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INTRODUCTION
Chronic kidney disease (CKD) is a progressive disease characterized by gradual renal function deterioration [1]. Among its various causes, type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) are particularly significant [2,3]. Among patients with T1DM, the risk of CKD is markedly elevated due to hyperglycemia-induced renal microvascular damage, leading to T1DM related CKD (T1DM-CKD) [3,4]. Approximately 30% to 40% of T1DM patients develop T1DM-CKD [2]. Simultaneously, T1DM-CKD significantly elevates the risk of cardiovascular disease (CVD) and all-cause mortality, consequently increasing the economic burden on patients and the healthcare systems [5-7].
Recent studies have indicated a persistent increase in the burden of T1DM among global youth populations [8-10]. Adolescents and young adults (aged 15 to 39 years) with T1DM are currently in a critical phase of their physical and social development, and they also contend with health complications and societal pressures [11-13]. Moreover, the prevalence of T1DM-CKD is elevated in young patients, but relevant studies remain limited [9,14]. The Global Burden of Disease (GBD) study, which offers extensive data on prevalence, incidence, mortality and disability-adjusted life years (DALYs), has proven invaluable in analyzing the global burden of various diseases [15-17].
This study aimed to systematically analyze the global burden of T1DM-CKD among adolescents and young adults, and forecast future trends using GBD study 2021 [16]. Our findings indicated a significant increase in the prevalence and incidence of T1DM-CKD, coupled with a decrease in mortality and DALYs. Notably, the trends varied considerably across genders, sociodemographic index (SDI), geographical region, and country. High fasting blood glucose still persisted as the primary risk factor for T1DM-CKD, whereas exposure to extreme temperatures significantly contributed to severe disease burden. The forecast analysis suggested a continued global increase in T1DM-CKD cases by 2035.
METHODS
Data source
This study used data from the GBD study 2021. It is the largest and most comprehensive global observational epidemiological database, covering the global burden of 371 diseases, injuries and 88 risk factors in 204 countries and regions from 1990 to 2021. The GBD study 2021 is publicly available via the Global Health Data Exchange (GHDx) query tool (http://ghdx. healthdata.org/GBD-results-tool). This interactive platform provides comprehensive health metrics including prevalence, incidence, mortality, years of life lost due to premature death, years of life lived with disability, DALYs and their respective rates of change. The methodological framework, including research objectives, data acquisition protocols, and analytical approaches of the GBD study, have been thoroughly detailed in previous literatures [18-20]. Based on etiological factors, CKD was stratified into five distinct categories: T1DM, T2DM, hypertension, glomerulonephritis, and other unspecified causes. T1DM-CKD was identified according to the International Classification of Diseases codes version 9 (ICD-9) and version 10 (ICD-9: 250.41, 250.43; ICD-10: E10.2, E10.21, E10.22, E10.29) [18,19]. For mortality estimation, it was defined (ICD-10: E10.2) [20]. Three standardized tools were mainly used in the GBD 2021 study: Cause of Death Ensemble model (CODEm), spatiotemporal Gaussian process regression (ST-GPR), and Disease Modelling Meta-Regression version 2.1 (DisMod-MR 2.1) for consistency across regions and time. Detailed descriptions of these methods can be found in literature [18,19].
Study population
Our study constituted a secondary analysis of estimates derived from the GBD 2021 study. Utilizing the GHDx query tool (https://vizhub.healthdata.org/gbd-results/), we extracted epidemiological metrics, including prevalence, incidence, mortality, and DALYs rates, for T1DM-CKD in the 15 to 39 years age group from 1990 to 2021, and DALYs for associated risk factors.
Sociodemographic index
The SDI is a composite measure, calculated based on factors such as fertility rate, education level, and per capita income, to assess the socioeconomic development level of a country or region. Its range is 0–1, with higher values indicating higher levels of socioeconomic development. The countries and regions are divided into five SDI areas (low, low-middle, middle, high-middle, and high) to explore the relationship between the burden of T1DM-CKD among adolescents and young adults and socioeconomic development [18,19].
Statistical analysis
Descriptive analysis
Age-standardized rate (ASR) is an important statistical tool that allows for the comparison of disease incidence or mortality rates across different geographic regions and time periods by applying a standard global population structure. We calculated the ASR of T1DM-CKD per 100,000 and reported the 95% confidence interval (CI) according to the GBD algorithm [21].
