1.0 INTRODUCTION:

Urolithiasis is a prevalent condition that affects people all over the world. Its origins can be traced back to 4800 BCE Egyptian mummies that contained kidney and bladder stones. The cause of urolithiasis, a multifactorial disease in which stones can form anywhere in the urinary tract, is a sequence of events that upset the balance between the urinary system's promoters and inhibitors of crystallization.

These include low urine volume, urine pH, the presence of calcium, sodium, oxalate, and urate, which are known to promote crystallization, and citrate, pyrophosphate, magnesium, glycosaminoglycans, urinary prothrombin fragment 1, osteopontin, and acid polypeptides that inhibit crystallization.^1,2,3,4,5

1.1 Theories on Stone Formation:

1. Free particle theory

2. Fixed particle theory

3. Randall’s plaque hypothesis

4. Blocked lymphatic theory

5. Vascular theory

1.1.1 Free Particle Theory:

According to the free particle theory, as urine passes through the kidney, crystals of one of the components that causes stones spontaneously precipitate out of the supersaturated urine and start to collect or enlarge in the nephron lumen. One of these many crystals may be kept at a narrow or distant part of the nephron, where it could serve as a nidus for the creation of stones.^1,6,7

1.1.2 Fixed Particle Theory:

The fixed particle theory states that crystals that precipitate out of supersaturated urine adhere to the renal epithelium at the site of renal tissue damage, which can be brought on by infectious pathogens or the crystals themselves. Because the renal epithelium is frequently exposed to supersaturated urine, these crystals serve as foci for the formation of stones.^1,8,9

1.1.3 Randall’s Plaque Hypothesis:

According to Randall's plaque hypothesis, stone production occurs at the location of renal lesions. More precisely, according to this theory, calcium phosphate depositions (apatite), a type of renal lesion, begin along the basement membranes of thin loops of Henle and subsequently spread to the interstitium and then to the urothelium, eventually eroding the same, because of the environment produced by low urine pH and volume and elevated urinary calcium levels. These apatite deposits termed as Randall’s plaques, on being constantly exposed to calyceal urine due to the loss of urothelium then attract organic substances like lipids, glycosaminoglycans and urinary proteins such as osteopontin and Tamm- Horsfall protein that form a matrix on which accumulate apatite crystals that again get coated with a layer of urinary proteins and other organic substances and so on, forming a multilayered sandwich of apatite and organic matrix. These several layers subsequently create a location where calcium oxalate crystals can attach, develop, and eventually form stones.^1,10-14

1.1.4 Blocked Lymphatic Theory:

According to the notion, the renal lymphatic system keeps precipitating salts from building up and aggregating in the kidney by draining the renal pelvis. However, when these renal lymphatics are damaged or impaired, salt precipitates have a tendency to enlarge into larger concretions as they pass through the lymph vessels. These concretions become blocked at the calyces' fornices, which are located just outside the collecting system. There, they erode the surrounding membrane, resulting in urine percolation, and because they are constantly in contact with the salts and other organic materials in the urine, they eventually grow into larger renal stones.^1,15,16

1.1.5 Vascular Theory:

Similar to the bifurcated arteries, the vasa recta and other capillaries in the renal papillary region are susceptible to abrupt shifts in blood flow from laminar to turbulent because of their many bifurcations. They are subject to illnesses and injuries because of these frequent blood flow changes, as well as their hyperosmolar and hypoxic environment. Similar to arteries, these blood flow changes and susceptible tissue structures cause atherosclerotic plaques to form in the renal papilla's vasculature, which is followed by calcification. When these calcareous materials come into frequent touch with urine, they may erode their way into the renal interstitium and Bellini's papillary ducts, where they develop into bigger stones.^1,17

2.0 Modern Pathogenetic Aspects:

Numerous intricate physicochemical processes that take place in the kidney and urinary system as well as throughout the body are linked to the disease's development. These days, urolithiasis is thought to be a multi-etiological disease that arises from metabolic, hormonal, genetic, and urinary system abnormalities. Despite the fact that the genesis of urolithiasis is significantly influenced by the so-called "nonmodifiable" elements of gender, ethnicity, geographic location, and genetic traits.^18,19,20

