William Fissell, MD, Associate Professor of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, talks about the development of a new implant for kidney disease patients.
Can you explain the concept of the artificial kidney? What exactly is it?
Dr. Fissell: When we think about kidney failure and how we manage it, it’s organized around this paradigm of scarcity. There’s never enough of anything. Patients go to the dialysis unit and want to get in and out. They don’t want to spend their whole lives sitting in the dialysis chair. And maybe 20 or 30 percent of all patients who develop kidney failure ever get a kidney transplant. There are just not enough kidneys to go around. We want to break that model. The treatment that we have today, dialysis saves over a half a million lives in the United States and probably four million lives worldwide. But it’s got barriers to being the best possible treatment. Your kidneys work 24 hours a day, seven days a week. Dialysis is typically prescribed in three short bursts over a week. In between times waste products build up, fluid builds up and even that short dialysis session isn’t enough to get rid of all the waste products that your body has absorbed. If you meet a dialysis patient, they’ve come to the emergency room and for some reason you didn’t know they were a dialysis patient and you performed a physical examination on them and looked at their labs, the very first thing you would say is, this patient needs dialysis. If the patient who is treated with the best dialysis treatment we have to offer still looks like they desperately need dialysis, there’s some headroom for improvement there. We wanted to address the two big pressure points in terms of what makes patients who receive hemodialysis ill. First one is this kind of roller coaster of fluid. We drink a liter and a half a day, maybe a little bit more, that dialysis session has to get rid of all that fluid. It’s as though you suddenly bled half of your fluid volume, half of your blood out over a course of an hour or two. Of course, people become ill, that creates cardiac stress which leads to cardiac damage. So, can we make a device that will operate around the clock so you never get too wet, or you never get too dry? Can we make a device that will allow you to eat? The best dialysis that we prescribe today isn’t able to get rid of all of the waste products of what you take in. We treat that in part with the dialysis, in part with drugs that soak up excess nutrients in your food. We also treat it with a very restricted diet.
So, then how does the artificial kidney differ from dialysis?
Dr. Fissell: The key innovation is to try to be able to make a medical device that will act like a healthy kidney. The genesis of the project was that dialysis membranes that we use to separate toxins from blood are all the good stuff in blood, the red blood cells, the white blood cells, the antibodies, stay in the blood. The waste products which tend to be small molecules have to come out. It’s essentially a sieve, or a colander. It’s like you’re straining peas. The ones that we use today in the dialysis unit are big and require huge pressures and pumps to push the blood through them which is not feasible to fit inside a human body. So, we came up with a new membrane technology. We took the same technology that’s used to make smartphones. Your smartphone knows which way is up because it’s got a little mechanical accelerometer in it. It’s microscopic but it can feel gravity. It’s a process that was inherited from the microelectronics industry. Instead of making integrated circuits or Pentium chips or airbag accelerometers for your car, we made a filter because the pores in this filter are controlled by an engineer with a CAD program saying I want this pore this size. Rather than the thermodynamics of a polymer mill, we’re able to optimize the performance of the membrane and shrink it down small enough to fit in a body and reduce the pressure requirements low enough that a patient’s own beating heart is enough to push blood through it and filter the blood. That was really our germinal innovation. And that was 15 to 18 years ago that we started down that path. We’ve moved that from concept to prototypes in the lab bench, to being able to routinely implant this in preclinical studies for weeks or months at a time with filtration happening continuously with no need for blood thinners, anticoagulants, or special additional drugs. We were told at the outset that you could never put this material in contact with blood because blood would clot immediately. We were told that you could never put a blood conduit inside the human body because the blood would clot, or the red blood cells would fracture. We were told you can never sew to these vessels in a long period of time. Yet, we’ve done all of those things! We joke that we do at least one impossible thing a year.
Can you explain more about the filter and what its function is in this process?
Dr. Fissell: The filter generates a watery portion of blood that’s loaded with toxins and it generates 20 to 30 liters a day. I can’t carry 30 liters a day of fluid around with me or I’d be going to the bathroom every 10 minutes. We took a page from Mother Nature’s research and development program and copied the architecture of the native kidney. The native kidney has filters and cells that reabsorb salt and water from the filtrate and concentrate of all those wastes and toxins down into a liter or two of urine every day. Fortunately, those cells, called tubule cells, grow promiscuously in laboratory. We’re able to harvest them from human kidneys, expand them in tissue culture in the lab, and then coax them into reproducing the function they have inside a healthy kidney. We were told years ago that our project was flawed because cultured cells lose their identity. When you put a cell on a plastic dish it doesn’t like it. It likes the texture of real tissue. It has fluid flowing over it all the time, flowing from your blood through the filters out to your bladder and out to the toilet bowl. In the lab it just sits in the lab dish. So, we set about trying to understand what are the cues that a cell in culture is getting from how we culture the cells that drive it to lose its features? And can we turn those knobs? Can we adjust those things to get the cells to do the right thing, or to get the cells to look like and act like healthy cells inside a healthy kidney? The answer is yes. It turns out that using a couple of cues from the literature that we know about how other cells respond to the stiffness of what they’re sitting on, we were able to convince cultured kidney cells to start reabsorbing salt and water and maintain a barrier to back-leak of toxins. Within a couple of years we moved from cells that looked like these kind of flat fried egg things sitting on a dish, not transporting anything, to now cells that when coaxed the right way reabsorb salt and water, reabsorb glucose, reabsorb amino acids, and act like healthy cells. We have a filter that separates waste products and salt and water from blood and have a bioreactor of cultured kidney cells that concentrate that filtrate down into a manageable amount of fluid. Patients can go have the device sewn into them when we are successful and go about their business. No need for immunosuppressive drugs. The cells are behind a protective barrier that blocks communication between the immune system and the cells. So, you don’t have all the problems of immunosuppression, the expense, the risk of cancer, or the risk of infection.