Joinpoint regression analysis
To assess the time trends of the age-standardized prevalence rate (ASPR), age-standardized incidence rate (ASIR), age-standardized mortality rate (ASMR), and age-standardized disability-adjusted life years rate (ASDR), we employed joinpoint regression analysis. The average annual percentage change (AAPC) and 95% CI were calculated to measure time trends. The criteria for determining trend changes were increase (AAPC >0 and 95% CI not including 0), decrease (AAPC <0 and 95% CI not including 0), or stable (95% CI including 0) [22]. Additionally, we used Pearson correlation analysis to evaluate the correlation between SDI and population indicators and AAPC of T1DM-CKD to assess the strength and direction of their linear relationship in different regions.
Bayesian age-period-cohort model
The Bayesian age-period-cohort (BAPC) model is an advanced statistical tool that integrates prior knowledge of unknown parameters with sample data to estimate posterior distributions and infer these parameters. The BAPC model has shown high accuracy in predicting disease burden [23]. We used the R packages BAPC and integrated nested Laplace approximation (INLA) to predict global disease trends of T1DM-CKD across all age groups and among individuals aged 15 to 39 years from 2022 to 2035. All data analyses were conducted using the open-source software R version 4.3.3 (R Foundation for Statistical Computing, Vienna, Austria).
RESULTS
Global trends of T1DM-CKD among adolescents and young adults
From 1990 to 2021, the prevalence cases of T1DM-CKD among adolescents and young adults increased by 107.5%, reaching 3.32 million, accounting for more than 50% of all age groups (Fig. 1A), while the proportion of incidence rose from 8.42% to 14.92% (Fig. 1B). However, the proportion of mortality and DALYs significantly decreased, consistent with the global trend of the disease (Fig. 1C and D).
In 2021, the ASPR of T1DM-CKD aged 15 to 39 rose to 111.44 per 100,000 (AAPC, 1.33%) (Table 1). Similarly, the ASIR increased to 0.48 per 100,000 (AAPC, 2.19%) (Table 1). However, the ASMR decreased from 0.65 to 0.50 per 100,000 (AAPC, –0.87%), and ASDR declined from 39.45 to 30.61 per 100,000 (AAPC, –0.83%) (Supplementary Table 1).
Notably, compared to other age groups (0–14, 40–64, ≥65 years), the 15–39 years cohort experienced the most substantial increases in both ASPR and ASIR, with AAPCs of 1.33% and 2.19%, respectively (Supplementary Table 2). The result suggested that the young population was facing a severe burden of T1DM-CKD. Furthermore, between 1990 and 2021, the ASIR of T1DM-CKD aged 15–39 showed a notable increase compared to T1DM and other CKD subtypes, with an AAPC reaching 2.19% (Supplementary Fig. 1).
Global trends of T1DM-CKD among adolescents and young adults by genders
Between 1990 and 2021, there were significant gender differences in T1DM-CKD among adolescents and young adults. Except for ASPR, other indicators (ASIR, ASMR, ASDR) were higher in males than in females (Table 1, Fig. 2). By 2021, the ASPR of T1DM-CKD was higher in females (141.48 per 100,000) than in males (82.22 per 100,000) (Table 1). However, the AAPC of ASPR in females (AAPC, 1.31%) was slightly lower than that in males (AAPC, 1.38%) (Table 1, Fig. 2A). The ASIR was lower in females (0.37 per 100,000) than in males (0.58 per 100,000) and the AAPC in females (1.94%) was lower compared to males (AAPC, 2.36%) (Table 1, Fig. 2B). Interestingly, the AAPC of ASMR showed a greater decline in females (–1.37%) than in males (–0.47%). Similarly, the decrease in ASDR was more pronounced in females (AAPC, –1.31%) than in males (AAPC, –0.45%) (Fig. 2C and D, Supplementary Table 1).
SDI regional trends of T1DM-CKD among adolescents and young adults
From 1990 to 2021, the ASPR and ASIR of T1DM-CKD among adolescents and young adults showed an increasing trend across all SDI subgroups (Fig. 3A and B). For prevalence, the ASPR of T1DM-CKD in this age group was the highest in the high SDI region (144.51 per 100,000) and lowest in the low SDI region (92.59 per 100,000) (Table 1). The most significant increase in ASRP was observed in the high-middle SDI region (AAPC, 2.05%), while the smallest increase in ASPR occurred in the high SDI region (AAPC, 0.85%) (Supplementary Fig. 2A). Regarding incidence, the ASIR for T1DM-CKD in this age group was highest in the middle SDI region (0.54 per 100,000) and lowest in low SDI region (0.39 per 100,000) (Table 1). Furthermore, the increase was highest in high-middle SDI region (AAPC, 2.99%) and lowest in high SDI region (AAPC, 1.15%) (Supplementary Fig. 2B).
