The data in this investigation was extracted from GBD 2021 study database. This study conducted a thorough and systematic assessment of 371 diseases and injuries, 81 risk factors across 204 nations and territories, spanning the years 1990 to 2021 (20). Based on the geographical distribution, 204 nations and territories were grouped into 21 super regions and 54 regions following GBD taxonomy, which also incorporates World Bank classifications (21). Furthermore, these nations and territories were classified into five socio-demographic index (SDI) levels (low, low-middle, middle, high-middle, and high SDI scores) according to SDI index that ranges of 0 to 1. This index indicates a nation’s or region’s progress in relation to birth rates, educational achievement, and per capita income.

In this study, we gathered data on the numbers of cases and the corresponding ASRs of T2DM-related DKD attributable to LPA collected from 1990 through 2021, including death, DALYs, years of life lost (YLLs), and years lived with disability (YLDs). The calculation of DALYs involves summing YLDs and YLLs. We utilized these metrics to characterize the disease burden. Each rate is reported per 100000 individuals, with 95% uncertainty interval (UI) (22) at gender, age, SDI, GBD regions, and countries. The dynamics of DKD due to LPA were analyzed by calculating Estimated Annual Percentage Change (EAPC) to identify temporal changes in illness burden with 95% Confidence Intervals (CIs) of EAPCs by linear modeling from 1990 to 2021. In the GBD study, the assessment of disease burden attributable to LPA was aimed at adults aged 25 years and older; the population was further segmented into 15 age groups, each spanning 5 years: 25-29, 30-34, 35-39, 40-44, 45-49, 50-54, 55-59, 60-64, 65-69, 70-74, 75-79, 80-84, 85-89, 90-94, and 95+ years. The ethical review by the Ethical Board of People’s Hospital of Ningxia Hui Autonomous Region was not required for this study protocol, since GBD data were anonymized and presented in an aggregated format.

In the GBD 2021 study, DKD due to T2DM was defined as ICD-10 code E11.2-E11.29 (23). Specifically, the definition of T2DM indicates a fasting plasma glucose value of ≥7 mmol/L (≥126 mg/dL) or administration of diabetes medications or insulin (24).DKD is characterized by persistent kidney dysfunction lasting over three months, identified through either an increased urinary albumin-to-creatinine ratio (UACR ≥30 mg/g) and/or lower estimated glomerular filtration rate (eGFR <60 mL/min/1.73 m²) (25).

Data on physical activity (PA) were collected using standardized surveys: the International Physical Activity Questionnaire (IPAQ) and the Global Physical Activity Questionnaire (GPAQ). More specifically, PA was quantified in total metabolic equivalent (MET) minutes weekly, integrating the frequency and duration of various activities coupled with associated MET values based on each activity’s intensity (26). PA levels were classified into four categories according to the quartiles of total global METs: inactive (<600 MET-minutes/week), low-active (600–3999 MET-minutes/week), moderately active (4000–7999 MET-minutes/week), and very active (>=8000 MET-minutes/week) (27). According to GBD 2021 study, the theoretical minimum risk exposure level of physical inactivity ranged from 3600 to 4400 MET-minutes/week, therefore, LPA was defined as <3600 MET-minutes/week (28).

Initially, the cases of deaths, DALYs, YLLs, and YLDs of DKD due to LPA and their corresponding ASRs were documented for the year 2021 at the global level and across various subcategories, including age, sex, SDI, GBD regions, and nations. Second, we assessed the worldwide evolution of disease burden across distinct areas and subtypes between 1990 and 2021. The EAPC was derived from ASRs calculations to assess the change over time with linear regression model. A hierarchical cluster analysis was conducted utilizing the EAPC data to elucidate the evolving patterns in the DKD attributable to LPA pressure across each GBD region. This analysis aimed to pinpoint regions exhibiting analogous trends in disease burden over time. All 54 GBD regions were grouped into four distinct categories on associated EAPC values: (1) significant increase, (2) minor increase, (3) remained stable or minor decrease, and (4) significant decrease. We further used the Slope Index of Inequality and Concentration Index—standard metrics for absolute/relative gradient inequality—to measure the distribution inequality across the globe and five SDI regions. Health inequality monitoring underpins evidence-based health planning and refines initiatives to narrow health outcome disparities.

