodium retention, and central nervous system symptoms. Although these doses may cause side effects in up to 60% of patients, indomethacin is generally better tolerated than colchicine and is probably the drug of choice for acute gouty arthritis. To increase the effectiveness of treatment and reduce the manifestations of pathology, the patient should be warned that taking anti-inflammatory drugs should be started at the first sensation of pain. Drugs that stimulate uric acid excretion and allopurinol are ineffective in acute gout.
In acute gout, especially when colchicine and non-steroidal anti-inflammatory drugs are contraindicated or ineffective, systemic or local (i.e. intra-articular) administration of glucocorticoids is beneficial. For systemic administration, whether oral or intravenous, moderate doses should be given over several days as glucocorticoid concentrations decrease rapidly and their effect ceases. Intra-articular administration of a long-acting steroid drug (for example, triamsinolone hexacetonide at a dose of 15-30 mg) can relieve monoarthritis or bursitis within 24-36 hours. This treatment is especially appropriate if it is impossible to use a standard drug regimen.
Prevention. After relief of an acute ptup, a number of measures are used to reduce the likelihood of relapse. These include: 1) daily prophylactic use of colchicine or indomethacin; 2) controlled weight loss in obese patients; 3) elimination of known triggers, such as large amounts of alcohol or foods rich in purines; 4) use of antihyperuricemic drugs.
Daily intake of small doses of colchicine effectively prevents the development of subsequent acute attacks. Colchicine in a daily dose of 1-2 mg is effective in almost 1/4 of patients with gout and is ineffective in approximately 5% of patients. In addition, this treatment program is safe and has virtually no side effects. However, if the serum urate concentration is not maintained within normal limits, the patient will only be spared from acute arthritis, and not from other manifestations of gout. Maintenance treatment with colchicine is especially indicated during the first 2 years after starting antihyperuricemic drugs.
Prevention or stimulation of the reverse development of gouty deposits of monosubstituted sodium urate in tissues. Antihyperuricemic drugs are quite effective in reducing serum urate concentrations, so they should be used in patients with: 1) one or more episodes of acute gouty arthritis; 2) one or more gouty deposits; 3) uric acid nephrolithiasis. The purpose of their use is to maintain serum urate levels below 70 mg/l; i.e., at 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 decreasing the production of uric acid. Antihyperuricemic agents generally do not have anti-inflammatory effects. Uricosuric drugs reduce serum urate levels by increasing its renal excretion. Although a large number of substances have this property, the most effective ones used in the United States are probenecid and sulfinpyrazone. Probenecid is usually prescribed at an initial dose of 250 mg twice daily. Over several weeks, it is increased to ensure a significant reduction 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. Major side effects include hypersensitivity, skin rash and gastrointestinal symptoms. Despite rare cases of toxicity, these adverse reactions force almost 1/3 of patients to stop treatment.
Sulfinpyrazone is a metabolite of phenylbutazone that lacks anti-inflammatory effects. Treatment with it begins at a dose of 50 mg twice a day, gradually increasing the dose to a maintenance level of 300-400 mg/day 3-4 times. The maximum 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, treatment failure may be due to a violation of the drug regimen, concomitant use of salicylates, or impaired renal function. Acetylsalicylic acid (aspirin) at any dose blocks the uricosuric effect of probenecid and sulfinpyrazone. They become less effective when creatinine clearance is below 80 ml/min and cease action at creatinine clearance of 30 ml/min.
With a negative urate balance caused by treatment with uricosuric drugs, the serum urate concentration decreases and urinary excretion of uric acid exceeds the baseline 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 its original values. A transient increase in its excretion, usually lasting only a few days, can cause the formation of kidney stones in 1/10 of the patients. In order to avoid this complication, uricosuric drugs should be started with small doses, gradually increasing them. Maintaining increased urinary output with adequate hydration and alkalinization of the urine by oral administration of sodium bicarbonate alone or with acetazolamide reduces the likelihood of stone formation. The ideal candidate for treatment with uricosurics is a patient under 60 years of age, on a regular diet, with normal renal function and uric acid excretion of less than 700 mg/day, and with no history of renal stones.
Hyperuricemia can also be corrected with allopurinol, which reduces the synthesis of uric acid. It inhibits xanthine oxidase (reaction 8 to 309-4), which catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid. Although allopurinol has a half-life of only 2-3 hours in the body, it is converted primarily to oxypurinol, which is an equally effective xanthine oxidase inhibitor 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 allopurinol's main metabolite, it can be administered once daily. Because oxypurinol is excreted primarily in the urine, its half-life is prolonged in renal failure. In this regard, in case of 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 often develop in renal failure. Only in 5% of patients their severity forces them to stop treatment with allopurinol. When prescribing it, drug-drug interactions should be taken into account, as it increases the half-life of mercaptopurine and azathioprine and increases the toxicity of cyclophosphamide.
Allopurinol is preferred to uricosuric drugs for: 1) increased (more than 700 mg/day when following a general diet) excretion of uric acid in the urine; 2) impaired renal function with creatinine clearance less than 80 ml/min; 3) gouty deposits in the joints, regardless of kidney function; 4) uric acid nephrolithiasis; 6) gout, which is not affected by uricosuric drugs due to their ineffectiveness or intolerance. In rare cases of ineffectiveness of each drug used separately, allopurinol can be used simultaneously with any uricosuric agent. This does not require a change in drug dose and is usually accompanied by a decrease in serum urate levels.
No matter how rapid and pronounced the decrease in serum urate levels is, acute gouty arthritis may develop during treatment. In other words, starting treatment with any antihyperuricemic drug can provoke acute pt. 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 gouty symptoms may occur. Therefore, before starting antihyperuricemic drugs, it is advisable to start prophylactic colchicine and continue it until the serum urate level is within the normal range for at least a year or until all gouty deposits have 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 their dietary intake of purines.
Prevention of acute uric acid nephropathy and treatment of patients. In case of acute uric acid nephropathy, intensive treatment must be started immediately. Initially, urine output should be increased with large fluid loads and diuretics, such as furosemide. The urine is alkalinized so that uric acid is converted into the more soluble monosodium urate. Alkalinization is achieved using sodium bicarbonate - alone or in combination with acetazolamide. Allopurinol should also be administered to reduce the formation of uric acid. Its initial dose in these cases is 8 mg/kg per day once. After 3-4 days, if renal failure persists, the dose is reduced to 100-200 mg/day. For uric acid kidney stones, treatment is the same as for uric acid nephropathy. In most cases, it is sufficient to combine allopurinol with large amounts of fluid intake only.
Management of patients with hyperuricemia. Examination of patients with hyperuricemia is aimed at: 1) determining its cause, which may indicate another serious disease; 2) assessing damage to tissues and organs and its degree; 3) identification of associated disorders. In practice, all these problems are solved simultaneously, since the decision regarding the meaning of hyperuricemia and treatment depends on the answer to all these questions.
The most important results for hyperuricemia are urine test results for uric acid. If there is a history of urolithiasis, a survey of the abdominal cavity and intravenous pyelography are indicated. If kidney stones are detected, testing for uric acid and other components may be helpful. In case of joint pathology, it is advisable to examine the synovial fluid and take x-rays of the joints. If there is a history of lead exposure, urinary excretion following a calcium-EDTA infusion may be necessary to diagnose gout associated with lead poisoning. If increased uric acid production is suspected, 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 does not have a clear answer. Typically, no treatment is required unless: 1) the patient has no 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. Hypoxanthine guanine phosphoribosyltransferase deficiency. Hypoxanthine guanine phosphoribosyltransferase catalyzes the conversion of hypoxanthine to inosinic acid and guanine to guanosine (reaction 2 to 309-4). PRPP serves as a phosphoribosyl donor. Hypoxanthine guanyl phosphoribosyltransferase deficiency leads to a decrease in the consumption of PRPP, which accumulates in higher than normal concentrations. Excess PRPP accelerates denovo purine biosynthesis and, therefore, increases uric acid production.
