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Blood-incompatibility is an inevitability of all blood-contacting device applications and therapies, including haemodialysis (HD). Blood leaving the environment of blood vessels and the protection of the endothelium is confronted with several stimuli of the extracorporeal circuit (ECC), triggering the activation of blood cells and various biochemical pathways of plasma. Prevention of blood coagulation, a major obstacle that needed to be overcome to make HD possible, remains an issue to contend with. While anticoagulation (mainly with heparin) successfully prevents clotting within the ECC to allow removal of uraemic toxins across the dialysis membrane wall, it is far from ideal, triggering heparin-induced thrombocytopenia in some instances. Soluble fibrin can form even in the presence of heparin and depending on the constitution of the patient and activation of platelets, could result in physical clots within the ECC (e.g. bubble trap chamber) and, together with other plasma and coagulation proteins, result in increased adsorption of proteins on the membrane surface. The buildup of this secondary membrane layer impairs the transport properties of the membrane to reduce the clearance of uraemic toxins. Activation of complement system-dependent immune response pathways leads to leukopenia, formation of platelet-neutrophil complexes and expression of tissue factor contributing to thrombotic processes and a procoagulant state, respectively. Complement activation also promotes recruitment and activation of leukocytes resulting in oxidative burst and release of pro-inflammatory cytokines and chemokines, thereby worsening the elevated underlying inflammation and oxidative stress condition of chronic kidney disease patients. Restricting all forms of blood-incompatibility, including potential contamination of dialysis fluid with endotoxins leading to inflammation, during HD therapies is thus still a major target towards more blood-compatible and safer dialysis to improve patient outcomes. We describe the mechanisms of various activation pathways during the interaction between blood and components of the ECC and describe approaches to mitigate the effects of these adverse interactions. The opportunities to develop improved dialysis membranes as well as implementation strategies with less potential for undesired biological reactions are discussed., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA.)

Background: Calcific uraemic arteriolopathy (CUA; calciphylaxis) is a rare disease seen predominantly in patients receiving dialysis. Calciphylaxis is characterized by poorly healing or non-healing wounds, and is associated with mortality, substantial morbidity related to infection and typically severe pain. In an open-label Phase 2 clinical trial, SNF472, a selective inhibitor of vascular calcification, was well-tolerated and associated with improvement in wound healing, reduction of wound-related pain and improvement in wound-related quality of life (QoL). Those results informed the design of the CALCIPHYX trial, an ongoing, randomized, placebo-controlled, Phase 3 trial of SNF472 for treatment of calciphylaxis., Methods: In CALCIPHYX, 66 patients receiving haemodialysis who have an ulcerated calciphylaxis lesion will be randomized 1:1 to double-blind SNF472 (7 mg/kg intravenously) or placebo three times weekly for 12 weeks (Part 1), then receive open-label SNF472 for 12 weeks (Part 2). All patients will receive stable background care, which may include pain medications and sodium thiosulphate, in accordance with the clinical practices of each site. A statistically significant difference between the SNF472 and placebo groups for improvement of either primary endpoint at Week 12 will demonstrate efficacy of SNF472: change in Bates-Jensen Wound Assessment Tool-CUA (a quantitative wound assessment tool for evaluating calciphylaxis lesions) or change in pain visual analogue scale score. Additional endpoints will address wound-related QoL, qualitative changes in wounds, wound size, analgesic use and safety., Conclusions: This randomized, placebo-controlled Phase 3 clinical trial will examine the efficacy and safety of SNF472 in patients who have ulcerated calciphylaxis lesions. Patient recruitment is ongoing., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA.)