Urolithiasis is now understood to be a polyetiological illness. Its causes are conventionally separated into endogenous and external categories. In certain situations, one of the reasons can be easily identified, and in other situations, they are closely related. Climate, soil biogeochemical properties, water quality, dietary considerations, and societal aspects are examples of exogenous causes. The human body contains endogenous etiological elements by nature. They can be acquired during the course of a person's life, congenital, or inherited. The importance of external variables in the etiology of urolithiasis has given particular attention in the scientific literature. These include geographic and climatic conditions, food habits, iatrogenic conditions, socioeconomic factors, occupations, and more.^{18,21,22,23,
24}

Changes in renal tissue are one type of endogenous etiology. Pathological alterations in the kidneys, urinary tract, and urodynamics; decreased kidney microcirculation and infection; altered urine composition; and elevated excretion of lithogenic substances.^18,25-29

Genetic factors are considered to be one of the most important endogenous etiological factors in the development of nephrolithiasis. These factors can lead to the development of metabolic nephropathies, tubulopathies, congenital and acquired enzymopathies, polygenically inherited membranopathy, and certain monogenic forms of lithogenic substance metabolism disorders. Finding urolithiasis correlation with polymorphic variations of a certain gene has been the primary focus of research on the genetic risk factors for its development over the past ten years. Studies conducted abroad have shown a correlation between the polymorphism of some genes, including KL, VDR, CASR, and ORAI1, and the incidence of urolithiasis. Studies on the relationship between urolithiasis and polymorphisms of several candidate genes are also being carried out by the N. A. Lopatkin Research Institute of Urology and Interventional Radiology. The polymorphism of the VDR and ORAI1 genes was discovered to be associated with the prevalence of urolithiasis in the Russian population. The genes TNFRSF11B, TNFSF11, ESR1, KL, CASR, and SLC26A6 did not exhibit this reliance.^18,30-34

3.0 Diagnostic Modalities:

3.1 Urine Analysis:

It is the initial diagnostic procedure for determining whether urinary tract stones are present. Urine volume, pH, calcium, creatinine, sodium, phosphate, oxalate, citrate, uric acid, and cystine levels are all determined, along with the presence of blood visually. Evaluation by appearance, dipstick, chemical testing, and microscopic inspection are all part of urine analysis. Reddish pee is a sign of haematuria, while cloudy urine typically indicates the presence of bacteria and pus. The pH and specific gravity of urine, as well as the presence of blood, leukocyte esterase, albumin, and nitrite, can all be determined with the use of a dipstick.

The pH of urine can occasionally reveal the type of stone that is present. For example, it is widely known that an acidic pH is favorable for the creation of cystine and uric acid stones, whereas an alkaline pH encourages the formation of struvite and calcium phosphate stones. Urine with pus typically implies an illness. It is evident that struvite stones are present if pus is discovered in alkaline urine; however, if pus is found in acidic urine, it can be inferred that the infection is secondary and that the stone may be organic, such as a uric acid stone, cystine stone, or xanthine stone. A urine culture is typically conducted to confirm the existence of a urinary tract infection. White blood cells (WBCs), red blood cells (RBCs), and crystals that form stones are all examined under a microscope. While a high RBC count suggests haematuria, an elevated WBC count once more suggests a UTI. Under a microscope, stones can take on various shapes, such as dumbbell-shaped calcium oxalate monohydrate crystals (COM), tetrahedral or bipyramidal-shaped calcium oxalate dihydrate crystals (COD), narrow and elongated calcium phosphate stones, struvite stones that resemble rectangular prisms like a coffin lid, uric acid stones that resemble yellow or reddish-brown diamond-shaped crystals (rhomboidal) or needles, and cystine stones that have a hexagonal shape. On the other hand, 2, 8-dihydroxyadenine stones are round, brown crystals. Finding the underlying metabolic disorders and risk factors is aided by testing urine for the presence of substances such calcium, creatinine, salt, phosphate, oxalate, citrate, magnesium, uric acid, and cystine.^1,35,36,37

3.2 Serum analysis:

As markers of renal function and underlying metabolic reasons, serum analysis includes measuring the levels of urea, uric acid, creatinine, sodium, potassium, bicarbonate, albumin, calcium, magnesium, and phosphate. The glomerular filtration rate and renal tissue integrity, which are negatively impacted in renal stone disease, are depicted by serum urea, uric acid, and creatinine levels. Serum parathyroid hormone levels must be measured in order to check for hyperparathyroidism if increased calcium levels are found. Since leukocytosis is evident in infected patients, haematological analysis is done in addition to serum analysis to determine the leukocyte count.^38,39

