INTRODUCTION:

Urolithiasis ranks as the third most prevalent kidney disease, with a global rise in its occurrence^1,2. The recurrence rate is notably high, affecting 70-81% of males and 47-60% of females^3,4. Men are three times more likely to develop this condition compared to women, as testosterone promotes stone formation, while estrogen inhibits it. When these stones migrate from the renal pelvis into the ureters, bladder and urethra, the condition is referred to as urolithiasis (from 'ouron' meaning urine and 'lithos' meaning stone)⁵.

Kidney stones are solid, hard fragments that develop in the urinary system^6,7.The formation of calculi, or mineral crystals such as calcium oxalate, in the kidney or other urinary system components, can result in abdominal pain ranging in intensity, blood in the urine, and even urinary tract infections⁸ . Urinary calculi disease seems to be more common in those who live in rocky places with hot and dry climates⁹. Because of its complicated etiology and high recurrence rate, stone formation is regarded as a medical challenge. Urinary stones can be categorized based on several factors, including size, location, composition, etiology of production, and recurrence risk¹⁰. Urinary stones consist of a combination of organic and inorganic crystals along with proteins. The primary components of these stones include calcium, uric acid, struvite, and ammonium acid. Generally, the formation of urinary stones occurs when the urine loses its natural inhibitors of stone formation or becomes saturated with stone forming constituents. Several environmental and nutritional factors, including diets high in animal protein and low urine volume, can contribute to urolithiasis. Stone development may also be influenced by metabolic changes (such as hypercalciuria and hyperuricosuria) and a lack of components that inhibit the formation of stones (such as citrate, magnesium, and glycosaminoglycans¹¹.

Urinary System and Stones:

Once formed in the glomerulus, the urine filtrate enters the tubules where secretions or reabsorption alter its volume and composition. Most solute reabsorption happens in the proximal tubules, while the distal tubule and collecting ducts are responsible for fine-tuning urine composition¹². Urine is composed of 95% water, 2.5% urea, and 2.5% a mixture of minerals, salts, hormones, and enzymes. In the proximal tubules, reabsorbed glucose, sodium, chloride, and water are returned to the bloodstream, along with essential elements such as proteins, amino acids, bicarbonate, calcium, phosphate, and potassium. The distal tubule plays a crucial role in balancing the acid-base and salt levels in the blood¹³.

Types of Kidney Stone:

Abnormalities in the chemical composition of urine can influence the formation of kidney stones, which vary in size, structure, and chemical makeup¹⁴.

The different types of kidney stones are summarized in Table 1.

Table 1. Stones with Constituents^15,16

Stone Name	Estimated Frequency
Calcium oxalate	70 %
Calcium phosphate	10 %
Uric acid	5-10 %
Struvite	10 %
Cystine	<1%

Pathophysiology:

A kidney stone is a solid mass that forms in one or both kidneys due to the accumulation of crystals from stone-forming substances. Their size can range from a few millimeters to several centimeters. The pathogenesis of kidney stones involves two fundamental components¹⁷:

a. increased excretion of components that might form stones in the urine, such as cystine, calcium, phosphorus, uric acid, and oxalate.

b. physical and chemical changes, such as urine's pH, stone matrix, and protective substance content, that affect the growth of stones.

Supersaturation of urine with constituents that form stones is essential for stone development. Additionally, substances that can alter the urine’s pH and affect nucleation, crystallization, and aggregation also play a crucial role in the formation of stones^18,19

Reasons for Stone Formation:

Common causes of stone formation include inadequate urine discharge, urinary tract microbial infections, diets rich in oxalates and calcium, vitamin imbalances such as vitamin A deficiencies or excess vitamin D, and various metabolic disorders like hyperthyroidism, cystinuria, gout, and intestinal dysfunction. Urolithiasis is a complex condition resulting from an imbalance between crystallization promoters and inhibitors within the kidneys²⁰. Table 2 shows promoter and inhibitor of kidney stone formation.

