The Wearable Artificial Kidney, Why and How: From Holy Grail to Reality

Victor Gura,* Claudio Ronco,† and Andrew Davenport‡
*Cedars Sinai Medical Center, UCLA, The David Geffen School of Medicine, Los Angeles, California, †Department of Nephrology Dialysis & Transplantation, San Bortolo Hospital, Vicenza, Italy, and ‡UCL Center for Nephrology, Royal Free & University College Medical School, London, United Kingdom

ABSTRACT Once hemodialysis had become established as a treatment for chronic kidney disease, the early pioneers realized the limitations of the treatment, particularly in terms of the impact intermittent thrice weekly hemodialysis had on a patient’s quality of life—not only time spent on dialysis and time traveling to and from treatment, but also dietary and fluid restrictions. This led to the search for the holy grail—a wearable hemodialysis device (WAK), that would allow patients to receive continuous treatment, while going on with the normal activities of daily life. Such a device would not only provide adequate solute clearances and control both electrolyte and acid–base status, but also improve blood pressure control—all while allowing a liberal diet. Despite many attempts, to develop such a wearable artificial kidney, it is only recently, with the advent of microtechnologies, that it has been possible to construct a truly wearable device, which can accurately regulate ultrafiltration and achieve adequate solute clearances. One such device has recently completed successful human pilot studies, designed to test device reliability, safety, and efficacy.

Today routine outpatient dialysis is now regarded as a well-established technique, typically delivered in satellite dialysis units, private clinics, or minimal care centers, well away from the main hospital base. However, in the early pioneering days, many obstacles had to be overcome, not only in the development of technology, but also the issues of reimbursement and patient eligibility. Besides the fundamental technological advances required to develop dialyzers and dialysis machines (1), other key advances were required to move treatment forward from its restrictive beginnings limited to patients with acute kidney injury, to the provision of chronic dialysis treatments. These included reliable vascular access (2) and heparin anticoagulation to prevent circuit clotting. Once the early pioneers had conquered these major hurdles and could deliver successful hemodialysis to patients with chronic kidney disease (CKD), they realized the limitations of the therapy, particularly its effects on patients’ lifestyle. As such, the search for a dialysis
Address Correspondence to: Victor Gura, MD, Attending Physician. Cedars Sinai Medical Center, Associate Clinical Professor of Medicine. UCLA, The Geffen School of Medicine, 9100 Wilshire Blvd. Suite 360W, Beverly Hills, CA 90212, or e-mail: vgura@cs.com. Disclosures: Victor Gura is the Chief Medical Officer and a director of Xcorporeal Inc. Seminars in Dialysis—Vol 22, No 1 (January–February) 2009 pp. 13–17 DOI: 10.1111/j.1525-139X.2008.00507.x ª 2008 Copyright the Authors. Journal compilation ª 2008 Wiley Periodicals, Inc. 13

device that could be worn on a patient’s body can be traced back several decades to these early pioneers (3–7). The main rationale for these attempts to attain wearability, were patient convenience and improved quality of life. These initial attempts to develop a WAK were hampered because of the need for large amounts of fresh water for dialysate, the size and weight of then available blood and dialysate pumps, and the lack of portable energy sources to power these pumps. Sorbents were used to reduce the amount of fresh dialysate required, but the typical sorbent cartridge weight of over 2 kg reduced mobility. None of these devices could be commercially developed. Others created wearable hemofilters (3), typically using arterial or arterio-venous access (5), but to achieve adequate solute clearances then encountered the formidable obstacle of replacing large amounts of ultrafiltrate effluent with suitable replacement solutions for intravenous infusion or oral replacement. While these techniques proved useful in the relief of fluid overload, they were not a commercially viable renal replacement therapy (CRRT) for treating chronic kidney failure patients. Traditionally, hemodialysis patients have been offered thrice weekly hemodialysis. Over time, with further advances in membrane technology, dialysis sessions continued thrice weekly but times were shortened from 8 hours down to a worldwide average of 4 hours (8). However, shortening the dialysis session, with a compensatory increase in ultrafiltration rate, leads to increased frequency of intradialytic hypotension (9, 10),

