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 ion-tophoresis has also been proven to effec-tively 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 posi-tively charged molecule and moves to-wards 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 concen-tration 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 hypothe-size that reverse iontophoresis can efficiently perform the task of a dialysis machine in a non-in-vasive 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 applica-tion 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 re-place 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-inva-

sive and has the potential to dramatically reduce the amount of time neces-

sary 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 diag-

nosed 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 con-

nected 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 Peri-

toneal 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 com-

pany 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 dial-

ysis to be performed, and the company is unsure of the long-term user costs. Another break-

through has been the Wearable Artificial Kidney (Figure 3), which allows dialysis to occur con-

tinuously for twenty-four hours a day, seven days a week13. The downsides to this device in-

clude 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 ex-

pectancy. 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 re-

verse iontophoresis.

A2) Critical Barriers: Currently the use of reverse iontophoresis has been pre-

dominantly relegated to matters involving glucose levels in the body. For the

method of reverse ion-

tophoresis to be applicable

as an alternative for kidney

dialysis, its use as a tech-

nique of urea removal must

first be proven. In a previ-

ous study, reverse ion-

tophoresis 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 µA 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 in-

clude 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 be-

ing so the reverse iontophoresis device must operate under this range17. Not only must the cur-

rent be held under this range, but there is also the psychological issue of having a current on

one’s 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 appli-

cability of reverse iontophoresis as an alternative for kidney dialysis a

greater understanding of the overall process will be achieved and its compat-

ibility for other treatment types can be assessed. While dialysis has been an effec-

tive 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 tech-

nique to draw certain substances in bodily fluids out through the skin. Today, it is currently be-

ing 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 patient’s

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 glu-

cose 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 patient’s 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 success-

fully utilized in a glucose monitoring device called the GlucoWatch4 (Figure 5). The GlucoW-

atch 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 GlucoW-

atch 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 Glu-

coWatch 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 ver-

sus the traditional method of kidney dialysis, which is usually administered

at the hospital. Due to the GlucoWatch successfully utilizing reverse iontophoresis in a pas-

sive 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 µA 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 di-

rectly 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 possi-

ble 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 treat-

ment 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 im-

portant 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 aver-

age 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. Fac-

toring in the cost of the dialysis treatment, which runs about $1385 per week for one without in-

surance, 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 patient’s body. This value

needs to be greater than 1.2 for most applications, with the higher values resulting in a more effi-

cient 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 approxi-

mately 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 un-

desirable, 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 alterna-

tive 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 per-

formed on patients with chronic kidney disease and healthy individuals it was determined that

through application of a 250 µA 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 be-

tween 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 re-

verse 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 simu-

late the urea and potassium concentrations in the body, a solution of urea and potassium was in-

fused 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 dis-

ease and end stage renal failure.

C3) Aim 3. Integration of reverse iontophoresis for treatment of kidney ail-

ments. 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 µA with the as-

sistance of an iontophoresis controller1. The machine, unlike the large and inconvenient compo-

nents of a dialysis machine, is quite optimal for travel to one’s home or workplace. The instru-

ment has small dimensions of 70 x 150 x 140 mm, and it only weighs 1.21 lbs. even with the bat-

teries19.

In addition, other inventions have been created as methods of portable iontophoresis.

The Companion 80’s 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 pro-

duce. It is exceptionally flexible, and the incorporated electrode allows patients to spend mini-

mal time in a hospital clinic. The battery in the Companion 80 patch is able to supply a 55 µA

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 ion-

tophoresis process can pull greater amounts of

urea solutes out of the skin. There have been

studies that have utilized larger currents up to

800 µA, in which no adverse or harmful effects

have been reported1. Eventually, reverse ion-

tophoresis can be perfected as a flawless alterna-

tive to dialysis treatments.

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