Urolithiasis was one of the first diseases discovered in humans, as early as 4800 BC, 6800 years ago in the tomb of ElAmrah in Egypt. In 1200 BC, 3200 years ago, Susrua performed the first perineal lithotripsy. In the fourth century B.C., the Hippocratic Oath reads, “I will not operate on stone patients, but will give way to skilled artisans. In the eighteenth century, there is a record of 53s removal of bladder stones in England, and more than 2000 years ago Hippocrates noticed kidney stones and kidney abscesses, and also described gout. Two thousand years ago, there were also records of “stone gonorrhea” and “sand gonorrhea” in the ancient medical books of China. The formation of urinary stones is mainly due to an imbalance between the opposite forces of urinary supersaturation and crystallization inhibitory factors. In general, the formation of urinary stones is the process of changing liquid substances in urine into solid substances. This process requires a certain amount of energy, and urinary supersaturation due to high levels of lithogenic material in the urine is the energy source driving stone formation. Supersaturation of urine alone cannot explain urinary stone formation. Many urine specimens are placed with crystals, but do not form urinary stones; those with urinary stone formation often excrete larger than healthy crystals and have crystals aggregated. In normal subjects, there are inhibitors to the formation, growth and aggregation of crystals in urine. The most important inhibitors of crystallization in urine identified so far are citrate, magnesium, pyrophosphate, TH protein, nephrocalcin, urinary bridging protein and glucosaminoglycan. For the rare uric acid and cystine stones, the urinary supersaturation levels of uric acid and cystine are mainly affected by urinary pH, and no crystallization inhibitory factors have been identified. In normal subjects, the contradiction between urinary supersaturation and urinary crystallization inhibitory factor always maintains the dynamic balance of urine without causing stone formation. With these two opposing forces and the involvement of crystallization promoting factors and matrix, stone formation occurs through the following steps: nucleation → crystallization growth → crystallization aggregation → crystallization retention → stone formation. The causes of urolithiasis are complex, and urinary stones of different nature may be caused by the same cause; while urinary stones of the same nature may be caused by different causes, and often have more than two causative factors. Except for infectious urinary stones, most urinary stones are composed of metabolic products of the body. Therefore, the different components of urinary stones can reflect the metabolic abnormalities of the corresponding components in the body. The common lithogenic components of urine include calcium, oxalate, uric acid, phosphate and cystine. Any physiological system disorder that causes high supersaturation of these lithogenic components in the urine or a decrease in the crystallization inhibitory factor in the urine may initiate stone formation and promote stone growth. The common lithogenic components of urine include calcium, oxalate, uric acid, phosphate, and cystine. Any physiologic system disorder that causes a high degree of supersaturation of these lithogenic components in the urine or a decrease in urinary crystallization inhibitory factors may initiate stone formation and promote stone growth. The causes of urolithiasis are complex, and stone composition can reflect the causes of stone formation. 1. Calcium oxalate stones Calcium oxalate stones account for the majority of urinary stones in clinical practice. Calcium oxalate stones may be a polygenic genetic disorder. The causes of calcium oxalate stones formation are as follows. 1.1, hypercalciuria Parks et al. considered hypercalciuria defined as a dietary intake of 400 mg of calcium and 100 mEq of sodium per day and urinary calcium excretion >200 mg/d or >4 mg/(kg?d)-1 after 1 week. Lerolle et al. concluded that 40% of patients with stones had congenital familial hypercalciuria. Hypercalciuria promotes stone formation by increasing urinary saturation and binding to anion-inhibiting factors (citrate, glucosaminoglycan).In 1974, Pak and coworkers identified three main types of hypercalciuria: 1) absorptive hypercalciuria, due to excessive intestinal absorption of calcium; 2) renal hypercalciuria, due to decreased renal reabsorption of urinary calcium; and 3) reabsorptive hypercalciuria, due to Enhanced mobilization of calcium by the bones. Absorptive hypercalciuria: The main cause of this disorder is the overabsorption of calcium by the intestine, which increases the filtration load of calcium by the kidneys; at the same time, the rise in blood calcium feedback inhibits the secretion