ABSTRACT
The hemodialysis (HD) population carries a substantial burden of cognitive impairment and ischemic brain
pathology, especially small vessel ischemic disease with white matter disease, lacunae, and atrophy. Risk of
cognitive impairment in HD patients is twice that of peritoneal dialysis patients, suggesting the HD process
itself may contribute to ischemic brain pathologies and the associated cognitive impairment. Conventional HD
is associated with myocardial dysfunction and intravascular fluid shifts, which can lead to significant decline in
blood pressure (BP) during the HD session. To maintain cerebral perfusion during decline in systemic BP the
downstream cerebral microvasculature must vasodilate, a physiological response that occurs as part of
cerebral autoregulation (CA). The same vasodilation occurs in response to chemo stimuli (i.e. pCO2) using
cerebrovascular reactivity (CVR) mechanisms. In the HD population, increased arteriosclerosis, diabetes,
hypertension, inflammation, and vascular calcification may combine to impair these cerebral blood flow
regulatory mechanisms and lead to increased risk of cerebral hypoperfusion and ischemia during HD-induced
decline in BP. Through this R03 proposal we will investigate cerebral blood flow regulation during HD by
measuring CVR in an HD cohort and determining if impaired CVR is associated with greater risk of decline in
cerebral perfusion during HD. We focus on CVR as it can be measured safely and non-invasively in older
patients with vasculopathy—compared to inducing hypotension to measure CA—and can be done prior to
dialysis initiation. In Aim 1, we measure CVR in an HD cohort and identify risk factors, including renal disease
specific factors, for lower CVR. We will measure CVR with breath-hold induced hypercapnia and quantify the
change in blood flow velocity through cerebral vessels using transcranial Doppler. In Aim 2, we will measure
the association between CVR and change in cerebral perfusion during HD, to determine if CVR can be used to
identify patients who are at greatest risk for cerebral ischemic disease on HD. This will provide important
clinical knowledge needed to optimize dialysis therapy to avoid cerebral ischemic injury. Finally, in Aim 3 we
will explore the relationship between CVR and CA—distinct mechanisms that control cerebral blood low—to
see if small vessel cerebral vascular disease may be a common underlying pathology to both mechanisms in
HD patients. This proposal will improve our understanding of cerebral blood flow regulation in HD patients, and
determine if CVR can be used to identify patients at risk for cerebral ischemic injury during HD. The results will
inform the design of an R01 evaluating CVR changes over time in pre-dialysis kidney disease patients and
comparing to those on conventional HD and other dialysis modalities (peritoneal dialysis or nocturnal HD) that
avoid rapid BP changes. This information could be used in dialysis decision-making to guide our high-risk
patients to dialytic therapy that is concordant with preserving cognitive capacity.