Management of recurrent urolithiasis: advances in prevention strategies

INTRODUCTION

Urolithiasis is a common disorder marked by the development of stones in the urinary tract, most frequently the kidney, due to the urine becoming oversaturated with minerals like calcium oxalate, phosphate, or uric acid.¹ About 1 in 11 people worldwide are afflicted by urolithiasis in their lifetime, which presents with variable degrees of severity and frequency.² A longitudinal study conducted in 204 countries stated that the rate of nephrolithiasis increased in most countries.^3,4 Up to 50% of people who get stones end up getting them again within 5-10 years.⁵ In addition to causing severe pain and discomfort, recurrent episodes raise the risk of permanent renal damage and raise medical expenses for hospital stays, surgeries, and diagnostic tests.^6,7

Genetic predispositions, metabolic syndromes, environmental exposures, and dietary factors are all part of the complex pathophysiology of urolithiasis.^8,9 The main causes of stone formation are crystal nucleation, growth, aggregation, retention in the kidneys or lower urinary tract, and urine supersaturation.^10,11 Stones are classified as calcium oxalate, calcium phosphate, uric acid, struvite (infection stones), and cystine stones based on their biochemical makeup.^12,13 Each of these types of stones requires a different approach to treatment.¹⁴ Calcium oxalate stones are the most common kind, with more than 70% of all cases.

Although acute stone removal procedures like ureteroscopy, percutaneous nephrolithotomy, and extracorporeal shock wave lithotripsy (ESWL) are effective, recurrence is still a substantial risk.^15,16 Therefore, after the first stone events, preventive care needs to be given priority. To pinpoint specific risk factors and customize interventions appropriately, urological societies' guidelines stress the significance of comprehensive metabolic workups, which include 24-hour urine testing and stone analysis.¹⁶

Conventional preventive strategies include limiting dietary sodium and oxalate, consuming animal protein in moderation, and increasing fluid intake to dilute urine.^17,18 Commonly used pharmaceuticals include potassium citrate (for hypocitraturia and uric acid stones), thiazide diuretics (for hypercalciuria), and allopurinol (for hyperuricosuria).¹⁹ But new research has raised questions about the long-term safety and effectiveness of some drugs, indicating the need for a more complex and customized strategy.

New developments in genetics and microbiome research present promising avenues for enhancing prevention.²⁰ Oxalate has been demonstrated to be broken down by gut bacteria such as Oxalobacter formigenes, and genetic profiling may be used to identify patients who are more likely to experience a recurrence.^21,22 Precision medicine in the prevention of stones is made possible by these developments.²³ By highlighting evidence-based recommendations, identifying gaps in current practices, and suggesting future directions, this review aims to assess both established and new approaches for the prevention of recurrent urolithiasis. The review seeks to assist physicians in managing this difficult condition thoroughly and in a patient-centered manner.

LITERATURE SEARCH

A narrative approach was used in this article to investigate both new and current approaches to prevent recurrent urolithiasis. Electronic databases such as PubMed, Scopus and Google Scholar were used to perform a thorough literature search. Only studies written in English and released between 2010 and 2025 were included in the search. “Recurrent kidney stones”, “urolithiasis prevention”, “fluid intake and kidney stones” “dietary oxalate” “citrate therapy “, “thiazide diuretics”, “probiotics and oxalate” “and genetic susceptibility to kidney stones” were among the keywords that were used. RCTs, cohort studies, clinical practice guidelines and systematic reviews and meta-analyses pertaining to adult populations with a documented history of recurrent kidney stones were all involved in the inclusion criteria. Particular focus was placed on research examining risk-stratified or customized approaches as well as studies contrasting traditional and innovative preventative strategies. Using themes such as lifestyle interventions, pharmacological management, gut microbiota modification, and genomic risk stratification data were extracted and synthesized. To highlight current guidelines gaps in the evidence and potential avenues for future research in recurrent stone prevention a qualitative synthesis was conducted instead.

