Blood is filtered through urinary system, where waste products accumulate in the urine. This system includes kidneys, renal pelvis, ureters, urinary bladder, and urethra. Kidneys are the organs responsible for filtration. By removing acids produced by cells, they maintain the balance of water, salts, and minerals in the blood [1]. One common problem in the urinary system is the formation of kidney stones, also called renal calculi, nephrolithiasis, or urolithiasis. Kidney stones are hard deposits, made of minerals and salts that form within the kidneys when there is an imbalance in the concentration of substances present in the urine. Stone formation usually begins when substances such as calcium, oxalate, or uric acid become highly concentrated in the urine. This can occur due to various factors, including insufficient fluid intake, dietary habits, metabolic disorders, urinary tract infections, and medications. Once these substances become highly concentrated, they can crystallize and form small solid particles, which can aggregate, grow, and develop into kidney stones. The size of these stones can vary from small (nanometre-sized) grains to larger (centimetre-sized) solid masses [2]. The stone can be located anywhere between the kidneys and urethra, with symptoms and pains that can vary in relation not only to the size but also to the position of the stones. Typically, stone formation does not cause any symptoms initially. Successively, most common signs and symptoms of the stone disease consist of renal colic (intense cramping pain), pain in the backside (flank pain), blood in the urine (hematuria), urinary tract disease (obstructive uropathy), urinary tract infections, frequent urination or blockage of urine flow, and dilation of the kidney (hydronephrosis). These conditions are often associated with nausea and vomiting, which increase the pain caused by the stone [3]. Therefore, besides the quality of life, treatment and time away from work involve substantial social costs [4]. KSD is the most common chronic disease of the urinary tract, affecting up to 13% of the world’s population [5] and representing a growing burden on healthcare systems worldwide [6, 7]. Moreover, with recurrence rates ranging from 30% to 50% within 5–10 years after the first attack [8], there is an urgent need to find the best means for secondary prevention.

This review brings together recent information on the epidemiology, composition, and types of kidney stones, focusing on biochemical factors and biomineralisation pathways of KSD. Much attention has been paid to risk factors, highlighting the role of climate, trace elements in local environments, lifestyle, and diet. Genetic variability was also analyzed to understand genetic architecture underlying individual predisposition, summarizing recent findings in both rare monogenic conditions of KSD studies and common genes associated with nephrolithiasis, including an overview of Genome-Wide Association Studies (GWAS) in different populations.

Finally, the review discusses how a targeted approach can address different aspects of the disease development based on the comprehensive patient’s risk profiles derived from omics, stone, and genetic data. The future perspective is that with the convergence of environmental, clinical, and genetic data, more personalised and effective strategies can be applied to prevent the global epidemic of kidney stones.

Kidney stone is a common, complex disease, among the oldest ones identified by medicine [9]. Studying the epidemiology of kidney stones may help to identify high-risk populations, understand the underlying factors contributing to stone formation, and guide preventive strategies to manage and control kidney stone disease. The epidemiology of kidney stones is subject to changing trends over time. Its prevalence and incidence are influenced by several variables, such as age, gender, ethnicity, food heritage, especially in areas of geographical segregation and occupation, but also by multiple environmental factors, including changes in lifestyle and dietary habits, as well as global warming [10–12]. Furthermore, the presence of diseases such as bone fractures, diabetes, hyperparathyroidism, systemic, vascular, and chronic kidney disease is considered a risk factor for kidney stones, and, conversely, urolithiasis is also considered a risk factor for these systemic diseases, perhaps highlighting common risk factors [13–19].

Despite considerable improvements in the development of new therapies, the worldwide prevalence of kidney stones has increased in the last three decades [5]. The prevalence varies across different populations (range 7%–13% globally), with some regions and ethnic groups having higher rates than others. It has been estimated that prevalence rates differ between economically developed and developing countries. This gap, however, could be partly due to higher detection of asymptomatic cases in economically developed countries. In addition, unbalanced dietary habits, such as increased salt and protein intake, together with an increasing prevalence of metabolic syndrome and lack of physical activity, may be one of the causes leading to an increase in the prevalence of urolithiasis in developed countries and, sometimes also in metropolitan areas. Conversely, in developing countries, malnutrition and water deprivation may contribute to the increased prevalence of stone disease [5].

