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Toward the wearable artificial kidney

Claudio RONCO,1 Andrew DAVENPORT,2 Victor GURA3
Department of Nephrology, Ospedale San Bortolo, Vicenza, Italy; 2Department of Nephrology, Royal Free Hospital, London, UK; 3Department of Nephrology, Cedars Sinai Medical Center, Los Angeles, California, U.S.A.
1

Abstract The evolution of technology in hemodialysis has gone through several steps including the feasibility phase, the search for reliability, the implementation of automation to improve efciency and the quest towards increased tolerance and treatment adequacy. Today, a new challenge is appearing on the scene and it concerns miniaturization, transportability, wearability and the possibility of developing implantable devices for renal replacement therapies. Although we are not there yet, a new series of papers have recently been published disclosing interesting and promising results on the application of wearable ultraltration systems (WUF) and wearable articial kidneys (WAK). Some of these use extracorporeal blood cleansing as a method of blood purication while others use peritoneal dialysis as a treatment modality. This manuscript presents the initial results with these new devices and proposes an effort to make a quantum leap in technology making the wearable articial kidney a reality rather than a dream. Key words: Dialysis, ultraltration, miniaturization, ambulatory dialysis, wearable articial kidney WAK, ViWAK

INTRODUCTION
Although the rst human patients with acute renal failure were treated with a hemodialysis technique in the 1920s,1 it was only at the end of the Second World War that hemodialysis effectively became life-saving for acute renal failure. This was due to the purication and commercial availability of unfractionated heparin, an effective extracorporeal anticoagulant, and the pioneering work developing the cellophane drum dialyzer.2,3 However, hemodialysis remained a treatment for acute renal failure until the 1960s when improvements in vascular access4 and dialyzer technology,5 allowed the long-term treatment of patients with end-stage kidney failure.6 Similarly, forms of peritoneal dialysis were used in the 1920s and before the Second World War.7 Even following the introduction of a simplied method of irrigating the peritoneal cavity using a single disposable catheter and commercially available dialysis solutions,8 peritoneal dialysis essentially remained a treatment for acute renal failure. It
Correspondence to: C. Ronco, MD, Ospedale San Bortolo, Vicenza, 361000 Italy. E-mail: cronco@goldnet.it

was only when Tenckhoff described the use of a permanent indwelling silicone-rubber catheter with Dacron cuffs that intermittent periodic peritoneal dialysis treatments really became feasible9 and continuous peritoneal dialysis for chronic renal failure was described only in 1976.10 Once reliable dialysis treatments became available for end-stage renal failure, the holy grail was to develop a truly wearable or portable dialysis device, mimicking the native kidney, so that patients could be treated 24 hours a day, allowing a liberal diet and uid intake. Although there are many reports of wearable hemodialysis devices, these generally refer to hemoltration circuits, often using indwelling femoral arterial and venous catheters, and/or arteriovenous shunts.11 Often these devices lacked safety features, being simply strapped to the thigh, with no alarms in case of disconnection or air detection monitors, and with very basic volumetric controls.11 More sophisticated devices recycled ultraltrate by passage through sorbent cartridges.12 However, these pioneers were unable to develop their devices because of their size, weight, and low clearance rates. Only recently, with the development of miniature pumps, has it been possible to develop the ideas of these early pioneers into potentially effective wearable hemodialysis and/or hemoltration devices.

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Although continuous ambulatory peritoneal dialysis and automated peritoneal dialysis can be considered as forms of continuous daily dialysis, allowing the patient to be ambulant during the day, only a minority of patients are treated by peritoneal dialysis worldwide. Even though patients may be ambulant, large volumes of dialysate have to be stored and disposed of, particularly with the automated forms of peritoneal dialysis. Thus the development of a peritoneal dialysis system with regeneration of peritoneal efuent, hence reducing storage requirements, would potentially allow more patients to be treated by peritoneal dialysis.