DISCUSSION

Recurrent urolithiasis remains a significant clinical challenge due to its high prevalence, tendency for recurrence, and associated healthcare burden. The risk of recurrence is influenced by a variety of factors, including genetic predisposition, metabolic abnormalities, dietary habits, dehydration, and comorbid conditions such as obesity, hypertension, and diabetes. This recurrent nature not only impacts patients’ quality of life but also contributes to increased healthcare costs due to repeated imaging, surgical interventions, and hospital admissions. Effective management relies heavily on thorough risk assessment and patient stratification to guide individualized preventive strategies.

Dietary and lifestyle modifications

The easiest and most economical way to stop recurrent urolithiasis is to make dietary and lifestyle adjustments. The amount of lithogenic substances in urine is greatly decreased by adequate fluid intake, with a daily urine output of at least 2 to 5 liters as the goal.²⁴ A Mendelian randomization study showed that patients who continued to consume large amounts of fluid had recurrence rates that were almost 50% lower.²⁵ Studies indicate that beverages like citrus juices, especially lemonade and orange juice, may also aid in prevention because of their citrate content, which binds calcium and prevents crystal formation.²⁶ Another important variable that can be changed is sodium intake. By inhibiting proximal sodium and calcium reabsorption, too much sodium in the diet raises urinary calcium excretion.^27,28 This mechanism raises the risk of calcium-based stones and causes hypercalciuria. According to clinical recommendations, sodium consumption should not exceed 2-3 grams per day.²⁹ Consuming animal protein also raises the acid load, decreases the pH of the urine, elevates the excretion of calcium and uric acid, and lowers protective citrate levels.^30,31 Reducing animal protein intake to less than 0.8-1.0 g/kg/day is therefore frequently recommended.³² It is especially crucial to manage oxalate in calcium oxalate stone formers. Oxalate is found in foods like spinach, tea, chocolate, rhubarb, and nuts. When taken in excess, particularly when calcium intake is low, oxalate absorption rises, which encourages the development of stones.³³ Oxalate bioavailability can be decreased, though, if calcium-containing meals are consumed with oxalate-rich foods. Another layer of complexity is added by emerging evidence that suggests the composition of the gut microbiota as a whole may have an impact on gut oxalate metabolism.³⁴ Lastly, stone risk is independently correlated with metabolic syndrome, obesity, and a sedentary lifestyle. Higher lithogenic substance excretion is correlated with higher body mass index (BMI).³⁵ Thus, it may be protective to promote physical activity, weight loss, and dietary patterns like the DASH or Mediterranean diets.³⁶

Pharmacologic methods

When a 24-hour urine analysis reveals metabolic abnormalities in a patient, pharmacologic therapy is usually indicated. These drugs work particularly well when combined with lifestyle modifications. Thiazide diuretics such as chlorthalidone or hydrochlorothiazide lower calcium levels in the urine by encouraging distal tubular reabsorption. For idiopathic hypercalciuria, they are the first line of treatment.³⁷ However, prolonged use may result in dyslipidemia, hypokalemia, and glucose intolerance.³⁸ Recent experiments (e. g., the NOSTONE study), its effectiveness might rely on assessing the effectiveness of different hydrochlorothiazide doses in preventing kidney stones.³⁹ Another popular treatment, especially for hypocitraturia or acidic urine, is potassium citrate.⁴⁰ It is especially useful in preventing calcium and uric acid stones because it not only raises urine citrate but also alkalinizes the urine.⁴¹ Potassium citrate improves bone mineral density, which is frequently weakened in recurrent stone formers, and lowers recurrence rates.⁴² Particularly for calcium oxalate stone formers with elevated uric acid, allopurinol is helpful in cases of hyperuricosuria. By blocking xanthine oxidase, it reduces the production of uric acid. Although it may pose cardiovascular risks to some populations, febuxostat is an alternative for patients who are unable to tolerate allopurinol. Acetohydroxamic acid, a urease inhibitor that lowers ammonia production, may be necessary for patients with infection-related struvite stones. But only refractory cases can use it due to its side effects, which include neurotoxicity and gastrointestinal intolerance. Patient adherence, electrolyte levels, and kidney function must all be closely monitored during long-term medication treatment. For high-risk stone formers, the best course of action continues to be a combination of pharmacological and nutritional approaches.

