The Bioartificial Kidney and Bioengineered Membranes in Acute Kidney Injury
Summary
This paper examines the current advances in the creation of a bioartificial kidney. Advances in both tissue engineering and the design of biological filtration systems have set the stage for the next generation of artificial kidneys. Essentially the scientists have been attempting to mimic the filtration function of the kidney using scaffolds that mimic the natural tubules of the kidney. However, the next challenge was to integrate renal tubule progenitor cells into the scaffold so that the artificial kidney would serve as a normal endocrine organ. It is important to note that these are both separate but crucial function of the kidney and only by integrating them together can a science come closer to creating an implant that can replacement the need for a kidney transplant.
This paper examines the bioartificial kidney’s completion of Preclinical, Phase I/II and Phase II Clinical trials. In the preclinical trials the goal was to show that renal tubule progenitor cells could be grown on a biomatrix-coated hemofilter. Once this was goal was accomplished large-animal studies were conducted using animals proving that the renal tubule assist device (RAD) both provided that filtration and endocrine functions that would be seen in a kidney. These promising results laid the path for Phase I/II Clinical trials. Ten patients were chosen with APACHE scores, a predictive indicator of mortality, of >85%. In this study the RAD was implanted with human renal proximal tubule cells and the device was also connected to a CVVH external pump that would provide external support for the RAD and maintain constant blood flow and filtration rates from the device. Of the 10 patients, 6 survived past 28 days while also recovering kidney function when only one was supposed to survive according to the predictive score. More promising was the finding that plasma cytokine levels suggested that the device assists the patient’s individual pathological conditions. Finally, phase II clinical trials were conducted by using a randomized test of 58 patients with Acute Renal Failure (ARF) in order to do a head to head comparison between RAD and CRRT, Continuous Renal Replacement Therapy, which only replaces that filtration function lost during ARF. In this trial it was seen that RAD treatment provided increase recovery of renal function as well as decreased mortality rates. The results suggest that the renal tubule cell therapy does make a difference in treating patients with ARF.
Significance
An artificial kidney is a great target for tissue engineers because it requires both mechanical and biological engineering. Currently, patients who suffer from acute kidney injury (AKI) must rely on dialysis in order to compensate for the filtration functions of the kidney. However, dialysis is not a permanent solution and requires multiple treatments per week. Even under the best cases dialysis only compensates for the filtration function of the kidney. The kidney is also responsible for providing hormones and other molecular signals for the body. Therefore an artificial kidney should be able to provide the filtration needs of the body while also being an important endocrine organ. Although the RAD system is meant for patients in ICU that have AKI the advances in this system can provide the groundwork for an implantable device that can replicate all of the functions of the kidney.
11 comments:
From the stage that the artificial kidney is currently at, what is the difference between a dialysis machine and this kidney? Both are reliant upon a source outside of the body (though hopefully in the future, that won't be the case with the bioartificial kidney) and serve for important filtration functions. I understand that the kidney isn't perfected yet, but again - at its current state, are there any benefits of it over a dialysis machine?
Also, do you think there is any potential in the future for enhanced kidney function? This might be entering a slippery slope region, but could you comment on the feasibility of a 'super kidney' if you will - a kidney that could perform all the functions of two regular kidneys? This could open the doors to a vast number of kidney donors, a much-needed organ in the medical industry of implants.
You said the artificial kidney has a "biomatrix hemofilter". What does this mean? I'm guessing a hemofilter is the same as the bundle of hollow fibers used in current dialysis devices. So, what is the biomatrix and what does that do?
I've done quite a bit of work in the hemodialysis field, so I'd be super interested to read this paper. Can you please post the name of the paper and the journal?
And you are absolutely right. Dialysis devices barely compensate for the loss of filtration in kidneys. Incorporating kidney cells into a RAD could resume secretion of kidney hormones (erythropoietin, etc). Did these researchers look at how well this device clears out different compounds like urea, creatinine and NaCl? Super interesting work.