How do you then take the filter and the cells to make the device?
Dr. Fissell: We spent a king’s ransom on something called computational fluid dynamics. The same tools that are used to design jumbo jets, for example, we used to design blood conduits and the connections between a patient’s blood vessels and our silicon membranes. And that was really the key to being able to make a device for treating a patient as opposed to an experimental oddity on a lab bench. It’s not that hard to make a membrane that will separate things on a lab bench. However, it’s very hard to make a membrane that you can implant in a living mammal that will continue to function in the hostile environment of blood. Your blood is designed to clot if it sees something foreign. Your blood is designed to attack foreign objects. But we’ve been able to get through those things.
So, with this artificial kidney concept, would all patients be able to take part in this?
Dr. Fissell: Yes, that is the goal. The goal is that we eradicate the concept of scarcity. The goal is this is available to anyone who wants or could benefit from one as opposed to the present system where patients are evaluated for a renal transplant to decide if there’s a good fit between this scarce resource of donor organs and this huge ocean of need of 500,000 Americans who don’t have a working kidney anymore and desperately need one. Our goal is that a patient comes into the clinic and if they’re fortunate, they get a real kidney from a real donor or they go to the surgeon, the surgeon pulls one of our devices off the shelf and sews it in.
Would this eradicate the need for dialysis at all?
Dr. Fissell: That’s the goal. Dialysis saves half a million lives in the United States and four million lives worldwide. It’s the first mechanical replacement for a failed vital organ. It’s given people years of life, time to see their children graduate from high school, and children get married. It is lifesaving. But, we can still do better.
How do you believe this artificial kidney concept would change their quality of life?
Dr. Fissell: When physicians look at the dialysis process, they look at laboratory studies, fluid volume, all these parameters of how the instrument is modifying the patient’s physiology. Patients on the other hand have a very different set of priorities. Patients want to be able to sleep, to feel some energy, to not feel so fatigued and tired all the time. Patients want to have spontaneity in terms of their diet. If they are going to an event with family, it’s stigmatizing to have your own special dialysis meal while everybody else eats the real food. If you have a family member who is graduating or a wedding, it’s hard to travel if you’re a dialysis patient. You must work way in advance with the social workers to schedule that. The things that patients state are the most devastating consequences of dialysis is the fact that they can’t travel. So the goal of the artificial kidney is that we confer the benefits of transplant. Patients who receive a kidney transplant, they live longer than patients who receive maintenance dialysis. They have more spontaneity. They can travel. They have energy. Even things like being able to get pregnant and bear a healthy child. That’s unheard of for a dialysis patient, but it’s routine for a kidney transplant patient. So, our goal is to restore life back to patients who desperately want some more life.
Would there be ever a point that the artificial kidney would be the main source of treatment, or would there be a need to have the kidney transplant from a donor?
Dr. Fissell: Kidney transplants are probably never going to be the main source of treatment for patients with renal failure because the supply is so limited. So the goal would be for everybody else that there is an implanted device, like a pacemaker, that replaces the function of the kidney. I think that there’s going to be the right solution for individual patients. Suppose you have a patient who’s had a bad malignancy or has a malignancy that’s in partial remission and develops kidney failure. That patient is not a candidate for a kidney transplant because the immunosuppression could unleash the cancer. So artificial kidney, no immunosuppression. If you have a patient who’s young and has a whole life ahead of them, there’s a donor available. There’s going to be right and wrong answers depending on who the patient is and what the patient wants. Some patients will probably opt for dialysis. The goal is to create choice by overcoming the supply limitations that are present today.
How far down the line do you think this will be in a clinical setting?
Dr. Fissell: Predictions are hard about the future. We have a staged approach to getting the technology to patients. It’s a big ask to go to a patient and say, will you let me do this major surgery on you and sew something inside you just so we can see if it’ll work? So, we have a staged way of implementing the technologies so we can learn about the silicon membranes. We can have a concise approval pathway from regulatory agencies so that they don’t have to take a big bite. So first the filter, then the cells. We’re limited really by resources. We’ve moved past the unknowns. We’ve moved past the discovery science stage. We’ve moved past hypothesis testing. We’re now doing product development. We’re overcoming regulatory barriers. We’re satisfying safety requirements. The time scale over which we can reach patients is directly related to money. We’ve got a couple of steps to take to be able to move this into patients. They’re moving processes out of the academic laboratory and out of the research environment to a commercial environment. I’d like to have our technology connected to a human being for testing purposes within the next two years. And, I feel it’s completely doable.
Interview conducted by Ivanhoe Broadcast News.
END OF INTERVIEW
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