Emerging personalized therapies

Customized treatment regimens based on microbial genetic and biochemical profiling have gained attention as a result of recent developments in our understanding of the pathophysiology of stone disease. One area of significant research interest is the function of gut microbiota in oxalate metabolism. In the colon, oxalate is broken down by the gram-negative anaerobe Oxalobacter formigenes, hyperoxaluria is linked to its absence, which is frequently brought on by the use of antibiotics or dietary habits.^43,44 Probiotic supplementation of formigenes targeting oxalate degradation is under investigation, with early-phase trials indicating promise for more recent bacterial restoration therapies.^45,46 In the future, engineered probiotics might provide a sustainable and safe way to lower urine oxalate levels.^47,48

More is being learned about the genetic predisposition to stone formation. Variants in genes that affect renal calcium phosphate and oxalate handling including CLDN14, SLC26A1 and SLC34A1, have been found by genome-wide association studies (GWAS).^49,50 Individualized treatments and early genetic diagnosis are beneficial for patients with monogenic disorders like cystinuria or primary hyperoxaluria.⁵¹ Additionally, polygenic risk scores may eventually direct to the intensity of the preventive strategies in populations that are at risk. Predicting the recurrence of stones is being investigated using artificial intelligence and machine learning.^52-54 It has been demonstrated that algorithms trained on sizable datasets that include biochemical clinical and demographic factors can accurately predict which patients will benefit from particular treatments.^55,56 By offering customized risk profiles these models may support clinical decision-making and enhance patient involvement.^57,58 Furthermore, new treatments that use enzymes that break down oxalate (e. g. oxalate decarboxylase) and RNA-based treatments for monogenic disorders, and targeted transport inhibitors are being developed.^59,60 The prevention landscape may change over the next ten years as a result of these tactics.

CONCLUSION

Since recurrent urolithiasis is a complex condition, prevention must be both comprehensive and tailored to each patient. Lifestyle changes remain fundamental, especially proper hydration, normalizing calcium intake, reducing sodium and oxalate, and taking supplements of citrate. Although pharmacological treatments like citrate therapy, allopurinol, and thiazides are useful, they must be customized according to risk profiles and metabolic abnormalities. These new strategies could improve treatment regimens and more successfully lower recurrence. Clinical integration, cost-effectiveness analyses, and additional research are necessary for broad adoption, though. Precision medicine, better diagnostic instruments, and digital health initiatives that improve patient education and adherence should be the main focuses of future research. In nephrology and urology practice, maximizing prevention will continue to be a top priority due to the rising incidence of kidney stone disease worldwide.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

