Global, Regional, and National Incidence and Disability-Adjusted Life-Years for Urolithiasis in 195 Countries and Territories, 1990–2019: Results from the Global Burden of Disease Study 2019

Purpose: Urolithiasis is highly prevalent worldwide. The aim of this study was to report the results of the Global Burden of Disease 2019 study on urolithiasis burden estimates grouped by gender, regions, countries or territories, and sociodemographic index (SDI) from 1990 to 2019 globally. Methods: We reported detailed estimates and temporal trends of the burden estimates of urolithiasis from 1990 to 2019 in 195 countries and territories and further evaluated the relationship between these estimates and SDI, a composite indicator of income per person, years of education, and fertility as a measurement of country/region socio-economic level. Urolithiasis incidence and disability-adjusted life years by gender, regions, countries or territories, and SDI were reported. The percentage change and estimated annual percentage change of these burden estimates were calculated to quantify temporal trends. Results: From 1990 to 2019, the age-standardized incidence rate (ASIR) and disability-adjusted life years (DALYs) of urolithiasis decreased globally by 0.459% and 1.898% per year, respectively. Such a trend of ASIR was prominently due to the decline in the middle, high-middle, and high SDI countries, including Eastern Asia, high-income Eastern Europe, and high-income North America. During this period, these estimates increased in low and low-middle SDI countries, particularly in South Asia, Andean Latin America, and Western Europe. A decline in DALYs was observed in all SDI countries. An approximate positive linear association existed between the burden estimate’s decreased APC and SDI level, except at the high SDI level. Both males and females showed the same trend. Conclusions: This study provides comprehensive knowledge of the burden estimate of urolithiasis. Although the burden estimates of urolithiasis showed a global decrease during the past 29 years, this progress has yet to be universal; the increasing trends were observed in countries with low and low-middle SDI countries. Research in these countries is needed and helps with the appropriate allocation of health resources for prevention, screening, and treatment strategies.


Introduction
Urolithiasis is a highly prevalent disease worldwide with prevalence rates ranging from 1% to 20% [1], it is characterized by significant morbidity, economic costs and days lost from work [2]. In addition, about half of the stone formers have one lifetime recurrence [3]. High recurrence is observed in more than 10% of urolithiasis patients [4]. There is significant variation in rates based on geography, climate, diet style, ethnicity, gender, and age [5]. In countries such as Sweden, Canada or the United States, the prevalence of stones are notably high (more than 10%) [3,6,7]. However, in Asian countries, there was little epidemiologic data about urolithiasis. Yasui et al. [8] reported that the incidence of urolithiasis in Japan was 134.0 per 100,000 person/year, which was significantly lower than that reported in Western countries. Due to the high rates of new and recurrent stones, management of stones is expensive.
Understanding the epidemiology of urolithiasis measures among different regions/nations, and changing trends is crucial for treatment outcome. Furthermore, reliable and accurate statistics on patterns and disease trends in various geographic locations give policy makers the proof they need to allocate resources properly. However, few evaluations have been carried out at the national level, and there is no study addressing the trend in disease burden of urolithiasis. The majority of epidemiological studies of urolithiasis were based on general practice surveys, selected population surveys, or hospitals [9]. For understanding of a nation's actual demographic status, they are insufficient. A historical evaluation and a comparison of different countries are also impossible. The global burden of disease (GBD) study evaluated the prevalence of urolithiasis in 195 nations and territories, offering a rare chance to comprehend the epidemiology of this condition. By combining several forms of data, it gives a thorough assessment of changes in disease health status. A cycle of continuous quality improvement of this database has additionally led to substantial changes, including new data sources, identification of novel causes of death, and updated methods, which serve as global information freely available for policy makers and public groups seeking to improve human health [10].
Although there were several studies addressing this issue based on GBD 2019 [11][12][13], they did not demonstrate the global disease burden of urolithiasis stratified by sex, countries and territories. Therefore, we have reported an in-depth examination of the global burden of urolithiasis from a complete time series of incidence from 1990 to 2019, with disabilityadjusted life years (DALYs), and investigated the disease burden to determine the temporal trends of these estimates at global, regional, and national levels. The relationships of estimates of the global burden of urolithiasis with socioeconomic development level, and measured SDI, were further assessed.

