What causes kidney stones?
(A) Causes of development
Kidney stones are formed when certain factors cause an increase in the concentration or decrease in the solubility of crystalline material in the urine, which becomes supersaturated, precipitates crystals and grows and aggregates locally, eventually forming stones. The two most important factors in this process are the formation of supersaturation of urinary crystalline material and the decrease in the amount of inhibitors of crystallization in urine.
The formation of supersaturation state is seen in low urine volume, excessive absolute excretion of certain substances in urine, such as calcium, oxalic acid, uric acid, cystine and phosphate; urinary pH changes: uric acid solubility decreases when urinary pH decreases (<5.5); calcium phosphate, ammonium phosphate and sodium urate solubility decrease when urinary pH increases; urinary pH changes have little effect on calcium oxalate saturation. Sometimes the supersaturation state is transient and can be caused by a short period of decreased urine volume or a transient increase in urinary excretion of certain substances after a meal, so the measurement of 24h urine volume and urinary excretion of certain substances cannot help determine whether there is a transient supersaturation state.
(2) The reduction of inhibitors of crystallization in urine contains certain substances that inhibit the formation and growth of crystals, such as pyrophosphate inhibits the formation of calcium phosphate crystals; mucin and citrate inhibit the formation of calcium oxalate crystals, and stones are formed when such substances are reduced in urine.
(iii) Nucleation Homogeneous nucleation refers to the formation of crystals of one type of crystal. In the case of calcium oxalate, for example, these two ions form crystals when there is supersaturation, and the higher the ion concentration, the more and larger the crystals. The ions on the exterior of smaller crystals are continuously shed, and studies suggest that only when crystals containing more than 100 ions have sufficient affinity to keep the ions on the exterior of the crystals from being shed, can the crystals grow. The required ion concentration is lower than when the crystals are first formed. Heterogeneous nucleation means that if two crystals are similar in shape, one crystallization can act as a core to promote the other crystallization to aggregate on its surface. For example, sodium urate crystals can promote the formation and growth of calcium oxalate crystals. The formation of crystals in the urine that remain in the area of growth is conducive to the development of stones. Many crystals and small stones can be flushed out of the body by the urine. When certain factors such as local strictures and obstruction cause the urine flow to be blocked or slowed, stone formation is facilitated.
1, Factors affecting stone formation include.
(1) Increased excretion of urinary crystalline material
(1) High calcium urine: In normal people, urinary calcium excretion is <7.5mmol (or 0.1mmol/kg) per day when 25mmol of calcium and 100mmol of sodium are consumed; when 10mmol is consumed per day, urinary calcium excretion is <5mmol. Persistent high calcium urine is the most common independent abnormal factor in kidney stone patients, and the resulting stones are mostly calcium oxalate stones; correcting high calcium urine can effectively prevent kidney stone Correction of hypercalciuria can effectively prevent recurrence of kidney stones. Therefore, hypercalciuria plays a very important role in the development of kidney stones. According to its pathogenesis, it can be divided into the following four types.
Absorptive hypercalciuria: The most common type of hypercalciuria is found in 20% to 40% of kidney stone patients. Its etiology is mostly due to some intestinal diseases (e.g. jejunum) that cause increased intestinal calcium absorption and elevated blood calcium, which inhibits parathyroid hormone (PTH) secretion. As elevated blood calcium leads to increased glomerular filtration of calcium and decreased PTH leads to decreased renal tubular reabsorption of calcium, resulting in increased urinary calcium and a return to normal blood calcium. Increased calcium intake, VitD toxicity and increased VitD due to nodal disease can also lead to absorptive hypercalciuria. In these patients, the blood calcium concentration is often in the normal range due to increased compensatory calcium excretion.