Rationale for a wearable articial kidney (WAK)

The outcomes of renal replacement therapy in end-stage renal disease (ESRD) remain dismal regarding the quality of life, morbidity, and mortality of these unfortunate patients. During the last few years, a growing body of literature of several hundreds of peer-reviewed publications indicates that more frequent and prolonged dialysis treatment is associated with strikingly improved outcomes in these patients.1318 In healthy individuals, blood is ltered by the native kidneys for 168 hours a week. Obviously, ltering the blood only for 12 h/week with dialysis (as typically prescribed in the United States) is both unphysiologic and most inadequate, resulting in poor quality of life and unacceptably high mortality. As patients are shifted from the typical 3-dialysis treatments per week regime to one of daily dialysis, signicant improvement in the quality of life was reported (i.e., liberalization of diet, uid restrictions, etc.) alongside substantial reductions in medication consumption, complications, psychological symptoms, admissions, and hospitalization.19 The reported advantages of daily dialysis are improved volume control, elimination of the need for phosphate binders, no sodium retention, improvement in appetite and nutrition, less hypertension, decreased need for blood pressure drugs, no hyperkalemia, decreased expected morbidity and mortality, no hyperphosphatemia from bone disease, lesser degree of anemia, no metabolic acidosis, less cardiovascular disease and stroke, and improved serum albumin. With the recent technological breakthroughs, the major dilemma that arises is whether society wishes to maintain the status quo and bear the present morbidity, mortality, and cost of treating ESRD patients, or move forward to create new, innovative, and cost-effective

dialysis devices with the potential for alleviating the plight and misery of these patients. Such innovations may provide daily or even continuous dialysis, without imposing an unbearable burden on already scarce nancial healthcare resources. In the United States alone, the number of ESRD patients has been growing steadily and is currently approaching 400,000. The total cost of treating these patients tops $30 billion a year. Furthermore, the cost of ESRD to society during the current decade is estimated at $1 trillion.20 Even so, the mortality in ESRD patients remains unacceptably high, reaching that of metastatic carcinoma of the breast, the colon, or the prostate. The implementation of daily dialysis encounters obstacles that make its accomplishment on a large scale practically impossible. Some of these are the inability or unwillingness of most patients to dialyze at home, the lack of manpower both in nurses and in technicians to provide more treatments in the dialysis units, and the reluctance of governmental payers to shoulder the expense of additional procedures.2127 Thus, there is a growing need for a practical aroundthe-clock solution that will afford to ESRD patients the ability of receiving signicantly increased dialysis dosages, while increasing efciency and reducing the overall cost, the need for dedicated brick and mortar, and the utilization of manpower. Continuous renal replacement therapy (CRRT) allows signicantly higher doses of dialysis but is unsuitable for treating ESRD patients because the machines are heavy, attached to a wall electrical outlet, and require many gallons of water. Technological breakthroughs that will facilitate daily or continuous dialysis will materialize in a miniaturized and wearable CRRT machine or WAK.1116 Listed below are some of the technological challenges to overcome in this endeavor: 1. The device must be wearable and therefore, independent of an electrical outlet. However, a device consuming large amounts of energy would require large and heavy energy sources. Thus, the need for light, energy-efcient, and cost-effective parts as well as small, light, and potent batteries. The amount of dialysate has to be minimal. Hence, the need for a small amount of dialysate that can be continuously regenerated and reused. A commercially available sorbent system used for many decades in dialysis must be recongured and adapted as the purifying medium, facilitating the use of sterile and pure dialysate in quantities lower than 500 cm3. The patient should be able to wear the device and ambulate without impinging on his ability to perform

2.

3.

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Figure 1 The wearable ultraltration device in place in a uid overloaded patient.

pertension, but also result in liberalizing salt intake for ESRD patients. Improved quality of life and better nutrition are obviously the expected direct results of this new proposed treatment. The amounts of potassium and phosphorus removed with the device at this stage of development might result in eliminating the restrictions on the oral intake of both these elements and the elimination of oral phosphate binders. The high dialysis dose as expressed both in clearances and in weekly Kt/V Urea may achieve all the benets currently demonstrated in daily dialysis schedules. The long-term effects of this technology on the well-being of these patients, although expected to be signicant, will be the subject of much needed clinical research.

