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Albuminuria and Cognitive Decline in People with
Diabetes and Normal Renal Function
 
 
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CJASN 2013
 
"In summary, we identify adults with diabetes, whose eGFR at baseline was approximately 90 ml/min per 1.73 m2, with persistent or progressive albuminuria as a group at risk for cognitive decline. Such observations offer a possible new avenue for understanding subsequent cognitive impairment in persons with diabetes and offer an opportunity for intervention.
 
Diabetes and albuminuria are vascular risk factors. The cognitive findings described here may therefore be vascular in origin. Several mechanisms by which albuminuria and cognitive impairment are related can be offered. One possibility is that the two microcirculatory systems share common pathomechanisms: both are low resistance beds exposed to high circulatory flow (27). Impaired autoregulation from small vessel endothelial dysfunction can increase pressure in both circulatory systems, leading to organ damage. For example, with impaired renal function, nitric oxide inhibitor levels increase. Nitric oxide regulates the microcirculation and the blood-brain barrier, which are implicated in brain white matter disease (28). Alternatively, complications associated with albuminuria, such as anemia, acidosis, hyperparathyroidism, and hypertension, can affect cognitive function(29).
 
In the Cardiovascular Health Study (3), an increase in serum creatinine from 1.0 to 2.0 mg/dl was associated with a 26% increased risk (95% CI, 1.02 to 1.60) of dementia. That study did not have measures of eGFR. In our study, there was a trend for a 1 ml/min per 1.73 m2 per year eGFR decline (approximately double the median annual eGFR decline) to be associated with lower DSST scores in the cohort. Two population-based studies with unimpaired renal function and a low prevalence of diabetes reported that only an eGFR decline of >3-4 ml/min per 1.73 m2 per year was significantly associated with cognitive decline (5,42).”
 
Summary
 
Background and objectives
Diabetes mellitus is associated with increased risk of cognitive impairment. This study examines whether microvascular disease, as measured by albuminuria and decline in estimated GFR (eGFR), is associated with cognitive decline during 3.3 years of follow-up in individuals with diabetes with a normal baseline eGFR (approximately 90 ml/min per 1.73 m2).
 
Design, setting, participants, & measurements Participants were from the Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes study (N=2977; mean age 62.5±5.8 years; recruitment from August 2003 to December 2005, followed through June 2009), which examined the association of intensive versus standard glucose control on cognitive function. Participants underwent three neuropsychologic tests at baseline, 20 months, and 40 months. Tests included information processing speed, verbal memory, and executive function. Mixed-effects models were used to assess the association of albuminuria and eGFR on the percentage decline in each test.
 
Results Participants with albuminuria at baseline and follow-up (persistent albuminuria) (−5.8% [95% confidence interval (CI), −7.3 to −4.2]) and participants with albuminuria at follow-up but none at baseline (progressive albuminuria) (−4.1% [95% CI, −5.6 to −2.7]) had greater percentage declines on information processing speed than participants without albuminuria at baseline and at follow-up (no albuminuria) (−2.6% [95% CI, −3.4 to −1.9]) (P=0.001 and P=0.10, respectively). There were borderline percentage changes in the test of verbal memory (4.8% [95% CI, 2.4 to 7.1] and 4.7% [95% CI, 2.5 to 7.0] versus 7.1% [95% CI, 6.0 to 8.3]; P=0.11 and P=0.08, respectively). On logistic regression analysis, persistent albuminuria (odds ratio, 1.37 [95% CI, 1.09 to 1.72]) and progressive albuminuria (odds ratio, 1.25 [95% CI, 1.02 to 1.56]) were associated with a ≥5% decline in information processing speed scores but not with verbal memory or executive function performance. A 1 ml/min per 1.73 m2 per year eGFR decline had a borderline association with decline in tests of cognitive function.
 
Conclusions Persistent albuminuria and progressive albuminuria are associated with a decline in cognitive function in relatively young individuals with diabetes with unimpaired eGFR. These findings do not rule out the possibility of other processes causing cognitive decline.
 
Introduction
 
Individuals with type 2 diabetes (DM) are at a 50%-60% increased risk of cognitive impairment compared with people without DM (1). They also develop cognitive decline more rapidly and at an earlier age (2). Identifying markers for very early cognitive decline in people with DM before the onset of evident impairment is therefore of interest and importance.
 
Moderate CKD (estimated GFR [eGFR] <60 ml/min per 1.73 m2) and end stage renal failure are associated with an increased risk of cognitive impairment (3,4). Davey et al. (5) recently examined cognitive function in people with mild CKD (eGFR of approximately 78 ml/min per 1.73 m2). Those with a rapid decline in eGFR of ≥3 ml/min per 1.73 m2 per year over 5 years had a greater risk of cognitive impairment than those without such a decline. This finding not only expanded the range of renal function associated with cognitive impairment, but also suggested that dynamic markers of renal function, such as a decline in eGFR, and not only levels of attained eGFR, are important in determining cognitive decline.
 
Albuminuria is another marker of renal microvascular disease. Its prevalence has increased over the past 2 decades, owing to the increasing prevalence of hypertension, diabetes, and obesity (6). In people with DM, its prevalence reaches 37.6% by age 60-69 years (7). We have shown that albuminuria, based on a single measurement, is associated with an increased prevalence and risk of cognitive impairment in people with and without DM (8-10).
 
