Abstract
Background
Kidney stone formation is driven by an imbalance between lithogenic substances and crystallization inhibitors. Current guidelines recommend a 24-h urine collection in patients with kidney stone disease to assess the risk of stone formation and monitor therapy compliance. However, real-world data on adherence to these guidelines remain limited and outdated.
Methods
We used the Health Search Database to examine laboratory test data of patients with kidney stone disease between 2013 and 2022 in Italy. Adults with at least one episode of kidney or ureteral stones during this period were included. We used the prescription of urinary calcium, oxalate, and citrate levels as a proxy for full metabolic testing.
Results
A total of 21,907 adult patients were identified (44.6% women). Only 4.8% (n = 1059) underwent 24-h urine testing, and just 0.6% had all three target measurements. Testing rates were slightly higher in recurrent stone formers (6.1%). The likelihood of receiving a test increased nearly sixfold after a nephrology visit (OR 6.09, 95% CI 5.27–7.05, p < 0.001), compared to a lower increase after urology visits (OR 1.95, 95% CI 1.71–2.23, p < 0.001). Nonetheless, fewer than 10% of kidney stone disease patients consulted a nephrologist, and only half of those with coexisting chronic kidney disease (CKD) had such a referral.
Conclusion
Awareness of 24-h urine testing and nephrology referral in stone formers remains low, despite their role in guiding personalized treatment. Promoting their use could enhance patient care by identifying urinary abnormalities and reducing the risk of recurrence and complications.
Graphical Abstract
Supplementary Information
The online version contains supplementary material available at 10.1007/s40620-025-02389-0.
Keywords: Kidney stone disease, Nephrolithiasis, Stone former, 24-h urine test
Introduction
In the last decades, kidney stone disease has shown an increasing prevalence worldwide [1, 2], with a high recurrence rate [3] and a significant economic impact on healthcare systems [4]. Due to present-day lifestyles and unhealthy dietary habits [5, 6], the incidence of kidney stone disease is expected to rise further in the coming years [7].
Most kidney stones (about 80%) are composed of calcium oxalate or calcium phosphate [8]. Stones form due to urinary supersaturation, typically growing on Randall’s plaques in the loops of Henle. These plaques, made up of interstitial apatite crystals, reach the renal papillary surface and become exposed to the pelvic urine, providing a surface for layers of calcium oxalate and/or calcium phosphate and organic matrix [9]. Less frequently, urinary supersaturation favors precipitation of dissolved salts directly into the tubular lumen, forming crystals [8]. This mechanism is more common in uric acid, cystine, struvite, and drug-related stones.
Stone formation is usually favored by an altered equilibrium between lithogenic elements (oxalate, calcium, phosphate) and crystallization inhibitors (citrate, magnesium) [10, 11]. Urinary chemistries may be heterogeneous and complex, with variable associations of different factors on kidney stone disease risk. The previous concept of an “all-or-nothing” effect of each urinary factor on stone risk, with arbitrary thresholds, is not biologically plausible and is outdated. A recent study [12] demonstrated that the key urinary parameters have a linear or almost-linear association with kidney stone disease risk. Stone risk increases with higher urinary levels of calcium, oxalate, phosphorous, and sodium. Conversely, higher urine volume, citrate, magnesium and potassium are related to a lower risk. The study established a hierarchical ranking of urinary factors, with calcium, urine volume, and citrate being the most significant, followed by oxalate, potassium, and magnesium.
Therefore, accurate evaluation of urinary chemistries is fundamental both to highlight the tendency of certain chemical species to precipitate in urine (e.g. supersaturations) and to monitor patient compliance to a given therapeutic strategy and its efficacy. This is also true for monogenic forms of kidney stone disease, such as primary hyperoxaluria and cystinuria, considering the essential role of oxalate and cystine excretion evaluation for their diagnosis and management, respectively.
Both the American Urological Association (AUA) and the European Association of Urology (EAU) guidelines recommend a metabolic assessment through 24-h urine collection in kidney stone disease patients [13, 14]. Moreover, 24-h urine testing is essential for an accurate evaluation of recurrent stone formers, aiming at establishing a tailored treatment for these patients.
