Association of Kidney Function Biomarkers with Brain MRI Findings: The BRINK Study

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Abstract

<div class="section"> <a class="named-anchor" id="S1">  </a> <h5 class="section-title" id="d7419579e254">Background</h5> <p id="P1">Chronic kidney disease (CKD) studies have reported variable prevalence of brain pathologies, in part due to low inclusion of participants with moderate to severe CKD. </p> </div><div class="section"> <a class="named-anchor" id="S2">  </a> <h5 class="section-title" id="d7419579e259">Objective</h5> <p id="P2">To measure the association between kidney function biomarkers and brain MRI findings in CKD. </p> </div><div class="section"> <a class="named-anchor" id="S3">  </a> <h5 class="section-title" id="d7419579e264">Methods</h5> <p id="P3">In the BRINK (BRain IN Kidney Disease) study, MRI was used to measure gray matter volumes, cerebrovascular pathologies (white matter hyperintensity (WMH), infarctions, microhemorrhages), and microstructural changes using diffusion tensor imaging (DTI). We performed regression analyses with estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR) as primary predictors, and joint models that included both predictors, adjusted for vascular risk factors. </p> </div><div class="section"> <a class="named-anchor" id="S4">  </a> <h5 class="section-title" id="d7419579e269">Results</h5> <p id="P4">We obtained 240 baseline MRI scans (150 CKD with eGFR <45 in ml/min/1.73 m <sup>2</sup>; 16 mild CKD: eGFR 45–59; 74 controls: eGFR ≥ 60). Lower eGFR was associated with greater WMH burden, increased odds of cortical infarctions, and worsening diffusion changes throughout the brain. In eGFR models adjusted for UACR, only cortical infarction associations persisted. However, after adjusting for eGFR, higher UACR provided additional information related to temporal lobe atrophy, increased WMH, and whole brain microstructural changes as measured by increased DTI mean diffusivity. </p> </div><div class="section"> <a class="named-anchor" id="S5">  </a> <h5 class="section-title" id="d7419579e277">Conclusions</h5> <p id="P5">Biomarkers of kidney disease (eGFR and UACR) were associated with MRI brain changes, even after accounting for vascular risk factors. UACR adds unique additional information to eGFR regarding brain structural and diffusion biomarkers. There was a greater impact of kidney function biomarkers on cerebrovascular pathologies and microstructural brain changes, suggesting that cerebrovascular etiology may be the primary driver of cognitive impairment in CKD. </p> </div>

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Most cited references 33

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Stroke and cerebrovascular diseases in patients with chronic kidney disease.

Kazunori Toyoda, Toshiharu Ninomiya (2014)

Chronic kidney disease, defined as a reduced glomerular filtration rate or increased urinary albumin excretion, is recognised as a rapidly growing global health burden, and increasing evidence suggests that it contributes to the risk and severity of cerebrovascular diseases. In particular, chronic kidney disease is an established risk factor for stroke and is also strongly associated with subclinical cerebrovascular abnormalities and cognitive impairment, partly because it shares several traditional and non-traditional risk factors, and sometimes uraemia-related and dialysis-related factors, with cerebrovascular diseases. The effect of chronic kidney disease on incident stroke differs among regions and races and is greater in Asian than in non-Asian people. Chronic kidney disease seems to be predictive of severe neurological deficits and poor vital and functional outcomes after both ischaemic and haemorrhagic strokes, which is partly due to the limitations of pharmacotherapies, including limited use and effects of novel oral anticoagulants, other antithrombotic treatments, and reperfusion treatment for hyperacute ischaemic stroke. In view of the strong two-way association between stroke and kidney disease, the pathophysiological interactions between the brain and kidney should be the subject of intensive study.

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Moderate renal impairment and risk of dementia among older adults: the Cardiovascular Health Cognition Study.

Catherine Stehman-Breen, A L Fitzpatrick, Stephen Seliger … (2004)

Renal impairment is associated with an increased risk of carotid atherosclerosis and stroke, determinants of cognitive dysfunction and dementia. The purpose of this study was to determine whether moderate renal impairment is associated with incident dementia among community-dwelling older adults. Participants in the Cardiovascular Health Cognition Study without prevalent dementia (n = 3349) were included in the analysis. Incident dementia was confirmed through neurologic testing. Renal function at baseline was estimated by the inverse of serum creatinine (1/SCr); moderate renal impairment was defined as SCr > or = 1.3 mg/dl for women and > or = 1.5 mg/dl for men. Cox regression models were used to estimate the association of renal impairment with incident dementia. Because SCr is also a function of muscle mass, the authors determined whether the relationship between SCr and dementia was particularly strong among individuals without severe co-morbidity at baseline, as reflected by self-reported general health status. There were 477 incident dementia cases over a median 6 yr follow-up. After adjustment for potential confounders, moderate renal insufficiency was associated with a 37% increased risk of dementia (95% CI = 1.06 to 1.78). Similarly, a 0.5-unit decrement in 1/SCr (equivalent to an increase in SCr from 1.0 to 2.0 mg/dl) was associated with a 26% increased risk (95% CI = 1.02 to 1.60). These associations were present only among the 84% of older adults who reported good-excellent health. Among those in good-excellent health, higher SCr was associated with vascular-type dementia but not Alzheimer-type dementia. Moderate renal impairment, reflected by a higher SCr, is associated with an excess risk of incident dementia among individuals in good-excellent health. Strategies to prevent or delay the onset of dementia in patients with moderate renal impairment are needed.