activities of daily life. Thus, the need for lightweight and ergonomic design that would be unobtrusive and adapt to the body contour. These challenges have been met in developing the prototype of a WAK to be tested in clinical settings (Figure 1). Unique innovations in the development of a miniaturized, dual-channel, adjustable ow, battery-operated, pulsatile pump for driving both blood and dialysate through the wearable device, and the miniaturized conguration of microdispensing pumps for delivering various solutions at adjustable rates have led to the successful completion of the working prototype. The WAK is intended to be used for continuous renal replacement therapy, 24 hours a day, 7 days a week. It would deliver higher doses of dialysis than commonly administered today. In addition, it may reduce the utilization of nursing resources and the cost of treating ESRD patients.1728 The efciency of the device was evaluated by achieving the removal of urea, creatinine, potassium, phosphorus, and ultraltrate in amounts that would normalize the volume status and the above chemistries in uremic humans when the device was worn continuously. The capability of the device to remove uid steadily from the vascular space, a volume similar to that physiologically removed by normal kidneys, gives the treating physician the ability to keep the patients euvolemic with this device, regardless of the amount of uid they may ingest. Furthermore, the elimination of excess uid may well result in a better control of hypertension. In addition, the sodium content of the ultraltrate is equal to that of the plasma. Thus, the removal of 1.5 to 2 L of uid a day will result in the removal of 13.5 to 18 g of salt.2934 This would not only contribute to better control of hy-

History and development of the conceptual model for a wearable kidney

Although treatment for acute kidney injury was available prior to the 1960s, treatment for chronic kidney failure only became generally available in North America and Western Europe in the 1970s with the development of more reliable vascular access and heparin-based anticoagulation. Albeit the development of hemodialysis for patients with chronic kidney failure was a major technological breakthrough, there were obvious limitations in terms of dietary restriction, uid allowance, and lifestyle. In particular, in those days, patients with chronic kidney disease fortunate enough to be treated by dialysis were young with single organ failure, yet their lives revolved around the hospital dialysis center, typically being treated for 8-hour dialysis sessions, unable to go away on holiday. To improve patient lifestyle, home hemodialysis was developed, and it became popular in the 1960s. However, even from the start of developing hemodialysis as a treatment for chronic kidney disease, the eventual goal of the early pioneers was to develop a truly wearable device that would allow the patient to have a more normal lifestyle, yet be treated. The earliest attempts date back to Kolffs team in the 1960s.34 Many nephrologists have subsequently tried to create a truly wearable device that would allow patients to carry out their normal daily living activities or go to work, while being treated.3540 The early pioneers were confronted with many technical problems, including vascular access, anticoagulation, and both the size and reliability of any such device. Some of the earlier devices used an arterial blood supply, and those that worked only with venous blood access required a blood pump and an electrical power source.

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Recent result with new models of WAK

Based on the studies of the past and relying on the technology of today, new WAK devices have been developed. In particular, it is only now, with miniaturization of a double channel pulsating blood and dialysate pump, in combination with accurate, reliable volumetric pumps (meeting United States FDA and European CE approved standards), that a truly wearable device is possible. We have recently reported our experience with both a wearable ultraltration device31 and an articial kidney.33 Patients were lmed in both trials to show that they could walk and move around independently while still being treated, and in one of the studies, patients walked out from the hospital into a neighboring park while being treated (Figure 2). Thus, although we would not claim any originality to the concept of a wearable hemolter or dialysis device, we have reported pilot studies of a truly wearable device that allows patients to ambulate and even walk out of the hospital grounds while being treated. As such, these are landmark proof of concept studies.3133 The WUF The number of patients with symptomatic congestive heart failure continues to increase in North America and Europe. As cardiac output falls, the natural compensatory response to arterial underlling is an increase in neuro-hormonal activation, which can paradoxically lead to further reduction in cardiac output, compromising renal and gut blood ow.41 This may result in deteriorating renal function and diuretic resistance. Peritoneal and hemodialysis have therefore been advocated as useful adjunctive treatments in severe cases of congestive heart failure and other uid retention states, refractory to diuretic therapy.42 In the early 1980s, Kramer et al. described a simple ultraltration device designed to remove uid from uid overloaded intensive care patients.43 This required arterial access, which drove the ow through the hemolter by hydrostatic pressure, leading to ultraltration. It took more than 25 years before specic devices designed for ultraltration of patients with refractory heart failure were available.44 However, this machine was devised to be used intermittently in hospitalized bed-bound inpatients. To create a truly wearable device that would allow patients to ambulate while being treated, and hence offer the possibility of outpatient therapy, other workers pursued Kramers original concept.45 To allow mobility, patients required a dual lumen central venous access catheter, coupled with a miniaturized blood pump, with accurate battery-powered minipumps

Figure 2 The wearable ultraltration device applied to a walking patient.