Recently, our understanding of the natural history of albuminuria has changed. Unlike the paradigm of the 1980s, which posited that albuminuria was a first step in a committed process that inexorably leads to renal failure, it is now known that albuminuria can be dynamic. It can be stable, intermittent, progressive, or remitting (hereafter called albuminuria status) (11,12). How albuminuria status is associated with cognitive change has not been studied.
 
In this study, we examine the association between albuminuria status with performance on three tests of cognitive function in a cohort of adults with DM whose baseline eGFR level was approximately 90 ml/min per 1.73 m2. We further test whether decline in eGFR during follow-up was an independent risk factor for cognitive impairment. Participants for this analysis were from the Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes (ACCORD MIND) study. It examined whether intensive lowering of hemoglobin A1c (HbA1c) levels prevents decline in cognitive function compared with standard treatment of blood glucose levels. The study reported no differences in cognitive outcomes between the two groups (13).
 
Discussion
 
In this study of middle-aged adults with diabetes with preserved baseline eGFR (approximately 90 ml/min per 1.73 m2), the DSST declined in participants with persistent and progressive albuminuria compared with participants without albuminuria. Decline was greater in participants with persistent albuminuria compared with those with progressive albuminuria, suggestive of a dose effect. The findings were independent of baseline eGFR and declining eGFR, which were only mildly diminished (0.54-0.60 ml/min per 1.73 m2 per year) at the end of follow-up, leaving most participants with normal to near normal renal function. These findings extend prior studies of the association of renal disease and cognitive decline to an even earlier stage of renal disease than previously reported. Diabetes and albuminuria are vascular risk factors. The cognitive findings described here may therefore be vascular in origin. Several mechanisms by which albuminuria and cognitive impairment are related can be offered. One possibility is that the two microcirculatory systems share common pathomechanisms: both are low resistance beds exposed to high circulatory flow (27). Impaired autoregulation from small vessel endothelial dysfunction can increase pressure in both circulatory systems, leading to organ damage. For example, with impaired renal function, nitric oxide inhibitor levels increase. Nitric oxide regulates the microcirculation and the blood-brain barrier, which are implicated in brain white matter disease (28). Alternatively, complications associated with albuminuria, such as anemia, acidosis, hyperparathyroidism, and hypertension, can affect cognitive function (29).
 
Our findings should be put into context. Participants had on average normal baseline cognitive function (MMSE score >26), and were generally well educated, a factor that protects against cognitive decline (30). The changes in the DSST were modest and on an individual level would not likely be clinically significant. However, the average age of the cohort was 10-15 years younger than the age at which cognitive impairment is usually recognized (31). If the rate of information processing speed decline persisted, evident cognitive impairment would likely develop with aging. Participants with persistent and progressive albuminuria had the equivalent of 7.2 and 3.2 years of cognitive aging relative to 1 year of calendar aging, respectively. On a population level, these findings could have large effects.
 
Our findings are consistent with studies that have shown that the DSST detects small cognitive changes in people with high levels of cognition (32) and in people with DM (1,33). The Stroop test, which measures executive function, did not show change in association with albuminuria status. However, previous studies using other measures of executive function have found (34-36) associations of albuminuria with decline in executive function.
 
In our study, albuminuria progressors were more likely to experience DSST decline. This is similar to a study in which progressors had increased odds of cognitive decline as measured by the MMSE (8). In that study, like ours, albuminuria remitters were similar in terms of cognitive change to participants without any albuminuria. Another study with longitudinal data reported poorer cognitive function in participants with progressive albuminuria compared with those with stable albuminuria (37). These findings emphasize that dynamic characteristics of albuminuria are important determinants of cognitive decline.
 
Several studies have shown that moderate CKD can be associated with impaired cognition (38-41). There are few studies, however, that have longitudinally examined the effect of eGFR decline on cognition. In the Cardiovascular Health Study (3), an increase in serum creatinine from 1.0 to 2.0 mg/dl was associated with a 26% increased risk (95% CI, 1.02 to 1.60) of dementia. That study did not have measures of eGFR. In our study, there was a trend for a 1 ml/min per 1.73 m2 per year eGFR decline (approximately double the median annual eGFR decline) to be associated with lower DSST scores in the cohort. Two population-based studies with unimpaired renal function and a low prevalence of diabetes reported that only an eGFR decline of >3-4 ml/min per 1.73 m2 per year was significantly associated with cognitive decline (5,42).
 
Our results suggest that in an exclusively diabetic population, small declines in eGFR may have a stronger negative association with cognitive decline than in populations without DM.
 
Our findings are characterized by prospective data collection, repeated measures of cognitive testing, near complete data capture, characterization of albuminuria over time, and a large number of participants. Risk factors for cognitive decline were captured, permitting for adjustment. We recognize that the follow-up was short and may not be predictive of subsequent cognitive decline. A follow-up study, entitled ACCORDION, will add 3-5 years of follow-up.
 
In summary, we identify adults with diabetes, whose eGFR at baseline was approximately 90 ml/min per 1.73 m2, with persistent or progressive albuminuria as a group at risk for cognitive decline. Such observations offer a possible new avenue for understanding subsequent cognitive impairment in persons with diabetes and offer an opportunity for intervention.
 

 
 
 
 
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