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Dialysis for aging: Removal of SASP

Image credit: https://www.satellitehealth.com/

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Shubhankar Kulkarni
Shubhankar Kulkarni Aug 06, 2020

[1]Tchkonia T, Zhu Y, van Deursen J, Campisi J, Kirkland JL. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest. 2013;123(3):966–972.

[2]Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med [Internet]. 2014 Jun 4;20(6):659–63. Available from: http://www.nature.com/articles/nm.3569

General comments

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Brett M.
Brett M.16 days ago
This is a very interesting idea. I think this has incredible utility if we consider the use of kidney transplants in the aged population, which appear to provide a better quality of life compared to dialysis, specifically in the geriatric population (see https://pubmed.ncbi.nlm.nih.gov/20006794/). Because dialysis can result in a state of "dialysis washout," mainly as a result of restricting blood filtration to ~12-hour dialysis treatments, the rebalancing of the blood in the dialysis-free period (between dialysis treatments) may yield discomfort and shock to the body (not to mention the substantial cost of dialysis = $91,000 USD/year; see https://www.nature.com/articles/d41586-020-00671-8).

Fortunately, there are groups that are attempting to downsize dialysis equipment and cost, and make the treatment more eco-friendly, given standard dialysis in the clinic requires anywhere from 120-180 L per 4 hour session (https://www.nature.com/articles/d41586-020-00671-8). For example, NextKidney has developed an at-home dialysis kit that is more accessible and requires less water (https://www.nextkidney.com/), while surgically implantable kidney prototypes are being constructed in a collaborative effort by researchers at UCSF in San Francisco and Vanderbilt University in Tenessee, USA (https://www.nature.com/articles/d41586-020-00671-8). As well, initiatives such as KidneyX (https://www.kidneyx.org/) are trying to accelerate the ways we treat kidney disease and focuses on the cost, accessibility, and feasibility of innovative approaches to overcome the current challenges.

With this information, I'm seeing two possibly viable options (the first one being more feasible in the near future):

1) Manufacture the at-home dialysis kits to include SASP-specific antibodies that are coated onto the dialysis bags to capture the SASP molecules, in a similar way that enzyme-linked immunosorbent assays (ELISA) are performed to detect unknown volume of antigens in solution (https://en.wikipedia.org/wiki/ELISA).

2) Kidney prototypes that are surgically implanted could include a reservoir of proteolytic enzymes that specifically target SASP molecules. In this context, SASP particles could be filtered into the reservoir perhaps by engineering the prototype with a modified flow cytometry technology (https://en.wikipedia.org/wiki/Flow_cytometry) that can filter molecules based on size and identification of the cells infrastructure. Further channeling of the "toxic" metabolites (for example, excess amino acids yielded from cytokine degradation) could be filtered into the urine and excreted as any other toxin is typically filtered by the original kidneys. This approach would require some serious engineering, but would provide a continuously functioning and incredibly accessible technology to the geriatric population for both dialysis and to promote longevity by filtering SASP molecules.
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Shubhankar Kulkarni
Shubhankar Kulkarni15 days ago
Brett M. Thank you for your comment. Thank you for pointing out the latest developments in dialysis!

Flow cytometry is what I had in mind when I thought of filtering out unnecessary and toxic products. However, as you correctly pointed out, some serious engineering is needed to precisely detect and filter out SASP molecules. What can be done currently is somehow make the senescent cells enter the circulation (for detailed description, see https://brainstorming.com/ideas/removal-of-senescent-cells-via-epithelial-to-mesenchymal-transition/11) and then filter them out using flow cytometry.

