Dialysis on the Mind: The Evolution of Hemodialysis-Related Acute Brain Injury

In recent years, there has been growing interest in the "kidney-brain axis" as the burden of stroke, cerebral small vessel disease and cognitive dysfunction in patients with CKD is increasingly recognized.¹ Structural brain changes, including silent cerebral infarctions, white matter hyperintensities, and cerebral atrophy, have been well-described in hemodialysis-dependent patients and shown to portend cerebrovascular and all-type vascular events, as well as vascular cognitive impairment and executive dysfunction.

Kidney function, as determined by eGFR, demonstrates an inverse step-wise relationship with incident stroke risk, increasing by 3-fold, 4.1-fold, 5.4-fold, and 7.1-fold for CKD stage 3–5 and dialysis compared with the general population.² Peridialysis initiation is a particularly vulnerable period for acute stroke because the 30-day period before and after dialysis initiation is associated with a 3-fold increase in stroke, TIA, or recurrent stroke risk.³ Hemodialysis patients seem to be at particularly high risk of stroke compared with peritoneal dialysis patients and kidney transplant recipients, which suggests intrinsic risk factors, although selection bias and confounding factors remain.⁴

Severe cognitive impairment has been reported in more than one third of hemodialysis patients, which is more than triple the estimated prevalence of dementia in US population-based studies of non-ESKD participants.⁵ Furthermore, the 10-year risk of dementia after commencing hemodialysis is 20% at age 65 years, increasing linearly with age.⁶ The pattern of vascular cognitive impairment with deficits in attention and executive function is most commonly described.

Multiple mechanisms may underpin these cerebro-renal associations, but changes in cerebrovascular physiology may contribute to susceptibility because eGFR is independently associated with lower cerebral blood flow.⁷ These changes may be accentuated in dialysis-dependent patients because global cerebral blood flow acutely declines by 10% during an intermittent hemodialysis session.⁸ Myocardial stunning can develop during hemodialysis, causing or worsening preexisting cerebral hypoperfusion. Such circulatory stress could produce cumulative ischemic brain insults, resulting in “hemodialysis-related acute brain injury.”⁹

In a prior hemodialysis study, intradialytic hypotension below a mean arterial pressure of 60 mmHg was associated with a marked increase in ischemic events as represented by cerebral oxygen desaturation measured using near-infrared spectroscopy. ¹⁰ These transient intradialytic cerebral ischemic events correlated with decreased executive dysfunction 1 year later.

Similarly, in a prospective observational cohort study of 97 maintenance hemodialysis patients, cerebral arterial mean flow velocity measured using transcranial Doppler ultrasound declined significantly during dialysis. This decline correlated with acute intradialytic decline in cognition, including global function, executive function, and verbal fluency.¹¹ The decline in cerebral blood flow also correlated significantly with progression of white matter burden and cerebral atrophy on brain magnetic resonance imaging (MRI) at 12 months of follow-up.

In this issue of the JASN, Udunna Anazodo and colleagues rigorously investigate this hypothesis of hemodialysis-related acute brain injury by performing detailed intradialytic cognitive and neuroimaging phenotyping of 17 hemodialysis patients.¹² These patients underwent intradialytic anatomical MRI, diffusion tensor imaging, and proton magnetic resonance spectroscopy (1H-MRS) to examine the acute impact of hemodialysis on the brain structure and neurochemistry relevant to ischemia. A key finding was that multiple white matter tracts developed diffusion imaging changes characteristic of cytotoxic edema with increase in global brain volumes. The investigators also observed intradialytic decreases in 1H-MRS—measured prefrontal N-acetyl aspartate and choline concentrations during hemodialysis, consistent with energy deficit, perfusion anomaly, and regional ischemia.

This study elegantly demonstrates, for the first time, that significant intradialytic changes occur in brain volume, white matter diffusion metrics, and brain metabolite concentrations consistent with cerebral hypoperfusion and ischemic injury, providing direct evidence of acute brain injury during a single hemodialysis treatment session. In the context of previous studies^10,11 that provided evidence of longitudinal structural white matter injury and cognitive changes associated with intradialytic ischemic events, these findings suggest that hemodialysis may be associated with longer-term brain injury and that it may play an important role in cognitive decline.

Hemodialysis patients have impaired vascular compliance and cerebral autoregulation, rendering them less well able to buffer against hemodynamic shifts on dialysis and more susceptible to ischemic brain injury. They exhibit a well-defined pattern of white matter injury^10,11 not only correlated with cognitive decline but also strongly associated with elevated risk of ischemic stroke, as well as deficiencies in gait and balance performance.¹³

This study raises many questions. Are other modalities of dialysis associated with a similar profile of brain injury, or do they offer better cerebral protection? Continuous renal replacement therapy (CRRT) has been proposed to be associated with greater intracranial stability compared with standard intermittent hemodialysis and/or hemofiltration because of its slower blood flow rates and changes in osmolality and urea levels. For this reason, CRRT is generally recommended as the dialysis modality of choice for patients with acute brain injury. However, this is a consensus-based recommendation rather than an evidence-based one.¹⁴

There is evidence that dialysate cooling may protect against hemodialysis-induced brain injury by increasing hemodynamic stability and reducing circulatory stress. A group of 73 hemodialysis patients randomized to 0.5°C below their core body temperature and followed for 1 year had better preservation of brain white matter microstructure parameters, including fractional anisotropy, axial diffusivity, and radial diffusivity, when compared with those dialyzed at 37°C.⁹ Kidney transplant has also been associated with improvement in white matter parameters, including fractional anisotropy (a measure of cerebral diffusion), memory, and executive function.¹¹

Direct evidence of dialysis-mediated ischemic brain injury in a group that bears such a disproportionate burden of stroke and dementia is striking. However, although this study presents compelling evidence of acute brain injury, the relationship between cumulative hemodialysis-induced white matter damage and longer-term stroke and cognitive risk has yet to be fully established. Nonetheless, this study should be a call to arms to the nephrology community to find ways to prevent and mitigate this acute brain injury through greater research prioritization and clinical trials of potential cerebroprotective dialysis interventions.

Disclosures

The author has nothing to disclose.

Funding

D.M. Kelly is an Atlantic Fellow for Equity in Brain Health at the Global Brain Health Institute (GBHI) and is supported with funding from GBHI, Alzheimer's Association, and Alzheimer's Society (GBHI ALZ UK-22-868940).

Author Contributions

Conceptualization: Dearbhla M. Kelly.

Writing – original draft: Dearbhla M. Kelly.

Writing – review & editing: Dearbhla M. Kelly.