At last, the future burden of DKD attributable to LPA from 2021 to 2050 was projected using two advanced modeling approaches: AutoRegressive Integrated Moving Average (ARIMA) and Exponential Smoothing (ES) models. The ARIMA excels at capturing complex patterns, including trends and seasonality, while the ES model prioritizes recent observations, providing a robust and comprehensive framework for forecasting future disease burden across multiple dimensions. Statistical analyses were performed using R software (v4.4.2) for database construction, management, and analytical procedures.

The world burden of DKD associated with LPA in 1990 and 2021 is shown in Tables 1 , 2 and Supplementary Table S1 , Supplementary Table S2 . In 1990, the DKD cases linked to LPA resulted in 11253 (95%UI: 4651-18635) deaths globally, with an age-standardized deaths rate of 0.33 (95%UI: 0.14-0.54) per 100000 people. Overall, there were 297698 (95%UI: 114900-493524) DALYs, consisting of 66127 (95%UI: 24806-116887) YLDs and 231571 (95%UI: 91970-388024) YLLs. By 2021, DKD due to LPA accounted for 30835 (95%UI: 12346-51646) deaths and 698484 (95%UI: 275039-1158032) DALYs, with 128134 (95%UI: 49280-226865) YLDs and 570350 (95%UI: 226001-965286) YLLs. The corresponding ASRs of death and DALYs were 0.38 (95%UI: 0.15-0.63) and 8.19 (95%UI: 3.21-13.6) per 100000 individuals, respectively.

As depicted in the bars of Figure 1 , during 1990 to 2021, there has been a rise in the cases of deaths, DALYs, and their components (YLDs, YLLs) related to the disease. The ASRs of these metrics demonstrated a general upward trend. The EAPC was 1.22 (95%CI: 0.83-1.61) for death, 0.83 (95%CI: 0.55-1.12) for DALYs, 0.33 (95%CI: 0.06-0.60) for YLDs, and 0.96 (95%CI: 0.67-1.25) for YLLs.

There were some sex disparities in the DKD attributable to LPA in terms of deaths and disability outcomes (DALYs, YLDs, YLLs), as illustrated in the bar charts for 2021 ( Figure 2 ). After factoring in the effects of population growth and demographic aging, it was found that males generally face a greater disease burden than females based on regarding ASRs. Specifically, the age-standardized deaths rate for males was 0.39 (95%UI: 0.16-0.66) per 100000 males and for females at 0.36 (95%UI: 0.15-0.6) per 100000 females. A similar difference was observed in the ASRs of DALYs and YLLs ( Table 2 , Supplementary Table S2 ). However, when considering the raw numbers of these four measures, females had slightly higher counts than males. In 2021, there were 17053 (95%UI: 6929-28269) deaths among females compared to 13783 (95%UI: 5524-23345) among males ( Table 1 , Figure 2 ).

From 1990 to 2021, the deaths and disability outcomes numbers demonstrated a steady increase for both sexes, with females consistently reporting higher figures than males. Regarding the DALYs rate, both genders exhibited a fluctuating pattern. Initially, there were fluctuations, with a significant spike around 2000, followed by a decline until around 2015-2020, after which an upward trend emerged again ( Figure 3 ). The EPAC was 0.14 (95%CI: 0.06-0.21) for females and 0.12 (95%CI: 0.08-0.17) for males ( Table 2 ). The ASR of deaths and YLLs exhibited a generally upward trend with minor variations, while the age-standardized YLDs rate presented a downward trend. For females, the EPAC was -0.25 (95%CI: -0.36–0.14) and for males was -0.47 (95%CI: -0.56–0.38). ( Supplementary Table S1 ; Figure 3 ). This evidence underscores a significant worsening of the overall disease burden for both sexes.

In 2021, the cases and ASRs of deaths and DALYs and its components across different age groups were analyzed ( Figure 4 .). The ASRs of four metrics rose steadily with age, except for YLDs in the 95+ group. Here, the ASR of YLDs dropped to 4.36 (95%UI: 1.7-7.88) per 100,000 population, showing a decline relative to other age groups( Supplementary Table S1 ). The numbers of these measures initially rose with age, peaking in the 70–74 category, then decreased. For the number of deaths, however, a more prominent peak was noted in 80–84 age stratum with 4508 (95%UI: 1824-7544) death cases ( Table 1 ).