Nephrogenic hypercalciuria: It is a type of idiopathic hypercalciuria and accounts for about 1% to 3% of patients with kidney stones. It is due to abnormal renal tubular function, especially in the proximal tubule, resulting in reduced calcium reabsorption. These patients often have secondary hyperparathyroidism, with increased PTH secretion; and increased synthesis of 1,25(OH)2VitD3, resulting in increased bone calcium mobilization and intestinal calcium absorption, and often normal blood calcium.
Bone resorption hypercalciuria: mainly seen in primary hyperparathyroidism, which accounts for about 3% to 5% of patients with kidney stones; and 10% to 30% of patients with primary hyperparathyroidism are complicated by kidney stones. It is also seen in hyperthyroidism, metastatic bone tumors, bone resorption due to prolonged bed rest, and Cushing’s syndrome.
Starvation hypercalciuria without PTH elevation: seen in about 5-25% of patients with renal calculi. Certain factors such as increased renal phosphorus excretion causes hypophosphatemia and leads to increased synthesis of 1,25(OH)2VitD3, which inhibits PTH secretion and thus increases urinary calcium excretion.
High oxaluria: The daily urinary oxalic acid excretion in normal subjects is 15-60 mg. Oxalic acid is the second most important component of kidney stones besides calcium, but most patients with calcium oxalate kidney stones do not have abnormal oxalic acid metabolism. Hyperoxaluria is mostly seen in abnormal intestinal oxalic acid absorption, or gut-derived hyperoxaluria, which accounts for 2% of patients with kidney stones. In normal people, the combination of calcium and oxalic acid in the intestinal lumen can prevent oxalic acid absorption. Ileal diseases (such as ileal resection, post-jejuno-ileal bypass formation, infectious small bowel diseases, chronic pancreatic and biliary diseases) lead to increased absorption of oxalic acid in the colon because fat absorption is reduced and fat binds to calcium in the intestinal lumen, thus there is not enough calcium to bind oxalic acid; and unabsorbed fatty acids and bile salts themselves can also damage the colonic mucosa, leading to The unabsorbed fatty acids and bile salts themselves can also damage the colonic mucosa, leading to increased oxalic acid absorption in the colon. In addition, in absorptive hypercalciuria, increased intestinal absorption of calcium can also lead to increased oxalic acid absorption. Hyperoxaluria is occasionally seen with excessive oxalic acid intake, VitB deficiency, excessive VitC intake, and primary hyperoxaluria. The latter is divided into type I and type II. Type I is caused by defective alanine-glyoxylate transaminase (AGT) in the liver; type II is caused by increased urinary oxalate and glyoxylate excretion due to deficiencies in hepatic D-glycerate dehydrogenase and glyoxylate reductase. Any cause of hyperoxaluria can lead to tubular and interstitial damage, resulting in renal calculi.
Hyperoxaluria is the only biochemical abnormality in 10% to 20% of patients with calcium oxalate stones, and is referred to as “hyperoxaluric calcium oxalate stones” and as a separate type of kidney stone. Another 40% of patients with hyperuricemia have both hypercalciuria and hypocitraturia. The causes of hyperuricuria are primary and myeloproliferative diseases, malignancies especially after chemotherapy, glycogen accumulation disorder and Lesch-Nyhan syndrome. Chronic diarrhea such as ulcerative colitis, focal enterocolitis and post-jejuno-ileal bypass surgery can cause a decrease in urinary pH due to loss of intestinal alkali on the one hand, and a decrease in urine volume on the other, thus contributing to the formation of uric acid stones.
Homocystinuria: This is a genetic disorder caused by impaired transport of cystine and lysine in the proximal tubules and jejunum. A large amount of cystine is excreted from the urine due to impaired renal tubular transport. The saturation of cystine in the urine is pH dependent. When the urine pH is 5, the saturation is 300mg/L; when the urine pH is 7.5, the saturation is 500mg/L.
