Causes and pathogenesis of urolithiasis

There is no single theory of the etiology of urolithiasis, since in each specific case it is possible to identify its own factors (or groups of factors) and diseases that led to the development of metabolic disorders, such as hyperuricosuria, hypercalciuria, hyperoxaluria, hyperphosphaturia, changes in urine acidification, and the occurrence of urolithiasis. In the occurrence of these metabolic shifts, some authors attribute the leading role to exogenous factors, while others attribute it to endogenous causes.

Etiological factors in the development of urolithiasis

Endogenous factors		Exogenous factors
Hereditary	Acquired
Hereditary disorders of urodynamics of the upper and/or lower urinary tract; Hereditary tubulopathies; Hereditary disorders of enzyme activity, hormones or deficiency/excess of vitamins	Urinary tract infection; Diseases of the digestive tract, liver and biliary tract; Congenital and acquired disorders of urodynamics of the upper and/or lower urinary tract; Long-term or complete immobilization; Secondary disturbances of enzyme activity, Hormones or vitamin deficiency/excess; Secondary tubulopathies; Diseases leading to urolithiasis (osteoporosis, leukemia, bone metastases, multiple myeloma, etc.)	Climate; Geological structure of the soil; Chemical composition of water and flora; Food and drinking regimes of the population; Living and working conditions, including environmental and occupational hazards; Iatrogenic factors

Pathogenesis of urolithiasis

Different authors associate the pathogenesis of urolithiasis with one of three main hypotheses:

• enhanced precipitation-crystallization;
• matrix formation - nucleation;
• deficiency of crystallization inhibitors.

The first hypothesis of precipitation-crystallization emphasizes the importance of supersaturation of urine with crystalloids, which leads to their precipitation in the form of crystals. This mechanism obviously prevails in a number of cases (cystinuria, uraturia, triple phosphate crystalluria, etc.). However, this cannot explain the origin of oxalate-calcium stone formation, in which the excretion of the main stone-forming components is practically not increased. In addition, a transient increase in the concentration of stone-forming compounds is possible, which cannot always be detected.

The matrix hypothesis of stone formation is based on the assumption that a number of organic substances initially form a nucleus on which the stone subsequently grows due to precipitation of crystals. Some authors include urinary microglobulin, collagen, mucoproteins, etc. among such substances. Despite the fact that urinary microglobulin is always found in kidney stones, there is no evidence of its primary role in the formation of stones. Urine can retain a significantly larger amount of salts in a dissolved state than aqueous solutions due to the presence of crystal formation inhibitors in it.

The third hypothesis links the development of urolithiasis with the absence of inhibitors even with normal concentration of salts in the urine. However, there is no evidence of the absence of any one inhibitor in stone formation or a constant deficiency of the main inhibitors of crystal formation in patients with urolithiasis.

The mentioned hypotheses of stone formation undoubtedly reflect some mechanisms of development of urolithiasis.

However, it is absolutely necessary to consider the pathogenesis of stone formation from the point of view of the sources of origin of significant quantities of crystalloids, matrix substances, and the reasons for the decrease in the concentration of crystal formation inhibitors excreted in the urine.

An increase in stone-forming substances in the blood serum leads to an increase in their excretion by the kidneys, the main organ involved in maintaining homeostasis, and to urine supersaturation. In a supersaturated solution, salts precipitate in the form of crystals, which subsequently serves as a factor in the formation of microliths first, and then, due to the sedimentation of new crystals, urinary stones. However, urine is often supersaturated with salts (due to changes in the nature of nutrition, climatic conditions, etc.), but no stones are formed. The presence of urine supersaturation alone is not enough for the formation of stones. Other factors are also necessary for the development of urolithiasis, such as impaired urine outflow, urinary tract infection, etc. In addition, urine contains substances that help maintain salts in a dissolved form and prevent their crystallization: citrate, magnesium ions, zinc, inorganic pyrophosphate, glycosaminoglycans, nephrocalcin, Tamm-Horsvall protein, etc. Low citrate concentration may be idiopathic or secondary (metabolic acidosis, decreased potassium, thiazide diuretics, decreased magnesium concentration, renal tubular acidosis, diarrhea). Citrate is freely filtered by the glomeruli and 75% is reabsorbed in the proximal convoluted tubule. Most secondary causes result in decreased urinary citrate excretion due to increased reabsorption in the proximal convoluted tubule.

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