Clinic for Nephrology and Intensive Care Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Campus Virchow-Clinic, Augustenburger Platz 1, 13353, Berlin, Germany.
Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Sci Rep. 2021 Jan 13;11(1):1144. doi: 10.1038/s41598-020-80016-7.
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.
由于心血管疾病发病率过高，终末期肾病患者的死亡率远远超过普通人群。大分子量物质（LMM），包括促炎细胞因子，是导致尿毒症心血管毒性的主要因素，而常规高通量（HFL）血液透析不能充分清除这些物质。我们检测了 19 名接受高流量（HFL）与高截留（HCO）透析膜对比试验的血液透析患者的血浆，这些患者的血浆可以促进间充质基质细胞（MSC，血管前体细胞）钙化。HCO 透析可改变血浆成分，降低促钙化活性，有利于清除 LMM。与常规 HFL 相比，HCO 透析更有效地清除了包括 FGF23 在内的 LMM，我们发现 FGF23 可促进 MSC 的成骨细胞分化。在筛选实验中，具有已知心血管毒性的蛋白结合尿毒症潴留溶质（而非 LMM）抑制 MSC 增殖，但无直接毒性。我们无法将 HCO 透析对 MSC 钙化的影响归因于特定的介质。然而，我们发现炎症持续减轻的证据，这可能与改变细胞外囊泡的生成等其他抗钙化机制平行。我们的研究结果表明，针对 LMM 清除的新型透析技术可以保护 MSC 免受功能失调的分化。HCO 透析可能会保留其在血管再生中的生理作用，并改善透析患者的预后。