3.3 Stone Analysis:

An essential component of research into recurrent stone formers is stone analysis, which gives an overview of the mineral components of stones and, consequently, of the variables and metabolic conditions that may be connected to stone formation. This aids in appropriate medical management. In order to identify the components of a stone and their locations within it, stone analysis entails analyzing the entire crust and core of the stone. The results are then summarized in order to strategically determine the underlying reason and, consequently, guide the diagnosis and therapy. For stone analysis, X-ray crystallography and infrared spectroscopy are the most often used methods.^{1, 40}

3.4 Imaging:

One of the initial imaging tests is radiography, which is just a simple abdominal X-ray. It facilitates finding the stones and imagining their size, shape, and quantity. Compared to less radio-dense uric acid, struvite, and cystine stones, it is more effective at detecting calcium-rich, radiopaque stones. Bowel gas, stool, and extra-urinary calcifications severely restrict its effectiveness and, thus, its applicability, despite the fact that it is very cost-effective. Additionally, there is a significant risk of radiation exposure.⁴¹

High frequency sound waves are used in ultrasound, an imaging technique, to create an image of solid objects like stones by bouncing or echoing off of them. Since there are no radiation exposure hazards, such as teratogenicity, mutagenicity, or carcinogenicity to the fetus, real-time ultrasound is now being employed as a first-line imaging method for urolithiasis during pregnancy. Additionally, it is the preferred imaging method for identifying and finding kidney stones in youngsters.^42,1

Iodinated contrast media, which travels in blood and is eventually filtered by the kidneys and removed from the ureters and bladder during micturition, is given to the patient intravenously as part of the Intravenous Pyelography (IVP) procedure. The structure and operation of the urinary system, as well as any obstruction or stone therein, are clearly depicted by a series of X-rays of the kidneys, ureters, and bladder obtained at predetermined intervals using contrast medium.⁴³

A radiopharmaceutical substance labeled with technetium-99 is administered intravenously as part of isotope renography, also known as nuclear imaging. A gamma camera detects the radiation emitted as the radioactive substance passes down the urinary tract, producing images of the same.^1,44

Urinary stones can be imaged using magnetic resonance imaging, which occasionally calls for the addition of paramagnetic contrast material. It also uses radio waves, magnets, and the body's inherent magnetic properties. Because of its superior soft tissue contrast and lack of ionizing radiation risk, it was found to be useful in visualizing pathological changes caused by stones in the urinary tracts of pregnant and pediatric patients. However, high doses of paramagnetic contrast were later found to be teratogenic. However, it has turned out to be a safer substitute because administering contrast media is not required.^45,46A relatively new imaging method is digital tomosynthesis. Compared to the commonly used noncontrast CT, it has been shown to carry a significantly lower risk of radiation exposure and may offer additional advantages and more adoption.^47,1

4.0 CONCLUSION:

Urolithiasis remains a globally prevalent, multifactorial disorder influenced by both environmental and genetic factors. Multiple theories, including the Free and Fixed Particle theories, Randall’s Plaque Hypothesis, and Vascular and Lymphatic theories, provide insight into stone formation mechanisms. Modern research emphasizes the polyetiological nature of the disease, with contributions from metabolic, hormonal, and genetic abnormalities, as well as lifestyle and environmental exposures. Diagnostic evaluation involves a combination of urine and serum analyses, stone composition assessment, and various imaging modalities, each offering specific advantages depending on clinical context. A comprehensive understanding of pathogenetic pathways and diagnostic tools is crucial for accurate diagnosis, prevention, and personalized management of urolithiasis.

5.0 ACKNOWLEDGEMENT:

The authors express sincere gratitude to all the supervisors and professors of DCS’S A.R.A. College of Pharmacy, Nagaon, Dhule who extended their contribution and support in this work and specially thanks for Dr. H. V. Deore, Dr. R.B. Patil and Dr. R.L. Shirole sir for guided.

6.0 REFERENCES:

1. Bawari S, Sah AN, Tewari D. Urolithiasis: an update on diagnostic modalities and treatment protocols. Indian J Pharm Sci. 2017 Mar 1; 79(2): 164-74.

