4. Inhibitors and Promoters of Kidney Stone:

Urolithiasis is becoming more common over the world, despite significant progress in the area of novel medicines for the treatment of urinary stones. Many elements of the genesis of renal stones are yet unknown. Renal cell damage, cell apoptosis, crystal retention, randall's plaque and associated stone inhibitors or promoters are all known to play a part in kidney stone development³⁷.

The creation of more effective medicines is possible by the identification of novel therapeutic targets which is based on molecular alterations related to stone formation. Additionally, a deeper understanding of the urolithiasis mechanisms associated with stone blockers or stimulants is essential for stone-removal medications. Additionally, it is also hoped that improved understanding of the pathophysiology, aetiology and genetic basis of kidney stone generation soon result in the creation of novel treatments and drugs for urolithiasis^,38.

Inhibitors are molecules that slows the beginning of supersaturation, nucleation, crystals growth, aggregation rate or any other process involved in stone formation. Urine contains these molecules to prevent the production of crystals. Organic anions like citrate, inorganic anions like pyrophosphates, multivalent metallic cations like magnesium or macromolecules like osteopontin, glycosaminoglycans, glycoproteins, urinary prothrombin fragment-1, and Tamm–Horsfall proteins are examples of inhibitors in urine. These inhibitors do not appear to operate equally well for everyone and the person develop stones. However, if the crystals formed are small enough, they normally pass out of body through the urinary system with a splash of urine without being recognised. Inhibitors can affect the urine environment either indirectly or directly by interacting with the crystal. Nucleation, crystals growth, aggregation, and crystal-cell adhesion are all inhibited when inhibitory chemicals adsorbed onto the crystal's surface. Table 3 summarizes several inhibitors and their mechanism.

Table 3: Inhibitors and their Mechanism

S. No	Inhibitors	Mechanism	Reference
1	Citrate (Organic anions)	Prevents crystal development, nucleation, aggregation and crystal cell adhesion	39
2	Pyrophosphate (Inorganic anions)		40
3	Magnesium (Metallic anions)		41
4	Macromolecules e.g.Osteoponin, Glycoaminoglycans, Tamm-Horsfall protein glycoprotein)		42

Promoters on the other hand are chemicals that aid in the formation of stones through variety of methods. Cellular membrane fats (cholesterol, phospholipids and glycolipids), calcitriol hormone stimulation via parathyroid hormone stimulation⁴³, calcium, sodium, oxalate, salt, cystine and reduced urine volume are few of the promoters. Among recurrent stone formers, oxalate excretion is higher and citrate excretion was low ⁴⁴. Oxalate increases chloride, salt and water reabsorption in the proximal tubule and activate several signalling pathways in renal epithelial cells⁴⁵. Stone formation is thought to be caused by an imbalance between stone inhibitors and promoters. Table 3 summarizes several promoters and their mechanism.

Table 4: Promoters and their Mechanism

S. No	Promoters	Mechanism	Reference
1	Lipids of Cell Membrane (Phospholipids, Glycolipids, Cholesterol)	Increases the calcium oxalate nucleation	46
2	Calcitriol (hormone)	Increases calcium reabsorption	47
3	Cysteine	Increases growth and aggregation of oxalate	48

5. Types of Kidney Stone:

The composition of renal stones is determined by anomalies in urine chemical composition. The form, size, and chemical content (mineralogy) of kidney stone vary⁴⁹. Kidney stones are classified into five categories based on differences in mineral content and aetiology.

6.1 Calcium Stones:

Calcium oxalate and calcium phosphate stones are two types of calcium stones. These renal stones account for nearly 80% of all urinary calculi and are most common type⁵⁰. Pure calcium oxalate (50%), calcium phosphate (also known as apatite) (5%), and a combination of both (45%) may account for calcium stones⁵¹. CaOx monohydrate (COM, whewellite) and CaOx dihydrate (COD, weddellite) are the common forms of calcium oxalate identified in kidney stones, present in more than 60% of all cases⁵². In clinical stones, COM is seen more common than COD. Hypercalciuria, hyperuricosuria, hyperoxaluria, hypercitraturia, hypomagnesuria, and hypocystinuria are all variables that lead to CaOx stone generation⁵³. CaOx stones are most commonly caused in urine pH of 5.0 to 6.5⁵⁴, whereas calcium phosphate stones are formed in pH more than 7.5. Calcium stones return more frequently than other kinds of kidney stones.

Management of Calcium Stones

Thiazide diuretics:

Thiazide diuretics lower sodium reabsorption by blocking the NaCl cotransporter in the distal convoluted tubule and increasing calcium reabsorption by an unknown mechanism⁵⁵. The hypocalciuric impact of thiazide diuretics has been studied in several randomised controlled studies to see if it prevents the formation of stones. An analysis by the Agency for Healthcare Research and Quality (AHRQ) of seven randomised controlled trials with an average follow-up of three years indicated that using thiazide diuretics reduced stone recurrence by 29% absolute risk⁵⁶. In individuals with hypercalciuria or recurrent calcium stones, thiazide diuretics are suggested⁵⁷.

