The Pandemic of Diabetes and Kidney Disease

The rising prevalence of diabetes, hypertension, and obesity is largely responsible for a global pandemic of chronic kidney disease (CKD), which is associated with adverse health outcomes, including kidney failure, cardiovascular disease, and death. The public health and societal burdens associated with this pandemic are considerable because of the high cost of treating these patients and the loss of productivity from disability. These problems are greatly amplified among those in low-income and middle-income countries, where 78% of the nearly 700 million persons with CKD reside. In this review, we briefly examine the role of diabetes in this pandemic of CKD.

The International Diabetes Federation estimates that in 2019, 463 million adults worldwide had diabetes, of whom 90% had type 2 diabetes (1). Half of those with diabetes are unaware they have the disease, and 79% of them live in low-income and middle-income countries. The International Diabetes Federation projects a 65% increase in the number of people with diabetes by 2045; thus, within 26 years, 762 million people, or 9.6% of the adult world population, are expected to have diabetes (Figure 1). Factors responsible for the increasing prevalence of diabetes include population growth and aging, the frequency and severity of obesity, and exposure to diabetes in utero, which now affects one in six live births globally. The prevalence of diabetic kidney disease is increasing worldwide alongside the rising prevalence of diabetes, so the magnitude of the pandemic of diabetic kidney disease is expected to increase into the foreseeable future.

Figure 1.

Prevalence of diabetes among adults (20–79 years) in International Diabetes Federation Regions, by age-adjusted comparactive diabetes prevalence [1].

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Serial cross-sectional surveys of adults with diabetes by the National Health and Nutrition Examination Survey found that the prevalence of diabetic kidney disease in the United States (defined by a persistent urine albumin-to-creatinine ratio of ≥30 mg/g, or a persistent estimated GFR [eGFR] of <60 mL/min per 1.73 m2), has not changed appreciably during 1988 to 2014. The prevalence was 28.4% from 1988 to 1994 and 26.2% from 2009 to 2014; thus, about 8 million of the more than 30 million people in the United States who have diabetes are affected (2). The prevalence of persistent albuminuria, however, declined from 20.8% to 15.9% during that study period, and the prevalence of persistently low eGFR increased from 9.2% to 14.1%. The lower prevalence of albuminuria over time was observed only among non-Hispanic white adults and those younger than 65 years, whereas the higher prevalence of low eGFR was observed among all ages and races or ethnicities. The increasing average duration of diabetes and improvements in diabetes management over time may be responsible for the evolving clinical presentation of diabetic kidney disease (2). Estimates from the 2017 global burden of disease study of diabetic CKD among 21 geographic regions are generally consistent with these findings, suggesting that within diabetic populations in most regions, the prevalence of diabetic kidney disease has remained fairly stable since 1990; however, there are important regional differences. For example, the highest prevalence of diabetic kidney disease is found in Oceania and Eastern Europe, whereas the lowest is found in Western Europe (Figure 2) (3). Despite the relative regional stability of diabetic kidney disease prevalence among those with diabetes, the rapidly increasing prevalence of diabetes worldwide means that the total number of cases of diabetic kidney disease will continue to increase in proportion to the prevalence of diabetes.

Figure 2.

Prevalence of diabetic kidney disease among 21 geographic regions, stratified by sex, in 1990 and 2017, per 1000 capita [3].

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The proportion of incident ESKD attributable to diabetes among the general population also varies widely among countries, ranging from 10% to 67% in 2016 among countries that report these data (Figure 3) (4). In the United States, 47% of incident ESKD in 2016 was attributable to diabetes. Many of the countries with high proportions of incident CKD attributable to diabetes have experienced steep increases in the number of people with ESKD during the past 2 decades in response to a rising prevalence of type 2 diabetes. Malaysia, South Korea, and the Philippines, for example, have each more than doubled their diabetes-related ESKD incidence during the 2 decades ending in 2016 (Figure 4). Declines in incident ESKD due to diabetes have been observed among some European countries, including Austria, Belgium, Denmark, Finland, and Sweden, where a high proportion of diabetes is type 1 (1).

Figure 3.

Percentage of incident ESKD caused by diabetes in 2016, by country [4].

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Figure 4.

Trends in the unadjusted incidence of diabetes-related ESKD, 2003–2016 [4]. The countries with the largest average yearly change in ESKD incidence from 2003 to 2016 are represented, plus the United States.

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An Australian study in which analyses were restricted to the diabetes population found that the annual incidence of ESKD was stable among those with type 1 diabetes but increased progressively among those with type 2 diabetes; the increase was caused in part by a trend toward an earlier age at onset of type 2 diabetes (5). Moreover, the incidence of ESKD was four times as high among indigenous people with diabetes than among nonindigenous people, with poorer nutrition, higher blood pressure, obesity, recurrent infections, smoking, and limited access to healthcare playing roles in this disparity.

