BBB-UT · Deciphering the role of the blood-brain barrier in uremic toxins-induced neuropathies

Deciphering the role of the blood-brain barrier in uremic toxins-induced neuropathies

Importance of the project: Chronic kidney disease (CKD) is a common and long-term pathology characterized by a progressive loss of kidney structure and function. Currently, CKD is underdiagnosed mainly because of a lack of symptoms until the advanced stages. Without effective patient care, the disease develops into End-Stage Kidney Disease (ESKD) when the kidneys are no longer able to carry out their cleansing function. Moreover, several CKD patients suffer from associated pathologies, including neurological disorders such as cognitive impairment or dementia. These CKD-related neuropathies worsen the quality of life of the patients and are still poorly understood. Over the past years, the substantial burden of CKD and the increased prevalence of ESKD have been highlighted. This trend is likely due to the ageing population, Western lifestyle evolution and the significant increase in related diseases such as diabetes and hypertension. In Europe, CKD affects nearly 100 million people, and it is projected to become the fifth leading cause of death globally by 2040. In addition, CKD is among the most expensive diseases for health care systems, with a cost estimated at EUR 140 billion annually in Europe. Face to these dismal projections, there is an urgent need to implement an EU action focused on CKD, including CKD-associated pathologies. Research hypothesis, objectives and collaborative network: I hypothesize that the reduction in kidney tubular transporters’ functionality in CKD leads to (1) the systemic retention of protein-bound uremic toxins (PBUTs), (2) a disruption of the blood-brain barrier (BBB) integrity and (3) a reduction in the activity of BBB-endothelial cell (BBBec) membrane transporters. This phenomenon could play a part in the evolution of CKD-associated neurological pathologies (e.g., uremic encephalopathy and cognitive impairment) driven by the kidney-brain crosstalk impairment. This project aimed to develop an appropriate and innovative multi-organs-on-chip model to decipher underlying mechanisms of CKD-induced neurotoxicity. The project was achieved using a combined biofabrication and experimental approach, following research objectives: (i) Development of an appropriate physiologically based BBB-on-chip (ii) Characterization of the impact of PBUTs on BBB integrity and propriety (iii) Elaboration of a multi-organ-on-chip system to recapitulate the kidney-brain crosstalk (iv) Assessment of kidney tubular function on BBB uremic toxins-exposure and toxicity This fellowship was carried out at the Division of Pharmacology of Utrecht Institute for Pharmaceutical Sciences (Utrecht University, NL) under the supervision of Prof. dr. Roos Masereeuw. This fellowship aimed at developing bioengineered, animal-free and advanced in vitro models to tackle a major healthcare problem through a collaborative and multi-scale approach (from polymer to human) including biofabrication and 3D printing and in vitro barrier function modelling.

Data: CORDIS, © European Union