Reduced stone formation is linked to hydrochlorothiazide (25mg twice a day), chlorthalidone (24mg/d) and indapamide (1.25 to 2.5mg/d). Limiting dietary sodium enhances the hypocalciuric impact of thiazide diuretics. Sodium restriction also reduces potassium losses caused by thiazide therapy. The effects of thiazide in vertebral bone density is one of the risks of taking them. In a group of patients from Rochester who were given thiazides for a first episode of symptomatic urolithiasis, the incidence of fractures in vertebra was shown to considerably higher⁵⁸.

Potassium Citrate:

Potassium citrate has shown to lower the risk of stone development in patients with recurrent calcium stones or lower urinary citrate. Potassium citrate treatment increases urinary citrate, pH and potassium levels, resulting in much less stone formation⁵⁹. The effects on urine pH and citrate have found to begin in less than a year and last for over three years⁶⁰. The AHRQ examined six randomised controlled studies and discovered that calcium consumption reduced risk by 41 percent.

Allopurinol:

By acting as a competitive inhibitor of xanthine oxidase, the enzyme that transforms xanthine to uric acid, allopurinol limits the synthesis of uric acid. Allopurinol reduces the risk of recurrent calcium oxalate stones in patients with hyperuricosuria and normal urinary calcium⁶¹. According to the AHRQ review, the absolute risk decrease in patients with increased uric acid blood or urine levels was 22%. Although the efficacy of allopurinol medication in patients without hyperuricosuria has not been proven, hyperuricosuria is not a need for allopurinol therapy.

6.2 Uric Acid Stones:

This type of stone accounts for 3–10% of all stone types. Purine-rich diets, particularly those containing animal protein such as meat and fish cause hyperuricosuria, low urine volume and a low urinary pH (pH 5.05) that exacerbates the formation of uric acid stones⁶². Gouty arthritis patients may also develop kidney stones. Uric acid stones are more common in males than in women⁶³.

Management of Uric Acid Stones:

These are 15 percent of all urolithiasis are uric acid stones. Urinary uric acid derives from both endogenous and external sources, including production and catabolism of nucleic acids⁶⁴. Animal protein raises urine calcium and uric acid levels, lowers urinary citrate and pH levels, and accelerates bone resorption. Fish because of their high protein content are particularly high in purines and should be avoided by patients with uric acid stones⁶⁵.

Organ meats, glandular tissue, gravies and meat extracts are all high in purine. Patients should enhance their alkaline load by eating more fruits and vegetables since uric acid stones grow in acidic settings. Plant proteins do not appear to acidify the urine as much as animal proteins, making them a better choice. High-fructose corn syrup should be avoided by patients with uric acid stones as it is linked to hyperuricemia and hyperuricosuria⁶⁶. A fall in urinary pH is the most frequent risk factor for uric acid stones. As a result, the first-line medical treatment for uric acid stones is Potassium Citrate, which raises urine pH levels to a target of 6 pH.

Patients who have failed to respond to nutritional treatment and have high urine acid levels (>900 mg/d) are benefited from allopurinol. These individuals should be initially on 100mg/d and gradually increased to 300 mg/d if necessary. Allopurinol does not dissolve existing stones, but it does assist prevent new ones from forming.

6.3 Cystine Stones:

These stones are found fewer than 2% of all stone kinds. It's a cystine and amino acid transport disease caused by a hereditary mutation. It causes cystinuria, an autosomal recessive condition caused by a deficiency in the rBAT gene on chromosome 2⁶⁷, which causes reduced renal tubule absorption of cystine or cystine leakage into urine. It does not disintegrate in urine, resulting in cystine stones. Cystinuria causes people to excrete more than 600 millimoles of insoluble cystine every day. The only clinical sign of cystine stone disease is the formation of urinary cystine.

Management of Cystine Stones:

Cystine stones are formed by cystinuria, an autosomal recessive condition characterised by a deficiency in dibasic amino acid re-absorption in the renal tubules. The production of cystine stones is caused by this deficiency in dibasic amino acid reabsorption in renal tubules, which is compounded by cysteine's relative insolubility in urine pH levels⁶⁸. Increasing cystine solubility by increased water intake is the single most essential strategy in patients with cystine stones. Adults with kidney stones should aim for a daily urine output of at least 3L and a cystine concentration of less than 200 mg/L⁶⁹. Sodium excretion stimulates cystine excretion, sodium limitation is also important^70,71. Furthermore, because meats are rich in cysteine and methionine which is converted into cysteine, it is usually recommended to limit animal protein intake⁷².

Cystine solubility in urine rises with rising pH.Potassium Citrate is the first-line treatment for cystinuria, with a pH aim of seven⁷³. Therapy with cystine-binding thiol medicines should be started if the urine cystine concentration is higher than 500mg/L. Thiol medicines break the disulphide bond between two cysteine molecules of cystine, forming a cysteine-thiol complex that is significantly more soluble than cystine. D-penicillamine, alpha-mercaptopropionyl glycine and Tiopronin are three extensively utilised thiols. Tiopronin is started at 200mg twice a day and gradually raised until the amount of cystine in the urine is less than 200mg/L. Penicillamine has considerable side effects, such as fever, arthralgia, leukopenia and neuropathy.Tiopronin is usually the preferred option. When the urine pH is more than 7, tiopronin is more efficient. Hence maintaining a high level of hydration is essential.

