Kidney Stone Disease (KSD) prevalence is currently rising worldwide reaching approximately 10% in the US, Europe, and Asia (1). Half of stone formers will experience recurrence within 5–10 years and 75% within 20 years, this leading to an increased risk of chronic kidney disease (CKD) and kidney failure (2).

Calcium stones are reported in 94% of first-time stone former patients, followed by uric acid (4.8% of first-time stone formers), while brushite and struvite compositions are rare (0.9%) and cystine very rare (0.1%). Among common calcium stones, calcium oxalate (76%) is the most common composition (3).

Stone formation may have an underlying genetic base which can therefore explain a high risk of recurrence and thus needs to be investigated for better prevention and treatment.

Indeed, in the last years has emerged that KSD has an important genetic basis with a heritability approximately of 50%, as observed in twin studies (46% for female twins and 62% for male twins) (4, 5). The pathogenesis of KSD remains unclear in many cases, but it is likely due to both genetic and environmental factors. In the past decades, numerous Genome-Wide Association Studies (GWAS) and New Generation Sequencing (NGS) studies demonstrated a genetic cause in several cohort of nephrolithiasis patients, paving the way for new possible opportunities of therapy and prevention through precision medicine-based strategies (2, 6–9), likely reducing the burden on the healthcare system and offering new treatments besides surgical management of KSD (10, 11).

The guidelines on urolithiasis from the European Association of Urology (EAU) and from American Urological Association (AUA) (12, 13) suggest attending a first step analysis, with no distinction between low- and high-risk patients, on all first-time stone formers and repeated in case of early recurrence after complete stone clearance intervention, early recurrence while under prevention therapy or late recurrence after long stone-free period. In this first step biochemical work-up of urine and blood and, when possible, stone composition analysis are suggested.

Once the results are obtained, the patient is assigned to a low-risk or high-risk group for stone formation based on the stone type. Only high-risk stone formers undergo specific metabolic evaluation by biochemical analysis of two consecutive 24 h-urine samples.

Several studies underline the clinical importance of genetic testing in kidney stone formers: a missed diagnosis can easily lead to kidney failure, even after a kidney transplant (23) and in the majority of the cases the kidney stones are just the first symptom of presentation of a more complex disease.

Cogal et al. in a cohort of 703 families suspected of Primary Hyperoxaluria and a cohort of 111 families suspected of Dent Disease found by targeted NGS a monogenic cause of stone formation different from the initial hypothesis in 29/285 (10.2%) and 16/59 (27.1%) respectively (24). The most common biallelically mutated gene was CLDN16 (8 families) that together with CLDN19 is responsible for Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis, variants were also found in SLC34A1 and SLC34A3 (5 families), accounting for Hypophosphatemic/Hypercalciuric Stone Formation with Bone Defects. Among the other monogenic diseases identified there were Infantile Hypercalcemia due to 24-Hydroxylase Deficiency (CYP24A1), Adenine Phosphoribosyl-transferase deficiency (APRT), Bartter Syndrome, Distal Renal Tubular Acidosis, Autosomal Dominant Hypocalcemia (CASR) and Dominant Fanconi Syndrome (HNF4A) (24). Amlie-Wolf et al. (25) observed 28/86 pathogenic/likely pathogenic (P/LP) variants in a cohort of patients from a nephrology unit, 27/28 (96%) variants led to a change in medical management of the patient and allowed cascade testing and management of the families. In 2021 Jayasinghe et al. (26) analyzed 204 patients with a suspected monogenic cause of kidney disease with exome sequencing (WES) and a molecular diagnosis was found in 80/204 patients (34% with a P/LP variant). Among the 80 positive results, 27/80 had a confirmed diagnosis (34%), 22 had a clarified diagnosis (28%), and 31 had a reclassified diagnosis (39%), allowing a better management of the patient and a more personalized treatment (26). Andregg et al. (27) conducted a WES analysis in 901 individuals, of which 787 were kidney stone formers, 23 of them had a mendelian form of KSD and 68 had a pathogenic/likely pathogenic that not corresponded to a mendelian form but likely predisposed to nephrolithiasis. In 5 (21.5%) of the 23 mendelian form, WES established a new or corrected a priori diagnosis.

These are just some of the studies where a molecular diagnosis shows a high impact on the management and treatment of not just the patients themselves but also of their families.

Therefore, genetic testing in KSD could be a useful tool to predict the prognosis and the onset of other clinical features, preventing unnecessary procedures and relapses, allowing individualized treatment that are increasingly available for monogenic kidney disorders (see section 4), and offering genetic counseling for family members.

Although the availability of genetic panels for kidney stones is increasing worldwide, access varies significantly across different Countries. This contributes to the global underutilization of genetic testing in clinical practice, beside the lack of standardized guidelines (28–31).

Therefore, it is necessary to establish how to select patients eligible for genetic testing (32, 33).

Preventive strategies are selected based on etiology, stone type, and cost-effectiveness. Main preventive measures include fluid intake (>2.5 L/day), lifestyle changes (body weight control, adequate hydration during physical activity), and dietary management (controlled intake of calcium, sodium, and animal proteins, reduced ingestion of oxalate-rich foods).

