It is far from clear, however, why (HV)HDF is associated with an improved survival. Both long term and short term effects may be involved. With respect to the latter, the intra-dialytic removal of middle molecular weight (MMW) uremic retention products and a superior bio-incompatibility (BI) profile may play a role. In addition, treatment with HDF may induce less intra-dialytic hypotension (IDH) and less tissue injury. Enhanced removal of the MMW substance FGF23 may reduce the intra-dialytic acute phase reaction (APR), which is regarded a chief element of HD-induced BI. Other key components which may contribute to IDH and are supposed to be alleviated by HDF, include dialysis-induced hypoxia and intra-dialytic extracellular vesicle release. Patho-physiologically, IDH depends both on a decline in the circulating blood volume and an impaired response to hypovolaemia. As a result, venous return, cardiac output and peripheral vascular resistance are impaired. Since IDH is reduced by HD with cool dialysate (C-HD), thermal factors may play an important role.