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Gura et al. On the other hand, implementing more frequent and longer, or daily dialysis programs is easier said than done. There are major practical issues, including appropriate manpower (nurses and technicians to supervise more treatments in the dialysis units), building new dialysis facilities to cope with this expansion in dialysis requirement, and the reluctance of governments and other payers to shoulder the expense of longer and more frequent dialysis (19–22). In addition, patients may not wish to dialyze longer or more frequently and may be unable or unsuitable to dialyze at home. Even if governments and payers would agree to pay for the additional costs of daily dialysis, executing such a task would take time. One alternative would be to miniaturize a dialysis machine and make it feasible for a patient to wear it. Requirements for Continuous Renal Replacement Therapy The various modes of continuous CRRT can deliver significantly higher doses of dialysis, by treating patients 24 hours a day, 7 days a week. However, CRRT machines are not suitable to treat CKD patients, as they require constant nursing time to treat a single patient. In addition, they are heavy, tethered to a wall electrical outlet, and require large volumes of sterile replacement fluid or dialysate (23). Whilst treated, patients are unable to mobilize and perform their activities of daily life. A miniaturized and wearable CRRT machine (Fig. 1A) could potentially solve these problems. In order to build a WAK the following challenges had to be overcome: Power Source Traditional hemodialysis machines run on mains electricity, with a back up heavy battery. So to be portable, a WAK must have a battery that, though small and light, will provide enough energy to power all the necessary systems for a significant period of time to make the WAK independent of a fixed electrical outlet. Dialysate Standard hemodialysis therapy requires large volumes of fresh dialysate. The volume of fresh dialysate would require a huge weight burden that would render wearability impossible. Thus, a WAK requires a sorbent system which can purify and regenerate effluent dialysate, so avoiding the need for fresh dialysate. In addition, there is emerging evidence that dialysate should be ultrapure and free not only of bacteria but also of toxins and pyrogens. To provide such quality dialysate, the WAK uses sterile 0.45% saline in the dialysate circuit and both the tubing and sorbent systems are gamma sterilized. Additives The final dialysate is made by adding an electrolyte solution and bicarbonate to the dialysis water, using a proportionating system in the dialysis machine.

with corresponding cardiac stunning. There is now mounting evidence that increased dialysis frequency and prolonging dialysis sessions improve patient quality of life, and potentially increase life expectancy for CKD patients (11–15). Increasing the duration of the dialysis session allows increased clearance of so called ‘‘middle molecules,’’ and a slower, better tolerated rate of fluid removal. The emerging data on the benefits of daily dialysis seem to indicate that frequent and incremental dialysis session time are key for improving the dismal outcomes we currently achieve for CKD patients. The concept that filtering blood for 9–12 hours ⁄ week can restore the health of CKD patients back to that of a normal person, in whom the native kidneys filter blood 24 hours a day, 7 days a week, appears somewhat naive. Further complicating the time issue is the physical chemical fact that solutes of different size travel through dialysis membranes at different speeds, according to their molecular weight and charge. Thus, larger molecules diffuse slower, and may not adequately transit from the plasma water to the dialysate in the limited time provided. In addition, several uremic toxins [e.g., p-cresol, reported to be associated with increased mortality (16)] are protein bound, and as such only a small amount is free in plasma and available for removal. Time is required for protein bound toxins to re-equilibrate and raise the plasma level of free toxin, and permit additional removal. Continuous removal of the free fraction would create a gradient from bound to free fraction resulting in the effective removal of toxins. Sorbents can increase the removal of these protein-bound toxins, such as p-cresol (17). It has also been shown that phosphate, an independent factor of all cause mortality in CKD patients, is only efficiently removed when dialysis session time is extended (18). Therefore, it seems that more frequent and longer treatments may be far more physiological than the current paradigm of 9–12 hours a week treatment. The advantages of daily extended dialysis are summarized in Table 1.

TABLE 1. The potential benefits of extended daily dialysis leading to improved outcomes in the treatment of CKD patients Improved solute clearances No hyperkalemia Improved appetite and nutrition Less bone disease and hyperparathyroidism Eliminate the need for phosphate binders Improved acid-base control Less pruritus Fewer sleep disturbances Reduced restless legs Less anemia and reduced ESA requirement Appropriate sodium balance Improved blood pressure control Decreased use of anti hypertensive drugs Reduced intradialytic hypotension Reduced risk of cardiac death and stroke Fewer cerebrovascular events Lower expected morbidity and mortality Less sleep apnea

Improved volume control

Improved serum albumin Improved sleep patterns

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(A)

(B)

Fig. 1. (A) Photograph of WAK. (B) Circuit diagram of WAK.

Similarly, the WAK was designed to have two additional pumps, one for a bicarbonate solution and a second for an electrolyte solution to be added to the dialysate compartment (Fig. 1B). Fluid Removal Standard hemodialysis machines allow controlled ultrafiltration. Thus, the WAK must have a volumetric pump to remove fluid at a physiological rate to avoid hemodynamic problems and yet maintain euvolemia. Ergonomic For the WAK to be truly portable for prolonged periods, it has to be light and ergonomically adapted to the body contour so that it can be worn continuously without impinging on the patient’s ability to sleep, ambulate or perform the activities of daily life. Pumps Standard hemodialysis machines use large heavy roller pumps to propel blood and dialysate. A WAK based on these pumps would be too heavy to be portable. So a unique double channel pump was developed to propel both blood and dialsyate in opposite phase for

