Urolithiasis is one of the most common benign urologic diseases, and approximately 5%-15% of the population will develop urolithiasis in their lifetime.¹ Although both intrinsic and environmental factors are believed to contribute to urinary stone formation,^{2, 3, 4, 5, 6, 7, 8 and 9} the exact cause is not fully understood. More precise knowledge about the etiology of urolithiasis could potentially improve both treatment and disease prevention.

Although considerable differences exist in the rate of obesity among countries and between the sexes, the prevalence of obesity is increasing in most countries and is associated with several medical problems.^10 and 11 An increased body mass index (BMI) and obesity are closely associated with urinary metabolic abnormalities and recurrent stone disease.^{4, 5 and 6} Recent epidemiologic studies have suggested a persistent increase in the prevalence of stone disease in industrialized and developing countries.^{12, 13 and 14} Although this trend has been suggested to a result from the influence of Western lifestyles and dietary habits,¹³ it is unclear whether urinary metabolic risk factors have changed because of the modifications in diet and lifestyle.

Korea has recently experienced a rapid increase in obesity because of economic growth.¹⁵ To determine whether this trend is associated with an increased prevalence of stone disease and urinary metabolic abnormalities, we assessed the changes and sex-specific differences in urinary metabolic risk factors in patients with first-time stone formation (SF) during 2 successive periods from 1994 to 2007.

Material and Methods

Study Population

We performed a retrospective analysis of patients with first-time calcium SF, who had been diagnosed and treated from 1994 to 2007 at our institution. The data included stone history, medication, and metabolic evaluation, including serum chemistry, 24-hour urinary chemistry, and radiographic images of the urinary tract. The diagnosis of calcium stones was determined from the abdominal radiograph and ultrasound examination findings. The metabolic evaluation was performed ≥6 weeks after the last stone episode. The exclusion criteria were pediatric patients (age <16 years), incomplete 24-hour urine collection, impaired renal function (serum creatinine >1.5 mg/dL), staghorn calculi, urinary tract obstruction, malformation of the urologic system, hypercalcemia, and a previous diagnosis of primary hyperparathyroidism or other systemic diseases that might affect calcium and bone metabolism. Medications that could affect the 24-hour urine chemistry parameters were discontinued 2 weeks before the urine samples were collected. The patients with SF were advised to continue their usual diet, and none were instructed to consume a low-calcium diet. On the basis of these criteria, 619 patients with first-time SF, who had complete metabolic assessments, were included in the final analysis. We categorized the patients into 2 groups, according to the year of the initial diagnosis: group 1, diagnosed from 1994 to 1999, and group 2, diagnosed from 2000 to 2007.

Study Definitions

Using the BMI measurements (weight in kg/height in m²), the patients with SF were categorized as nonobese (BMI <25 kg/m²) or obese (BMI ≥25 kg/m²), according to the redefined World Health Organization criteria for the Asia Pacific region.¹⁶ Urinary metabolic abnormalities were classified into 5 categories, as defined by Lifshitz et al.²

Statistical Analysis

The clinical characteristics and patterns of urinary metabolites in the patients with SF were stratified by sex. The results are expressed as the mean ± SD. The differences in urinary variables between the subgroups were assessed using the Student t test, and categorical variables were compared using the χ² test. Pearson correlation coefficients were performed to evaluate the association between the BMI and urine parameters. Statistical analysis was performed using the Statistical Package for Social Sciences, version 12.0, software (SPSS, Chicago, IL). All tests were performed using a 2-tailed analysis, and P < .05 was considered statistically significant.

Results

Baseline Characteristics

The mean age of the study population was 43.7 years (range 17-78). The median BMI was 23.7 kg/m²(range 14.1-37.1). The 619 patients were classified into 2 groups: group 1 SF (n = 353, 57.0%) and group 2 (n = 266, 43.0%). No significant differences were found in the age or sex distribution between the 2 groups (P > .05). The patients in group 2 had a significantly greater BMI than those in group 1 (24.1 ± 3.4 vs 23.4 ± 2.9 kg/m², P = .001). Thus, obesity was more common in group 2 than in group 1 (P = .006). Stratified by sex, obesity was more prevalent in male patients in group 2 than in male patients in group 1. The prevalence of obesity was similar in female patients in both groups ( Table 1). When the BMI was examined in groups 1 and 2 according to obesity, no significant difference was found in the nonobese patients with SF (group 1, 22.0 ± 1.9 kg/m² vs group 2, 22.1 ± 1.9 kg/m², P = .652). However, the BMI was signficantly increased in the obese patients in group 2 (27.5 ± 2.5 kg/m²) compared with the obese patients in group 1 (26.8 ± 1.8 kg/m²; P = .022).

Urinary Parameters

Group 2 had a lower urinary volume, lower average urinary pH, and greater uric acid excretion level than group 1. Stratified by sex, group 2 male patients had a significantly greater urinary uric acid excretion level than did group 1 male patients. Compared with male group 1 patients, male group 2 patients tended to have a lower average urinary pH; this difference approached statistical significance (P = .053). The women in group 2 had a reduced urinary volume and urine pH compared with group 1. No significant differences were found in the excretion of other urinary metabolites, as determined by subgroup analysis ( Table 2). The incidence of metabolic abnormalities is listed in Table 2. A low urine volume and hyperuricosuria were significantly more prevalent in group 2 than in group 1. In the subgroup analysis by sex, increased hyperuricosuria was detected only in male patients with SF (P = .007). No significant differences were found in the other metabolic risk factors in the subgroup analysis. The prevalence of urinary metabolic abnormalities between groups 1 and 2 with obesity, except for the greater incidence of hyperuricosuria in the obese patients in group 2 compared with the incidence in the obese patients in group 1, was similar (Table 3).