The risk of kidney stone formation progressively increases in the third decade of life and gradually decreases in the seventh [20, 21] with a peak between the ages of 40 and 60 [22]. In particular, it has been estimated that the highest incidence occurs in men aged 20–49 years [11, 23], although the incidence of stone formation is growing among females [24]. Moreover, kidney stone formation is often recurrent during life, and individuals who have had a kidney stone have a higher risk of developing another stone in the future. In particular, stone recurrence rate varies from 30% to 50% within 5–10 years, and 75% within 20 years after the initial stone episode [8].

Due to its high prevalence in working-age adults, kidney stone disease has become a public health issue with a significantly high financial burden on healthcare systems, particularly in populations residing in regions with a hot and dry climate [6, 7].

Kidney stones differ in chemical and mineralogical composition, size and shape, and position of crystallization within the urinary system. Major inorganic/organic constituents of calculi are calcium phosphate (hydroxyapatite), calcium oxalates (whewellite and weddellite), and urates [25]. Two or more of these components form most of the urinary calculi in various combinations [26]. Among these stone types, calcium stones are certainly the most frequent, accounting for about 70%–80% of all kidney stones.

According to several authors [[27, 28] and references therein], 11 main groups of urinary stones may be distinguished (Figure 1) based on mineral composition, presence of trace constituents, site of nucleation, and aetiologic factors [25, 29–32].

From a mineralogical point of view, kidney stones have distinct chemical and structural characteristics that reflect their origin and transformation processes. Table 1 summarizes the principal mineral types identified in kidney calculi, such as calcium, phosphate, urate, cystine, and drug-induced, demonstrating their chemical composition, typical morphology, colour, and internal organization.

Urinary supersaturation is the driving force for kidney stone crystallization and consists of a fluid characterized by a content of dissolved substances higher than that normally dissolved under specific conditions. Supersaturation of urine strongly depends on its pH, and the resulting mineralization is determined by both the presence and the specific concentration of stone-forming chemical constituents required for biomineral precipitation. For example, brushite crystals frequently affect patients with hypercalciuria and alkaline urine with pH values higher than 6. Struvite crystallization, instead, occurs in the presence of urine with a pH typically higher than 7, because of the low solubility of phosphate minerals in alkaline fluids. Conversely, uric acid precipitates in the presence of low urine volume and low urine pH (pH < 5); cystine stones form by precipitation and accumulation of cystine not dissolved in urine as a result of an excess of cystinuria in urinary excretions [29].

Multiple modulator molecules also influence crystal formation in the human body. Although they may work differently for everyone, such molecules act as inhibitors or promoters of crystallization. Inhibitors are urine chemicals that prevent crystal formation, from supersaturation to crystal nucleation and growth. Organic (citrate, glycosaminoglycans, glycoproteins), as well as inorganic (pyrophosphates, metallic cations) molecules, play this role in a direct mode, by interacting with crystals, or in an indirect way, by modifying the urinary environment [36]. Conversely, promoters are substances that favor calculi formation by various mechanisms recently overviewed by Bazin et al. [37–39]. Cholesterol, phospho- and glyco-lipids, calcium, sodium, oxalate, cystine, and low urine volume are thought to be the principal chemical promoters. In general, the discrepancy between urinary stone inhibitors and promoters is responsible for stone formation.

According to Worcester [40], one of the most common causes of stone formation is the presence of Randall’s plaques (RPs) [41]. The RPs are suburothelial papillary mineral deposits whose formation is generally associated with low urine volume, low pH, and hypercalciuria. Although the pathogenesis of Randall’s plaque itself is not clearly known and its presence was detected also in most human kidneys without stones, it has been established that RPs may act as nucleating sites for the growth and attachment of idiopathic calcium phosphate kidney stones [42, 43].

In addition to the physicochemical mechanisms and Randall’s plaques, Wang et al. [44] documented the importance of sex hormones, microbiome, and immune response as determining factors of kidney stone formation, although their role is not yet fully understood. For example, emerging data suggest that COM, COD, and urate stones are more common in males, whereas higher percentages of hydroxyapatite and struvite stones can be detected in females [44]. However, how sex differences influence the pathophysiological mechanisms of urinary stone disease is not clear and needs further studies to be explained. Similarly, further and detailed studies are necessary for a comprehensive knowledge of the role and mechanisms of kidney and urinary tract microorganisms, and of immune response in kidney stone formation. Also, it remains unclear the precise mechanism of kidney stone formation via endocytosis. Most researchers agree about the role played by renal tubular cells during the initial phase of kidney stone formation when they may act as the preferred mean for the internalization of CaOx crystals. In addition, it has been suggested that exposure to CaOx crystals induces epithelial cellular injury which is a common predisposing factor to subsequent crystal nucleation and growth [36]. As demonstrated by an in vitro study [45], apoptosis at the level of renal tubular cells also may lead to stone formation through cellular demise and postapoptotic necrosis.