The actual adherence to these recommendations is inadequate according to different studies [15–17] that reported a rate of application of 24-h urine test in fewer than 20% of patients affected by kidney stone disease. However, available data are obsolete and fragmented, and do not consider settings besides the US health system, where the reimbursement mechanism differs from other areas of the world.
Our goal is to define the actual application of metabolic testing on 24-h urine collection, specifically assessing the number of requests for urinary calcium, oxalate, and citrate levels in 24-h urine samples of patients affected by kidney stone disease, as a proxy for the full metabolic testing in an Italian setting; in Italy, access to health care is universal and free. Additionally, we investigated potential demographic, geographic and clinical drivers for ordering the test. To address this issue, we examined an Italian primary care data source.
Methods
We accessed the Italian Health Search Database to analyze data concerning laboratory exams of patients with kidney stone disease between 2013 and 2022. The Health Search Database is an Italian general practice database established in 1998 that includes the data of 1,109,502 adults from all over Italy [18], corresponding to about 2% of the current Italian population (60,103,708 individuals) according to the Italian National Institute of Statistics (ISTAT). These computer-based clinical records are actively collected by a selected group of 800 volunteer general practitioners (GPs), uniformly distributed throughout Italy, who attended specific training courses for data entry to meet standard quality requirements [18, 19]. Diagnoses reported in this database are coded following the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). The validity of the Health Search Database has been demonstrated by several publications over the years [19–21].
All individuals with at least one episode of kidney or ureteral stones in the period 2013–2022 were included, while patients with a stone episode before 2013 were excluded. Patients with more than one stone episode in this timeframe were considered recurrent stone formers. Patients affected by kidney stone disease with an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2, according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 formula, were defined as having a coexisting chronic kidney disease (CKD).
Only data concerning measurements of calcium, oxalate, and citrate excretions from 24-h urine collection were extracted, while other urinary excretions were not considered. Indeed, as mentioned above, these parameters have a key role in the management of stone formers and their prescription was considered a specific proxy for 24-h urine testing. We chose not to include other parameters, such as sodium, potassium or urea, considering that they may be requested even in the presence of other conditions (such as CKD or tubulopathies), thus rendering our ascertainment of 24-h urine testing inaccurate. Our choice is similar to that made in previous studies by Dauw et al. [16], who considered urinary calcium, oxalate, citrate and uric acid, Milose et al. [17],who opted for urinary calcium, and Ganesan et al. [15],who evaluated urinary calcium, oxalate, citrate, or sulfate. Therefore, all patients who underwent at least one evaluation of the above-mentioned excretions were considered to have undergone 24-h urine testing. The simultaneous quantification of calcium, oxalate, and citrate on the same 24-h sample was considered a surrogate marker of the completeness of the test.
The frequencies, proportions and completeness of tests performed were tabulated for the whole study population and across subgroups including age categories, sex, clinical features (recurrent stone formers, CKD), geographic area (North-East, North-West, Center, South and Islands), and whether or not the patient had undergone a nephrologist and/or urologist consultation. Results for pre-specified combinations of such characteristics were also reported.
This study complied with the Declaration of Helsinki and the EnCePP Guide on Methodological Standards in Pharmacoepidemiology [22]. The Italian College of General Practitioners and Primary Care's Scientific Committee approved the protocol. Given its retrospective nature, ethical approval was not needed at the time of the study [23].
Results
Cohort
We identified 21,907 adult patients (9770 women, 44.6%) with at least one episode of kidney stone formation between 2013 and 2022, representing about 2% of the whole population registered in the Health Search Database. The cohort included 1966 patients with recurrent kidney stone disease (9%), 1556 of whom saw a nephrologist (7%), 11,345 who had a urological consultation (52%), 1134 who saw both a nephrologist and a urologist (5%), and 1225 with CKD (5.6%) (Table 1). In the recurrent kidney stone disease group (n = 1966), 195 patients (9.9%) saw a nephrologist, 1211 (61.6%) had a urological visit, 161 (8.2%) saw both specialists, and 126 (6.4%) had CKD (Supplemental Table 1).