Table 2: Promoter and inhibitors of stone formation

Promoters	Inhibitors
Cistein	Citrate
Calcium	Flavonoids
High urine pH	Hydration
Low urine volume	Magnesium
Uric acid	Potassium
	Phytate

Mechanism of Oxalate Crystal Formation:

It is suggested that stone formation results from a series of physiological processes occurring within the urinary system²¹. Supersaturation of urine with urine forming constituents and an imbalance between lithiatic promoters and inhibitors in bodily fluids. Mineral salts such as calcium, sodium, urates, oxalates, and Tamm-Horsfall protein are examples of promoters. Lithiasis is also promoted by low urine pH^22,23,24. Inhibitors are made up of organic substances like protease inhibitors, nephrocalcin and inorganic substances like citrates, glycossaminoglycans, pyrophosphates, magnesium. When a healthy person's naturally existing stone inhibition capacity fails, there is an occurrence of lithiatic stone. The damage to renal epithelial cells creates a favorable environment and surface for mineral crystals to attach, which also aids in crystal formation²⁵. In urine, heterogeneous nucleation occurs when nuclei often develop on pre-existing surfaces. Urinary casts, red blood cells (RBCs), epithelial cells, and other crystals can serve as nucleating centers. The mechanism of stone formation is illustrated in Fig 1.

Prevention of Urolithiasis Diseases:

Despite considerable advancements in technology for stone removal over the past 30 years, the issue of recurring stone formation persists. The recurrence rate for kidney stones is 15% within the first year and may increase to 50% within five years following the initial occurrence²⁶. Determining the type of stone and the risk factors for stone formation is necessary for effective kidney stone prevention. In order to prevent the development of new stones, personalized therapy including dietary modifications, supplements, and medicine can be designed. To manage kidney stones, individuals should ensure they consume enough fluids to achieve a urine output of at least 2 liters per day, irrespective of the stone's underlying cause. High sodium intake can elevate urinary calcium levels and reduce the reabsorption of calcium by the renal tubules, thereby increasing the risk of stone formation²⁷. Such patients should not consume more than 2000–3000 mg/day of sodium from food. Reducing animal protein consumption is advised due to the high levels of sulfur-containing amino acids in these proteins, which contribute to an increased acid load. Consequently, a diet rich in animal protein decreases urine pH and citrate levels, enhances calcium excretion through urine by promoting bone resorption, and reduces calcium absorption in the kidneys²⁸. Reduced calcium intake increases oxalate absorption in the gut, which can lead to an increased risk of stone formation²⁹. As ascorbic acid is converted to oxalate in vivo, vitamin C has been associated with the development of stones. As a result, it is advised to restrict vitamin C supplementation to 500 mg/day or less.

Fig 1: Mechanism of kidney stone formation

Role of Natural Diet in the Prevention of Kidney Stones:

Recent research on humans has indicated that diets rich in fruits and vegetables may help to avoid urolithiasis³⁰. Epidemiological research indicates that dietary intake may be a major risk factor for kidney diseases. Small-scale human studies have shown that diets higher in plant-based protein than in animal-based protein can lower glomerular filtration rate (GFR) and improve metabolic acidosis, which reduces the progression of nephropathy in chronic kidney disease patients³¹. One of the primary preventative treatments for individuals with lower GFR is the use of sodium-based alkalis to reduce acidity through diet³². Consuming a diet rich in plant-based, natural foods has been demonstrated to increase both the pH and volume of urine, along with elevating the levels of stone-inhibiting compounds such as magnesium, potassium, citrate, and phytate. These changes are linked to a reduction in the supersaturation of uric acid and calcium oxalate³³. Phytate is the main natural source of phosphate. Its consumption is associated with the formation of insoluble calcium complexes in the gut, which may lower the risk of urolithiasis and inhibit crystal formation in the urine³⁴. A natural diet that raises alkali load can enhance urinary citrate, which significantly delays the development of kidney stones³⁵. Dietary fiber, abundant in fruits and vegetables, helps prevent stone formation by binding with fats and minerals in the digestive tract, thus reducing calcium and oxalate excretion in the urine³⁶. Increased fruit and vegetable intake is linked to a lower risk of urolithiasis³⁷. Epidemiological data indicate that high intake of carbohydrates, fats, proteins, purines, dairy products, oxalates, and sodium chloride is associated with a higher incidence of urinary stone disease.

