The prevalence of elevated albuminuria is significantly higher in Pima Indian youth with type 2 diabetes than in those without. In those with diabetes, elevated albuminuria is more likely to persist and is highly predictive of progression to persistent macroalbuminuria, whereas in those without diabetes it is largely transient. The persistence of elevated ACR in diabetic youth is consistent with previous findings in diabetic Pima adults [29
]. The frequency of persistent albuminuria is higher than in youth with type 1 in the Steno Diabetes Study [6
] or the Oxford Regional Prospective Study [7
The prevalence of micro- and macroalbuminuria in diabetic Pima youth was lower than in diabetic adults, perhaps because of the youths’ shorter average duration of diabetes—more than half of the ACR measurements in the youth were made at the diagnosis of diabetes. Nevertheless, the prevalence of elevated albuminuria was similar to that reported among youth with type 2 diabetes in the SEARCH for Diabetes in Youth Study (SEARCH), but much higher than the 9% reported among those with type 1 diabetes in the same study [30
]. Youth with type 2 diabetes from other populations are also reported to have a significantly higher prevalence of elevated albuminuria than those with type 1 diabetes, despite shorter duration of diabetes and lower HbA1c; however long-term follow-up was not available in these previous studies [8
At baseline, only one nondiabetic subject had eGFR <60 ml/min/1.73m2
and 15 had eGFR of 60-89 ml/min/1.73m2
; no diabetic youth had eGFR <90 ml/min/1.73m2
. Because only one diabetic subject developed eGFR <60 ml/min/1.73m2
and four developed eGFR of 60-89 ml/min/1.73m2
during follow-up, progression of diabetic kidney disease was assessed only by the incidence of macroalbuminuria. The present study indicates that microalbuminuria strongly predicts progression to macroalbuminuria in diabetic youth. A similar probability of progression to macroalbuminuria was reported in the Oxford Regional Prospective Study [7
] in youth and adults with type 1 diabetes. Moreover, previous findings indicate 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 [31
], reflecting the importance of diabetes duration, regardless of age, in the development of kidney disease in both types of diabetes.
Although the relationship between ACR and kidney disease progression is continuous, for clinical purposes a cut point is useful for identifying those at substantially increased risk. In adults, we previously arbitrarily selected an ACR cut point of ≥30 mg/g as abnormal, since this level was approximately the 95th
percentile of ACR in a “healthy” subset of Pima Indians aged ≥15 years who had NGT, took no medicines, had no known renal or cardiovascular diseases, normal blood pressure, and normal serum creatinine [15
]. This cut point is equivalent to ≥20 μg/min or ≥30 mg/24 hr from timed urine collections [21
]. In diabetic youth with microalbuminuria by this ACR definition, the age-sex-adjusted incidence of macroalbuminuria was 7.6 times (95% CI, 1.8-32.8) as high as in those with normal ACR, suggesting that the adult cut points are useful for identifying increased risk of more advanced kidney disease in diabetic youth. In nondiabetic youth, the incidence of macroalbuminuria was also much higher in those with ACR≥30 mg/g, but the risk of developing macroalbuminuria was much lower than in those with diabetes and macroalbuminuria was more often transient. Furthermore, most nondiabetic individuals with ACR ≥30 mg/g regressed to normoalbuminuria. Thus, the clinical utility of measuring albuminuria is less certain in nondiabetic youth.
The prevalence of microalbuminuria in nondiabetic Pima youth was 6.5%; lower than 9.5% prevalence in nondiabetic youth in NHANES III [33
]. The higher prevalence in NHANES may be due, in part, to the higher probability of undiagnosed diabetes, since subjects in that study were not tested for diabetes with an oral glucose tolerance test, as in the present study. Urinary albumin excretion in youth may also be influenced by a number of other factors, as in adults. Lower creatinine excretion for a given level of albumin excretion will increase the prevalence of microalbuminuria, particularly in younger children, due to their lower muscle mass. This effect is illustrated in by the higher 75th
percentiles of ACR in the younger nondiabetic children. Likewise, in adults, low muscle mass is an important confounder of ACR as a marker of microalbuminuria [34
Precision of albuminuria estimates is enhanced by obtaining multiple specimens, so guidelines from the American Diabetes Association [35
] and the National Kidney Foundation [21
] recommend repeated measurements when screening diabetic patients. Nevertheless, single measures of albuminuria, as used in the present study, are highly predictive of progressive kidney disease in both children and adults with type 2 diabetes [36
]. Moreover, a recent study in the Pima Indians [29
] finds that preceding ACR measures add minimal predictive value beyond the latest measurement. Accordingly, we do not believe a single measurement of albuminuria represents a serious limitation. Furthermore, we propose that in screening situations in which multiple measurements are not feasible, a single screening test is useful for identifying persons with diabetic kidney disease.
Observations in the Pima Indians are relevant to other populations. The bimodality of plasma glucose, first described in this population [37
], combined with the presence of retinopathy and nephropathy among those in the upper component of the distribution [38
] led to standardized criteria for the diagnosis of diabetes adopted by the National Diabetes Data Group [39
], the World Health Organization [16
], and the American Diabetes Association [41
]. In the Diabetes Prevention Program [42
], a clinical trial of diabetes prevention, Southwestern American Indians (many of whom were Pima), had the same risk of type 2 diabetes and the same reductions in risk from the interventions as members of other race/ethnic groups. Each of the major determinants of diabetic kidney disease found in the Pima Indians has been reported in other populations. Of note, type 2 diabetes in children was first reported in the Pima Indians [43
]. Decades of follow-up of this population-based cohort permits us to examine the impact of elevated albuminuria in children with type 2 diabetes before it can be adequately assessed in other populations. Findings from the Pima Indians may therefore provide clinicians with potentially useful information as they encounter children with type 2 diabetes and elevated albuminuria in their practice.