Lesch-Nyhan syndrome is an X-linked disorder. A characteristic biochemical disorder with it is a pronounced deficiency of hypoxanthine guanine phosphoribosyltransferase (reaction 2 to 309-4). Patients experience hyperuricemia and excessive overproduction of uric acid. In addition, they develop peculiar neurological disorders, characterized by self-mutilation, choreoathetosis, spastic muscle condition, as well as delayed growth and mental development. The incidence of this disease is estimated at 1:100,000 newborns.
Approximately 0.5-1.0% of adult patients with gout with excess production of uric acid have a partial deficiency of hypoxanthine guanine phosphoribosyltransferase. Typically, their gouty arthritis manifests itself at a young age (15-30 years), the frequency of uric acid nephrolithiasis is high (75%), sometimes some neurological symptoms are combined, including dysarthria, hyperreflexia, impaired coordination and/or mental retardation. The disease is inherited as an X-linked trait, so it is transmitted to men from female carriers.
The enzyme whose deficiency causes this disease (hypoxanthine guanine phosphoribosyltransferase) is of significant interest to geneticists. With the possible exception of the globin gene family, the hypoxanthine guanine phosphoribosyltransferase locus is the most studied single gene in humans.
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 hypoxanthine guanine phosphoribosyltransferase (Table 309-2). In each of them, the replacement of one amino acid leads to either a loss of the catalytic properties of the protein or a decrease in the constant concentration of the enzyme due to a decrease in synthesis or acceleration of the breakdown of the mutant protein.
The DNA sequence complementary to the messenger RNA (mRNA) that encodes gyloxanthine guanine phosphoribosyltransferase has been cloned and deciphered. As a molecular probe, this sequence was used to identify carrier status in women from group ka, in whom carrier status could not be detected by conventional methods. The human gene was transferred into a mouse using a bone marrow transplant infected with a vectored retrovirus. The expression of human hypoxanthine guanine phosphoribosyltransferase in the mouse treated in this way has been determined with certainty. Recently, a transgenic line of mice has also been obtained in which the human enzyme is expressed in the same tissues as in humans.
The accompanying biochemical abnormalities that cause pronounced neurological manifestations of Lesch-Nyhan syndrome have not been sufficiently deciphered. Post-mortem examination of the patients' brains revealed signs of a specific defect in the central dopaminergic pathways, especially in the basal ganglia and nucleus accumbens. Relevant in vivo data were obtained using positron emission tomography (PET) in patients with hypoxanthine guanine phosphoribosyltransferase deficiency. In the majority of patients examined by this method, a disturbance in the metabolism of 2-fluoro-deoxyglucose in the caudate nucleus was detected. The relationship between the pathology of the dopaminergic nervous system and disorders of purine metabolism remains unclear.
Hyperuricemia caused by partial or complete deficiency of hypoxanthine guanine phosphoribosyltransferase can be successfully treated with the xanthine oxidase inhibitor allopurinol. In this case, 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 associated with Lesch-Nyhan syndrome.
Variants of PRPP synthetase. Several families were identified whose members had increased activity of the enzyme PRPP synthetase (reaction 3 to 309-4). All three known types of mutant enzymes have increased activity, which leads to an increase in the intracellular concentration of PRPP, acceleration of purine biosynthesis and increased excretion of uric acid. This disease is also inherited as an X-linked trait. 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 often form. In several children, increased activity of PRPP synthetase was combined with nerve deafness.
Other disorders of purine metabolism. Adenine phosphoribosyltransferase deficiency. Adenine phosphoribosyltransferase catalyzes the conversion of adenine to AMP (reaction 4 to 309-4). The first person who was found to be deficient in this enzyme was heterozygous for this defect and had no clinical symptoms. It was then found that heterozygosity for this trait is quite widespread, probably with a frequency of 1:100. Currently, 11 homozygotes for deficiency of this enzyme have been identified, whose kidney stones consisted of 2,8-dioxyadenine. Because of its chemical similarity, 2,8-dihydroxyadenine is easily confused with uric acid, so these patients were initially misdiagnosed as uric acid nephrolithiasis.
Table 309-2. Structural and functional disorders in mutant forms of human hypoxanthine guanine phosphoribosyltransferase
| Mutant enzyme | Clinical manifestations | Functional disorders |
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| amino acid replacement | position | intracellular concentration | maximum speed | Michaelis constant |
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| hypoxanthine | |||||||
| GFRT Toronto | Reduced | Within normal limits | Within normal limits | Within normal limits |
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| GFRT London | Increased 5 times | ||||||
| GFRT Ann Arbor | Nephrolithiasis | Unknown | Within normal limits | ||||
| GFRT Munich | Within normal limits | Reduced by 20 times | Increased 100 times | ||||
| GFRT Kinston | Lesch-Nyhan syndrome | Within normal limits | Increased 200 times | Increased 200 times |
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Note. PRPP stands for 5-phosphoribosyl-1-pyrophosphate, Arg for arginine, Gly for glycine, Ser for serine. Leu - leucine, Asn - asparagine. Asp-aspartic acid,®-replaced (according to Wilson et al.).
Adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency in Chapter 256.
Xanthine oxidase deficiency. Xanthine oxidase catalyzes the oxidation of hypoxanthine to xanthine, xanthine to uric acid and adenine to 2,8-dioxyadenine (reaction 8 to 309-4). Xanthinuria, the first congenital disorder of purine metabolism deciphered at the enzymatic level, is caused by a deficiency of xanthine oxidase. As a result, in patients with xanthinuria, hypouricemia and hypouricaciduria are detected, as well as increased urinary excretion of oxypurines - hypoxanthine and xanthine. Half of the patients do not complain, and in 1/3 xanthine stones form in the urinary tract. Several patients developed myopathy, and three developed polyarthritis, which could be a manifestation of ctallium-induced synovitis. In the development of each of the symptoms, great importance is attached to the precipitation of xanthine.
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 main defect was postulated to be a deficiency of the molybdate cofactor necessary for the functioning of both enzymes, treatment with ammonium molybdate was ineffective. A patient who was completely on parenteral nutrition developed a disease simulating combined deficiency of xanthine oxidase and sulfate oxidase. After treatment with ammonium molybdate, enzyme function was 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 (IPA). This reaction is an integral part of the purine nucleotide cycle and appears to be important for maintaining the processes of energy production and utilization in skeletal muscle.
Deficiency of this enzyme is detected only in skeletal muscle. Most patients experience myalgia, muscle spasms and a feeling of fatigue during physical activity. 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 for metabolic myopathy. Creatinine kinase levels are elevated in less than half of the cases. Electromyographic studies and conventional histology of muscle biopsies can reveal nonspecific changes. Presumably, adenylate deaminase deficiency can be diagnosed based on the results of a performance test of the ischemic forearm. In patients with deficiency of this enzyme, ammonia production is reduced because the deamination of AMP is blocked. The diagnosis should be confirmed by direct determination of AMP deaminase activity in a skeletal muscle biopsy, since. reduced 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.
Adenylsuccinase deficiency. Patients with adenylsuccinase deficiency are retarded in mental development and often suffer from autism. Moreover, they suffer seizures, their psychomotor development is delayed, and a number of movement disorders are noted. Urinary excretion of succinylaminoimidazole carboxamide riboside and succinyladenosine is increased. The diagnosis is established when partial or complete absence of enzyme activity is detected 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.
The invention relates to the field of medicine, namely to the physical analysis of liquid biological materials, and can be used to diagnose disorders 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 coverslip. Keeping the environmental conditions constant, the preparation is kept until pronounced typical structures appear on the slide. The drug is examined by examining the entire surface. If single typical crystals of uric acid and in small quantities round yellow non-birefringent crystals, birefringent hexagonal or rosette-shaped small crystals, small skeletal dendrites are simultaneously observed on a glass slide, then the absence of a disorder in purine metabolism is diagnosed. If a large number of atypical uric acid crystals of various shapes, birefringent needle-shaped crystals, atypical birefringent and non-birefringent crystals, as well as large numbers of cholesterol crystals and large skeletal dendrites in combination or separately are simultaneously observed on a glass slide, then a disorder of purine metabolism is diagnosed. . The technical result is to increase the sensitivity and accuracy of diagnosis.
