Abstract
Mortality of patients with end-stage renal disease tremendously exceeds that of the general population due to excess cardiovascular morbidity. Large middle-sized molecules (LMM) including pro-inflammatory cytokines are major drivers of uremic cardiovascular toxicity and cannot be removed sufficiently by conventional high-flux (HFL) hemodialysis. We tested the ability of plasma from 19 hemodialysis patients participating in a trial comparing HFL with high cut-off (HCO) membranes facilitating removal of LMM to induce calcification in mesenchymal stromal cells (MSC) functioning as vascular progenitors. HCO dialysis favorably changed plasma composition resulting in reduced pro-calcific activity. LMM were removed more effectively by HCO dialysis including FGF23, a typical LMM we found to promote osteoblastic differentiation of MSC. Protein-bound uremic retention solutes with known cardiovascular toxicity but not LMM inhibited proliferation of MSC without direct toxicity in screening experiments. We could not attribute the effect of HCO dialysis on MSC calcification to distinct mediators. However, we found evidence of sustained reduced inflammation that might parallel other anti-calcifying mechanisms such as altered generation of extracellular vesicles. Our findings imply protection of MSC from dysfunctional differentiation by novel dialysis techniques targeted at removal of LMM. HCO dialysis might preserve their physiologic role in vascular regeneration and improve outcomes in dialysis patients.
Highlights
Mortality of patients with end-stage renal disease tremendously exceeds that of the general population due to excess cardiovascular morbidity
We studied the effect of high cut-off (HCO) dialysis on phenotype conversion of mesenchymal stromal cells (MSC) functioning as vascular progenitors to osteoblast-like calcifying cells involved in uremic media calcification
Pre-dialytic plasma obtained from patients after 3 weeks of HCO dialysis was more than one third less potent to facilitate osteoblastic differentiation and calcification in MSC compared to HFL dialysis
Summary
Mortality of patients with end-stage renal disease tremendously exceeds that of the general population due to excess cardiovascular morbidity. Large middle-sized molecules (LMM) including pro-inflammatory cytokines are major drivers of uremic cardiovascular toxicity and cannot be removed sufficiently by conventional high-flux (HFL) hemodialysis. An alternative promising strategy with recent technical advances is enhanced removal of LMM by dialysis membranes with higher molecular weight cut-offs (HCO) between 50 and 60 kDa similar to healthy kidneys[5]. As an example, this approach has been shown to reduce. Protection of the undifferentiated physiologic state of MSC preserving their regenerative properties holds promise to offset accelerated vascular calcification in patients suffering from chronic kidney disease more effectively than strategies solely targeted at VSMC with a terminally differentiated phenotype. We describe the effects of HCO dialysis on osteoblastic differentiation and calcification of MSC and investigate possible protective mechanisms
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