Table 1.
Characteristics of enrolled stone formers
| Stone formers | n, % |
|---|---|
| Whole cohort | 21,907 (100.0) |
| Male | 12,137 (55.4) |
| Female | 9770 (44.6) |
| Recurrent KSD | |
| Yes | 1966 (9.0) |
| No | 19,941(91.0) |
| With a nephrology visit | |
| Yes | 1556 (7.0) |
| No | 20,351 (93.0) |
| With a urology visit | |
| Yes | 11,345 (52.0) |
| No | 10,562 (48.0) |
| With both a nephrology and urology visit | |
| Yes | 1134 (5.0) |
| No | 20,773 (95.0) |
| Coexisting CKD | |
| Yes | 1225 (5.6) |
| No | 20,682 (94.4) |
KSD Kidney Stone Disease; CKD Chronic Kidney Disease
Most patients were from the South of Italy (28.5%), followed by the North-West (23.5%), Center (20.4%), Islands (16.1%), and North-East (11.5%). The regional distribution in the recurrent formers subgroup was similar, with the majority from the South (60.4%), followed by the North-West (13.9%), Islands (10.5%), Center (10.1%), and North-East (5.1%) (Supplemental Table 2).
24-h urine test application in the whole cohort
Overall, 1059 patients underwent at least one evaluation of calcium, oxalate, or citrate excretions on 24-h urine, corresponding to 4.8% of the whole cohort (Table 2). Most tests were carried out in the female subgroup (58%) (Supplemental Table 3). 24-h urine tests were variably ordered by general practitioners according to different age groups, with a progressive increase in the number of tests from adolescence (15–24 years, 2.8%) to the seventh decade (65–74 years, 25%), subsequently dropping in the elderly (≥ 85 years, 3%) (Supplemental Table 3).
Table 2.
Application of 24-h urine measurement of calcium, oxalate, and citrate in different subgroups
| n, % | With a 24-h urine test | Without a 24-h urine test | Total |
|---|---|---|---|
| Whole cohort | 1059 (4.8) | 20,848 (95.2) | 21,907 (100.0) |
| With a nephrology visit | 298 (19.0) | 1258 (81.0) | 1556 (7.0) |
| With a urology visit | 710 (6.3) | 10,635 (93.7) | 11,345 (51.8) |
| With both a nephrology and urology visit | 218 (19.2) | 916 (80.8) | 1134 (5.2) |
| Recurrent KSD | 119 (6.1) | 1847 (93.9) | 1966 (100.0) |
| With a nephrology visit | 51 (26.2) | 144 (73.8) | 195 (9.9) |
| With a urology visit | 96 (7.9) | 1115 (92.1) | 1211 (61.6) |
| With both a nephrology and urology visit | 44 (27.3) | 117 (72.2) | 161 (8.2) |
| Coexisting CKD | 134 (10.9) | 1091 (89.1) | 1225 (100.0) |
| With a nephrology visit | 89 (14.2) | 537 (85.8) | 626 (51.1) |
| With a urology visit | 102 (12.0) | 747 (88.0) | 849 (69.3) |
| With both a nephrology and urology visit | 72 (15.4) | 395 (84.6) | 467 (38.1) |
KSD Kidney Stone Disease; CKD Chronic Kidney Disease
Data showed that 852 of 1059 patients (80.5%) were prescribed only one of the investigated analytes, while only 6 patients (0.6%) underwent all three determinations (Supplemental Table 4). Analysis of the 1272 single measurements showed that calcium excretion was the most commonly requested exam (58.6%), followed by oxalate (34.4%), and citrate (6.9%), with no variation in this trend, even in the recurrent stones and coexisting CKD subgroups (Supplemental Table 5).
Focusing on patients who underwent a nephrological outpatient visit (n = 1556), 298 of them (19%) underwent at least one estimation. On the other hand, even though many patients underwent a urological consultation (n = 11,345), few of them (6.3%) had 24-h urine testing (Fig. 1). Considering the subgroup with nephrological and urological referrals (n = 1134), 218 of them (19.2%) underwent testing (Table 2).
Fig. 1.