of PTH, which decreases calcium reabsorption by the renal tubules, which together leads to an increase in urinary calcium excretion, and the maintenance of blood calcium homeostasis due to high urinary calcium offsetting the overabsorption of calcium by the intestine. It is thought that the intestinal overabsorption of calcium is due to increased synthesis of 1,25 dihydroxyvitamin D and low blood phosphorus. There are three types of absorptive hypercalciuria: Type I is the most severe, with persistent hypercalciuria regardless of the amount of calcium intake; Type II increases urinary calcium only when calcium intake is high, and decreases vice versa; Type III is due to low renal phosphorus threshold and renal phosphorus leakage, causing mild hypophosphorus, the latter promoting 1,25 dihydroxyvitamin D synthesis, resulting in increased intestinal absorption of calcium and bone decalcification, which eventually increases urinary calcium, so Type III is also known as phosphorus-losing hypercalciuria. Therefore, type III is also known as hypercalciuria. Menon & Koul suggest that the intestinal absorption of magnesium is normal but oxalic acid is increased in patients with absorptive hypercalciuria. Nephrogenic hypercalciuria: The physiological disorder of this disorder lies in primary renal calcium leak, i.e., increased urinary calcium excretion due to impaired calcium reabsorption from the renal tubules. The excessive renal calcium loss results in a decrease in blood calcium, which in turn stimulates a secondary increase in PTH excretion, which in turn increases the synthesis of 1,25 dihydroxyvitamin D, leading to an increase in intestinal absorption and ultimately maintaining blood calcium homeostasis. One-third of patients with renal hypercalciuria have a history of urinary tract infection, but it is not certain that it is a renal infection.Barilla et al. suggested that abnormal tubular function causes renal hypercalciuria.Muldowney suggested that renal hypercalciuria is due to excessive sodium intake.Buck showed that prostaglandins increase glomerular filtration rate and renal calcium secretion. Resorption hypercalciuria: This is mainly caused by hyperparathyroidism, which is a combination of increased bone resorption and bone decalcification due to excessive PTH secretion by the parathyroid glands, and increased intestinal absorption of calcium due to enhanced renal synthesis of 1,25 dihydroxyvitamin D. The combined effect of these factors disrupts the blood calcium balance and results in an increase in blood calcium. Although PTH also enhances renal tubular reabsorption of calcium, it cannot overcome renal calcium loss, and the net effect is hypercalciuria. 1.2, hyperoxaluria Hyperoxaluria is defined as urinary oxalate excretion >45 mg/d. Approximately 80% of the body’s oxalate is synthesized in the liver and is the end product of vitamin C metabolism, with the remainder coming from oxalic acid in food. In the urine, oxalic acid is 10 times more effective than calcium in increasing urinary calcium oxalate saturation. Therefore, increased urinary oxalic acid excretion is a more dangerous lithogenic factor. There are three main types of hyperoxaluria: 1) primary hyperoxaluria, due to excessive production of endogenous oxalic acid; 2) enterogenic hyperoxaluria, due to excessive absorption of exogenous oxalic acid; 3) idiopathic hyperoxaluria, also known as mild metabolic hyperoxaluria, the cause of which is unknown, but Baggio et al. The cause is unknown. Primary hyperoxaluria: This is an autosomal recessive disorder, which is very rare, and is divided into two types. Type I is due to a deficiency of alanine glyoxylate aminotransferase in the mitochondria, which prevents the conversion of glyoxylate to glycine, resulting in the oxidation of glyoxylate to oxalate as a metabolic end product. The pathogenesis of type II is due to a defective dehydroxypyruvate dehydrogenase, which fails to convert hydroxypyruvate into dehydroglyceric acid, resulting in the formation of oxalic acid and levoglyceric acid, which are excreted in large quantities in the urine to form hyperoxaluria with levoglyceric acid urine. Enterogenic hyperoxaluria: The common cause of hyperoxaluria is intestinal diseases, including various inflammatory bowel diseases and short bowel syndrome. Enterogenic hyperoxaluria is generally characterized by a moderate increase in urinary oxalic acid excretion of approximately 60 mg/d. The mechanism of its occurrence is related to disturbances in intestinal fat absorption. The bile acids produced during digestion are mostly reabsorbed in the proximal gastrointestinal tract, and when this function is impaired, saponification occurs, i.e. bile acids bind to divalent cations such as calcium and magnesium, so that soluble calcium no longer binds to oxalic acid in the intestine. This