⑤ Xanthinuria: a rare metabolic disease in which the conversion of hypoxanthine to xanthine and xanthine to uric acid is blocked by the lack of xanthine oxidase, resulting in elevated urinary xanthine (>13mmol/24h) and decreased urinary uric acid. During the application of allopurinol therapy, urinary xanthine increases due to inhibition of xanthine oxidase activity, but in the absence of an underlying impairment of the body’s pre-existing xanthine metabolism, xanthine stones generally do not occur.
(2) The influence of other components in urine on stone formation
(1) Urine pH: Changes in urine pH have an important effect on the formation of kidney stones. A decrease in urinary pH favors the formation of uric acid stones and cystine stones; while an increase in pH favors the formation of calcium phosphate stones (pH>6.6) and magnesium ammonium phosphate stones (pH>7.2).
② Urine volume: too little urine volume increases the concentration of crystalline material in the urine, which favors the formation of supersaturation. It is seen in about 26% of kidney stone patients, and 10% of patients have no other abnormalities except for daily urine volume less than 1L.
③Magnesium ion: magnesium ion can inhibit the absorption of intestinal oxalic acid as well as inhibit the formation of crystals of calcium oxalate and calcium phosphate in the urine.
④Citrate: It can significantly increase the solubility of calcium oxalate.
⑤ Low citrate urine: citrate reduces the saturation of calcium salts in urine by binding to calcium ions and inhibits the crystallization of calcium salts. The decrease in urinary citrate facilitates the formation of calcium-containing stones, especially calcium oxalate stones. Hypocitraturia is seen in any acidified state such as renal tubular acidosis, chronic diarrhea, post-gastrectomy, hypokalemia due to thiazide diuretics (intracellular acidosis), excessive intake of animal protein, and urinary tract infections (bacterial breakdown of citrate). Some other causes of hypocitraturia are not clear. Hypocitraturia can be the only biochemical abnormality in patients with kidney stones (10%) or coexist with other abnormalities (50%).
(3) Urinary tract infection: persistent or recurrent urinary tract infections can cause infectious stones. Bacteria containing urea-degrading enzymes such as Aspergillus, certain Klebsiella, Serratia, Enterobacter aerogenes and Escherichia coli can decompose urinary urea to produce ammonia, which raises urinary pH, prompting magnesium ammonium phosphate and phosphate carbonate stones to be in a supersaturated state. In addition, pus clots and necrotic tissues from infections, etc. also encourage crystals to collect on their surface to form stones. In some diseases with abnormal kidney structure such as ectopic kidney, polycystic kidney, and horseshoe kidney, kidney stones can occur due to repeated infections and poor urinary flow. Infections still occur as a complication of other types of kidney stones and are mutually causal.
(4) Diet and medications: drinking hardened water; malnutrition, lack of VitA can cause urinary epithelium to shed and form stone cores; taking aminoglutethimide (as a stone matrix) and vincristine (acetazolamide). In addition, about 5% of kidney stone patients do not have any biochemical abnormalities, and the cause of their stones is not clear.
2, kidney stones rarely consist of just one crystal, most of them have two or more, and one of them is the main body. 90% of kidney stones contain calcium, such as calcium oxalate, calcium carbonate phosphate and magnesium ammonium phosphate. Stones that do not contain calcium are formed from a core of uric acid and cystine. The majority of calcium-containing kidney stones can be visualized on X-ray. The density of the stone on X-ray and the degree of smoothness or irregularity of its surface are helpful in determining the stone composition.
(1) Calcium oxalate nephroliths: the most common, accounting for 71% to 84%. The urinary monohydrate calcium oxalate crystals are often similar to red blood cells and may be dumbbell-shaped. They are birefringent in shape and size. Calcium oxalate dihydrate crystals are biconcave-shaped and weakly birefringent. The stones are spherical, oval, rhombus or mulberry shaped, dark brown, very hard, rough surface, so they can easily damage the tissue and cause hematuria, mostly seen in alkaline urine. Sometimes small spherical stones with smooth edges can be formed, and spherical stratification can be seen. The stones can also be arranged in a tree-like pattern or exist alone. The X-ray features are deep mottling in the kidney stones with irregular margins, sometimes in the shape of the renal pelvis or calyces.
