In clinical practice, commonly used drugs for alkalinizing urine include potassium sodium citrate, sodium bicarbonate, acetazolamide, etc., and the specific introductions are as follows: (1) Potassium sodium citrate: It is a strong base-weak acid salt with the molecular formula K₆Na₆H₃(C₆H₅O₇)₅, having a good physiological ratio of potassium, sodium, and hydrogen ions. After absorption in the body, it can be metabolized into bicarbonate, further increasing the alkaline load of the body, raising the pH value of urine, and thereby increasing the solubility of uric acid stones and cystine stones^[7]. However, it is known that potassium sodium citrate has some adverse reactions such as abdominal pain, diarrhea, nausea, and gastrointestinal symptoms, as well as hyperkalemia and allergic reactions. Moreover, there are clear contraindications, such as hyperkalemia, chronic or acute renal failure, urinary tract infections, peptic ulcers, and severe acid-base imbalance. Additionally, excessive intake of potassium sodium citrate may cause overalkalization of urine. If the pH value exceeds the recommended range (6.2-6.8) for several consecutive days, it will lead to metabolic alkalosis and increase the risk of phosphate stone formation, thus promoting the formation and growth of infectious stones^[3]. (2) Sodium bicarbonate: Its ability to alkalinize urine not only promotes the dissolution of uric acid and cystine stones but also promotes the dissolution of urolithiasis caused by melamine^[8]. The mechanism of sodium bicarbonate alkalinizing urine is that after oral administration, it first enters the digestive tract to neutralize gastric acid. The part that does not participate in neutralizing gastric acid is absorbed into the blood and finally excreted into the urine in the form of bicarbonate ions, thereby achieving the effect of alkalinizing urine. However, sodium bicarbonate has many adverse reactions, which easily lead to alkalosis and serious gastrointestinal reactions. When it causes sodium accumulation in the body, it can lead to edema, hypertension, and even congestive heart failure^[9]. (3) Acetazolamide: It is a carbonic anhydrase inhibitor. By blocking the reabsorption of HCO^3- in the proximal renal tubules and inhibiting the secretion of H⁺, it achieves the purpose of alkalinizing urine and promotes stone dissolution. However, acetazolamide can easily cause overalkalization of urine, thus increasing the risk of calcium phosphate stone formation. It can also cause gastrointestinal reactions, systemic metabolic acidosis, and electrolyte disorders^[9]. Therefore, during the treatment process of using drugs to alkalinize urine and promote stone dissolution, attention should be paid to the adverse reactions of the drugs, timely symptomatic treatment should be provided, and the changes in urine pH values should be monitored to avoid the occurrence of infectious stones.

Studies have shown that the formation mechanism of infectious calculi is relatively complex and may be closely related to urease-producing microorganism infection or alkaline urine [sup][10][/sup]. Urease-producing microorganisms can hydrolyze urea into ammonium ions, increase the pH value of urine, make it alkaline, and lead to the formation of infectious calculi; at the same time, over-saturated ammonium ions in urine combine with phosphate ions and magnesium ions to form calculi. The key to treating infectious calculi lies in antibiotic anti-infection treatment, surgical removal of all calculus fragments, and prevention of postoperative recurrence of calculi. In the removal of residual stones after surgery, acidifying urine and anti-infection treatment also play an important role [sup][11][/sup]. It has been reported that drugs such as ammonium chloride, vitamin C, and L-methionine have the effect of acidifying urine and have been used for the treatment of residual stones after surgery for infectious calculi [sup][12][/sup]. However, when there is an infection, these drugs' ability to acidify urine will decrease to varying degrees. Therefore, when using drugs that acidify urine, it is necessary to strengthen anti-infection treatment. Anti-infection treatment not only synergizes with acidic drugs to promote calculus dissolution but also significantly reduces the risk of urinary tract infections, sepsis, and postoperative bleeding in patients [sup][11][/sup]. In addition, Suby solution and Renacidin solution are both acidic solutions. They can directly dissolve calculi by chemical dissolution method with relatively high success rates [sup][13][/sup]. The specific method of chemical dissolution is to inject the solution through one nephrostomy tube and drain the solution from another nephrostomy tube. Although the method of chemical dissolution has a high success rate, the risk of sepsis is relatively high, and it is rarely used in clinical practice currently. In addition, after surgery, urease inhibitors such as acetohydroxamic acid and hydroxyurea can be used to inhibit the catalytic action of urease, thereby reducing the conversion of urea in urine into ammonium ions, thus reducing the over-saturation of pH value and ammonium ions in urine [sup][11][/sup], and promoting the dissolution of infectious calculi. For postoperative patients with infectious calculi, residual stones can be dissolved through combined acidification of urine and anti-infection treatment or the use of urease inhibitors.