Data Sources
The Global Burden of Disease (GBD) is a systematic, scientific effort to quantify the comparative magnitude of health loss due to diseases, injuries, and risk factors by age, sex, and geography over time. The conceptual and analytical framework for GBD 2019, with details of the hierarchy of causes and risk factors, data inputs and processing, and analytical methods, has been published elsewhere [14][15][16]. GBD Results Tool provides the details of different risk factors, causes and impairments related to health in terms of deaths, Disability-Adjusted Life Years (DALYs), Years Lived with Disability (YLDs), Years of Life Lost (YLLs) and prevalence via age, year, gender, and location. Results from the GBD 2019 study, which evaluated 354 causes and 3484 sequelae, were obtained from 195 different nations [14]. These results were generated using a total of 68,781 data sources, including a thorough literature review, hospital and clinical data, surveillance and survey data from various sources, and inpatient and outpatient medical records [14,17]. In our study, data on urolithiasis incidence and DALYs and their uncertainty intervals were curated from GBD 2019 data sources (http://ghdx.healthdata.org/gbd-results-tool (accessed on 1 December 2021)) provided by the Institute for Health Metrics and Evaluation. The present study complies with the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER) recommendations (Table S1).

Modeling
The major data inputs for the distribution of urolithiasis globally included national health surveys, population representative surveys and cohort studies, and a variety of published and unpublished studies which were described in the appendix (Supplementary  Materials, Supplementary Tables S2-S6). In the GBD 2019, urolithiasis was defined as stone formation located anywhere along the genitourinary tract. Using DisMod-MR, version 2.1, a disease modeling computational tool that is the standard GBD modeling approach for nonfatal health outcomes, the incidence of urolithiasis was estimated by region, age, sex, and year ( Figure S1). The identification of all accessible data sources, their evaluation for data extraction based on inclusion criteria, the determination of sequelae severity distributions, the incorporation of disability weights to quantify severity, and comorbidity adjustment of sequelae were all steps in the process of estimating the incidence of urolithiasis.
DALYs, a summary measure of total health loss, were calculated for urolithiasis by summing YLLs and YLDs for each location, age, sex, and year ( Figure S1). YLD captures years lived with less-than-ideal health because of urolithiasis and was estimated by a multiplication of prevalent cases of urolithiasis and a disability weight [16,18]. YLL is a measure of the years lost owing to premature mortality due to urolithiasis and was based on the remaining life expectancy compared with a reference standard life table at age of death [16].

The Socio-Demographic Index
The Socio-demographic Index (SDI) is a summary measure that estimates a location's position on a spectrum of development [19]. Briefly, the SDI was computed on the basis of the geometric mean of three indicators: lag-distributed income per capita, educational attainment over the age of 15 years, and total fertility rate in women aged 15-49 years. SDI scores were scaled from 0 to 1, and each location was assigned an SDI score for each year. A total of five SDI quintiles, high, high-middle, middle, low-middle, and low, were selected based on SDI values (Table S7). Average relationships between SDI and incidence and DALYs of urolithiasis were estimated using spline regressions, which were then used to estimate expected values at each level of SDI. The results presented for SDI quintiles in this study reflect each country's position based on its SDI values in 2019.

Statistical Analysis
To measure the trend in the global burden of urolithiasis, we utilized the age-standardized incidence rate (ASIR), DALYs, percentage change (PC), and estimated annual percentage change (APC) [20]. When comparing populations with varied age structures or for the same population across time when the age profiles change proportionally, standardization is required. By adding the products of the age-specific rates and the number of people in the same age subgroup of the chosen reference standard population, and then dividing the total by the standard population weights, the age-standardized rates according to the direct approach were determined. The GBD world population standard was used for calculation of age-standardized rates. APC is a widely used measure of the ASR trend over a specific time interval. A regression line was fitted to the natural logarithm of the rates. APC and 95% confidential interval (CI) values can also be obtained from the linear regression model [21]. We employed a generalized additive model with Loess smoother on SDI to estimate the associations between SDI and ASIR and DALYs using GBD estimates from all national locations across the years from 1990 to 2019 [22]. Uncertainty intervals (UI) were defined as the 2.5th and 97.5th values of the ordered draws. All statistical analyses were performed using SPSS (Version 23, SPSS Inc., Chicago, IL, USA) and the R program (Version 3.4.4, R core team, Vienna, Austria), with p-Values <.001 considered significant.