The invention relates to medicine, in particular to the physical analysis of liquid biological materials, and can be used as additional test for rapid diagnosis of kidney disease in children in the early stages and rapid assessment of the effectiveness of therapy.
There is a known method for diagnosing pathology of kidney function, including in children, according to which a general examination of urine is carried out (Kamyshev V.S. \Clinical laboratory tests from A to Z, their diagnostic profiles\, reference manual, Minsk: Belaruskaya Navuka, 1999, p. .229).
The disadvantage of this known method is that it allows one to identify only the fact of the presence of impaired renal function and does not allow one to determine the presence of a specific disease, in particular a disorder of purine metabolism.
Thus, the known method for diagnosing pathology of renal function does not ensure the achievement of a technical result, which consists in the possibility of diagnosing disorders of purine metabolism.
The closest to the proposed method is a method for diagnosing disorders of purine metabolism, including in children, according to which a morphological examination of urine is carried out, namely: the level of uric acid in the urine is determined and, if it deviates from the norm, a disorder of purine metabolism is diagnosed. (Kamyshev V.S. \Clinical laboratory tests from A to Z and their diagnostic profiles\, reference manual, Minsk: Belaruskaya Navuka, 1999, p. 233-235).
The disadvantage of this known method is, first of all, that it determines only the amount of uric acid in the urine and does not allow determining the form of uric acid, namely, identifying its presence atypical shape, which is characterized by the presence in the urine of sodium urates - monosodium salt of uric acid. The latter is a characteristic sign of a disorder of purine metabolism. This reduces the reliability of diagnosis. The presence of certain normal limits for the quantitative content of uric acid in urine makes it possible to state 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 diagnosing the pathology at earlier stages, when the disease has not yet developed, and preventing its chronicity. For the same reason, the known method makes it possible to evaluate the effectiveness of therapy only when there is 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 body, does not allow the diagnosis to take into account directly individual characteristics specific patient, which also reduces the reliability of diagnostic results. In addition, the known method is complex to implement and requires highly qualified personnel to obtain reliable diagnostics. The dependence of diagnostic results on the personal qualities of the laboratory assistant reduces their reliability.
Thus, the known method for diagnosing disorders of purine metabolism, including in children, identified as a result of a patent search, when implemented, does not allow achieving the technical result of increasing the reliability of diagnosis, increasing the sensitivity of the method, or simplifying the diagnostic method.
The present invention solves the problem of creating a method for diagnosing disorders of purine metabolism in children, the implementation of which makes it possible to achieve a technical result consisting in increasing the reliability of diagnosis, increasing the sensitivity of the method, and simplifying the diagnostic method.
The essence of the invention is that in the method for diagnosing disorders of purine metabolism in children, including a morphological examination of urine, analysis of the results and a statement of the absence or presence of a disorder 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 environmental conditions constant, the preparation 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 drug, the results of the examination are recorded, and if single typical crystals of uric acid in small quantities are simultaneously observed on the glass slide: round yellow non-birefringent crystals, birefringent hexagonal or rosette-shaped small crystals, small skeletal dendrites, then the absence of a violation of purine metabolism is diagnosed if On a glass slide, large quantities of uric acid crystals of various shapes, birefringent needle-shaped crystals, atypical birefringent and non-birefringent crystals, as well as large quantities of cholesterol crystals and large skeletal dendrites in combination or separately are simultaneously observed, then the presence of a disorder of purine metabolism is diagnosed.
The technical result is achieved as follows. Many liquid biological media of the human body are capable of crystallizing and, under certain conditions, transforming into an intermediate liquid crystalline state. In the liquid crystalline state, the medium, while maintaining fluidity, displays specific crystalline 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 the components. The composition of biofluids adequately reflects the physiological state of the human body, as well as its functional usefulness individual organs and systems. For example, regulatory mechanisms and pharmacological factors influence the quantitative content of protein and calcium salts in the urine, the ratio of saturated and unsaturated lipids in the blood serum, the nature of aggregation of the lipid complex of bile, the amount of phospholipids, derivatives of cholesterol and its esters that exhibit liquid crystalline properties. These changes at the fine molecular level are manifested, in particular, in the features of aggregation of biological fluids at the microstructure level. The morphology of the textures of the liquid crystalline phase correlates with the state of the body and changes in the presence of pathology, which makes it possible to observe this in dynamics in a bright field and in polarized light with conventional optical magnifications (AS USSR No. 1209168, A 61 V 10/00, 07.02. 86; A.S. USSR No. 1486932, G 01 N 33/92, 15.06.89; A.S. USSR No. 1723527, G 01 N 33/92, 30.03.92; 48, 33/68, 09/10/2001; RF patent No. 2170432, G 01 N 33/48, 33/68, 07/10/2001).
In the proposed method, to diagnose purine metabolism disorders in children, a morphological study of the biological environment, namely urine, is used. Biological fluid - urine - is a product of the kidneys and its composition adequately reflects them functional state. Due to the fact that urine is capable of crystallizing, passing through an intermediate liquid crystalline state, it is possible to morphologically study urine by studying the texture of the liquid crystalline 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, a drug is prepared from urine for research, for which a drop of urine is applied to a glass slide. Due to the fact that the preparation remains open, it is possible for the liquid medium to evaporate from it and form a crystalline pattern - texture - on the glass slide. Maintaining constant environmental conditions during aging of the drug ensures the reliability of the research results. The formation of pronounced typical base textures on the glass slide means the end of the aggregation process. This makes it impractical to further increase the exposure time of the drug and determines the start time of texture research.
After this, the preparation is examined by examining the entire surface of the sample in a bright field, and then a polarization optical examination of the preparation is performed, and the inspection results are recorded. Since the surface of the preparation is examined twice: in a bright field and in polarized light, this makes it possible to reliably identify texture crystals. This is explained by the fact that, 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. Sodium urate crystals have a common needle-like shape, but unlike others, they are birefringent in polarized light.
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, round yellow non-birefringent crystals in small quantities, birefringent hexagonal or rosette-shaped small crystals, small skeletal dendrites are simultaneously observed, then the absence of a purine disorder is diagnosed exchange. This is explained as follows. A sign of a disorder in 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 the 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 small crystals listed above of the test drop of urine in combination with single typical crystals of uric acid, with the simultaneous absence of crystals indicating the presence of sodium urate in the test drop of urine, indicates compliance with the norm of the qualitative and quantitative composition of the test urine. Moreover, the presence of precisely small birefringent hexagonal or rosette-shaped crystals and small crystals of skeletal dendrites indicates the presence of calcium oxalates and crystals of protein-lipid-salt complexes in a small amount in the test drop of urine. This is additional information confirming the absence of renal dysfunction and increases the reliability of diagnosis using the proposed method.
If a large number of atypical uric acid crystals of various shapes, birefringent needle-shaped crystals, atypical birefringent and non-birefringent crystals, as well as cholesterol crystals and large skeletal dendrites in combination or separately are observed on a glass slide, then a disorder of purine metabolism is diagnosed.
The presence of atypical uric acid crystals of various shapes indicates a qualitative change in the composition of urine, which is not typical for the composition of normal urine. 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 of both atypical uric acid crystals and sodium urate crystals - birefringent needle-shaped crystals - makes it possible to reliably diagnose a disorder of purine metabolism.