Based on the analysis of changing trends across age cohorts over three decades. The ASRs of deaths, DALYs, and its components for age groups above 40 years showed an increasing trend ( Figure 5 ). We observed the greatest rise in the group aged 95 and above, which showed an EPAC of 1.72 (95%CI: 1.60-1.85) for death, 1.62 (95%CI: 1.50-1.73) for DALYs, with 1.67 (95%CI: 1.55-1.79) for YLLs ( Tables 1 , 2 , Supplementary Tables S1 , S2 ). Conversely, YLD age-standardized rates consistently decreased in the 60+ demographic cohort. The most significant decrease was in the 90–94 years group, with an EAPC of -1.20 (95%CI: -1.24–1.15). The numbers of the four indicators showed increasing trends in most age groups ( Tables 1 , 2 , Supplementary Tables S1 , S2 , Figure 5 ).

In 2021, the burden of DKD due to LPA stratified by SDI quintiles showed distinct differences. The middle SDI region exhibited the highest disease burden. Specifically, the figures for deaths, DALYs, and corresponding age-standardized rates were 11476 (95%UI: 4552-19421), 269337 (95%UI: 104002-454534), 0.49 (95%UI: 0.19-0.83) per 100000 people, and 10.35 (95%UI: 4.04-17.29) per 100000 people, respectively ( Figure 6 , Tables 1 , 2 ). In the cases of four measures, high-middle and high SDI regions followed closely behind. However, these two regions showed relatively lower ASRs of deaths, DAYLs, and YLLs compared to others ( Figure 6 ).

Between 1990 and 2021, the high SDI region experienced the most notable surge in age-standardized death rates among the five SDI regions, displaying an EAPC of 1.19 (95%CI: 1.09-1.29), followed by high-middle SDI with an EAPC of 0.2 (95%CI: 0.06-0.33) ( Table 1 , Figure 7 ). In contrast, the other SDI regions exhibited declining trends in the age-standardized mortality rate. The ASRs of DALYs and YLLs showed a consistent distribution pattern ( Table 2 , Supplementary Table S2 ). However, analysis of age-standardized YLDs rates revealed consistent increases across all SDI quintiles over three decades, most dramatically in middle SDI populations ( Figure 7 , Supplementary Table S1 ).

The disease burden of DKD attributable to LPA in 2021, along with its trend, was compared across 54 GBD regions and 204 nations and territories.

In 2021, Andean Latin America possessed the largest ASRs for deaths, DALYs, and YLLs, reaching 0.86/100000 (95%UI: 0.34-1.45), 17.77/100000 (95%UI: 7.19-30.48), and 16.78/100000 (95%UI: 6.85-28.78), respectively, across 54 GBD regions. Conversely, Eastern Europe had the lowest health burden, with ASRs of 0.06/100000 (95%UI: 0.02-0.1) for deaths, 1.93/100000 (95%UI: 0.71-3.31) for DALYs, and 0.97/100000 (95%UI: 0.36-1.66) for YLLs ( Supplementary Tables S3 – S6 ). Asia reported the highest figures for deaths and DALYs, with 18,459 (95% UI: 7,271-32,091) and 425,214 (95% UI: 163,523-727,831), respectively. followed by Basic Health System. Similar disparities were also evident in the number of YLDs and YLLs for the disease ( Supplementary Tables S3 – S6 , Figure 8 ).

Between 1990 and 2021, the majority of 54 GBD regions exhibited a rising pattern in ASRs of deaths and DALYs. High-income North America demonstrated the pronounced escalations in both metrics with EAPCs of 3.16 (95%CI: 2.51-3.81) and 2.53 (95%CI: 1.97-3.09) per 100,000 individuals, respectively. Conversely, Southern Sub-Saharan Africa experienced a decline in the ASRs of deaths and DALYs ( Supplementary Tables S3 , S4 ). After a comprehensive analysis of the EAPC of all indicators and cluster analysis, it was determined that DKD caused by LPA burden increased slightly in 15 areas like World Bank Upper Middle Income regions. In 15 regions, including Africa, the burden remained stable or decreased slightly. A significant decrease was observed in 15 regions, notably Southern Sub-Saharan Africa, while a significant increase occurred in 9 regions, including certain North American regions ( Figure 9 ).