free oxalic acid is absorbed and leads to higher excretion of oxalic acid in the urine. In addition, unresorbed bile salts and lipids in the intestine increase the permeability of the colonic mucosa to oxalic acid, which further increases the concentration of oxalic acid in the urine. Pinto suggests that high protein intake and excessive renal oxalic acid secretion may cause hyperoxaluria. Coe & Kavalich suggest that the main cause of hyperoxaluria is excessive protein intake, followed by excessive uric acid synthesis in the body, which cannot be corrected by restricting protein intake. Deganello & Chou showed that hyperuricuria can cause calcium oxalate stones (called hyperuricemic renal calcium oxalate stones HUCN).The formation of HUCN has been largely elucidated, and it is the formation of calcium oxalate stones induced by sodium urate through an orientation attachment mechanism. Robertson suggests that excessive urinary sodium urate may also bind to certain urinary inhibitors of calcium oxalate crystallization, thus indirectly promoting the formation of calcium oxalate crystals. The incidence of hypocitraturia in calcium-containing stones ranges from 19% to 63%, according to Menon & Mahle, who define hypocitraturia as urinary citrate < 220 mg/d. Renal tissue is rich in the enzymatic system of citrate metabolism and is therefore an important site for the synthesis and breakdown of citrate. Under normal conditions, about 75% of the citrate entering the primary urine is reabsorbed by the renal tubules and the remaining 25% is excreted in the final urine. This process is influenced by the acid-base balance in the body. In moderate acidity, renal tubular reabsorption of citrate is enhanced and urinary excretion of citrate is reduced; in moderate alkalinity, the opposite is true. Citrate has an inhibitory effect on urinary calcium oxalate crystals. The inhibitory effect is related to the following factors. 1. citric acid is a crystallization inhibitor, which can directly inhibit the nucleation, growth and aggregation process of calcium oxalate crystals, and although its inhibitory activity is lower than other inhibitory factors in terms of molar concentration, it is an important inhibitory factor because its concentration in urine is higher than other inhibitory factors. 2. citric acid is a complexing agent, which can complex with calcium ions in urine, thus reducing It can reduce the saturation of calcium oxalate and indirectly inhibit the formation of calcium oxalate crystals. The rest of low citrate urinary stones are often combined with other metabolic disorders, such as high calcium urine can be combined with low citrate urine, which is due to the increase in urinary calcium concentration, too much calcium combined with citrate, which consumes citrate. Conway believes that hypocitraturia is the result of bacterial infection. 1.5, hypomagnesuria low urinary magnesium is the urinary excretion of magnesium <50mg/d. About 3% of calcium stone patients suffer from hypomagnesuria, Preminger pointed out that most of them also combined with hypocitraturia. Magnesium is a crystallization inhibitor for calcium oxalate and calcium phosphate, directly inhibiting nucleation, growth and aggregation of crystals; magnesium is a divalent cation that binds oxalic acid in the intestine, reducing the absorption of free oxalic acid; magnesium is also a complexing agent that forms soluble complexes with urinary oxalic acid, competitively reducing urinary calcium oxalate saturation. Causes the urinary magnesium to reduce the factors are generally two types: 1, gastrointestinal loss of excess, seen in the small intestine large resection and chronic diarrhea caused by magnesium absorption reduction, fatty diarrhea can be due to magnesium and intestinal fat formation "magnesium soap" affect its absorption; 2, intake reduction, seen in hunger and long-term fasting and only input does not contain magnesium liquid, etc.. 2, uric acid stones uric acid stones account for about 5-10% of the total number of stones. 75-80% of Uhlman reported pure uric acid stones, the rest of the other contains oxalic acid. The formation of uric acid stones depends on three factors: 1) urinary excretion of uric acid; 2) urinary pH; and 3) urine volume. Unlike calcium stones, no inhibitory factor for uric acid crystallization has been found so far. 2.1, hyperaciduria Seegmiller believes that there are two metabolic defects in patients with gout ancient or uric acid stones: excessive uric acid production and impaired renal secretion of uric acid. The end products of uric acid catabolism are mainly excreted by the kidneys. Clinically, uric acid excretion in the urine >600 mg/d is considered hyperuricemia. The common cause of excessive endogenous uric acid production is gout, which is associated with uric acid stones in about 11% of cases, followed by glucose 6 phosphatase deficiency, which presents with gout symptoms and uric acid stones at an early age. Increased uric acid excretion due to increased endogenous nucleic acid breakdown is seen in lymphoproliferative disorders such as lymphoma and leukemia, which result in high uric aciduria due to a large increase in purines in the body as a result of vigorous nucleic acid metabolism. In addition, the decomposition of tissue necrosis after tumor chemotherapy and radiotherapy can also produce a large amount of purine, resulting in high uric acid urine. 