6.4 Struvite Stones:

Struvite stones are also known as infectious stones and tri phosphate stones.Thesestones are seen in 10–15 percent of people. It occurs in patients with urease-producing chronic urinary tract infections, the most frequent of which is Proteus mirabilis; other pathogens that are less prevalent include Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterobacter. Urease is required to split/cleave urea into ammonia and CO2, resulting in an alkaline urine with a higher pH (usually >7). Because phosphate is less soluble at alkaline than acidic pH, it precipitates on the insoluble ammonium compounds, resulting in the creation of a huge staghorn stone⁷⁴. Women are more likely than men to produce this form of stone.

Management of Struvite Stones:

Struvite stones are generated by urease-producing organisms such as Pseudomonas, Klebsiella, Proteus, Staphylococcus and Escherichia coli infecting the urinary system. Dietary therapy has no place in the treatment of struvite stones. The majority of the time, surgery is used to treat the condition. Patients can be treated medically with 250mg of Acetohydroxamic Acid (AHA) three times a day in case surgical procedure have been exhausted⁷⁵. AHA decreased the development of struvite stones in randomised controlled trials⁷⁶. Patients receiving AHA therapy, on the other hand, must be closely monitored for significant adverse effects such as phlebitis and hypercoagulable episodes⁷⁷.

6.5 Drug Induced Stones:

About 1% of kidney stone types are this type. Medicines including triamterene, guaifenesin, atazanavir and sulfa medications induce these stones. People who use the protease inhibitor e.g., indinavir sulphate, which is used in treating HIV infection, is at risk of formation of kidney stones. These lithogenic medicines or their metabolites can form a nidus or deposit on existing renal stones. These medications may also promote the development of calculi by interfering with the calcium oxalate and purine metabolisms.

Management of Drug-Induced Stone:

Most drug-induced kidney stones can be managed conservatively by increasing fluid intake and ensuring a high urine output.

Patients of metabolically induced calculi due to using unrestricted calcium/vitamin D supplements are being managed by carbonic anhydrase inhibitors like Acetazolamide or Topiramate are examples of metabolically produced calculi⁷⁸. Diagnosis is based on a comprehensive clinical examination to distinguish between common calculi and calculi generated metabolically, the incidence of which is likely underestimated. There are also specific patient-dependent risk variables in respect to urine pH, diuresis volume, and other aspects which gives a foundation for stone prevention or treatment⁷⁹.

6. Phytoconstituents on Urolithiasis:

The phytochemicals present in the extract contribute to the plant's antiurolithiatic abilities. Previous investigations shows that several kinds of phytochemicals have a favourable effect in the antiurolithiatic impact against CaOx crystals or in terms of dissolving or inhibitory capabilities .

7.1 Flavonoids:

Rutin, diosmin, catechin and epicatechin have shown to have an inhibitory effect on the production of urinary stones when used as particular flavonoids. Rutin contains anti-inflammatory and antioxidant properties and has been utilised in indigenous medicine for generations to treat a variety of ailments⁸⁰.

Ghodasaraand colleaguesinvestigated the effects of rutin [20 mg/kg BW for 28 days] They found that animals given rutin had considerably lesser oxalate and calcium in kidneytissue homogenate and urine⁸¹. This is due to rutin effect in calculi-induced rats on suppressing oxalate production and increasing nitric oxide bioavailability to sequester calcium via the cGMP (3', 5' cyclic guanosine monophosphate) pathway. Rutin, as an anti-inflammatory and antioxidant compound that interactthe cells of epithelium which are damaged by CaOx crystals and inhibit inflammation.

Green tea which isused commonly in China, Japan, Korea and Morocco because of its high antioxidant content which includes flavonoids, phenolic acids and tannins. Green tea has antimutation, antiatherosclerotic and antitumor properties. Green tea's antiurolithiasis activity on urinary stones is previously demonstrated in a study. Green tea therapy significantly reduced CaOx stone development, osteopontin (OPN) and renal tubular cell apotosis in rat kidney tissues and increase superoxide dismutase (SOD) activity⁸². Green tea antioxidants may block NF-B activation (a pro-inflammatory cytokine that can promote human aroticendothelial cell apoptosis and death while also maintaining the expression of other cytokines), according to the researchers, which explains its anti-apoptotic activity.

In vitro and in vivo studies of catechin, one of the primary components in green tea, on renal calcium crystallisation were conducted by Zhai and colleagues in 2013. In an in vitro investigation, catechin given to renal proximal tubular cell line exposed to COM (CaOx monohydrate crystals) reduces the expression of SOD, lipid peroxidation products, cytochrome c and cleaved caspase and also changes the mitochondrial membrane potential⁸³. Apoptosis has been shown to be tightly correlated with the amounts of cytochrome cells. In an in vivo study, catechin reduced the mitochondrial breakdown and increase in OPN, malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (indicator for observing DNA damage) expression caused by ethylene glycol in the kidneys of rats. Accordingly, the research's findings show that catechin can prevent renal calcium crystallisation in rat cells by reducing the severity of COM-induced injury of mitochondria. Epicatechin can suppress renal calculi similarly to catechin because of the structural resemblance. In particular, Grases and his co-workers discovered that epicatechin treatment for 24 days with 100mg/L of epicatachin specifically prevented the development of stone in the kidneys of rats⁸⁴. According to that, epicatechin has the potential to prevent kidney stones formation by reducing the lipid peroxidation and hyperoxaluria damage to the renal tubular membrane.

