Increased Blood-Brain Barrier Permeability and Cognitive Impairment in Patients With ESKD

Abstract

Introduction: Chronic kidney disease (CKD) is associated with an increased risk of cognitive impairment. This cognitive impairment is associated with an increased permeability of blood-brain barrier (BBB) in rodents with CKD, linked to activation of aryl hydrocarbon receptor (AhR) by indoxyl sulphate (IS). The objective of the BREIN study was to confirm the increased BBB permeability in humans with CKD.

Method: The BREIN comparative study (NCT04328415) prospectively included patients with end-stage kidney disease (ESKD) and controls healthy volunteers matched in age, sex, and level of education to a patient. In all participants, BBB permeability was quantified by brain ^99mTc-DTPA SPECT/CT as a percentage of injected activity (% IA). A battery of neurocognitive tests was performed, and serum uremic toxins accumulation and AhR activation were assessed.

Results: Fifteen patients with ESKD and 14 healthy volunteers were analyzed. Patients with ESKD had higher BBB permeability compared to controls: 0.29 ± 0.07 versus 0.14 ± 0.06 %IA, P = 0.002. Patients with ESKD displayed lower Montreal Cognitive Assessment test (MoCA) score: 22.0 ± 5.0 versus 27.3 ± 2.8, P = 0.008; impaired short-term memory (doors test): 12.5 ± 3.4 versus 16.5 ± 3.4, P = 0.005; higher Beck depression score 8.1 ± 9.1 versus 2.7 ± 3.4, P = 0.046; and slightly more daily cognitive complaints: 42.5 ± 29.3 versus 29.8 ± 14.0 P = 0.060. Patients with ESKD displayed higher IS levels (86.1 ± 48.4 vs. 3.2 ± 1.7 μmol/l, P = 0.001) and AhR activating potential (37.7 ± 17.8% vs. 24.7 ± 10.4%, P = 0.027). BBB permeability was inversely correlated with MoCA score (r = -0.60, 95% confidence interval [-0.772 to -0.339], P = 0.001) in the overall population.

Conclusion: Patients with ESKD display an increased BBB permeability compared to matched healthy volunteers. Association with uremic toxins and cognitive impairment needs to be assessed in larger cohorts of patients.

Keywords: blood-brain barrier; chronic kidney disease; cognitive impairment; indoxyl sulphate; kidney-brain axis; uremic toxins.

Graphical abstract

Figure 1

Study design. BBB, blood-brain barrier; ESKD, end-stage kidney disease; HD, hemodialysis session; MoCA, Montreal Cognitive Assessment; SPECT/CT, single-photo emission computed tomography coupled with computed tomography scanner.

Figure 2

Blood-brain barrier permeability by brain (^99mTc)-DTPA SPECT/CT imaging in patients and controls. Ctrl, controls (healthy volunteers); ESKD, end-stage kidney disease; % IA, percentage of injected activity.

Figure 3

Front and profile 3D maximal intensity projection (MIP) of (^99mTc)-DTPA SPECT/CT of a healthy volunteer (A; % IA = 0.0697) and a patient with end-stage kidney disease (B; % IA = 0.4136).