Since 1965, each individual ≥5 years old who resides in the Gila River Indian Community in Arizona has been invited to participate in a research examination approximately every 2 years, regardless of health. These biennial examinations include measurements of venous plasma glucose concentration obtained 2 h after a 75-g oral glucose load and assessment for the complications of diabetes. Diabetes was diagnosed by 1985 World Health Organization criteria (6), and the date of diagnosis was determined from these research examinations or from review of clinical records if diabetes was diagnosed in the course of routine medical care. Since 1 July 1982, albumin concentration was measured with a nephelometric immunoassay in urine specimens collected at the end of the 2-h glucose tolerance test (7). Values <6.8 mg/l, the threshold beneath which albuminuria cannot be detected by the assay, were assigned the value of 6.8 mg/l. Urine creatinine concentration in the same specimen and serum creatinine were measured by a modification of the Jaffé reaction (8). Elevated albuminuria was defined by a urinary albumin-to-creatinine ratio (ACR) ≥30 mg/g. eGFR was determined using the four-variable Modification of Diet in Renal Disease (MDRD) Study equation (9) (using the racial classification of nonblack for American Indians), and an eGFR of <60 ml/min per 1.73 m² was considered low. BMI was defined as weight in kilograms divided by the square of height in meters. Mean arterial pressure (MAP) was calculated as MAP = ⅔ diastolic arterial pressure + ⅓ systolic arterial pressure. HbA_l was measured by agar gel electrophoresis (10) through December 1989, and A1C was measured by high-performance liquid chromatography (11) thereafter. The correlation between the two measures was 0.92, as shown in a previous study, and a linear regression formula A1C = 0.99 × HbA_l − 1.535 was used to estimate A1C in the 794 subjects in whom HbA_l was measured (12). The study population included subjects who resided in the community at any time from 1 July 1982 through 30 June 1988 and from 1 January 2001 through 31 December 2006, attended research examinations at ≥15 years of age, and had diabetes.

Clinical and demographic characteristics of the diabetic subjects in the two time periods are presented in Table 1. More subjects received hypoglycemic and antihypertensive medicines in the late time period (54.4 and 51.1%, respectively) than in the early period (42.0 and 19.8%, respectively). Although subjects in the late period had longer mean duration of diabetes and higher mean BMI than those included in the early period, their fasting plasma glucose, MAP, and ACR were significantly lower. A total of 223 subjects were included in both time periods.

In the early period, 6.5% (n = 54) of the 837 subjects with type 2 diabetes had eGFR <60 ml/min per 1.73 m². Of these, 9.3% (n = 5) had normal ACR, 7.4% (n = 4) had microalbuminuria, and 83.3% (n = 45) had macroalbuminuria. Among the 1,310 diabetic subjects in the late period, the prevalence of low eGFR was similar: 6.6% (n = 87). Among those with low eGFR, the prevalence of normal ACR had nearly doubled to 17.2% (n = 15), the prevalence of microalbuminuria had nearly tripled to 19.5% (n = 17), and the prevalence of macroalbuminuria had declined to 63.2% (n = 55). The age- and sex-adjusted logarithm of the average ACR level changed significantly over time in the study population (P = 0.01) (Table 1), more significantly in those with low eGFR (P = 0.0003) than in those with normal eGFR (P = 0.02).

Clinical and demographic characteristics of those with eGFR <60 ml/min per 1.73 m² and elevated or normal ACR in the two time periods are presented in Table 2. Subjects with elevated ACR in the late period had higher BMI but lower MAP and ACR than subjects in the early period. All but two of the subjects with low eGFR and normal ACR were women. Those with normal ACR in the late period had longer duration of diabetes than subjects in the early period. Moreover, >90% of the subjects in the late period received antihypertensive medicines (n = 67 with elevated ACR and n = 14 with normal ACR), and two-thirds of them were taking RAS inhibitors. They were also twice as likely to take hypoglycemic medicines as in the earlier time period, although the total number of subjects was quite small.

Table 3 shows unstandardized and standardized prevalence of eGFR and albuminuria categories in diabetic Pima Indians in the two time periods. Significant changes in the overall age-, sex-, and diabetes duration–standardized distribution of ACR occurred between time periods (P = 0.001) (Fig. 1). These changes were present in subjects with both normal eGFR (P = 0.002) and low eGFR (P = 0.001) (Fig. 2). In the low eGFR group, the distributional change reflects the increase in the frequency of normal ACR. No significant changes in the standardized distribution of eGFR (P = 0.45) (Fig. 1) or the adjusted prevalence of low eGFR occurred between time periods (P = 0.42).

