Global Trends in Incidence and Burden of Urolithiasis from 1990 to 2019: An Analysis of Global Burden of Disease Study Data

Take Home Message The total burden of urolithiasis in terms of incidence, disability-adjusted life years, and deaths has increased globally since 1990, while age-standardized rates have decreased. Importantly, areas of lower sociodemographic index have seen an increased burden. Understanding variation and factors affecting the burden of urolithiasis is necessary for policymakers.


Introduction
Urolithiasis is one of the most common urologic diseases worldwide, with an estimated prevalence ranging from 1% to 13% in different regions across the globe [1,2]. Recent evidence demonstrates that the prevalence of urolithiasis is on the rise globally due to a multitude of factors, including changes in social conditions, dietary habits, climate, and disease comorbidities [1,[3][4][5]. With this change comes increases in disease burden, associated costs of diagnosis and treatment borne by healthcare systems, and economic burden due to the deleterious effects of urolithiasis [3,6,7].
While the burden of urolithiasis is universally increasing, the epidemiology of urolithiasis varies across regions of the globe [8]. The societal cost of a case of urolithiasis varies by region, but saliently the trends in incidence and prevalence vary in conjunction with imbalances in economic development, obesity rates, diet, climate change, and other health conditions. Thus, measuring and effectively addressing the burden of urolithiasis require a culturally and geographically adapted approach. Few global and national estimates and reviews describing this varying burden exist, meriting a comprehensive global comparison of the incidence, disability burden, and mortality associated with urolithiasis [9,10].
The Global Burden of Disease (GBD) 2019 study provides a systematic assessment of published and publicly available evidence of incidence, prevalence, and mortality for 369 diseases and injuries between 1990 and 2019 for 204 countries and territories and 21 regions [11]. However, no analyses highlighting and analyzing the trends and incidence of urolithiasis specifically using GBD study data have been published previously. Using estimates of the disease burden of urolithiasis provided by the GBD study, this study aims to describe and analyze global, regional, and national epidemiologic trends and disease burden of urolithiasis from 1990 to 2019 in order to better understand and address the burden of urolithiasis going forward.

Patients and methods
Data on the age-standardized incidence rate (ASIR) per 100 000 population, age-standardized rate (ASR) of disability-adjusted life years (DALYs) estimated based on the addition of the years lived with disability and the years of life lost, and age-standardized death rate (ASDR), as well as the total for these measures, attributed to urolithiasis were available from the publicly available Global Health Data Exchange (GHDx) query tool [12]. These measures are considered the objective index in understanding trends related to disease occurrence and burden. The GBD study provides estimates of incidence, prevalence, DALYs, and other health indicators for 369 diseases and injuries. Detailed methods of the GBD study have been described previously [11,13,14]. Data from the GBD study on urolithiasis were collected from national and international vital registries of hospital claims and outpatients data, verbal autopsy data, and a systematic literature review. Estimates by age, sex, year, and country were calculated using a Bayesian meta-regression modeling tool, DisMod-MR 2.1, for consistency [15].
We extracted case data for all ages and annual ASRs of these measures of urolithiasis from 1990 to 2019 for 21 regions, including 204 countries and territories. Data were analyzed at the global and regional levels, as well as stratified by the Socio-Demographic Index (SDI), which is based on national income per capita, average years of education of adults, and total fertility rate, to assess geographic and socioeconomic trends.
The average annual percentage change (AAPC) was calculated at the global, regional, and national levels as a summary statistic for the trends in ASRs of incidence, DALYs, and deaths. AAPC is a single number that describes disease occurrence in a population by using the weighted averages of annual percent changes [16]. To calculate the AAPC, Joinpoint Trend Analysis software was used to estimate an underlying model with the best fit for each region's ASRs for urolithiasis. The AAPC of each interval is calculated as the weighted average of the slope of the underlying Joinpoint linear regression lines. This weighted average of slopes is then converted to an annual percentage change. Joinpoint developed a model for each country that combined the best fit of varying numbers of linear regressions y = b0 + b1x + c such that y = ln(ASR) and x = calendar year.
Generalized additive modeling was then used to demonstrate the relationship of country AAPCs with SDI in 2019, which is used as a surrogate for current country socioeconomic profile, as well as with ASRs in 1990 in order to compare the influence of baseline ASRs on change over the study period. Generalized additive modeling is used widely for time series data in health and allows for incorporation of nonlinear relationships into the linear model framework [18][19][20]. Pearson's correlation coefficient and p value were also calculated to determine directionality and significance of the relationship. Significance was determined at the p < 0.05 level.    Fig. 1). When analyzed by GBD region, Eastern Europe demonstrated the highest ASIRs of urolithiasis for all regions from 1990 to 2019, not falling below 4000 cases per 100 000 population throughout the study period (Table 1 and Fig. 1). A country map of ASIRs in 1990 and 2019 is shown in Figure 2. The global age composition of urolithiasis incidence for 1990 and 2019 is shown in Figure 3. Males demonstrated higher rates of global incidence for all age groups in both 1990 and 2019, with the highest rates occurring from ages 50 to 69 yr for both males and females across both years.