(2) Calcium phosphate and calcium carbonate nephrolites: calcium phosphate crystals are amorphous and too small to determine their refractoriness. The stones are granular, grayish white, and can increase rapidly in alkaline urine, but simple ones are rare, and mostly mixed with calcium oxalate or magnesium ammonium phosphate to form stones. x-ray image is clear, laminar pattern is more obvious, and sometimes fill the entire lumen of the pelvis and calyces in an antler shape.
(3) Uric acid stones: 5% to 10% of the stones. Anhydrous uric acid crystals are small and amorphous. Dihydrate uric acid crystals are “teardrop” or square-shaped, with double refractive properties. The stones are round or oval in shape, with smooth, orange-red surface, hard texture, and radially arranged in section.
(4) Cystine nephroliths: about 1%, their crystals are hexagonal in shape. Stone yellowish, smooth surface, soft texture, because of the sulfur and easy to show on the X-ray film.
(5) Magnesium ammonium phosphate stones: fast growing, most of the stones are “antler” shaped, clear X-ray image, stone density is not uniform. The crystals in the urine are rectangular.
(B) Pathogenesis
1.Theories of kidney stone formation
(1) renal calcium plaque theory: some scholars have repeatedly reported that calcified plaques were found in the renal papillae. In 1154 examined kidneys, 19.6% of the cases, 65 stones grew on calcified plaques, so it is presumed that calcified plaques are the basis of stone occurrence. From the current understanding, the cause of intrarenal calcification and microstones can be a manifestation of systemic stone salt supersaturation (ectopic calcification) or calcification due to necrosis of renal tissue by various factors. Both ectopic calcification and renal damage are closely related to stone formation, but those with such pathological damage do not always form stones, and stone formation does not have to be based on calcified foci.
(2) Urinary supersaturation crystallization theory: This theory suggests that stones are formed on the basis of urinary precipitation of crystalline components. Tests have been performed with supersaturated solutions alone, in which no matrix-like substances are attached, or with fibrous films to remove macromolecular substances in the urine can also form artificial stones, suggesting that supersaturated solutions may be one of the mechanisms of stone formation.
(3) Lack of inhibitory factors theory: The concept of inhibitory factors in urine was first derived from colloid chemistry. At present, scholars have done a relatively systematic study of two systems of calcium oxalate and calcium phosphate, as well as low and large molecular substances that play an inhibitory role in all aspects of homogeneous nucleation, heterogeneous nucleation, growth, and aggregation. The reproducibility and comparability of urinary inhibitor activity measurements have been significantly improved. On this basis, synthetic drugs that inhibit stone formation have been studied.
(4) Free particles and fixed particles theory: One of the views of the free particles formation theory is that the saturation of stone components in the urine increases, and the precipitation of crystals continues to grow into stones. Free particles cannot grow large enough to block the collecting duct as they flow through the renal tubules. Therefore, there must be a fixed number of particles to grow into a stone. Crystals can grow in large aggregates under certain conditions, or they can rapidly aggregate into large masses that adhere to the cell wall with the help of mucin. In addition, damage to the renal tubules facilitates crystal attachment. Retention of particles in the urinary tract is an important factor in stone growth.
(5) The theory of oriented attachment: most stones are mixed. Calcium oxalate stones often contain hydroxyapatite (or have this as the core), and it is not uncommon for calcium oxalate stones to have uric acid as the core. In addition, many patients with calcium oxalate stones have elevated urinary uric acid, and treatment with allopurinol may reduce stone recurrence. According to the theory of orientation attachment, the lattice arrangement of the various crystal faces of a stone often has obvious similarities with each other, and two crystal faces can be oriented to attach if they have a high degree of coincidence. The importance of this mechanism in complex urine has yet to be confirmed.