The frequency distribution of albuminuria among diabetic Pima Indians has changed significantly over the past 20 years. The redistribution of ACR toward lower values without a concomitant change in eGFR has led to an increase in the proportion of those with CKD characterized by low eGFR and normoalbuminuria, a condition virtually nonexistent in diabetic Pima Indians in the 1980s. We are unaware of other studies that systematically examined time trends in the distribution of ACR and eGFR in a population with type 2 diabetes. The doubling in the prevalence of this condition over the past two decades coincides with the introduction and widespread use of more effective medicines to manage hyperglycemia and blood pressure in this community (13) and elsewhere. Although a causal relationship cannot be determined from an observational study, these results suggest that the finding of low eGFR and normal urinary albumin excretion in patients with type 2 diabetes is due, at least in part, to recent improvements in therapeutic management of diabetes and diabetic kidney disease rather than the emergence or recognition of an atypical form of diabetic kidney disease, as some have suggested (1,14,15). Despite the increase in the prevalence of normoalbuminuria in diabetic Pima Indians with low eGFR, the proportion of subjects with this condition remains low at about 1.2% of the diabetic population.

In the more recent time period, the prevalence of normoalbuminuria among diabetic Pima Indians with low eGFR was 17.2%, consistent with studies in other diabetic populations from the same time period in which prevalence estimates ranged between 13 and 42% (1–5,14,16), but twice that of 9.3% found in the Pima Indians in the 1980s. Atherosclerosis may contribute to the appearance of low eGFR and normoalbuminuria in some diabetic populations (15), but in diabetic Pima Indians, clinical atherosclerosis generally occurs only after the onset of proteinuric CKD and hence is an unlikely explanation for normoalbuminuric CKD in this population (17). On the other hand, improved therapeutic management of diabetes may be a major contributing factor to the appearance of normoalbuminuria among diabetic patients with low eGFR in these diabetic populations. Indeed, studies in which diabetic patients taking RAS inhibitors were excluded from the analysis showed a significant reduction in the prevalence of normal albuminuria among those with low eGFR (3,5). To our knowledge, no one has examined the role of improved management of hyperglycemia on the appearance of normoalbuminuria among diabetic patients with low eGFR, yet there is abundant evidence that improvements in glycemic control reduce the frequency of elevated albuminuria in both types of diabetes (18–20). The extent to which RAS inhibitors and improved glycemic management contribute to the shift in ACR distribution, however, cannot be determined in this observational study.

We do not have morphological data from kidney biopsies in Pima Indians with CKD characterized by low eGFR and normal urinary albumin excretion. Nevertheless, postmortem histological examinations of the kidneys in diabetic and nondiabetic Pima Indians and morphological studies of kidney biopsies in Pima Indians with type 2 diabetes reveal that intercapillary glomerulosclerosis is by far the predominant form of kidney disease among diabetic Pima Indians (21). The extent to which the course of kidney disease in Pima Indians with low eGFR and normal urinary albumin excretion differs from that in Pima Indians with elevated urinary albumin excretion is not known. In the present study, only one person with CKD characterized by low eGFR and normoalbuminuria progressed to kidney failure, and this person developed elevated urinary albumin excretion as the disease progressed.

Because Pima Indians with diabetes often have substantially elevated GFR in the early years after diagnosis (22), a GFR <60 ml/min per 1.73 m² may represent a more significant loss of kidney function than in Caucasian populations with similar levels of CKD. With the use of 90 ml/min per 1.73 m² to define low eGFR instead of 60 ml/min per 1.73 m², 20.5% of the diabetic subjects had low eGFR in the early period and 20.2% in the late period, with a higher proportion of subjects with low eGFR having normal ACR in the late period (39.0%) than in the early period (26.7%). By this definition of CKD, the overall change in the standardized distribution of ACR between time periods remained significant in subjects with normal or low eGFR (for the normal eGFR group: P = 0.02; for the low eGFR group: P = 0.0001). At higher GFR, however, the MDRD equation estimates are more biased (underestimating measured GFR for eGFR between 60 and 119 ml/min per 1.73 m² and overestimating measured GFR for eGFR ≥120 ml/min per 1.73 m²) and less precise on both an absolute and percentage basis, particularly so among populations not included in the MDRD study, such as Pima Indians (23).

A total of 223 individuals were examined in both time periods. Because the lack of independence of these observations could affect the results, we repeated the analyses after randomly assigning each of these 223 individuals to only one of the time periods. By this approach, the differences between the ACR distributions in the two time periods were even greater and the conclusions of the study were unchanged (data not shown).

In summary, the distribution of albuminuria changed significantly among diabetic Pima Indians over the past 20 years without a concomitant change in the distribution of eGFR. As a result, the frequency of CKD characterized by normoalbuminuria and low eGFR in diabetic Pima Indians doubled and is now consistent with reports in other populations from the same time period. The frequency of low eGFR with normoalbuminuria increased significantly during a time when effective treatments for diabetes and diabetic kidney disease, which are known to lower albuminuria, were introduced, suggesting that improvements in therapeutic management are responsible, at least in part, for the emergence of this condition. Whether the clinical course in these patients differs from that in persons with more typical diabetic CKD characterized by elevated albuminuria is uncertain, but studies in Pima Indians suggest that newer treatments for diabetic kidney disease, while not preventing the development of kidney disease, may slow its progression and reduce the incidence of end-stage renal disease (24).