The presence in the texture of the test drop of urine, in combination or separately, of cholesterol crystals and large skeletal dendrites, provides additional supporting information for the diagnosis of purine metabolism disorders, 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 cell membranes of the kidneys, and the presence of large skeletal dendrites in the urine indicates the presence of protein-lipid-salt complexes in large quantities 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 liquid under study - urine - gives us a complete picture of its qualitative and quantitative composition, and inspection of the texture of the test drop of urine on a glass 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 full information about the morphology of the examined drop of urine, both in terms of qualitative and quantitative content, which makes it possible to increase the reliability of diagnosing disorders of purine metabolism. In this case, a highly qualified laboratory technician 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. This 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 the urine depends on the acidity of the urine. In a slightly acidic environment with a urine pH below 5.75, sodium urate in the urine is represented by uric acid. At a urine pH of 5.75, uric acid and its monosodium salt are equimolar. When urine pH is above 5.75, i.e. When the pH of the environment changes to the alkaline side, sodium urates become the dominant form of uric acid. This once again confirms that the presence and quantity of sodium urate crystals in the test drop of urine can be used to judge the acidity of urine, which is reliable information for diagnosing disorders of purine metabolism and increases the reliability of diagnosis.
The proposed method, unlike the prototype, makes it possible to diagnose the disease at an early stage. This is explained by the fact that in the prototype method there is a tolerance for the normal level of uric acid in the urine. As a result, this does not allow us to take into account that in the initial stage of a disorder of purine metabolism, the acidity of urine is heterogeneous, and both uric acid in a typical form and crystals of sodium urate may be present in the urine at the same time. The claimed method, in contrast to the prototype, allows one to obtain a complete true picture of the morphological composition of urine at a given 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 character of textures (crystalline pattern) as an evaluation criterion, which corresponds to a very specific composition of the studied biological fluid, 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 body of a particular patient, which increases the information content and reliability of the method.
In addition, the proposed method for diagnosing disorders of purine metabolism in children, in comparison with the prototype, achieves 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 disorders 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 test drop of urine when the qualitative or quantitative composition of urine changes or when they change together 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 point in time, i.e. combined with the increased sensitivity of the proposed method.
Thus, the claimed method for disrupting purine metabolism in children, when implemented, ensures the achievement of a technical result consisting in increasing the reliability of diagnosis, increasing the sensitivity of the method, simplifying the diagnostic method, and also allows, in comparison with the prototype, to obtain an additional technical result consisting in the possibility of using the claimed a method for rapid assessment of the effectiveness of therapy used in the treatment of purine metabolism disorders.
A method for diagnosing purine metabolism disorders in children is carried out 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. Why is a drop of urine applied to the surface of a glass slide? Then, keeping the environmental conditions constant, the preparation is kept until pronounced typical textures appear on the slide. After that, the preparation is examined by examining the entire surface of the sample in a bright field, and then a polarization optical examination of the preparation is performed. The results of the inspection are recorded. Moreover, if single typical crystals of uric acid are simultaneously observed on a glass slide in small quantities: round yellow non-birefringent crystals, birefringent hexagonal or rosette-shaped small crystals, small skeletal dendrites, then the absence of a disorder in purine metabolism is diagnosed. If a large number of atypical uric acid crystals of various shapes, birefringent needle-shaped crystals, atypical birefringent and non-birefringent crystals, as well as large numbers of cholesterol crystals and large skeletal dendrites in combination or separately are simultaneously observed on a glass slide, then a disorder of purine metabolism is diagnosed. .
In all examples of the method, pre-treated glass slides were taken to prepare preparations from urine. Pay attention to the quality of the glass slide processing to avoid artifacts during 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, appears in the peripheral areas, so viewing began from the peripheral areas. Then the central areas were examined.
An insignificant (or small) number of crystals was taken when crystals occupy no more than 20% of the area of the field of view at 150x magnification and in no more than 2 out of five...seven fields of view.
The small size of crystals was taken to be the case when the crystal is located in 1/4 of the field of view and occupies less than 0.1 of it.
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 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 field of view.
All detected features were recorded. Microscopes of the BIOLAM (with polarized filters), POLAM, and MBI series can be used for research. Example
1. Patient A., 6 years old, examination. Express diagnostics were previously carried out in accordance with the stated method.
When examining an open drop of urine in a bright field and in polarized light, the following were simultaneously observed on a glass slide: single crystals of uric acid of a typical shape, non-birefringent, round yellow non-birefringent crystals mainly along the edge of the drop, birefringent hexagonal or rosette-shaped small crystals in small quantities, small non-birefringent skeletal dendrites along a small amount to the center of the drop.
Diagnosis: no disorders of purine metabolism.
2. Patient D., 7 years old, examination. Express diagnostics were previously carried out in accordance with the stated method.
When examining an open drop of urine in a bright field and in polarized light, atypical crystals of uric acid, birefringent needle-shaped crystals of sodium urate, atypical birefringent and non-birefringent crystals, and also a large number of cholesterol crystals in combination were observed on the glass slide simultaneously throughout the surface of the drop. and large skeletal dendrites.
Diagnosis: disorders of purine metabolism.
In both cases, the diagnosis was confirmed by standard laboratory tests.
A method for diagnosing disorders of purine metabolism in children, including a morphological examination of urine, analysis of the results and a statement of the absence or presence of a disorder 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, maintaining the environmental conditions constant, the preparation 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 a polarization optical examination of the preparation is performed, the results of the examination are recorded, and if single typical crystals of uric acid and in small quantities round yellow non-birefringent crystals, birefringent hexagonal or rosette-shaped small crystals, small skeletal dendrites are simultaneously observed on the slide glass, then the absence of a disorder of purine metabolism is diagnosed if on the slide glass at the same time If atypical uric acid crystals of various shapes, birefringent needle-shaped crystals, atypical birefringent and non-birefringent crystals are observed in large quantities, as well as cholesterol crystals and large skeletal dendrites in large quantities in combination or separately, then a disorder of purine metabolism is diagnosed.
The invention relates to the field of medicine, namely to the physical analysis of liquid biological materials, and can be used to diagnose disorders of purine metabolism in children
Purine metabolism is a complex cascade biochemical reactions, in which many enzyme systems take part. The content of purines in the body consists of their intake from food and endogenous synthesis. Most of the salts of uric acid - urates - are formed endogenously during the metabolism of nucleic acids, but there are other ways of biosynthesis of these substances. In all variants, the most important intermediate is inosinic acid, which subsequently undergoes hydrolysis. The resulting hypoxanthine is converted to xanthine and uric acid under the influence of the enzyme xanthine oxidase. From a biochemical point of view, disorders of purine metabolism represent various types of imbalance between enzyme systems responsible for the synthesis and transport of uric acid and its precursors. The intake of a significant amount of purines from food is also essential.
It is believed that the body of an adult healthy person contains about 1000 mg of uric acid. If purine metabolism is impaired, this figure can increase several times. The content of uric acid in the body is not a rigid parameter and does not have any diagnostic value. Even the main indicator of the state of purine metabolism - the concentration of uric acid in the blood serum is not particularly harsh. The minimum and maximum normal values differ by approximately 2.5 times - 200-450 µmol/l in men and 160-400 µmol/day in women. U healthy people per day, approximately 750 mg or 2/3 of the total volume of uric acid is excreted and synthesized again. Of this amount, about 80% or 600 mg is excreted by the kidneys. The remaining 20% is excreted through the gastrointestinal tract. According to P. M. Klimenko et al. (2010) normal uric acid clearance is 5.4-9.0 ml/min.
Renal excretion of urate is a complex and multistep process. Filtration of plasma urate occurs in the glomeruli. The urates that enter the ultrafiltrate are almost completely reabsorbed in the proximal tubule and then secreted into the lumen of the nephron. Some of the secreted urate is reabsorbed. The process of active secretion of urates is very sensitive to various chemical agents. It is believed that renal secretion of urates is increased by orotic acid, losartan, estrogens, and tetracycline breakdown products (expired tetracyclines are highly toxic!); renal excretion of urate is reduced by ethambutol, thiazides and thiazide-like diuretics, and to a lesser extent by furosemide and acetazolamide. It is quite obvious that the severity of the observed effects varies greatly from drug to drug and does not always have clinical application. In particular, the uricosuric properties of estrogens are not significant. Losartan in lately began to appear in treatment regimens for gouty tubulointerstitial nephritis in patients who do not have nephrolithiasis. The tendency of thiazides and indapamide to reduce the renal excretion of urate and increase their serum concentration is quite pronounced, which makes these drugs at least undesirable for articular gout and, especially, for gouty nephropathy.
