High cut-off dialysis mitigates pro-calcific effects of plasma on vascular progenitor cells

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.

Vascular calcification: from the perspective of crosstalk

“…Elevated levels of fibroblast growth factor 23 (FGF23) and phosphate have been recognised as cardiotoxins causing left ventricular hypertrophy and cardiac fibrosis, among others, and their elevated levels are strongly associated with cardiovascular disease in CDK patients [ 313 – 315 ]. FGF23 can promote MSC of vascular progenitor cells towards osteoblastic differentiation and calcification, leading to excessive deposition of calcified ECM [ 316 ]. By testing uremic plasma from 19 end-stage renal disease dialysis patients, it was found that using the novel dialysis technology HCO membrane compared to conventional high-flux haemodialysis (HFL), HCO membrane can effectively remove pro-inflammatory factors including FGF23 to alter plasma composition and thereby protect vascular progenitor cells from calcification [ 316 ].…”

“…FGF23 can promote MSC of vascular progenitor cells towards osteoblastic differentiation and calcification, leading to excessive deposition of calcified ECM [ 316 ]. By testing uremic plasma from 19 end-stage renal disease dialysis patients, it was found that using the novel dialysis technology HCO membrane compared to conventional high-flux haemodialysis (HFL), HCO membrane can effectively remove pro-inflammatory factors including FGF23 to alter plasma composition and thereby protect vascular progenitor cells from calcification [ 316 ]. Another study showed that in vitro, conversion of hemodialysis patients from bicarbonate hemodialysis (BHD) to mixed online hemodiafiltration (mOL-HDF) treatment significantly reduced the expression of miR-223 in plasma-derived EVs, which was associated with osteogenic differentiation of VSMCs [ 259 ].…”

“…Another study showed that in vitro, conversion of hemodialysis patients from bicarbonate hemodialysis (BHD) to mixed online hemodiafiltration (mOL-HDF) treatment significantly reduced the expression of miR-223 in plasma-derived EVs, which was associated with osteogenic differentiation of VSMCs [ 259 ]. This technique may parallel the altered extracellular vesicle production in the anti-calcification mechanism, but further research is needed to determine whether the novel dialysis technique can actually reduce cardiovascular loss and contribute to angiogenesis and improve the prognosis of dialysis patients [ 316 ]. We summarize the potential benefits of EVs as therapeutic agents for calcification in Table 2 .…”