2. López M, Hoppe B. History, epidemiology and regional diversities of urolithiasis. PediatrNephrol. 2010; 25:49-59.

3. Chen Y. Urolithiasis update: evaluation and management. UrolSci. 2012; 23:5-8.

4. Touhami M, Laroubi A, Elhabazi K, Loubna F, Zrara I, Eljahiri Y, et al. Lemon juice has protective activity in a rat urolithiasis model. BMC Urol. 2007; 7:2-3.

5. Wilikinson B, Hall J. Management of stone disease. Surgery. 2010; 28: 338-44.

6. Evan AP. Physiopathology and etiology of stone formation in the kidney and the urinary tract. PediatrNephrol 2010; 25:831-41.

7. Robertson WG. The scientific basis of urinary stone formation. In: Mundy AR, Fitzpatrick JM, Neal DE, George NJR, editors. The scientific basis of urology. 3rd ed. United Kingdom: T and F InformaUK Limited; 2010. p. 162-81.

8. Evan AP. Physiopathology and etiology of stone formation in the kidney and the urinary tract. PediatrNephrol. 2010; 25:831-41.

9. Robertson WG. The scientific basis of urinary stone formation. In: Mundy AR, Fitzpatrick JM, Neal DE, George NJR, editors. The scientific basis of urology. 3rd ed. United Kingdom: T and F InformaUK Limited; 2010. p. 162-81.

10. Evan AP. Physiopathology and etiology of stone formation in the kidney and the urinary tract. Pediatr Nephrol. 2010; 25:831-41.

11. Randall A. The origin and growth of renal calculi. Ann Surg. 1937; 105: 1009-27.

12. Evan AP, Coe FL, Lingeman JE, Shao Y, Sommer AJ, Bledsoe SB, et al. Mechanism of formation of human calcium oxalate renal stones on Randall’s plaque. Anat Rec. 2007; 290: 1315-23.

13. Matlaga BR, Coe FL, Evan AP, Lingeman JE. The role of Randall’s plaques in the pathogenesis of calcium stones. J Urol. 2007; 177:31-38.

14. Green W, Ratan H. Molecular mechanisms of urolithiasis. Urology. 2013; 81:701-04.

15. Carr RJ. A new theory on the formation of renal calculi. Brit J Urol. 1954; 26:105-17.

16. King JS Jr. Currents in renal stone research. ClinChem. 1971; 17: 971-82.

17. Stoller ML, Meng MV, Abrahams HM, Kane JP. The primary stone event: a new hypothesis involving a vascular etiology. J Urol. 2004; 171: 1920-24.

18. Azimova SB, Khalikov HD. Modern pathogenetic aspects of urolithiasis development. The American Journal of Medical Sciences and Pharmaceutical Research. 2025 Apr 16; 7(4):.21-4.

19. Leanez Jiménez M, Candau Vargas-Zúñiga F, Reina Ruiz C. Urinary lithiasis as a systemic disease. Arch Esp Urol. 2017;70(1): 28-39.

20. Scales CD, Smith AC, Hanley JM, Saigal CS. Prevalence of kidney stones in the United States. Eur Urol. 2012; 62: 160-165.

21. Prosyannikov M. Yu. et al. Prevalence of urolithiasis among women over 45 years old in the Chuvash Republic. Experimental and Clinical Urology. 2023; 3: 10-14.

22. Apolikhin O. I., Kalinchenko S. Yu., Kamalov A. A. et al. Urolithiasis as a new component of metabolic syndrome. Saratov Scientific Medical Journal. 2011; 7(2); 117.

23. Voshchula V. I. et al. Statistics and risk factors for urolithiasis in Belarus. Experimental and Clinical Urology. 2013; 2: 18-25.

24. Dutov V. V. Modern aspects of diagnostics and treatment of urolithiasis in elderly and senile patients. RMJ. 2014; 22(29); 2100-2104.

25. Koo K. C. et al. Monogenic features of urolithiasis: A comprehensive review. Asian Journal of Urology. 2023.

26. Yasui T. et al. Pathophysiology-based treatment of urolithiasis. International Journal of Urology. 2017; 24(1): 32-38.