(6) Immunosuppression theory: This theory suggests that there is an immune and immunosuppressive problem in the formation of stones. The role of infections or environmental factors can shorten or prolong the latency period of stone formation. Once the immune system is provoked, lymphocytes produce antibodies that are transported by alpha-globulin and invade the renal epithelial cells causing kidney stones.
(7) Multifactorial theory: There are various molecules and ions in the urine that attract or repel each other. Because of the extremely complex physicochemical environment in urine, it is difficult to explain the principle of stone formation by one doctrine or one simple phenomenon. To date, many basic and clinical findings have been more supportive of the multifactorial theory. Robertson proposed six risk factors for stone formation, which are.
(1) Lower or higher urinary pH may lead to stone formation;
②Increased urinary oxalic acid;
(iii) Increased urinary calcium;
④Increased urinary uric acid;
(5) Increase in urinary substances that promote stone formation, including increased urinary crystals, TH protein, cellular breakdown products, phospholipids, cells and their debris, etc;
(6) Decrease in urinary substances that inhibit stone formation, including pyrophosphate, citrate, magnesium ions, and diphosphate. Recently, the role of macrophages and cell growth factors in stone formation has also received attention.
2. Physicochemical processes and factors influencing stone formation From the physicochemical point of view, stone formation is closely related to at least 3 factors.
(i) supersaturation of stone salts in urine;
② Decrease of inhibitors or excess of promoters;
(3) Abnormalities in urinary tract patency and mucosal surface properties.
(1) Supersaturation of urine crystals: Supersaturation of urine is the source of “energy” for stone formation. The degree of supersaturation of stone salts in urine can be expressed as the ratio of the activity product (AP) to the solubility product (SP) of stone salt ions. It has the following relationship with the free energy of forming solid phase (△G), namely: △G=RT/n(AP/SP). Where R is the thermodynamic constant and T is the absolute temperature. When the activity product is lower than the solubility product, urine is in an unsaturated state; when the activity product is higher than the solubility product, urine is in a supersaturated state. It is also common to see various stone salt crystals in urine, suggesting that although these stone salts are supersaturated in urine, they do not necessarily form stones, indicating that urine supersaturation is only a prerequisite for stone formation. Therefore, it is more important to study the kinetic processes of stone formation and the factors affecting these processes (e.g., inhibitors, promoters) than the thermodynamic processes.
(2) Kinetic processes of stone formation: Urine is a very complex physicochemical system in which several stone salts can be supersaturated. What kind of crystals are precipitated from urine is determined by both thermodynamic and kinetic aspects. The chemical kinetics of stone formation include.
①Nucleation, which refers to the formation of a solid phase from a supersaturated solution;
② growth, nucleation growth consists of two basic processes, i.e. solute transport (from solution to the vicinity of the crystal) and solute incorporation into the lattice, i.e. transport processes and surface interaction processes. There are various types of crystal growth, among which the main ways are spiral growth and multinuclear growth;
(iii) Aggregation, where solid particles become larger, not necessarily by crystal growth alone, but sometimes also by flocculation of small particles to form larger clumps;
(iv) Solid phase transformation, where there are various different solid phase substances in urine, but with different chemical compositions, or with the same chemical composition and different degrees of hydration. Generally, the solid-phase material formed under kinetically favorable but thermodynamically unfavorable conditions is unstable, and the combined predecessor clumps will transform sequentially to form a stable phase, which is not only a simple lattice transformation but also contains a series of other changes, such as the calcium and phosphorus ratios and the degree of hydration and other chemical reactions.
During stone formation, nucleation and aggregation may be a fast kinetic process once large crystals are formed and attached to the urinary tract wall surface. Stone formation in a supersaturated urinary environment may be a slow kinetic process. The coexistence of minerals and matrix in stones also results in a series of dehydration and state phase transition processes during their growth, resulting in a dense and hard stone structure.