2.2, low urinary pH Low urinary pH is another factor in the formation of uric acid stones. The solubility of uric acid is pH-dependent, the solubility of uric acid is about 500mg/L when the urinary pH is 6.0, while it drops to 100mg/L when the urinary pH is 5.0. When the urinary pH is >6.5, uric acid mainly exists in the form of ionic urate, and generally no uric acid stone will be formed; however, when the urinary pH is lower than 5.5, all uric acid is in the non-dissociated state, and if it reaches supersaturation, it will be formed. Millman et al. found that urinary pH was 5.5 ± 0.4 in patients with uric acid stones and 6 ± 0.4 in patients with calcium oxalate stones. urinary pH below 5.5 for a long time is an important basis for the diagnosis of uric acid stones. Chronic persistent acidification may be a risk factor for the formation of uric acid stones in patients with gout, and the mechanism of persistent acidification of urine may be related to the decline of renal ammonia secretion function. In addition, a variety of gastrointestinal diseases can also cause uric acid stones, among which chronic enteritis and intestinal resection are the most common, which cause a large loss of bicarbonate, resulting in a decrease in urinary pH, thus triggering the formation of uric acid stones, but normal uric acid secretion. 2.3. Low urine output Uric acid stones are the most affected by temperature and water intake of all stones. In the high temperature environment, as well as in those who are physically active, they tend to lose a lot of body fluids and even become dehydrated, which reduces urine volume and concentrates urine, thus leading to uric acid supersaturation in the urine. Coe and Parks found that some professions such as drivers, surgeons and bankers are prone to uric acid stones. 3, bird droppings stone (ammonium magnesium phosphate stones) ammonium magnesium phosphate stones are mainly composed of ammonium magnesium phosphate hexahydrate and carbonate apatite. Nemoy & Stamey that guano stone crystals need to be in the urinary pH value of 7.2 or more and the presence of urinary ammonia. Ammonium magnesium phosphate stones are caused by urease producing bacteria in the urinary tract, mostly S. pyogenes, followed by Pseudomonas aeruginosa and Staphylococcus aureus, etc. The urease they produce catalyzes the decomposition of urea into ammonia and carbon dioxide, which is then combined with water to form ammonium hydroxide. Ammonium hydroxide can significantly increase the pH of urine. When the urine pH reaches 7.2, ionic ammonium can combine with magnesium and phosphate in the urine to form magnesium ammonium phosphate. During the decomposition of urea, a large amount of carbon dioxide is also produced, which is further hydrated into carbonic acid and then dissociated from carbonate. Also in alkaline solutions, calcium and phosphate into apatite, and then combined with carbonate to form carbonate apatite. Parsons points out that these crystals must adhere to the urinary epithelium before they can continue to grow into stones, and the ammonia from bacterial decomposition has an affinity for the charge of the mucopolysaccharide sulfate that protects the urinary epithelium, which can change the hydrophilicity of the mucopolysaccharide sulfate, and then the ammonium ions adsorb to the sulfate of the mucopolysaccharide sulfate, which then leads to The ammonium ions then adsorbed to the sulfate of mucopolysulfate, which then promoted the adhesion of magnesium ammonium phosphate crystals to the urinary epithelium. Depending on the adhesion mechanism of the lithogenic crystals and the supersaturation of the associated ions, stones can be formed and grow rapidly. Clinically, due to the rapid growth of these stones, they are easily shaped by the intrarenal collecting system and can often grow into large antler-shaped stones. Comarr et al. suggested that the susceptibility factors are urinary tract obstruction, neurogenic bladder, and long-term catheterization. Whether the magnesium ammonium phosphate stones are related to metabolism is unclear, Kristensen found that the glomerular filtration rate of patients with uric acid stones decreased, while urinary calcium secretion increased. 