Diosmin is a naturally occurring flavonoid glycoside. It has anti-inflammatory and anti-apoptotic properties. In a recent study on animals, the risk factors for development of kidney stone such as urine pH, urine protein, urinary magnesium, phosphorus, serum sodium, potassium, magnesium, creatinine, uric acid and blood urea nitrogen levels are significantly decreased, while stone forming inhibitors such as urine volume, urine magnesium, potassium, sodium, creatinine, uric acid, and serum calcium levels significantly increased due to effect of diosmin group⁸⁵. The scientists hypothesised that diosmin's anti-urolithiatic activity is similar to that of the common treatment cystone because of its preventive, anti-inflammatory and antioxidant properties.

7.2 Polysacchrides:

In comparison to the efficiency of flavonoids, polysaccharides had the most significant prophylactic effects of kidney stone in the model rats, decreasing blood urine nitrogen (BUN) and creatinine levels, mitigating histological changes, increasing urine C₂O₄^2- and Ca²⁺ excretion and reversing protein expressions of osteopontin (OPN) of kidney. Polysaccharides can also greatly reduce CaOx crystal nucleation and aggregation⁸⁶.

Orthosiphon stamineus Benth., a common medicinal herb from the Labiatae family, is frequently used in Southeast Asia to treat hyperuricemia, rheumatism, gout, jaundice, nephritis, nephrolithiasis, urethritis, and cystitis. Orthosiphon stamineusBenth extract contain polysaccharides which is the principal medicinal ingredients in OS. Polysaccharide act as an inhibitor of CaOx crystallisation and a controlling factor for OPN protein synthesis of OPN protein production. This merits additional investigation as a nephrolithiasis preventive agent. In OS, polysaccharides were the most common treatment ingredients⁸⁷. In nephrolithic rats, it demonstrated impressive prophylactic benefits against CaOx stones, acting as a governing factor of OPN protein production to promote urine C₂O₄^2- and Ca²⁺ excretion as well as a CaOx crystallisation inhibitor.

7.3 Saponins:

Saponin's anti-crystallization activities are attributed to its capacity to disintegrate mucoprotein suspensions which are promoters in the crystallisation process⁸⁸. The extracts of Kalanchoe pinnata, Daucus carota and Bergenia ciliatacontaining saponin shows to good stone-inhibiting capabilities⁸⁹.

The herb Kalanchoe pinnata is also called as panfuti (Hindi), life plant, air plant (Mexican), resurrection plant and miracle plant. The calcium oxalate monohydrate has a significant affinity for cell membranes and it also increases the likelihood of renal calculi formation. Kalanchoe pinnata containing saponins are well-known for their anti-crystallization capabilities. They precipitate the suspension of mucoproteins, which act as crystallisation promoters⁹⁰.

The saponin-rich butanol fraction, in combination with the pure aqueous extract of Terminalia arjuna inhibits the production of calcium phosphate in the early mineral phase and the growth of COM crystals. In an animal model, a saponin-rich portion of Herniariahirsuta was reported to be a powerful inhibitor of CaOx stone formation, as well as CaOx crystal development in vitro⁹¹.

CONCLUSIONS:

Urolithiasis incidence is rising globally despite significant advancements in the creation of novel medicines for the treatment of urinary stones. It's still unclear how kidney stone development occurs in many ways. However, it is evident that kidney stone development is significantly influenced by renal cell damage, crystal retention, cell death, Randall's plaque, and related stone inhibitors or promoters. These appear to be crucial targets that facilitate the creation of innovative preventative measures and anti-kidney stone medications. Additionally, finding new therapy targets based on cellular and molecular changes related to stone formation can aid in creating more effective medications. The chance of stone recurrence can be considerably reduced, and quality of life can be increased, by combining dietary and medicinal therapy for stone prevention. Some phytochemicals in the plant have antiurolithiatic properties. Variety of phytochemicals have beneficial effects in terms of their ability to dissolve or inhibit CaOx crystals or to have an antiurolithiatic impact.

REFERENCES:

1. C. O’Callaghan, P. V. Yangkul and L. Ammi Visnaga, Eds., Blackwell Publishing Ltd., Oxford, UK,doi.org/10.1155/2018/3068365 2006

2. K. Mikawlrawng, S. Kumar, and R. Vandana, “Current scenario of urolithiasis and the use of medicinal plants as antiurolithiatic agents in Manipur (North East India): a re-view,” International Journal of Herbal Medicine, vol. 2, no. 1, pp. 1–12, 2014.

3. V. K. Sigurjonsdottir, H. L. Runolfsdottir, O. S. Indridason et al., “Impact of nephrolithiasis on kidney function,” BMC Nephrology, vol. 16, no. 1, p. 149, 2015.

4. Z. M. El-Zoghby, J. C. Lieske, R. N. Foley et al., “Urolithiasis and the risk of ESRD,” Clinical Journal of the American Society of Nephrology, vol. 7, no. 9, pp. 1409–1415, 2012.

5. A. D. Rule, V. L. Roger, L. J. Melton et al., “Kidney stones associate with increased risk for myocardial infarction,” Journal of the American Society of Nephrology, vol. 21, no. 10, pp. 1641–1644, 2010.