In the United States, improvements in diabetes care have contributed to a 68% decline in cardiovascular events from 1990 to 2010 among people with diabetes (6). A decline in ESKD incidence attributable to diabetes was also observed during the same period, but it was more limited (28%), partly because cardiovascular disease is an important competing health event, and the dramatic reduction in cardiovascular disease events increased the likelihood that people with diabetes would progress to ESKD (6). Unfortunately, these declines in diabetes complications stalled or reversed after 2010, particularly among young and middle-aged adults, and the reasons for the resurgence in diabetes complications are unclear. Factors may include the increasing prevalence of obesity and also inconsistent clinical care, which is attributable in part to rapidly escalating costs that make care unaffordable for many (7). The effects of a resurgence in diabetes complications on future trends in diabetic kidney disease are uncertain because a disproportionate increase in fatal cardiovascular events could ameliorate the risk of diabetic kidney disease.

The onset of type 2 diabetes among youth is a rapidly emerging problem that affects populations worldwide and is driven by an increasing prevalence and severity of obesity among children and adolescents. Intrauterine exposure to maternal hyperglycemia, which occurs among one in six live births worldwide, further enhances the risk of obesity and type 2 diabetes among the offspring during childhood and adolescence, and it impairs the development of the fetal kidneys, reducing nephron development among humans and in animal models. Among adolescents and young adults with youth-onset diabetes, the prevalence of diabetes complications—particularly diabetic kidney disease—and other comorbidities is higher among those with type 2 diabetes than among those with type 1 diabetes (8).

Among the Pima Indians, a group of Native Americans living in central and southern Arizona, the contribution of youth-onset type 2 diabetes and of hyperglycemia in utero on the development of ESKD have been studied extensively because of the rapidly increasing prevalence of youth-onset type 2 diabetes among this population since the 1960s. The onset of type 2 diabetes among Pima Indians younger than 20 years is associated with a nearly fivefold increased incidence of ESKD between 25 and 54 years of age, compared with later onset of diabetes, and the longer duration of diabetes by middle age among those who received their diagnoses before the age of 20 years is largely responsible for this finding (9). Intrauterine diabetes exposure increased nearly fourfold among the Pima Indians during the 30 years from 1967 to 1996, and the prevalence of youth-onset type 2 diabetes doubled during this period (10). This intrauterine exposure to diabetes was associated with a fourfold higher incidence of diabetes-related ESRD in individuals before the age of 45 years than in those without this exposure (11).

Development of the fetal kidneys is also adversely affected by low birth weight, preterm birth, and vitamin A deficiency during pregnancy—exposures more likely to occur among persons from low-income and middle-income countries and among disadvantaged persons from high-income countries (12). Together, the effects of youth-onset type 2 diabetes and factors that adversely affect developmental programming of the kidneys are likely to exert a growing influence on the pandemic of diabetic kidney disease among populations worldwide in the coming years.

In conclusion, a global increase in the prevalence of diabetes is fueling a pandemic of diabetic kidney disease. The increasing prevalence and severity of obesity among children and young adults is shifting the onset of type 2 diabetes to younger ages and into the childbearing years, which is adversely affecting fetal kidney programming and further exacerbating the pandemic. Improvements in medical management have increased longevity, resulting in an aging population that is also at increased risk for diabetes and its complications. Advances in medical care have slowed the progression of diabetic kidney disease, but in low-income and middle-income countries and disadvantaged people in high-income countries, who together bear much of the disease burden, treatments are costly and may not be readily available to patients. These observations illustrate the urgency of identifying the underlying pathogenetic mechanisms of diabetic kidney disease and finding new, more efficacious therapies to treat them. Efforts to prevent the development of type 2 diabetes, or to delay its onset with lifestyle interventions, are also fundamental to stopping this advancing pandemic.

Disclaimer

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Acknowledgment

This research was supported by the Intramural Research Program at the National Institute of Diabetes and Digestive and Kidney Diseases.

References

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Pavkov ME, et al Effect of youth-onset type 2 diabetes mellitus on incidence of end-stage renal disease and mortality in young and middle-aged Pima Indians. JAMA 2006; 296:421–426. doi:10.1001/jama.296.4.421P

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Dabelea D, et al Increasing prevalence of Type II diabetes in American Indian children. Diabetologia 1998; 41:904–910. doi: 10.1007/s001250051006

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Pavkov ME, et al Effect of intrauterine diabetes exposure on the incidence of end-stage renal disease in young adults with type 2 diabetes. Diabetes Care 2010; 33:2396–2398. doi: 10.2337/dc10-0811

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Friedman D, Luyckx VA. Genetic and developmental factors in chronic kidney disease hotspots. Semin Nephrol 2019; 39:244–255. doi: 10.1016/j.semnephrol.2019.02.002

October-November 2020 (Vol. 12, Number 10 & 11)