Age Standardized Incidence Rate (ASIR) of Urolithiasis
Globally, ASIR of urolithiasis changed from 1146.048 per 100,000 individuals in 1990 to 1031.497 per 100,000 individuals in 2019, representing a shift of −0.459% per year (95%CI: −0.506%-−0.411%) and −9.995% in total. Both male and female showed a decrease in ASIR of urolithiasis, which were −0.557% and −0.312% per year, respectively (Table 1). There was a decreasing trend observed in 12 of 21 regions. The largest decrease in APC was observed in Eastern Asia (−1.396%), followed by high-income Eastern Europe (−0.317%) and high-income North America (−0.305%), which collectively contributed to 73.130% of the decreasing trend. Conversely, an increasing trend, was observed in another 9 regions. The largest increase in APC was detected in South Asia (0.568%), followed by Andean Latin America (0.381%) and Western Europe (0.261%). These three regions contributed 58.815% of the overall increasing trend ( Figure 1 and Table 2).
Between 1990 and 2019, APC of ASIR decreased in 53 of the 195 countries, among which statistical significance was reached in 38 countries (71.70%). The top three were China (−1.492%), Indonesia (−0.900%), and New Zealand (−0.673%). Almost three-fourths of the countries or territories (142/195) displayed an increasing trend during the observational period, the majority with statistical significance (89.29%). Territories of Taiwan (a part of China) showed the most pronounced increase with an average of 1.208% per year, followed by Ecuador (APC = 1.006%) and Belgium (APC = 0.891%) ( Figure 2 and Table 3).
When stratified by SDI quintiles, ASIR of urolithiasis increased in countries/regions at low and low-middle SDI quintiles but decreased in those at middle, high-middle and high SDI quintiles. There was an approximate positive linear association that existed between the decrease in APC and SDI except at high SDI levels. Both male and female demonstrated the same results. High-middle SDI (APC, −1.165%) and low SDI quintiles (APC, 0.335%) contributed most significantly to the decreasing and increasing trends, respectively (Table 4).
There was a decreasing trend observed in 12 of 21 regions. The largest decrease in APC was observed in Eastern Asia (−4.678%), followed by Central Europe (−2.776%) and Eastern Europe (−1.768%), which collectively contributed to 53.12% of the decreasing trend. Conversely, an increasing trend, was observed in another 9 regions. The largest increase in APC was detected in Tropical Latin America (3.248%), followed by the Caribbean (1.133%) and high-income Asia Pacific (0.670%). These three regions contributed 61.525% of the overall increasing trend (Figure 3 and Table 5).
Between 1990 and 2019, APC of DALYs decreased in 122 of the 195 countries, among which statistical significance was reached in 101 countries (82.79%). The top three were Bulgaria (−6.073%), American Samoa (−4.974%), and China (−4.811%). Almost onethird of the countries or territories (73/195) displayed an increasing trend during the observational period, the majority with statistical significance (72.60%). Brazil showed the most pronounced increase with an average of 3.279% per year, followed by Trinidad and Tobago (APC = 3.217%) and Armenia (APC = 0.1.995%) ( Figure 4 and Table 6).
The associations between global burden estimates of urolithiasis and SDI levels for each of the 21 GBD regions for all individual years between 1990 and 2019 are illustrated in Figure 3 and Table 7. In general, a decreasing trend was observed at all SDI levels, and there was an approximate positive linear association that existed between the decrease in APC and SDI except at the high SDI levels. High-middle SDI (APC, −3.096%) contributed most significantly to the decreasing trends. Both male and female demonstrated a similar demographic pattern.