In contrast to the increasing trends in prevalence and incidence, the ASMR and ASDR of T1DM-CKD in this population showed a decreasing trend across all SDI subgroups from 1990 to 2021 (Fig. 3C and D). In 2021, both ASMR and ASDR were the highest in the middle SDI region (ASMR, 0.76 per 100,000; ASDR, 45.70 per 100,000) and the lowest in the high SDI region (ASMR, 0.16 per 100,000; ASDR, 11.49 per 100,000) (Supplementary Table 1). Notably, the most rapid declines in both ASMR (AAPC, –1.43%) and ASDR (AAPC, –1.3%) were observed in the high-middle SDI region (Supplementary Fig. 2C and D).
Geographic regional trends of T1DM-CKD among adolescents and young adults
Between 1990 and 2021, the prevalence and incidence of T1DM-CKD among adolescents and young adults exhibited an upward trend across 21 regions worldwide (Table 1). In 2021, Eastern Europe demonstrated the highest ASPR (318.85 per 100,000) and a rapid increase (AAPC, 3.1%) (Supplementary Fig. 3A and B). Central Asia reported the highest ASIR (1.88 per 100,000), while the most significant rise was in Eastern Europe (AAPC, 4.2%) (Supplementary Fig. 3C and D). Regarding mortality and DALYs, Oceania had the highest ASMR (2.49 per 100,000) and ASDR (148.14 per 100,000) in 2021(Supplementary Table 1, Supplementary Fig. 3E and G). The most rapid increases were observed in Central Latin America for ASMR (AAPC, 1.63%) and in Australasia for ASDR (AAPC, 1.62%) (Supplementary Fig. 3F and H).
National trends of T1DM-CKD among adolescents and young adults
Data from 204 countries between 1990 and 2021 indicated that there were 80 countries experienced an ASPR higher than the global average, and 124 countries had an ASPR lower than the global average (Supplementary Table 3). By 2021, Canada (553.51 per 100,000) had the highest ASPR, while China (21.73 per 100,000) was the lowest (Fig. 4A). Ireland (AAPC, 3.99%) displayed the most rapid growth (Fig. 4B). In terms of incidence until 2021, among the 204 countries analyzed, 69 countries presented an ASIR above the global average, while 135 were below (Supplementary Table 3). Bulgaria demonstrated the highest ASIR (2.83 per 100,000), with China exhibiting the lowest at 0.06 per 100,000 (Fig. 4C). Albania demonstrated the fastest increase in ASIR (AAPC, 5.16%) (Fig. 4D).
Regarding mortality, countries with middle to high SDI tended to have higher ASMRs in 2021, with 52 countries above the global average and 152 below (Supplementary Table 4). American Samoa (8.37 per 100,000), Nauru (7.37 per 100,000), and the Marshall Islands (7.02 per 100,000) exhibited the top three ASMRs, while Norway (0.01 per 100,000) demonstrated the lowest (Supplementary Fig. 4A). Ukraine (AAPC, 9.79%), Armenia (AAPC, 4.36%), and Lesotho (AAPC, 3.76%) had the fastest growth, whereas Poland (AAPC, –4.60%), Singapore (AAPC, –3.69%), and Republic of Korea (AAPC, –3.47%) displayed the most substantial decreases (Supplementary Fig. 4B). For DALYs, T1DM-CKD in this age group increased in ASDR in 65 countries and decreased in ASDR in 139 countries globally, with the fastest growing and largest decreasing countries consistent with ASMR (Supplementary Table 4, Supplementary Fig. 4). American Samoa had the highest ASDR (490.59 per 100,000), with Iceland having the lowest at 1.46 per 100,000 (Supplementary Fig. 4C). Ukraine demonstrated the fastest increase in ASDR with an AAPC of 6.91% (Supplementary Fig. 4D).
