In this middle-aged to elderly diabetic population, UACR of 10–30 mg/g at previous examination, higher fasting glucose, residence in Arizona compared with Oklahoma, higher SBP, smoking, less use of ACE inhibitors, need for antidiabetic medications and higher plasma creatinine were significant, independent predictors of incident albuminuria. Diabetic participants with UACR of 10 to <30 mg/g at the previous examination had 2.7-fold odds of developing albuminuria compared with those with UACR<5 mg/g.
The odds of developing albuminuria between the 2nd
SHS examinations was significantly lower by 56% compared with that between the 1st
examinations after adjustment for other risk factors included in the multivariate model in . There are several possible explanations for the decline in odds for developing albuminuria over time. First is the possibility of misclassification (since the determination of albuminuria was based on a single random morning urine sample) at each evaluation; likewise, there were improvements in glycemic and blood pressure control which could have impacted the incidence of albuminuria27
. In the SHS study, 9.7% (67 of 690) diabetic participants with albuminuria at the 1st
examination became free of albuminuria at the 2nd
examination while 19.0% (119 of 625) diabetic participants at the 2nd
examination became free of albuminuria at the 3rd
examination; there was no significant difference between the percentage of diabetic participants under good glycemic control (HbA1c
<7%) at the 1st
examination (41.5% (311 of 750)) and the 2nd
examination (38.2% (217 of 568)) (P
=0.2); however, the percentage of participants using ACE inhibitors among those using antihypertensive medications increased from 17% (34 of 199) at the 1st
examination to 52% (102 of 197) at the 2nd
<0.001), although the percentage of using ACE inhibitors at the 1st
examination may be underestimated because 18% (36 of 199) of diabetic participants at the 1st
examination only reported using non-specific hypotensive or antihypertensive medications. It is also known from long-term observational studies that less than half of patients develop nephropathy, irrespective of glycemic control28, 29
. Thus, it seems most likely that the lower rate after the 2nd
examination might reflect depletion of susceptible diabetic individuals actually at risk for diabetic nephropathy, given the relatively long diabetes duration in the cohort.
We found differences for odds of incident albuminuria by site. Participants from Oklahoma had 35% lower odds of developing albuminuria compared with those from Arizona or North/South Dakota. Reasons for the different odds of incident albuminuria among study sites may be explained by differences in access to health care, environmental factors, or by genetic variation. The Oklahoma site had the highest use of ACE inhibitors (12.9% in Oklahoma vs. 10.2% in Arizona and 7.2% in North/South Dakota) and other antihypertensive medications (25.0% in Oklahoma vs. 18.4% in Arizona and 18.1 in North/South Dakota) (p<0.001); likewise, glycemic control (HbA1c<7%) tended to be less tight in Arizona (28.9% in Arizona vs. 38.8% in Oklahoma and 39.3% in North/South Dakota) (p<0.01). Because at the 1st SHS examination of the SHS only a small number of participants at each site underwent dietary assessment, we can not evaluate if environmental factor such as intake of sodium or protein contributed to site differences for odds of incident albuminuria.
In our study, odds of incident albuminuria is elevated even in people with baseline UACR lower than traditional cutoff value (UACR<30 mg/g), which is consistent with findings from other studies12–14
. Participants with UACR of 10–30 mg/g had 2.7-fold odds of developing albuminuria compared with those with UACR<5 mg/g. This increased odds of progression from “sub-threshold” levels of urinary albumin to frank albuminuria in our study adds to the current discussion of a possible new definition of albuminuria. Indeed, this observation is in accord with the results of several studies suggesting that either “high-normal levels of albuminuria” or “albuminuria within the normal range” are associated with increased risk of cardiovascular disease and death9, 24, 30–32
This is the first study to report that type of diabetes therapy independently predicts subsequent albuminuria after adjustment for other risk factors. Diabetic men and women receiving insulin therapy (including insulin alone or with oral hypoglycemic agent) had 2.4 times odds of incident albuminuria, while those receiving only oral hypoglycemic agents had twice the odds of developing albuminuria compared with those whose diabetes was controlled with diet or exercise alone after adjustment for other significant risk factors listed in . We are aware of only one other study which addressed the association of antidiabetic therapy with incident albuminuria. Our findings are consistent with those reported in Pima Indians, i.e., incident albuminuria in subjects treated with either insulin or oral agents was 2.8 times that in those who had not received either drugs at the time of the initial examination when only controlled for age, sex, and diabetes duration10
. The association of type of diabetes therapy with incident albuminuria may well reflect confounding by indication in the presence of more severe underlying diabetes; or unappreciated longer diabetes duration or impaired glucose tolerance because diabetes duration data were based only on self report and the need for antidiabetic medications may be a better indicator of duration and severity.