6. E. M. Worcester and F. L. Coe, “Nephrolithiasis,” Primary Care, vol. 35, no. 2, pp. 369–391, 2008.

7. E. N. Taylor, M. J. Stampfer, and G. C. Curhan, “Obesity, weight gain and the risk of kidney stones,” Journal of the American Medical Association, vol. 293, no. 4, pp. 455–462, 2005.

8. S. B. N. Kumar, K. G. Kumar, V. Srinivasa, and S. Bilal, “A review on urolithiasis,” International Journal of Universal Pharmacy and Life Sciences, vol. 2, no. 2, pp. 269–280, 2012.

9. J. M. Teichman and M. H. Joel, “Acute renal colic from ureteral calculus,” New England Journal of Medicine, vol. 350, no. 7, pp. 684–693, 2004.

10. K. P. Aggarwal, S. Narula, M. Kakkar, and C. Tandon, “Nephrolithiasis: molecular mechanism of renal stone formation and the critical role played by modulators,” BioMed Research International, vol. 2013, Article ID 292953, 21 pages, 2013.

11. S. R. Khan, D. J. Kok, “Modulators of urinary stone formation,” Frontiers In Bioscience, vol. 9, no. 1–3, pp. 1450–1482, 2004.

12. O. W. Moe, “Kidney stones: pathophysiology and medical management,” The Lancet, vol. 367, no. 9507, pp. 333–344, 2006.

13. Cappuccio, F.P., Kalaitzidis, R., Duneclift, S., Eastwood, J.B., 2000. Unravelling the links between calcium excretion, salt intake, hypertension, kidney stones and bone metabolism. J. Nephrol. 13(3), 169-177

14. Daudon, M., Frochot, V., Bazin, D., Jungers, P., 2018. Drug-induced kidney stones and crystalline nephropathy: pathophysiology, prevention and treatment. Drugs 78(2), 163-201.

15. Chaussy, C., Schmiedt, E., Jocham, B., Brendel, W., Forssmann, B., Walther, V., 1982. First clinical experience with extracorporeally induced destruction of kidney stones by shock waves. J. Urol. 127,417-20.

16. Odvina, C.V., Sakhaee, K., Heller, H. J., Peterson, R.D., Poindexter, J.R., Padalino, P.K., Pak, C.Y., 2007. Biochemical characterization of primary hyperparathyroidism with and without kidney stones. Urol. Res. 35(3), 123-128

17. D. R. Basavaraj, C. S. Biyani, A. J. Browning, and J. J. Cartledge, “The role of urinary kidney stone inhibitors and promoters in the pathogenesis of calcium containing renal stones,” EAU-EBU Update Series, vol. 5, no. 3, pp. 126–136, 2007.

18. M. S. Parmar, “Kidney stones,” British Medical Journal, vol. 328, no. 7453, pp. 1420–1424, 2004.

19. S. Ahmed, M. M. Hasan, and Z. M. Alam, “In vitro urolithiasis models: an evaluation of prophylactic management against kidney stones,” Journal of Pharmacognosy and Phytochemistry, vol.5, no. 3, pp. 28–35, 2016.

20. E. O. Kajander and N. Ciftcioglu, “Nanobacteria: an alternative mechanism for pathogenic intra-and extracellular calcification and stone formation,” Proceedings of the National Academy of Sciences, vol. 95, pp. 8274–8279, 1998.4, pp. 435–447, 2013.5.2. Crystal Growth

21. H. Xu, A. L. Zisman, F. L. Coe, and E. M. Worcester, “Kidney stones: an update on current pharmacological management and future directions,” Expert Opinion on Pharmacotherapy, vol. 14, no. 4, pp. 435–447, 2013.

22. V. N. Ratkalkar and J. G. Kleinman, “Mechanisms of stone formation,” Clinical Reviews in Bone and Mineral Metabolism, vol. 9, no. 3-4, pp. 187–197, 2011.

23. S. R. Khan, “Renal tubular damage/dysfunction: key to the formation of kidney stones,” Urological Research, vol. 34, no. 2, pp. 86–91, 2006.

24. M. Tsujihata, “Mechanism of calcium oxalate renal stone formation and renal tubular cell injury,” International Journal of Urology, vol. 15, no. 2, pp. 115–120, 2008.

25. C. F. Verkoelen, B. G. vander Boom, and J. C. Romijn, “Identification of hyaluronan as a crystal-binding molecule at the surface of migrating and proliferating MDCK cells,” Kidney Inernational, vol. 58, no. 3, pp. 1045–1054, 2000.

26. J. C. Lieske, H. Swift, T. Martin, B. Patterson, and F. G. Toback, “Renal epithelial cells rapidly bind and internalize calcium oxalate monohydrate crystals,” Proceedings of the National Academy of Sciences, vol. 91, no. 15, pp. 6987–6991, 1994.

27. B. Hess, “Tamm-Horsfall glycoprotein-inhibitor or promoter of calcium oxalate monohydrate crystallization processes,” Urological Research, vol. 20, no. 1, pp. 83–86, 1992.