REFERENCES

1. 1. Skolarikos A, Neisius A, Petřík A, Petřík A, Somani B, Tailly T, et al. Urolithiasis. Paper presented at: EAU Guidelines. Edn. presented at the EAU Annual Congress Amsterdam. 2022.
2. 2. Leslie SW, Sajjad H, Murphy PB. Renal calculi, nephrolithiasis. In: StatPearls. StatPearls Publishing; 2024.
3. 3. Borumandnia N, Fattahi P, Talebi A, et al. Longitudinal trend of urolithiasis incidence rates among world countries during past decades. BMC Urol. 2023;23(1):166.
4. 4. Dirie NI, Hassan J, Hussein AO, Bashiru G, Hodo AA, Orey FAH, et al. Burden of urolithiasis: a systematic review of epidemiological and clinical trends in Somalia. Afr J Urol. 2024;30(1):64.
5. 5. Sohgaura A, Bigoniya P. A review on epidemiology and etiology of renal stone. Am J Drug Discov Dev. 2017;7(2):54-62.
6. 6. Almaghlouth AK, Alqutayfi HM, Bohamad AH, Almarzooq AJ, Alamer MA, Alqattan DJ. Urolithiasis Symptoms and Risk Factors Among the General Population of Alahsa, Saudi Arabia. Cureus. 2023;15(5):e39645.
7. 7. Raheem OA, Khandwala YS, Sur RL, Ghani KR, Denstedt JD. Burden of Urolithiasis: Trends in Prevalence, Treatments, and Costs. Eur Urol Focus. 2017;3(1):18-26.
8. 8. Chang CW, Ke HL, Lee JI, Yung-Chin L, Jhen-Hao J, Hsun-Shuan W, et al. Metabolic Syndrome Increases the Risk of Kidney Stone Disease: A Cross-Sectional and Longitudinal Cohort Study. J Personalized Med. 2021;11(11):1154.
9. 9. Yang L, Wang L, Liu Y, Erhao B, Jiahao W, Long X, et al. Causal associations between 45 dietary intake habits and urolithiasis: insights from genetic studies. Translational Androl Urol. 2024;13(7):1074-84.
10. 10. Michibata U, Maruyama M, Tanaka Y, Masashi Y, Yoshikawa HY, Takano K, et al. The impact of crystal phase transition on the hardness and structure of kidney stones. Urolithiasis. 2024;52(1):57.
11. 11. Oner M, Koutsoukos PG, Robertson W. Kidney stone formation-Thermodynamic, kinetic, and clinical aspects. In: Water-Formed Deposits. Elsevier. 2022;511-41.
12. 12. Khan SR, Pearle MS, Robertson WG, Giovanni G, Benjamin KC, Steeve D, et al. Kidney stones. Nature Rev Disease primers. 2016;2:16008.
13. 13. Halinski A, Bhatti KH, Boeri L, Jonathan C, Kaloyan D, Ayman E, et al. Stone composition of renal stone formers from different global regions. Arch Ital Urol Androl. 2021;93(3):307-12.
14. 14. Skolarikos (Chair) A, Jung H, Neisius A, Petřík A, Kamphuis GM, Davis NF. EAU Guidelines on Urolithiasis. EAU Guidelines on Urolithiasis 2025.
15. 15. Baowaidan F, Zugail AS, Lyoubi Y, Culty T, Lebdai S, Brassart E, et al. Incidence and risk factors for urolithiasis recurrence after endourological management of kidney stones: A retrospective single-centre study. Progres Urol. 2022;32(8-9):601-7.
16. 16. Wang K, Ge J, Han W, Dong W, Yinjuan Z, Yanhao S, et al. Risk factors for kidney stone disease recurrence: a comprehensive meta-analysis. BMC Urol. 2022;22(1):62.
17. 17. Peerapen P, Thongboonkerd V. Kidney Stone Prevention. Advances in nutrition (Bethesda, Md). 2023;14(3):555-569.
18. 18. Szymanski J, Chlosta M, Dudek P, et al. Prevalence, correlates, and treatment behaviors for urolithiasis and renal colic-like pain symptoms at the population level in Poland. Scientific Reports. 2025;15(1):10827.
19. 19. Manzo BO, Cabrera JD, Emiliani E, Sánchez HM, Eisner BH, Torres JE. Impact of the adherence to medical treatment on the main urinary metabolic disorders in patients with kidney stones. Asian J Urol. 2021;8(3):275-279.
20. 20. Jung HD, Cho S, Lee JY. Update on the Effect of the Urinary Microbiome on Urolithiasis. Diagnostics (Basel, Switzerland). 2023;13(5):951.
21. 21. Knight J, Deora R, Assimos DG, Holmes RP. The genetic composition of Oxalobacter formigenes and its relationship to colonization and calcium oxalate stone disease. Urolithiasis. 2013;41(3):187-96.