Herbal Treatment of Kidney Stone:

Many medications, including thiazide diuretics and alkali citrate, are employed to lower the incidence of hypercalciuria and hyperoxaluria, which contribute to kidney stone formation³⁸. However, due to their limited efficacy and poor tolerability, these treatments are not highly effective. Given the limitations of surgical options and the scarcity of effective pharmacotherapies, exploring new pharmaceutical approaches for kidney stone treatment is crucial. Various medicinal plants with diuretic, antispasmodic, anti-inflammatory and antioxidant properties have been shown to reduce crystal nucleation, aggregation, and crystallization, making them valuable in managing urolithiasis.

Role of flavonoids in urolithiasis:

The prevention of calcium oxalate calculi is aided by the anti-inflammatory, antioxidant, ACE-inhibitory, and diuretic properties of flavonoids³⁹.

Antioxidants:

Reactive oxygen species (ROS) are free radicals encompassing singlet oxygen, superoxide anion (O2⁻), hydroxyl radical (OH⁻), and peroxy radical (ROO⁻)⁴⁰. Free radicals quickly react with proteins and lipids, leading to instability and initiating a cascade of chain reactions. An excess of reactive oxygen species (ROS) can damage renal epithelial cells. Endogenous antioxidants such as vitamin C, vitamin E, and reduced glutathione, along with free-radical scavenging enzymes like catalase and glutathione peroxidase, help maintain normal physiological levels of free radicals and protect against endothelial oxidative damage. Exposure of kidneys to oxalates results in lipid peroxidation and ROS production, triggering inflammation and renal cell damage. This damage disrupts membrane integrity, which fosters collagen production, fibrosis, and the adhesion, retention, and formation of calcium oxalate stones. ROS activate phospholipase A2 via the nuclear transcription factor NF-κB, leading to the production of arachidonic acid. This process increases ROS generation, further promoting inflammation, cellular damage, and crystal formation. Antioxidants can delay, inhibit, or prevent oxidative degeneration by reducing localized oxygen concentrations, scavenging ROS and their intermediates, binding or chelating metal ions, and breaking down lipid peroxides⁴¹.

Diuretics:

Flushing out salt deposits through diuretic action leads to an increased fluid flow through the kidneys. This rise in urine volume helps prevent crystal formation at physiological pH by decreasing the urine's supersaturation with substances that contribute to kidney stones⁴². Thiazide diuretics are often used to avert kidney stone formation⁴³

ACE inhibition:

In renal cells, the activation of NADPH oxidase by the renin-angiotensin-aldosterone system (RAAS) leads to the production of reactive oxygen species (ROS). Angiotensin-converting enzyme inhibitors (ACE-I) significantly reduce renal inflammation and calcium oxalate crystal formation by decreasing ROS generation. Captopril, an ACE inhibitor, contains a sulfhydryl ligand that bonds with cystine. The resulting cystine-captopril disulfide is 200 times more soluble than cystine, thus helping to prevent stone formation⁴⁴.

The active center of ACE is inhibited by the free hydroxyl groups of phenolic substances like flavonoids forming a chelate with the zinc atom⁴⁵.

Anti-inflammatory agents:

Flavonoids exhibit anti-inflammatory effects through several mechanisms. They can: 1) Reduce the production of prostaglandin-E2 (PG-E2), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), 2) Inhibit nitric oxide (NO) production, 3) Prevent the activation of nuclear factor-kappa B (NF-κB), thereby decreasing the activity of COX-1 and COX-2, and 4) Suppress the activity of phospholipase A2 (PLA2)⁴¹.

According to recent studies, plant flavonoids considerably lower the production of kidney stones both in vitro and in vivo. The flavonoids or plant extracts high in flavonoids linked to anti-urolithiasis action are elaborated as follows.