Change in deaths
Similarly, total deaths attributed to urolithiasis increased over the study period (Supplementary Table 2 Table 2).

Discussion
This study presents a comprehensive picture of the trends and patterns in incidence, DALYs, and deaths attributed to urolithiasis worldwide. We found that the gross global burden in terms of total cases, deaths, and mortality has increased since 1990, consistent with previous literature [21], while ASRs have decreased globally. These trends, however, are not consistent across countries, sociodemographic categories, and geographic regions.
The burden of disease is shared unequally. Three countries, India, China, and the Russian Federation, were burdened by nearly half of global incident cases in 2019. India itself had the burden of over one-fifth of global incident cases. These three countries also face the greatest number of urolithiasis-attributable DALYs and deaths. As population size is a likely factor in the gross burden faced by these countries, some policymak- ers may prefer to understand these results in terms of rates. Globally, there were 1394 incident cases per 100 000 population in 2019, a decrease from 1696.2 per 100 000 in 1990. The Russian Federation demonstrates the highest ASIR (4541.9 per 100 000) and the second-highest ASR of DALYs (24.7), second to Armenia (33.3). Armenia also had the greatest rates of deaths due to urolithiasis.
The findings of this study are consistent with the epidemiologic transitional model [22]. When examining incidence by SDI quintile, high-middle SDI countries demonstrated the highest ASIR, while low SDI countries had the lowest ASIR in 2019. Incidence rates in lowmiddle and low SDI quintiles have remained stagnant or have even increased, while those in the middle, highmiddle, and high SDI quintiles have seen significant decreases over the study period. Similarly, this study demonstrated regional variation in incidence, with countries in East Asia, high-income North America, and Central Europe demonstrating significant decreases, while regions such as the Caribbean, South Asia, and Andean Latin America demonstrated significant increases. Globally, incidence is higher in males than in females, and incidence is highest in the 50-69-yr age range. While there is a negative global AAPC of À0.7, several countries and regions also demonstrated positive AAPCs. The global ASR of DALYs likewise decreased with an AAPC of À1.6, and all SDI regions had a negative AAPC. Similarly, the ASDR decreased with an AAPC of À2.0 globally between 1990 and 2019, with all SDI regions demonstrating a negative AAPC. However, total DALYs and deaths attributable to urolithiasis have increased globally, and there is variation by GBD study region, with some regions demonstrating positive AAPCs for DALYs and/or deaths.
Previous studies have suggested that the probability of stone formation varies geographically and socioeconomically across the world [9,23]. The trends in incidence and burden by location and national SDI status, as shown in this study, can help elucidate the relationship between stone formation and climate, diet, country development level, and other factors suggested to play a role [4,5,8,9,[24][25][26][27]. A thorough understanding of the cause and effect relationship between these factors and urolithiasis merits further study.
It is important to note that urolithiasis carries substantial risks of its own. Those who develop urolithiasis are at 1.3 times greater risk of developing diabetes mellitus, 1.5 times greater risk of developing hypertension, as well as two times greater risk of developing metabolic syndrome and thus two to four times as likely to develop cardiovascular disease [28][29][30]. These risks further necessitate preventive policy.
Limitations of this study first and foremost include the limitations of the GBD study itself [11]. Primary data were collected from censuses, household survey, civil registration and vital statistics, satellite imaging, and several other sources. Hence, one of several limitations of the study is varying quality of obtained data and, where primary data were not available, the predictive value of modeling efforts. Additionally, urolithiasis types were not distinguished by the GBD study and may differ by regions based on the variables previously mentioned. Therefore, further research into epidemiologic trends of urolithiasis in different parts of the genitourinary tract and of different chemical compositions requires investigation. Additionally, a linear strategy was used to model ASIRs in different regions and SDI quintiles, when, in actuality, some groups may demonstrate an underlying nonlinear relationship. Finally, risk factors related to diet or climate may be related to trends found in this analysis, but more specific proxy variables were unavailable.

Conclusions
In conclusion, total cases, DALYs, and deaths attributed to urolithiasis have increased globally since 1990, while the ASRs of these measures have decreased. Importantly, ASIR in low SDI countries is increasing. With the substantial burden of disease attributed to urolithiasis, global and national strategies to address urolithiasis prevention and treatment are necessary. The distribution and trends regarding incidence, deaths, and DALYs analyzed and presented in this study can help inform policy to better address countryspecific needs moving forward.
Author contributions: Jacob Lang had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Analysis and interpretation of data: Lang, Narendrula.
Drafting of the manuscript: Lang, Narendrula.
Critical revision of the manuscript for important intellectual content: All authors.
Administrative, technical, or material support: None.
Financial disclosures: Jacob Lang certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.