22. 22. Kumar R, Mukherjee M, Bhandari M, Kumar A, Sidhu H, Mittal RD. Role of Oxalobacter formigenes in Calcium Oxalate Stone Disease: A Study from North India. Europ Urol. 2002;41(3):318-22.
23. 23. Gambaro G. Empirical therapy or precision medicine for kidney stone formers in the ‘-omics’ era? Urolithiasis. 2019;47(1):1-3.
24. 24. Gamage KN, Jamnadass E, Sulaiman SK, Pietropaolo A, Aboumarzouk O, Somani BK. The role of fluid intake in the prevention of kidney stone disease: A systematic review over the last two decades. Turki J Urol. 2020;46(1):S92-103.
25. 25. Zhang Q, Guo Z, Zhang J, Liu H, Yi L. Effects of multiple fluid intake on Urolithiasis by mendelian randomization study. Scientific Rep. 2024;14(1):23682.
26. 26. Liaquat H. A Study Regarding Citrus Juices Effect (lemonade and orange juices only) in Urolithiasis When Compared to Plain Drinking Water. Pak J Med Health Sci. 2015;9(1):239-42
27. 27. Mente A, O'Donnell M, Yusuf S. Sodium Intake and Health: What Should We Recommend Based on the Current Evidence? Nutrients. 2021;13(9):3232.
28. 28. Yatabe MS, Yatabe J, Takano K, Murakami Y, Sakuta R, Abe S, et al. Effects of a high-sodium diet on renal tubule Ca2+ transporter and claudin expression in Wistar-Kyoto rats. BMC Nephrol. 2012;13:160.
29. 29. Ticinesi A, Nouvenne A, Maalouf NM, Borghi L, Meschi T. Salt and nephrolithiasis. Nephrol Dialysis Transplantation. 2014;31(1):39-45.
30. 30. Ferraro PM, Mandel EI, Curhan GC, Gambaro G, Taylor EN. Dietary Protein and Potassium, Diet-Dependent Net Acid Load, and Risk of Incident Kidney Stones. Clin J Am Soc Nephrol. 2016;11(10):1834-44.
31. 31. Kanbara A, Miura Y, Hyogo H, Chayama K, Seyama I. Effect of urine pH changed by dietary intervention on uric acid clearance mechanism of pH-dependent excretion of urinary uric acid. Nutrition J. 2012;11(1):39.
32. 32. Skolarikos (Chair) A, Jung H, Neisius A, Petřík A, Kamphuis GM, Davis NF. EAU Guidelines on Urolithiasis. EAU Guidelines on Urolithiasis 2025.
33. 33. Mitchell T, Kumar P, Reddy T, Wood KD, Knight J, Assimos DG, et al. Dietary oxalate and kidney stone formation. Am J Physiol-Renal Physiol. 2019;316(3):F409-13.
34. 34. An L, Shujue L, Zhenglin C, Min L, Zhican H, Peng X, et al. Gut microbiota modulation via fecal microbiota transplantation mitigates hyperoxaluria and calcium oxalate crystal depositions induced by high oxalate diet. Gut Microbes. 2025;17(1):2457490.
35. 35. Güler Y. Effects of body mass index on urinary lithogenic factors in urinary system stone patients. Folia Medica. 2024;66(1):80-7.
36. 36. Zayed S, Goldfarb DS, Joshi S. Popular Diets and Kidney Stones. Advances in Kidney Disease and Health. 2023;30(6):529-36.
37. 37. Dizon S, Iliescu EA, Ross Morton A. Kidney Stones. In: Huhtaniemi I, Martini L, eds. Encyclopedia of Endocrine Diseases (Second Edition). Oxford: Academic Press. 2014;365-71.
38. 38. Perez-Stable E, Caralis PV. Thiazide-induced disturbances in carbohydrate, lipid, and potassium metabolism. Am Heart J. 1983;106(1-2):245-51.
39. 39. Ghazaani MZ, Rizi FSD, Malekpour E, Momeni E, Abbasi F. Hydrochlorothiazide and kidney stone recurrence; an in-depth analysis of the NOSTONE trial. J Renal Injury Prevent. 2024;13(3):e32279.
40. 40. Shen J, Zhang X. Potassium Citrate is Better in Reducing Salt and Increasing Urine pH than Oral Intake of Lemonade: A Cross-Over Study. Med Sci Monitor. 2018;24:1924-9.
41. 41. Wiegand A, Fischer G, Seeger H, Wiegand A, Fischer G, Seeger H, et al. Impact of potassium citrate on urinary risk profile, glucose and lipid metabolism of kidney stone formers in Switzerland. Clin Kidney J. 2019;13(6):1037-48.