Factors influencing the AAPC in the global burden of T1DM-CKD
A positive correlation was found between countries’ SDI levels and ASPR or ASIR in 2021 (P<0.01) (Supplementary Fig. 5A and B). Furthermore, we found that the AAPCs of ASPR and ASIR were positively correlated with the SDI levels (P<0.05) (Supplementary Fig. 6A and B). These findings suggest that the increasing trends in ASPR and ASIR for T1DM-CKD are closely linked to regional SDI levels. However, no significant correlations were observed between SDI levels and ASMR or ASDR, nor between SDI levels and their corresponding AAPCs (Supplementary Figs. 5C and D, 6C and D).
Risk factors for T1DM-CKD among adolescents and young adults
In this study, we analyzed the association between DALYs and various risk factors for T1DM-CKD among adolescents and young adults, including high fasting glucose, environmental/occupational risks, and temperature extremes (hypothermia and hyperthermia) (Supplementary Table 5). The results showed that high fasting blood glucose remained the major risk factor for T1DM-CKD among adolescents and young adults. In young T1DM-CKD patients, the ASDR due to high fasting glucose was 16.99 per 100,000 in 2021, but showed a decreasing trend (AAPC, –0.08%). Notably, high SDI countries experienced the most rapid increase in heat risk from 0.05 per 100,000 in 1990 to 0.25 per 100,000 in 2021 (AAPC, 5.39%). Globally, environmental/occupational risks decreased from 2.26 per 100,000 to 1.44 per 100,000 (AAPC, –1.41%), across most SDI regions. However, a slight increase was observed in high SDI regions, where the rates rose from 0.73 per 100,000 to 0.82 per 100,000 (Supplementary Table 5).
Forecasts of global burden of T1DM-CKD among adolescents and young adults
The forecast analysis indicated that the prevalence, incidence, mortality and DALYs of T1DM-CKD are expected to continue to increase by 2035 in all age groups compared to 2021(Fig. 5A). Among adolescents and young adults, the number of T1DM-CKD cases was expected to decline to 2.864 million by 2035, with an ASPR of 89.67 per 100,000 (Fig. 5A, Supplementary Table 6). The cases of incidence and ASIR showed a slight increasing trend, while mortality cases, ASMR, DALYs, and ASDR demonstrated modest declines (Fig. 5B-D). Moreover, by 2035, the 15 to 39 age group would still maintain over 40% of the total prevalence across all ages, with incidence proportion increasing to 16%. Notably, both mortality and DALYs proportions displayed downward trends (Fig. 5E).
DISCUSSION
The increasing prevalence of T1DM-related complications in recent years has led to growing attention on young patients with T1DM-CKD [24,25]. This study demonstrated a significant upward trend in the burden of T1DM-CKD among adolescents and young adults from 1990 to 2021. This age group accounted for over half of the global prevalence of T1DM-CKD, and its prevalence and incidence were projected to continue to increase. Global epidemiological studies have observed a trend towards earlier onset of T1DM, which may significantly contribute to the rising burden of T1DM-CKD among young adults [8,9,26]. Data reported from Philadelphia indicated that the incidence of T1DM in children exhibited a steadily increasing trend from 2000 to 2004, with the incidence in children under 5 years old increasing by 70% [27]. This trend may be attributed to a variety of factors, including environmental changes, genetic susceptibility and lifestyle changes [28-30]. For instance, environmental factors such as early exposure to viral infections, air pollution, and exposure to modern chemicals might increase the risk of T1DM among young children [28,29]. Furthermore, alterations in dietary structure might also affect the development of the immune system and promote the early onset of T1DM, such as premature intake of infant formula or cow’s milk [30]. Additionally, the overweight and obesity have increased significantly globally, which not only increases the incidence of T1DM in children but also contributes to the burden of T1DM-CKD among the young population [31,32].
Significant gender differences existed in the burden of T1DM-CKD among individuals aged 15 to 39 years. The incidence, mortality, and DALYs were notably higher in males, potentially due to gender-specific factors such as lifestyle choices, smoking, blood pressure management, and hormonal variations [33,34]. Furthermore, male patients with T1DM-CKD have a higher risk of developing severe complications like end-stage renal disease (ESRD) compared to females [35,36]. Consequently, males display a poorer prognosis. Conversely, the prevalence of T1DM-CKD was significantly higher in females. While this observation aligns with previous findings, the data found in this study differ from those of previous reports [37]. This discrepancy may be due to methodological changes in the GBD study 2021, including participant inclusion criteria adjustments and data modeling alterations [19,21]. Studies have found that female T1DM patients face challenges in controlling glycemic levels, body mass index, and managing incidences of hypoglycemia and diabetic ketoacidosis [34,36,38]. These challenges might diminish the protective effects of female hormones, resulting in a higher prevalence of T1DM-CKD among young females. Further studies are necessary to elucidate the potential mechanisms.