(3) Promoters and inhibitors of stone formation: urine is supersaturated with certain stone salts, but the reason why stones occur only in a minority of people is unknown. There may be a lack of inhibitors or an excess of promoters in the urine of stone patients. In addition, there are natural and synthetic inhibitors such as certain herbs, artificial semi-synthetic acidic mucopolysaccharides, etc.
3, stone matrix and stone formation Kidney stones are composed of crystalline components and organic material (matrix), but the significance of matrix on stone formation is not clear. Most scholars believe that the matrix determines the stone structure and is essential for stone formation.
(1) Effect of glycosaminoglycans on stone formation.
(1) Composition of glycosaminoglycans: glycosaminoglycans (GAG) are also known as acidic mucopolysaccharides. with a molecular weight of about 2-30 kD, GAG is an important component of the cell surface and connective tissue, and plays an important role in regulating extracellular fluid volume, electrolyte movement, calcium balance and deposition in tissues (ossification or calcification, etc.) and tissue fibrosis. There are seven types depending on the monosaccharides that make up the disaccharide unit: hyaluronic acid; chondroitin sulfate A; chondroitin sulfate B; chondroitin sulfate C; heparan sulfate; heparin; and keratin sulfate.
The acidic hydroxyl and hexosamine sulfate groups of GAG have a negative charge. With the exception of hyaluronic acid, all GAGs have sulfate groups that readily bind positively charged calcium and are antagonistic to negatively charged oxalic acid. Heparin and heparan sulfate have several different structural forms and different functions. The sulfated GAG has an important role in protein binding and is involved in the regulation of water distribution; one GAG can bind to hundreds of water molecules. Recently, it was reported that a part of urinary GAG is excreted as proteoglycans, and during crystallization and stone formation, GAG may be involved in the reaction as proteoglycans.
② Urinary GAG excretion: adults can produce 250 mg of GAG in 1 day, of which about 10% is excreted from the urine. Normal adult serum GAG is about 2-3mg/L, of which the main component is chondroitin sulfate. Most of the GAG in the urine is the product of proteoglycanolytic enzymes, which is filtered by the glomerulus or secreted into the urine by the renal tubules. Some of them are proteoglycans. 60% of urinary GAG is chondroitin sulfate A, 18% is keratin sulfate, 15% is heparan sulfate, 4% is hyaluronic acid, 2% is chondroitin sulfate B, but no heparin.
(③GAG in the matrix of stones: In 1956, Boyce decalcified the stones with EDTA and extracted GAG (mainly in the form of mucin) from the matrix. The matrix contained about 1/3 carbohydrate component and 2/3 protein. 1968, the presence of GAG was established by the discovery of hexosamine in the matrix.
Currently, it is believed that the type of matrix GAG differs in different types of stones, such as heparan sulfate as the main component in the matrix of calcium oxalate and uric acid stones, heparan sulfate and hyaluronic acid as the main components in the matrix of calcium oxalate stones dihydrate, and hyaluronic acid as the main component in calcium phosphate stones.
The effect of GAG on stone formation: Experimentally, chondroitin sulfate A can inhibit oxalate crystals agglutination, while heparan sulfate and hyaluronic acid do not inhibit or even promote the agglutination of calcium oxalate crystals. The increasing concentration of heparan sulfate and hyaluronic acid increased the promotion effect on the agglutination of calcium oxalate crystals. Heparan sulfate has a slightly greater effect than hyaluronic acid in promoting the agglutination of calcium oxalate crystals, while the mixture of the two has a very strong activity in promoting the agglutination of crystals.
(2) Role of matrix macromolecules on stone formation.
(1) Tamm-Horsfall protein (TH protein, THP): THP is the main mucin present in urine, synthesized by Golgi in the epithelial cells of the thick ascending branches of the renal medullary loops, and can bind to calcium. Most scholars believe that TH protein can both inhibit and promote stone formation.
