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Metabolic evaluation in urolithiasis – study of the prevalence of metabolic abnormalities in a tertiary centre

Introduction Metabolic abnormalities are one of the most important risk factors for urinary stone disease. Our objective was to determine the prevalence of metabolic abnormalities in patients referred to the urolithiasis outpatient clinic of a tertiary centre. Material and methods We performed a cross-sectional study evaluating 67 patients referred to the urolithiasis outpatient clinic. Metabolic evaluation was performed, including one 24-hour urine sample. Results Metabolic abnormalities could be identified in 92.5% patients. Almost a quarter of the patients had only one metabolic abnormality and 67.6% had more than one abnormality. The most prevalent metabolic abnormalities were hypercalciuria (54.5%), hyperoxaluria (34.7%) and hyperuricosuria (32.3%). Patients with hypercalciuria were older (54.7 vs. 47.8 years, p = 0.018) and family history of stone disease was significantly more frequent among patients with hyperoxaluria (71.4% vs. 28.6%, p = 0.013). There was a positive linear relationship between body mass index (BMI) and urinary calcium (r = 0.247, p = 0.048) and a negative linear relationship between BMI and urinary pH (r = −0.254, p = 0.046). Conclusions Given the high prevalence of metabolic abnormalities, metabolic evaluation should be performed in every patient with urolithiasis evaluated in a tertiary setting.

Introduction Metabolic abnormalities are one of the most important risk factors for urinary stone disease. Our objective was to determine the prevalence of metabolic abnormalities in patients referred to the urolithiasis outpatient clinic of a tertiary centre. Material and methods We performed a cross-sectional study evaluating 67 patients referred to the urolithiasis outpatient clinic. Metabolic evaluation was performed, including one 24-hour urine sample. Results Metabolic abnormalities could be identified in 92.5% patients. Almost a quarter of the patients had only one metabolic abnormality and 67.6% had more than one abnormality. The most prevalent metabolic abnormalities were hypercalciuria (54.5%), hyperoxaluria (34.7%) and hyperuricosuria (32.3%). Patients with hypercalciuria were older (54.7 vs. 47.8 years, p = 0.018) and family history of stone disease was significantly more frequent among patients with hyperoxaluria (71.4% vs. 28.6%, p = 0.013). There was a positive linear relationship between body mass index (BMI) and urinary calcium (r = 0.247, p = 0.048) and a negative linear relationship between BMI and urinary pH (r = −0.254, p = 0.046). Conclusions Given the high prevalence of metabolic abnormalities, metabolic evaluation should be performed in every patient with urolithiasis evaluated in a tertiary setting.

INTRODUCTION
Urinary stone disease or urolithiasis is a common, painful and costly condition [1]. The prevalence of urolithiasis is growing worldwide, irrespective of age, sex and race [2][3][4][5], with rates ranging from 7 to 13% in North America, 5-9% in Europe, and 1-5% in Asia [4]. This increase may be explained by changes in diet and lifestyle, higher prevalence of obesity and diabetes, global warming, with rising temperature resulting in dehydration and high urinary concentration of calcium and other stone-forming salts [4,6].