None of the papers quoted by Professors Shaldon and Lysaght details a battery-powered pump to propel blood through the hemolter, nor describes approved safety features to monitor blood leaks and/or air bubbles.39

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to regulate the ultraltration ow, and a heparin infusion for anticoagulation.46 A standard commercially available high-ux polysulfone hemolter (Medica, Medolla, Italy) was strapped to a belt, which was worn around the waist. The total weight of the device was 2.5 lb (1.135 kg). The rst human study using this wearable hemoltration device as a continuous ambulatory ultraltration device in 6 volume overloaded patients treated for 6 hours has been reported recently.45 Blood ow through the device was around 116 mL/min with an ultraltration rate ranging from 120 to 288 mL/hr, leading to an average of 151 mmol of sodium removed during the treatment. More importantly, during the study, all patients maintained cardiovascular stability. One of the main problems with traditional intermittent hemodialysis treatments is intradialytic hypotension which may cause further ischemic renal injury.47 Thus, this device, by being designed to operate continuously, can remove uid at a slower hourly rate compared with standard intermittent hemodialysis, such that relling of the plasma volume from the extravascular spaces can be maintained, thus avoiding episodes of cardiovascular instability. By returning heart failure patients back to the summit of their Starling curve, cardiac output improves, with a reduction in arterial underlling; thus, patients become diuretic responsive once again. Potentially, development of this device would allow patients with symptomatic congestive heart failure to be managed as outpatients or day ward attenders.

The WAK Only recently has a study been published of a truly wearable hemodialysis device.33 In this preliminary trial, the device was worn by 8 chronic hemodialysis patients, who were treated for times varying between 4 and 8 hours. The device was worn on a belt around the waist and weighed around 5 kg. The blood and other pumps were powered by standard batteries. Fluid removal was accurately controlled by an ultraltration pump, and as with a conventional hemodialysis machine, there were safety features to stop blood ow in case of air entry or disconnection. The device was connected using the patients standard vascular access, via stula needles in some patients and by central venous access catheter in others. In one case the arterial needle became disconnected; whereas the blood pump in a conventional hemodialysis machine would have continued to pump; with this device, the arterial disconnect was sensed and the blood pump stopped. This allowed almost immediate reinsertion of the dialysis needle, with no signicant loss of

blood, and the treatment promptly resumed. In 2 cases, as the heparin infusion was reduced before the planned termination of treatment, clotting occurred. Thus, as with standard intermittent hemodialysis, adequate anticoagulation is required for this device. The dialysate was continuously regenerated by passage through 3 sorbent canisters containing urease, activated charcoal, and both hydroxyl zirconium oxide and zirconium phosphate. Dialysate was regularly tested for ammonia to ensure that the canisters had not become saturated. Similarly, the dialysate was tested to ensure sterility. Blood and dialysate ows were much slower than the traditional thrice-weekly intermittent hemodialysis, being 59 and 47 mL/min, respectively. As expected, minute by minute small solute clearances were also much lower than those of intermittent hemodialysis, with an average whole blood urea clearance of 23 mL/min and a creatinine clearance of 21 mL/min, respectively. Although these minute by minute clearances are low and similar to those achieved by continuous arteriovenous dialysis circuits in the intensive care setting,48 the device was designed to be worn for protracted periods. If this wearable hemodialysis device could be worn daily, this would potentially provide an estimated urea clearance (Kt/V) of almost 6.0, well above that for conventional thrice-weekly intermittent hemodialysis. In addition to urea and creatinine clearances, b2 microglobulin clearance was also assessed. b2 microglobulin clearance was around 50% of that for urea and 55% for creatinine, respectively. Recent reevaluation of the HEMO study has suggested the importance of b2 microglobulin clearance in predicting patient survival.49 Adequacy of hemodialysis therapy is not simply a matter of small solute clearance. The b2 microglobulin clearances observed would suggest that the relative clearances for so-called middle molecules is somewhat greater than that for conventional intermittent hemodialysis. This is

Figure 3 The wearable articial kidney (WAK).