Clinical variants of kidney damage due to impaired purine metabolism
Diseases associated with disorders of purine metabolism are relatively common, which makes issues related to their treatment relevant. Urology specialists, as well as most general practitioners, are well acquainted with the features of urate nephrolithiasis. At the same time, these specialists often have no idea at all about the existence of other, sometimes more serious, diseases caused by disorders of purine metabolism. Meanwhile, they all occur with varying frequency in hospitals, as well as in the provision of outpatient medical care.
The most significant consequence of disorders of purine metabolism is an increase in the level of uric acid in the blood - hyperuricemia, which is the main etiological factor of various pathological conditions. Depending on the etiology, hyperuricemia is divided into primary (without an obvious cause) and secondary to a disease.
The clinical consequence of primary hyperuricemia is gout in the broad sense of the term. This includes classic acute microcrystalline arthritis, and various variants of gouty nephropathy, one of which is urate nephrolithiasis, and tophi of various locations, and complications of all these conditions.
In the group of diseases associated with primary hyperuricemia, genetically determined disorders of purine metabolism stand somewhat apart. Among them are Lesch-Nychen syndrome, Gierke's disease, various variants of hereditary defects in the transport systems of the renal tubules and others. Distinctive signs of hyperuricemia inherited as a monogenic type (that is, associated with a defect in a specific gene that determines the development of the entire symptom complex) are manifestation in early childhood, high overproduction of uric acid, rapid, sometimes even “malignant” progression of the disease up to the formation of terminal renal failure , often very moderate effectiveness of treatment measures, despite the most active therapy.
Clinical diagnosis of disorders of purine metabolism inherited in a polygenic manner is currently difficult. The manifestations and course of the disease in this case vary greatly depending on external factors, and the biological effect of a significant part of the genes is still not completely clear.
In nephrological and general therapeutic practice, the concept of “gouty kidney” was introduced several decades ago to determine kidney damage due to hyperuricemia, which in modern medicine has been transformed into “gouty nephropathy”. Considering the experimentally proven damaging effect of uric acid salts on renal structures, the term “urate nephropathy” was also proposed. All these concepts are generalizing and combine several processes that are quite different in their pathogenesis: acute uric acid nephropathy, urate nephrolithiasis and chronic tubulointerstitial nephritis. Some authors also note the possibility of immune complex glomerulonephritis, the triggering factor of which is overproduction of uric acid.
In urological practice, patients with urate nephrolithiasis are most often encountered. Up to 80% of such patients had an episode of acute arthritis at least once in their lives, and not necessarily of the classical localization - the first metatarsophalangeal joint. Recently, atypical variants of gouty arthritis, for example, gout, have become increasingly common. In addition, the widespread and uncontrolled use of non-steroidal anti-inflammatory drugs often blurs the clinical picture, increasing the proportion of arthritis with less activity of the inflammatory process. It may be noted that the combination of arthritis and urate nephrolithiasis is not mandatory, but rather characteristic.
The clinical picture of a kidney or ureteral calculus is well known, so there is no point in describing it in detail again. The only thing worth noting is that in the most severe, “malignant” course, along with the formation of urate stones in the lumen of the urinary tract, there may also be deposition of urate crystals in the renal interstitium, which is called “nephrocalcinosis”. Unlike nephrolithiasis, nephrocalcinosis in gout is always bilateral. Nephrocalcinosis does not have any specific symptoms. Clinical manifestations are reduced to the progression of renal failure due to nephrosclerosis. Nephrocalcinosis is in most cases detected by ultrasound scanning and requires specific therapy.
Chronic tubulointerstitial nephritis is a characteristic and common variant of gouty nephropathy. However, due to the less vivid clinical picture, it is known mainly to nephrologists and rheumatologists.
In the initial stages of tubulointerstitial nephritis, the pathological process mainly affects the tubules and renal interstitium, so the leading symptom is a violation of the concentration function of the kidneys - polyuria with low urine density (hyposthenuria). Proteinuria does not exceed 1 g/day or is completely absent - it is associated with impaired protein reabsorption by the tubules. Gouty interstitial nephritis is characterized by persistent uraturia, as well as persistent or episodic microhematuria, especially after a respiratory viral infection.
The level of blood urate is also naturally increased, but it must be remembered that the very fact of the presence of chronic renal failure is also the cause of hyperuricemia. With an obvious clinical picture of chronic tubulointerstitial nephritis, its connection with disorders of purine metabolism is beyond doubt with the following ratios of blood urate and creatinine levels: respectively > 536 µmol/l and< 132 мкмоль/л; >595 µmol/l and 132-176 µmol/l; > 714 µmol/l and > 176 µmol/l.
In an immunohistochemical study of renal biopsy specimens, some patients with a clinical picture of gouty tubulointerstitial nephritis showed fluorescence of the C3 fraction of complement and IgG, which is characteristic of immune complex glomerulonephritis. This made it possible to identify chronic glomerulonephritis as a separate variant of gouty nephropathy.
With the progression of gouty tubulointerstitial nephritis, the development of arterial hypertension and nephrosclerosis is natural.
Acute uric acid nephropathy (acute gouty kidney) is based on obstruction of the renal tubules by urate crystals, which leads to acute renal failure. The disease begins with oliguria. Some patients simultaneously complain about pain syndrome according to the type of renal colic, gross hematuria, which can be explained by the migration of large urate crystals through the ureter. Pathognomonic is high uraturia, which is not typical for acute renal failure of other etiologies, as well as a significant increase in the level of uric acid in the blood (above 850-900 µmol/l). In modern nephrological practice, it is believed that the diagnosis of acute uric acid nephropathy is beyond doubt when the ratio of blood urate and creatinine levels (in mg) is > 1.
The assumption of acute uric acid nephropathy is based on a combination of three clinical signs- highly active arthritis with characteristic localization, a sharp decrease in diuresis and brick-brown urine. The diagnosis is all the more likely if the patient indicates that there has been hypohydration of any origin - from visiting a bathhouse and physical work at high temperature air to inadequate infusion therapy and overdose of diuretics, as well as the consumption of significant amounts of meat products and/or alcohol. In the natural course of the disease, oliguria almost always progresses to anuria with a detailed clinical picture of acute renal failure.
The problem of acute uric acid nephropathy is closely related to secondary hyperuricemia. The reasons for increased levels of uric acid in the blood serum are quite numerous and varied. Among them: chronic renal failure, regardless of etiology, obesity, especially high degrees, poorly compensated diabetes mellitus, acromegaly, hypothyroidism, hypoparathyroidism, toxicosis of pregnancy, myeloproliferative diseases, sarcoidosis, chronic intoxication lead, chronic alcoholism. There is a clear connection between increased risk urate nephrolithiasis and the presence of severe psoriasis in the patient, especially articular psoriasis. In most cases, the severity of hyperuricemia in these diseases is mild, less often moderate. Thus, disorders of purine metabolism rarely significantly affect the clinical picture of the disease.
The most striking and clinically significant variant of secondary hyperuricemia is “tumor lysis syndrome” (“tumor decay syndrome”), which develops during chemotherapy and radiotherapy of lymphoproliferative diseases, less often of tumors of other localizations. A key component of this syndrome, along with hyperphosphatemia and hyperkalemia, is the overproduction of uric acid, leading to the development of acute uric acid nephropathy, often in intact kidneys. However, severe hyperuricemia due to genetic disorders, extremely rarely leads to acute uric acid nephropathy.
Drug therapy for kidney diseases caused by disorders of purine metabolism
Conservative therapy of any variant of gouty nephropathy is based on reducing the level of hyperuricemia, and therefore hyperuricuria, as well as increasing the solubility of urate in urine.
