Dialysis for dementia?

When I first began learning about Nephrology, I came across ‘dialysis dementia’, a progressive and fatal condition described in hemodialysis patients. Several studies in the 1970s implicated aluminium found in phosphorus binders and dialysate water as the cause. However, owing to modern techniques of water purification and the use of non-aluminium phosphorus binders, ‘dialysis dementia’ is now considered a rare adverse effect of dialysis, with a current estimated prevalence of 0.6–1.0%.

Nonetheless, moderate to severe cognitive impairment may affect 30–60% of patients undergoing hemodialysis (HD), and two-thirds of patients undergoing peritoneal dialysis (PD). The current pathophysiology of cognitive impairment in patients on dialysis might be mediated by traditional risk factors, such as older age, sex, diabetes mellitus, hypertension and cardiovascular disease; non-traditional factors, including hyperparathyroidism, elevated FGF-23 levels, vitamin D deficiency, anemia, malnutrition, inflammation, and oxidative stress; and dialysis-associated factors, such as adequacy, dialysis modality, hemodynamic instability during the procedure and solute shifts.

It was with interest then that I read recent research suggesting that peripheral clearance of amyloid-β (Aβ) by PD could help to reduce the amyloid plaque burden in the brain, potentially representing a new therapeutic approach for Alzheimer disease (AD). In this study, plasma Aβ levels before and immediately after PD in patients with CKD and in APP/PS1 mice (a standard animal model of AD) were measured. In both cases, plasma Aβ₄₀ and Aβ₄₂ levels were significantly reduced after dialysis. In the animal model, PD resulted in a decrease in Aβ levels in the brain interstitial fluid with reduced deposition even if plaque formation was well underway. The dialysis-treated mice showed reduced levels of hyperphosphorylated tau in the brain, suggesting a slowing of neurodegeneration along with decreased inflammation and increased microglial phagocytosis of Aβ in the brain. Attenuated cognitive decline was demonstrated by improved performance on the Y-maze and open-field tests.

According to the authors, this was a proof-of-concept study that restoration of the AD brain microenvironment and clearance of brain Aβ could be achieved by peripheral approaches. Yet how do we reconcile this promising experimental model with the high incidence of dementia in our PD patients? Although the USRDS data reports the risk of incident dementia to be lower for patients who started on PD than for those who started on HD, it still higher than the age-matched non-dialysis cohort. The tentative conclusion that we may draw from this is that vascular dementia is likely a far greater contributor to cognitive impairment in this population than AD.

In this study PD was very potent in removing Aβ from the blood in CKD patients. The authors highlight key differences in the PD procedure used in this study compared to standard practice. While CKD patients usually receive continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD) with long dwell times of 8 hours or more, the AD mice received only 2 hours of dialysis per day. This suggests that CAPD may be even more effective at depleting the brain Aβ burden in AD patients. Similarly brain Aβ deposition appears to be lower in patients who receive hemodialysis. 

What are the implications of this study for us as nephrologists? Will we be dialyzing people for ‘dementia’ in the future? Or for other neurodegenerative diseases that may benefit from peripheral clearances such as Huntington disease or motor neuron disease?  More research is definitely needed and there will be side-effects that non-nephrologists may not appreciate but it could be an exciting area in the future.

Post by Dearbhla Kelly