In 2021, China reported the greatest death cases from DKD attributable to LPA, with 8453 (95%UI: 3279-14480) cases, followed by the United States of America with 3323 (95%UI: 1393-5372) cases and India (2844 (95%UI: 1088-5036)) cases in 204 countries ( Supplementary Tables S3 ). A large number of countries, predominantly covering most of Africa, extensive parts of Europe, Australia, and various other dispersed regions worldwide, had a relatively low number of death cases, ranging from 0 to 1000 ( Figure 10A ). The distribution of DALYs, YLDs, YLLs across countries showed a consistent pattern ( Supplementary Tables S3 , S6 , Figure 10B , Supplementary Figure S1 ). American Samoa (4.36/100000 (95%UI: 1.78-7.46)) and Micronesia (Federated States of) (2.93/100000 (95%UI: 1.04-5.15)) had the highest ASR of death in 2021. Similar results can also be found in the ASR of DALYs and its components ( Supplementary Tables S3 – S6 , Figures 10C, D , Supplementary Figure S1 ).

From 1990 to 2021, concerning ASRs, Poland and Czechia exhibited a downward trend of deaths and YLLs. Poland experienced the most pronounced decrease in the death rate, with an EAPC of -2.28 (95%CI: -3.01–1.54) and -2.68 (95%CI: -3.4–1.95) in the YLLs rate. Luxembourg also showed a remarkable decline, with substantial drops in the EAPC of multiple metrics. The EAPC for the age-standardized deaths rate was -2.37 (95%CI: -3.09–1.65), for DALYs rate was -2.78 (95%CI: 3.4–2.16), for YLDs rate was -3.08 (95%CI: -3.61–2.54), and for YLLs rate (-2.59 (95%CI: -3.28–1.9) ( Supplementary Tables S3 – S6 . Figure 11 , Supplementary Figure S2 ). Conversely, Ukraine and Armenia witnessed significant increases. Ukraine had the most considerable growth in the death rate with an EPAC of 13.24 (95%CI: 11.74-14.75) and 13.72 (95%CI: 12.16-15.3) for YLLs rate. Armenia followed, with increases in the death rate (EAPC: 95%CI: 8.22 (7.4-9.05)) and YLLs rate (EAPC: 95%CI: 7.86 (6.99-8.74)). American Samoa and Mauritius showed a relatively significant rise in the age-standardized DALYs rate, with EPACs of 4.58 (95%CI: 3.82-5.35) and 4.22 (95%CI: 3.73-4.71), respectively. Additionally, Mauritius had an upward trend in the YLDs rate (EAPC: 2.59 (95%CI: 2.23-2.95)), trailed by the Republic of Korea, Singapore, and Japan ( Supplementary Tables S3 – S6 . Figure 11 , Supplementary Figure S2 ).

Significant absolute and relative inequalities in DKD attributable to LPA.

burden were observed across socioeconomic development level ( Figure 12 ). As demonstrated by the slope index of inequality, the crude death rate exhibited a negative correlation with the relative SDI rank; there was a decrease of -0.06 (95% CI: -0.29-0.16) deaths per 100,000 across globe and five SDI regions in 1990, which showed a downward trend of -0.2 (95% CI: -1.09-0.7) in 2021 as the SDI rank increased ( Figure 12A ), though the absolute death rates in 2021 were generally higher.

than in 1990 for most SDI ranks. The cumulative fraction of deaths by SDI-ranked population further provided relative gradient inequality in disease mortality burden ( Figure 12B ), In 2021, the cumulative distribution of deaths showed a steeper increase at lower SDI ranks compared to 1990, indicating a greater concentration of mortality burden in populations with relatively lower sociodemographic development over time.

In summary, the concentration index, a measure of relative inequality, reinforced this trend, with values of -0.469 in 1990 and -0.47 in 2021. These findings indicated that the mortality burden of DKD attributable to LPA was disproportionately concentrated in populations with lower SDI. More importantly, there was a marginal worsening of mortality burden inequality by SDI from 1990 to 2021. Similar health disparities were observed for DALYs ( Figures 12C, D ),YLDs and YLLs ( Supplementary Figure S3 ).

The forecasts derived from the ARIMA and ES models suggest an upward trend in the cases of deaths, DALYs, YLDs, and YLLs associated with DKD due to LPA for both genders globally from 2021 to 2050. ( Figures 13 , 14 ). Moreover, both models forecast a slight increase or stable trends in the ASRs of these four metrics for both males and females. Specifically, the ARIMA model forecasts a rise in death cases to 32623 for females and 27035 for males, with DALYs projected to reach 856848 for females and 640159 for males ( Figure 13 ). Meanwhile, the ES model forecasts an increase in mortality cases to 22598 among females and 18029 among males, and the number of DALYs will increase to 517922 in females and 414402 in males ( Figure 14 ).