28. L. Mo, H. Y. Huang, X. H. Zhu, E. Shapiro, D. L. Hasty, and X.-R. Wu, “Tamm-Horsfall protein is a critical renal defense factor protecting against calcium oxalate crystal formation,” Kidney International, vol. 66, no. 3, pp. 1159–1166, 2004.

29. R. Hackett, P. Shevock, and S. Khan, “Madin-Darby canine kidney cells are injured by exposure to oxalate and to calcium oxalate crystals,” Urological Research, vol. 22, no. 4, pp. 197–203, 1994.

30. J. M. Fasano and S. R. Khan, “Intra-tubular crystallization of calcium oxalate in the presence of membrane vesicles: an invitro study,” Kidney International, vol. 59, pp. 169–178, 2001.

31. T. Rashed, M. Menon, and S. Tamilselvan, “Molecular mechanism of oxalate-induced free radical production and glutathione redox imbalance in renal epithelial cells: effect of antioxidants,” American Journal of Nephrology, vol. 24, no. 5, pp. 557–568, 2004.

32. L. S. Chaturvedi, S. Koul, A. Sekhon, A. Bhandari, M. Menon, and H. K. Koul, “Oxalate selectively activates p38 mitogen activated protein kinase and C-Jun N-terminal kinase signal transduction pathways in renal epithelial cells,” Journal of Biological Chemistry, vol. 277, no. 15, pp. 13321–13330, 2002.

33. S. Koul, L. Khandrika, T. J. Pshak et al., “Oxalate upregulates expression of IL-2Rβ and activates IL-2R signaling in HK-2 cells, a line of human renal epithelial cells,” American Journal of Renal Physiology, vol. 306, pp. 1039–1046, 2014.

34. N. Hsieh, C. H. Shih, and H. Y. Chen, “Effects of Tamm- Horsfall protein on the protection of MCDK cells from oxalate induced free radical injury,” Urological Research, vol. 31, pp. 10–16, 2003.

35. Coe FL, Evan A, Worcester E. Kidney stone disease. J Clin Invest. 2005;115:2598-2608.

36. Reid DG, Jackson GJ, Duer MJ, et al. Apatite in kidney stones is a molecular composite with glycosaminoglycans and proteins: evidence from nuclear magnetic resonance spectroscopy, and relevance to Randall’s plaque, pathogenesis and prophylaxis. J Urol. 2011;185:725-730.

37. C. H. Dawson and C. R. V. Tomson, “Kidney stone disease: pathophysiology, investigation and medical treatment,” Journal of Clinical Medicine, vol. 12, no. 5, pp. 467–471, 2012.

38. M. Lopez and B. Hoppe, “History, epidemiology and regional diversities of urolithiasis,” Pediatric Nephrology, vol. 25, no.1, pp. 49–59, 2008.

39. Zacchia, M., Preisig, P., 2010. Low urinary citrate: an overview. J Nephrol. 23(6), S49.

40. O'neill, W.C., Lomashvili, K.A., Malluche, H.H., Faugere, M.C., Riser, B.L., 2011. Treatment with pyrophosphate inhibits uremic vascular calcification. Kidney international 79(5), 512- 517.

41. Wang, L., Zhang, W., Qiu, S.R., Zachowicz, W. J., Guan, X., Tang, R., Nancollas, G.H., 2006. Inhibition of calcium oxalate monohydrate crystallization by the combination of citrate and osteopontin. Journal of crystal growth 291(1), 160-165.

42. Atmani, F., Opalko, F.J., Khan, S.R., 1996. Association of urinary macromolecules with calcium oxalate crystals induced in vitro in normal human and rat urine. Urol Res. 24(1), 45-50.

43. V. Centeno, G. D. de Barboza, and A. Marchionatti, “Molecular mechanisms triggered by low-calcium diets,” Nutrition Research Reviews, vol. 22, no. 2, pp. 163–174, 2009. Advances in Urology 11

44. B. Cakıro˘glu, E. Eyyupo˘glu, A. I. Hazar, B. S. Uyanik, and B. Nuho˘glu, “Metabolic assessment of recurrent and first renal calcium oxalate stone formers,” ArchivioItaliano di Urologia e Andrologia, vol. 88, pp. 101–105, 2016.

45. S. R. Marengo and A. M. Romani, “Oxalate in renal stone disease: the terminal metabolite that just won’t go away,” Nature Clinical Practice Nephrology, vol. 4, no. 7, pp. 368–377, 2008

46. Aggarwal, K. P., Narula, S., Kakkar, M., & Tandon, C., 2013. Nephrolithiasis: molecular mechanism of renal stone formation and the critical role played by modulators. Bio. Med. Res. Int. 2013, 292953.

47. Evan, A.P., Worcester, E.M., Coe, F.L., Williams, J., Lingeman, J.E., 2015. Mechanisms of human kidney stone formation. Urolithiasis 43(1), 19-32.

48. Corbetta, S., Baccarelli, A., Aroldi, A., Vicentini, L., Fogazzi, G. B., Eller-Vainicher, C., Spada, A., 2005. Risk factors associated to kidney stones in primary hyperparathyroidism. J. Endocrinol. Invest. 28(4), 122-128.

49. N. Chhiber, M. Sharma, T. Kaur, and S. Singla, “Mineralization in health and mechanism of kidney stone formation,” International Journal of Pharmaceutical Science Invention, vol. 3, pp. 25–31, 2014.