The nephrocalcin: polyaspartic acid and polyglutamic acid can inhibit the growth of calcium oxalate crystals in monohydrate, which can be extracted from human urine by chromatographic chromatography.Nakagawa and Coe et al. elucidated the nature of this substance after more than 10 years of research, and named it nephrocalcin (14kD acidic glycoprotein). Its amino acid composition is characterized by its richness in aspartic acid and glutamic acid, and minimal content of lysine, arginine, tyrosine, phenylalanine, and tryptophan. Immunohistochemistry was applied to localize it to the proximal renal tubules and the superior branches of the medullary loops.
Crystal matrix protein (CMP): In 1991, Ryall et al. extracted a protein from calcium oxalate crystals with strong inhibitory effect on calcium oxalate crystals and named it CMP (31kD), whose N-terminal is identical to human thrombospondinogen and C-terminal is an active peptide (similar to human thrombospondinogen active peptide).CMP has a CMP strongly inhibited the growth of calcium oxalate crystals. Immunohistochemistry revealed that CMP was present in all parts of the renal unit except the glomerulus, and immuno-scanning electron microscopy showed that CMP was also present on the surface of the crystals.
Serum proteins: Dussol et al. found that serum proteins bound to calcium oxalate crystals could enter the stone matrix. In addition, the matrix contains α-globulin and occasionally γ-globulin.
OPN (osteopontine): OPN is a glycoprotein that connects osteoblasts to hydroxyapatite. Immunohistochemically, OPN was found to be scattered in the distal tubules of normal kidneys, and when rats were given glyoxalate to make a kidney stone model, it was found that the amount of OPN increased with the amount of glyoxalate, and caused hypertrophy and vacuolar degeneration of renal tubular cells, followed by calcium salt deposition and formation of stone cores. Animal experiments showed that PTH increased the expression of OPN in renal tissues. OPN expression can also be increased in renal tissue in the presence of hydronephrosis, urinary tract infection. Estrogen can down-regulate OPN expression.
(6) Calprotein (calprotection): renal calprotein may be secreted mainly by macrophages and is present in the distal renal tubules and their surrounding sites. When stones are formed in the kidney, the local calprotein is significantly increased.
4. Oxalic acid metabolism and stone formation Among kidney stone calculi, calcium oxalate stones are the most common (about 80%). Therefore, it is of practical significance to study the causes of calcium oxalate stones and their formation process.
(1) The nature of oxalic acid: Oxalic acid (HOOC-COOH) is a simple dihydroxy acid. Oxalic acid is a metabolic end product of many plants, animals and microorganisms. Oxalic acid exists as a salt formation in animals or plants, and the most common form in nature is calcium oxalate. Calcium oxalate forms the skeleton of plants or the mycelium of fungi. However, in animals (especially humans) it is often a factor in the production of stones.
(2) Source of urinary oxalic acid: About 10% of urinary oxalic acid originates from the daily diet and the rest from internal metabolism. Although dietary oxalic acid accounts for only 10% of urinary oxalic acid, it is an important cause of stone formation. For example, the Arab diet is high in oxalic acid and low in calcium, so the urinary calcium level can be maintained at a low level. Because of the increased urinary oxalic acid, the incidence of stones is significantly increased. In addition, intestinal absorption of oxalic acid increases significantly on a low-calcium diet or during fasting; an increase in urinary oxalic acid is generally seen after eating; fluctuations in urinary oxalic acid levels occur due to seasonal changes, i.e., higher levels of urinary oxalic acid in seasons when more vegetables are available.
