Reverse Iontophoresis: An Alternative Method for Kidney Dialysis

Antonio M Bunce, Joseph Hirneisen, Johnson Huynh

Reverse iontophoresis is a process in which molecules are removed from within the body via a negative charge on the skin that causes solvent flow towards a cation9. This process has already been extensively used as a monitoring device and is recognizable in the commercial device known as the GlucoWatch9. Reverse iontophoresis has also been proven to effectively monitor urea and potassium in in vitro experiments. When low amplitude current is applied to the skin, the barrier properties are altered, which allows for transport of molecules through the skin. Potassium is a positively charged molecule and moves towards the cathode via electro-migration. Urea, on the other hand, is an uncharged molecule6 and moves towards either the cathode or anode through a process called electro-osmosis, which is where an EMF is created by an applied potential that drives the flow of the molecule2 (Figure 1). A major benefit of this process is that it is non-invasive and can be completed in its entirety on the surface of the skin. Up to this point, reverse iontophoresis has been used primarily as a monitoring mechanism. However, since small amounts of molecules are already removed in order to monitor the concentration of molecules in the blood, it is logical to extrapolate that reverse iontophoresis could be used to perform the same function as a dialysis machine. This conclusion leads us to hypothesize that reverse iontophoresis can efficiently perform the task of a dialysis machine in a non-invasive manner. While it might seem like reverse iontophoresis could be a saving grace from invasive procedures, there are several downsides to the current procedure. One necessary improvement is the application time. Current dialysis takes three to five hours for the procedure itself, not including travel time, and reverse iontophoresis has a lag time of approximately fifteen minutes12. This lag time, although small in comparison, needs to be reduced to only a few minutes. In addition, there is an issue of safety with the actual device. While increasing the current will decrease the lag time, a current of 17 to 99 mA is sufficient to kill a human being17. Finally, the accuracy of the device, while already quite good, needs to be improved before reverse iontophoresis can potentially replace dialysis.

A) SIGNIFICANCE A1) Importance: Current methods of kidney dialysis are invasive and very time intensive for the patient. The use of reverse iontophoresis is non-invasive and has the potential to dramatically reduce the amount of time necessary for treatment. As of 2008, there were over 380,000 people in the US being treated for end stage renal disease (ESRD) at a cost of almost $40 billion11. The vast majority of those diagnosed with ESRD were treated with dialysis, the most common method being hemodialysis. With hemodialysis, an artificial kidney called a hemodialyzer is inserted into the body and connected to blood vessels with either a catheter or fistula (Figure 2). Then, three times a week for four to five hours, the patient must be hooked up to a dialysis machine so the blood can be cleaned and filtered. The only alternative to traditional dialysis is peritoneal dialysis. With this type of dialysis, you either insert a bag of dialysate into your peritoneal cavity, where it stays for four or five hours before being drained (Continuous Ambulatory Peritoneal Dialysis (CAPD)), or hook up to a machine called a cycler at night (Continuous Cycling Peritoneal Dialysis (CCPD)). The CAPD method needs to be done four to five times a day and the CCPD method needs to continuously cycle overnight12. Even once the hemodialyzer is inserted into the body, one cannot have a totally normal life like most others. Already mentioned was the necessity to have dialysis treatments performed on a weekly basis. For those diagnosed with ESRD, these treatments will continue for life be-

cause dialysis is not a cure to kidney disease; it merely keeps one in healthy condition until a donor kidney is available. In addition, patients on dialysis could have side effects directly from the dialysis treatments, may need an altered diet, and may need to find a new job or career if their previous job required heavy lifting12. Some progress has been made in the portability of dialysis machines, however. The company NxStage Medical has designed a portable dialysis unit that looks almost like a briefcase14. An immediate detriment to the unit is that the patient still needs to be tethered to the unit for dialysis to be performed, and the company is unsure of the long-term user costs. Another breakthrough has been the Wearable Artificial Kidney (Figure 3), which allows dialysis to occur continuously for twenty-four hours a day, seven days a week13. The downsides to this device include the fact that the patient has to continually wear the device, the device weighs ten pounds, which may be heavy for someone who has other medical issues, and the long-term side effects are unknown. However, both of these devices show promise for the future of portable dialysis units. A final issue with the current method of kidney dialysis is the life expectancy. The five year survival rate for those on kidney dialysis is only 34.5% and the ten year survival rate drops to 10.5%11. Clearly, there is a need for a quicker, more effective and cost efficient method of removing wastes from the body when the kidneys cannot. A method that has the potential to do this is reverse iontophoresis. A2) Critical Barriers: Currently the use of reverse iontophoresis has been predominantly relegated to matters involving glucose levels in the body. For the