Shyam,
Thanks for the great comment. The paper I reviewed focused on a bioartificial kidney that is able to replace both the filtration and endrocrine functions of the kidney. Currently, dialysis machines are only able to replace the filtration function of the kidney. The kidney is responsible for secreting critical hormones that are important for hemodynamics, bone metabolism, and red blood cell production. Furthermore, it is thought that part of the problem with acute kidney failure is the loss of progenitor cells that help regulate inflammation in the kidney, and by replacing these cells the kidney function can be rescued. You are correct, both do rely on external power sources, which is a problem, and this is an issue that is still being worked on. As far as a 'super kidney' I would say that this paper takes a major step forward in replacing the need for dialysis and also replaces the endorcine function of the kidney. Yet, it is based on progenitor cells from donor kidneys so I'm not sure if they could get any increased function from them. Maybe if these progenitor cells were manipulated for increased production and the filtration mechanism was improved could we see a bioartificial kidney that could outperform a natural kidney.
Lavanya,
You are correct, the "biomatrix hemofilter" is indeed a the standard high-flux hemofilter used in dialysis. However, it is has a coating that allows for renal progenitor cells to integrate into the membrane and keep their normal function. The name of the paper is "The Bioartificial Kidney and
Bioengineered Membranes in Acute
Kidney Injury" and was published just this past September in Nephron Experimental Nephrology. The researchers did not report any molecular clearance data, I am assuming that the since the normal hemofilter system was not changed the filtration rates were not significantly altered. The paper focused more on how adding renal progenitor cells allowed for increased rescue of kidney function and signs of less inflammation. I hope this answers your questions and thank you very much for your comment.
Hey Jeff,
Could you comment on how the artificial kidney replicates the structural aspects of the nephron, it it does at all?
As Shyam said, what is the difference between this kidney and dialysis; is there a quantitative data difference in the filtration rate?
Also you mentioned several times how the artificial kidney has the potential for endocrine as well as excretory replacement. Did this kidney exhibit any of those endocrine functions?
Interesting paper!
From what I understand, it seems that the external CVVH pump that provides external support for the RAD and maintain constant blood flow and filtration rates from the device does not make the RAD self-sufficient.
Currently, as other individuals have noted, it seems like the RAD is not much different from a dialysis machine. Does the paper mention what the future experiments/aims will be to develop the RAD into a fully working kidney?
I like the direction this paper is headed in, as I believe proper kidney replacement through an artificial device will need to incorporate more cellular interactions than just a simple diffusion-based device as they are using now with dialysis machines. Does this paper tell about how they dealt with cellular rejection? It seems to me that if you are using such a cellular scaffold that comes into contact with human blood, that clotting and other bodily defense mechanisms might interfere. I suppose to deal with this, they could use host stem cells, but this would seem to me to be less than cost effective.
Hi Dan,
This system relies on the RAD device for filtration to compensate for the nephrons. The novelty of this work is the use of renal progenitor cells that allow for the system to begin to restore the kidney's natural endocrine functions. The researchers postulated that the renal progenitor cells played a role in the decrease of inflammation in the kidneys and the restored function in some cases. This work did not give any quantitative data regarding the filtration rate. However, they did mention a new type of membrane, one with nano-pores that would allow smaller membranes with better filtration rates compared to the conventional polymer membranes.
Hi Cindy,
You are absolutely right, that system is not self-sufficient and relies on an external pump. The researchers focused on two aspects that will be critical for developing a bioartificial kidney: the incorporation of kidney progenitor cells to restore endocrine function, and the new membranes that will be smaller and more closely mimic the filtration in a nephron. However, they did not go into detail on what their next step is. I would assume that it would be to free the system from the external pump.
Ben,
You bring up a great point. I do not know what the source of renal progenitor cells was. Since it was not mentioned I cannot say for certain but it looks like they did not encounter and problems with clotting or rejection. I think this is something that should be looked at in detail and I would also be interested in what is found.
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