50. C. Barbasa, A. Garciaa, L. Saavedraa, and M. Muros, “Urinary analysis of nephrolithiasis markers,” Journal of Chromatography B, vol. 781, no. 1-2, pp. 433–455, 2002.

51. A. Chaudhary, S. K. Singla, and C. Tandon, “In vitro evaluation of Terminalia arjuna on calcium phosphate and calcium oxalate crystallization,” Indian Journal of Pharmaceutical Sciences, vol. 72, no. 3, pp. 340–345, 2010.

52. A. Bensatal and M. R. Ouahrani, “Inhibition of crystallization of calcium oxalate by the extraction of Tamarix gallica L,” Urological Research, vol. 36, no. 6, pp. 283–287, 2008.

53. F. Dal-Moro, M. Mancini, I. M. Tavolini, V. De Marco, and P. Bassi, “Cellular and molecular gateways to urolithiasis: a new insight,” Urologia Internationalis, vol. 74, pp. 193–197, 2005.

54. D. V. Kishore, F. Moosavi, and D. R. K. Varma, “Effect of ethanolic extract of Portulaca oleracea linn. on ethylene glycol and ammonium chloride induced urolithiasis,” International Journal of Pharmacy and Pharmaceutical Sciences, vol. 5, no. 2, pp. 134–140, 2013.

55. Nijenhuis T, Hoenderop JG, Loffing J, van der Kemp AW, van Os CH, Bindels RJ. Thiazide-induced hypocalciuria is accompanied by a decreased expression of Ca2+ transport proteins in kidney. Kidney Int 2003;64:555-64.

56. Guirguis-Blake J. Preventing recurrent nephrolithiasis in adults. Am Fam Physician 2014;89:461-3.

57. Pearle MS, Goldfarb DS, Assimos DG, Curhan G, Denu-Ciocca CJ, Matlaga BR, et al. Medical management of kidney stones: AUA guideline. J Urol2014;192:316-24.

58. Pak CY, Heller HJ, Pearle MS, Odvina CV, Poindexter JR, Peterson RD. Prevention of stone formation and bone loss in absorptive hypercalciuria by combined dietary and pharmacological interventions. J Urol2003;169:465-9.

59. Barcelo P, Wuhl O, Servitge E, Rousaud A, Pak CY. Randomized double-blind study of potassium citrate in idiopathic hypocitraturic calcium nephrolithiasis. J Urol1993;150:1761-4.

60. Robinson MR, Leitao VA, Haleblian GE, Scales CD Jr, Chandrashekar A, Pierre SA, et al. Impact of long-term potassium citrate therapy on urinary profiles and recurrent stone formation. J Urol2009;181:1145-50.

61. M. Dursun, A. Otunctemur, and E. Ozbek, “Kidney stones and ceftriaxone,” European Medical Journal of Urology, vol. 3, no. 1, pp. 68–74, 2015.

62. L. Giannossi and V. Summa, “A review of pathological biomineral analysis techniques and classification schemes,” in An Introduction to the Study of Mineralogy, C. Aydinalp, Ed., InTechOpen, InTech, IMAA-CNR, Italy, 2012, http://www.intechopen.com/books/.

63. T. C. Ngo and D. G. Assimos, “Uric acid nephrolithiasis: recent progress and future directions,” Reviews in Urology, vol. 9, pp. 17–27, 2007.

64. Fellstrom B, Danielson BG, Karlstrom B, Lithell H, Ljunghall S, Vessby B, et al. Effects of high intake of dietary animal protein on mineral metabolism and urinary supersaturation of calcium oxalate in renal stone formers. Br J Urol1984;56:263-9.

65. Best S, Tracy C, Bagrodia A, Poindexter J, Adams-Huet B, Sakhaee K, et al. Effect of various animal protein sources on urinary stone risk factors [Internet]. Linthicum, MD: American Urological Association; c2014 [cited 2014 Nov 24]. Available from: https://www.auanet.org/university/abstract_detail.cfm?id=2147&meetingID=11WAS.

66. Reiser S, Powell AS, Scholfield DJ, Panda P, Ellwood KC, Canary JJ. Blood lipids, lipoproteins, apoproteins, and uric acid in men fed diets containing fructose or high-amylose corn starch. Am J Clin Nutr1989;49:832-9.

67. K. Ahmed, P. Dasgupta, and M. S. Khan, “Cystine calculi: challenging group of stones,” Postgraduate Medical Journal, vol. 82, no. 974, pp. 799–801, 2006.

68. Sakhaee K, Maalouf NM, Sinnott B. Clinical review. Kidney stones 2012: pathogenesis, diagnosis, and management. J Clin Endocrinol Metab2012;97:1847-60.

69. Barbey F, Joly D, Rieu P, Mejean A, Daudon M, Jungers P. Medical treatment of cystinuria: critical reappraisal of long-term results. J Urol2000;163:1419-23.

70. Jaeger P, Portmann L, Saunders A, Rosenberg LE, Thier SO. Anticystinuric effects of glutamine and of dietary sodium restriction. N Engl J Med 1986;315:1120-3.

71. Rodríguez LM, Santos F, Malaga S, Martinez V. Effect of a low sodium diet on urinary elimination of cystine in cystinuric children. Nephron 1995;71:416-8.