As aforementioned, intrinsic factors such as age, gender, ethnicity, and family background, and extrinsic factors such as climate and environment, lifestyle and dietary habits, occupation, and education, are considered risk factors for kidney stone formation. In the following lines, social habits, environmental factors, genetic basis, and comorbidities concerning the risk of developing kidney stones will be analyzed.

The concepts summarized in the previous sections highlight the complexity of kidney stone disease (KSD) pathophysiology and support the view that KSD should increasingly be considered a heterogeneous and multifactorial disorder requiring individualized diagnostic and therapeutic strategies rather than a uniform management approach (Figure 2).

From a public health perspective, population-based prevention strategies, including hydration campaigns, reduction of dietary sodium and ultra-processed food consumption, workplace heat mitigation measures, and improved access to nutritional counseling, may substantially reduce the burden of KSD, particularly in high-risk geographic regions affected by climate change. Successful prevention of kidney stones requires the analysis of different aspects that contribute to stone formation to identify personalized strategies based on individual characteristics and risk factors, such as those shown in this review. Preventing primary KSD through dietary changes, for instance, is a cost-effective public health measure with a significant societal impact. In addition, nowadays, several efficient treatments exist for kidney stone disease. The most common approaches involve surgical removal procedures such as extracorporeal shock wave lithotripsy, ureteroscopy, percutaneous nephrolithotomy, and/or open surgery. The choice of treatment mainly depends on the stone’s size, composition, location, urinary tract anatomy, and the patient’s morphology. Medical management of urolithiasis often involves drugs or invasive surgical procedures that may cause side effects or complications, such as hemorrhage, hypertension, tubular necrosis, subsequent kidney fibrosis, renal failure, steinstrasse (small stones blocking the ureter), pancreatitis, infections, and persistent residual stones, which can act as a nidus for new stone formation. Stone recurrence after removal continues to be a significant challenge in the surgical management of kidney stone disease. A study carried out in Iceland, has revealed that the recurrence rate among children after stone removal varies from 26% at 5 years post-surgery to 46% at 20 years post-surgery [139, 140]. Therefore, research into alternative treatment and prevention methods remains an avenue worth exploring to prevent recurrence. Alternative methods, particularly those involving medicinal and aromatic plants (MAP), are prevalent worldwide, especially in developing countries. Ethnobotanical studies conducted in Morocco have revealed the potential of certain plants for treating lithiasis, preventing recurrence, and alleviating renal colic. In vitro studies have shown that plant extracts can inhibit stone formation at various stages of crystallization (nucleation, growth, aggregation). Examples of these plants include Rotula aquatica, Holarrhena antidysenterica, Origanum vulgare, Ammi visnaga, Phyllanthus niruri, Herniaria hirsuta, Apium Graveolens, and others, which have shown activity against calcium oxalate crystals. Other plants, like Commiphora wightii and Citrus medica, have been found to inhibit struvite crystal growth. Moreover, essential oils from Mentha pulegium and Eucalyptus camaldulensis have shown significant activity against bacteria responsible for infection-induced lithiasis. In vitro studies using cell culture models and animal studies also demonstrate the preventive effects of these plants on cell damage and stone formation [141]. However, further research is required to test and validate the efficacy of these traditional resources.

Precise identification of the primary cause of nephrolithiasis is crucial for determining the suitable treatment approach [142, 143]. Although common strategies like ensuring hydration can help to reduce stone formation in all patients, personalized therapies can be more appropriate for specific types of stones [142]. In this context, precision medicine may provide an actionable framework integrating clinical phenotype, metabolic abnormalities, dietary habits, environmental exposures, stone composition, and genetic susceptibility to improve prevention and treatment outcomes [142]. A stepwise patient stratification model may support clinical decision-making. Initial evaluation should include detailed phenotypic characterization, including age at onset, recurrence rate, family history, comorbidities, occupational heat exposure, dietary patterns, and previous urinary tract infections. Stone composition analysis and metabolic assessment through 24-h urine testing remain central for identifying lithogenic risk factors such as hypercalciuria, hyperoxaluria, hypocitraturia, and hyperuricosuria. In the case of non-calcium stone formers, the understanding of the composition of stones is essential, as it gives crucial diagnostic insights. For example, discovering a stone composed entirely of cystine or even the traces of cystine confirms cystinuria, an inherited autosomal recessive disorder. Additionally, detecting a mixed stone of struvite and calcium oxalate strongly indicates the presence of a metabolic disorder [144]. While the presence of apatite as a main component might suggest conditions like renal tubular acidosis or primary hyperparathyroidism, however, this is not always certain. The existence of brushite indicates a more aggressive form of stone disease that is less responsive to preventive measures and raises the risk of CKD [145].