On correlation analysis, the BMI correlated significantly with urinary uric acid excretion (r = 0.300; P < .001). In a separate analysis, these observations persisted in groups 1 (r = 0.229, P < .001) and 2 (r = 0.350, P < .001). Patients with hyperuricosuric SF had greater urinary volume, sodium, calcium, and citrate levels than did those with normouricosuric SF. Compared with those with normouricosuric SF, the average urinary pH was decreased in those with hyperuricosuric SF. These findings were not affected by sex (Table 4).

Comment

In the present study, we found that the prevalence of obesity in patients with stone disease has increased from 1994 to 2007 and that this trend was more prominent in male patients with SF. An important finding of the present study was that the total urine volume and average urinary pH has also decrease and uric acid excretion has increased with time. In particular, a significant increase was found in hyperuricosuria in male patients with SF during the study period. No significant differences were found in the incidence of hyperuricosuria in the female patients in groups 1 (1994-1999) and 2 (2000-2007).

Numerous reports have suggested that the frequency of urolithiasis has been increasing steadily during the past few decades.^{12, 13 and 14} Changes in diet and lifestyle can increase the risk of obesity and overweight and may also enhance the risk of stone disease.^{4, 5, 6 and 12} The correlation between escalating stone prevalence and the spread of Western-style diets and lifestyles in Japan has suggested that environmental factors may partially account for the changes in the prevalence of stone disease.¹³ Although the incidence of obesity has been dramatically increasing worldwide, sex-specific differences have not been consistently observed.^{11, 15 and 17} A recent Korean epidemiologic study showed that the rate of BMI has increased over time, with the greatest change among young men.¹⁵ In that study, the mean BMI increased by 0.8 kg/m² in men and 0.3 kg/m² in women from 1992 to 2000. Furthermore, the percentage of overweight individuals (BMI ≥25 kg/m² but <30 kg/m²) increased by 42% in men and 34% in women. These findings indicate that the BMI has markedly changed in men but not in women. The results of a Japanese nationwide survey showed a decreasing trend in BMI among women <50 years old and that this decline was more significant in young women in metropolitan areas.¹⁷ These and other results suggest that young women have a strong impetus to be thin and that the decreasing trend in BMI among younger women might have resulted from their use of extreme diets, which, in some cases, can lead to eating disorders, such as anorexia.¹⁸ Our findings are consistent with these previous results and indicate that the incidence of obesity is more common in men with SF than in women with SF.^15 and 17

A variety of factors influence urolithiasis, including sex, diet, lifestyle, obesity, other disease states, and the excretion of urinary metabolites.^{2, 3, 4, 5, 6, 7, 8 and 9} Recent studies have reported a close relationship between obesity and alterations in urinary chemistry that affect stone formation.^{4, 5, 6, 7 and 8} A greater proportion of obese patients with SF have hyperuricosuria, gouty diathesis, hypercalciuria, and uric acid stones compared with normal weight individuals.^{5, 6 and 7} Similarly, in a large cohort study of patients with stones, the urinary pH correlated negatively with the body mass, even when controlling for dietary factors.¹⁹ Type 2 diabetes mellitus is a common medical condition in obese patients,²⁰ and hyperinsulinemia and insulin resistance are associated with impaired ammonium excretion and urine acidification in the proximal tubule, resulting in a low urinary pH.^4 and 19 A persistent low urinary pH is a distinctive feature of idiopathic uric acid nephrolithiasis.²¹ In an excessively acidic urinary environment, the concentration of partially soluble undissociated uric acid increases, resulting in the formation of uric acid crystals by direct precipitation.²² We found a greater incidence of obesity in our group 2 patients (diagnosed from 2000 to 2007) and that this was associated with increased uric acid excretion and decreased urinary pH. Stratified by sex, these urinary metabolic changes were detected only in male patients with SF, consistent with the increased incidence of obesity in that subgroup. Other urinary metabolic risk factors for stone formation, such as hypercalciuria, hyperoxaluria, and hypocitraturia, were not significantly altered in subgroup analysis. Additionally, separately analyzed between groups 1 and 2 by obesity, the prevalence of metabolic abnormalities was not different, except for the increased rate of hyperuricosuria in group 2 obese patients compared with group 1 obese patients. A greater BMI in the group 2 obese patients than in the group 1 obese patients might have been responsible for these findings. Although the precise mechanism has not yet been determined, our results suggest that the increased prevalence of obesity, perhaps because of the influence of Western dietary habits and lifestyle, might be a factor in the differences in urinary metabolites between the earlier and later groups with SF.

Many putative factors could influence the urinary lithogenic solute composition over time in the Korean population. An accurate accounting of the changes in stone composition in patients with urolithiasis is important for determining the appropriate treatment of, and preventive strategies against, stone formation. A typical preventative measure against stone formation is the manipulation of the urine chemistry. The modification of dietary factors and lifestyle also plays a key role in the prevention of stone formation and recurrence. Normalizing the major risk factors, such as weight, physical activity, balanced nutrition, and circadian fluid intake, are simple and inexpensive. Given that urolithiasis is increasing in the Korean population, primary preventive approaches aimed at educating individuals about the affects of diet and lifestyle hold great promise for the prevention of stone formation and the treatment of patients with stone disease.

Conclusions

The results of the present study have demonstrated that urinary metabolic risk factors have been changing over time in the Korean population and that hyperuricosuria has become a more prevalent risk factor in recent years. The differences were prominent in men but not in women, possibly because of the increased incidence of obesity in the former subgroup. These trends in urinary metabolic abnormalities might be related, not only to changes in lifestyle and diet, but also to the increased prevalence of obesity.

Copyright © 2009 Elsevier Inc. All rights reserved.