Discussion
Based on the GBD 2019 data, we comprehensively assessed the recent burden estimates as well as temporal trends in urolithiasis from 1990 to 2019 at the global, regional, and national levels. During the study period, the global urolithiasis burden decreased as measured by ASIR and DALYs. However, the temporal trends of these burden estimates varied considerably by SDI levels and regions. The ASIR decrease in urolithiasis was observed in the middle, high middle, and high SDI countries, but an increase was shown in low and low middle SDI countries. A decline in DALYs was observed in all SDI levels. Additionally, an approximate positive linear association existed between the decreased APC of burden estimates and SDI, except for at the high SDI levels.
This study showed a slight decline in the incidence of urolithiasis globally for both genders, consistent with several previous evaluations of regional trends in urolithiasis. A recent population-based study from Rochester showed the incidence rates might have decreased in males and reached a plateau in females since 1990 [23]. This study reported relatively stable incidence rates from 1970 to 2000 and a downward trend in the overall incidence of kidney stones in the Caucasian population [23]. Numerous previous data reported that urolithiasis prevalence in most countries has been rising in recent decades [3,7,8,24,25], such as the United States, New Zealand, Germany, and Japan. While the incidence trend was slightly decreased or stable, it implies that new urolithiasis cases increased more slowly.
Although the consequences are not life-threatening in most stone patients, it is a significant cause of morbidity, hospitalization, and days lost from work [26]. There has been a significant decrease in the DALYs of urolithiasis globally, and it decreased linearly with SDI except for high SDI countries. From 1990 to 2019, Global DALYs of urolithiasis, with 122 of 195 countries or territories, had improved. Over the last three decades, this decreasing pattern in the age-standardized DALY rate of urolithiasis may be partly attributable to surgical innovations and better treatment guidelines [27]. These advances have made interventions safe, effective, and associated with shorter recovery duration and lesser discomfort [28].
There is significant geographic variation in urolithiasis incidence worldwide. Even though throughout a country, the incidence may have a drastic range [5]. The variation in demography is impacted by many factors, such as climate, ethnicity, environmental factors, availability of medical practice, dietary styles, and age distribution; these factors interact in complex ways. This study observed a decreasing trend in 12 of 21 regions. The most significant decrease in APC was observed in Eastern Asia, followed by high-income Eastern Europe and high-income North America, collectively contributing to 73.130% of the decreasing trend. In addition, the APC of ASIR decreased in 53 of the 195 countries; the top three were China, Indonesia, and New Zealand. This decreasing trend has been influenced by some regions, particularly in populous East Asia. For example, as the most populous country in the world, China has experienced a remarkable decline. In the last decades, the diet structure of China has greatly changed, and the consumption of fruits and vegetables is on the rise, which are protective factors for urolithiasis development [29]. This could partially help to explain the decreasing trend.
However, an increasing trend was observed in the other nine regions. The most significant increase in APC was detected in South Asia, followed by Andean Latin America and Western Europe. These three regions contributed 58.815% of the overall increasing trend. In addition, between 1990 and 2019, almost three-fourths of the countries or territories displayed a rising trend during the observational period, the majority with statistical significance. The territories of Taiwan (a part of China) showed the most pronounced increase, followed by Ecuador and Belgium. The progress in diagnostic procedures, such as sonography, has led to a significant improvement in early diagnosis of asymptomatic urolithiasis, which may increase the trend in low and low-middle SDI nations [30]. Significant changes in nutritional and environmental factors might also lead to progress in the burden of urolithiasis [30].