All patients in mandatory a diet is prescribed, the purpose of which is to reduce the intake of purines into the body from food. This is achieved by completely excluding meat from young animals, offal, meat broths, sausages, etc. from the diet; meat from full-aged animals and fish are allowed to a limited extent. Patients are recommended to have a predominantly plant-based diet, plenty of alkaline drinks, citrus fruits and drinks based on them, as well as complete abstinence from alcohol.
In the presence of renal failure, arterial hypertension, circulatory failure, and obesity, additional restrictions are introduced. First of all, it is recommended to reduce the consumption of table salt, since the effectiveness of ACE inhibitors, especially indicated for nephropathies complicated by arterial hypertension, and indeed all antihypertensive therapy directly depends on the amount of sodium entering the body. With severe filtration deficiency, there is a need to limit protein intake. In case of obesity, reduce the total caloric intake of the diet.
In a number of patients, for example, with rarely recurrent urate nephrolithiasis without renal failure, with sufficient motivation on the part of the patient, it is generally possible to limit oneself to diet correction and drinking regime without resorting to prescription medications.
Medicines used for the pathogenetic treatment of gouty nephropathy are divided into:
- drugs that affect purine metabolism (allopurinol, febuxostat);
- drugs that increase the renal excretion of purines (probenecid, benzbromarone);
- drugs that increase the solubility of uric acid and its salts (citric acid and its salts - citrates).
The basic drug that affects purine metabolism is allopurinol, which is an inhibitor of the enzyme xanthine oxidase. Under the influence of this enzyme, the last stage of uric acid synthesis occurs. The urate precursors xanthine and hypoxanthine have almost 10 times higher solubility in water compared to uric acid. Stopping purine metabolism at this stage reduces the risk of crystal formation, and therefore microcrystalline arthritis and nephropathy, to almost zero.
Allopurinol is indicated for gouty tubulointerstitial nephritis, acute uric acid nephropathy, urate nephrolithiasis in combination with hyperuricemia, as well as chemotherapy malignant neoplasms to prevent the development of secondary hyperuricemia and acute renal failure. The minimum effective dosage is 200 mg/day, the average therapeutic dosage is 300-400 mg/day. Chemotherapy for malignant tumors requires high, close to maximum, dosages of allopurinol - 600-900 mg/day.
Allopurinol tends to cause dyspeptic disorders and skin rashes, which occur in almost every fifth patient. The side effects of this drug are often unpleasant, but not dangerous, and due to the almost complete (until recently) lack of alternatives to this drug, most patients still continue treatment.
Recently, a new xanthine oxidase inhibitor febuxostat has appeared on the domestic market, which differs from allopurinol in higher selectivity. Domestic experience with the use of febuxostat is still extremely limited, but foreign researchers note that it is more high efficiency regarding hyperuricemia. However, it can already be noted that this drug is a complete replacement for allopurinol in conditions of intolerance, allergies, etc.
In conclusion, xanthine oxidase inhibitors are contraindicated in patients receiving azathioprine and 6-mercaptopurine, as this enzyme is involved in their metabolism. When administered together, the risk of toxicity, primarily bone marrow toxicity, increases sharply.
Recombinant urate oxidase, rasburicase, is also used abroad. The drug is significantly more effective than allopurinol in reducing hyperuricemia and is used mainly in hematological practice for the prevention of acute urate nephropathy.
Medicines that increase the renal excretion of purines - uricosuric drugs - inhibit the process of reabsorption of urate from the lumen of the renal tubules. In modern clinical practice, this group of drugs is used very limitedly. Not all patients demonstrate sufficient effectiveness. In addition, the result of direct pharmacological effect- An increase in renal excretion of urate increases the risk of nephrolithiasis. The most famous uricosuric drug, probenecid, is currently practically absent from the domestic market. Benzbromarone is registered in Russia, but is available only in very small quantities. All uricosuric drugs undergo hepatic metabolism in the body and have some hepatotoxicity. Another feature of these drugs is huge number drug interactions, which complicates their use as part of multicomponent regimens.
Citrate therapy is an integral part of the drug treatment of gouty nephropathy. The effect of citric acid salts on the process of crystal formation in urine is multifaceted. The solubility of uric acid varies significantly depending on the reaction of the medium. In an acidic environment, urates have very poor solubility and easily pass into the solid phase - they crystallize. With a neutral or alkaline reaction, the solubility of these salts increases. The main effect of citrates is the ability to alkalize urine, which prevents crystallization of urates and creates conditions for the dissolution of already formed crystals. This is the basis of litholytic therapy. However, with an alkaline reaction of the environment, the solubility of phosphates decreases. The layering of a phosphate film on the urate stone makes the process of further litholysis practically hopeless. This dictates the need for careful monitoring of the urine reaction throughout the course of treatment. IN modern conditions The empirical use of plant materials rich in citric acid and its salts has been replaced by drugs that include chemically pure citrate and a set of test strips for monitoring the reaction of urine.
Research 1980-90s demonstrated the effectiveness of litholysis of urate stones using citrate mixtures in monotherapy of about 75-80%. Currently, as a result of improving the technique, the efficiency of litholysis has been increased to 85-90%, depending on the characteristics of the chemical composition of the stones.
In recent years, studies have appeared indicating the advisability of including citrate preparations in multicomponent treatment regimens. In particular, with urate stones of the ureter, especially in its distal third, combination therapy, including citrate and tamsulosin, led to spontaneous passage of 84.8% of stones, which is significantly different from the groups of patients receiving monotherapy with these drugs (68.8% and 58. 8%, respectively), as well as from patients receiving placebo (26.1%).
There is convincing evidence for the effectiveness of the combination of allopurinol and citrate in gouty interstitial nephritis. A twelve-week course of combination therapy, including citrate 3 g/day and allopurinol 100-200 mg/day, led to an increase in glomerular filtration rate by an average of 15 ml/min compared to the control group. The clearance of uric acid also increased significantly. Note the low dosage of allopurinol. 200 mg/day is considered minimally effective, and 100 mg/day is generally a subclinical dosage; nevertheless, it turned out to be effective. An assumption can be made about the possible potentiation of the effects of allopurinol and citrate. An additional positive consequence should be a reduction in the frequency of side effects of allopurinol, which is a significant limiting factor in the drug treatment of gouty nephropathy. Unfortunately, the authors did not focus on this.
A more striking effect of citrate on renal function was noted in the treatment of chronic interstitial nephritis caused by hyperuricemia in obese patients.
The mechanism of action of citrate is not limited to alkalization of urine. Citrate is one of the physiological inhibitors of crystal formation. Since urine is normally a supersaturated saline solution, the presence of crystal formation inhibitors in it is a necessary condition for the adequate functioning of the entire urinary system. Hypocitraturia is one of the factors contributing to stone formation. This may explain the effectiveness of citrate mixtures not only for urate, but also for calcium-oxalate nephrolithiasis.
Along with the mechanisms of action described above, citric acid salts additionally have antiseptic, cytoprotective and metabolic effects, which can also be used in clinical practice. In particular, C. Strassner and A. Friesen reported the disappearance of candiduria in 16 out of 18 patients during therapy with citrate mixtures, which is likely due to a change in urine reaction. The conclusion about the cytoprotective effect of citrate was made based on the successful attempts of P. Bruhl et al. with its help, prevent chemical injury to the bladder mucosa during therapy with drugs from the oxazaphosphorine group - cyclophosphamide and ifosfamide (in modern oncological and nephrological practice, a drug from the mucolytic group - mesna, which has practically no effect on the acid-base state, is used for this purpose). Additionally, the use of citrate has been reported to correct acidosis due to ureterosigmostomy.
The main difficulty in citrate therapy for urate nephrolithiasis is selecting an adequate dosage of the drug. N.K. Dzeranov, who has studied and developed this aspect for many years, recommends starting with prescribing a diet and assessing the urine reaction for 5 days at a strictly defined time of day. Based on the obtained average values of urine pH level, the initial dose of the drug and, most importantly, its distribution during the day are determined. After 5 days of treatment, the average urine reaction is determined again at a strictly similar time of day and, if necessary, the dosage of the drug is adjusted. “Interactive”, that is, in real time, changing the dosage of citrate is ineffective and even unsafe, as it leads to jumps in pH levels, which can cause phosphate crystallization.