In most cases, calcium stones have a mixed composition reflecting the underlying pathogenetic mechanisms and/or simultaneous lithogenic processes involved in kidney stone formation. The calcium content of a stone can often be inferred from a plain abdominal X-ray of radiopaque stones, while dual-energy CT appears to be promising as a useful diagnostic tool for detecting uric acid stones [2, 146].

Ferraro et al. [143] provided a comprehensive review of clinical manifestations suggesting inherited disorders, such as hypophosphatemia, low-grade proteinuria, and renal hyperechogenicity. Some of these patients have a monogenic cause, which means they could benefit from genetic screening. Although today’s costs are too high for most individuals, academic funding and clinical research are anticipated to improve access to genetic testing by demonstrating its cost-benefit [147].

In extreme cases, failing to diagnose a monogenic stone-forming condition like primary hyperoxaluria or adenine phosphoribosyltransferase (APRT) deficiency can have serious consequences. For instance, overlooking a diagnosis of primary hyperoxaluria type 1 may result in the recurrence of the disease and oxalosis in a transplanted kidney [143], and the failure to consider the option of curative liver transplantation. In some cases, undiagnosed APRT deficiency can result in end-stage renal disease (ESRD) and is linked to the recurrence of stone disease in a renal transplant, which may cause the loss of graft function if it remains unaddressed [148].

Diagnosing such cases depends on a combination of different methods, such as stone investigation, urine biochemistry, and genetic screening. In the case of stone formers, precision medicine approaches are not only genetics-based; they also employ a wide range of phenotypic information [142]. Genetic screening may have potential in improving the clinical management of kidney stone disease. Despite the well-established contribution of genetics to stone formation, its integration into routine clinical care remains limited. It is important to note that many rare genetic causes of stones and other renal conditions have metabolic signs, which should be detected and diagnosed through clinical observations and systematic metabolic testing. Extensive lists of recognized monogenic causes of stones have been issued [88, 149].

In selected high-risk individuals, including patients with early-onset disease, nephrocalcinosis, recurrent bilateral stones, chronic kidney disease, or strong familial aggregation, genetic testing may help identify monogenic disorders and guide targeted management strategies [88]. There is a pressing need to translate these findings into clinical practice by evaluating genetic variants in real-world patient populations and correlating them with clinical phenotypes, including disease severity and stone composition. Integrating kidney-specific omics data has further highlighted the role of ion homeostasis, particularly calcium and magnesium, in stone formation, suggesting novel therapeutic targets. Additionally, stronger genetic correlations between kidney stone disease and genitourinary or digestive diseases underscore the multifaceted nature of stone pathogenesis. Therefore, comprehensive genetic screening could inform personalized treatment strategies and may help optimize existing treatment algorithms.

Within this framework, a personalized approach to the prevention, diagnosis, and management of kidney stone disease can be tailored according to the underlying pathogenic mechanisms and stone phenotype (Figure 2). For example, urine alkalinization may be particularly effective in uric acid stone formers, whereas thiazide diuretics and dietary sodium restriction may benefit patients with hypercalciuria. Similarly, potassium citrate supplementation may be indicated in hypocitraturic patients, while individuals with cystinuria often require intensive hydration and thiol-based therapies. Environmental and public health factors should also be integrated into individualized prevention strategies, particularly in populations exposed to chronic dehydration, high ambient temperatures, or limited access to healthy dietary resources. However, implementing personalized prevention strategies in routine clinical practice remains challenging because of poor long-term adherence to dietary modifications, difficulties in accurately assessing nutritional habits, variability in 24-h urine collections, and limited access to specialized multidisciplinary care. In addition, despite promising advances in genomics and omics technologies, important barriers still limit the implementation of precision medicine in clinical practice, including costs, limited accessibility to genetic testing, variability in patient adherence, and the lack of standardized clinical algorithms. Nevertheless, integrating phenotypic, metabolic, environmental, and genetic information may contribute to more accurate risk stratification, earlier diagnosis, reduced recurrence, and optimization of long-term management in patients with KSD.