|Home | About | Journals | Submit | Contact Us | Français|
Pima Indians from the Gila River Indian Community in Arizona have a high incidence rate of type 2 diabetes, and kidney disease attributable to diabetes is a major cause of morbidity and mortality in this population. Since 1965, each member of the population at least 5 years of age is invited to participate in a research examination every other year. During the past 43 years, the overall incidence of diabetes in the Pima Indians has not changed, but the incidence of diabetes among those less than 15 years of age has increased nearly 6-fold, as an increasing prevalence and degree of obesity in the youth has shifted the onset of diabetes to younger ages. The rising frequency of diabetes in the youth has led, in turn, to the emergence in mid-life of the major complications of diabetes, including kidney disease. On the other hand, the introduction and widespread use of medicines to control blood pressure, reduce hyperglycemia, and block the renin-angiotensin system has lead to improvements in the average blood pressure and glycosylated hemoglobin levels in the diabetic population. These countervailing forces have influenced the course of diabetic nephropathy in a generally favorable direction in the past few years, as evidenced by the decline in the overall incidence of end-stage kidney disease since 1990. A continued increase in the incidence of type 2 diabetes in youth, however, threatens to reverse this trend.
The Pima Indians who live in the Gila River Indian Community in Arizona have participated in a longitudinal study of diabetes and its complications since 1965. This study has shown that the prevalence of type 2 diabetes in this population is very high . The low prevalence of diabetes even today among Pima Indians from Maycoba, Mexico [2, 3], who share considerable genetic similarity with those in the U.S., supports the notion of an epidemic of diabetes in the Pima Indians from the Gila River Indian Community that coincides with increased contact with European-Americans and the ensuing change in lifestyle. Given the lack of systematic screening for diabetes before 1965, an epidemic rise in the incidence of diabetes in the Pimas is difficult to confirm. Nonetheless, the available evidence suggests that an abrupt rise did occur between the 1930s and the beginning of screening [4, 5], and this rise was followed by relatively stable incidence since that time, but with a shift to younger age at onset of diabetes as a consequence of increasing childhood obesity and increasing frequency of exposure to diabetes in utero [6–8]. This scenario, if true, may have profound implications on the course of diabetic kidney disease in this population and the relative importance of various risk factors for this complication of diabetes. The purpose of this review is to characterize the evolution of diabetic nephropathy in the Pima Indians and the role various factors may play in this evolution.
In the longitudinal study, each member of the community who is ≥5 years old is invited to have a research examination approximately every 2 years, regardless of health. These biennial examinations include measurements of venous plasma glucose concentration, obtained 2 hours after a 75 g oral glucose load, and assessment for the complications of diabetes. Urinary albumin concentration is measured by nephelometric immunoassay  and urinary protein concentration by the Shevky-Stafford method . Serum and urine creatinine concentrations are measured by a modification of the Jaffé reaction . Proteinuria is defined by a protein-to-creatinine ratio ≥0.5 g protein/g creatinine, reflecting an estimated protein excretion rate of at least 0.5 g/day. Microalbuminuria is defined by an albumin-to-creatinine ratio of 30–299 mg albumin/g creatinine and macroalbuminuria by an albumin-to-creatinine ratio ≥300 mg/g. Diabetes was diagnosed by 1985 World Health Organization criteria . Only the 2-hour post-load plasma glucose concentration (≥11.1 mmol/l) was used to diagnose diabetes at the research examinations, since this measurement was available throughout the longitudinal study period. The date of diagnosis is determined from these research examinations or from review of clinical records if diabetes is diagnosed in the course of routine medical care. Body mass index (BMI) is defined as weight divided by the square of height (kg/m2). End-stage kidney disease is defined as initiation of chronic dialysis or death from diabetic nephropathy if dialysis is not available or refused and is ascertained independently of the research examinations. The cause of kidney failure in those receiving dialysis is determined by review of clinical records. The cause of death is determined by review of clinical records, autopsy reports and death certificates. Deaths are attributed to diabetic nephropathy if the ICD-9 code 250.4 is specified as the underlying or a contributing cause of death.
Between 1965 and 2003, the average BMI in nondiabetic Pima Indians increased by 12 percent in the men and 19 percent in the women. An increase in obesity was found in all age groups, including children (Figure 1). Given the powerful effect of obesity on the development of type 2 diabetes , an increase in the incidence of diabetes might be expected as a consequence of the increasing obesity. Instead, the incidence rate of type 2 diabetes increased only among Pima Indians aged 5–14 years, decreased in those aged 25–34 years, and did not change significantly in other ages during the same period (Figure 2). These findings suggest that the vast majority of Pima Indians susceptible to diabetes were already developing the disease in the early years of the study, and the increasing obesity in youth combined with a nearly 4-fold increase in the frequency of exposure to diabetes in utero  simply shifted the onset of diabetes to younger ages in the most susceptible individuals . The age-specific prevalence of diabetes increased over the same time in subjects <25 years old, but did not show a similar trend in the older ages. Since mortality in young persons remained stable during this period, the increasing prevalence of diabetes in youth was believed to be largely attributable to the increasing incidence of diabetes in this age group .