Oxalic acid in the urine of patients with enterogenic hyperoxaluria mainly originates from diet. After ileal resection or performing jejuno-ileal anastomosis (inter-intestinal short circuit), fat absorption is poor and fatty acids in the intestine increase. At this time, calcium in the intestine combines with fatty acids to form fecal stones, which reduces the amount of calcium bound to oxalic acid and increases the amount of free oxalic acid that can be absorbed, so taking calcium supplements can reduce the amount of oxalic acid in the urine. However, oral calcium should not exceed 3.0 g/d, otherwise urinary calcium can be mildly elevated. After drinking large amounts of mineral water, urinary calcium increases while urinary oxalic acid decreases because of increased calcium intake.
(3) Factors influencing urinary oxalic acid excretion.
(1) Calcium intake: Due to the regulation of 1,25-(OH)2D3 and PTH, so even if calcium intake is increased, the intestinal absorption of calcium does not increase excessively. Oxalic acid absorption in the intestine lacks this feedback regulation mechanism. If the amount of oxalic acid in the diet increases, the amount of free oxalic acid that can be absorbed by the intestine also increases, and the amount of oxalic acid in the diet can directly determine the amount of oxalic acid absorbed by the intestine. If calcium intake is increased, oxalic acid absorption is reduced instead. It is generally accepted that oxalic acid is filtered from the glomerulus, secreted or reabsorbed in the proximal tubules, and that almost all of the endogenous oxalic acid and oxalic acid absorbed by the intestine is excreted by the kidneys. The excretion of oxalic acid in the urine can be reduced by taking calcium lactate and citrate preparations at the same time. Therefore, it may be important to reduce the incidence of stones in our country by having more calcium-containing diet in general.
②High protein diet: In recent years, the reason for the dramatic increase in the incidence of urinary stones is mainly related to the high protein diet (especially the excessive intake of animal protein). Therefore, excessive intake of protein increases oxalic acid in the urine and promotes stone formation. The reasons why a high-protein diet promotes stone formation may be: the consumption of a high-protein diet increases uric acid in the urine and decreases the pH of the urine, which predisposes to the formation of calcium oxalate stones; the increase in uric acid in the urine increases the formation of uric acid crystals and produces epithelial effects that contribute to the formation of mixed stones of uric acid and calcium oxalate.
③High-fat diet: Haruo Ito used multivariate analysis of the relationship between the nutrients consumed and urinary oxalate. It was found that calcium reduced urinary oxalic acid. And fat can increase urinary oxalic acid levels. Since the ingested fat was not fully absorbed, the fatty acids remaining in the intestine were bound to calcium, so the calcium that should have been bound to oxalic acid was reduced, resulting in an increase in free oxalic acid that was absorbed by the intestine, which increased urinary oxalic acid.
(4) Oxalic acid-degrading bacteria in the intestine: Bacteria that can break down oxalic acid have been isolated from the intestine (pepcidobacterium bifidum-sine of the genus Lactobacillus and propionibacterium of the genus Propionibacterium, etc.). The use of these intestinal bacteria can be explored as a new way to prevent the formation of kidney stones.
(4) Calcium oxalate stones: the vast majority of kidney stone calculi are calcium oxalate stones. Studies have shown that calcium oxalate stones are closely related to the following factors.
(i) the high oxalic acid environment at the site of stone formation;
②Calcium binding proteins are involved in the formation of calcium oxalate crystalline core;
(iii) The role of macrophages and cytokines in the formation of calcium oxalate stones;
(iv) The presence of calcium oxalate stone inhibitors in the stone matrix and urine.
The general process of calcium oxalate stone formation is as follows: crystals are formed in the lumen of the distal tubule or in the tubular cells of the kidney under the conditions of pathogenic factors of stones (e.g. hyperoxaluria, infection and hydronephrosis), and the local oxalic acid concentration in the kidney tissue is also increased. The former causes the crystals to continue to grow, agglomerate, adhere, and remain in the epithelial cells of the tubular lumen and form stone particles. The latter induces macrophage aggregation, engulfing oxalic acid and calcium oxalate crystals, and releasing bone bridging and calcium antibiotics, which, with the participation of cytokines, form stone cores and shed them into the tubular lumen to form stones.