Chenopodium album:

Chenopodium album Linn. leaves have traditionally been used to treat renal disorders and urinary stones. To validate its traditional use as an antilithiatic agent, researchers examined the effects of methanolic (CAME) and aqueous (CAAE) extracts of Chenopodium album leaves on experimentally-induced urolithiasis in rats. Urolithiasis was induced by administering 0.75% v/v ethylene glycol (EG) in distilled water. Subsequently, rats received daily oral doses of Cystone (750mg/kg), a vehicle, or CAME and CAAE at doses of 100, 200, and 400mg/kg for 28 days. Various parameters, including calcium, phosphorus, urea, uric acid, and creatinine levels in both urine and plasma, were measured to assess urolithiasis. Additionally, urine volume, pH and oxalate concentrations were recorded. Histological examination revealed calcium oxalate deposits, and the oxalate content in the kidneys was assessed. Both CAME and CAAE significantly reduced the EG-induced increases in calcium, phosphorus, urea, uric acid, and creatinine levels, along with reductions in urine volume, pH, and oxalate concentrations. Furthermore, treatment with CAME and CAAE diminished oxalate levels in renal tissue and inhibited oxalate crystal formation in the kidneys. These extracts demonstrated effects comparable to the widely used antilithiatic drug Cystone. The observed preventive effects against crystallization and stone formation are likely attributed to phytochemicals such as flavonoids and saponins present in CAME and CAAE⁴⁶.

Rubia tinctorum:

In a urolithic rat model induced with 0.75% ethylene glycol (EG) and 2% ammonium chloride (AC), Marhoume FZ et al. explored whether ethanolic and ethyl acetate (EA-RT) extracts of Rubia tinctorum L. could prevent the development of urolithiasis. The administration of EG/AC for 10 days led to the formation of bipyramid-shaped calcium oxalate crystals in the urine. Both the ethanolic and ethyl acetate extracts significantly reduced calcium oxalate levels in the urine. Additionally, they prevented renal tissue damage and alterations in serum and urine biochemistry associated with urolithiasis. The observed effects are attributed to the high polyphenol content of the extracts, which contributes to their potent antioxidant properties⁴⁷.

Phlogacanthus thyrsiformis:

Calcium oxalate kidney stones were treated in vivo, and struvite urinary stones were addressed in vitro using the aqueous extract of P. thyrsiformis flowers. Struvite stones, formed in tubes through the gel diffusion technique, were subjected to various amounts of the extract, with a portable microscope employed to monitor stone size over ninety-six hours. For the in vivo study, male Wistar rats were administered a mixture of ethylene glycol and ammonium chloride for 14 days to induce calcium oxalate stones. Urine, serum, and histological analyses were performed to evaluate the extract’s preventive and therapeutic effects. In vitro, the extract significantly reduced struvite stone size, and in vivo, it effectively eliminated calcium oxalate stones in rats. The anti-urolithiatic properties of the aqueous extract of P. thyrsiformis flowers are attributed to its flavonoid content⁴⁸.

Lepidagathis prostrata:

Petroleum ether (LPPE), ethyl acetate (LPEA), n-butanol (LPBU), methanol extract (LPM), and aqueous (LPAQ) extract of Lepidagathis prostrata were made. The ability of these extract/fraction concentrations to prevent calcium oxalate (CaOx) nucleation and aggregation for 30 minutes was studied to assess the in vitro antiurolithiatic activity. Compared to reference standard drug Cystone, LPEA demonstrated a considerably higher dose-dependent suppression of CaOx nucleation and aggregation. It is proposed that L. prostrata inhibits CaOx crystallization, which mediates its antiurolithiatic effect. The plant demonstrated strong free radical scavenging and iron chelation activity because of the presence of phenols and flavonoid components, which would support its usage to improve urolithiasis-induced oxidative stress⁴⁹.

Malva neglecta:

Saremi et al. investigated the anti-urolithiasis effects of aqueous extracts of Malva neglecta Wallr in a rat model with kidney stones induced by ethylene glycol and ammonium chloride. Their findings revealed that in preventive treatments, the extract significantly reduced tubulointerstitial damage and calcium oxalate (CaOx) deposits. A low dose of 200mg/kg of the extract led to decreased renal oxalate deposits and reduced tubulointerstitial damage in the curative treatments. Additionally, the high dose of 800mg/kg resulted in a marked reduction in both tubulointerstitial damage and crystal deposition. The high-dose preventive and curative groups showed superior results. These effects of Malva neglecta Wallr appear to be dose-dependent, with the plant’s constituents—flavonoids, mucilage, and phenolic compounds—likely contributing to these benefits⁵⁰