method of reverse iontophoresis to be applicable as an alternative for kidney dialysis, its use as a technique of urea removal must first be proven. In a previous study, reverse iontophoresis was used on the forearm of five healthy individuals and eighteen patients with chronic kidney disease1. The purpose of reverse iontophoresis in this application was to monitor blood urea levels without using invasive testing methods. It was determined through this study that it is possible to remove urea through reverse iontophoresis, and the concentration of urea present at the cathode of the iontophoresis controller (Figure 4) was linearly correlated with plasma urea. Due to the fact that urea removal from the body was successful in this study with a current of only 250 A for two hours, it seems plausible that by increasing the current of the controller, the concentration of urea removed from the body can be scaled up accordingly1. Other barriers for the use of reverse iontophoresis as an alternative to kidney dialysis include the properties of the skin and safety issues regarding the application of an electric current to the skin. As mentioned previously, a current in the range of 17 to 99 mA can kill a human being so the reverse iontophoresis device must operate under this range17. Not only must the current be held under this range, but there is also the psychological issue of having a current on ones skin that must be overcome in order for a reverse iontophoresis device to be applicable. According to OSHA, a current of at least 5 mA can be uncomfortable to a human and the current used in the device should be under this value as well17. The final barrier is that the pH of the skin

must be kept around a neutral value of 7.4 in order for reverse iontophoresis to be successful. This neutral pH is necessary as changes in pH can affect both the permeability of the skin and the ionization state of the solutes which the device is attempting to remove2. A3) Improvement of Scientific Knowledge: Through investigation of the applicability of reverse iontophoresis as an alternative for kidney dialysis a greater understanding of the overall process will be achieved and its compatibility for other treatment types can be assessed. While dialysis has been an effective solution to renal failure, other methods should be encouraged as a better alternative to the present system. One such method, reverse iontophoresis, is a non-invasive and convenient technique to draw certain substances in bodily fluids out through the skin. Today, it is currently being utilized as a method to monitor glucose levels in diabetic patients blood. Potentially, it can reduce the presence of the urea, potassium, phosphorus, and other constituents of the patients blood to levels similar to that of existing dialysis processes. In addition, reverse iontophoresis could be extended to an unlimited number of capabilities. Beyond the ability of monitoring glucose levels in the blood, devices could also be invented to perfect regular iontophoresis as a way to send insulin through the skin to regulate the sugar levels in the patients body. B) INNOVATION B1) Reverse iontophoresis has previously been used as a monitoring system for glucose levels, but its application as a method of removing molecules from the blood has not been investigated. Currently, reverse iontophoresis is successfully utilized in a glucose monitoring device called the GlucoWatch4 (Figure 5). The GlucoWatch uses the process of reverse iontophoresis and sends very low currents through the skin. This slightly breaks up the skin barrier and allows small of amounts of body fluid to escape. The GlucoWatch can then measure the amount of glucose in these samples and provide a blood sugar

reading9. The advantage of this method over the traditional method of measuring blood sugar is that the GlucoWatch is non-invasive and does not require the pricking of a finger and it can monitor blood sugar over the course of twelve hours7. Tests have shown that the GlucoWatch is safe for children older than seven and that the GlucoWatch is just as accurate as traditional methods9. While this is promising, the process of reverse iontophoresis in this case has only been used as a monitoring mechanism, not as an active filtration mechanism. B2) Reverse iontophoresis has the potential to be an at-home treatment versus the traditional method of kidney dialysis, which is usually administered at the hospital. Due to the GlucoWatch successfully utilizing reverse iontophoresis in a passive manner, it stands to reason that reverse iontophoresis can be used in a more active role. Studies have shown that reverse iontophoresis can successfully remove urea, which is a waste product of the body, from the blood1. Once again, however, this study was not done as a long-term treatment model. Our group believes that reverse iontophoresis can be extrapolated to the point where it is used in place of kidney dialysis. Typically, 500 A of current are sent through the skin when reverse iontophoresis is used in a monitoring capacity2. However, this value can be increased several times before a patient would feel pain (current in the range of 17 to 99 mA is considered enough to be lethal) 17. By doing so, we hypothesize that urea can be drawn directly out of the blood in a non-invasive manner. In addition, the time required to do so would be much shorter than a typical kidney dialysis treatment and the packaging of the device would be self-