Percentage of 24-h urine testing in patients with or without specialized referral
24-h urine test application in the recurrent kidney stone disease subgroup
In the recurrent formers subgroup (n = 1966), few patients (6.1%) underwent at least one measurement (Table 2), while all three urinary concentrations were measured in only 2 patients (0.1%) (Supplemental Table 4). An analysis of the test in recurrent patients who were seen by a nephrologist revealed that 51 out of 195 patients (26.2%) underwent at least one measurement, but none had all three concentrations evaluated. Conversely, 96 out of 1211 (about 8%) recurrent patients with a urological referral underwent testing, though only 2 of them were tested for all three concentrations (0.2%). Regarding recurrent stone formers visited by both a urologist and a nephrologist, the number of tests was 44 out of 161 (27.3%), with none of them who underwent all three measurements simultaneously (Table 2).
24-h urine testing application in the coexisting CKD subgroup
Concerning stone formers with a coexisting CKD (n = 1225), 134 of them (10.9%) underwent at least one urinary measurement on 24-h urine (Table 2). None of the patients underwent a complete test, and only 23 patients (about 17% of the subgroup) had two analytes requested (Supplemental Table 4). About 50% of this subgroup had a nephrological consultation, of whom 14.2% underwent the test. At the same time, 69.3% of patients included in this subgroup had a urological referral, with 12% who had at least one of the evaluated urinary concentrations measured. Instead, about 38% of this subgroup underwent both nephrological and urological visits, with only 15.4% of them undergoing the test (Table 2).
Differences in 24-h urine test application across geographic areas
Analysis of differences by macroregions (Supplemental Fig. 1A) showed that 24-h urine testing was least requested in the South (3.2%), Center (3.2%), and Islands (4.5%). In contrast, the North-East and North-West had about double the testing rates (7.5% and 7.2%, respectively) (Supplemental Table 6). The North also showed higher test completeness, while in the Islands, 99% of tests included only one analyte (Supplemental Table 7).
These results were similar to those observed in the recurrent subgroups (Supplemental Fig. 1B). In the recurrent kidney stone disease group, testing rates were highest in the North-West (15.3%) and North-East (15%), about 2–3 times higher than in the Center (7.6%), South (3.2%), and Islands (4.3%) (Supplemental Table 6). However, completeness in this subgroup was very low, with only 2 patients from the North-West completing all three tests (0.7%) (Supplemental Table 7).
All results reported are graphically synthesized in Supplemental Fig. 2.
Discussion
An analysis of the available data revealed that 24-h urine testing for kidney stone disease patients was rarely performed in the studied cohort, with only 5% undergoing a metabolic study between 2013 and 2022. Most tests were incomplete, with only 0.6% including all three measured concentrations, representing just 0.03% of the total cohort. Test application was slightly higher in the recurrent subgroup, where approximately 6% underwent the test. However, this rate is still lower than reported in previous studies [15–17], where test application was below 20%.
Despite a higher percentage of male patients in our cohort (55.4%), a notable difference in test prescription was observed, with women accounting for 58% of the tests (614 out of 1059). This trend may be partially attributed to the higher osteoporosis risk in women, which requires careful management.
Interestingly, 24-h urine test prescriptions increased from adolescence to the seventh decade. Only 30 of 332 patients under 25 years underwent the test, none measuring calcium, oxalate, and citrate together. This contrasts with what might be expected given the test's value in identifying inherited kidney stone diseases, which are more common in younger patients [24, 25]. The lower test application in this subgroup likely reflects reduced compliance with 24-h urine collection, as younger age has been shown to correlate with lower test completion [26]. Another possible explanation for the higher percentage of tests among the elderly could be the greater prevalence of CKD, which, in our dataset, is a key driver for nephrology consultations and, consequently, for the 24-h urine test.