Bryophyllum pinnatum:

In traditional ethnomedical practices, Bryophyllum pinnatum, known as Pattharcaṭṭa, is utilized for treating kidney stones and urinary insufficiency. This study evaluated the effect of Bryophyllum pinnatum on ethylene glycol (EG)-induced renal calculi in rats. The extract treatment counteracted the EG-induced reduction in body weight and the increase in serum biochemical markers (creatinine, uric acid, urea, calcium, phosphorus, and magnesium) and urine parameters (uric acid, calcium, phosphorus, and oxalate). Furthermore, the extract prevented oxidative and histological kidney damage induced by EG, as well as the decrease in urine volume, pH, magnesium levels, and creatinine clearance. The outcomes were comparable to those achieved with the reference drug Cystone. It is suggested that the notable presence of phenolics, flavonoids, and saponins in the extracts may be responsible for the observed antilithiatic effect⁵¹.

Aerva lanata:

The study investigated the antiurolithiatic potential of the ethyl acetate fraction of Aerva lanata (EAFAL), derived from the hydromethanolic extract of its aerial parts (HMEAL). Using an ethylene glycol (EG)-induced male Wistar albino rat model for urolithiasis, the in vivo pharmacological efficacy of EAFAL was assessed. EAFAL exhibited a significant antiurolithic effect by restoring the balance between urinary promoters and inhibitors and by decreasing urinary pH. The research highlighted that the presence of phenolic and flavonoid compounds in EAFAL contributes to its effectiveness in reducing abnormalities in urine, serum, and kidneys, thereby supporting its antiurolithiatic activity⁵².

Desmosium styracifolium:

Zhou J investigated the anti-urolithiatic properties of total flavonoids from D. styracifolium (TFDS) in the context of calcium oxalate (CaOx) kidney stones. Using male Sprague-Dawley rats, CaOx urolithiasis was induced by adding 5% w/w hydroxy-L-proline (HLP) to their regular diet. TFDS was administered orally for 28 days at doses of 100 and 400mg/kg, in conjunction with HLP. Urine and serum samples were collected for biochemical analysis and to assess crystalluria at the end of the treatment period. Kidney tissues were excised for histological examination and antioxidant parameter evaluation. The induction of CaOx nephrolithiasis was achieved through HLP-induced hyperoxaluria. Compared to the untreated HLP group, TFDS significantly reduced CaOx crystal deposits and crystalluria in kidney tissue sections. Furthermore, TFDS improved HLP-induced kidney dysfunction and renal epithelial cell injury, decreased urine oxalate excretion, and mitigated pro-acidosis. Additionally, TFDS inhibited MCP-1, OPN, and TGF-β protein expression, decreased MDA levels, and enhanced CAT and GSH-Px activities in renal homogenates, thereby offering protection against oxidative stress. The study concluded that TFDS effectively suppresses CaOx formation in rat kidneys, likely due to its anti-inflammatory, antioxidant, and urine-alkalinizing effects, as well as its ability to lower the concentration of stone-forming components in the urine⁵³.

Copaifera langsdorffii:

A study was conducted to validate the traditional use of Copaifera langsdorffii Desf. leaves against urolithiasis. Calcium oxalate pellets (CaOx) were implanted into the bladders of adult male Wistar rats to induce urolithiasis. For eighteen days, the treatment groups received the crude extract orally at a dose of 20mg/kg body weight daily. Treatment with the extract began thirty days after CaOx implantation. To evaluate whether the C. langsdorffii extract could inhibit stone formation, analyses were performed on pH, magnesium, phosphate, calcium, uric acid, oxalate, and citrate levels. HPLC analysis identified afzelin and quercitrin as the primary flavonoid constituents of the extract. Treated animals showed lower uric acid and higher magnesium levels in their urine. Additionally, both the mean number and size of calculi were significantly reduced in treated animals. The calculi from extract-treated animals were more brittle and fragile compared to those from untreated animals. The extract was rich in flavonoid glycosides and other phenolic compounds. The researchers suggested that the observed antiurolithiatic effect of the extract may be due to these chemical constituents⁵⁴.

