Reducing Hemodialysis Induced Recurrent Brain Injury to Improve Patients' Lives

Hemodialysis patients suffer severe cognitive impairment: Abnormalities of cognitive impairment (predominately sub-cortical defects in executive decision making) are almost universal in hemodialysis (HD) patients and appear early after starting dialysis. Around 75% of patients exhibit mild cognitive impairment (MCI) and a high proportion (˜15%) have dementia. Mechanisms of injury: It has been demonstrated that HD associated circulatory stress and recurrent regional ischemia drives brain injury. The extent of injury is determined by the degree of BP instability during HD. Peritoneal dialysis patients are not subject to the same stress and retain cognitive abilities. The injury is multifactorial, and amenable to HD based intervention. Optimizing dialysis to minimize harm requires understanding the wide range of potential of pathophysiological processes contributing to this injury. Putative components of pathophysiology that might be amenable to intervention include: a) Direct reduction in tissue perfusion is the characteristic consequence of HD driven multi-organ injury. The investigators have directly visualized this in multiple organ beds during dialysis (heart, gut and kidney), and have inferred it in the brain from the development of ischemic based white matter (WM) injury. b) Inflammation drives WM injury.Endotoxin (derived from gut bacteria) is profoundly pro- inflammatory and translocates from intestinal lumen into the circulation during HD treatment directly causing WM inflammation. Daily HD (gentler fluid removal) normalizes endotoxemia and markers of inflammation. c) Release of the excitotoxic neurotransmitter, glutamate, produces injury in ischemia. Plasma levels are lower in HD patients with less ongoing brain injury. Removal of glutamate by dialysis significantly reduces ischemic injury severity and functional consequences. Previous success in protecting the brain during dialysis: The Investigator recently completed a successful multi- centre RCT of cooled dialysis fluid to abrogate WM progressive injury- strongly supporting the integral role that the HD process plays in brain injury. Hemodialysis patients have specific patterns of progressive brain injury: Currently the problem of dialysis induced functionally significant brain injury is typically not well recognized or a focus of care. Leukoaraiosis describes rarefaction of brain WM, typically associated with vascular cognitive impairment. It is universally present in HD patients (even when correcting for BP). Severity of reduction in cognitive function is proportional to the amount of WM injury, with a predominant loss of subcortical functions (executive functioning). The Investigators have previously demonstrated that the signature of the change in fractional anisotropy in dialysis patients was entirely explained by changes in radial diffusivity, rather than axial diffusivity- pathognomonic of a vascular etiology. Urgent need to develop additional interventions: Although dialysis fluid cooling appears to be effective in helping to protect against WM injury, there are limitations. The degree of cooling that can be applied is limited in some patients by cold symptom tolerability and effectiveness has only been tested in patients new to HD. Patients with more established injury may require additional therapies. These need to be suitable for combination with other emerging dialysis based therapies. Ideally they will be universally applicable, independent of dialysis machine type, low-cost, safe, well tolerated, and simple-requiring few healthcare resources to apply. Remote ischemic preconditioning (RIPC): Ischemic conditioning occurs when a transient non-lethal episode of ischemia reduces the effect of a subsequent larger insult. Similar levels of protection can be achieved by applying brief episodes of ischemia (with a BP cuff on a limb) remote from a target organ. Successful clinical studies using RIPC have been performed to provide protection against ischemia in many organs, including acute stroke, and can prevent leukoaraiosis in animal models. RIPC provides protection against HD-induced acute myocardial injury: The investigators have recently completed a pilot RCT demonstrating a RIPC intervention reduced HD-induced acute cardiac injury by 50%, after only a single application. This effect was maintained over a period of 28 days. RIPC was effective, safe and well tolerated. The investigators are currently engaged in a larger Canadian based study to refine the optimum RIPC regime to provide protection against HD-induced cardiac injury. Interim analysis of this study has confirmed similar levels of efficacy in a Canadian population and allowed us to select the maximally effective RIPC regime, for use in the current proposed study. Clear translational pathway: This project is conceived in an integrated framework of new therapeutic target discovery, intervention development and sequential testing of safety and efficacy. The investigators will use clinically relevant surrogate imaging endpoints for rapid evaluation and refinement of candidate intervention, prior to large-scale testing with survival-based endpoints. The Investigators have already developed a prototype phase III equivalent study. MY-TEMP is an Ontario based cluster randomized study of individualized dialysate cooling (trials registration NCT 02628366), funded in partnership by the Heart and Stroke Foundation, Ontario Ministry of Health and US based large dialysis provider organizations. All 7000 patients will be randomized in Q3 2016. Impact: HD patients characteristically suffer from cognitive impairment. Understanding the mechanisms behind this will allow the development of therapies integrated into dialysis treatment delivery (anti-ischemic, but potentially also directed at issues such as inflammation and dialyzable injury factors), helping patients maintain cognitive vitality, independence and maximize quality of life.