contained so a patient could continue with normal daily activities in a manner not possible with traditional dialysis treatments. We intend to investigate the practicality of using reverse iontophoresis as an alternative to kidney dialysis as a quicker, more efficient, and cheaper treatment for individuals with ESRD. C) APPROACH C1) Aim 1. Explanation of the current method of kidney dialysis. The present method for performing dialysis was mentioned previously in the significance section. More important than the existing method of dialysis for this discussion is the amount of time required and the amount of waste (urea) removed per unit of time. As was briefly mentioned before, the average dialysis treatment takes three to four hours and must be performed three times a week. This means a day and a half of work are lost due to this treatment every week. Assuming the average yearly wage in the US to be $41,673.83, this works out to $240.16 a week in lost wages15. Factoring in the cost of the dialysis treatment, which runs about $1385 per week for one without insurance, the net total weekly outlay is $1625.16, which amounts to $84,508.32 a year. And this is for a treatment that has a five year life expectancy of only 34.5%11. The reason the present method of kidney dialysis takes so long is because of the dialyzer clearance. The equation K*t/V is used to determine dialysis adequacy, where K is the dialyzer clearance, t is the time on dialysis, and V is the volume of water in a patients body. This value needs to be greater than 1.2 for most applications, with the higher values resulting in a more efficient dialysis treatment16. For a 220lb person, using the standard dialyzer clearance of 500mL/min, this results in a total time of 144 minutes on dialysis. And this is only to remove approximately 63% of the waste products that were originally in the blood. Since the volume of water in the body is relatively constant, either the time on dialysis needs to increase, which

would be undesirable, or the dialyzer clearance needs to increase16. However, increasing this rate is difficult to do because it is hard to find a place on the body where it is safe to withdraw blood at a rate this high. C2) Aim 2. Assessment of applicability of reverse iontophoresis as an alternative for kidney dialysis. Previously reverse iontophoresis has been predominantly used as a method of monitoring for both urea and potassium levels in the human body. In a study performed on patients with chronic kidney disease and healthy individuals it was determined that through application of a 250 A current for two to three hours, the cathodal urea concentration in the iontophoresis controller was linearly correlated with the plasma urea concentration1. It was also determined in this study that the cathodal urea concentration in patients with chronic kidney disease was significantly greater than that found for the healthy patients and this disparity between healthy patients and those with chronic kidney disease only increased with time1. This conclusion of the study means that the iontophoresis controller which was used to perform reverse iontophoresis was more successful at extracting urea from the patients with chronic kidney disease versus the healthy patients who were used as a control in the study. In another study it has been determined that the reverse iontophoretic fluxes of urea and potassium closely modeled the decrease in concentration present in the subdermal compartment as would happen in hemodialysis3. This experiment was carried out on pigs ears where the skin was first taken off and then dermatomed to more closely resemble human skin. In order to simulate the urea and potassium concentrations in the body, a solution of urea and potassium was infused into the subdermal compartment of the pigs ears3. It was determined in the study that there exists a urea skin reservoir and before the urea was removed from the interstitial fluid this reservoir was first depleted by the reverse iontophoresis device. Since the urea concentration in

the interstitial fluid closely follows that in the blood, it was determined in this study that reverse iontophoresis is capable of mimicking hemodialysis3. Based on these studies and their results it appears feasible that reverse iontophoresis could be used as an alternative for kidney dialysis for patients suffering from chronic kidney disease and end stage renal failure. C3) Aim 3. Integration of reverse iontophoresis for treatment of kidney ailments. The studies that have already been performed on subjects with chronic kidney disease (CKD) show the potential of reverse iontophoresis as a substitute for existing dialysis methods1. The process involves equipment that is easily transportable to any given location. During the study on the CKD patients, two electrodes were placed on the non-dominant arm about 10 cm apart that had been thoroughly cleaned with 70% ethanol. The anode was an inert gel electrode, while the cathode contained a 1.5 mL buffer solution with a pH of 8.75 at 37 C. The cathode chamber itself containing the solution actually only covered about 3.8 cm2 of area. A potential difference was applied between the two electrodes to sustain the current at 250 A with the assistance of an iontophoresis controller1. The machine, unlike the large and inconvenient components of a dialysis machine, is quite optimal for travel to ones home or workplace. The instrument has small dimensions of 70 x 150 x 140 mm, and it only weighs 1.21 lbs. even with the batteries19. In addition, other inventions have been created as methods of portable iontophoresis. The Companion 80s patch18 is essentially just something that sticks onto the skin (Figure 6). It minimizes the skin irritation that the electrodes from the iontophoresis controller sometimes produce. It is exceptionally flexible, and the incorporated electrode allows patients to spend minimal time in a hospital clinic. The battery in the Companion 80 patch is able to supply a 55 A current to

the placed area to perform iontophoresis for twenty-four hours18. The chamber on the patch has a volume of 1 cm3. It is anticipated that an analog of the Companion 80 patch, with a larger chamber and greater applied current, can be used to perform reverse iontophoresis since it is already used for iontophoresis. Hopefully, in the near future, a slightly greater current can be applied so the reverse iontophoresis process can pull greater amounts of urea solutes out of the skin. There have been studies that have utilized larger currents up to 800 A, in which no adverse or harmful effects have been reported1. Eventually, reverse iontophoresis can be perfected as a flawless alternative to dialysis treatments.

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