Endothelial glycocalyx alterations in hemodialysis patients
|PhD ceremony:||J. Koch|
|When:||January 16, 2023|
|Supervisors:||dr. J. van den Born, dr. C.F.M. (Casper) Franssen|
|Where:||Academy building RUG|
|Faculty:||Medical Sciences / UMCG|
Hemodialysis patients have a very high prevalence of cardiovascular complications and endothelial dysfunction. Endothelial dysfunction can happen by disturbances of the luminal endothelial layer, the endothelial glycocalyx (eGC). Especially patients with chronic kidney disease (CKD) and hemodialysis patients have eGC dysfunction and/or damage. In this thesis, we provide direct evidence of eGC dysfunction/ damage by showing loss of the eGC marker Ulex europaeus agglutinin 1 and increased endothelial activation (VEGFR2) in CKD and hemodialysis patients, which we demonstrated by immunofluorescence stainings in dermal microvasculature. These changes were related to increased volume makers (i.e. increased NT-proBNP levels). Furthermore, we showed that higher plasma levels of the eGC plasma marker syndecan-1 are associated with a lower incidence of cardiovascular events, longer survival and less volume overload in hemodialysis patients. Thus, higher plasma syndecan-1 may reflect increased (endothelial) regenerative capacity. In a cross-over study, we compared the intradialytic course of plasma syndecan-1 levels between standard hemodialysis and Hemocontrol, a modality with initially higher dialysate sodium levels. Here, plasma syndecan-1 levels rose earlier and to a greater extent during Hemocontrol, suggesting that higher plasma sodium is a trigger for glycocalyx shedding. Lastly, we evaluated the effects of the phosphate hormone fibroblast growth factor 23 (FGF23) on the eGC and its underlying cortex by atomic force microscopy. Patient sera with high plasma levels of FGF23 reduced eGC height and stiffened the eGC and cortex. Recombinant c-terminal but not intact FGF23 induced similar effects suggesting that cFGF23 is a dominant trigger for endothelial disfunction.