the WAK; it requires less energy than the standard dialysis machine roller pumps. The flow patterns generated by this dual chamber pump differ from those of conventional blood pumps with an intermittent inversion of transmembrane pressures creating a ‘‘push pull’’ mechanism that further improves convective transport. Push-pull mechanisms for increasing convective mass transport have been previously proposed, by using a piston pump to propel dialysate (24) but never commercially developed. The pump currently weighs 300 gram and is battery operated. Safety Commercial dialysis machines are equipped with safety systems to prevent passage of air to the patient, and to stop the blood pump in case of a disconnection. Thus, the WAK was developed to include a servomechanism with a bubble detector sensor placed after the blood pump, designed to stop blood flow if air bubbles were detected in the blood circuit, and a second servomechanism to halt the ultrafiltration pump if the blood flow stopped for any reason. In addition, the pulsatile blood pump had a self-limited capacity to generate negative pressure for suction from the arterial side of the vascular access, such that significant negative pressures could not be applied to the vascular access. Thus, any

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Gura et al. hourly Kt ⁄ v of 0.035. Although one catheter clotted and one patient had a needle dislodged, there were no complications attributable to the WAK; the safety devices stopped blood and dialysate flows at the time of the incidents. The sorbent system generated CO2 bubbles in the dialysate circuit that partially interfered with the dialysate flow. This problem has now been successfully resolved in our laboratory. Following the initial human pilot studies, the initial WAK prototype is currently being transformed into a finalized model that can be commercially developed. The WAK has been designed for continuous use to deliver 168 h per week of dialysis, about 16 times more than that currently used with standard thrice weekly outpatient hemodialysis. Effective and slow removal of sodium and water will result in better control of hypertension and fluid overload (32), and may also eliminate the traditional need for dietary restrictions of water and salt (33). Similarly, the amounts of potassium and phosphate removed should also result in the elimination of draconian dietary restrictions, and may make phosphate binders obsolete (12, 14). These notions are supported by the results obtained with daily (11–14) or prolonged (8, 11, 34, 35) dialysis. Summary Technical Characteristic of WAK

disconnection on the arterial side would result in cessation of the blood pump. In addition to our development of a WAK, others have proposed a peritoneal dialysis version (25), based on regeneration of the peritoneal dialysate effluent (26). Laboratory and Animal Testing When all these challenges were met, a battery operated WAK was built in our laboratory (Fig. 1A). The initial prototype WAK could be worn as a belt, weighed approximately 10 lbs and was tested both in vitro and in a porcine uremic model where we demonstrated its safety and efficacy (27). The WAK, conceived as a wearable CRRT machine, was also configured as a hemofilter for the treatment of fluid overload; when studied in fluid overloaded animals, it achieved ultrafiltration rates of up to 700 ml per hour, without difficulties or complications (28). This application may be potentially useful in the treatment of NYH class III and IV congestive heart failure patients who develop a cardiorenal syndrome, given the current interest in the use of isolated ultrafiltration in these patients (29).

The WAK used in our preliminary studies, used a standard commercial 0.6 m2 high flux polysulfone dialyzer (Gambro Dialysatoren, Germany). The dialysate was regenerated by using a series of three sorbent canisters, containing urease, activated charcoal, and both hydroxyl zirconium oxide and zirconium phosphate. Patients were connected to the WAK by their usual vascular access for hemodialysis, either by central venous catheters or native arteriovenous fistulae, and were anticoagulated with unfractionated heparin, using their standard loading dose and maintenance dose as per a typical hemodialysis session, and the adjusted, aiming for an aPTTr of 1.5–2.0. The mean blood flow around 60 ml ⁄ minute, with a dialysate flow of 50 ml ⁄ minute. The ultrafiltrate rate was set according to clinical need and controlled by a volumetric pump. The total weight of the device was approximately 5 kg. Human Studies Following the successful animal trials, pilot studies were performed in human subjects. In one study, isolated ultrafiltration was achieved safely and efficiently, without any side effects or complications, in six patients with CKD (30). Subsequently, the WAK was tried in a proof of concept, feasibility study in eight humans for periods varying between 4 and 8 hours (31). In this study, all patients tolerated treatment with the WAK without symptoms or complaints. They were able to sleep, walk around, sit, eat, and drink without hindrance. Urea clearance was 22.7 Æ 5.2 ml ⁄ minute and creatinine clearance was 20.7 Æ 4.8 ml ⁄ minute, with an

Although it has taken more than 40 years to develop a prototype of a truly wearable artificial kidney, the holy grail of the original pioneers in the field of dialysis, our wearable device has successfully completed its pilot safety and efficacy trials. The WAK could potentially provide patients with a solution to increasing the duration and frequency of dialysis therapies, without the capital investments and nursing manpower needed today to provide more frequent or prolonged dialysis to CKD patients. Further clinical studies are now required to substantiate the efficacy and safety of the WAK and obtain regulatory approval. Provided this is accomplished, the WAK has the potential to become the standard of care for dialysis in the future. References
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