Concerning the relationship between 24-h urine testing and specialized referrals (Table 3), the likelihood of 24-h urine testing prescription increases approximately sixfold after a nephrology visit for kidney stone disease patients (OR 6.09, 95% CI 5.27–7.05, p < 0.001). The same does not apply to patients seen by a urologist (about twofold, OR 1.95, 95% CI 1.71–2.23, p < 0.001). In the subgroup with both urological and nephrological referrals, the odds of prescription were similar to those with only nephrological referrals (about 5.6-fold, OR 5.64, 95% CI 4.79–6.64, p < 0.001). These results differ from previous studies. Milose et al. [17] reported a 2.9-fold increase in test prescription after a nephrology visit and a threefold increase with urological follow-up. Dauw et al. [16] found a 1.32-fold increase with nephrology visits and a 0.76-fold decrease with urology visits. Ganesan et al. [15] showed a 1.26-fold increase with specialized stone referrals, without distinguishing between nephrology and urology visits.
Table 3.
Odds of undergoing a 24-h urine test according to specialized referrals
| Variable | Odds Ratio | 95% Confidence Interval | p-value |
|---|---|---|---|
| Whole population | |||
| With a nephrology visit | 6.09 | 5.27–7.05 | < 0.001 |
| With a urology visit | 1.95 | 1.71–2.23 | < 0.001 |
| With both a nephrology and urology visit | 5.64 | 4.79–6.64 | < 0.001 |
| Recurrent KSD | |||
| With a nephrology visit | 8.86 | 5.94–13.24 | < 0.001 |
| With a urology visit | 2.74 | 1.72–4.36 | < 0.001 |
| With both a nephrology and urology visit | 8.67 | 5.71–13.15 | < 0.001 |
| Coexisting CKD | |||
| With a nephrology visit | 2.04 | 1.40–2.98 | < 0.001 |
| With a urology visit | 1.47 | 0.97–2.23 | 0.07 |
| With both a nephrology and urology visit | 2.05 | 1.43–2.94 | < 0.001 |
KSD Kidney Stone Disease; CKD Chronic Kidney Disease
Unlike previous studies, we also analyzed the odds of undergoing a 24-h urine test in the recurrent subgroup and in stone formers with coexisting CKD (Table 3). Recurrent kidney stone disease patients who received a nephrological evaluation had an approximately ninefold increase in odds of prescription (OR 8.86, 95% CI 5.94–13.24, p < 0.001), while a minor effect is seen in patients with a urological consultation (OR 2.74, 95% CI 1.72–4.36, p < 0.001). Patients with both specialized referrals showed an 8.7-fold (OR 8.67, 95% CI 5.71–13.15, p < 0.001) increase in the odds of receiving the test. In the coexisting-CKD subgroup, the odds of test prescription increased twofold after a nephrology visit (OR 2.04, 95% CI 1.40–2.98, p < 0.001), while urological evaluation resulted in a 1.5-fold increase (OR 1.47, 95% CI 0.97–2.23, p = 0.07). In stone formers with CKD who received both nephrology and urology visits, the odds increased twofold (OR 2.05, 95% CI 1.43–2.94, p < 0.001).
It is noteworthy that specialized referral improves the application of current guidelines concerning 24-h urine testing in kidney stone disease patients, aside from the status of recurrent stone formers or a coexisting CKD.
Collaterally, an important consideration needs to be made. Only 7% of kidney stone disease patients underwent a nephrological evaluation, and this percentage slightly increased to nearly 10% in recurrent stone formers (Supplemental Table 8). Moreover, only half of patients with a coexisting CKD underwent a nephrology visit (Supplemental Table 8). These findings are consistent with those of Thomas et al. [27], where only 5.6% of patients saw a nephrologist within 6 months of stone diagnosis, with this percentage increasing in patients with CKD. Therefore, our data underscore that there is still a lack of awareness regarding the importance of nephrology referral in such patients.
Concerning differences across geographic areas, the greater percentage of patients from southern Italy, especially in the recurrent subgroup (about 60%), might be a consequence of the higher temperatures experienced in these regions, considering that hotter climates increase the likelihood of stone formation [28]. Another possible explanation is that patients from southern Italy exhibit higher urinary sodium excretion, due to increased salt intake, as previously demonstrated by the study by Cappuccio et al. [29].