4, calcium phosphate stones According to Ciftcioglu statistics calcium phosphate stones account for about 10% of the total number of stones. Calcium phosphate stones are usually mixed with calcium oxalate stones. Since the interrelationship between calcium oxalate and calcium phosphate in the stone formation process has not been completely elucidated, at present, in clinical practice, calcium oxalate stones and calcium phosphate stones are often collectively referred to as calcium stones, and the etiology of mixed stones of these two components is basically grouped together. The incidence of pure calcium phosphate stones is not high, and the cause is mostly tubular acidosis. Renal tubular acidosis is a metabolic acidosis caused by dysfunctional acidification of the renal tubules. There are 4 types of tubular acidosis. Of these, only the distal type (type I) renal tubular acidosis and the proximal type (type II) renal tubular acidosis cause urinary tract stones. The mechanism of stone formation in this condition is due to the weakened acidification function of the kidney, which increases the urinary pH and makes it easier for calcium phosphate to precipitate and precipitate crystals in an alkaline environment. 4.1, distal type (type I) tubular acidosis Primary cases are mostly due to congenital defects in renal tubular function, which are autosomal dominant; secondary cases are seen in many diseases, most of which are secondary to pyelonephritis and sponge kidney. The pathogenesis may be due to the failure of the tubular hydrogen pump to secrete hydrogen and to establish and maintain a large hydrogen ion gradient between the luminal and peritubular fluids. Urine pH tends to be alkaline due to impaired acidification of the urine. At the same time, the systemic metabolic acidosis enhances the transfer of citrate in the mitochondria, resulting in a decrease in the urinary citrate content, and this metabolic factor is also an important cause of stone formation. About 70% of patients have renal calculi as a complication. The clinical features are: low blood potassium, high blood chloride, normal anion gap despite metabolic acidosis, and a urinary pH consistently above 6. 4.2, proximal type (type II) renal tubular acidosis This syndrome is caused by excessive loss of HCO-3 due to impaired renal tubular reabsorption of HCO-3. In addition to hyperchloremic metabolic acidosis and hypokalemia, the most important feature is the large amount of HCO-3 excreted in the urine due to impaired reabsorption. The large amount of HCO-3 in the urine leads to excessive secretion of urinary citrate, so it is believed that proximal type (type II) renal tubular acidosis is less likely to cause renal stones and renal calcification. 5, Cystinuria Cystinuria is the only cause of cystine stones, which is a rare chromosomal recessive disorder. Urinary tract stones are the most important clinical manifestation of cystinuria. In cystinuria, there is a defect in the absorption and transport of four dihydroxyamino acids, including cystine, by the basement membrane of the renal proximal tubule and the intestinal mucosa epithelium, resulting in increased urinary excretion of these dihydroxyamino acids. Cystine is almost insoluble in the physiological range of urinary pH, and when it reaches a state of excess, it crystallizes and eventually forms stones. Urinary cystine excretion in normal subjects is <20 mg/d. The upper limit of cystine solubility in urine in the normal pH range is 300 mg/L. The solubility of cystine also depends on urinary pH and almost doubles when urinary pH is increased to 7.5. However, because of the acidic nature of urine at night and the decrease in urine volume compared to daytime, the solubility of cystine is greatly reduced, and therefore cystine crystals are formed mainly at night. Only 10-20% of patients with cystinuria grow stones. The peak incidence of cystine stones is between 20 and 40 years of age, but they can also occur in childhood, accounting for about 6% to 8% of all stones in children. Although cystine stones are not calcium stones, they are moderately opaque on KUB films because of the presence of sulfur atoms in the cystine molecule, and typically appear as a uniform "frosted glass" image. Some cystine stones are mixed with calcium oxalate, so they may appear as highly opaque stones. In conclusion, urinary stone formation is mainly due to urinary supersaturation, followed by a disturbance in the balance between urinary saturation and various other modifying factors (inhibitory factors, promotive factors, pH, etc.). In this paper, we only analyzed the cause of urolithiasis from the composition of urinary stones, however, the formation of urinary stones is a complex process and the mechanism of its occurrence has not been fully understood so far, therefore, it needs to be further explored.