MATERIAL AND METHODS
We performed a cross-sectional study including 108 patients over 18 years old admitted in the urolithiasis outpatient clinic of a tertiary centre. These patients were referred to the study centre mainly by general practitioners. The recruitment process took place during a period of 6 months, between January 2017 and June 2017. Forty-one patients were excluded due to their medication chart, concerning allopurinol, citrate or thiazides, which could change the urinary metabolic profile, or due to the unavailability of assessment of the 24-hour urine samples ( Figure 1). Patient demographic data were obtained from medical records and during the medical appointment, including age, sex, tobacco (non-smoker, former or present smoker; pack-years) and alcohol (yes/ no) consumption, physical exercise (no exercise, 1-3 days/ week, 4-5 days/week, 6-7 days/week), weight and height to calculate the body mass index (BMI), comorbidities such as hypertension, diabetes mellitus type 2 and dyslipidaemia, medical or surgical history (including past history of urologic interventions such as extracorporeal shock wave lithotripsy, ureteroscopy laser stone fragmentation or nephro-of urolithiasis. Although a genetic component is often considered part of the stone formers' diagnostic work-up, patients with known genetic causes appear to be less frequent [4]. Age, sex, race, climate, seasonal and geographic variation are also recognised predictors [4]. In general, 50% of patients experience recurrent urinary stones within five years without prophylactic intervention and about ten percent of patients even experience three or more recurrences during their lifetime [2,11,12], especially if the metabolic causes remain untreated. In order to apply effective recurrence prevention (metaphylaxis), understanding the metabolic environment of each patient is required, so that a personalized treatment can be addressed. To our knowledge, there are scarce epidemiological data concerning the prevalence of metabolic abnormalities among patients diagnosed with urolithiasis. For that reason, we conducted a cross-sectional study in order to determine the prevalence of metabolic abnormalities in patients with urolithiasis referred to the urolithiasis outpatient clinic of a tertiary centre. A second objective was to evaluate potential risk factors associated with several metabolic abnormalities. Excluded n = 14 Patients taking allopurinol, citrate or thiazides Excluded n = 27 24-hour urine samples not available 1) the sample collected at home was not delivered to the hospital; 2) recent acute event of urolithiasis; 3) the results were not provided by the laboratory at the time of the present study lithotomy), medication chart, personal history and family stone history. Initial evaluation of every patient also included: urinalysis, 24-hour urine sample (with analysis of urinary calcium, oxalate, phosphate, uric acid, sodium and magnesium), bacteriologic examination of urine, serum analysis of creatinine, urea, ionised calcium and parathyroid hormone (PTH) and non-contrast computerized tomography (CT). Hydrochloric acid (HCl) was added into the container for oxalate measurement in the 24-hour urine sample. For the other measurements, patients received an empty container and were instructed to keep it in a cool place during the collection. We considered the following metabolic abnormalities: hyperoxaluria, hypercalciuria, raised PTH, hypercalcemia, hyperuricosuria, hypomagnesuria and hyperphosphaturia.
Reference laboratory values for urine and serum biochemical parameters in adults were made according to the European Association of Urology (EAU) Guidelines for Urolithiasis [13]. Since the reference values for serum PTH and urinary sodium are not given in these guidelines, we used those from our hospital laboratory (high levels for serum PTH was 65 pg/ml and 220 mmol/day for urinary sodium). Statistical analysis was performed using the software Statistical Package for the Social Sciences (SPSS), version 24.0. Descriptive statistics were calculated for the sociodemographic, clinical and metabolic abnormalities. We used t-test for independent samples and nonparametric Mann-Whitney U test for comparisons between categorical and continuous variables, Chi-square for categorical variables and linear correlation for assessment between continuous variables. We considered statistically significant results for a p value <0.05. Ethical approval was granted by the local Ethical Committee. Participants were informed about the study and methods and confidentiality was ensured. All participants signed a written informed consent according to the Declaration of Helsinki for human research ethics.

Participant characterization -demographic and clinical characterization
The majority of the population were women, making a female/male ratio of 1.39:1. The median age at the time of the consultation was 52 years old, with most patients between 43 and 60 years of age. Frequencies of smoking and alcohol consumption and physical activity are shown in Table 1.
As depicted in Table 1

DISCUSSION
In our series, the most striking finding was the very high prevalence of metabolic abnormalities (92.5%), resembling the findings of several other studies, which considered metabolic abnormalities as one of the most important factors for stone formation [10,14,15]. Hypercalciuria (detected in 54.5% of patients) was the most frequent metabolic abnormality, followed by hyperolaxuria (34.7%) and hyperuricosuria (32.3%), a finding also observed in larger studies, most of them with patients with recurrent stone formation history [10,14,16,17]. We included 17 patients with first self-reported episode of stone disease and, interestingly, all of them presented at least one metabolic abnormality. Nevertheless, in some studies, a predominance of other abnormalities such as hyperoxaluria [10] or hypomagnesuria [18] was found. These disparate results may be explained by climate, seasonal, dietary or lifestyle variations, which highlights the importance of studying the prevalence of different metabolic changes in each population. This matter assumes a preponderant role, given the ability to modify these metabolic abnormalities with preventive (metaphylatic) measures, including diet and lifestyle changes along referred one first degree relative while 9.6% mentioned two or more first degree relatives.  Table 2.