27. Glybochko P. V., Chekhonatskaya M. L., Piskunova L. V. State of urodynamics of the lower urinary tract of the fetus in intrauterine growth retardation. Saratov Scientific-Medical Journal. 2011; 7(2): 513- 517.

28. Nazarov T. Kh. et al. Urolithiasis: etiopathogenesis, diagnosis and treatment. Andrology and Genital Surgery. 2019; 20(3): 42-50.

29. Apolikhin O.I., Sivkov A.V., Moskaleva N.G., Solntseva T.V., Komarova V.A. Analysis of urological morbidity and mortality in the Russian Federation over a ten-year period (2002-2012). Experimental and Clinical Urology. 2014; 2: 4-12.

30. Bartoletti R. et al. Treatment of urinary tract infections and antibiotic stewardship. European Urology Supplements. 2016; 15(4); 81-87.

31. Xu C., Song R., Yang J., Jiang B., Wang X.L., Wu W., Zhang W. Klotho gene polymorphism of rs3752472 is associated with the risk of urinary calculi in the population of Han nationality in Eastern China. Gene. 2013; 2: 494–497

32. Vezzoli G., Terranegra A., Aloia A. Decreased transcriptional activity of calciumsensing receptor gene promoter 1 is associated with calcium nephrolithiasis. J. Clin. Endocrinol. Metab. 2013; 98: 3839–3847.

33. Wang S., Wang X., Wu J., Lin Y., Chen H., Zheng X., Zhou C., Xie L. Association of vitamin D receptor gene polymorphism and calcium urolithiasis in the Chinese Han population. Urol. Res. 2012; 4: 277–284.

34. Chou Y., Juo S., Chiu Y., Liu M.E., Chen W.C., Chang C.C., Chang W.P., Chang J.G., Chang W.C. A polymorphism of the ORAI1 gene is associated with the risk and recurrence of calcium nephrolithiasis. J. Urol. 2011; 5: 1742–1746.

35. Pietrow PK, Karellas ME. Medical management of common urinary calculi. SA Fam Pract. 2007; 49:44-48.

36. Kambadakone AR, Eisner BH, Catalano OA, Sahani DV. New and evolving concepts in the imaging and management of urolithiasis: urologists’ perspective. Radiographics. 2010; 30: 603-23

37. Leehey DJ, Moinuddin IK. Handbook of Nephrology. 1st ed. Philadelphia (US): Lippincott Williams and Wilkins; 2013.

38. Thomas B, Hall J. Urolithiasis. Surgery. 2005; 23: 129

39. Rathod NR, Biswas D, Chitme HR, RatnaS, Muchandi IS, Chandra R. Antiurolithiatic effects of Punicagranatum. J Ethnopharmacol. 2012; 140: 234-38.

40. Mandel NS, Mandel GS. Physicochemistry of urinary stone formation. In: Pak CY, editor. Renal stone disease: pathogenesis, prevention, and treatment. 1st ed. Boston: Martinus Nijhoff Publishing. 1987: 1-24.

41. Portis AJ, Sundaram CP. Diagnosis and initial management of kidney stones. Am Fam. Physician. 2001; 63: 1329-38.

42. http://uroweb.org/wp-content/uploads/22Urolithiasis_LR_full.pdf.

43. McKenzie G, Hall J. Management of stone disease. Surgery. 2013; 31: 354-61.

44. Malhotra KK. Medical aspects of renal stones. J Indian Acad Clin Med. 2008; 9: 282-86.

45. Villa L, Giusti G, Knoll T, Traxer O. Imaging for urinary stones: update in 2015. EU Focus. 2016; 2: 122-29.

46. O’ DonoghuePM, McSweeney SE, Jhaveri K. Genitourinary imaging: current and emerging applications. J Postgrad Med. 2010; 56: 131-39

47. Neisius A, Astroza GM, Wang C, Nguyen G, Kuntz NJ, Januzis N, et al. Digital tomosynthesis: a new technique for imaging nephrolithiasis. Specific organ doses and effective doses compared with renal stone protocol noncontrast computed tomography. Urology. 2014; 83: 282-87.

Received on 15.07.2025 Revised on 16.08.2025

Accepted on 11.09.2025 Published on 04.10.2025

Available online from October 10, 2025

Asian J. Res. Pharm. Sci. 2025; 15(4):418-422.

DOI: 10.52711/2231-5659.2025.00062

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