Endogenous oxalate is produced by hepatic metabolism and is one of the products generated when glyoxylate is acted upon by lactate dehydrogenase. An increase in its concentration can lead to an increased excretion of oxalate in urine, thereby increasing the risk of oxalate stone formation. Wen Tianbin et al.^[21] reported that oral vitamin B6 can reduce the incidence of encrustation on ureteral stents after surgery for calcium oxalate stones, effectively lowering the postoperative recurrence risk of calcium oxalate stones. It has been reported that vitamin B6 can be used to treat primary hyperoxaluria because it reduces the excretion of oxalate in urine. The specific mechanism of action is that vitamin B6 is a coenzyme for alanine-glyoxylate aminotransferase, and the metabolic product of glyoxylate under the action of alanine-glyoxylate aminotransferase is glycine rather than oxalate^[22]. Therefore, vitamin B6 can reduce the production of endogenous oxalate, thereby reducing the renal oxalate load and preventing the formation and recurrence of calcium oxalate stones.

Researchers have divided known intestinal bacteria capable of degrading oxalate into two categories: (1) General oxalate-degrading bacteria: such as Lactobacillus, Bifidobacterium, Escherichia coli, etc.; (2) Special oxalate-degrading bacteria, such as Oxalobacter formigenes (O.f.) which uses oxalate as the sole carbon source and energy source^[23]. Paul et al.^[24] showed that oxalate decarboxylase secreted by Lactobacillus can prevent the formation of calcium oxalate stones by degrading intestinal oxalate in rats. A case-control study showed a strong negative correlation between the recurrence of calcium oxalate stones and the colonization of Oxalobacter formigenes (Oxf). It can reduce the risk of stone recurrence by about 70%. Conversely, the use of antibiotics will inhibit the colonization of Oxf in the intestine^[25]. It is evident that Oxf can prevent the formation of calcium oxalate stones, mainly achieved by reducing the excretion of oxalate in urine. The specific mechanisms include two types: (1) degradation of oxalate in the intestine; (2) reduction of oxalate absorption in the intestinal mucosa and promotion of endogenous oxalate secretion in the intestinal mucosa^[26]. This is because the oxalate metabolism mediated by Oxf is mainly achieved through the membrane transporter OxlT (encoded by the OxIT gene) to take up extracellular oxalate and convert it into formate. The specific process is as follows: formyl coenzyme A transferase activates oxalate by adding a coenzyme A molecule to generate oxalyl coenzyme A, then oxalyl coenzyme A is decarboxylated into carbon dioxide and formate, and formate can exchange with oxalate, further promoting the metabolism of oxalate^[27], i.e., increased oxalate degradation in the intestine and reduced absorption lead to decreased oxalate saturation in urine, thereby inhibiting stone formation. Therefore, theoretically, calcium oxalate stones can be prevented from forming by taking probiotics (Lactobacillus, Bifidobacterium, Oxalobacter formigenes, etc.) orally to reduce the oversaturation of oxalate in urine; however, the degradation of oxalate may be the result of multiple bacterial species working together. The currently known oxalate-degrading bacteria may not produce significant effects. In addition, during the prevention of calcium oxalate stone formation, studies have shown that compared with pure large-volume drinking water, potassium sodium citrate hydrogensodium group has a more obvious decrease in urinary oxalate content^[28]. Another report shows that the effect of Puerarin combined with potassium sodium citrate hydrogensodium is better than monotherapy with potassium sodium citrate hydrogensodium, and the decrease in urinary oxalate content is more significant^[29]. Large amounts of drinking water (2.5-3.0 L/day), high-calcium diet, restriction of vitamin C and oxalate intake can all reduce the concentration of oxalate in urine^[30], thus preventing the formation of calcium oxalate stones. Therefore, for patients after calcium oxalate stone surgery, the recurrence rate of calcium oxalate stones can be reduced to some extent by adjusting dietary habits, taking vitamin B6, probiotics, potassium sodium citrate, and Puerarin.