Our current longitudinal analysis confirms previous suggestions that systolic blood pressure, fasting glucose, and plasma creatinine are risk factors for incident albuminuria in type 2 diabetes as identified in previous prospective studies4, 10–12, 33, 34
. In addition, we found that diabetic men and women who were current smokers had 49% higher odds of developing albuminuria after adjustment for other risk factors. This is consistent with findings from a prospective study in a population with older-onset type 2 diabetes35
. In contrast, history of smoking, rather than current smoking, was found to be associated with microalbuminuria in one study of 108 patients with type 2 diabetes34
but not in another study of 191 patients with type 2 diabetes12
Many other studies36–40
show that either ACE inhibitors or angiotensin II receptor blockers (ARBs) decrease both incident microalbuminuria and progression from microalbuminuria to macroalbuminuria (while also preserving renal function) in individuals with diabetes, irrespective of hypertension. We also found that participants using ACE inhibitors had 40% lower odds of developing albuminuria within four-year follow-up. None of our participants used ARBs at either the 1st
Age, male sex, cholesterol concentration, and plasma triglycerides have been reported as risk factors for incident albuminuria in some studies10, 12, 14
but not in others11, 13
. The different results could be due to different definitions for albuminuria, sample size, and statistical models (logistic regression vs. Cox proportional hazards models). Although in our primary analysis, none of these variables listed above were significant risk factors, in an alternative analysis when albuminuria was defined using sex-specific cutpoints (UACR ≥17 mg/g in men, ≥25 mg/g in women), male sex and low HDL cholesterol were predictors of incident albuminuria. These sex-specific cutpoints may be warranted.
The strengths of the present study are its longitudinal design, the large sample size, and multivariable-adjusted analyses. A key limitation relates to outcome ascertainment: a single random morning urine specimen rather than multiple specimens or a timed specimen was collected to measure albumin and creatinine. A recent American Diabetes Association consensus guideline41
suggests that at least two urine collections be performed in a 3-to 6-month period to appropriately classify individual patients as normo-, micro- or macroalbuminuric. Because our study was not originally designed for clinical diagnosis of albuminuria in individuals, the collections were not performed accordingly. However, our methods are in accord with recent guidelines indicating that UACR calculated from a spot urine random sample (preferably a first morning specimen) correlates well with results of 24-hour urine collections42
. This study was conducted in a single population, American Indians. However this population has been shown in many previous analyses to provide data that are relevant to all men and women with type 2 diabetes. Finally an intrinsic limitation of this and other studies focusing on incidence rates of an abnormality in a population initially free of that abnormality is that it will tend to overestimate the increase in its prevalence in the entire population because individuals who are reclassified from abnormal to normal (e.g., if UACR went from 31 to 29 mg/g) are not considered in this type of analysis.
In conclusion, in middle-aged to elderly diabetic men and women, higher UACR at previous examination, higher fasting glucose level, higher SBP, smoking, lack of ACE inhibitors use, place of residence, need for antidiabetic medications, and higher plasma creatinine were significant independent predictors of incident albuminuria. These data suggest that the odds for incident albuminuria may be substantially reduced by emphasis on blood pressure and glucose control, smoking cessation, and use of ACE inhibitors.