Stroke in Patients with Kidney Diseases: A Not-So-Silent Killer?

In February 2020, while news of a novel virus was beginning to spread beyond the eastern hemisphere, a multidisciplinary group of experts convened in Dublin as part of Kidney Disease: Improving Global Outcomes' (KDIGO's) fourth clinical Controversies Conference on the heart, kidney, and vasculature (1). Of the many goals that the committee set out to achieve, one priority was to address existing knowledge gaps regarding cerebrovascular disease in patients with advanced chronic kidney disease (CKD).

Although cardiac disease is one of the leading causes of death in patients with end stage kidney disease, the relationship between non-cardiac vascular diseases and kidney diseases is not well understood. A recent review article by Bobot et al. (2) discusses an important, but often ignored, cause of significant morbidity and mortality in patients with underlying kidney diseases: stroke. The incidence of stroke is 13.4 per 1000 person-years in patients with CKD, and this increases for patients receiving dialysis (2). Understanding the unique features of this patient population allows us to provide better and more targeted care.

Although there are traditional risk factors, such as diabetes and hypertension, that predispose patients with kidney diseases to stroke, there are also kidney disease-related, non-traditional risk factors. These include the accumulation of uremic toxins, reactive oxygen radicals, and increased inflammatory products. In addition, patients receiving hemodialysis also have dialysis-specific risk factors, such as left ventricular hypertrophy, vascular calcifications, dialysis-induced dysregulation of cerebral blood flow, and intradialytic hemodynamic instability. More information is needed regarding the interplay of these risk factors to optimize and identify novel therapeutic targets.

Most of the current available therapies revolve around prevention and lifestyle modification. Anti-hypertensive agents, lipid-lowering therapies, and sodium-glucose cotransporter-2 inhibitors comprise the majority of current preventative therapies. As for individuals receiving hemodialysis, certain adjustments to the dialysis prescription and using cooled dialysate can lead to fewer hemodynamic variations during treatments.

Despite the increased morbidity in patients with advanced kidney diseases, fewer therapeutic options are available to them in cases of an acute stroke. For example, patients with CKD have less access to revascularization techniques, like thrombolysis and thrombectomy (3). Also, patients with advanced kidney diseases and those receiving dialysis are typically excluded from or under-represented in large randomized clinical trials. The ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study) trial was a multicenter, randomized trial comparing low-dose to standard-dose alteplase in patients with acute ischemic stroke. Patients with an estimated glomerular filtration rate <30 mL/min/1.73 m² had a twofold increased mortality risk compared with those with normal kidney function (4). However, patients with advanced kidney diseases comprised only about 3% of the study population. Since patients with advanced kidney diseases are disproportionately affected, more trials are needed that include this unique population to decipher optimal management.

The 2020 KDIGO meeting was the first step in describing best practices in the diagnosis and management of patients with dialysis and cerebrovascular disease, as well as proposing areas that require further research and investigation. Many aspects of care remain unanswered, and further research is needed to better elucidate the pathophysiological mechanisms that predispose patients with kidney diseases to higher rates of cerebrovascular disease.