The protective effects of bioactive components are still to be explored, except for coffee which has been shown to be protective. Thiazides are indicated in people with recurrent calcium stones, and alkaline citrate for a variety of stones. Allopurinol is recommended in some forms of hyperuricosuria. Bacterial eradication and antibiotic use may be important in certain situations, but they must be closely monitored due to the possibility of antimicrobial resistance. Finally, probiotics may help in prevention, but further research is needed to prove their efficacy (54).

Recent research has identified various protein receptors and enzymes as potential therapeutic targets in urolithiasis, including calcium-sensing receptors, vasopressin V2 receptors, and angiotensin II receptors, which regulate calcium excretion, water reabsorption, and electrolyte balance. By focusing on particular pathways involved in crystal formation, aggregation, and adhesion, these receptor-targeted therapies present promising prospects for precision medicine approaches, especially in preventing stone recurrence (55).

While hyperhydration remains the foundation of prevention, understanding genetic etiology could help personalize preventive strategies.

Primary Hyperoxaluria type 1 (PH1) serves as a prime example of how understanding the genetic basis of the disease has led to targeted therapy directly addressing the pathogenesis. PH1 is caused by pathogenic variants in the AGXT gene, encoding for the liver enzyme alanine glyoxylate aminotransferase (AGT), leading to excess oxalate production (56). Pyridoxine acts as a cofactor for AGT enzyme, increasing its activity and reducing oxalate production in specific AGXT variants (57). Lumasiran is a RNA interference therapeutic agent administered subcutaneously and directed at the liver. In patients with PH1, Lumasiran reduces hepatic oxalate production and increases glycolate concentrations by degrading the messenger RNA that encodes AGT (8). Other examples are the specific therapy in patients with CYP24A1 gene variants comprises azole drugs (e.g., ketoconazole and fluconazole), which inhibit cytochrome P450 enzymes, leading to normalization of biochemical parameters (58, 59). Another approach is to induce CYP3A4 activity with the drug rifampicin, providing an alternative method for the inactivation of active vitamin D metabolites (60). For SLC34A1 gene variants, the specific therapy consists of oral phosphorus supplementation, which leads to rapid correction of hypophosphatemia, normalization of calcium metabolism, and significant clinical improvement, as demonstrated by weight gain in patients. Sodium chloride supplementation may also be necessary to correct hypercalcemia in patients who also present with polyuria and polydipsia (61). For Cystinuria, cystine-binding drugs such as Tiopronin and D-penicillamine, are effective in reducing free urine cystine levels (62). Moreover, l-Cystine diamides, inhibitors of l-cystine crystallization (63), and α-Lipoic acid that inhibits cystine stone formation (64) have shown great promise in the treatment of Cystinuria but are still under evaluation. Early diagnosis of Adenine phosphoribosyltransferase (APRT) deficiency allows for treatment with allopurinol, which inhibits xanthine oxidase and reduces 2,8-DHA formation, potentially preventing, arresting, or even reversing kidney failure in both native and transplanted kidneys (65). In clinical trials Febuxostat showed better results than allopurinol in reducing DHA excretion in the prescribed doses (66).

Thus, early genetic diagnosis can enable targeted therapies, sparing kidney-liver transplantation to the patients and long-term complication (67).

Despite the KSD genetic predisposition is not yet fully understood, the present data are sufficient to recommend genetic testing of a stone-gene panel in high-risk KSD patients. In conclusion, Red Flags to recognize genetic forms in KSD patients can be: recurrent nephrolithiasis, first episode of KSD before the age of 18 years old, nephrocalcinosis, family history of stones, 24-h urine alterations, impaired kidney filtration, abnormal tubular function and syndromic conditions (Figure 1). The clinical utility of genetic diagnosis goes far beyond therapeutic applications only. It includes pre-symptomatic identification of monogenic forms before the development of irreversible renal damage, support for clinical management through more targeted monitoring, detection of recessive disorder heterozygous carriers who may be at increased risk, and utilization of tailored preventive interventions based on the individual genetic pattern. Furthermore, it allows for counseling of high-risk relatives, offers the possibility of prenatal diagnosis in the most severe cases, and directs future research toward new treatments this broader vision of the utility of genetic diagnostics highlights the importance of integrating genetic testing into the diagnostic workup of patients with recurrent renal lithiasis or with clinical features suggestive of hereditary forms.

Undoubtedly, genetics will not be the only key to better understanding. Indeed, multi-omic studies have consistently shown that kidney stone patients exhibit gut and urinary dysbiosis with reduced oxalate-degrading bacteria (e.g., O. formigenes, Lactobacillus, Bifidobacterium) and enrichment of pathogens (e.g., Streptococcus, E. coli), alongside metabolic alterations involving tryptophan, fatty acids, and oxalic acid (68–70). These changes correlate with inflammation, oxidative stress, and urinary metabolite shifts (e.g., pyroglutamic acid, FAHFA), supporting the need of biomarker discovery and microbiome-targeted therapies such as probiotics and FMT (Fecal Microbiota Transplantation) (68, 69).