I also like the idea of using the ELISA technique here, even that is very specific and, therefore, probably, less harmful (may have fewer side-effects). The tricky part is to replace the bound antibodies with free ones since after the antibodies get saturated, the SASP molecules would not bind and then enter the body again. This replenishment with fresh antibodies could be accomplished using free-floating antibodies in the filtration chamber and then monitoring the concentration of the free antibodies and supplying them once the concentration drops beyond a certain threshold. Simultaneously, the SASP-bound antibodies should be removed from the chamber. The tricky part in the case of using free-floating antibodies is restricting them from entering the patient's body.
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Brett M.
Brett M.15 days ago
Shubhankar Kulkarni No problem! Your idea is very thought-provoking. Thanks for routing me towards the other session - interesting concept of transitioning the cells to become unbound and thus available for filtering.

In the context of using the ELISA technique to provide antibody-specificity, I was thinking more in line that the dialysis bag could be coated with the antibody. Therefore, during each session of dialysis that the patient has, a new bag is used and thus, new antibodies are provided to further remove the SASP molecules from circulation. Your suggestion of free-floating antibodies is a great idea and feasible alternative as well. I'm thinking... maybe the free-floating antibodies could be enzyme-linked with horseradish peroxidase and a colorimetric reaction could be carried out in the bag as antibodies bind the SASP molecules during the dialysis process. In this way, we could visualize in real-time the saturation of antibodies (free-floating or pre-coated) in the dialysis bag... off the top of my head, so I'm hoping this makes sense. But, essentially, by allowing a colorimetric reaction to proceed as antibodies become saturated, this could signal replacement with a new dialysis bag to optimize SASP removal.
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Shubhankar Kulkarni
Shubhankar Kulkarni14 days ago
Brett M. The calorimetric method is a perfect supplement to the free-floating antibodies concept. Yes, the signal from the calorimetric reaction can be used to replace the bound antibodies with fresh ones. When the dialysis bag is coated with antibodies, it might limit the filtration of SASP factors to the quantity of the antibodies present. Extra SASP factors will then enter the body. The way around this is to initially perform a blood test and measure the concentration of the factors and then coat the bag with antibodies accordingly. The downside here may be an increased cost and time consumed due to personalization. The dialysis bag would have to be made-to-order. Furthermore, with age, the concentrations of the SASP factors might change and regular blood tests will be needed before dialysis.
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Brett M.
Brett M.14 days ago
Shubhankar Kulkarni the concentration of antibodies coating the bag is certainly a limitation, you are right there. And, yes, these would have to be monitored to ensure bags are specifically formulated to achieve adequate removal of SASP from the bloodstream. I'm thinking... is the goal here to completely remove SASP particles or to mitigate their influence on aging processes? Or, are you trying to reduce the amount in circulation (which should still have a beneficial effect)?

Speaking to your important consideration about regular blood tests, there may be a way to make this more accessible as well to avoid continuous visits to the doctor or have regularly scheduled in-home blood withdrawals. I'm in the midst of writing about it on brainstorming here, but the utility of smartwatches, wearable devices, and even skin patches (like a Nicoderm patch for smokers) substantially increase the feasibility of at-home dialysis machines. In terms of your concept here, Stanford is developing sensors that detect stress hormone levels (https://www.myhealthyapple.com/stanford-wearable-stress-sensor/) and a wearable silicon-dioxide patch that senses biomarkers such as cytokines in sweat (https://pubs.rsc.org/en/content/articlelanding/2018/NR/C8NR04315A#!divAbstract).

These two innovations can substantially improve our ability to self-monitor. If these products were engineered with your concept in mind here, I see a "smart" technology that continuously monitors SASP concentrations in sweat (would need to confirm if this correlates with blood levels), which would synchronize with an app on a smartphone or smart device. Alternatively, the surgically implanted prototype would have this technology engineered as part of its infrastructure.

From there, a useful function of this technology would be the ability to send automatic updates to the manufacturer to adjust the required concentration of antibodies in the dialysis bag for the next shipment. Kind of like how your smartphone or computer automatically updates to the newest version.

Of course, this still presents the issue that you mentioned of increased cost/time, but I'm thinking that eventually, this technology could become predictive in a sense to make production time-sensitive.