Beyond gender, the SDI also significantly impacted the global burden of T1DM-CKD. As an indicator of socioeconomic development levels, the SDI elucidates the characteristics of the burden of disease in different regions. For instance, regions with low SDI primarily suffer from communicable, maternal, neonatal, and nutritional diseases (CMNNs), while regions with high SDI have a severe burden of noncommunicable diseases [15,19,39]. The burden of T1DM-CKD, a chronic metabolic noncommunicable disease, is more pronounced in developed regions [37]. Our study demonstrated that regions with high-middle and middle SDI experienced the highest prevalence and incidence of T1DM-CKD, yet these regions had a significant reduction in mortality and DALYs. Notably, the prevalence and incidence of T1DM-CKD was rapidly increasing in regions with low-middle and low SDI, likely driven by global T1DM trends and regional disparities in health policies [8]. These results underscore the need to enhance prevention and control strategies of T1DM-CKD across different regions.
T1DM-CKD is a complex disease influenced by multiple factors [2]. In this study, despite a reduction in DALYs associated with high fasting glucose, it persisted as a predominant risk factor for T1DM-CKD. This finding indicates the essential role of glycemic control in disease management, and reaffirms the critical role of glycemic control in preventing and decelerating the progression of T1DM-CKD [40,41]. Furthermore, our research revealed that extreme temperatures (low and high) significantly influenced the DALYs of T1DM-CKD, while the high temperature was associated with substantial increases in DALYs. This finding is consistent with recent studies on the impact of extreme temperature on CKD [42,43]. Temperature changes would affect insulin sensitivity [44]. Moreover, extreme temperature exacerbates the risk of diabetes mellitus, possibly because extreme temperature would increase the incidence of obesity, insulin resistance, and CVD [45,46]. However, since the data of risk are estimated and bases on the cross-sectional design in the GBD database [18], the correlation between extreme temperature and T1DM-CKD should be cautiously interpreted. Future cohort studies incorporating multivariate analysis are necessary to substantiate the impact of extreme temperatures on T1DM-CKD.
Remarkably, the projection model demonstrated an upward trend in the prevalence and incidence among young patients with T1DM-CKD, reflecting a significance towards younger onset. This highlights the critical need for improved screening, early diagnosis, and prompt intervention in young T1DMCKD patients. Nevertheless, the forecasts also disclosed encouraging trends: The prevalence, mortality and DALYs associated with T1DM-CKD in the 15 to 39 age group continued to show a declining trend. Furthermore, their proportion relative to global indicators also contracted. This improvement may be attributed to advancements in medical technology, enhanced patient education and optimized allocation of healthcare resources worldwide. Additionally, the promising trend may be attributed to the introduction of sodium-dependent glucose transporter 2 (SGLT2) inhibitors, a game-changing treatment for diabetic nephropathy and CKD [47]. SGLT2 inhibitors have demonstrated the potential to not only reduce the risk of CKD in patients with DM by 30% to 49%, but also to significantly decrease the risk of ESRD and cardiovascular events [48,49].
This study has several limitations. (1) Data availability and quality vary across regions. (2) Owing to the complexity of T1DM-CKD, certain potential risk factors or interactions may not have been thoroughly considered, and their varied impact on different subgroups (e.g., age, genders) might be overlooked. (3) Since the data of GBD study 2021 were derived from systematic data processing and modeling methods, it is not feasible to access the source data for multivariate corrections. Future research should delve into these intricate relationships to enable more precise risk assessments and intervention strategies.
In conclusion, the global burden of T1DM-CKD among individuals aged 15 to 39 years had increased from 1990 to 2021 and was projected to rise further by 2035. Notable disparities in the disease burden were observed across gender, SDI levels, and geographic regions. This study provides critical scientific evidence for improving the prevention and treatment of T1DM-CKD in young populations globally. It underscores the importance of early diagnosis and intervention among young patients with T1DM-CKD. Additionally, future research should delve into the underlying mechanisms of these disparities to develop more precise and personalized intervention strategies.
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