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Chronic kidney disease is associated with white matter hyperintensity volume: the Northern Manhattan Study (NOMAS).

Ralph Sacco, Thomas Nickolas, Myunghee C. Paik … (2007)

White matter hyperintensities have been associated with increased risk of stroke, cognitive decline, and dementia. Chronic kidney disease is a risk factor for vascular disease and has been associated with inflammation and endothelial dysfunction, which have been implicated in the pathogenesis of white matter hyperintensities. Few studies have explored the relationship between chronic kidney disease and white matter hyperintensities. The Northern Manhattan Study is a prospective, community-based cohort of which a subset of stroke-free participants underwent MRIs. MRIs were analyzed quantitatively for white matter hyperintensities volume, which was log-transformed to yield a normal distribution (log-white matter hyperintensity volume). Kidney function was modeled using serum creatinine, the Cockcroft-Gault formula for creatinine clearance, and the Modification of Diet in Renal Disease formula for estimated glomerular filtration rate. Creatinine clearance and estimated glomerular filtration rate were trichotomized to 15 to 60 mL/min, 60 to 90 mL/min, and >90 mL/min (reference). Linear regression was used to measure the association between kidney function and log-white matter hyperintensity volume adjusting for age, gender, race-ethnicity, education, cardiac disease, diabetes, homocysteine, and hypertension. Baseline data were available on 615 subjects (mean age 70 years, 60% women, 18% whites, 21% blacks, 62% Hispanics). In multivariate analysis, creatinine clearance 15 to 60 mL/min was associated with increased log-white matter hyperintensity volume (beta 0.322; 95% CI, 0.095 to 0.550) as was estimated glomerular filtration rate 15 to 60 mL/min (beta 0.322; 95% CI, 0.080 to 0.564). Serum creatinine, per 1-mg/dL increase, was also positively associated with log-white matter hyperintensity volume (beta 1.479; 95% CI, 1.067 to 2.050). The association between moderate-severe chronic kidney disease and white matter hyperintensity volume highlights the growing importance of kidney disease as a possible determinant of cerebrovascular disease and/or as a marker of microangiopathy.

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Author and article information

Journal

Title: Journal of Alzheimer's Disease

Abbreviated Title: JAD

Publisher: IOS Press

ISSN (Print): 13872877

ISSN (Electronic): 18758908

Publication date Created: December 06 2016

Publication date (Print): December 06 2016

Volume: 55

Issue: 3

Pages: 1069-1082

Affiliations

[1 ]Department of Radiology, Mayo Clinic, Rochester, MN, USA

[2 ]Department of Neurology, Mayo Clinic, Rochester, MN, USA

[3 ]Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA

[4 ]Department of Internal Medicine, Nephrology Division, University of Minnesota, Minneapolis, MN, USA

[5 ]Veteran’s Affairs Medical Center, Minneapolis, MN, USA

[6 ]Department of Neurology, University of Minnesota, Minneapolis, MN, USA

[7 ]Division of Epidemiology & Community Health, University of Minnesota School of Public Health, Minneapolis, MN, USA

[8 ]Biostatistical Design and Analysis Center, University of Minnesota Clinical and Translational Science Institute, Minneapolis, MN, USA

[9 ]Berman Center for Clinical Research and Outcomes, Minneapolis Medical Research Foundation, Minneapolis, MN, USA

[10 ]Department of Internal Medicine, Geriatrics Division, Hennepin County Medical Center, Minneapolis, MN, USA

[11 ]Department of Medicine, University of Minnesota, Minneapolis, MN, USA

Article

DOI: 10.3233/JAD-160834

PMC ID: 5621389

PubMed ID: 27767995

SO-VID: 10e09e88-e866-4162-899b-29d6583eaa5c

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Association of Kidney Function Biomarkers with Brain MRI Findings: The BRINK Study

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Most cited references 33

Stroke and cerebrovascular diseases in patients with chronic kidney disease.

Moderate renal impairment and risk of dementia among older adults: the Cardiovascular Health Cognition Study.

Chronic kidney disease is associated with white matter hyperintensity volume: the Northern Manhattan Study (NOMAS).

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