Rosa canina:

1% ethylene glycol(EG) was used to assess Rosa canina's (RC) potential for use as a prophylactic treatment against experimentally-induced calcium oxalate (CaOx) nephrolithiasis in rats. The extract notably enhanced citrate excretion, reduced both the size and quantity of CaOx calculi in the kidneys, and lowered renal and urinary calcium levels, without altering urine volume, pH, or oxalate concentrations compared to the control group. These results indicate that RC could be beneficial as a preventive measure against the formation of CaOx kidney stones⁵⁵.

Prunus mahaleb:

Rsearcher studied how Prunus mahaleb L. seed extract affects BALB/c mice's urolithiasis caused by ammonium chloride and ethylene glycol. Male BALB/c mice were given ammonium chloride (AC) 2% (w/v) and ethylene glycol (EG) 0.75% (v/v) in their drinking water for 21 days to induce urolithiasis. Less damage to the kidney tissue was seen in extract treated groups, and the group treated with 500 mg/kg of Prunus mahaleb L. extract produced highest efficay. The plant's antioxidant qualities—which are also a result of its high phenol and flavonoid content—are responsible for the extract's ability to prevent kidney stones formation⁵⁶.

Trachyspermum ammi:

The antiurolithic properties of Trachyspermum ammi seed crude extract (Ta.Cr) were evaluated through both in vivo and in vitro studies. The findings suggest that Ta.Cr's antiurolithic effect may involve several mechanisms: acting as a diuretic, inhibiting the aggregation of CaOx crystals, providing antioxidant benefits, protecting renal epithelial cells, and exhibiting antispasmodic properties⁵⁷.

Isolated flavonoids for urolithiasis:

Isolated flavonoids, such as rutin, catechin, epicatechin, and diosmin, have demonstrated an inhibitory effect on experimentally-induced urinary stone formation in rats. Rutin, renowned for its potent anti-inflammatory and antioxidant properties, has been used for millennia in traditional medicine to treat various ailments. Ghodasara et al. investigated the effects of rutin (20mg/kg body weight, administered orally for 28 days) on calcium and oxalate levels in urine and kidney tissue homogenate, as well as the pathological structure of kidneys in rats exposed to ethylene glycol (EG) at 0.75% v/v for 28 days and ammonium chloride (NH4Cl) at 1% w/v for the first three days to induce urolithiasis. The study found that rats treated with rutin, in addition to EG and NH4Cl, exhibited significantly lower calcium and oxalate levels in both urine and renal tissue homogenate compared to those exposed to EG and NH4Cl alone. This outcome is likely attributed to rutin's role in inhibiting oxalate synthesis and enhancing nitric oxide bioavailability to bind calcium through the cGMP (3', 5' cyclic guanosine monophosphate) pathway. Furthermore, histopathological analysis revealed minimal tissue damage and fewer CaOx deposits in the kidneys of rats treated with rutin compared to the urolithiatic controls^58,59. The researchers suggested that rutin's anti-inflammatory and antioxidant effects could suppress inflammation by mitigating epithelial cell injury induced by CaOx crystals⁶⁰

Azimi et al. reported that apigenin exhibits strong antioxidant properties and reduces crystal deposition in urolithiatic rats by inhibiting the TGF-β pathway. Additionally, vitexin, which is apigenin 8-C-glucoside, has been shown to diminish crystal deposition and renal oxidative stress damage by preventing pyroptosis, epithelial–mesenchymal transition in renal tubular epithelial cells, and macrophage infiltration^61,62.

