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

The evolving role of PET imaging in Nephrology

Positron emission tomography (PET) is a nuclear imaging modality that provides functional imaging of structures based on their ability to metabolize glucose and concentrate specific molecules that have been labeled with a positron-emitting radionuclide. Metabolically active cells (e.g, malignant or inflammatory) utilize and import more glucose than other tissues and, thus, take up 18F-fluorodeoxyglucose (18F-FDG) more avidly. Integrated PET/CT is preferred, because it allows for more exact anatomic localization of isotope uptake and more accurate staging of cancers. PET is escaping oncology however and starting to find a role in nephrology.

In post-transplant lymphproliferative disorders, integrated PET/CT is used as a measure of disease activity. It has also been reported to differentiate fat-poor angiomyolipomas from renal cell carcinoma with 94% sensitivity and 98% specificity. Integrated PET/CT scanning may also be of utility in differentiating benign versus malignant fractures and highlighting impending ones in patients with multiple myeloma.

What about APKD? Cyst infection is common and may be difficult to diagnose in the presence of sterile urine. Bobot et al compared PET-CT to CT and MRI for a diagnosis of cyst infection. Cyst wall hypermetabolism was considered as a positive PET-CT result. A diagnosis of cyst infection was made in 18 of 32 cases: 14 with positive PET-CT findings, and 4 false negatives. There were no false positives and no hypermetabolism of cyst walls in 9 ADPKD control patients. PET-CT had a sensitivity of 77%, a specificity of 100%, and a negative predictive value of 77% compared to CT alone which had a sensitivity of 7% and a negative predictive value of 35%. Radiation doses were comparable and injection of nephrotoxic contrast was avoided in the former.

Similarly PET-CT may be useful the detection of vasculitis in the large arteries with 29/35 patients with known giant cell arthritis showing active arterial inflammation (sensitivity >80%) . Patients suffering from granulomatosis polyangiitis (GPA) show marked aortic FDG uptake although it is unclear whether this is indicative of atherosclerosis or large vessel involvement. If it is indeed the latter this calls into question the traditional classification of vasculitis. FDG-PET/CT accurately identified organ localizations in 16 patients with GPA, other than in nervous system, eye and skin, but may not bring additional benefit to the usual organ screening.

Retroperitoneal fibrosis is a rare fibro-inflammatory disorder that is most commonly idiopathic (>75%) and part of the IgG4-disease related spectrum. PET-CT has emerged as a useful tool for the assessment of disease activity and also detects any post-treatment residual disease. It may lead to early diagnosis of relapses and may also detect diseased sites other than the peri-aortoiliac tissue.

Could PET imaging have a role in the detection of occult malignancy, inflammation or infection in secondary glomerulonephritis? If we extrapolate from studies involving venous thromboembolism (VTE), a prospective cohort of 99 patients with a first episode of VTE reported occult cancer identified by PET/CT in 23% of cases with a sensitivity and negative predictive value of 77% and 97% respectively. However this sensitivity is still too low to justify its use as a widespread screening tool in this capacity as nearly 1/4 cancers may be missed.

Patients with ESRD undergoing maintenance hemodialysis are highly susceptible to infections. Of 104 study patients, 73 (70.2%) had positive 18F-FDG PET/CT findings, and a total of 95 major infection foci were identified. 7 (53.8%) of the 13 patients with primary vascular access-related infections had concurrent metastatic foci. 28 patients (26.9%) had their treatments modified by PET/CT results. In this population, positive PET/CT findings led to a significant change in clinical management and independently predicted mortality.

PET/CT may also help non-invasively prevent avoidable transplant biopsies in kidney transplant recipients with suspected antibody-mediated rejection. In 31 transplant recipients, PET/CT was performed in those who underwent biopsy with a positive correlation between mean SUV and acute composite Banff score (r2 =0.49). The area under the receiver operating characteristic curve was 0.93, with 100% sensitivity and 50% specificity using a mean SUV threshold of 1.6.

But are there any side-effects or limitations to use of PET-CT in our patients? For example, use of IV contrast may be precluded in certain cases of renal impairment and this may impair the optimal detection of small lung and liver lesions. IV contrast increases lesion conspicuity, which is of particular importance in the evaluation of lesions that do not always accumulate FDG. However use of PET-CT without IV contrast has become more widespread and differentiation of benign from malignant lesions is less relevant in Nephrology. The whole-body FDG distribution in patients on hemodialysis may be different from those with normal renal function, because they lack urinary FDG excretion and remain in a constant volume overload. There may be significantly higher physiological FDG uptake in the soft tissues, spleen and blood pool.

In conclusion, I believe that combined PET-CT imaging has the potential to be a very useful and versatile tool for Nephrologists. Whether we are dealing with metastatic infections, occult malignancy, suspicious GN or vasculitic relapses, it may be a revealing diagnostic test at times when our concern exceeds the objective evidence that we have to hand. That said, it is not without cost or risk, and therefore should only be employed judiciously when likely to change clinical management.

Post by Dearbhla Kelly,

NSMC Intern