Modern view on pathogenetic mechanisms of hyperuricemia

Gout is a systemic tofus disease characterized by the deposition of sodium monoaurate crystals in various organs and tissues and developing in connection with this inflammation in persons with hyperuricemia caused by external and / or genetic factors. At the heart of the pathogenesis of gout is the violation of uric acid (purine) metabolism and an increase in the content of uric acid in the blood (MC). At the heart of uric acid metabolism lies its hyperproduction and a decrease in the secretion of the kidneys. At the same time, only 10% of patients with primary gout have violations only of endogenous formation of uric acid. In the remaining patients, the main factor in the formation of hyperuricemia is a disturbance in the excretion of uric acid by the kidneys.

In addition to the defeat of the musculoskeletal system for gout, the presence of visceral manifestations is characteristic, one of which is urate nephropathy. Ural nephropathy is a variant of chronic tubulointerstitial nephritis characterized by the accumulation of uric acid crystals in the interstitium with the development of a secondary inflammatory process in it and damage to the epithelium of the tubular apparatus with a disturbance of its function and reabsorption processes.

Transport of uric acid by the kidneys is a cascade of 4 processes: glomerular filtration, almost complete reabsorption of filtered uric acid, secretion and post-secretory reabsorption in the proximal tubules. Urates do not bind to proteins and therefore are freely filtered in the renal glomeruli. The rate of tubular secretion is much lower than the rate of tubular reabsorption, and therefore the contribution of secreted urates to the total number of isolated urates is small. Virtually 98-100% of filtered uric acid is reabsorbed in the proximal tubules, after which 50% of the filtered urates are again secreted, and then almost 80% of the recovered urate is reabsorbed and about 7-10% of the filtered urates are finally released. The phases of reabsorption, secretion and post-secretory reabsorption occur in the proximal tubule. Reabsorption and secretion processes are carried out at the expense of specific molecules (transporters) located on the brush border of the epithelium of the proximal tubules.

Most urate transporters belong to the OAT family. The tubular reabsorption of urate is carried out by a transporter of organic anions (urate-anion exchange), identified as URAT1 (encoded by the SLC22A12 gene). This transporter is only present in humans. Numerous studies, including those with familial hyporuricemia, indicate a mutation of the SLC22A12 gene encoding the URAT1 transporter. It was revealed that these patients practically do not have the influence of probenecid and pyradinamide (antituberculous drug with antiuricosuric effect) on uric acid release.

In addition to URAT1, there are other transporters: URATv1, SLC5A8 coded sodium-dependent counterparts, organic anion transporters of the OAT family (OAT1 and OAT3, OAT2 and OAT4), ABCG2 (urate conveyor in collecting tubes), SLC2A3 (sodium / phosphate cotransporter of proximal tubules). OAT2 and OAT4 are located on the apical membrane of the proximal tubules OAT1 and OAT3 on its basolateral part, their main function is the exchange of organic anions and bicarboxylate, but at the same time there are data on their effect on urate transport.

URATv1 (OATv1), which later became known as GLUT9, encoded by the SLC2A9 gene, is a potential-dependent carrier of organic ions, mainly glucose and fructose, as well as a urate transporter, the polymorphism of this gene is associated with hypo-uricemia, as confirmed in genetic studies.

Less studied are the mechanisms that affect the secretion of uric acid. Violation of its secretion is associated with changes in the ATP-dependent pump, the mutation of the MRP4 gene, which codes for the formation of uromodulin (Tamm-Horsfall protein, the ABSG2 gene). The precise mechanism by which uromodulin affects urate secretion is not yet known, perhaps this is due to an increase in sodium reabsorption in the proximal tubules and, at the same time, uric acid.

Disorders of the kidney transporter with an increase in the reabsorption of uric acid can lead to the development of hyperuricemia and, ultimately, gout. In a number of studies on the disruption of urate transport, genetic mutations have been identified, while most of these studies have focused on the presence of genetic mutations of urate transporters in patients with hypouricemia, and at the same time the issue of the presence of mutations in patients with hyperuricemia remains less studied. Attention is drawn to data on the activation of URAT1 and GLUT9 transporters in a diet rich in purines, arterial hypertension and local ischemia, which in turn causes an increase in the reabsorption of uric acid. There is evidence that apical tubular reabsorption of urates and sodium through URAT1 is disrupted, followed by the development of hyperuricemia under the influence of diabetic ketoacidosis, intoxication with ethanolamine, in the treatment of pyrazinamide, hyperinsulinemia and metabolic syndrome. Thus, a violation of the excretion of uric acid by the kidneys can be a secondary process due to damage to the tubular kidney apparatus.

The work of the tubular apparatus in patients with gout can be estimated by daily excretion, clearance, excreted fraction (EF), reabsorption of uric acid, calcium (Ca), phosphorus (P), excretion of ammonia. And the "standard" examination of the patient does not allow to reveal signs of a violation of renal function. The simplest and most accessible method is to estimate the uric acid clearance with subsequent recalculation on the surface area of the body. Our studies in patients with gout showed quite high informative value of this test for revealing signs of urate nephropathy, so the value of uric acid clearance less than 7 ml / min / 1.73 m2 has a sensitivity of 90% and a specificity of 66%.

Post-graduate student of the Department of Hospital Therapy Khalfina Tamila Nilovna. A modern view of the pathogenetic mechanisms of hyperuricemia // Practical medicine. 8 (64) December 2012 / volume 1

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