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probably due to the degree of internal hemodialtration within the dialyzer because of the pressures generated by the blood pump. The blood pump differed in design from that of a conventional hemodialysis machine blood pump. Instead of being a roller pump, which occluded the dialysate tubing, this blood pump comprised 2 chambers, 1 for blood and 1 for dialysate, such that when the blood chamber was full, the dialysate chamber was empty and vice versa. This resulted in a different pattern of pulsatility and pressure generation in terms of blood and dialysate ows through the dialyzer compared with standard dialysis, resulting in increased internal hemodialtration. Obviously, this device is in its early stages of development, and clearances could potentially be improved by redesigning the blood pump, to increase the volume of blood pumped, or similarly by increasing the ows (Figure 3).

The Vicenza wearable articial kidney (ViWAK) Recently, the structure and operational characteristics of a new wearable system for continuous peritoneal dialysis for CKD patients have been described in a paper50 and called ViWAK (Figure 4). The ViWAK system consists of a double lumen peritoneal catheter, a dialysate outow line, a miniaturized rotary pump, a circuit for dialysate regeneration featuring a waterproof container with cartridges connected in parallel

with a mixture of activated carbon and polystyrenic resins, a lter for deaeration and microbiological safety, a dialysate inow line, and a Palm computer as a remote control. The system has been tested circulating 12 L of exhausted PD solution through the experimental adsorption unit at the rate of 20 mL/min. Creatinine, b2 microglobulin, and angiogenin were measured before and after the adsorption unit at baseline, and after 4 and 10 hours of use. The cartridges containing polystyrenic resin completely removed b2 microglobulin and angiogenin from the uid batch. Those with the ion exchange resin completely removed urea and creatinine. The nal result was 11.2 L of net solute clearance. The system is designed to be used as follows: the peritoneal cavity is loaded in the morning with 2 L of fresh PD solution. After 2 hours, when dialysate/plasma equilibration of approximately 50% has occurred, recirculation is activated for 10 hours at the rate of 20 mL/min. After this period, recirculation stops and glucose is optionally added to the peritoneal cavity to achieve ultraltration if needed. After 2 hours the uid is drained and a 2-L icodextrin exchange is performed overnight to achieve further ultraltration. The clearance provided by the minicycler is further increased by the 2-L exchange and the overnight exchange. Therefore, the system operates 24 hr/day and provides creatinine and b2 microglobulin clearance in the range of 15 to 16 L/day, corresponding to a weekly clearance of 100 to 110 L.

Figure 4 The Vicenza wearable articial kidney (ViWAK) for ambulatory peritoneal dialysis.

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The device reduces the number of exchanges compared with CAPD and uses less uid than in APD. Furthermore, the Palm Pilot allows for prescription and assessment of the therapy, providing information on cartridge saturation, ow, and pressure conditions and offering the possibility of remote wireless control of operations. Some problems still remain to be solved in the present conguration, including the addition of an injection system for glucose and bicarbonate when needed, a system to reduce brin delivery to the sorbent, and nally a more complex mixture of sorbents to make sure a complete removal of small molecules including urea is achieved. In conclusion, the wearable peritoneal dialysis system may become a possible alternative to APD or CAPD, reducing the time dedicated to performing exchanges and improving peritoneal dialysis adequacy and patients rehabilitation.

CONCLUSIONS
In conclusion, the WAK is becoming a reality, although many improvements are still required. The change in paradigm may help future development and contributions coming from scientists and industry, oriented toward the renement of the WAK concept. The same concept might be useful in developing new strategies for the treatment of the critically ill patient.5153 Miniaturization and nonthrombogenic surfaces will probably represent the most important challenges in the immediate future. Nevertheless, the future in this eld is probably tomorrow.

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