Osteopontin (OPN) plays a crucial role in the formation of kidney stones, but whether it exerts an inhibitory or promoting effect remains controversial. Some studies have shown that OPN can inhibit the formation of kidney stones, while others suggest that it can promote the formation of kidney stones. Domestic and international relevant literature indicates that there is more evidence supporting the promoting effect of OPN on the formation of kidney stones than its inhibitory effect^[33]. The mechanism by which OPN promotes the formation of kidney stones may be related to its mediation of renal oxidative stress responses. Studies have shown that after renal cell damage produces large amounts of OPN, OPN can drive macrophages into the kidneys and differentiate them into M1-type macrophages (pro-inflammatory macrophages)^[34]. M1-type macrophages not only release inflammatory factors such as tumor necrosis factor-α, interleukin-12, and interleukin-23, inducing inflammation in renal tissues, but also increase the expression of pro-inflammatory and adhesion-related genes (such as interleukin-6, nitric oxide synthase, and tumor necrosis factor-α), promoting the aggregation and adhesion of stones^[35]. Additionally, it has been reported that OPN can enhance the degranulation and migration of mast cells mediated by immunoglobulin E^[36], causing or exacerbating inflammatory reactions and promoting renal tissue injury. Furthermore, OPN can also promote the differentiation of naive T cells into inflammatory T cells^[37]. These inflammatory cells can trigger renal inflammatory responses, leading to crystal deposition and calcification within the kidney, thereby promoting stone formation. OPN is a secreted protein that is highly phosphorylated and can promote stone aggregation. Its degree of phosphorylation can not only affect the degree of cell adhesion but also influence the interaction between OPN and other proteins^[33]. Therefore, theoretically, the formation of kidney stones can be prevented by inhibiting the expression of OPN. Basic research has confirmed that broadleaf goldthread^[38], potassium citrate^[39], and metformin^[40] can reduce the expression of OPN, alleviate oxidative stress injury, and inhibit the formation of calcium oxalate stones in rat kidneys.

Animal experimental studies have shown that sulforaphane may achieve antioxidant damage protection of rat renal tubules and inhibit the formation of calcium oxalate stones by activating Nrf2 protein (a transcription factor that plays an important role in cell oxidative stress) and its downstream signaling pathways^[41]. Zhu et al.^[42] confirmed that dimethyl fumarate can inhibit the formation of calcium oxalate stones in rats through antioxidant effects. The possible mechanism is to up-regulate the level of Nrf2 protein in the nuclei of renal tubular cells, inhibit the expression of Nox4 and p22 subunits of reduced nicotinamide adenine dinucleotide phosphate oxidase induced by high oxalate, improve the oxidative stress response in renal cells, correct mitochondrial metabolic abnormalities, and inhibit cellular inflammatory responses, differentiation, and apoptosis, thereby achieving the effect of preventing stone formation. Deng Maofang et al.^[43] showed that the extract of Prunus mume can protect renal function and inhibit the formation of kidney stones. Its mechanism may be achieved by inhibiting the expression of monocyte chemotactic protein-1 (which can promote the release of inflammatory mediators by mediating monocytes-macrophages and T lymphocytes, inducing local inflammatory reactions in the body^[44]) and OPN. Theaflavins are the main active components extracted from black tea, which have anti-tumor, antioxidant, anti-inflammatory, and anti-infection functions. Ye et al.^[45] showed through animal experiments that theaflavins can inhibit the formation of calcium oxalate stones in the kidneys by inhibiting renal oxidative stress reactions. The specific mechanism may be as follows: when stone crystals cause renal injury, theaflavins can up-regulate the expression of silent information regulator 1 (stimulating its expression can reduce the occurrence of oxidative stress and inflammatory reactions) and down-regulate the expression of miR-128-3p (overexpression of which can promote renal inflammation and oxidative stress), reduce the oxidative stress reaction in the kidneys, alleviate the oxidative damage of tubular epithelial cells caused by calcium oxalate crystals, and then reduce the expression of adhesion molecules CD44 and OPN, thereby reducing the adhesion and deposition of crystals in the kidneys and achieving the purpose of inhibiting stone formation. However, its clinical efficacy and safety need further study.