While most countries in the low and low-middle SDI quintiles showed an increase in ASIR, these values declined in the middle, high-middle, and high SDI quintile countries. Between-country variations in factors, such as socioeconomic status (per-capita income, fertility, and education levels), access to prevention, diagnosis, and treatment facilities, and differences in clinical practice, could further lead to heterogeneity in these burden estimates. Socioeconomic status (SES) differences in health outcomes are among the most consistent epidemiological findings [31]. An earlier ecological study also reported an association of diversity of income and education levels with incidence and mortality differences of disease in each region [32], patients with higher SES levels might have less unhealthy living behavior than lower SES patients [32]. Furthermore, compared to countries with low income, high-income countries have more advocacy, media attention, and funding for the prevention and treatment of disease [33]. Therefore, to further reduce the disease burden, more regions, especially countries with low or middle SDI, should consider increasing the investment in health careers [34]. Changes in socioeconomic conditions over time, and the subsequent changes in dietary styles, have affected not only the incidence rate but also the location and composition of stones [2]. In addition, the observed variation in urolithiasis estimated burden among the SDI quintiles levels was not only due to differences in socioeconomic status but also to differences in genetic background, lifestyles, and exposure to environmental and nutritional factors.
In addition, due to global warming from climate change, it is expected that the prevalence of kidney stone disease will increase due to more significant insensible water losses, resulting in more concentrated urine and altered urinary flow. In line with this, Kaufman et al. found that an increased burden of kidney stone disease on healthcare systems attributed to climate warming is very likely [35]. Especially the burden of greenhouse gas emissions was more prominently observed in low-income countries [36], which may be another plausible reason for explaining the disease burden trend discrepancy between various income levels of regions and countries.
The Asian-Africa stone-forming belt includes the Philippines, Indonesia, Thailand, Myanmar, India, Pakistan, Iran, the United Arab Emirates, Saudi Arabia, Egypt, and Sudan. In this area, urolithiasis was detected in all age groups, with prevalence ranging from 4% to 20% [37]. The higher prevalence in these stone-forming belt countries is possibly determined by the high consanguinity among ethnic groups [38]. In the current study, we found that this stone belt still exists. However, the estimated burden of a few countries declined, and the decreased trend was significant in Indonesia, Thailand, and Sudan.
There were several limitations of the study. First, GBD estimates are a combination of data and largely depend on the quality and quantity of data used in the modeling [10]. The health surveys and other data systems in different countries result in wide uncertainty in these estimates. Several statistical procedures have been developed to address this flaw, including modeling based on regional patterns and disease-specific covariates [39]. Furthermore, differences in data collection practices and coding systems and the quality of data sources remain major challenges. However, the GBD 2019 study has made a substantial effort to solve these difficulties in the methodological framework, including applying corrections for under-registration and garbage code redistribution algorithms [40]. Secondly, given the misclassification of urolithiasis and the adoption of different disease coding systems in the input data sources, we failed to estimate temporal trends in the burden of urolithiasis stratified by stone location and composition. Thirdly, SDI utility is restricted in countries with income inequality. The applicability of SDI could therefore be enhanced by taking into account social heterogeneity within countries [41]. However, data from GBD is the most thorough and standardized when compared to other sources because it provides complete time series and outcomes at the country level. This is useful for policymakers who need to effectively distribute the limited resources in their healthcare systems.

Conclusions
Since urolithiasis is a common disease worldwide, elucidating the trends and burden estimates over time is essential to establish policies and accurately set priorities for action. The GBD 2019 study provides an opportunity to assess the latest evidence, and monitor these trends to determine where interventions exert an effect. Our findings collectively indicate that while progress has been made in reducing the global burden of urolithiasis in the middle, high-middle, and high-SDI countries, more effective prevention strategies are required for low and low-middle SDI countries.
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/jcm12031048/s1, Figure S1: Flowchart, urolithiasis incidence to DALY estimation; Table S1: GATHER checklist; Table S2: The geographical coverage of urolithiasis data by measure in GBD 2019; Table S3: Covariates selected for CODEm for urolithiasis and expected direction of covariate; Table S4: Total number of site years by cause and source type for GBD 2019; Table S5: Results for CODEm model testing; Table S6: Comparison of GBD 2016 and GBD 2019 covariates used and level of covariates; Table S7: Socio-Demographic Index groupings by location, based on 2019 values. References [42][43][44][45][46]  Data Availability Statement: The datasets generated during and/or analyzed during the current study are available from the Global Health Data Exchange query tool (http://ghdx.healthdata.org/ gbd-results-tool (accessed on 1 December 2021)).