Effect of obesity and metabolic health on urolithiasis: A nationwide population-based study

The probability of developing urolithiasis during an individual’s lifetime is estimated at 5% to 10% [1, 2]. The rate of relapse after the onset of the first urinary stone is known to be as high as 50% for 5 years and 80% to 90% for 10 years [3]. Dietary and lifestyle factors play an important role in the epidemiological changes of urinary stone disease. In parallel to the epidemic increase of obesity and diabetes, the prevalence of urinary stone disease is also increasing [4]. In Korea, it is estimated that 6.0% of men and 1.8% of women will experience urolithiasis during their lifetime and the composition of commonly occurring urolithiasis was uric acid stones in men and struvite and calcium phosphate stones in women [5, 6]. The annual incidence of urinary stone disease is increasing, and the noninvasive treatment of symptomatic urinary stone disease is increasing every year [7]. Body mass index (BMI) is the most widely used measure of obesity, and higher BMI is associated with pathological physiology, which can lead to the development of various metabolic diseases and the symptomatic urinary stone diseases. Metabolic status and corresponding clinical outcomes in the same BMI group may vary depending on metabolic health status. Some obese patients are classified as having a metabolically healthy obese (MHO) phenotype because they exhibit low levels of insulin resistance and visceral fat and more favorable cardiovascular risk profile despite high BMI [8, 9]. In contrast, people with a metabolically unhealthy non-obese (MUNO) phenotype are characterized by impaired insulin sensitivity, higher levels of abdominal adiposity, blood pressure (BP) and oxidative stress, lower physical activity energy expenditure, more atherogenic lipid profiles, and unfavorable adipokine profiles [10, 11]. Several studies showed that people in the MHO or MUNO group have different risks in terms of the incidence of type 2 diabetes, cardiovascular diseases, and mortality [12, 13]. There is a need for MHO and MUNO individuals to assess the risk of symptomatic urolithiasis that require active treatment. But there has been no large-scale study to date. For these reasons, we defined urolithiasis in patients who had undergone active treatment such as extracorporeal shockwave lithotripsy (ESWL) and surgery, as symptomatic urolithiasis and conducted this study. Therefore, we aimed to investigate the risk of symptomatic urinary stone diseases requiring surgical treatment according to BMI and metabolic health status using a nationwide dataset of the Korean population.

Obesity and metabolic syndrome interact with urolithiasis risk factors to produce a myriad of body responses that induce stone formation. Obesity is the leading cause of type 2 diabetes worldwide and fatty liver disease and cardiovascular disease. But of the obese, about one tenth had the metabolically healthy phenotype. These metabolically healthy but obese individuals are insulin sensitive, have normal BP, a favorable lipid profile, a lower proportion of visceral fat, less liver fat, and a normal glucose metabolism despite having an excessive amount of body fat [16]. Velho et al. [17] reported among obese (BMI ≥30 kg/m²) participants, prevalence of MHO ranged between 3.3% and 32.1% in men and between 11.4% and 43.3% in women according to the criteria used. MHO participants had a lower prevalence of family history of type 2 diabetes. After multivariate adjustment, the odds ratio (OR) of presenting with MHO decreased with increasing age, whereas no relationship was found with gender, alcohol consumption or tobacco smoking using most sets of criteria. Physical activity was positively related, whereas increased waist was negatively related with BMI-defined MHO [17].

The association between metabolic syndrome and nephrolithiasis is well documented, with several studies showing a dose-response effect of metabolic syndrome traits toward resultant stone disease [18, 19]. Obesity, which is one of these traits, has itself been stated to increase the risk of nephrolithiasis up to 75% compared with normal weight patients [20]. Several large patient cohort studies have shown a correlation between metabolic syndrome and the development of kidney stones. West et al. [21] analyzed the United States National Health and Nutrition Examination Survey III (NHANES III) and found that patients with metabolic syndrome had 2 times the risk of developing a kidney stone based on self-reporting. Rendina et al. [22] reported that 50.9% of patients with sonographic evidence of nephrolithiasis qualified for a diagnosis of metabolic syndrome in a longitudinal study of 2,132 patients in Southern Italy. Jeong et al. [23] reported that among almost 35,000 residents of South Korea who were screened with ultrasonography or computed tomography, 2.4% had radiologic evidence of kidney stones, and 13.7% diagnosed with metabolic syndrome. The presence of metabolic syndrome had an OR of 1.25 (95% CI, 1.03–1.50) for kidney stone prevalence [23]. In this study, the metabolically unhealthy groups had a higher age distribution with or without obesity. After adjusting for age and sex, the risk of treatment for symptomatic stone diseases was higher in the MUNO group and MHO group than in the MHNO group, and the risk was higher in MUO than in the MUNO group and MHO group, respectively. Therefore, the key point we would like to argue in this study is that obesity and metabolic health status individually influence the occurrence of symptomatic stone diseases, and the combination of these two factors has a synergistic effect on the occurrence of symptomatic stone diseases. Our results also showed that ESWL was 8.1 times more than the surgery as a method of active treatment for symptomatic urolithiasis in Korean population.

Obesity is a multifactorial derangement of energy homeostasis causing a complex increase in nephrolithiasis risk, leading to the need for comprehensive metabolic evaluation in these patients. Obesity produces insulin resistance, abnormalities in acid-base handling, changes in urine chemistry, and is associated with dietary misadventures, producing an increased risk of nephrolithiasis [24, 25]. Preventive medical therapy for the obesity-associated nephrolithiasis risk can be accomplished through a typical mix of dietary management, fluid intake, and common medical therapy, although physical activity and weight loss are additionally useful [26].

It is known that components of metabolic syndrome independently influence nephrolithiasis formation. West and associates reported that the kidney stone prevalence was 3.7% with no traits, 7.5% for three traits, and 9.8% for five traits [21, 27]. Similar correlations have been reported in Japan and South Korea [27]. Patients with metabolic syndrome typically harbor calcium oxalate and uric acid stones. Kadlec et al. [28] found calcium oxalate stone was the most prevalent and uric acid was the next most common component in patients with metabolic syndrome. Ekeruo et al. [29] reported that, in obese stone formers, uric acid stones were more prevalent, apatite stones were less common, and calcium oxalate stones seemed to be equally distributed between the obese and the non-obese. Insulin resistance is associated with decreased ammonium production in the proximal tubule resulting in decreased urine pH, the major driver of uric acid stone formation [30]. Based on our data, metabolic health and obesity can be judged to have synergistic effects, independently affecting the occurrence of symptomatic stone diseases.

There are limitations in our study. First, because disease codes might not represent a participant’s exact disease status and prescription of medications does not guarantee compliance, there might be errors in the classification of metabolic health status. Second, this study included symptomatic patients who received ESWL or surgery for urolithiasis, however did not include patients who received chemolysis or medical expulsive therapy. Third, because approximately 40% of subjects in customized NHIS database participated in the health examination, our dataset is not representative of the general population and a possibility of healthy user bias should be considered.

Metabolic health disorders and obesity individually affect the development of symptomatic urinary stone diseases. Because the combination of metabolic health disorders and obesity has a synergistic effect, metabolic unhealthy and obese patients have a higher risk for symptomatic urinary stone diseases.