Frequency and type of metabolic abnormality in patients with urolithiasis
As for other urinary parameters, the median of the 24-hour urinary volume was 1650 ml, with 62.7% of patients presenting a 24-hour urinary volume below 2000 ml. The majority of urinary samples had a pH between 5.5 and 6.5 -almost a third (29%) of patients with a urinary pH less than 5.5 and 16.1% higher than 6.5. Approximately one-sixth (15.3%) of patients presented a positive urinary bacteriologic exam, with Escherichia coli as the most frequent isolated agent (5 in 9). Body mass index was associated with urinary calcium and urinary pH. There was a positive linear relationship between BMI and urinary calcium (r = 0.247, p = 0.048) and a negative linear relationship between BMI and urinary pH (r = −0.254, p = 0.046). There was also a positive linear relation- Patients with hypercalciuria were older than those without this metabolic abnormality, with a median age around 55 years. Otto et al. also observed that middle age patients are more likely to be hypercalciuric [20]. The higher prevalence of present and former smokers among patients with hyperoxaluria sustains the studies of Hamano et al. The authors suggested an interplay between cigarette smoking and arginine vasopressin, resulting in a further decrease of urinary output and enhancing stone formation. Therefore, smoking cessation can be effective in reducing calcium stone recurrence [21]. According to the European Association of Urology Guidelines for Urolithiasis [13], one preventative risk for stone formation relies on a higher fluid intake, 2.5-3.0 l/day, in order to maintain a urinary volume between 2 and 2.5 l/day. We observed that 62.7% of patients presented a lower 24-hour urine output (<2 l in 24 h) and recommending an increased fluid intake should be considered the first option as a general treatment of these patients. Despite our findings, in clinical practice the implementation of an extensive metabolic evaluation is still controversial. In our opinion, given the high prevalence of metabolic abnormalities in our population, it seems to be worth performing an extended metabolic evaluation in all patients admitted to with the introduction of some pharmacological options (i.e. allopurinol, citrate or thiazides) that might prevent urinary stone formation [10]. There is great variability in the literature regarding the prevalence of urolithiasis according to gender. Our sample revealed a predominance of women (1.39:1), the same ratio pointed by Amaro et al. [14], but different from other studies, with a gender ratio male/female of 1.5-2.5 across the world. The gender ratio discussion of this study is precluded by the methods of patients' referral which influences our outpatient clinic representativeness of the general population.

Comparison between clinical and metabolic abnormalities
It is known that obesity and weight gain increase the risk of stone formation [8]. In our study, the majority (60.6%) of patients were overweight or obese and the increase of BMI was associated with a higher urinary calcium excretion. These patients may benefit from nutritional counseling for weight loss, aiming for the reduction of stone recurrence and decreasing cardiovascular risk. We also observed that BMI was inversely related to urinary pH, explained by the hypothesis that obesity may induce excessive production of acidic urine secondary to insulin resistance [19]. Almost a third (29%) of patients presented a urinary pH less than 5.5, a documented risk for uric acid nephrolithiasis. Patients with persistently low urinary pH benefit from urine alkalization [7,19]. profiles as predictors of therapeutic success and recurrence outcomes. The identification of metabolic abnormalities and the implementation of specific diet changes and pharmacological treatment, when clinically indicated, should be complemented with a close follow-up of all patients in order to estimate future recurrence rates, clinical outcomes for ER admission and the need for surgical procedures.

CONCLUSIONS
Given the significant burden of urinary stone disease in our clinical practice along with the significantly high prevalence of metabolic abnormalities, we support the metabolic evaluation, irrespective of the presence or absence of recurrence, as an invaluable step in the clinical work-up of these patients. This immediate metabolic evaluation is the key for a better and individualized management, guiding the selection of proper pharmacological and dietary measures to prevent recurrent stone formation and to relieve all clinical and economic burden behind this condition.