Park HK investigated quercetin's effects on oxalate-induced renal tubular cell damage and its role in inhibiting urinary crystal formation in rats. MDCK cells were exposed to varying oxalate concentrations with or without quercetin. The study assessed quercetin's antioxidant properties using MTT assays for cell viability, as well as measurements of malondialdehyde and catalase activity. The study included three groups of male Sprague-Dawley rats: Group 1 received normal rat chow, while Groups 2 and 3 were given regular chow supplemented with 3% sodium oxalate for four weeks. Groups 2 and 3 also received gentamicin for the first eight days of this period, with Group 3 additionally receiving quercetin for the full four weeks. After four weeks, the rats were sacrificed, and their renal tissue was analyzed for malondialdehyde, superoxide dismutase, and catalase activity. Kidney sections were examined microscopically to count crystal deposits. In the presence of oxalate, MDCK cell viability significantly decreased, accompanied by increased malondialdehyde levels. However, quercetin treatment effectively mitigated oxalate-induced lipid peroxidation and preserved cell viability. Group 3 rats showed markedly lower malondialdehyde levels and higher superoxide dismutase and catalase activity compared to Group 2⁶³. According to research by Guzel et al., quercetin may reduce oxidative stress by inhibiting the p38-MAPK route⁶⁴. In order to hinder the reabsorption of calcium, salt, and water and further prevent the formation of stones, quercetin can help to preserve a tighter epithelial barrier⁶⁵. Quercetin and hyperoside, also known as quercetin 3-O-galactoside, were combined by Zhu et al. to treat urolithiatic rats, and the combination demonstrated a strong inhibitory effect on crystal deposition⁶⁶.

Researchers explored the impact of catechin on renal calcium crystallization, given its known antioxidant properties. They assessed catechin's effects on calcium oxalate monohydrate (COM) formation in NRK-52E cells by measuring alterations in mitochondrial membrane potential, superoxide dismutase (SOD) expression, 4-hydroxynonenal (4-HNE) levels, cytochrome c, and cleaved caspase 3. For in vivo studies, Sprague-Dawley rats were treated with 1% ethylene glycol (EG) to induce kidney stones, followed by catechin administration (2.5 and 10 mg/kg) for 14 days. Urine and serum parameters were evaluated at seven and fourteen days post-EG treatment. Additionally, the kidney tissues were analyzed for cleaved caspase 3, SOD, osteopontin (OPN), malondialdehyde (MDA), and 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels. Catechin treatment was found to mitigate COM-induced changes in NRK-52E cells' mitochondrial membrane potential and reduced the levels of SOD, 4-HNE, cytochrome c, and cleaved caspase 3. In the in vivo model, catechin also inhibited EG-induced kidney calcium crystallization. Following EG exposure, levels of SOD, OPN, MDA, and 8-OHdG were elevated, but catechin treatment reduced these increases and protected against mitochondrial damage caused by EG⁶⁷.

Licoisoflavone-A, extracted from the roots of Glycyrrhiza glabra (liquorice), exhibits inhibitory effects on Xanthine Oxidase (XO). XO facilitates the conversion of hypoxanthine to xanthine and subsequently xanthine to uric acid. Elevated levels of uric acid in the blood, known as hyperuricaemia, can lead to severe conditions such as gout and kidney stones⁶⁸. Umamaheswari et al. explored the XO-inhibitory potential of flavonoids through in silico docking studies. The flavonoids examined included butein, fisetin, diosmetin, tricetin, genistein, tricin, vitexycarpin, herbacetin, biochanin, rhamnetin, isorhamnetin, robinetin, peonidin, and okanin. Their findings revealed that all the tested flavonoids exhibited inhibitory activity⁶⁹.

CONCLUSION:

Urolithiasis presents a significant health challenge with intricate pathophysiology, multifactorial causes, and a high rate of recurrence. It is a prevalent condition worldwide, initiating with the crystallization of oxalates in renal tissue. Many individuals experience various forms of lithiatic disorders. Factors contributing to urinary stone formation include precipitation, crystal nucleation, aggregation, growth, and eventual retention in renal tubule epithelial cells. Due to the lack of effective allopathic treatments and the increased risk of recurrence associated with surgical interventions, patients are increasingly turning to herbal remedies. Herbal treatments offer numerous advantages, such as fewer side effects, safety, efficacy, affordability, and easy accessibility. Although many plants have been shown to be beneficial for treating urinary stones, there remains a need to explore additional plants for their pharmacological properties.

CONFLICT OF INTEREST:

Authors does not have any conflict of interest

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Received on 23.07.2024 Revised on 29.10.2024

Accepted on 02.12.2024 Published on 12.06.2025

Available online from June 14, 2025

Research J. Pharmacy and Technology. 2025;18(6):2910-2918.

DOI: 10.52711/0974-360X.2025.00418

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