Due to the fact that citrate is normally present in the body, drugs based on it are practically free of toxicity. However, there are clinical situations where the use of these drugs requires caution. The use of citrate mixtures is undesirable for acute uric acid nephropathy and, in general, for acute renal failure of any etiology. The limiting factor here is not the citrate ion, but potassium, the removal of which is difficult in this clinical situation. In acute uric acid nephropathy, it is advisable to administer a 4% sodium bicarbonate solution, saline solution, etc. in combination with loop diuretics. It is necessary to maintain diuresis at a level of at least 100-150 ml/hour, urine pH not lower than 6.5. If possible, xanthioxidase inhibitors are prescribed. Citrate mixtures are advisable when diuresis is restored and the glomerular filtration rate reaches 25-30 ml/min, when the risk of hyperkalemia is practically absent.
In severe circulatory failure, the limiting factor is the increased intake of sodium into the body, also contained in citrate mixtures. Sometimes acetazolamide is preferable in this situation. This drug from the group of diuretics - carbonic anhydrase inhibitors strongly, and most importantly, uncontrollably alkalinizes the urine, which makes it uncompetitive compared to citrate in drug therapy urate nephrolithiasis. However, acetazolamide is practically the only way to increase the pH level of urine without resorting to the introduction of salts, which is extremely undesirable in conditions of severe heart failure.
Thus, drug treatment patients with kidney diseases caused by disorders of purine metabolism, despite the very limited choice of drugs and the apparent simplicity of their choice, is a complex and multifaceted problem that requires an interdisciplinary approach.
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S. K. Yarovoy 1, Doctor of Medical Sciences
R. R. Maksudov
Federal State Budgetary Institution Research Institute of Urology, Ministry of Health of the Russian Federation, Moscow
Purine (adenine, guanine) and pyrimidine (cytosine, uracil and thymine) bases are part of nucleic acids - RNA and DNA. Violation of their metabolism leads to an increase in the level of uric acid and is observed in various kidney diseases, leukemia, but especially clearly in gout, known since the time of Hippocrates.
Gout(podagra; Greek trap, aches, weakness in the legs; gout from podos - leg, foot + agra - seizure, attack) is a chronic disease caused by a violation of purine metabolism. It is characterized by the deposition of uric acid salts in tissues with the development of first inflammatory and then destructive-sclerotic changes in them. It manifests itself mainly as recurrent arthritis, the formation of subcutaneous nodules, and symptoms of urolithiasis. Currently, the term “gout” refers to a group of diseases manifested by:
1) hyperuricemia;
2) repeated attacks of acute arthritis, in which sodium urate crystals are found in leukocytes from the synovial fluid;
3) large deposits of sodium urate, most often in and around the joints of the limbs, which is often accompanied by joint deformation and severe lameness;
4) damage to the kidneys, including interstitial tissues and blood vessels;
5) the formation of stones from uric acid.
These symptoms can occur either separately or V various combinations. Gout is considered a multifactorial disease. Due to the fact that two specific causes of gout (lack of hypoxanthine guanine phosphoribosyltransferases and hyperactivity 5-phosphoribosyl-1-pyrophosphate synthetase) are linked to the X chromosome, then gout is a disease of older men; Women account for up to 5% of cases. Children and adolescents rarely get sick. The peak incidence occurs in the fifth decade of life. In general, gout affects from 0.13 to 0.37% of the total population.
So, a mandatory symptom of gout is hyperuricemia. An absolute increase in the level of urate in serum is said to occur when its concentration exceeds the solubility limit of sodium urate in serum. For urates, this limit is 60 mg/l in women and 70 mg/l in men. Serum urate concentrations greater than 70 mg/l (the effect of serum urate saturation) increases the risk of gouty arthritis and nephrolithiasis. Urate levels are affected by gender, age (obviously through the effect on the renal clearance of urate by estrogens and androgens), body weight, blood pressure, blood urea nitrogen and creatinine levels, and alcohol consumption (chronic alcohol consumption increases the production of uric acid and reduces its excretion) .
Hyperuricemia is found in 2-18% of the population. Frequency And The prevalence of gout is less than hyperuricemia, and is 0.20-0.35 per 1000 people. Hyperuricemia is a necessary condition for the development of gout. Uric acid is formed by the oxidation of purine bases. 2/3 of uric acid is excreted in the urine (300-600 mg/day), and 1/3 is excreted through the gastrointestinal tract, in which it is destroyed by bacteria.
Hyperuricemia may be caused by an increased rate of uric acid production, decreased uric acid secretion by the kidneys, or both. In this regard, gout and hyperuricemia are divided into metabolic and renal.Metabolic hyperuricemia and gout is caused by increased production of uric acid, as can be judged by increased excretion (more than 600 mg/day) of uric acid even under conditions of limited intake of purines with food. This type of gout accounts for less than 10% of all cases of this disease.
Urinary acid, is known to be the end product of purine metabolism. The rate of uric acid synthesis in humans is determined by the intracellular concentration of 5-phosphoribosyl-1-pyrophosphate (FRPP): with an increase in the level of PRPP in the cell, the synthesis of uric acid increases, and with a decrease, it decreases.
Excessive production of uric acid can be primary or secondary. Primary hyperuricemia is caused by congenital deficiency of hypoxanthine guanine phosphoribosyltransferase or increased activity of PRPP synthetase and is inherited linked to the X chromosome. Secondary hyperuricemia, caused by overproduction of uric acid, can be associated with many reasons:
1) acceleration of de novo purine biosynthesis;
2) deficiency of glucose-6-phosphatase (for example, in glycogen storage disease type I), in which there is increased production of uric acid and accelerated de novo synthesis of purines;
3) acceleration of the synthesis of PRPP;
4) acceleration of the breakdown of purine nucleotides.
The last two reasons are included when there is a deficiency in the cell
glucose as a source of energy. It is believed that in most patients with secondary hyperuricemia due to excess production of uric acid, the main disorder is the acceleration of the turnover of nucleic acids, which is characteristic of many diseases: myelosis, lymphocytic leukemia, myeloma, secondary polycythemia, pernicious anemia, thalassemia, hemolytic anemia, infectious mononucleosis, carcinoma, etc. Acceleration of nucleic acid turnover leads to hyperuricemia and a compensatory increase in the rate of de novo purine biosynthesis.
Renal hyperuricemia and gout due to decreased excretion of uric acid by the kidneys. It accounts for up to 90% of all cases of gout. Excretion of uric acid depends on glomerular filtration, tubular reabsorption and secretion.
A decrease in the filtration rate (1st factor), increased reabsorption in the proximal tubules (2nd factor) or a decrease in the rate of secretion (3rd factor) of uric acid reduces its renal excretion. It is likely that all three factors are present in patients with gout.
The renal type of hyperuricemia and gout can be primary or secondary. Primary renal gout occurs in patients with kidney pathology: polycystic disease, lead nephropathy. Secondary renal hyperuricemia can occur when taking diuretics that reduce circulating plasma volume, which is accompanied by a decrease in filtration of uric acid, increased tubular reabsorption and decreased secretion of uric acid. A number of other drugs (low-dose aspirin, nicotinic acid, pyrazinamide, ethanol, etc.) also cause hyperuricemia by reducing the excretion of uric acid, but the mechanisms have not yet been established.
Nephrogenic diabetes insipidus, adrenal insufficiency, reducing the central nervous system, induce hyperuricemia. Hyperuricemia may result from competitive inhibition of uric acid secretion by excess organic acids, which are secreted by similar renal tubular mechanisms as uric acid. Excess of organic acids is observed during fasting (ketosis, free fatty acids), alcoholic and diabetic ketoacidosis, lactic acidosis of any origin.