72. Rodman JS, Blackburn P, Williams JJ, Brown A, Pospischil MA, Peterson CM. The effect of dietary protein on cystine excretion in patients with cystinuria. Clin Nephrol 1984;22:273-8.

73. Saravakos P, Kokkinou V, Giannatos E. Cystinuria: current diagnosis and management. Urology 2014;83:693-9.

74. D. P. Griffith, “Struvite stones,” Kidney International, vol. 13, no. 5, pp. 372–382, 1978.

75. Williams JJ, Rodman JS, Peterson CM. A randomized double blind study of acetohydroxamic acid in struvite nephrolithiasis. N Engl J Med 1984;311:760-4.

76. Griffith DP, Gleeson MJ, Lee H, Longuet R, Deman E, Earle N. Randomized, double-blind trial of Lithostat (acetohydroxamic acid) in the palliative treatment of infection-induced urinary calculi. EurUrol1991;20:243-7.

77. Rodman JS, Williams JJ, Jones RL. Hypercoagulability produced by treatment with acetohydroxamic acid. Clin PharmacolTher1987;42:346-50.

78. Saltel E, Angel JB, Futter NG, et al. Increased prevalence and analysis of risk factors for indinavir nephrolithiasis. J Urol. 2000;164:1895–1897.

79. Sundaram CP, Saltzman B. Urolithiasis associated with protease inhibitors. J Endourol. 1999;13:309–312.

80. Janbaz, K. H., Saeed, S. A., and Gilani, A. H. (2002). Protective effect of rutin on paracetamol- and CCl4-induced hepatotoxicity in rodents. Fitoterapia, 73(7-8):557-653.

81. Ghodasara, J., Pawar, A., Deshmukh, C., et al. (2011). Inhibitory effect of rutin and curcumin on experimentally-induced calcium oxalate urolithiasis in rats. Pharm Res, 2(6):388-392.

82. Cabrera, C., Artacho, R., and Giménez, R. (2006). Beneficial Effects of Green Tea—A Review. J Am Coll Nutr, 25(2):79-99.

83. Zhai, W., Zheng, J., Yao, X., et al. (2013). Catechin prevents the calcium oxalate monohydrate induced renal calcium crystallization in NRK-52E cells and the ethylene glycol induced renal stone formation in rat. BmcComplem Altern M, 13(1):228.

84. Grases, F., Prieto, R. I., Sanchis, P., et al. (2009). Phytotherapy and renal stones: the role of antioxidants: A pilot study in Wistar rats. Urolithiasis, 37(1):35-40.

85. Barberán, F. A. T., Gil, M. I., Tomás, F., et al. (1985). Flavonoid Aglycones and Glycosides from Teucrium gnaphalodes. J Nat Prod, 48(5):859-860.

86. Hollingsworth JM, Rogers MA, Kaufman SR, Bradford TJ, Saint S, Wei JT, et al. Medical therapy to facilitate urinary stone passage: A meta-analysis. Lancet. 2006;368:1171–9.

87. Granados Loarca EA. Medical treatment of uric acid lithiasis of the urinary tract and usefulness of double J catheter. Arch Esp Urol. 2001;54:157–61

88. Phatak R S and HendreA S 2015 In-vitro antiurolithiatic activity of Kalanchoe pinnata extract,” Int. J. Pharmacogn. Phytochem. Res. 7 275–279

89. Shashi Alok, Sanjay Kumar Jain, Amita Verma, Mayank Kumar, Monika Sabharwal. Pathophysiology of kidney, gallbladder and urinary stones treatment with herbal and allopathic medicine: A review. Asian Pac J Trop Dis 2013; 3(6): 496-504.

90. Bawari S, Negi Sah A and Tewari D 2018 Antiurolithiatic activity of Daucus carota: an in vitro study Pharmacogn. J. 10 880–884

91. Saha S and Verma R J 2013 Inhibition of calcium oxalate crystallisation in-vitro by an extract of Bergenia ciliata Arab J. Urol. 11 187–192

Received on 14.07.2022 Modified on 17.11.2022

Res. J. Pharmacognosy and Phytochem. 2023; 15(1):53-62.

DOI: 10.52711/0975-4385.2023.00009

Risk factors	Type of urolithiasis	Mechanism of urolithiasis	Reference
High blood pressure	Uric acid stone Calcium stone	Increased calciuria and oxaluria. Calcium oxalate and uric acid supersaturation	13
Diabetes	Uric acid stones. Calcium stones	Uric kidney stones are brought on by low urine pH.Calcium kidney stones are brought on by renal acid excretion problems. Calcium salt supersaturation is a result of increased insulin resistance.	14
Renal ailment	Calcium stones. Uric acid stones. Calcium phosphate stones.	Reduced glomerular filtration results in lower calcium excretion and higher oxalate excretion, which together create calcium stones. Uric acid stones are brought on by an elevated GFR.Calcium phosphate stones are caused by a reduced GFR.	15
Hyperparathyroidism	Calcium stones.	Enhanced synthesis of 1.25 dihydroxy vitamin D increases the resorption of intestinal calcium due to improper calcium homeostasis caused by overproduction of parathyroid hormone, which also causes phosphaturia.	16