Furthermore, our data confirm an undeniable imbalance in terms of application of this tool in different Italian regions (Supplemental Fig. 2), highlighting a higher application of 24-h urine testing in northern Italy, compared with the Center, the South, and Islands, with a gradual negative trend from the north to the south of Italy. This is probably the result of a tighter collaboration between GPs and stone care specialists in northern macroregions, considering that 62.2% of patients from the north of Italy underwent at least one specialized consultation, compared with the lower percentage in the remaining regions (57.1%). This evidence confirms the crucial role of GPs in the management of kidney stone disease, guiding high risk patients to a correct follow-up [30].
Our study has several strengths. To the best of our knowledge, this is the first study on 24-h urine testing prevalence in the Italian population. Secondly, the Health Search Database guarantees a large and heterogeneous cohort with great variability in terms of age, sex and geography, ensuring the generalizability of these results. On the other hand, this study also has some limitations. First, we examined the rate of GPs ordering a 24-h urine test, but there could be a difference between the number of prescribed tests and the number of patients who actually underwent the test. Nonetheless, considering that in this case the number of tests that were actually completed could only have been lower, we do not believe this would impact the final results or the purpose of our study. It is important to note that the Health Search Database includes only laboratory tests prescribed by general practitioners; therefore, any tests ordered directly by specialists, such as nephrologists or urologists, would not be captured. Second, from the Health Search Database, it is not possible to define the reason behind the limited use of 24-h urine testing in patients affected by kidney stone disease.
Conclusions
Although 24-h urine testing is universally considered an essential tool for the assessment of stone formers and for a targeted treatment focused on the correction of urinary abnormalities responsible for kidney stone disease, less than one in twenty patients underwent this exam in the period 2013–2022 in Italy, and in most cases it was incomplete. Close collaboration between nephrologists, urologists and GPs is necessary to improve the awareness of this test, to increase its implementation and, consequently, to reduce the risk of kidney stone disease recurrence and complications, thanks to the important information that can be gleaned from an accurate evaluation of a 24-h urine test.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
Our heartfelt thanks go to Dr. Serena Pecchioli for her invaluable support during the initial phase of data extraction.
Author contributions
P.M.F. conceptualized the research idea and study design. A.S. contributed to data extraction and curation. P.M.F. and A.S. contributed to data analysis and interpretation. P.M.F. and A.S. drafted the paper. A.S. contributed to visualization. P.M.F., D.P., F.L. and G.P. contributed to supervision. Each author contributed important intellectual content during manuscript drafting of the overall work. All authors read and approved the final version of the manuscript.
Funding
Open access funding provided by Università degli Studi di Verona within the CRUI-CARE Agreement. This research received no external funding.
Data availability
All data generated or analyzed are included in this article. Further inquiries can be directed to the corresponding author.
Declarations
Conflict of interest
P.M.F. received consultant fees and grant/other support from Alnylam, Amgen, AstraZeneca, Bayer, Novo Nordisk, and royalties as an author for UpToDate. G.G. received consultant fees and grant/other support from Roche Diagnostics, Fresenius kabi, Alexion, Alnylam, Astra Zeneca, Medtronics, Vifor Pharma, Samsungbioepis and royalties as an author for UpToDate. D.P. received consultant fees and grant/other support from Alnylam. F.L. received consultant fees and grant/other support from AstraZeneca. A.S. and G.P. declare no conflicts of interest about the content of this paper.
Ethical approval
The study protocol was approved by the Scientific Committee of the Italian College of General Practitioners and Primary Care. The research complied with the principles of the Declaration of Helsinki and followed the ENCePP Guide on Methodological Standards in Pharmacoepidemiology. Conducted in 2022, this was a retrospective, non-interventional, non-pharmacological observational study. As such, according to the Italian Medicines Agency (AIFA) note dated August 3, 2007 and GU No. 31, February 7, 2023, ethics committee approval was not required.
Human and animal rights
This study was in accordance with the principles of the Declaration of Helsinki and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.
Informed consent to participate
Conducted in 2022, this was a retrospective, non-interventional, non-pharmacological observational study. As such, according to the Italian Medicines Agency (AIFA) note dated August 3, 2007 and GU No. 31, February 7, 2023, informed consent was not required.
Footnotes
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