The AGES-Reykjavik Study suggests that change in kidney measures is associated with subclinical brain pathology in older community-dwelling persons

Abstract

Decreased glomerular filtration rate (GFR) and albuminuria may be accompanied by brain pathology. Here we investigated whether changes in these kidney measures are linked to development of new MRI-detected infarcts and microbleeds, and progression of white matter hyperintensity volume. The study included 2671 participants from the population-based AGES-Reykjavik Study (mean age 75, 58.7% women). GFR was estimated from serum creatinine, and albuminuria was assessed by urinary albumin-to-creatinine ratio. Brain MRI was acquired at baseline (2002-2006) and 5 years later (2007-2011). New MRI-detected infarcts and microbleeds were counted on the follow-up scans. White matter hyperintensity progression was estimated as percent change in white matter hyperintensity volumes between the two exams. Participants with a large eGFR decline (over 3 ml/min/1.73m2 per year) had more incident subcortical infarcts (odds ratio 1.53; 95% confidence interval 1.05, 2.22), and more marked progression of white matter hyperintensity volume (difference: 8%; 95% confidence interval: 4%, 12%), compared to participants without a large decline. Participants with incident albuminuria (over 30 mg/g) had 21% more white matter hyperintensity volume progression (95% confidence interval: 14%, 29%) and 1.86 higher odds of developing new deep microbleeds (95% confidence interval 1.16, 2.98), compared to participants without incident albuminuria. The findings were independent of cardiovascular risk factors. Changes in kidney measures were not associated with occurrence of cortical infarcts. Thus, larger changes in eGFR and albuminuria are associated with increased risk for developing manifestations of cerebral small vessel disease. Individuals with larger changes in these kidney measures should be considered as a high risk population for accelerated brain pathology.

Albuminuria as a risk factor for mild cognitive impairment and dementia—what is the evidence?

“…Similarly, a high urinary albumin-to-creatinine ratio (UACR) was significantly associated with the presence of imaging markers of cerebral small vessel disease in middle-aged and elderly participants of the general population-based Rotterdam Study [ 10 ], and with an increase of the white matter hyperintensities (reflecting deteriorating cerebral white matter due to myelin breakdown) volume to the intracranial volume ratio in the Hisayama Study [ 11 ]. More recently, this association has been confirmed in the population-based AGES–Reykjavik Study (mean age 75 years), showing that participants with incident albuminuria (UACR >30 mg/g) had 21% more white matter hyperintensity volume progression compared with participants without incident albuminuria [ 12 ]. Recent studies, including a prospective Atherosclerosis Risk in Communities (ARIC) study [ 13 ], the Hisayama Study [ 14 ] and others, also found that increased albuminuria is consistently associated with the incidence of dementia.…”

Cadmium and Lead Exposure, Nephrotoxicity, and Mortality

“…Diabetes and hypertension are the most common risk factors universally, while obesity is an additional risk factor, especially in industrialized countries [ 272 , 273 , 274 , 275 , 276 , 277 , 278 , 279 ]. CKD is a cause of morbidity and mortality as it is an important predictor of end-stage kidney disease (ESKD), stroke and cardiovascular disease (CVD) [ 280 , 281 , 282 , 283 , 284 , 285 ]. CKD is characterized by albuminuria (a urinary albumin to creatinine ratio, uACR, above 30 μg/g) and/or a decrease of GFR to ≤60 mL/min/1.73 m 2 that persists for at least three months [ 48 , 49 , 50 ].…”

“…The associations between [Cd] u , [NAG] u and [RBP] u were only seen in workers who had high levels of [Pb] b (≥21.9 μg/dL), corresponding to the 75th percentile or higher. In addition, the associations between [Cd] b , [NAG] u and [intestinal alkaline phosphatase] u only became statistically significant in workers who had [Pb] b ≥ 21.9 μg/dL [ 285 ]. This Cd–Pb interaction was seen although blood Pb in Belgian workers of 21.9 μg/dL was 6-fold higher than the 90th percentile blood Pb level of 3.66 μg/dL in a Korean study [ 300 ].…”

Proteinuria and Reduced Estimated Glomerular Filtration Rate are Independently Associated With Lower Cognitive Abilities in Apparently Healthy Community-Dwelling Elderly Men in Japan: A Cross-sectional Study

“…31,36 This is not surprising given the common anatomic and vaso-regulatory features of the brain and the kidneys, lowresistant end organs that are susceptible to vascular damage, as both organs receive high-volume blood flow. 31 Individuals with proteinuria or reduced GFR are likely to have subclinical small vessel disease in the brain, [36][37][38] which is believed to play a causal role in cognitive impairment and dementia. 39 Another potential explanation would be shared risk factors between CKD and Figure 1.…”