Hyperuricemia, characteristic of hyperpara- and hypoparathyroidism, hypothyroidism, may also have a renal basis, but the mechanism of its occurrence is unclear. The evolution of gout goes through 4 stages:
1) asymptomatic hyperuricemia,
2) acute gouty arthritis,
3) intercritical period,
4) chronic gouty deposits in the joints.
Stage of asymptomatic hyperuricemia characterized by increased serum urate levels, but no symptoms of arthritis, gouty joint deposits, or uric acid stones. In men susceptible to classical gout, hyperuricemia begins during puberty, and in women at risk - with the onset of menopause. Asymptomatic hyperuricemia may persist throughout life. Despite the fact that hyperuricemia is detected in almost all patients with gout, only 5% of people with hyperuricemia ever develop this disease.
The stage of asymptomatic hyperuricemia ends with the first attack of gouty arthritis or nephrolithiasis.
Arthritis, as a rule, precedes nephrolithiasis, which usually develops after 20-30 years of persistent hyperuricemia.Next stage - acute gouty arthritis. The reasons that cause the initial crystallization of sodium urate in the joint after a long period of asymptomatic hyperuricemia are not fully understood, although it is known that the deposition of urates in tissues is facilitated by a shift in pH to the acidic side and a disturbance in the metabolism of mucopolysaccharides that maintain urates in a dissolved state. Persistent hyperuricemia ultimately leads to the formation of microdeposits in the squamous cells of the synovium and to the accumulation of sodium urate in cartilage on proteoglycans that have a high affinity for it. Various reasons, but most often trauma, accompanied by destruction of the microenvironment and acceleration of the turnover of cartilage proteoglycans, cause the release of urate crystals into the synovial fluid. Low temperature in the joint, inadequate reabsorption of water and urate from the synovial fluid in the joint cavity, causes the accumulation of a sufficient number of urate crystals in it. Uric acid crystals are phagocytosed in the joints by neutrophils, then destroy them with the release of lysosomal enzymes, which are mediators of acute gouty inflammation. An acute attack of arthritis is triggered by a number of factors, including:
1) phagocytosis of crystals by leukocytes with the rapid release of chemotactic proteins from them;
2) activation of the kallikrein system;
3) activation of complement with the subsequent formation of its chemotactic components;
4) destruction of lysosomes of leukocytes by urate crystals and release of lysosomal products into the synovial fluid.
While some progress has been made in understanding the pathogenesis of acute gouty arthritis, many questions regarding the spontaneous cessation of an acute attack and the effect of colchicine still await answers.
Initially, extremely painful arthritis affects one of the joints with scant general symptoms. Later, several joints are involved in the process against the background of a feverish state. The duration of attacks varies, but is still limited. They are interspersed with asymptomatic periods. Acute gouty arthritis is a disease primarily of the legs. The more distal the location of the lesion, the more typical the attacks. Sometimes gouty bursitis develops, and most often the bursae of the knee and elbow joints are involved in the process. Before the first sharp attack of gout, patients may feel constant pain with exacerbations, but more often the first attack is unexpected and has an “explosive” character. It usually begins at night, the pain in the inflamed joint is extremely severe.
An attack can be triggered by injury, consumption of alcohol and certain medications, errors in diet, or surgery. Within several hours, the intensity reaches its peak, signs of progressive inflammation clearly appear, leukocytosis increases, body temperature rises, and ESR increases.
Attacks of gout can last for one or two days or several weeks, but they usually resolve spontaneously. There are no consequences, and the recovery seems complete, i.e. stage 3 begins - asymptomatic phase, called the intercritical period, during which the patient does not make any complaints. In 7% of patients, the second attack does not occur at all, and in 60% the disease recurs within a year.
However, the intercritical period can last even up to 10 years and end with repeated attacks, each of which becomes longer and longer, and remissions become less and less complete. With subsequent attacks, several joints are usually involved in the process; the attacks themselves become more severe, longer lasting and are accompanied by fever.In untreated patients, the rate of urate production exceeds the rate of its elimination. As a result, accumulations of sodium urate crystals appear in cartilage, synovial membranes, tendons and soft tissues. Gouty deposits are often localized along the ulnar surface of the forearm in the form of protrusions of the bursa of the elbow joint, along the Achilles tendon, in the area of the helix and antihelix of the auricle. They may ulcerate and secrete a whitish, viscous fluid rich in sodium urate crystals. Gout deposits rarely become infected.
In 90% of patients with gouty arthritis, varying degrees of renal dysfunction are detected - nephropathy. Before the introduction of hemodialysis, 17-25% of patients with gout died from renal failure.
There are several types of damage to the renal parenchyma:
1) urate nephropathy, caused by the deposition of sodium urate crystals in the interstitial tissue of the kidneys;
2) obstructive nephropathy, caused by the formation of uric acid crystals in the collecting ducts, renal pelvis or ureters.
The factors contributing to the formation of urate deposits in the kidneys are unknown. Nephrolithiasis occurs with a frequency of 1-2 cases per 1000 patients with gout. The leading factor contributing to the formation of uric acid stones is increased excretion of uric acid. Hyperuricaciduria may result from primary gout, an inborn error of purine metabolism leading to increased uric acid production, myeloproliferative disease, and other neoplastic processes.
If uric acid excretion in urine exceeds 1100 mg/day, the incidence of stone formation reaches 50%.
The formation of uric acid stones also correlates with hyperuricemia: with a uric acid level of 130 mg/l and above, the incidence of stone formation reaches approximately 50%. The formation of uric acid stones is promoted by excessive acidification of urine; urine concentration. Uric acid crystals can serve as a nucleus for the formation of calcium stones.
Principles of pathogenetic prevention and treatment sick With violation of purine metabolism. Since acute gouty arthritis is inflammatory process, then anti-inflammatory treatment should be carried out, primarily with colchicine (stabilizes lysosome membranes, suppresses chemotaxis and phagocytosis, has an antimitotic effect on neutrophils) until the patient’s condition improves or adverse reactions from the gastrointestinal tract appear (with intravenous administration of colchicine, side effects from gastrointestinal tract do not occur). Side effects include: bone marrow suppression, alopecia, liver failure, mental depression, convulsions, ascending paralysis, respiratory depression. Other anti-inflammatory drugs that are effective include indomethacin, phenylbutazone, naproxen, and fenoprofen. Drugs that stimulate uric acid excretion and allopurinol are ineffective in an acute attack of gout. If colchicine and nonsteroidal anti-inflammatory drugs are ineffective or contraindicated, systemic (intravenous or oral) or local (into the joint) administration of glucocorticoids is used. This treatment is especially appropriate if it is impossible to use a standard drug regimen.
Hyperuricemia caused by partial or complete deficiency of hypoxanthine guanine phosphoribosyltransferase (deficiency of this enzyme reduces the consumption of phosphoribosyl pyrophosphate, which accumulates in higher than normal concentrations, accelerating de novo biosynthesis of purines, which causes hyperproduction of uric acid), will successfully respond to the influence of allopurinol, a xanthine oxidase inhibitor, which catalyzes the conversion of xanthine and hypoxanthine to uric acid.
To reduce the likelihood of recurrence of an acute attack, it is recommended:
Daily prophylactic administration of colchicine or indo-methacin;
Controlled reduction of body weight in obese patients;
Elimination of a number of provoking factors (alcohol);
The use of antihyperuricemic drugs to maintain serum urate levels below 70 mg/l, i.e. at the minimum concentration at which urate saturates the extracellular fluid. Uricosuric drugs (probenecid, sulfinpyrazone) increase renal excretion of urate.
Limiting the consumption of foods rich in purines (meat, fish, liver, beans).
Hyperuricemia can be corrected with allopurinol, which inhibits xanthine oxidase and thereby reduces the synthesis of uric acid. In order to prevent uric acid nephropathy, they resort to water loads and diuretics, alkalization (sodium bicarbonate) of urine so that uric acid is converted into soluble sodium urate, and the appointment of allopurinol.