If the incidence of diabetes did rise abruptly over a relatively short period prior to the onset of the longitudinal study, as we propose, the average duration of diabetes among community members would be shorter in the 1960s and 1970s than in the 1990s and beyond. In keeping with this hypothesis, the proportion of Pima Indians with diabetes of long duration has increased with time , and the increasing average duration of diabetes combined with a shift to younger age at onset could have important effects on the development of diabetic kidney disease.
The impact of the longer average duration of diabetes in recent years is illustrated by the rising incidence of proteinuria in diabetic Pima Indians . The age-sex-adjusted incidence increased from 24.3 cases/1000 person-years in 1967–1978 to 38.9 cases/1000 person-years in 1991–2002. After adjustment for changes in the duration of diabetes, however, the incidence of proteinuria was stable, indicating that the incidence is rising in response to the increasing duration of diabetes . Although the development of kidney disease has accelerated in the Pima Indians, its progression has slowed, with the incidence of end-stage kidney disease declining since 1990 (Figure 3). The slowing in the rate of progression of kidney disease may be due, at least in part, to improvements in the therapeutic management of diabetes and diabetic kidney disease.
Clinical trials indicate that medicines that block the renin-angiotensin system (RAS) control hypertension, slow the progression from micro- to macroalbuminuria, increase the rate of regression from micro- to normoalbuminuria, and preserve the glomerular filtration rate in persons with diabetes [15–17]. Moreover, the effect is present regardless of the type of diabetes, stage of diabetic nephropathy, and duration of treatment . In the Pima Indians, therapeutic interventions to block the RAS were introduced in November 1986, with only limited use until September 1989 . Subsequently, their use increased gradually, as did the use of combination therapy for diabetes and blood pressure control . Improved therapeutic management, involving increased use of RAS inhibitors as well as increased use of other blood pressure and hypoglycemic medicines are associated with significant improvements in average blood pressure and glycosylated hemoglobin levels in diabetic Pima Indians . To what extent these enhancements in patient management have contributed to the decline in the incidence of end-stage kidney disease cannot be determined from an observational study, but most clinical trial data support a role for these agents in delaying the progression of kidney disease [15–18, 21, 22].
The decline in the incidence of kidney failure despite the increasing incidence of early kidney disease suggests that therapeutic advances, at least for the moment, are keeping pace with the changing pattern of diabetes in this population. The extent to which the increase in youth-onset diabetes affects the development of diabetic kidney disease, however, may negatively influence these relationships.
Diabetes in Pima Indian children and adolescents was first reported in the 1970s . It is entirely type 2 and is characterized by the lack of insulin dependence , absent or low levels of islet cell and glutamic acid decarboxylase antibodies [25, 26], and absence of strong linkage or association with maturity-onset diabetes of youth loci [27–29]. Of concern, the onset of diabetes in Pima Indians younger than 20 years of age is associated with a duration-specific incidence rate of proteinuria that is virtually identical to that in adult-onset type 2 diabetes, indicating that an equivalent duration of type 2 diabetes in a young person is as damaging to the kidneys as it is in an older person . Without a protective effect of youth, youth-onset diabetes is associated with a nearly 5-fold increase in the incidence of end-stage kidney disease between 25 and 54 years of age than in adult-onset disease (Figure 4) . The more modest decline in the incidence of end-stage kidney disease in those below 45 years of age (Figure 3) may reflect less aggressive management of diabetic nephropathy in younger patients or lower death rates from competing causes of death, such as cardiovascular disease, or both.
Several factors influence the course of diabetic kidney disease in the Pima Indians. Among them is an increasing average duration of diabetes, which is responsible for a rise in the incidence of early kidney disease, and improvements in therapeutic management which are, for the moment, reducing the rate of progression and the overall incidence of kidney failure. A continued increase in the incidence of type 2 diabetes in youth combined with the impact of the increasing average duration of diabetes could ultimately reverse this trend as improvements in therapy are overshadowed by the greater number of patients developing kidney disease and the greater likelihood of surviving to kidney failure among those with an earlier onset of diabetes.
The prevalence of type 2 diabetes worldwide is expected to increase rapidly in the coming decades  and more populations are reporting the emergence of youth-onset type 2 diabetes in recent years . If the experience in the Pima Indians is relevant to these populations, as we believe it is, substantially higher rates of kidney failure may occur in the coming years despite therapeutic advances.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Conflict of interest statement