42. 42. Krieger NS, Asplin JR, Frick KK, Ignacio G, Christopher DC, Adeline N, et al. Effect of Potassium Citrate on Calcium Phosphate Stones in a Model of Hypercalciuria. J Am Society Nephrol. 2015;26(12):3001-8.
43. 43. Nazzal L, Francois F, Henderson N. Effect of antibiotic treatment on Oxalobacter formigenes colonization of the gut microbiome and urinary oxalate excretion. Scientific Rep. 2021;11(1):16428.
44. 44. Li X, Ellis ML, Knight J. Oxalobacter formigenes Colonization and Oxalate Dynamics in a Mouse Model. Applied Environ Microbiol. 2015;81(15):5048-54.
45. 45. Hoppe B, Niaudet P, Salomon R, Menghan L, Huilin L, Hyunwook K, et al. A randomised Phase I/II trial to evaluate the efficacy and safety of orally administered Oxalobacter formigenes to treat primary hyperoxaluria. Pediat Nephrol (Berlin, Germany). 2017;32(5):781-90.
46. 46. Chen Y, Ling Z, Ji J. The combination of oxalic acid and uric acid degrading probiotic from traditional Chinese fermented food reduces calcium accumulation and prevents kidney stones formation in rats. Food Biosci. 2024;62:105099.
47. 47. Wigner P, Bijak M, Saluk-Bijak J. Probiotics in the Prevention of the Calcium Oxalate Urolithiasis. Cells. 2022;11(2).
48. 48. Ma J, Lyu Y, Liu X. Engineered probiotics. Microbial Cell Factories. 2022;21(1):72.
49. 49. Elshamaa MF, Fadel FI, Kamel S, Farouk H, Alahmady M, Ramadan Y. Genetic polymorphisms in CLDN14 (rs219780) and ALP (rs1256328) genes are associated with risk of nephrolithiasis in Egyptian children. Turk J Urol. 2021;47(1):73-80.
50. 50. Lovegrove CE, Goldsworthy M, Haley J, Diane S, Caroline G, Fadil MH, et al. Genetic variants predisposing to increased risk of kidney stone disease. J Clin Investigation. 2025;e186915.
51. 51. Rusu EE, Sorohan BM, Pandele R, Andreea Popescu 1, Raluca Bobeica 2, Sonia Balanicaet al. Phenotypes and the Importance of Genetic Analysis in Adult Patients with Nephrolithiasis and/or Nephrocalcinosis: A Single-Center Experience. Genes. 2025;16(5):501.
52. 52. Shee K, Liu AW, Chan C. A Novel Machine-Learning Algorithm to Predict Stone Recurrence with 24-Hour Urine Data. J Endourol. 2024;38(8):809-16.
53. 53. Doyle P, Gong W, Hsi R, Kavoussi N. Machine Learning Models to Predict Kidney Stone Recurrence Using 24 Hour Urine Testing and Electronic Health Record-Derived Features. Research square. 2023.
54. 54. Mahmoodi F, Andishgar A, Mahmoudi E, Monsef A, Bazmi S, Tabrizi R. Predicting symptomatic kidney stones using machine learning algorithms: insights from the Fasa adults cohort study (FACS). BMC Res Notes. 2024;17(1):318.
55. 55. Nedbal C, Adithya S, Naik N, Gite S, Juliebø-Jones P, Somani BK. Can Machine Learning Correctly Predict Outcomes of Flexible Ureteroscopy with Laser Lithotripsy for Kidney Stone Disease? Results from a Large Endourology University Centre. Eur Urol Open Sci. 2024;64:30-7.
56. 56. Alghafees MA, Abdul Rab S, Aljurayyad AS. A retrospective cohort study on the use of machine learning to predict stone-free status following percutaneous nephrolithotomy: An experience from Saudi Arabia. Ann Med Surg. 2022;84:104957.
57. 57. Mahmoodi F, Andishgar A, Mahmoudi E, Monsef A, Bazmi S, Tabrizi R. Predicting symptomatic kidney stones using machine learning algorithms: insights from the Fasa adults cohort study (FACS). BMC Res Notes. 2024;17(1):318.
58. 58. Abraham A, Kavoussi NL, Sui W, Bejan C, Capra JA, Hsi R. Machine Learning Prediction of Kidney Stone Composition Using Electronic Health Record-Derived Features. J Endourol. 2022;36(2):243-50.
59. 59. Malieckal DA, Ganesan C, Mendez DA, Pao AC. Breaking the Cycle of Recurrent Calcium Stone Disease. Adv Kidney Dis Heal. 2023;30(2):164-76.
60. 60. Burns Z, Knight J, Fargue S, Holmes R, Assimos D, Wood K. Future treatments for hyperoxaluria. Curr Opin Urol. 2020;30(2):171-6.